ICOS agonist vopratelimab modulates follicular helper T cells and improves B cell function in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is an immune defect characterized by hypogammaglobulinemia and impaired development of B cells into plasma cells. As follicular helper T cells (TFH) play a central role in humoral immunity, we examined TFH cells in CVID, and investigated whether an inducible T cell co-stimulator (ICOS) agonist, vopratelimab, could modulate TFH, B cell interactions and enhance immunoglobulin production. CVID subjects had decreased TFH17 and increased TFH1 subsets; this was associated with increased transitional B cells and decreased IgG+ B and IgD-IgM-CD27+ memory B cells. ICOS expression on CVID CD4+ T cells was also decreased. However, ICOS activation of CD4+ T cells by vopratelimab significantly increased total CVID TFH, TFH2, cell numbers, as well as IL-4, IL-10 and IL-21 secretion in vitro. Vopratelimab treatment also increased plasma cells, IgG+ B cells, reduced naïve & transitional B cells and significantly increased IgG1 secretion by CVID B cells. Interestingly, vopratelimab treatment also restored IgA secretion in PBMCs from several CVID patients who had a complete lack of endogenous serum IgA. Our data demonstrate the potential of TFH modulation in restoring TFH and enhancing B cell maturation in CVID. The effects of an ICOS agonist in antibody defects warrants further investigation. This biologic may also be of therapeutic interest in other clinical settings of antibody deficiency.

Unilateral microscopic approach for lumbar spinal stenosis decompression: a scoping review.

BACKGROUND: Microscopic unilateral laminotomy for bilateral decompression (ULBD) is a minimally invasive technique used in the treatment of lumbar spinal stenosis and could limit spinal instability and be associated with better clinical outcomes. However, there is ongoing debate regarding its utility compared to conventional laminectomy (CL). The primary objective was to collate and describe the current evidence base for ULBD, including perioperative parameters, functional outcomes, and complications. The secondary objective was to identify operative techniques. METHODS: A scoping review was conducted between January 1990 and August 2022 according to the PRISMA extension for scoping reviews (PRISMA-ScR) guidelines. Major databases were searched for full text English articles reporting on outcomes following microscopic unilateral laminotomy in patients with lumbar spinal stenosis. RESULTS: Seventeen articles met the inclusion criteria. Two studies were randomised controlled trials. Two studies were prospective data collection and the rest were retrospective analysis. Three studies compared ULBD with CL. ULBD preserves the osteoligamentous complex and may be associated with shorter operative time, less blood loss, and similar clinical outcomes when compared to CL. CONCLUSION: This review highlights that ULBD aims to minimise disruption to the normal posterior spinal anatomy and may have acceptable clinical outcomes. It also highlights that it is difficult to draw valid conclusions given there are limited data available as most studies identified were retrospective or did not have a comparator group.

Resolving solitary osteolytic lumbar tuberculosis in young adult.

Lumbar vertebral tuberculosis presenting with a focal solitary osteolytic lesion is rare in spinal tuberculosis (TB) and the English literature describing this entity is scant. The differential diagnosis includes primary and secondary malignancies. In this report, we describe a case of 35-year-old woman who presented with low back pain and was found to have a focal L4 vertebral lytic lesion on MRI and CT. Whole body CT was carried out as a potential malignancy staging procedure and demonstrated lung lesions suggestive of TB. Her neurological and general examination were entirely normal. Her blood test was positive for QuantiFERON Gold. She was managed conservatively with anti-TB medications and serial imaging which showed evidence of resolution of the osteolytic lesion. Although it is unusual for TB to present as an isolated osteolytic vertebral body lesion, the possibility should always be considered in the differential diagnosis, along with neoplastic processes. Conservative medical management, in the absence of neurological deficits and deformity, is the main stay of management with a very good outlook.

Spinal anaplastic ganglioglioma.

