Citations

Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.

Attempts to activate an anti-tumor immune response in glioblastoma (GBM) have been met with many challenges due to its inherently immunosuppressive tumor microenvironment. The degree and mechanisms by which molecularly and phenotypically diverse tumor-propagating glioma stem cells (GSCs) contribute to this state are poorly defined. In this study, our multifaceted approach combining bioinformatics analyses of clinical and experimental datasets, single-cell sequencing, and the molecular and pharmacologic manipulation of patient-derived cells identified GSCs expressing immunosuppressive effectors mimicking regulatory T cells (Tregs). We showed that this immunosuppressive Treg-like (ITL) GSC state is specific to the mesenchymal GSC subset and is associated with and driven specifically by TGFβ type II receptor (TGFBR2) in contrast to TGFBR1. Transgenic TGFBR2 expression in patient-derived GBM neurospheres promoted a mesenchymal transition and induced a six-gene ITL signature consisting of CD274 (PD-L1), NT5E (CD73), ENTPD1 (CD39), LGALS1 (galectin-1), PDCD1LG2 (PD-L2), and TGFB1. This TGFBR2-driven ITL signature was identified in clinical GBM specimens, patient-derived GSCs, and systemic mesenchymal malignancies. TGFBR2high GSCs inhibited CD4+ and CD8+ T cell viability and their capacity to kill GBM cells, effects reversed by pharmacologic and shRNA-based TGFBR2 inhibition. Collectively, our data identify an immunosuppressive GSC state that is TGFBR2-dependent and susceptible to TGFBR2-targeted therapeutics.

Abstract Background: Resilience, quantified by the brief resilience scale (BRS), has been recognized for its role in pain and symptomatology in musculoskeletal conditions. The role of psychological factors in the clinical presentation and outcomes of FAI surgery continues to be poorly understood. Methods: This is a prospective multicenter study of FAI patients undergoing primary hip arthroscopy. PROMs were administered at baseline, 3-, and 6-months post-op and included the Patient Reported Outcomes Measurement Information System (PROMIS) domains of anxiety and depression, as well as Hip Disability and Osteoarthritis and Outcome Score (HOOS), modified Harris Hip Score (mHHS), and International Hip Outcome Tool (iHOT-12). Resilience was characterized by BRS score and divided into low (“L”, score<3), normal (“N”, score 3-4.3), and high resilience (“H”, score>4.3). Results: 675 patients were included with a mean age of 24.9±7.8 years and female predominance (56%). Mean BRS scores were 3.7±0.7 (1.5-5.0). 13.8% (n=93) had low resilience, 65.9% (n=445) had normal resilience, and 20.3% (n=137) had high resilience. Lower resilience had more severe symptoms in HOOS pain (p<0.001), HOOS sports (p=0.003), HOOS ADL (p<0.001), HOOS QoL (p<0.001), iHOT-12 (p=0.002), and mHHS (p<0.001). Anxiety (L: 50.5%/N: 14.4%/H: 2.2%) and depression (L: 38.7%/N: 8.8%/H: 2.9%) were higher in lower resilience groups (all p<0.001) and this trend stayed consistent in female and male sub-analyses with females having greater anxiety and depression symptoms. The follow-up cohort with 3- and 6-months follow-up was 487 patients and had similar baseline characteristics as the baseline cohort. Lower resilience had lower postoperative PROs (with similar change) (p<0.05). After treatment, rates of anxiety or depression decreased from 22.1% to 15.6% with the low resilience group having the highest change from 62.9% to 45.9%. Conclusion: Low resilience correlates with more severe symptoms and predicts anxiety/depression in FAI. 13.8% had low resilience while 20.3% had high resilience. Lower resilience had worse postoperative PROs. Particularly in patients with low resilience at presentation, rates of anxiety or depression symptoms decreased postoperatively. Further studies are needed to understand the role of resilience in longer-term outcomes of FAI and whether concurrent psychological treatment will help improve patient outcomes after hip arthroscopy for FAI.

