Citations

Background Rapid stroke type identification is essential for time‐sensitive interventions, yet timely neuroimaging remains limited, especially in pre‐hospital and resource‐constrained settings. The EMVision emu™ Brain Scanner is a portable neurodiagnostic device using non‐ionizing electromagnetic signals to distinguish stroke subtypes. In an Australian prevalidation study enrolling 277 suspected stroke patients, it demonstrated diagnostic accuracy with sensitivity and specificity of 92% and 85% for hemorrhagic and 95% and 80% for ischemic strokes, respectively. Case studies and image reconstructions provided (figures 1 and 2). This follow‐up study aims to validate the diagnostic performance of emu™ for detecting intracranial hemorrhage in an international cohort, targeting ≥80% sensitivity and specificity. Methods A prospective, multi‐center, international, paired diagnostic accuracy study, with 4 US sites and 2 Australian sites. It will enroll 300 patients presenting within 12 hours of stroke onset. Patients will be stratified into two arms: intracranial hemorrhage, and ischemic stroke, TIA, or stroke mimic. Participants will undergo standard imaging, followed by non‐invasive scan by the emu™ device. Ground‐truth diagnoses will be adjudicated by a blinded expert panel. The primary endpoints are the sensitivity and specificity of the emu™ device for detecting hemorrhage, calculated against the reference standard. Statistical inference will rely on whether the lower bound of the 95% confidence interval for sensitivity and specificity exceeds 80%. Results First Australian and US enrollments occurred on June 11, 2025, and July 3, 2025, respectively. Latest progress in the study will be presented at the time of conference. Conclusion This is the first international validation study of a portable electromagnetic brain scanner for intracranial hemorrhage detection; a novel, non‐ionizing, diagnostic tool that can revolutionize acute stroke triage, enabling earlier treatment decisions, improved workflows, and equitable access to neuroimaging. image image

Background The efficacy of EVOKE therapy, a closed-loop spinal cord stimulation (SCS) system, has been demonstrated in a double-blinded randomized controlled trial (RCT). RCT evidence, however, may not be generalizable to clinical practice, while limitations of real-world evidence may affect its validity. The aim of this study was to evaluate the effectiveness of EVOKE therapy in routine clinical practice employing a rigorous data collection approach. Methods The ECAP study was a prospective, multicenter, single-arm, pragmatic study that enrolled SCS candidates with chronic, intractable trunk and/or limb pain in 22 US investigational sites. PROMIS-29 questionnaire and objective neurophysiological metrics were collected, and minimal clinically important differences (MCIDs) were used to characterize baseline dysfunction and response to EVOKE therapy both at trial end and maximal analgesic effect post-implant visit. Pre-specified subgroup analyses were conducted based on diagnosis. Results EVOKE therapy observed included a dose ratio of 1.3 and neural dose accuracy of 2.8 μV. Improvements of >1 MCID were observed for all domains and improvements of ≥2 MCIDs were observed for six of the seven domains. Improvements observed at trial end were maintained or improved at post-implant visit, with statistically significant improvement in holistic MCID (MD 0.2, 95% CI 0.1 to 0.4, p=0.004), and a significantly greater proportion of patients considered holistic MCID responders (p=0.047). Subgroup analysis by diagnosis showed similar outcomes. Conclusions EVOKE therapy was associated with clinically meaningful improvements in a real-world chronic pain population across different subgroups and disease pathologies, with effects observed at trial end reproduced at post-implant visit.

ABSTRACT Background Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis highly associated with systemic comorbidities. Accurate diagnosis and treatment remain challenging due to its rarity and clinical mimickers. Objectives To evaluate demographic, clinical features and treatment outcomes in patients referred with suspected PG at a tertiary wound care centre. Methods A prospective observational study was conducted of patients referred for suspected PG between April 2021 and June 2023. Demographic, clinical and laboratory data, including biopsies and tissue cultures, were collected. Patients were categorised as having PG vs alternative diagnoses based on diagnostic criteria from Su, Maverakis and the PARACELSUS score. Results Of 60 patients (female, 51.7%; mean [SD] age 52.9 [14.0] years), 44 (73.3%) met at least one published diagnostic criterion for PG. The most common comorbidity was IBD (63.6%), followed by inflammatory arthritis (25.0%) and monoclonal gammopathy of undetermined significance (MGUS) (4.5%). Systemic corticosteroids were used by 40.9% of patients before referral, but steroid‐sparing agents and biologics were the primary treatments after consultation. Biologics and steroid‐sparing agents were associated with significant improvement in disease activity using the PGA score (average score decreased from 2.3 to 1.5, p < 0.005), with 40.9% achieving complete remission. Elevated serum inflammatory markers and faecal calprotectin were observed in PG patients but absent in non‐PG cases. Conclusions These prospective data support previously published rates of association between PG and systemic comorbidities. Steroid‐sparing anti‐neutrophilic and targeted therapies are effective steroid‐sparing strategies in managing PG. Small sample size and referral bias may limit generalisability.

