A common tumour in a rare location: a single centre case series of cerebellar glioblastoma.

Although glioblastoma is the commonest primary brain tumour in adults, its location in the cerebellum is extremely rare. We present thirteen cases (3 female, 10 male; median age at presentation 56 [age range 21-77]) of surgically managed, histologically confirmed, primary cerebellar glioblastoma (cGB) over a 17 year period (2005-2022). Pre-operative radiological diagnosis was challenging given cGB rarity, although MRI demonstrated ring enhancement in all cases. Surgical management included posterior fossa craniectomy and debulking in 11 cases and burr hole biopsy in two. CSF diversion was necessary in four cases. No evidence of IDH or ATRX gene mutations was found when tested. Survival ranged from 1 to 22 months after diagnosis (mean 10.9 months). We also seek to understand why glioblastoma is rare in this location and discuss potential reasons for this. We hypothesise that increasing anatomical distance from germinal regions and decreased local endogenous neural stem cell activity (which has been associated with glioblastoma) may explain why glioblastoma is rare in the cerebellum. We hereby seek to add to the limited literature on cGB as this is the largest UK cGB series to date.

Airway and Systemic Immunoglobulin Profiling and Immune Response in Adult Asthma.

INTRODUCTION: Immunoglobulins play a vital role in host immune response and in the pathogenesis of conditions like asthma. Therapeutic agents such as monoclonal antibodies target specific elements of the asthmatic inflammatory cascade. Decisions to utilize these medications are often based on systemic inflammatory profiling without direct insight into the airway inflammatory profile. We sought to investigate the relationship between immunoglobulin and cytokine profiles in the airway and systemic immune compartments of adult asthmatics. METHODS: Blood sampling and bronchoscopy with bronchoalveolar lavage (BAL) were performed in 76 well-defined adult asthmatics. Antibody and cytokine profiles were measured in both BAL and serum using ELISA and quantibody arrays. RESULTS: There was no relationship between BAL and serum levels of IgE. This is of significance in an asthma population. For some analytes, correlation analysis was significant (P < 0.05) indicating representativeness of our cohort and experimental setup in those cases. Nevertheless, the predictive power (r2) of the BAL-to-serum comparisons was mostly low except for TNF-α (r2 = 0.73) when assuming a simple (linear) relationship. CONCLUSION: This study highlights the importance of sample site when investigating the roles of immunoglobulins and cytokines in disease pathogenesis and suggests that both localized and systemic immune responses are at play. The prescription of asthma monoclonal therapy is generally based on systemic evaluation of cytokine and immunoglobulin levels. Our research suggests that this approach may not fully reflect the pathophysiology of the disease and may provide insight into why some patients respond to these targeted therapies while others do not.

Eosinophil Plasticity and Diversity: Proceedings of the 2023 International Eosinophil Society Symposium.

This issue highlights and details the programme and scientific presentations at the International Eosinophil Society's 12th biennial Symposium, which was held in Hamilton, Ontario, Canada in July 2023. The meeting included sessions on regulation of eosinophil development; cell death, stress, and autophagy in eosinophils; local immunity interactions of eosinophils with multiple cell types; eosinophils in host defense; eosinophils and mast cells in gastrointestinal disorders; reciprocal interactions between eosinophils and the microbiome in homeostasis and dysbiosis; and, eosinophils in tissue injury and repair, in tumor biology and cancer therapy. There was a mixture of special invited lectures and cutting-edge abstracts on specific aspects of eosinophil science, as well as enlivened pro-con debates on targeting eosinophils with biologics. A major thrust and overarching theme was that eosinophils exhibit remarkable plasticity and heterogeneity in executing their functions both in homeostasis and in pathobiology; there is a new "Eo-verse" to understand. We trust that this special volume of the Journal of Leukocyte Biology will be of interest across many disciplines and medical sub-specialties in biomedical sciences and demonstrate both the complexity and versatility of the eosinophil in biology and medicine.

Neuromedin-U Mediates Rapid Activation of Airway Group 2 Innate Lymphoid Cells in Mild Asthma.

