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BackgroundA well-coordinated adaptive immune response is crucial for limiting COVID-19 disease. Some individuals with immunodeficiency are at a high risk of developing severe COVID-19. Therefore, the development of standardized methods for measuring different arms of the vaccine response in the setting of immunodeficiency is of particular interest. In this study, we compared the vaccine response of individuals living with immunodeficiency with healthy controls in terms of interferon gamma (IFN-γ) production and spike protein-specific antibody level post primary COVID-19 vaccination and booster vaccines. Additionally, the disease severity of those individuals who contracted COVID-19 was assessed.MethodsWhole blood was stimulated overnight from 71 participants and 99 healthy controls. Commercially available PepTivator® peptide pool and trimeric spike protein stimulation were used. ELISA was used to analyze IFN-γ levels. The total SARS-CoV-2 spike protein antibody titre was measured using a Roche Elecsys® S total antibody assay. Patient characteristics, COVID-19 infection status and IDDA 2.1 ‘Kaleidoscope’ scores were recorded. Vaccine responses were scored from zero to three.Results99% of healthy controls, 89% of individuals with IEI and 76% with secondary immunodeficiency (SID) had an IFN-γ level above the validated reference range after peptide mix stimulation following primary vaccination. There was an increase in IFN-γ levels in patients with inborn errors of immunity (IEI) following the booster vaccine (p = 0.0156). 100% of healthy controls, 70% of individuals living with IEI and 64% of individuals living with SID had detectable spike protein-specific antibody levels following the primary vaccination. 55% of immunodeficiency patients who had mild COVID-19 and 10% with moderate/severe COVID-19 had detectable antibody and IFN-γ levels post vaccine. The mean pre-infection IDDA 2.1 scores were higher in individuals who developed moderate/severe COVID-19 (25.2 compared to 9.41).ConclusionsCovid whole-blood IGRA is a highly accurate, straightforward and robust assay and can be easily adapted to measure cellular response to COVID-19. A complete evaluation of the vaccine response may be particularly important for individuals living with immunodeficiency. A clinical immunodeficiency score and a validated vaccine response score may be valuable tools in estimating COVID-19 disease risk and identifying individuals living with immunodeficiency who may benefit from enhanced vaccination schedules.