Abstract Background Historically, 25-hydroxyvitamin D (25OHD) assays have under- or over-recovered 25-hydroxyvitamin D2 (25OHD2), but assay manufacturers have modified their reagents to address this problem. In this study, we compared the second- and third-generation Roche assays as well as two contemporary offerings from Diasorin and Beckman against liquid chromatography–tandem mass spectrometry (LC-MS/MS). Methods We identified 50 remnant serum samples with 25OHD concentrations from across the analytical range of the second-generation Roche assay. To increase 25OHD2 representation, we identified 25 additional samples from individuals prescribed high-dose vitamin D2 supplements. We tested samples on Roche assays and circulated to laboratories performing Beckman and Diasorin 25OHD assays. We tested samples by LC-MS/MS to obtain concentrations for 25OHD2 and 25-hydroxyvitamin D3. Results Mean overall bias for each assay was 5.1 ng/mL or less against the LC-MS/MS measurement; mean proportional bias was 8.7% to 12.1%. Some individual specimens had much larger bias. 25OHD2 was under-recovered on average, but the bias for the third-generation Roche assay represents a significant improvement over the previous assay, and mean bias for current generation assays was no worse than −3.2 ng/mL. In most cases, clinical classification by automated assay values agreed with clinical classification by LC-MS/MS; where present, disagreements occurred near classification thresholds. Conclusions Automated 25OHD assays continue to improve, and 25OHD2 recovery no longer appears to be a significant concern for the assays evaluated here. All assays evaluated were adequate for clinical classification of vitamin D nutritional status and are suitable for routine use, including in patients prescribed high-dose vitamin D2.

Purpose Hip arthroscopy is a minimally invasive procedure which has been increasingly used among athletes for several hip joint related pathologies as it allows for a faster recovery. However, objective return to sport criteria have not been described previously among this population. Objective To systematically review the literature to evaluate and describe the objective return-to-sport (RTS) criteria to release patients back to sport following hip arthroscopy. Methods We conducted a comprehensive literature search according to the PRISMA guidelines. Studies were included in the review if patients underwent a hip arthroscopy procedure and the study described criteria for their patients to RTS. Two independent reviewers selected studies for inclusion and extracted study characteristics and objective RTS criteria. Results Of the 306 that were a part of our original search, 6 studies fit our inclusion criteria. There were 250 athletes (average age: 26.1) and 263 hips which underwent hip arthroscopy surgery. Of these athletes, the cohort was on average 46.5% female and an average of 91.2% of athletes returned to sport about 6 months following surgery. The primary sports these athletes participated in were soccer, swimming, skiing/snowboarding, and hockey. The objective RTS measures that were generally described included sport specific tests, range-of-motion, hip strength, and performance-based criteria. Conclusion There are minimal studies who described objective RTS criteria to release patients back to sport following hip arthroscopy procedures. Sports specific tests, hip strength, and performance-based criteria were mentioned as objective criteria to release patients back to sport.

Abstract Description Peripheral nervous system innervation of various organs has been associated with the development and maintenance of the immune system. Various neurological insults including brain tumors induce thymic involution. Using flow cytometry and confocal microscopy, we identified a population of cells within the thymus that contained neuronal markers and morphology. Subsets expressed tyrosine hydroxylase, BIII tubulin and/or NeuN, distinguishing them from thymic epithelial cells. These cells do not express AIRE. Neuronal cell bodies and/or axonal processes were identified within the thymus. Using retrograde rabies vector neurotracers, we confirmed axonal connections and the identity of thymic neurons. To determine developmental T cell stages that support neuronal development, we evaluated RAG1/2 KO, TCRβ KO, TCRα KO, TCRγδ KO, CD4 KO, CD8 KO and OT-I and -II transgenics. RAG1/2 and TCRβ deficiency resulted in complete loss of thymic neurons. This is while TCRα KO, TCRγδ KO, CD4/8 KO and OT-II transgenics had normal thymic neuron development. Importantly, OT-I transgenics had a significant loss of neuron-like cells, indicating developing CD8 T cells pre-alpha arrangement control thymic innervation. Finally, introduction of healthy bone marrow into irradiated RAG KO mice can restore neuron development. To summarize, we describe a novel population of neuronal cells within the thymus that interact with developing thymocytes to establish optimal thymic innervation. Funding Sources R00NS117799 Topic Categories Neuroimmunology (NEUR)