Anaplastic gangliogliomas of the spinal cord are extremely rare with only four cases reported in the literature. Here we present the case of a 22-year-old female who presented acutely with quadraparesis and urinary retention. Radiographic imaging demonstrated an intramedullary lesion within the cervical spine. She underwent a cervical laminectomy and resection of the lesion under neurophysiological monitoring. Post-operatively, she regained some function, but remained paraparetic. Histopathology demonstrated an anaplastic ganglioglioma (WHO Grade 3). She subsequently underwent radiotherapy. Following surgery, she remained stable and had MRC Grade 3 Power in all four limbs. Herein, we describe a previously undescribed case of cervical anaplastic ganglioglioma and review the existing literature.

Dural tear repair surgery comparative analysis: a stitch in time saves nine.

PURPOSE: A dural tear is a common iatrogenic complication of spinal surgery associated with a several post-operative adverse events. Despite their common occurrence, guidelines on how best to repair the defect remain unclear. This study uses five post-operative outcomes to the compare repair methods used to treat 106 dural tears to determine which method is clinically favourable. METHODS: Data were retrospectively collected from Southampton General Hospital's online databases. 106 tears were identified and grouped per repair method. MANOVA was used to compare the following five outcomes: Length of stay, numbers of further admissions or revision surgeries, length of additional admissions, post-operative infection rate and dural tear associated neurological symptoms. Sub-analysis was conducted on patient demographics, primary vs non-primary closure and type of patch. Minimal clinically important difference (MCID) was calculated via the Delphi procedure. RESULTS: Age had a significant impact on patient outcomes and BMI displayed positive correlation with three-fifth of the predefined outcome measures. No significant difference was observed between repair groups; however, primary closure ± a patch achieved an MCID percentage improvement with regards to length of original stay, rate of additional admissions/surgeries and post-operative infection rate. Artificial over autologous patches resulted in shorter hospital stays, fewer readmissions, infections and neurological symptoms. CONCLUSION: This study reports primary closure ± dural patch as the most efficient repair method with regards to the five reported outcomes. This study provides limited evidence in favour of artificial over autologous patches and recommends that dural patches be used in conjunction with primary closure. LEVEL OF EVIDENCE I: Diagnostic: individual cross-sectional studies with consistently applied reference standard and blinding.

Olfactory sensory neurons mediate ultrarapid antiviral immune responses in a TrkA-dependent manner.

The nervous system regulates host immunity in complex ways. Vertebrate olfactory sensory neurons (OSNs) are located in direct contact with pathogens; however, OSNs' ability to detect danger and initiate immune responses is unclear. We report that nasal delivery of rhabdoviruses induces apoptosis in crypt OSNs via the interaction of the OSN TrkA receptor with the viral glycoprotein in teleost fish. This signal results in electrical activation of neurons and very rapid proinflammatory responses in the olfactory organ (OO), but dampened inflammation in the olfactory bulb (OB). CD8α+ cells infiltrate the OO within minutes of nasal viral delivery, and TrkA blocking, but not caspase-3 blocking, abrogates this response. Infiltrating CD8α+ cells were TCRαß T cells with a nonconventional phenotype that originated from the microvasculature surrounding the OB and not the periphery. Nasal delivery of viral glycoprotein (G protein) recapitulated the immune responses observed with the whole virus, and antibody blocking of viral G protein abrogated these responses. Ablation of crypt neurons in zebrafish resulted in increased susceptibility to rhabdoviruses. These results indicate a function for OSNs as a first layer of pathogen detection in vertebrates and as orchestrators of nasal-CNS antiviral immune responses.

Presentation and management of spinal meningioma and its association with breast carcinoma-case series and systematic review.

OBJECTIVE: Benign spinal intradural tumors are rare entities and there have been relatively few case series describing the epidemiology and characteristics of these tumors. Here, we evaluate the presentation, demographics, pathology and outcomes associated with the surgical management of spinal meningioma in our unit over a 6-year period. RESULTS: A total of 68 cases presented to the operating surgeon during a 6-year period. Of these, over 80% (n = 55) were in females. Seventy-nine percent of the meningiomas were observed in the thoracic region (n = 54). Weakness and gait disturbance were the most common presenting complaints. Surgery significantly improved both motor outcome (p < 0.001) and health related qualities of life (SF36, p < 0.01).Seventeen percent of spinal meningioma cases (n = 12) had a preceding cancer diagnosis. Of these 75% (n = 9/12) were attributable to breast cancer. Overall, breast cancer preceded a diagnosis of a spinal meningioma in 16.4% of female cases (9/55). This is higher than expected number of breast cancer based on UK population and those reported in literature for breast cancer and intracranial meningioma. CONCLUSION: Spinal meningioma is disproportionately over-represented in females. Patients present with neurological deficits and surgery improved both neurology and patient reported quality of life. Relative to the known UK prevalence of breast cancer, there is a significantly higher than expected association between spinal meningioma and a preceding history of breast cancer.