Abstract Introduction: Low-dose computed tomography (CT) has been increasingly utilized in FAI due to its improved ability to characterize the complex and variable hip morphologies of FAI patients, compared to plain radiographs. This study defined FAI morphology between females and males as well as across adolescents, young adults, and older adults. Methods: A multi-center, prospective cohort of FAI patients undergoing primary arthroscopy was performed. Patients 14-45 years of age with idiopathic FAI were included. Low-dose CT was used for preoperative planning. Analysis focused on acetabular and femoral morphology and the differences between females/males and adolescents (A,14-18.9)/young adults (Y,19-24.9)/older adults (O,25+). Adolescents were the reference group during analysis. Results: There were 604 patients with CT data. Mean age was 24.9 years with 55.9% female. Males had more anterosuperior coverage (i.e. 64.2% vs 62.5% at 1:00), lower version (14.1° vs 18.0°), smaller femoral neck-shaft angles (130.9° vs 133.4°), and larger alpha angles (i.e. 72.1° vs 58.6° at 1:00) compared to females. Multivariable analysis demonstrated that females had associations with more femoral anteversion (OR: 1.05,CI: 1.03-1.07) and larger femoral neck-shaft angles (OR: 1.11,CI: 1.06-1.16). Males has associations with larger alpha angles at 1:00 (OR: 1.05,CI: 1.02-1.07) and 1:30 (OR: 1.03,CI: 1.00-1.06) as well as radial coverage at 1:00 (OR: 1.18,CI: 1.11-1.26). For females, adolescents had slightly less radial coverage at 2:00 (49.9%) compared to young (51.2%) and older adults (51.4%). Femoral neck-shaft angle decreased across age groups (A: 134.4°,Y: 133.0°,O: 132.7°). Alpha angles increased at 2:00 with age (A:54.6°,Y:55.3°,O:58.7°). Multivariable analysis had femoral neck-shaft angle decreasing for young (OR: 0.932,CI: 0.87) and older adults (OR:0.92,CI: 0.86-0.98) and it also had alpha angle at 1:15 increasing for young adults (OR: 1.03,CI: 1.00-1.06) and older adults (OR: 1.03,CI: 1.01-1.06). Males did not have any appreciable differences alpha angles, femoral version, or acetabular coverage across age groups. Conclusion: Differences in morphology identified on CT exist between females and males as well as across age groups for females. These differences may offer insight into disease pathomechanics between these patient populations. Further studies should confirm these findings and look at how they affect patient outcomes after treatment.

Abstract Introduction: Femoroacetabular impingement commonly causes labral and cartilage damage. Understanding what clinical and CT-morphological factors are associated with increased labral and acetabular cartilage damage may give insight into the FAI pathophysiology. The present study aims to identify factors associated with labral and cartilage damage. Method: This is a prospective, multicenter cohort of patients undergoing primary arthroscopy for treatment of symptomatic FAI. Enrollment was between 2020 and 2022. The current study investigated predictive factors of advanced labral damage (detachment or full-thickness tear length >4cm) and advanced acetabular cartilage damage (delamination or full-thickness defect ≥200mm2). Finally, we performed external validation for the previously reported RAPID score that predicts high-grade cartilage injury. Results: There were 647 patients in the cohort. For labral injuries, there were 384/647 (59.4%) detachments and 154/647 (23.8%) full-thickness defects, with labral tears ≥4cm was present in 100/558 (17.9%) hips. Older age (OR:1.04, p=0.002), males (OR:1.83,p=0.005), and larger alpha angles at 2:00 (OR:1.02,p=0.04) were associated with full-thickness labral injuries. Older age (OR:1.06,p<0.001) and larger alpha angles at 2:00 (OR:1.03,p=0.01) were associated with tears ≥4cm. 258/679 (38.0%) patients had delamination or full-thickness cartilage defects. Older age (OR:1.09,p<0.001), males (OR:1.91 p=0.003), decreased IRF (OR:0.95,p<0.001), higher femoral version (OR:1.02,p=0.04), and larger alpha angles at 1:30 (OR:1.06,p<0.001) were associated with delamination or defect cartilage injuries. Advanced acetabular cartilage damage ≥200mm2 was present in 109/679 (16.8%) hips and was associated with larger alpha angles at 2:00 (OR:1.07,p<0.001), decreased IRF (OR:0.95,p<0.001), and males (OR:2.52,p=0.002), and age (OR:1.05,p=0.002). For RAPID score external validation, we used our data for their model (sex, Tonnis OA Grade, radiographic alpha angle) and found an AUC of 0.685. With an adjusted model using CT alpha angles, AUC improved to 0.703. Our final model improved the AUC to 0.809 and included age, sex, IRF, femoral version, and CT alpha angles. Conclusion: FAI commonly has associated labral and cartilage injuries. The current study found multiple predictive factors for advanced labral and cartilage injuries as well as for larger lesions. A model including age, sex, IRF, femoral version, and CT alpha angles appears to best predict acetabular cartilage damage. Further research should investigate how these affect outcomes.

