Skin and gut imprinted helper T cell subsets exhibit distinct functional phenotypes in central nervous system autoimmunity.

Multidimensional single-cell analyses of T cells have fueled the debate about whether there is extensive plasticity or 'mixed' priming of helper T cell subsets in vivo. Here, we developed an experimental framework to probe the idea that the site of priming in the systemic immune compartment is a determinant of helper T cell-induced immunopathology in remote organs. By site-specific in vivo labeling of antigen-specific T cells in inguinal (i) or gut draining mesenteric (m) lymph nodes, we show that i-T cells and m-T cells isolated from the inflamed central nervous system (CNS) in a model of multiple sclerosis (MS) are distinct. i-T cells were Cxcr6+, and m-T cells expressed P2rx7. Notably, m-T cells infiltrated white matter, while i-T cells were also recruited to gray matter. Therefore, we propose that the definition of helper T cell subsets by their site of priming may guide an advanced understanding of helper T cell biology in health and disease.

Visualizing the activation of encephalitogenic T cells in the ileal lamina propria by in vivo two-photon imaging.

Autoreactive encephalitogenic T cells exist in the healthy immune repertoire but need a trigger to induce CNS inflammation. The underlying mechanisms remain elusive, whereby microbiota were shown to be involved in the manifestation of CNS autoimmunity. Here, we used intravital imaging to explore how microbiota affect the T cells as trigger of CNS inflammation. Encephalitogenic CD4+ T cells transduced with the calcium-sensing protein Twitch-2B showed calcium signaling with higher frequency than polyclonal T cells in the small intestinal lamina propria (LP) but not in Peyer's patches. Interestingly, nonencephalitogenic T cells specific for OVA and LCMV also showed calcium signaling in the LP, indicating a general stimulating effect of microbiota. The observed calcium signaling was microbiota and MHC class II dependent as it was significantly reduced in germfree animals and after administration of anti-MHC class II antibody, respectively. As a consequence of T cell stimulation in the small intestine, the encephalitogenic T cells start expressing Th17-axis genes. Finally, we show the migration of CD4+ T cells from the small intestine into the CNS. In summary, our direct in vivo visualization revealed that microbiota induced T cell activation in the LP, which directed T cells to adopt a Th17-like phenotype as a trigger of CNS inflammation.

Days alive and out of hospital after liver transplant: comparing a patient-centered outcome between recipients of grafts from donation after circulatory and brain deaths.

We retrospectively compared outcomes between recipients of donation after circulatory death (DCD) and donation after brain death (DBD) liver allografts using days alive and out of hospital (DAOH), a composite outcome of mortality, morbidity, and burden of care from patient perspective. The initial length of stay and duration of any subsequent readmission for the first year after liver transplantation were recorded. Donor category and perioperative and intraoperative characteristics pertinent to liver transplantation were included. The primary outcome was DAOH365. Secondary outcomes included early allograft dysfunction and hepatic arterial and biliary complications. Although the incidence of both early allograft dysfunction (P < .001) and ischemic cholangiopathy (P < .001) was significantly greater in the recipients of DCD, there were no significant differences in the length of stay and DAOH365. The median DAOH365 was 355 days for recipients of DBD allografts and 353 days for recipients of DCD allografts (P = .34). Increased transfusion burden, longer cold ischemic time, and non-White recipients were associated with decreased DAOH. There were no significant differences in graft failure (P = .67), retransplantation (P = .67), or 1-year mortality (P = .96) between the 2 groups. DAOH is a practical and attainable measure of outcome after liver transplantation. This metric should be considered for quality measurement and reporting in liver transplantation.

Postoperative statin therapy is not associated with reduced incidence of venous thromboembolic events following kidney transplantation.