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare, progressive genetic disease, characterised by immune deficiency and dysregulation, affecting individuals from birth. In a 12-week phase III randomised placebo-controlled trial, leniolisib, a selective PI3Kδ inhibitor, was well-tolerated and met both co-primary endpoints (change from Baseline in log 10 -transformed sum of product of diameters of index lymph nodes and percentage of naïve/total B cells at Day 85). Here, prespecified subgroup analyses are reported in adolescents aged 12-17 years (leniolisib, n = 8; placebo, n = 4) and adults aged ≥18 (leniolisib, n = 13; placebo, n = 6). In both subgroups, leniolisib reduced lymphadenopathy (least squares mean change versus placebo: adolescents, -0.4 versus -0.1; adults, -0.3 versus 0.1) and increased the percentage of naïve B cells (least squares mean change: adolescents, 44.5 versus -16.5; adults, 28.4 versus -1.1). Leniolisib was well-tolerated in both adolescents and adults. These results show leniolisib is an effective APDS treatment in both subpopulations. PLAIN LANGUAGE SUMMARY: What is activated PI3Kδ syndrome (APDS)? APDS is an ultra-rare disease in which the immune system does not work correctly. People with APDS have a wide range of symptoms, including infections, certain organs associated with the immune system becoming larger, and worse quality of life. These symptoms generally start in childhood. Why was this study carried out? Current treatments only treat the symptoms of APDS, rather than correcting the cause of the problem. These treatments can also have significant side effects. A new medication for APDS called leniolisib aims to treat the underlying cause of the disease. This publication reports results from a clinical trial of leniolisib which compared patients who received leniolisib with patients who received a placebo. The aim of this report was to examine these clinical trial results to understand if leniolisib is effective and safe when treating both adolescents (12-17 years old) and adults (18 years and older) with APDS. What were the results of this study? Leniolisib improved the number of certain immune cells, compared to patients who did not receive leniolisib, in both adolescents and adults with APDS. Leniolisib also reduced the size of the enlarged immune system organs in both adolescents and adults with APDS. There were no major safety concerns for either age group who received leniolisib. What do these results mean? These results show that leniolisib can help the immune system to work in a way that is closer to those without APDS. This new treatment is effective and generally well-tolerated for both adolescents and adults. These results indicate that people with APDS are able to start treatment with leniolisib during adolescence, which may slow the build-up of symptoms and may also have a positive impact on the quality of their lives., Competing Interests: Declaration of competing interest VKR: None; AŠ: Consultant and Lecturer to Takeda and Octapharma; Lecturer to CSL Behring; VASHD: Consultant for/honoraria from AstraZeneca, CSL Behring, GSK, Pharming Group, Takeda; AP: None; CS: None; AS: Honoraria from and is a consultant for Octapharma, CSL Behring, and Novartis; AT: None; YZ: None; AO: None; EK: None; SW: Consultant to Pharming Group; JK: Received travel expenses and honoraria from Pharming Group; VL: None; YR: None; NC: None; TC: None; JB: Current employee and stock options holder of Pharming Group; holds individual stock in Neoclone; AR: Current employee and stock options holder of Pharming Group; GU: None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Investigating the contributory role that epithelial cell metabolism plays in allergic inflammation is a key factor to understanding what influences dysfunction and the pathogenesis of the allergic disease eosinophilic esophagitis (EoE). We previously highlighted that the absence of hypoxia signaling through hypoxia-inducible factor (HIF)-1α in EoE contributes to esophageal epithelial dysfunction. However, metabolic regulation by HIF-1α has not been explored in esophageal allergy., Objectives: We sought to define the role of HIF-1α-mediated metabolic dysfunction in esophageal epithelial differentiation processes and barrier function in EoE., Methods: In RNA sequencing of EoE patient biopsy samples, we observed the expression pattern of key genes involved in mitochondrial metabolism/oxidative phosphorylation (OXPHOS) and glycolysis. Seahorse bioenergetics analysis was performed on EPC2-hTERT cells to decipher the metabolic processes involved in epithelial differentiation processes. In addition, air-liquid interface cultures were used to delineate metabolic dependency mechanisms required for epithelial differentiation., Results: Transcriptomic analysis identified an increase in genes associated with OXPHOS in patients with EoE. Epithelial origin of this signature was confirmed by complex V immunofluorescence of patient biopsy samples. Bioenergetic analysis in vitro revealed that differentiated epithelium was less reliant on OXPHOS compared with undifferentiated epithelium. Increased OXPHOS potential and reduced glycolytic capacity was mirrored in HIF1A-knockdown EPC2-hTERT cells that exhibited a significant absence of terminal markers of epithelial differentiation, including involucrin. Pharmacologic glucose transport inhibition phenocopied this, while rescue of the HIF-1α-deficient phenotype using the pan-prolyl hydroxylase inhibitor dimethyloxalylglycine