RATIONALE: In asthma, sputum group 2 innate lymphoid cells (ILC2) are activated within 7h after allergen challenge. Neuroimmune interactions mediate rapid host responses at mucosal interfaces. In murine models of asthma, lung ILC2 co-localize to sensory neuronal termini expressing the neuropeptide, neuromedin U (NMU) and NMU stimulates type 2 cytokines secretion by ILC2 with additive effects to alarmins, in vitro. OBJECTIVES: Investigate effect of NMU/NMUR1 axis on early activation of ILC2 in asthma. METHODS: M ild asthmatics (n=8) were enrolled in a diluent-controlled, allergen-inhalation challenge study. Sputum ILC2 expression of NMU receptor 1 (NMUR1) and T2 cytokines were enumerated by flow cytometry and airway NMU levels were assessed by ELISA. This was compared to samples from moderate-severe asthmatics (n=9). Flow sort-purified and ex-vivo expanded ILC2 were used for functional assays and transcriptomic analyses. RESULTS: Significant increases in sputum ILC2 expressing NMUR1 were detected 7h post- allergen versus diluent challenge where the majority of NMUR1+ILC2 expressed IL-5/IL-13. Sputum NMUR1+ILC2 were significantly greater in mild versus moderate-severe asthmatics and NMUR1+ILC2 correlated inversely with the dose of inhaled corticosteroid in the latter group. Co-culturing with alarmins upregulated NMUR1 in ILC2, which was attenuated by dexamethasone. NMU stimulated T2 cytokine expression by ILC2, maximal at 6h was abrogated by dexamethasone or specific signaling inhibitors for mitogen-activated protein kinase ½, phospho-inositol 3 kinase but not IL-33 signaling moiety MyD88, in vitro. CONCLUSIONS: The NMU/NMUR1 axis stimulates rapid effects on ILC2, and maybe an important early activator of these cells in eosinophilic inflammatory responses in asthma.

Contrasting terrestrial and marine ecospace dynamics after the end-Triassic mass extinction event.

Mass extinctions have fundamentally altered the structure of the biosphere throughout Earth's history. The ecological severity of mass extinctions is well studied in marine ecosystems by categorizing marine taxa into functional groups based on 'ecospace' approaches, but the ecological response of terrestrial ecosystems to mass extinctions is less well understood due to the lack of a comparable methodology. Here, we present a new terrestrial ecospace framework that categorizes fauna into functional groups as defined by tiering, motility and feeding traits. We applied the new terrestrial and traditional marine ecospace analyses to data from the Paleobiology Database across the end-Triassic mass extinction-a time of catastrophic global warming-to compare changes between the marine and terrestrial biospheres. We found that terrestrial functional groups experienced higher extinction severity, that taxonomic and functional richness are more tightly coupled in the terrestrial, and that the terrestrial realm continued to experience high ecological dissimilarity in the wake of the extinction. Although signals of extinction severity and ecological turnover are sensitive to the quality of the terrestrial fossil record, our findings suggest greater ecological pressure from the end-Triassic mass extinction on terrestrial ecosystems than marine ecosystems, contributing to more prolonged terrestrial ecological flux.

Evaluation of the reproducibility of responses to nasal allergen challenge and effects of inhaled nasal corticosteroids.

BACKGROUND: Similar immune responses in the nasal and bronchial mucosa implies that nasal allergen challenge (NAC) is a suitable early phase experimental model for drug development targeting allergic rhinitis (AR) and asthma. We assessed NAC reproducibility and the effects of intranasal corticosteroids (INCS) on symptoms, physiology, and inflammatory mediators. METHODS: 20 participants with mild atopic asthma and AR underwent three single blinded nasal challenges each separated by three weeks (NCT03431961). Cohort A (n = 10) underwent a control saline challenge, followed by two allergen challenges. Cohort B (n = 10) underwent a NAC with no treatment intervention, followed by NAC with 14 days pre-treatment with saline nasal spray (placebo), then NAC with 14 days pre-treatment with INCS (220 µg triamcinolone acetonide twice daily). Nasosorption, nasal lavage, blood samples, forced expiratory volume 1 (FEV1), total nasal symptom score (TNSS), peak nasal inspiratory flow (PNIF) were collected up to 24 h after NAC. Total and active tryptase were measured as early-phase allergy biomarkers (≤30 min) and IL-13 and eosinophil cell counts as late-phase allergy biomarkers (3-7 h) in serum and nasal samples. Period-period reproducibility was assessed by intraclass correlation coefficients (ICC), and sample size estimates were performed using effect sizes measured after INCS. RESULTS: NAC significantly induced acute increases in nasosorption tryptase and TNSS and reduced PNIF, and induced late increases in nasosorption IL-13 with sustained reductions in PNIF. Reproducibility across NACs varied for symptoms and biomarkers, with total tryptase 5 min post NAC having the highest reproducibility (ICC = 0.91). Treatment with INCS inhibited NAC-induced IL-13 while blunting changes in TNSS and PNIF. For a similar crossover study, 7 participants per treatment arm are needed to detect treatment effects comparable to INCS for TNSS. CONCLUSION: NAC-induced biomarkers and symptoms are reproducible and responsive to INCS. NAC is suitable for assessing pharmacodynamic activity and proof of mechanism for drugs targeting allergic inflammation.