BACKGROUND: The pleiotropic effects of statin therapy on inflammation and coagulation may reduce the risk of venous thromboembolism. This study evaluated whether statin therapy is associated with decreased venous thromboembolic (VTE) events following kidney transplantation. METHODS: We performed a retrospective analysis of all primary kidney transplants performed between January 2014 and December 2019 at Mayo Clinic Arizona. Patients were divided into two groups depending on sustained statin therapy during the first year following transplantation. Recipient and donor clinical and demographic data were collected. The primary outcome was admission for symptomatic VTE events (deep vein thrombosis [DVT] or pulmonary embolism [PE]). RESULTS: Sustained statin therapy in the first year following transplant was observed in 16.1% (n = 223) of 1384 kidney transplants. The overall incidence of VTE events in the year following kidney transplant was 3.8%. VTE occurred in 4.1% of recipients treated with statins and 3.8% of the controls - (hazard ratio [HR] .92, 95% confidence interval [95% CI] .39, 2.21, p = .86). However, there were significant differences between the groups in terms of age, sex, race/ethnicity, body mass index, indication for transplant, diagnosis of diabetes and discharge antiplatelet or anticoagulant therapy. Following sensitivity analysis in which cohort matching was performed to account for these differences, there was no difference in VTE event-free survival (HR .89, 95% CI .41, 1.96, p = .78) or overall survival (HR .54, 95% CI .15, 1.94, p = .35) between patients treated with statins compared to controls. CONCLUSION: Statin therapy in the year following successful kidney transplant was not associated with a reduction in risk of VTE.

Statin Therapy and the Incidence of Thromboembolism and Vascular Events Following Liver Transplantation.

Statin therapy may reduce the risk of venous thromboembolism (VTE), which may impact solid organ transplant outcomes. We evaluated the incidence of VTE and other complications after liver transplantation stratified by hyperlipidemia status and statin use using a retrospective cohort study approach. We reviewed all primary orthotopic liver transplantation (OLT) records from January 2014 to December 2019 from our center. Intraoperative deaths were excluded. Recipient, donor clinical and demographic data were collected. We developed risk-adjusted models to assess the effect of statin use on the occurrence of VTE, hepatic artery complications (HACs), graft failure, and death, accounting for clinical covariates and competing risks. A total of 672 OLT recipients were included in the analysis. Of this cohort, 11.9% (n = 80) received statin therapy. A total of 47 patients (7.0%) had VTE events. HACs occurred in 40 patients (6.0%). A total of 42 (6.1%) patients experienced graft loss, whereas 9.1% (n = 61) of the cohort died during the study interval. Eighty OLT recipients (29.8%) were treated with statins. In the statin treated group, 0% of patients had VTE versus 7.9% of those not on statins (P = 0.02). HACs were identified in 1.2% of the statin group and 6.8% of the nonstatin group. Untreated hyperlipidemia was associated with a 2.1-fold higher risk of HACs versus patients with no hyperlipidemia status (P = 0.05). Statin therapy was associated with significantly better risk-adjusted thromboembolic event-free survival (absence of VTE, cerebrovascular accident, myocardial infarction, HACs, and death); hazard ratio, 2.7; P = 0.01. These data indicate that statin therapy is correlated with a lower rate of VTE and HACs after liver transplantation.

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy.

In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell-mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT. In vitro activated T cells first settle in secondary (2°) lymphatic tissues (e.g., the spleen) where, in the absence of autoantigen, they establish transient contacts with stroma cells as indicated by sporadic short-lived calcium spikes. The T cells then exit the spleen for the CNS where they first roll and crawl along the luminal surface of leptomeningeal vessels without showing calcium activity. Having crossed the blood-brain barrier, the T cells scan the leptomeningeal space for autoantigen-presenting cells (APCs). Sustained contacts result in long-lasting calcium activity and NFAT translocation, a measure of full T-cell activation. This process is sensitive to anti-MHC class II antibodies. Importantly, the capacity to activate T cells is not a general property of all leptomeningeal phagocytes, but varies between individual APCs. Our results identify distinct checkpoints of T-cell activation, controlling the capacity of myelin-specific T cells to invade and attack the CNS. These processes may be valuable therapeutic targets.

Streptococcus uberis strains isolated from the bovine mammary gland evade immune recognition by mammary epithelial cells, but not of macrophages.

Streptococcus uberis is frequently isolated from the mammary gland of dairy cattle. Infection with some strains can induce mild subclinical inflammation whilst others induce severe inflammation and clinical mastitis. We compared here the inflammatory response of primary cultures of bovine mammary epithelial cells (pbMEC) towards S. uberis strains collected from clinical or subclinical cases (seven strains each) of mastitis with the strong response elicited by Escherichia coli. Neither heat inactivated nor live S. uberis induced the expression of 10 key immune genes (including TNF, IL1B, IL6). The widely used virulent strain 0140J and the avirulent strain, EF20 elicited similar responses; as did mutants defective in capsule (hasA) or biofilm formation (sub0538 and sub0539). Streptococcus uberis failed to activate NF-κB in pbMEC or TLR2 in HEK293 cells, indicating that S. uberis particles did not induce any TLR-signaling in MEC. However, preparations of lipoteichoic acid (LTA) from two strains strongly induced immune gene expression and activated NF-κB in pbMEC, without the involvement of TLR2. The immune-stimulatory LTA must be arranged in the intact S. uberis such that it is unrecognizable by the relevant pathogen receptors of the MEC. The absence of immune recognition is specific for MEC, since the same S. uberis preparations strongly induced immune gene expression and NF-κB activity in the murine macrophage model cell RAW264.7. Hence, the sluggish immune response of MEC and not of professional immune cells to this pathogen may aid establishment of the often encountered belated and subclinical phenotype of S. uberis mastitis.