resulted in restored expression of epithelial differentiation markers., Conclusions: An OXPHOS-dominated metabolic pattern in EoE patients, brought about largely by the absence of HIF-1α-mediated glycolysis, is linked with the deficit in esophageal epithelial differentiation., Competing Interests: Disclosure statement This publication emanated from research conducted with the financial support of Science Foundation Ireland under grants 18/FRL/6201 (E.N.M.) and 17/FRL/4863 (J.C.M.), and from the Health Research Board under grant ILP-POR-2022-026 (J.C.M.). Financial support for Attune NxT was provided to Maynooth University Department of Biology by Science Foundation Ireland (16/RI/3399). G.T.F. received support via appointment to the La Cache Chair in Gastrointestinal and Immunologic Diseases. The study sponsors played no role in the study design; in the collection, analysis, and interpretation of data; or in the preparation of the report. Contents do not necessarily represent the views of the official funder. Disclosure of potential conflict of interest: J. M. Espinosa reports providing consulting services to Eli Lilly, Gilead, Biohaven, and Perha Pharmaceuticals. The rest of the authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Healthcare workers (HCWs) are at increased risk of SARS-CoV-2 infection. Despite widespread vaccination, some HCWs develop frequent symptomatic infection. We hypothesised that HCWs with frequent symptomatic COVID-19 have impaired T and B cell mediated immunity to SARS-CoV-2. Vaccinated HCWs with no prior COVID infection (n = 9), asymptomatic recent infection (n = 10), and frequent recent infection (n = 15) were recruited from a longitudinal HCW cohort study. Whole blood stimulation with SARS-CoV-2 variants (Wuhan, B.1.617, BA.2, BA.2.75, BA.4/5, XBB.1.5, BQ.1.1) was performed, with IFNγ and IL-2 responses, total IgG produced, and anti-Spike antibody neutralising capacity measured. Frequent infections had similar IFNγ and IL-2 responses to the never infected group, with significantly higher responses in the asymptomatic group. The frequent cohort had higher IgG responses to Delta and BA.4/5 and higher neutralising capacity against Omicron variants. An immune signature of blunted IL-2 and IFNγ in frequent infections may identify HCWs at increased risk of further infection., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: CRUSE® is an app that allows patients with chronic spontaneous urticaria (CSU) to monitor their daily disease activity through the use of visual analogue scales (VASs). We aimed to determine the concurrent validity, reliability, responsiveness and minimal important difference (MID) of CRUSE® VASs., Methods: We evaluated the properties of three daily VASs: VAS for how much patients were affected by their CSU ('VAS urticaria'), VAS for the impact of urticaria on work/school productivity ('VAS productivity') and the VAS of EQ-5D. Concurrent validity was assessed by measuring the association between each VAS and the Urticaria Activity Score (UAS). Intra-rater reliability was determined based on the data of users providing multiple daily questionnaires within the same day. Test-retest reliability and responsiveness (ability to change), respectively, were tested in clinically stable and clinically unstable users. MIDs were determined using distribution-based methods., Results: We included 5938 patients (67,380 days). Concurrent validity was high, with VAS urticaria being more strongly associated with the UAS score than the remaining VASs. Intra-rater reliability was also high, with intraclass correlation coefficients (ICC) being above 0.950 for all VASs. Moderate-high test-retest reliability and responsiveness were observed, with reliability ICC being highest for VAS EQ-5D and responsiveness being highest for VAS urticaria. The MID for VAS urticaria was 17 (out of 100) units, compared to 15 units for VAS productivity and 11 units for VAS EQ-5D., Conclusion: Daily VASs for CSU available in the CRUSE® app display high concurrent validity and intra-rater reliability and moderate-high test-retest reliability and responsiveness., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Neutrophilia occurs in patients infected with SARS-CoV-2 (COVID-19) and is predictive of poor outcomes. Here, we link heterogenous neutrophil populations to disease severity in COVID-19. We identified neutrophils with features of cellular aging and immunosuppressive capacity in mild COVID-19 and features of neutrophil immaturity and activation in severe disease. The low-density neutrophil (LDN) number in circulating blood correlated with COVID-19 severity. Many of the divergent neutrophil phenotypes in COVID-19 were overrepresented in the LDN fraction and were less detectable in normal-density neutrophils. Functionally, neutrophils from patients with severe COVID-19 displayed defects in neutrophil extracellular trap formation and reactive oxygen species production. Soluble factors secreted by neutrophils from these patients inhibited T cell proliferation. Neutrophils from patients with severe COVID-19 had increased expression of arginase-1 protein, a feature that was retained in convalescent patients. Despite this increase in intracellular expression, there was a reduction in arginase-1 release by neutrophils into serum and culture supernatants. Furthermore, neutrophil-mediated T cell suppression was independent of arginase-1. Our results indicate the presence of dysfunctional, activated, and immature neutrophils in severe COVID-19.