Abstract Description Therapeutic in situ chimeric antigen receptor (isCAR) T cells can be generated by targeting activated T cells within a lymph node (LN) with retroviruses encoding CARs. While isCAR T cells are successfully generated by intradermal LN priming using adenovirus encoding allogeneic MHC in all mouse lines tested, differences in emerging therapeutic peripheral isCAR T cells are found in a strain dependent manner. Potentially harmful off target retroviral transduction of B cells with CARs is observed within the targeted LN. Here we report the blockade of B cell transduction using anti-CD20 antibody B cell depletion with the introduction of anti-CD19 chimeric antigen receptors into the activated CD8+ T cells. Lymphocytes were analyzed in blood and LN following isCAR T cell generation. When B cells were depleted by systemic administration of anti-CD20 antibodies during isCAR T cell induction, &gt;97.5% systemic depletion of B cells was achieved. Whereas very small numbers of CAR transduced B cells were found in the blood of mice not treated with anti-CD20, none were observed in animals systemically depleted of B cells. In contrast, CAR B cells persisted in the LN of local anti-CD20 treated animals. However, animals expressing dominant CD8+ isCAR T cell populations eliminated LN B cells expressing CARs by week two. Furthermore, systemic treatment of lymphoma in animals with anti-CD20 antibody complemented anti-CD19 isCAR T therapy while blocking off target B cell transduction. Funding Sources Mayo Clinic Ventures Mayo Clinic Graduate School of Biomedical Sciences Mayo Clinic Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Abstract Description Glioblastoma (GBM) is an aggressive brain cancer with poor survival. GBM patients have severe peripheral immunosuppression, including defective T cell responses. We showed that serum-derived factors were sufficient to inhibit T cell proliferation. This factor was nonsteroidal and larger than 100kDa. Mass-spectrometry and pathway analysis of suppressive serum implicated proteins involved in DNA response elements. We hypothesized that the suppressive factor is cell-free DNA (cfDNA). In support of this, serum levels of cfDNA are increased in glioma-bearing mice. Exposure to cfDNA from serum of glioma-bearing mice was sufficient to directly and potently inhibit T cell proliferation. Exposure to genomic DNA was not sufficient to induce proliferation defects in T cells, highlighting the unique features of cfDNA. Importantly, reducing cfDNA content using DNaseI was sufficient to partially restore proliferation capacity. We determined that the T cell proliferation defects were independent of AIM2 DNA sensing mechanisms, implicating a novel pathway of DNA sensing in T cells. Finally, to determine the origin of the cfDNA, we used methylation-seq and found that the majority of cfDNA originated from neutrophils, implicating NETosis. Together, we contend that cfDNA from neutrophils induces immunosuppressive effects in GBM. Our work highlights a potential role for targeting cfDNA, neutrophils, and/or NETs in order to reverse T cell dysfunction and improve patient outcomes in GBM. Funding Sources R00NS117799 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)

Abstract Description The importance of microglia class I restricted antigen presentation to brain-infiltrating CD8 T cells has been difficult to define. To address this question, our laboratory generated novel single MHC Class I conditional knockout mice in which H-2Kb or H-2Db can be deactivated specifically in Tmem119+ microglia with tamoxifen administration. Recombinant Theiler’s murine encephalomyelitis virus (TMEV) encoding the model antigen OVA enabled analysis of virus antigen-specific CD8 T cells restricted to Kb class I molecules while Daniel’s strain TMEV Db class I molecules enabled analysis of Db:VP2 specific CD8 T cells. Our results revealed profound differences between MHC class I molecules. Conditional knockout of Kb in Tmem119+ microglia reduced Kb:OVA epitope specific CD8 T cells in the brain compared to Cre negative littermate controls. Employing methodology using FTY720 and BrdU labeling, we determined that deletion of Kb in Tmem119+ microglia reduced proliferation and numbers of Kb:OVA specific CD8 T cells in the brain compared to Cre negative littermate controls. Meanwhile, mice with deletion of Db in Tmem119+ microglia had reduced levels of perforin in Db:VP2 CD8 T cells. These findings demonstrate there are discrete roles for specific MHC Class I molecules on microglia during CNS viral infection. These results plus transgenic mouse systems will help further our understanding of brain infiltrating CD8 T cell responses in neurologic disease. Funding Sources Supported by R01NS122174 and R01NS103212 Topic Categories Neuroimmunology (NEUR)

Abstract Description Tauopathies are a subset of neurological diseases associated with pathologic tau protein accumulation and the formation of neurofibrillary tangles in the brain. There is growing evidence of immune cell infiltration including T cells and an increase of inflammatory microglia in human brains from patients that have Tauopathies. However, the effect of T cells and how they interact with CNS-resident immune cells in these pathologies is not well understood. To answer this question, we developed a neurotropic AAV1 encoding human mutant P301L-Tau. AAV-Tau transduction of neurons in neonatal mice recapitulates features of Tauopathies found in human patients. As microglia are the predominant resident antigen presenting cells within the CNS, we hypothesized that CD8 T cells may be dependent on MHC class I presentation by microglia in mice with Tauopathy to achieve full infiltration and expansion in the brain. To address this hypothesis, we introduced AAV-Tau into our novel transgenic mice for which MHC class I antigen presentation by H-2Kb on microglia can be conditional ablated. We observed lower frequencies of CD8 T cell populations and less CD8 T cell CD69+CD103+ expression in mice with Tauopathy when MHC class I was ablated in microglia. We conclude that microglia class I restricted antigen presentation contributes to the expansion of resident memory CD8 T cells in experimental Tauopathy and therefore are an important driver of the immune response observed in this dementia model. Funding Sources NIH/NINDS: R01NS122174 Mayo Graduate School of Biomedical Sciences Topic Categories Neuroimmunology (NEUR)