Differences in management of isolated spinal fractures between neurosurgery and orthopaedics: a 6-year retrospective study.

INTRODUCTION: The acute management of spinal fractures is traditionally split between neurosurgeons and orthopaedic surgeons and the specialities have varying approaches to management. This study investigates differences between neurosurgeons and spinal orthopaedic surgeons in the management of spinal fractures at a single trauma centre in the United Kingdom. METHODS: A retrospective study at a single trauma centre of patients identified using the Trauma Audit and Research Network (TARN). Case notes and radiological investigations were reviewed for demographics, fracture classification, clinical management and outcomes. Polytrauma cases and patients managed by non-neurosurgical/orthopaedic specialties were excluded. RESULTS: A total of 465 patients were included in this study (neurosurgery n = 266, orthopaedics n = 199). There were no significant differences between groups for age, gender, Charlson co-morbidity score or distribution of fractures using the AO spine classification. Patients admitted and managed under the orthopaedic surgeons were more likely to undergo a surgical procedure when compared to those admitted under the neurosurgeons (n = 71; 35.7% vs n = 71; 26.8%, p = 0.042, OR 1.56 95%CI 1.056 to 2.31). The median overall length of stay was 8 days and there was no significant difference between teams; however, the neurosurgical cohort were more likely to be admitted to an intensive care unit (24.3% vs 16.2%, p = 0.04). CONCLUSION: This study is the first in the United Kingdom to compare neurosurgical and orthopaedic teams in their management of spinal fractures. It demonstrates that differences may exist both in operating rates and outcomes.

Neurosurgical management of head injuries incurred during sports: a single centre experience.

Introduction: Accidents during sporting activities are a common cause of head injury, particularly in children and young adults. Whilst most sporting head injuries are minor, there remains a proportion which is associated with high morbidity and mortality. The epidemiology of sports associated head injuries is variable based on geographical region so the aim of this study was to review the management and outcomes of sporting head injuries managed by a single neurosurgical unit in the South of England.Method: A retrospective review of the Trauma Audit and Research Network database was conducted for all patients admitted to a tertiary neurosurgical centre over a six-year period (January 2011-December 2016). Case notes were reviewed for demographics, mechanism of injury, injury severity score, intensive care admission, surgical interventions and Glasgow Outcome Score at discharge.Results: Seventy-six patients (mean age: 37.6 ± 18.4 years, male gender n = 43; 56.6%) were eligible for inclusion in this series. Horse riding accidents were identified as the most common cause of head injury (n = 31; 40.8%). Fifteen patients (19.7%) in this series had a severe head injury (GCS 3-8 on admission). Twenty-eight (36.8%) patients required admission to an intensive care unit and 26 (34.2%) patients underwent neurosurgical intervention. At discharge, 68 (89.5%) patients had a Glasgow Outcome Score 4-5.Conclusion: The majority of patients with head injuries admitted to a neurosurgical unit can expect a good functional outcome despite the need for intensive care or neurosurgical intervention. The range of sports resulting in head injury is likely influenced by geographic location; however, further national study is required for wider comparison.

CK12a, a CCL19-like Chemokine That Orchestrates both Nasal and Systemic Antiviral Immune Responses in Rainbow Trout.