Cocaine usage is increasing at a rate faster than population growth worldwide. The habitual and chronic insufflation of pulverised cocaine is associated with the progressive destruction of the osseocartilaginous structures of the midface, termed cocaine-induced midline destructive lesions (CIMDLs). These entities present a challenging diagnostic picture, mimicking other infectious, malignant and inflammatory conditions associated with midface destruction. CIMDLs can present along a wide spectrum of disease, with minimal palatal perforation to extensive sinonasal destruction. With the increasing usage of cocaine, there is likely to be a concurrent increase in patients presenting to emergency departments with these destructive entities. Therefore, there is a need to create awareness of this uncommon entity and to document a systematic approach that must be adopted to reach a definitive diagnosis which will subsequently inform management. We report four clinical cases of CIMDLs at varying stages of the disease process which presented to the Dublin Dental University Hospital between January 2023 and June 2024 and document their multidisciplinary management from initial presentation to eventual treatment., (© 2024. The Author(s).)

Background: Chronic spontaneous urticaria (CSU) is a common, debilitating skin disorder characterized by recurring episodes of raised, itchy and sometimes painful wheals lasting longer than 6 weeks. CSU is mediated by mast cells which are absent from peripheral blood. However, lineage - CD34 hi CD117 int/hi FcεRI + cells in blood have previously been shown to represent a mast cell precursor., Methods: We enumerated FcεRI - , FcεRI + and FcεRI hi lineage - CD34 + CD117 + cells using flow cytometry in blood of patients with CSU (n = 55), including 12 patients receiving omalizumab and 43 not receiving omalizumab (n = 43). Twenty-two control samples were studied. Disease control and patient response to omalizumab was evaluated using the urticaria control test. We performed single-cell RNA sequencing (scRNA-Seq) on lineage - CD34 hi CD117 hi blood cells from a subset of patients with CSU (n = 8) and healthy controls (n = 4)., Results: CSU patients had more lineage - CD34 + CD117 + FcεRI + blood cells than controls. Lineage - CD34 + CD117 + FcεRI + cells were significantly higher in patients with CSU who had an objective clinical response to omalizumab when compared to patients who had poor disease control 90 days after initiation of omalizumab. scRNA-Seq revealed that lineage - CD34 + CD117 + FcεRI + cells contained both lymphoid and myeloid progenitor lineages, with omalizumab responsive patients having proportionally more myeloid progenitors. The myeloid progenitor lineage contained small numbers of true mast cell precursors along with more immature FcεRI - and FcεRI + myeloid progenitors., Conclusion: Increased blood CD34 + CD117 + FcεRI + cells may reflect enhanced bone marrow egress in the setting of CSU. High expression of these cells strongly predicts better clinical responses to the anti-IgE therapy, omalizumab., (© 2024 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Aims: Diagnosis of hydatidiform mole or molar pregnancy based on morphology alone can be challenging, particularly in early gestation, necessitating the use of ancillary techniques for accurate diagnosis. We sought to adapt the VENTANA HER2 dual-colour dual-hapten in-situ hybridisation (D-DISH) assay by using the internal chromosome 17 enumeration probe to determine ploidy status., Methods: We selected 25 products of conception, consisting of molar and non-molar cases, to validate the HER2 D-DISH assay. These cases had prior morphological assessment by a perinatal pathologist and ploidy analysis using molecular cytogenetics. Three independent observers, blinded to the original histopathological and genetic diagnosis, scored 10 representative areas on each slide. Interobserver variability was assessed by comparing the total scores of each observer using analysis of variance (ANOVA) and the kappa statistic., Results: Our ploidy scoring system accurately determined the correct number of diploid and triploid conceptuses, demonstrating complete concordance with pre-existing ploidy status and the initial diagnosis. Interobserver agreement between three independent scorers was robust: ANOVA (p=0.36) and kappa statistic (0.812, p<0.001). We achieved clear separation of average nuclear signals for diploid and triploid conceptuses, which was statistically significant (p<0.05). Employing our innovative scoring system, known as the 'rule of 5', we established ploidy decision thresholds for all 25 cases., Conclusions: Our modified HER2 D-DISH ploidy assay simplifies the process of ploidy determination and improves the accuracy of morphological diagnosis of molar pregnancy. The HER2 D-DISH assay was selected for ploidy analysis due to the widespread availability of in-situ hybridisation in pathology laboratories., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background: General anaesthesia is in common use for patients undergoing surgical procedures, with the option of both inhalational and intravenous anaesthetic techniques. Anaesthetic gases are often excluded from discussions on sustainable healthcare delivery, despite being a significant contributor to the overall environmental impact of healthcare services., Methods: A literature review was carried out on previously published papers on the impact anaesthetic gases have on our environment and at ways to reduce their impact in current anaesthetic practice. The aim was to write a narrative review detailing the areas of concern as well as the current clinical situation in the European setting., Summary/conclusions: The two classes of inhaled anaesthetic agent most frequently used are nitrous oxide and volatile agents (most commonly sevoflurane, isoflurane and desflurane). Both are recognised greenhouse gases that contribute to climate change. Minor modifications in the use of anaesthetic gases can have a significant environmental impact. These modifications include avoiding nitrous oxide whenever possible, avoiding desflurane (and using sevoflurane instead), using low flow anaesthesia during maintenance, swapping volatile-based anaesthesia for a TIVA technique when clinically appropriate and considering the use of central neuraxial or regional anaesthesia in place of general anaesthesia when possible., Competing Interests: Declaration of competing interest All authors have declared no conflicts of interest., (Copyright © 2024 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Expedited development of SARS-CoV-2 vaccines led to public concerns regarding impacts of the novel vaccine on gametes in patients seeking assisted reproduction. In cases of an acute intermittent illness or fever in men, it is often advised to postpone ART treatments so that efforts can be made to enhance wellbeing and improve sperm parameters. However, it is unknown whether sperm parameters are altered in the acute (24-72 hour) phase following COVID-19 vaccination. We performed a longitudinal cohort study of 17 normospermic male patients attending a fertility clinic for semen analysis. Semen and matched peripheral blood samples were collected prior to vaccination, within 46 + 18.9 hours of vaccine course completion (acute) and at 88.4 + 12 days (3 months) post-vaccination. No overall change from baseline was seen in symptoms, mean volume, pH, sperm concentration, motility, morphology or DNA damage in the acute or long phase. Seminal plasma was found to be negative for anti-SARS-CoV2 Spike antibody detection, and MCP-1 levels showed an acute but transient elevation post-vaccine, while IL-8 was marginally increased 3 months after completion of vaccination. A modest, positive correlation was noted between serum levels of the anti-inflammatory cytokine IL-10 and self-reported symptoms post-vaccine. Our findings are reassuring in that no significant adverse effect of vaccination was noted and provide evidence to support the current recommendations of reproductive medicine organisations regarding timing of vaccination during fertility treatment., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Immunosuppressive treatment in patients with rheumatic diseases can maintain disease remission but also increase risk of infection. Their response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is frequently blunted. In this study we evaluated the effect of immunosuppression exposure on humoral and T cell immune responses to SARS-CoV-2 infection and vaccination in two distinct cohorts of patients; one during acute SARS-CoV-2 infection and 3 months later during convalescence, and another prior to SARS-CoV-2 vaccination, with follow up sampling 6 weeks after vaccination. Results were compared between rituximab-exposed (in previous 6 months), immunosuppression-exposed (in previous 3 months), and non-immunosuppressed groups. The immune cell phenotype was defined by flow cytometry and ELISA. Antigen specific T cell responses were estimated using a whole blood stimulation interferon-γ release assay. A focused post-vaccine assessment of rituximab-treated patients using high dimensional spectral cytometry was conducted. Acute SARS-CoV-2 infection was characterised by T cell lymphopenia, and a reduction in NK cells and naïve CD4 and CD8 cells, without any significant differences between immunosuppressed and non-immunosuppressed patient groups. Conversely, activated CD4 and CD8 cell counts increased in non-immunosuppressed patients with acute SARS-CoV-2 infection but this response was blunted in the presence of immunosuppression. In rituximab-treated patients, antigen-specific T cell responses were preserved in SARS-CoV-2 vaccination, but patients were unable to mount an appropriate humoral response.