Self-Massage Techniques for the Management of Pain and Mobility With Application to Resistance Training: A Brief Review.

ABSTRACT: MacLennan, M, Ramirez-Campillo, R, and Byrne, PJ. Self-massage techniques for the management of pain and mobility with application to resistance training: a brief review. J Strength Cond Res 37(11): 2314-2323, 2023-Fascial restrictions that occur in response to myofascial trigger points (MTrP), exercise-induced muscle damage (EIMD), and delayed onset of muscle soreness (DOMS) cause soft tissue to lose extensibility, which contributes to abnormal muscle mechanics, reduced muscle length, and decrements in joint range of motion (ROM) and actively contributes to musculoskeletal pain. Resistance training and in particular, weightlifting movements have unique mobility requirements imperative for movement efficacy and safety with ROM restrictions resulting in ineffective volume and intensity tolerance and dampened force output and power, which may lead to a failed lift or injury. Self-massage (SM) provides an expedient method to promote movement efficiency and reduce injury risk by improving ROM, muscular function, and reducing pain and allows athletes to continue to train at their desired frequency with minimal disruption from MTrPs-associated adverse effects. Thus, the aim of this review was to determine the efficacy of various self-massage tools in managing pain and mobility and to explore the potential benefits of SM on resistance training performance. Many SM devices are available for athletes to manage ROM restrictions and pain, including differing densities of foam rollers, roller massagers, tennis balls, and vibrating devices. To attenuate adverse training effects, a 10-to-20-minute bout consisting of 2-minute bouts of SM on the affected area may be beneficial. When selecting a SM device, athletes should note that foam rollers appear to be more effective than roller massagers, with vibrating foam rollers eliciting an increased reduction to pain perception, and tennis balls and soft massage balls were shown to be efficacious in targeting smaller affected areas.

Burden of chronic cough on social participation, healthcare resource utilisation and activities of daily living in the Canadian Longitudinal Study on Aging (CLSA).

BACKGROUND: Chronic cough is a common troublesome condition, but it is unclear whether dry or productive chronic cough and sex, impacts the burden of cough differently. METHODS: The Canadian Longitudinal Study on Aging is a nationally generalizable, stratified random sample of adults aged 45-85 years. Chronic cough was identified based on a self-reported daily cough in the last 12 months assessed at baseline (2011-2015) and follow-up (2015-2018). Odds ratios (95 % CI) for cough status and change in social participation activities (SPA), healthcare resource utilisation (HCRU), basic activities of daily living (ADLs) and instrumental activities of daily living (IADLs) were estimated using a weighted generalised estimating equation (WGEE). Results were stratified by sex, and adjusted for age, sex, smoking, body mass index, education, respiratory diseases and retirement status. RESULTS: Overall, chronic cough was associated with less SPA, greater HCRU and impaired ADL/IADLs. Productive chronic cough in males was associated with SPA limited by health, ED visits and hospitalisation. Females with productive chronic cough was associated with reduced frequency of SPA and ED visit. Dry chronic cough in females was associated with SPA limited by health and ED visits. Both types of cough was associated with at least 1 impaired basic ADL, but only in females with productive chronic cough was there an association with any impairment in IADLs. CONCLUSION: Chronic cough is associated with a greater burden on social participation, healthcare use and personal care.

Efficacy and Tolerability of Gefapixant for Treatment of Refractory or Unexplained Chronic Cough: A Systematic Review and Dose-Response Meta-Analysis.