Extracellular milieu grossly alters pathogen-specific immune response of mammary epithelial cells.

BACKGROUND: Considerably divergent data have been published from attempts to model the E. coli vs. S. aureus specific immune reaction of the udder using primary cultures of bovine mammary epithelial cells from cows (pbMEC). Some groups reported a swift, strong and transient inflammatory response against challenges with E. coli and only a weak and retarded response against S. aureus, in agreement with the respective reaction of the udder. Others found almost the reverse. Presence or absence of fetal calf serum distinguished the experimental setting between both groups. We examined here if this causes the divergent reaction of the pbMEC towards both pathogen species. We challenged pbMEC with proteins from heat killed E. coli or S. aureus pathogens or purified TLR2 and TLR4 ligands. The stimuli were applied in normal growth medium with (SM10) or without (SM0) 10% fetal calf serum, or in the basal medium supplemented with 10 mg/ml milk proteins (SM Milk). RESULTS: Withdrawal of FCS slowed down and decreased the extent by which E. coli or LPS enhanced the expression of cyto- and chemokine encoding genes through impaired TLR4 signalling but enforced their expression during stimulation with S. aureus. SM Milk strongly quenched the induction of those genes. S. aureus strain specific differences in the reaction of the pbMEC could only be recorded in SM0. NF-κB factors were activated by E. coli in all stimulation media, but only to a small extent by S. aureus, solely in SM0. Purified ligands for TLR2 stimulated expression of those genes and activated NF-κB equally well in SM10 and SM0. The mRNA destabilizing factor tristetraproline was only induced by E. coli in SM10 and by purified PAMPs. CONCLUSIONS: Our data cross validate the correctness of previously published divergent data on the pathogen-specific induction of key immune genes in pbMEC. The differences are due to the presence of FCS, modulating signalling through TLR4 and TLR-unrelated pathogen receptors. S. aureus does not substantially activate any TLR signalling in MEC. Rather, receptors distinct from TLRs perceive the presence of S. aureus and control the immune response against this pathogen in MEC.

Laser Interstitial Thermal Therapy as a Treatment Option for Malignant Peripheral Nerve Sheath Tumor Metastases to the Brain: A Case Report.

We present the unique case of a 60-year-old female with neurofibromatosis type 1 (NF1) who underwent laser interstitial thermal therapy (LITT) for metastatic malignant peripheral nerve sheath tumor (MPNST) of the brain. She presented to the emergency room complaining of one week of dysarthria and facial droop. An MRI of the brain demonstrated a homogeneously enhancing left frontal mass; although rare, given her history of pulmonary MPNST, brain invasion was considered likely. No generally accepted guidelines for the treatment of MPNST with cerebral metastases exist; however, LITT was chosen due to tumor morphology and proximity to eloquent brain structures. She did not experience any new or worsening neurological deficits post-operatively. Post-ablation MRI showed white matter edema surrounding the lesion, which is consistent with previously reported cases. This case illustrates the use of LITT for cytoreduction for rare brain metastases located near eloquent brain structures.

Trainability of affordance judgments in right and left hemisphere stroke patients.