Background and Objectives: Epstein-Barr virus (EBV) has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Despite this, there are no routinely used tests to measure cellular response to EBV. In this study, we analyzed the cellular response to EBV nuclear antigen-1 (EBNA-1) in people with MS (pwMS) using a whole blood assay., Methods: This cross-sectional study took place in a dedicated MS clinic in a university hospital. We recruited healthy controls, people with epilepsy (PWE), and pwMS taking a range of disease-modifying treatments (DMTs) including natalizumab, anti-CD20 monoclonal antibodies (mAbs), dimethyl fumarate (DMF), and also treatment naïve. Whole blood samples were stimulated with commercially available PepTivator EBNA1 peptides and a control virus-cytomegalovirus (CMV) peptide. We recorded the cellular response to stimulation with both interferon gamma (IFN-γ) and interleukin-2 (IL-2). We also compared the cellular responses to EBNA1 with IgG responses to EBNA1, viral capsid antigen (VCA), and EBV viral load., Results: We recruited 86 pwMS, with relapsing remitting MS, in this group, and we observed a higher level of cellular response recorded with IFN-γ (0.79 IU/mL ± 1.36) vs healthy controls (0.29 IU/mL ± 0.90, p = 0.0048) and PWE (0.17 IU/mL ± 0.33, p = 0.0088). Treatment with either anti-CD20 mAbs (0.28 IU/mL ± 0.57) or DMF (0.07 IU/mL ± 0.15) resulted in a cellular response equivalent to control levels or in PWE ( p = 0.26). The results of recording IL-2 response were concordant with IFN-γ: with suppression also seen with anti-CD20 mAbs and DMF. By contrast, we did not record any differential effect of DMTs on the levels of IgG to either EBNA-1 or VCA. Nor did we observe differences in cellular response to cytomegalovirus between groups., Discussion: This study demonstrates how testing and recording the cellular response to EBNA-1 in pwMS may be beneficial. EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE. In addition, we show a differential effect of currently available DMTs on this response. The functional assay deployed uses whole blood samples with minimal preprocessing suggesting that employment as a treatment response measure in clinical trials targeting EBV may be possible.

Objective: ANCA-associated vasculitis (AAV) is a relapsing-remitting disease, resulting in incremental tissue injury. The gold-standard relapse definition (Birmingham Vasculitis Activity Score, BVAS>0) is often missing or inaccurate in registry settings, leading to errors in ascertainment of this key outcome. We sought to create a computable phenotype (CP) to automate retrospective identification of relapse using real-world data in the research setting., Methods: We studied 536 patients with AAV and >6 months follow-up recruited to the Rare Kidney Disease registry (a national longitudinal, multicentre cohort study). We followed five steps: (1) independent encounter adjudication using primary medical records to assign the ground truth, (2) selection of data elements (DEs), (3) CP development using multilevel regression modelling, (4) internal validation and (5) development of additional models to handle missingness. Cut-points were determined by maximising the F1-score. We developed a web application for CP implementation, which outputs an individualised probability of relapse., Results: Development and validation datasets comprised 1209 and 377 encounters, respectively. After classifying encounters with diagnostic histopathology as relapse, we identified five key DEs; DE1: change in ANCA level, DE2: suggestive blood/urine tests, DE3: suggestive imaging, DE4: immunosuppression status, DE5: immunosuppression change. F1-score, sensitivity and specificity were 0.85 (95% CI 0.77 to 0.92), 0.89 (95% CI 0.80 to 0.99) and 0.96 (95% CI 0.93 to 0.99), respectively. Where DE5 was missing, DE2 plus either DE1/DE3 were required to match the accuracy of BVAS., Conclusions: This CP accurately quantifies the individualised probability of relapse in AAV retrospectively, using objective, readily accessible registry data. This framework could be leveraged for other outcomes and relapsing diseases., Competing Interests: Competing interests: PAM declares the following disclosures: Consulting and Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Neutrolis, Takeda. Consulting only: Cabaletta, CSL Behring, Dynacure, EMDSerono, Immagene, Jannsen, Jubilant, Kiniksa, Kyverna, Magenta, MiroBio, Mitsubishi, Novartis, Pfizer, Q32, Regeneron, Sparrow, Vistera. Research Support only: Eicos, Electra, Sanofi, Star. Stock options: Kyverna. Royalties: UpToDate. All other authors declare that they have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

The effective transition from pediatric to adult care for individuals with chronic medical conditions should address the medical, psychosocial and educational needs of the cohort. The views and experiences of service users and their families are an integral component of service development. This study sought to evaluate the current provision of transition services from pediatric immunology services to adult immunology services for patients with a diagnosis of an inborn error of immunity at St. James's Hospital, Dublin. We gathered patient perspectives on the experience of the transition process using a structured survey. In addition, we adopted a micro-costing technique to estimate the cost of implementing the current standard of care for these patients. Results of a micro-costing analysis suggest that the most significant component of cost in assessing these patients is on laboratory investigation, an area where there is likely significant duplication between pediatric and adult care. Perspectives from patients suggested that the transition period went well for the majority of the cohort and that they felt ready to move to adult services, but the transition was not without complications in areas such as self-advocacy and medication management. The transition process may benefit from enhanced communication and collaboration between pediatric and adult services., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 King, Ridge, Smyth, Flinn, Leahy and Conlon.)