Chemokines and chemokine receptors have rapidly diversified in teleost fish but their immune functions remain unclear. We report in this study that CCL19, a chemokine known to control lymphocyte migration and compartmentalization of lymphoid tissues in mammals, diversified in salmonids leading to the presence of six CCL19-like genes named CK10a, CK10b, CK12a, CK12b, CK13a, and CK13b. Salmonid CCL19-like genes all contain the DCCL-conserved motif but share low amino acid sequence identity. CK12 (but not CK10 or CK13) is constitutively expressed at high levels in all four trout MALT. Nasal vaccination with a live attenuated virus results in sustained upregulation of CK12 (but not CK10 or CK13) expression in trout nasopharynx-associated lymphoid tissue. Recombinant His-tagged trout CK12a (rCK12a) is not chemotactic in vitro but it increases the width of the nasal lamina propria when delivered intranasally. rCK12a delivered intranasally or i.p. stimulates the expression of CD8α, granulysin, and IFN-γ in mucosal and systemic compartments and increases nasal CD8α+ cell numbers. rCK12a is able to stimulate proliferation of head kidney leukocytes from Ag-experienced trout but not naive controls, yet it does not confer protection against viral challenge. These results show that local nasal production of CK12a contributes to antiviral immune protection both locally and systemically via stimulation of CD8 cellular immune responses and highlight a conserved role for CK12 in the orchestration of mucosal and systemic immune responses against viral pathogens in vertebrates.

Lumbar intravertebral disc herniation secondary to idiopathic calcific discitis.

Calcific discitis is a well recognized entity in the paediatric population but more recently has been increasingly reported in adults. It typically involves the lower thoracic vertebrae and is of unknown aetiology. Herniation of the calcified fragment is rare but typically occurs out through the annulus fibrosus into the canal space. Herein we describe the first reported case of calcific discitis involving the lumbar vertebrae with subsequent herniation of the calcified disc into and through the anterior aspect of the L5 vertebra. The patient first presented with a history of right back pain and leg sciatica. Radiographic imaging demonstrated calcification within the L4/5 interspace, which was managed with simple analgesia. She subsequently re-presented 24-months later with worsening sciatica, right leg weakness and faecal incontinence. No evidence of cord or root compression was noted on MRI. However, an abnormality was noted at the anterior body of L5 with evidence of superior endplate depression and marrow signal change. Subsequent radionucleide bone studies confirmed a solitary focus of increased linear activity extending across the width of the L4-L5 interspace. Her symptoms were managed medically. Serial radiographic imaging demonstrated regression of the disc space calcification and healing of the L5 fracture. Despite its sinister presentation this condition was self-limiting. We describe the radiographic evolution of this pathology and postulate a putative hypothesis through which it may have arisen.

Tissue Microenvironments in the Nasal Epithelium of Rainbow Trout (Oncorhynchus mykiss) Define Two Distinct CD8α+ Cell Populations and Establish Regional Immunity.

Mucosal surfaces require balancing different physiological roles and immune functions. To effectively achieve multifunctionality, mucosal epithelia have evolved unique microenvironments that create unique regional immune responses without impairing other normal physiological functions. Whereas examples of regional immunity are known in other mucosal epithelia, to date, no immune microenvironments have been described in the nasal mucosa, a site where the complex functions of olfaction and immunity need to be orchestrated. In this study we identified the presence of CD8α+ cells in the rainbow trout (Oncorhynchus mykiss) nasal epithelium. Nasal CD8α+ cells display a distinct phenotype suggestive of CD8+ T cells with high integrin ß2 expression. Importantly, nasal CD8α+ cells are located in clusters at the mucosal tip of each olfactory lamella but scattered in the neuroepithelial region. The grouping of CD8α+ cells may be explained by the greater expression of CCL19, ICAM-1, and VCAM-1 in the mucosal tip compared with the neuroepithelium. Whereas viral Ag uptake occurred via both tip and lateral routes, tip-resident MHC class II+ cells are located significantly closer to the lumen of the nasal cavity than are their neuroepithelial counterparts, therefore having quicker access to invading pathogens. Our studies reveal compartmentalized mucosal immune responses within the nasal mucosa of a vertebrate species, a strategy that likely optimizes local immune responses while protecting olfactory sensory functions.

Symbiont-derived sphingolipids regulate inflammatory responses in rainbow trout (Oncorhynchus mykiss).