OBJECTIVE Previous research suggests elective surgical procedures performed later in the week have worse outcomes. This study investigated whether the day of the week on which elective anterior cervical discectomy and fusion (ACDF) surgery was performed impacts clinical outcomes. METHODS Using data from the Quality Outcomes Database, a nationwide, multicenter prospective registry, this study included patients undergoing elective ACDF for cervical spondylosis. Patients were categorized into groups based on the surgery day (early week, Monday and Tuesday; late week, Thursday and Friday). Analyzed outcomes included postoperative complications, readmissions, reoperations, and patient-reported outcomes. Statistical methods included the independent t-test, Pearson’s chi-square test, and multivariable logistic regression. RESULTS The study analyzed 19,818 patients, with 41.7% undergoing surgery early in the week and 36.9% later. There were no significant differences in 30-day mortality, readmissions, or reoperations between the two groups. Early-week surgical procedures were associated with a higher incidence of postoperative dysphagia requiring nasogastric tubes (0.6% vs 0.3%, p = 0.02) and a higher incidence of vocal cord paralysis (0.5% vs 0.3%, p = 0.01). The data indicate a surgical selection bias with more complex surgical procedures and higher risk patients typically scheduled earlier in the week, which likely contributed to the increased rates of dysphagia. Conversely, patients who underwent operations on Fridays were more likely to be discharged on the same day compared to those earlier in the week (p = 0.02), without a significant difference in length of stay overall. Surgical procedures performed later in the week were more likely to be performed at ambulatory surgical centers rather than inpatient facilities (p < 0.01), indicating a strategic selection of healthier patients for end-of-week procedures. CONCLUSIONS The day of elective ACDF surgery does not affect mortality, readmissions, or reoperation rates. However, early-week surgical procedures may see slightly higher rates of postoperative dysphagia and vocal cord paralysis, likely due to the scheduling of more complex cases or higher risk patients during these days. Overall, the authors’ data confirm that day of surgery does not influence overall patient recovery significantly. This information is useful for surgical planning and for providing patient reassurance that the day of the week does not significantly impact surgical outcomes.

ABSTRACTAnetumab ravtansine, like other ADC drugs, has high inter‐patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0‐inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

Abstract Engrams are neuronal alterations that encode associations between environmental contexts and subjectively rewarding or aversive experiences within sparsely activated neuronal assemblies that regulate behavioral responses. How positive- or negative-hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate or maladaptive behavior, respectively. It is well-known that animals avoid noxious stimuli and experiences. Little is known, however, how the conditioning of environmental or contextual stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations leading to compulsive maladaptive behavior. Here we have studied engrams that encode the conditioned effects of alcohol-related stimuli associated with the reversal of the dysphoric withdrawal state in alcohol dependent rats and document the recruitment of engrams in the paraventricular nucleus of the thalamus (PVT), the central nucleus of the amygdala (CeA), and the Dorsal Striatum (DS). The findings suggest that the encoding of associations between reversal of negative hedonic states and environmental contexts in these engrams may serve as a neural mechanism for compulsive alcohol seeking and vulnerability to relapse associated with dysregulation of reward to a pathological allostatic level.

ABSTRACT Engrams are neuronal alterations that encode associations between environmental contexts and subjectively rewarding or aversive experiences within sparsely activated neuronal assemblies that regulate behavioral responses. How positive- or negative-hedonic states are represented in brain neurocircuits is a fundamental question relevant for understanding the processing of emotionally meaningful stimuli that drive appropriate or maladaptive behavior, respectively. It is well-known that animals avoid noxious stimuli and experiences. Little is known, however, how the conditioning of environmental or contextual stimuli to behavior that leads to amelioration of dysphoric states establishes powerful associations leading to compulsive maladaptive behavior. Here we have studied engrams that encode the conditioned effects of alcohol-related stimuli associated with the reversal of the dysphoric withdrawal state in alcohol dependent rats and document the recruitment of engrams in the paraventricular nucleus of the thalamus (PVT), the central nucleus of the amygdala (CeA), and the Dorsal Striatum (DS). The findings suggest that the encoding of associations between reversal of negative hedonic states and environmental contexts in these engrams may serve as a neural mechanism for compulsive alcohol seeking and vulnerability to relapse associated with dysregulation of reward to a pathological allostatic level.