Vascular disruption has been implicated in coronavirus disease 2019 (COVID-19) pathogenesis and may predispose to the neurological sequelae associated with long COVID, yet it is unclear how blood-brain barrier (BBB) function is affected in these conditions. Here we show that BBB disruption is evident during acute infection and in patients with long COVID with cognitive impairment, commonly referred to as brain fog. Using dynamic contrast-enhanced magnetic resonance imaging, we show BBB disruption in patients with long COVID-associated brain fog. Transcriptomic analysis of peripheral blood mononuclear cells revealed dysregulation of the coagulation system and a dampened adaptive immune response in individuals with brain fog. Accordingly, peripheral blood mononuclear cells showed increased adhesion to human brain endothelial cells in vitro, while exposure of brain endothelial cells to serum from patients with long COVID induced expression of inflammatory markers. Together, our data suggest that sustained systemic inflammation and persistent localized BBB dysfunction is a key feature of long COVID-associated brain fog., (© 2024. The Author(s).)

Reversal or mitigation against an age-related decline in NAD + has likely benefits, and this premise has driven academic and commercial endeavour to develop dietary supplements that achieve this outcome. We used a systems-based approach to improve on current supplements by targeting multiple points in the NAD + salvage pathway. In a double-blind, randomised, crossover trial, the supplement - Nuchido TIME+® (NT) - increased NAD + concentration in whole blood. This was associated with an increase in SIRT1 and an increase in nicotinamide phosphoribosyltransferase (NAMPT) in peripheral blood mononucleocytes, lower concentrations of pro-inflammatory cytokines in plasma, including a reduction in interleukin 2 (IL2), a reduction in glycated serum protein and a shift in the glycosylation profile of immunoglobulin G (IgG) toward a younger biological age, all of which are likely to promote a healthier ageing trajectory., (© 2024. The Author(s).)

Introduction: Human-robot teams are being called upon to accomplish increasingly complex tasks. During execution, the robot may operate at different levels of autonomy (LOAs), ranging from full robotic autonomy to full human control. For any number of reasons, such as changes in the robot's surroundings due to the complexities of operating in dynamic and uncertain environments, degradation and damage to the robot platform, or changes in tasking, adjusting the LOA during operations may be necessary to achieve desired mission outcomes. Thus, a critical challenge is understanding when and how the autonomy should be adjusted. Methods: We frame this problem with respect to the robot's capabilities and limitations, known as robot competency. With this framing, a robot could be granted a level of autonomy in line with its ability to operate with a high degree of competence. First, we propose a Model Quality Assessment metric, which indicates how (un)expected an autonomous robot's observations are compared to its model predictions. Next, we present an Event-Triggered Generalized Outcome Assessment (ET-GOA) algorithm that uses changes in the Model Quality Assessment above a threshold to selectively execute and report a high-level assessment of the robot's competency. We validated the Model Quality Assessment metric and the ET-GOA algorithm in both simulated and live robot navigation scenarios. Results: Our experiments found that the Model Quality Assessment was able to respond to unexpected observations. Additionally, our validation of the full ET-GOA algorithm explored how the computational cost and accuracy of the algorithm was impacted across several Model Quality triggering thresholds and with differing amounts of state perturbations. Discussion: Our experimental results combined with a human-in-the-loop demonstration show that Event-Triggered Generalized Outcome Assessment algorithm can facilitate informed autonomy-adjustment decisions based on a robot's task competency., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Conlon, Ahmed and Szafir.)

Background: Concern about disease exacerbations and fear of reactions after coronavirus disease 2019 (COVID-19) vaccinations are common in chronic urticaria (CU) patients and may lead to vaccine hesitancy., Objective: We assessed the frequency and risk factors of CU exacerbation and adverse reactions in CU patients after COVID-19 vaccination., Methods: COVAC-CU is an international multicenter study of Urticaria Centers of Reference and Excellence (UCAREs) that retrospectively evaluated the effects of COVID-19 vaccination in CU patients aged ≥18 years and vaccinated with ≥1 dose of any COVID-19 vaccine. We evaluated CU exacerbations and severe allergic reactions as well as other adverse events associated with COVID-19 vaccinations and their association with various CU parameters., Results: Across 2769 COVID-19-vaccinated CU patients, most (90%) received at least 2 COVID-19 vaccine doses, and most patients received CU treatment and had well-controlled disease. The rate of COVID-19 vaccination-induced CU exacerbation was 9%. Of 223 patients with CU exacerbation after the first dose, 53.4% experienced recurrence of CU exacerbation after the second dose. CU exacerbation most often started <48 hours after vaccination (59.2%), lasted for a few weeks or less (70%), and was treated mainly with antihistamines (70.3%). Factors that increased the risk for COVID-19 vaccination-induced CU exacerbation included female sex, disease duration shorter than 24 months, having chronic spontaneous versus inducible urticaria, receipt of adenovirus viral vector vaccine, having nonsteroidal anti-inflammatory drug/aspirin intolerance, and having concerns about getting vaccinated; receiving omalizumab treatment and Latino/Hispanic ethnicity lowered the risk. First-dose vaccine-related adverse effects, most commonly local reactions, fever, fatigue, and muscle pain, were reported by 43.5% of CU patients. Seven patients reported severe allergic reactions., Conclusions: COVID-19 vaccination leads to disease exacerbation in only a small number of CU patients and is generally well tolerated., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder., Competing Interests: No conflict of Interest., (© 2023 The Authors. Published by Elsevier B.V.)