Farmed fish live in association with diverse bacterial communities that produce wide arrays of metabolites. In rainbow trout, the skin and the gills are colonized by Flectobacillus major, a bacterium known to produce sphingolipids (SLs). The goal of this study is to evaluate the ability of F. major SLs to regulate rainbow trout inflammatory responses. F. major SLs were delivered by themselves or in combination with Freund's Complete Adjuvant (FCA), an oil-based adjuvant known to cause severe abdominal inflammation when injected to fish. Trout injected with SL + FCA showed decreased severity of FCA toxic effects including necrosis, granuloma formation and presence of oil droplets. However, inclusion of SLs in the FCA preparation did not decrease infiltration of immune cells intramuscularly at the site of injection. Intraperitoneal or intravenous delivery of F. major SLs resulted in increased expression of IgT, IgM and TGFß transcripts in the gills but not the head-kidney and had no effects on IL-10 expression. These results indicate the F. major SLs regulate rainbow trout inflammatory responses and indicate that this compound can have important applications in farmed fish health management.

Long-term efficacy of nasal vaccination against enteric red mouth (ERM) disease and infectious hematopoietic necrosis (IHN) in juvenile rainbow trout (Oncorhynchus mykiss).

Previous research demonstrated that bacterial and viral vaccines delivered via the nasal route in rainbow trout (Oncorhynchus mykiss) at 7 and 28 days post-vaccination are highly protective (>95% protection). Long-term protection following nasal vaccination in teleosts has not been evaluated. The goal of this study was to assess efficacy and immune responses at 6 months (mo) post-vaccination (mpv), and long-lasting immune responses at 12 mpv of two different vaccines: an inactivated enteric red mouth disease (ERM) Yersinia ruckeri bacterin and a live attenuated infectious hematopoietic necrosis virus (IHNV) vaccine. Juvenile rainbow trout were vaccinated for Y. ruckeri via intraperitoneal (I.P.) and intranasal (I.N.) routes, and for IHNV by intramuscular (I.M.) and I.N. routes, then challenged at 6 mpv. Immune responses were determined at 6 and 12 mpv. ERM vaccine I.P. delivery elicited significantly higher serum IgM-specific titers that remained elevated compared to mock-vaccinated fish at 6 mpv. By 12 mpv, antibody titers to Y. ruckeri were not significantly different across all treatments. Following Y. ruckeri challenge at 6 mpv, a significant difference in cumulative percent mortality (CPM) was found for I.P.-vaccinated fish but not I.N.-vaccinated fish. I.M. and I.N. vaccination with live attenuated IHNV did not result in significant specific serum IgM titers at 6 or 12 mpv. Yet, I.N.-vaccinated fish showed the lowest CPM 6 mpv indicating long-term protection that does not correlate with systemic IgM responses. Repertoire analyses confirmed unique expansions of VH-JH rearrangements in the spleen of rainbow trout 12 mpv that varied with the type of vaccine and route of vaccination. Combined, these data demonstrate that I.N. vaccination with a live attenuated viral vaccine confers long lasting protection, but I.N. ERM vaccination does not and booster before 6 mpv is recommended.

The Effect of COVID-19 National Lockdown on the Time from Presentation to Surgery of Patients with Suspected Cauda Equina Syndrome: Two UK Tertiary Centers' Study.

OBJECTIVE: To investigate if COVID-19 UK lockdown measures resulted in a delay in the presentation and treatment of patients with cauda equina syndrome (CES). METHODS: This is a multicenter retrospective study of patients with surgically treated CES across 3 time periods: April-May 2020 (first lockdown), August-September 2020 (no-lockdown group), and January-February 2021 (second lockdown). Data regarding duration of symptoms, time from referral to admission, time from admission to surgery, and postoperative outcomes were collected. RESULTS: A total of 56 patients (male: 26, female: 30, mean age: 44.3 years) were included in the study (n = 14, n = 18, and n = 24 in the 3 time periods, respectively). There was no significant difference in duration of symptoms across the time periods (12.6 days vs. 8.2 days vs. 3.8 days) (P = 0.16). Nearly all the patients were admitted within 48 hours of referral (n = 55, 98.2%). The majority of patients were operated on within 48 hours: first lockdown (n = 12, 85.7%), no-lockdown (n = 16, 88.9%), and second lockdown (n = 21, 87.5%). The length of hospital stay was significantly shorter in the second lockdown (3.3 days) versus the other 2 time periods (4.4 days and 6.4 days) (P = 0.02). Thirteen complications were present, with dural tear being the most common (n = 6, 10.7%). Majority reported symptom improvement (n = 53, 94.6%), with a similar number discharged home (n = 54, 96.4%). CONCLUSION: Despite the pandemic, patients with CES were promptly admitted and operated on with good outcomes. Shorter duration of hospital stay could be attributed to adaptation of spinal services.