Importance: Gefapixant represents an emerging therapy for patients with refractory or unexplained chronic cough. Objective: To evaluate the efficacy and tolerability of gefapixant for the treatment of adults with refractory or unexplained chronic cough. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science from November 2014 to July 2023. Study Selection: Two reviewers independently screened for parallel and crossover randomized clinical trials (RCTs) that compared, in patients with refractory or unexplained chronic cough, either gefapixant with placebo, or 2 or more doses of gefapixant with or without placebo. Data Extraction and Synthesis: Two reviewers independently extracted data. A frequentist random-effects dose-response meta-analysis or pairwise meta-analysis was used for each outcome. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to rate the certainty in whether patients would perceive the effects as important (greater than the minimal important difference [MID]) or small (less than the MID). Main Outcomes and Measures: Cough frequency (measured using the VitaloJAK cough monitor; MID, 20%), cough severity (measured using the 100-mm visual analog scale [VAS]; higher score is worse; MID, 30 mm), cough-specific quality of life (measured using the Leicester Cough Questionnaire [LCQ]; score range, 3 [maximal impairment] to 21 [no impairment]; MID, 1.3 points), treatment-related adverse events, adverse events leading to discontinuation, and taste-related adverse events. Results: Nine RCTs including 2980 patients were included in the primary analysis. Compared with placebo, gefapixant (45 mg twice daily) had small effects on awake cough frequency (17.6% reduction [95% CI, 10.6%-24.0%], moderate certainty), cough severity on the 100-mm VAS (mean difference, -6.2 mm [95% CI, -4.1 to -8.4]; high certainty), and cough-specific quality of life on the LCQ (mean difference, 1.0 points [95% CI, 0.7-1.4]; moderate certainty). Compared with placebo, gefapixant (45 mg twice daily) probably caused an important increase in treatment-related adverse events (32 more per 100 patients [95% CI, 13-64 more], moderate certainty) and taste-related adverse events (32 more per 100 patients [95% CI, 22-46 more], high certainty). High-certainty evidence suggests that gefapixant (15 mg twice daily) had small effects on taste-related adverse events (6 more per 100 patients [95% CI, 5-8 more]). Conclusions and Relevance: Compared with placebo, gefapixant (45 mg orally twice daily) led to modest improvements in cough frequency, cough severity, and cough-specific quality of life but increased taste-related adverse events.

A multi-stem cell basis for craniosynostosis and calvarial mineralization.

Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC1 (CTSK+ CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs, with DDR2+ CSC expansion being a direct maladaptive response to CTSK+ CSC depletion. DDR2+ CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2+ CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Finally, the human counterparts of DDR2+ CSCs and CTSK+ CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency.

The added value of haemoglobin to height, age, and sex to predict DLCO in subjects with preserved exercise capacity.

BACKGROUND: The single breath diffusion capacity for carbon monoxide (DLCO) captures several aspects of the role of the lung in meeting the metabolic demands of the body. The magnitude of the independent contributors to the DLCO is unknown. The aim of this study was to investigate the factors that independently contribute to the DLCO. OBJECTIVES: The objective was to investigate the impact of height, age, sex and haemoglobin on DLCO, alveolar volume (VA) and carbon monoxide transfer coefficient (KCO). METHODS: Study participants were pre-screened based on normal exercise capacity achieved during an incremental cardio-pulmonary exercise testing (CPET) using cycle ergometry at McMaster University Medical Center between 1988-2012. Participants who had an FEV1>80% predicted, with an FEV1/FVC ≥0.7 and who achieved a maximum power output ≥80% were selected for analysis. In total, 16,298 subjects [61% male, mean height 1.70m (range 1.26-2.07), age 49 yrs (10-94), weight 79 kg (23-190) had DLCO measured while demonstrating normal spirometry and exercise capacity. RESULTS: The DLCO increased exponentially with height, was 15% greater in males, increased with age yearly until 20, then decreased yearly after the age of 35, and was 6% higher per gram of haemoglobin (5.58*Height(m)1.69*1.15 in Males*(1-0.006*Age>35)*(1+0.01*Age<20) *(1+0.06*Hb gm/dl), (r = 0.76). CONCLUSION: Height, age, sex, and haemoglobin all have independent influence on the DLCO in subjects with normal spirometry and preserved exercise capacity.

Effect of Biologic Therapies on Airway Hyperresponsiveness and Allergic Response: A Systematic Literature Review.

Background: Airway hyperresponsiveness (AHR) is a key feature of asthma. Biologic therapies used to treat asthma target specific components of the inflammatory pathway, and their effects on AHR can provide valuable information about the underlying disease pathophysiology. This review summarizes the available evidence regarding the effects of biologics on allergen-specific and non-allergen-specific airway responses in patients with asthma. Methods: We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, including risk-of-bias assessment. PubMed and Ovid were searched for studies published between January 1997 and December 2021. Eligible studies were randomized, placebo-controlled trials that assessed the effects of biologics on AHR, early allergic response (EAR) and/or late allergic response (LAR) in patients with asthma. Results: Thirty studies were identified for inclusion. Bronchoprovocation testing was allergen-specific in 18 studies and non-allergen-specific in 12 studies. Omalizumab reduced AHR to methacholine, acetylcholine or adenosine monophosphate (3/9 studies), and reduced EAR (4/5 studies) and LAR (2/3 studies). Mepolizumab had no effect on AHR (3/3 studies), EAR or LAR (1/1 study). Tezepelumab reduced AHR to methacholine or mannitol (3/3 studies), and reduced EAR and LAR (1/1 study). Pitrakinra reduced LAR, with no effect on AHR (1/1 study). Etanercept reduced AHR to methacholine (1/2 studies). No effects were observed for lebrikizumab, tocilizumab, efalizumab, IMA-638 and anti-OX40 ligand on AHR, EAR or LAR; benralizumab on LAR; tralokinumab on AHR; and Ro-24-7472 on AHR or LAR (all 1/1 study each). No dupilumab or reslizumab studies were identified. Conclusion: Omalizumab and tezepelumab reduced EAR and LAR to allergens. Tezepelumab consistently reduced AHR to methacholine or mannitol. These findings provide insights into AHR mechanisms and the precise effects of asthma biologics. Furthermore, findings suggest that tezepelumab broadly targets allergen-specific and non-allergic forms of AHR, and the underlying cells and mediators involved in asthma.