Whenever we are confronted with action opportunities in everyday life, e.g., when passing an opening, we rely on our ability to precisely estimate our own bodily capabilities in relation to the environmental conditions. So-called affordance judgments can be affected after brain damage. Previous studies with healthy adults showed that such judgments appeared to be trainable within one session. In the current study, we examined whether stroke patients with either right brain damage (n = 30) or left brain damage (n = 30) may similarly profit from training in an aperture task. Further, the role of neuropsychological deficits in trainability was investigated. In the administered task, stroke patients decided whether their hand would fit into a presented opening with varying horizontal width (Aperture Task). During one training session, patients were asked to try to fit their hand into the opening and received feedback on their decisions. We analyzed accuracy and the detection theory parameters perceptual sensitivity and judgment tendency. Both patients with right brain damage and patients with left brain damage showed improved performance during training as well as post training. High variability with differential profiles of trainability was revealed in these patients. Patients with impaired performance in a visuo-spatial or motor-cognitive task appeared to profit considerably from the target-driven action phase with feedback, but the performance increase in judgments did not last when the action was withdrawn. Future studies applying lesion analysis with a larger sample may shed further light on the dissociation in the trainability of affordance judgments observed in patients with versus without visuo-spatial or motor-cognitive deficits.

Outcome differences between males and females undergoing deep brain stimulation for treatment-resistant depression: systematic review and individual patient data meta-analysis.

BACKGROUND: Treatment-resistant depression (TRD) occurs more commonly in women. Deep brain stimulation (DBS) is an emerging treatment for TRD, and its efficacy continues to be explored. However, differences in treatment outcomes between males and females have yet to be explored in formal analysis. METHODS: A PRISMA-compliant systematic review of DBS for TRD studies was conducted. Patient-level data were independently extracted by two authors. Treatment response was defined as a 50 % or greater reduction in depression score. Percent change in depression scores by gender were evaluated using random-effects analyses. RESULTS: Of 737 records, 19 studies (129 patients) met inclusion criteria. The mean reduction in depression score for females was 57.7 % (95 % CI, 64.33 %-51.13 %), whereas for males it was 35.2 % (95 % CI, 45.12 %-25.23 %) (p < 0.0001). Females were more likely to respond to DBS for TRD when compared to males (OR = 2.44, 95 % CI 1.06, 1.95). These differences varied in significance when stratified by DBS anatomical target, age, and timeframe for responder classification. LIMITATIONS: Studies included were open-label trials with small sample sizes. CONCLUSIONS: Our findings suggest that females with TRD respond at higher rates to DBS treatment than males. Further research is needed to elucidate the implications of these results, which may include connectomic sexual dimorphism, depression phenotype variations, or unrecognized symptom reporting differences. Methodological standardization of outcome scales, granular demographic data, and individual subject outcomes would allow for more robust comparisons between trials.

C2 versus C3 or C4 as the upper instrumented vertebra for long-segment cervical fusions: a systematic review and meta-analysis.

OBJECTIVE: Selecting C2 versus C3 or C4 (i.e., C3/C4) as the rostral anchoring level in long-segment cervical fusions is a common clinical conundrum. The data regarding proximal failure in long constructs of the cervical spine is scarce. The objective of this study was to systematically review the published literature and perform a meta-analysis of the incidence for proximal adjacent-segment disease (ASD) in the context of long cervical fusions and cervicothoracic fusions ending in C2 versus those ending in the subaxial spine (C3 or C4). METHODS: Using the PRISMA guidelines, the authors performed a search of the PubMed/MEDLINE, Embase/Ovid, and Cochrane Central databases to identify all full-text articles in the English-language literature with the following inclusion criteria: 1) studies including patients with the upper instrumented vertebra (UIV) at C2 versus C3/C4; 2) patients undergoing ≥ 3-level posterior cervical fusion; and 3) indication for surgery of degenerative disc disease, cervical spondylotic myelopathy, or cervical deformity. Studies that were not published in the English language, case reports, review articles, letters to the editor, and meeting abstracts were excluded. A meta-analysis was conducted using a fixed-effects model when I2 values were below 70%. Conversely, when I2 values were equal to or greater than 70%, a random-effects model was used. A funnel plot was used to assess the presence of publication bias. RESULTS: Seven studies consisting of 1215 patients were included in the meta-analysis. There were 403 (32.8%) patients in the C2 UIV group and 812 (67.2%) patients in the C3/C4 UIV group. When the 7 studies were analyzed, the overall rate of reoperation was comparable between the C2 (9.2%) and C3/C4 (9.4%) UIV groups (p = 0.93) but the rate of surgical ASD due to proximal pathology was 1.2% and 3%, respectively (OR 0.36, 95% CI 0.15-0.86; p = 0.02). When comparing between groups, no statistical difference was found regarding the rate of reoperation due to distal pathology or surgical infection. CONCLUSIONS: Long-segment cervical or cervicothoracic constructs that anchor into C2 may have similar complication rates but lower revision rates for proximal ASD than constructs that anchor into the subaxial spine.