Schnitzler syndrome (SchS) is an autoinflammatory disease that is defined by the presence of 2 obligate criteria; an IgM or IgG monoclonal paraprotein and a chronic urticarial rash. Typically, there is an excellent clinical response to IL-1 antagonism. There are reports in the literature of a variant type of SchS that does not fulfil the 2 obligate criteria but responds to IL-1 blockade. Equally, there are reports of an urticarial rash preceding the development of a paraprotein by several years. We describe 3 cases in this manuscript. The first fits the Strasbourg diagnostic criteria of SchS, Simon and Asli (2013); however, with several decades of diagnostic delay. The second case at initial presentation did not fit the major criteria for SchS; however, later developed a monoclonal IgM. Finally we report, a third case that has not yet been confirmed to have a monoclonal IgM/IgG at the time of writing despite 12 years of symptoms and in whom a somatic autoinflammatory disorder remains within the differential. All cases responded strikingly to anakinra, an IL-1 receptor blocker. We propose a new clinical entity, paraprotein negative IL-1 mediated inflammatory dermatosis (PANID), that may act as a precursor or risk factor for the development of SchS or other autoinflammatory conditions., (© 2023 The Author(s).)

Introduction: As the COVID-19 pandemic moves towards endemic status, testing strategies are being de-escalated. A rapid and effective point of care test (POCT) assessment of SARS-CoV-2 immune responses can inform clinical decision-making and epidemiological monitoring of the disease. This cross-sectional seroprevalence study of anti-SARS-CoV-2 antibodies in Irish healthcare workers assessed how rapid anti-SARS-CoV-2 antibody testing can be compared to a standard laboratory assay, discusses its effectiveness in neutralisation assessment and its uses into the future of the pandemic., Methods: A point of care lateral flow immunoassay (LFA) detecting anti-SARS-CoV-2 spike (S)-receptor binding domain (RBD) neutralising antibodies (Healgen SARS-CoV-2 neutralising Antibody Rapid Test Cassette) was compared to the Roche Elecsys/-S anti-SARS-CoV-2 antibody assays and an in vitro surrogate neutralisation assay. A correlation between anti-spike (S), anti-nucleocapsid (N) titres, and in vitro neutralisation was also assessed., Results: 1,777 serology samples were tested using Roche Elecsys/-S anti-SARS-CoV-2 assays to detect total anti-N/S antibodies. 1,562 samples were tested using the POC LFA (including 50 negative controls), and 90 samples were tested using an in vitro ACE2-RBD binding inhibition surrogate neutralisation assay. The POCT demonstrated 97.7% sensitivity, 100% specificity, a positive predictive value (PPV) of 100%, and a negative predictive value (NPV) of 61% in comparison to the commercial assay. Anti-S antibody titres determined by the Roche assay stratified by the POC LFA result groups demonstrated statistically significant differences between the "Positive" and "Negative" LFA groups ( p < 0.0001) and the "Weak Positive" and "Positive" LFA groups ( p < 0.0001). No statistically significant difference in ACE2-RBD binding inhibition was demonstrated when stratified by the LFA POC results. A positive, statistically significant correlation was demonstrated between the in vitro pseudo-neutralisation assay results and anti-S antibody titres (rho 0.423, p < 0.001) and anti-N antibody titres (rho = 0.55, p < 0.0001)., Conclusion: High sensitivity, specificity, and PPV were demonstrated for the POC LFA for the detection of anti-S-RBD antibodies in comparison to the commercial assay. The LFA was not a reliable determinant of the neutralisation capacity of identified antibodies. POC LFA are useful tools in sero-epidemiology settings, pandemic preparedness and may act as supportive tools in treatment decisions through the rapid identification of anti-Spike antibodies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McGrath, O'Doherty, Conlon, Dunne, Brady, Ibrahim, McCormack, Walsh, Domegan, Walsh, Kenny, Allen, Fleming and Bergin.)