Questions in Mild Asthma: An Official American Thoracic Society Research Statement.

Background: Patients with mild asthma are believed to represent the majority of patients with asthma. Disease-associated risks such as exacerbations, lung function decline, and death have been understudied in this patient population. There have been no prior efforts from major societies to describe research needs in mild asthma. Methods: A multidisciplinary, diverse group of 24 international experts reviewed the literature, identified knowledge gaps, and provided research recommendations relating to mild asthma definition, pathophysiology, and management across all age groups. Research needs were also investigated from a patient perspective, generated in conjunction with patients with asthma, caregivers, and stakeholders. Of note, this project is not a systematic review of the evidence and is not a clinical practice guideline. Results: There are multiple unmet needs in research on mild asthma driven by large knowledge gaps in all areas. Specifically, there is an immediate need for a robust mild asthma definition and an improved understanding of its pathophysiology and management strategies across all age groups. Future research must factor in patient perspectives. Conclusions: Despite significant advances in severe asthma, there remain innumerable research areas requiring urgent attention in mild asthma. An important first step is to determine a better definition that will accurately reflect the heterogeneity and risks noted in this group. This research statement highlights the topics of research that are of the highest priority. Furthermore, it firmly advocates the need for engagement with patient groups and for more support for research in this field.

Intra- and Inter-Day Reliability of Inertial Loads with Cluster Sets When Performed during a Quarter Squat on a Flywheel Device.

The aims of this study were to (i) estimate the intra- and inter-day reliability of mean concentric (CON) and eccentric (ECC) power at different inertial loads during a flywheel quarter-squat using a cluster set approach and (ii) to determine the acute effect of internal and external attentional focus on mean power when performing the flywheel quarter squat. Twelve collegiate field sport male athletes (age 22.4 ± 3.2 years, weight 81.4 ± 10.3 kg, height 1.81 ± 0.06 m) attended four cluster set testing sessions separated by 7 days. Sessions consisted of 4 sets of 15 repetitions using 4 inertial loads (0.025, 0.050, 0.075, and 0.100 kg·m2). A cluster block consisted of 5 repetitions, including "momentum repetitions" (4 × 5 + 5 + 5). Mean power (MP), CON power, ECC power, and ECC overload were recorded for both internal and external attentional focus groups. The external instructional group attained familiarization after two flywheel sessions (ES = 0.03-0.15) with little volatility between performance measures (CV% = 3.39-9.22). The internal instructional group showed large differences in MP output from session 2 to session 3 for all loads (ES = 0.59-1.25). In conclusion, the flywheel cluster set approach is a reliable training modality for maintaining MP output during all repetitions.

Impact of Airway Virus in Severe Asthmatic Patients: A Pilot Study.

The lungs have their own microbiota which seems to be altered in disease processes such as asthma. Viral infection accounts for many asthma exacerbations. Little is known about the lung virome, and the role that viruses play in non-exacerbating asthmatics. We aimed to assess if detection of virus in bronchoscopy samples of asthmatic patients in a non-exacerbating state influences their asthma control and modulates airway cytokine composition. Patients were recruited from a specialist asthma clinic and underwent bronchoscopy with standardised bronchoalveolar lavage (BAL). Viral analysis was performed; cell differential and cytokine levels were measured. Forty-six samples were obtained of which 10.8% demonstrated evidence of airway virus, and 91.3% of patients in the cohort were classed as severe asthmatics. Oral steroid use was significantly higher in severe asthmatic patients with virus detected, and the forced expiratory volume in one second tended to be lower in the virus-detected group. It was also found that BAL interleukin-13 and tumor necrosis factor-α levels were significantly higher in severe asthmatic patients with virus detected. Our results suggest that in severe asthmatics in a non-exacerbating state, the presence of virus resulted in overall poorer asthma control. The pattern of cytokine elevation seen in asthmatic patients with virus detected may provide insight to the pathophysiology involved.