Clinical Outcomes and Complication Profile of Spine Surgery in Septuagenarians and Octogenarians: Case Series.

OBJECTIVE: The aging global population presents an increasing challenge for spine surgeons. Advancements in spine surgery, including minimally invasive techniques, have broadened treatment options, potentially benefiting older patients. This study aims to explore the clinical outcomes of spine surgery in septuagenarians and octogenarians. METHODS: This retrospective analysis, conducted at a US tertiary center, included patients aged 70 and older who underwent elective spine surgery for degenerative conditions. Data included the Charlson Comorbidity Index (CCI), ASA classification, surgical procedures, intraoperative and postoperative complications, and reoperation rates. The objective of this study was to describe the outcomes of our cohort of older patients and discern whether differences existed between septuagenarians and octogenarians. RESULTS: Among the 120 patients meeting the inclusion criteria, there were no significant differences in preoperative factors between the age groups (P > 0.05). Notably, the septuagenarian group had a higher average number of fused levels (2.36 vs. 0.38, P = 0.001), while the octogenarian group underwent a higher proportion of minimally invasive procedures (P = 0.012), resulting in lower overall bleeding in the oldest group(P < 0.001). Mobility outcomes were more favorable in septuagenarians, whereas octogenarians tended to maintain or experience a decline in mobility(P = 0.012). A total of 6 (5%) intraoperative complications and 12 (10%) postoperative complications were documented, with no statistically significant differences observed between the groups. CONCLUSIONS: This case series demonstrates that septuagenarians and octogenarians can achieve favorable clinical outcomes with elective spine surgery. Spine surgeons should be well-versed in the clinical and surgical care of older adults, providing optimal management that considers their increased comorbidity burden and heightened fragility.

Is young adult idiopathic scoliosis a distinct clinical entity from adolescent idiopathic scoliosis? a Systematic Review and Meta-analysis comparing pre-operative characteristics and operative outcomes.

PURPOSE: This study aims to conduct a systematic review of the literature comparing pre-operative, intraoperative, and post-operative characteristics between adolescent idiopathic scoliosis (AIS) and young adult idiopathic scoliosis (YAdIS) patients. METHODS: Following PRISMA guidelines, we conducted a search of the PubMed/Medline, EMBASE, and Cochrane Central databases to identify full-text articles in the English-language literature. Our inclusion criteria were studies that compared preoperative, intraoperative, and postoperative characteristics between AIS and YAdIS patients. We performed a meta-analysis reporting mean difference (MD) for continuous variables and Odds ratios (ORs) to assess differences in postoperative complications. RESULTS: Seven studies consisting of 1562 patients were included in the meta-analysis. The AIS group exhibited less intraoperative bleeding and shorter surgical procedures, with a mean difference between groups of 122.3 ml (95% CI 46.2-198.4, p = 0.002) and 28.7 min (95% CI 6.5-50.8, p = 0.01), respectively. Although the preoperative Cobb angle did not differ between groups (p = 0.65), patients with AIS achieved superior postoperative deformity correction, with a mean difference of 7.3% between groups, MD - 7.3 (95% CI - 9.7, - 4.8, p < 0.00001), and lower postoperative Cobb angles of the major curve, MD 4.2 (95% CI 3.1, 5.3, p < 0.00001). YAdIS patients were fused, on average, 0.2 more vertebral levels than AIS patients, MD 0.2 (95% CI 0.01, 0.5, p = 0.04). AIS patients experienced a significantly shorter length of stay after the surgical procedure, with an MD of 0.8 days (95% CI 0.1, 1.6, p = 0.02). No significant difference was found between groups in terms of complications (p = 0.19). CONCLUSIONS: YAdIS should be regarded as a distinct surgical entity, characterized by increased bleeding, longer surgical duration, greater deformity correction challenges, and the need for fusion of additional vertebral levels compared to AIS. Surgeons should be mindful of these differences and discuss them with patients and their families, especially in cases where the correction of the AIS deformity is delayed and there is a high risk of progression after skeletal maturity. Further research is needed to explore alternative surgical techniques and enhance outcomes for YAdIS patients.

Diagnosing homo digitalis: towards a standardized assessment for digital tool competencies.