First-in-Human Phase I/II ICONIC Trial of the ICOS Agonist Vopratelimab Alone and with Nivolumab: ICOS-High CD4 T-Cell Populations and Predictors of Response.

PURPOSE: The first-in-human phase I/II ICONIC trial evaluated an investigational inducible costimulator (ICOS) agonist, vopratelimab, alone and in combination with nivolumab in patients with advanced solid tumors. PATIENTS AND METHODS: In phase I, patients were treated with escalating doses of intravenous vopratelimab alone or with nivolumab. Primary objectives were safety, tolerability, MTD, and recommended phase II dose (RP2D). Phase II enriched for ICOS-positive (ICOS+) tumors; patients were treated with vopratelimab at the monotherapy RP2D alone or with nivolumab. Pharmacokinetics, pharmacodynamics, and predictive biomarkers of response to vopratelimab were assessed. RESULTS: ICONIC enrolled 201 patients. Vopratelimab alone and with nivolumab was well tolerated; phase I established 0.3 mg/kg every 3 weeks as the vopratelimab RP2D. Vopratelimab resulted in modest objective response rates of 1.4% and with nivolumab of 2.3%. The prospective selection for ICOS+ tumors did not enrich for responses. A vopratelimab-specific peripheral blood pharmacodynamic biomarker, ICOS-high (ICOS-hi) CD4 T cells, was identified in a subset of patients who demonstrated greater clinical benefit versus those with no emergence of these cells [overall survival (OS), P = 0.0025]. A potential genomic predictive biomarker of ICOS-hi CD4 T-cell emergence was identified that demonstrated improvement in clinical outcomes, including OS (P = 0.0062). CONCLUSIONS: Vopratelimab demonstrated a favorable safety profile alone and in combination with nivolumab. Efficacy was observed only in a subset of patients with a vopratelimab-specific pharmacodynamic biomarker. A potential predictive biomarker of response was identified, which is being prospectively evaluated in a randomized phase II non-small cell lung cancer trial. See related commentary by Lee and Fong, p. 3633.

Dietary fiber metabolites regulate innate lymphoid cell responses.

Innate lymphoid cells (ILCs) rapidly undergo expansion in population size and functional maturation in response to cytokines that signal infection, tissue damage, or changes in physiology. Optimal ILC responses are shaped, in part, by the microbiota but the mechanisms remain unclear. We report that short-chain fatty acids (SCFAs), produced by the commensal microbiota from dietary fibers, support optimal expansion of ILCs, including ILC1, ILC2, and ILC3 in the intestines through their G-protein-coupled receptors (GPCRs). While this function is primarily important for intestinal ILC populations, it can also boost ILC responses in other tissues depending on host condition. ILCs express multiple GPCRs that detect SCFAs. Interestingly, we found that the expression of SCFA receptors, such as Ffar2 and Ffar3, by ILCs is induced by SCFAs. GPCR triggering by SCFAs co-stimulates the activation of phosphoinositide 3-kinase (PI3K), Stat3, Stat5, and mammalian target of rapamycin (mTOR), which is important for ILC proliferation. While Ffar2 signaling promotes ILC2 proliferation, SCFAs can suppress ILC2 proliferation through a non-Ffar2-mediated mechanism. In conclusion, our findings indicate that SCFAs, as the major mediator of healthy microbiota and nutritional status, function to maintain optimal numbers of ILCs in peripheral tissues during infection and inflammatory responses.