Introduction: In the 21st century, digital devices have become integral to our daily lives. Still, practical assessments designed to evaluate an individual's digital tool competencies are absent. The present study introduces the "Digital Tools Test" ("DIGI"), specifically designed for the evaluation of one's proficiency in handling common applications and functions of smartphones and tablets. The DIGI assessment has been primarily tailored for prospective use among older adults and neurological patients with the latter frequently suffering from so-called apraxia, which potentially also affects the handling of digital tools. Similar to traditional tool use tests that assess tool-selection and tool-action processes, the DIGI assessment evaluates an individual's ability to select an appropriate application for a given task (e.g., creating a new contact), their capacity to navigate within the chosen application and their competence in executing precise and accurate movements, such as swiping. Methods: We tested the implementation of the DIGI in a group of 16 healthy adults aged 18 to 28 years and 16 healthy adults aged 60 to 74 years. All participants were able to withstand the assessment and reported good acceptance. Results: The results revealed a significant performance disparity, with older adults displaying notably lower proficiency in the DIGI. The DIGI performance of older adults exhibited a correlation with their ability to employ a set of novel mechanical tools, but not with their ability to handle a set of familiar common tools. There was no such correlation for the younger group. Conclusion: In conclusion, this study introduces an innovative assessment tool aimed at evaluating common digital tool competencies. Our preliminary results demonstrate good acceptance and reveal expected group differences. For current cohorts of older adults, the results seem to indicate that the ability to use novel tools may aid digital tool use. In the next step, the psychometric properties of the DIGI assessment should be evaluated in larger and more diverse samples. The advancement of digital tool competency assessments and rehabilitation strategies is essential when we aim at facilitating societal inclusion and participation for individuals in affected populations.

Indications for Fusion With Intradural Spine Tumor Resection in Adults: A Systematic Review and Meta-analysis.

BACKGROUND: The evidence for instrumented fusion in the setting of degenerative, traumatic, or congenital deformity is well established. Data on fusion indications in intradural spinal tumors (IDST) are scarce and reduced to retrospective studies. The objective of this work is to systematically review the published literature since 2015 and analyze the change of practice patterns for stabilization and fusion after intradural tumor resection in adults. METHODS: A systematic literature review was performed via PubMed with the terms: "intradural spinal tumors", "intramedullary spinal tumors", and "intraspinal tumors". The analysis was limited to adult patients with IDST and studies with more than 10 patients. Data on the proportion of patients who underwent instrumentation and had postoperative deformity was pooled in a meta-analysis. RESULTS: A total of 1073 articles were identified and 47 papers were selected. All the studies were retrospective series and a total of 2473 patients were included. The follow-up ranged from 1 to 96 months, the pooled spinal fixation rate was 6% (95% CI 4.5%-7.6%), the pooled laminoplasty rate was 14.4% (95% CI 5.9%-23%), the pooled rate of postoperative deformity or malalignment in patients with a follow up of at least 6 months was 2.1% (95% CI 1.2%-3%) and just 7 patients were reoperated due to progressive deformity. CONCLUSIONS: Based on existing evidence, the rate of fusion during resection of intradural spinal tumors is low. Prophylactic fixation is often unnecessary and only indicated in unique cases that require extensive bony resection.

A genome-wide in vivo CRISPR screen identifies essential regulators of T cell migration to the CNS in a multiple sclerosis model.

Multiple sclerosis (MS) involves the infiltration of autoreactive T cells into the CNS, yet we lack a comprehensive understanding of the signaling pathways that regulate this process. Here, we conducted a genome-wide in vivo CRISPR screen in a rat MS model and identified 5 essential brakes and 18 essential facilitators of T cell migration to the CNS. While the transcription factor ETS1 limits entry to the CNS by controlling T cell responsiveness, three functional modules, centered around the adhesion molecule α4-integrin, the chemokine receptor CXCR3 and the GRK2 kinase, are required for CNS migration of autoreactive CD4+ T cells. Single-cell analysis of T cells from individuals with MS confirmed that the expression of these essential regulators correlates with the propensity of CD4+ T cells to reach the CNS. Our data thus reveal key regulators of the fundamental step in the induction of MS lesions.

Trends in Spinal Orthosis Utilization Among Patients Insured through Medicare Part B.

STUDY DESIGN: Retrospective population-based database analysis from the Physician/Supplier Procedure Summary Medicare/Medicaid Dataset. OBJECTIVE: To provide a comprehensive analysis of trends in spinal orthosis utilization over a 12-year period. SUMMARY OF BACKGROUND DATA: Widespread prescription of spinal orthosis persists, despite evidence suggesting equivocal efficacy in many spinal conditions. The utilization of spinal orthosis on a national level, including prescribing specialty data, has not been previously analyzed. METHODS: Healthcare common procedure coding system (HCPCS) codes for cervical (CO), thoracic-lumbar-sacral (TLSO), lumbar (LO), lumbar-sacral (LSO), and cervical-thoracic-lumbar-sacral (CTLSO) orthosis were used to determine spinal orthosis utilization from 2010 to 2021. Provider specialty codes were utilized to compare trends between select specialties. Additionally, a neurosurgical CO analysis, based on subclassifications of cervical bracing, was performed. Linear trendlines were implemented to elucidate and present trends by slope (ß). RESULTS: Among 332,241 claims, decreases in CO (ß=-0.3387), TLSO (ß=-0.0942), LO (ß=-0.3485), and LSO (ß=-0.1545) per 100,000 Medicare Part B enrollees and CTLSO (ß=-0.052) per 1,000,000 Medicare Part B enrollees were observed. Decreases among neurosurgery (ß=-7.9208), family medicine (ß=-1.0097), emergency medicine (ß=-2.1958), internal medicine (ß=-1.1151), interventional pain management (ß=-5.0945), and chiropractic medicine (ß=-49.012), and increases among orthopedic surgery (ß=5.5891), pain management (ß=30.416), physical medicine and rehabilitation (ß=4.6524), general practice (ß=79.111), and osteopathic manipulative medicine (ß=45.303) in total spinal orthosis use per 100,000 specialty claims were observed. Analysis on subclassifications of cervical orthosis among neurosurgeons revealed decreases in flexible (ß=-1.7641), semi-rigid (ß=-0.6157), and collar bracing (ß=-2.7603), and an increase in multi-post collar bracing (ß=2.2032) per 100 neurosurgical cervical orthosis claims. CONCLUSIONS: While utilization of spinal orthosis decreased between 2010-2021, increased utilization was observed among a subset of specialties. Identifying these specialties allows for focused research and educational efforts to minimize unnecessary durable medical equipment use for effective healthcare spending.

Surgical management of dropped head syndrome: A systematic review.

Background: Dropped head syndrome (DHS) is uncommon and involves severe weakness of neck-extensor muscles resulting in a progressive reducible cervical kyphosis. The first-line management consists of medical treatment targeted at diagnosing underlying pathologies. However, the surgical management of DHS has not been well studied. Methods: Here, we systematically reviewed the PubMed and Cochrane databases for DHS using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. All relevant articles up to March 31, 2022, were analyzed. The patient had to be ≥18 years with DHS and had to have undergone surgery with outcomes data available. Outcomes measurements included neurological status, rate of failure (RF), horizontal gaze, and complications. Results: A total of 22 articles selected for this study identified 54 patients who averaged 68.9 years of age. Cervical arthrodesis without thoracic extension was performed in seven patients with a RF of 71%. Cervicothoracic arthrodesis was performed in 46 patients with an RF of 13%. The most chosen upper level of fusion was C2 in 63% of cases, and the occiput was included only in 13% of patients. All patients neurologically stabilized or improved, while 75% of undergoing anterior procedures exhibited postoperative dysphagia and/or airway-related complications. Conclusion: The early surgery for patients with DHS who demonstrate neurological compromise or progressive deformity is safe and effective and leads to excellent outcomes.

Induction of aquaporin 4-reactive antibodies in Lewis rats immunized with aquaporin 4 mimotopes.

Most cases of neuromyelitis optica spectrum disorders (NMOSD) harbor pathogenic autoantibodies against the water channel aquaporin 4 (AQP4). Binding of these antibodies to AQP4 on astrocytes initiates damage to these cells, which culminates in the formation of large tissue destructive lesions in the central nervous system (CNS). Consequently, untreated patients may become permanently blind or paralyzed. Studies on the induction and breakage of tolerance to AQP4 could be of great benefit for NMOSD patients. So far, however, all attempts to create suitable animal models by active sensitization have failed. We addressed this challenge and identified peptides, which mimic the conformational AQP4 epitopes recognized by pathogenic antibodies of NMOSD patients. Here we show that these mimotopes can induce the production of AQP4-reactive antibodies in Lewis rats. Hence, our results provide a conceptual framework for the formation of such antibodies in NMOSD patients, and aid to improve immunization strategies for the creation of animal models suitable for tolerance studies in this devastating disease.