Background: Psychosocial factors have been informally associated with Chronic Spontaneous Urticaria (CSU); however, the relationship between psychosocial factors and CSU remains relatively unexplored in the scientific literature., Objective: This review aims to provide an evaluation of peer reviewed studies exploring psychosocial factors and CSU., Methods: A systematic search was performed over four databases identifying studies exploring psychosocial factors in relation to CSU published between the years 1995 and 2022., Results: Eighteen studies were included for narrative analysis, and 33 psychosocial factors were identified. These were split into two subgroups: psychosocial factors that were associated with CSU symptoms aggravation/onset (n = 20), and psychosocial factors expected to be impacted by CSU symptoms (n = 13)., Conclusion: This review has highlighted a need for more research and interventions to support individuals with psychosocial factors involved in CSU., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one of the leading causes of mortality worldwide. Recently, type I interferon (IFN) signaling has been shown to be required for tissue factor (TF; gene name F3) release from macrophages, a critical initiator of coagulation, providing an important mechanistic link between innate immunity and coagulation. The mechanism of release involves type I IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 is a type I IFN-stimulated gene. Furthermore, F3 induction by lipopolysaccharide (LPS) is inhibited by the anti-inflammatory agents dimethyl fumarate (DMF) and 4-octyl itaconate (4-OI). Mechanistically, inhibition of F3 by DMF and 4-OI involves suppression of Ifnb1 expression. Additionally, they block type I IFN- and caspase-11-mediated macrophage pyroptosis, and subsequent TF release. Thereby, DMF and 4-OI inhibit TF-dependent thrombin generation. In vivo, DMF and 4-OI suppress TF-dependent thrombin generation, pulmonary thromboinflammation, and lethality induced by LPS, E. coli, and S. aureus, with 4-OI additionally attenuating inflammation-associated coagulation in a model of SARS-CoV-2 infection. Our results identify the clinically approved drug DMF and the pre-clinical tool compound 4-OI as anticoagulants that inhibit TF-mediated coagulopathy via inhibition of the macrophage type I IFN-TF axis., (© 2023. The Author(s).)

Clinical outcomes from infection with SARS-CoV-2, the cause of the COVID-19 pandemic, are remarkably variable ranging from asymptomatic infection to severe pneumonia and death. One of the key drivers of this variability is differing trajectories in the immune response to SARS-CoV-2 infection. Many studies have noted markedly elevated cytokine levels in severe COVID-19, although results vary by cohort, cytokine studied and sensitivity of assay used. We assessed the immune response in acute COVID-19 by measuring 20 inflammatory markers in 118 unvaccinated patients with acute COVID-19 (median age: 70, IQR: 58-79 years; 48.3% female) recruited during the first year of the pandemic and 44 SARS-CoV-2 naïve healthy controls. Acute COVID-19 was associated with marked elevations in nearly all pro-inflammatory markers, whilst eleven markers (namely IL-1β, IL-2, IL-6, IL-10, IL-18, IL-23, IL-33, TNF-α, IP-10, G-CSF and YKL-40) were associated with disease severity. We observed significant correlations between nearly all markers elevated in those infected with SARS-CoV-2 consistent with widespread immune dysregulation. Principal component analysis highlighted a pro-inflammatory cytokine signature (with strongest contributions from IL-1β, IL-2, IL-6, IL-10, IL-33, G-CSF, TNF-α and IP-10) which was independently associated with severe COVID-19 (aOR: 1.40, 1.11-1.76, p=0.005), invasive mechanical ventilation (aOR: 1.61, 1.19-2.20, p=0.001) and mortality (aOR 1.57, 1.06-2.32, p = 0.02). Our findings demonstrate elevated cytokines and widespread immune dysregulation in severe COVID-19, adding further evidence for the role of a pro-inflammatory cytokine signature in severe and critical COVID-19., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hawerkamp, Dyer, Patil, McElheron, O’Dowd, O’Doherty, Mhaonaigh, George, O’Halloran, Reddy, Kenny, Little, Martin-Loeches, Bergin, Kennelly, Donnelly, Bourke, Long, Sui, Doherty, Conlon, Cheallaigh and Fallon.)

Background: A well-coordinated adaptive immune response is crucial for limiting COVID-19 disease. Some individuals with immunodeficiency are at a high risk of developing severe COVID-19. Therefore, the development of standardized methods for measuring different arms of the vaccine response in the setting of immunodeficiency is of particular interest. In this study, we compared the vaccine response of individuals living with immunodeficiency with healthy controls in terms of interferon gamma (IFN-γ) production and spike protein-specific antibody level post primary COVID-19 vaccination and booster vaccines. Additionally, the disease severity of those individuals who contracted COVID-19 was assessed., Methods: Whole blood was stimulated overnight from 71 participants and 99 healthy controls. Commercially available PepTivator ® peptide pool and trimeric spike protein stimulation were used. ELISA was used to analyze IFN-γ levels. The total SARS-CoV-2 spike protein antibody titre was measured using a Roche Elecsys ® S total antibody assay. Patient characteristics, COVID-19 infection status and IDDA 2.1 'Kaleidoscope' scores were recorded. Vaccine responses were scored from zero to three., Results: 99% of healthy controls, 89% of individuals with IEI and 76% with secondary immunodeficiency (SID) had an IFN-γ level above the validated reference range after peptide mix stimulation following primary vaccination. There was an increase in IFN-γ levels in patients with inborn errors of immunity (IEI) following the booster vaccine (p = 0.0156). 100% of healthy controls, 70% of individuals living with IEI and 64% of individuals living with SID had detectable spike protein-specific antibody levels following the primary vaccination. 55% of immunodeficiency patients who had mild COVID-19 and 10% with moderate/severe COVID-19 had detectable antibody and IFN-γ levels post vaccine. The mean pre-infection IDDA 2.1 scores were higher in individuals who developed moderate/severe COVID-19 (25.2 compared to 9.41)., Conclusions: Covid whole-blood IGRA is a highly accurate, straightforward and robust assay and can be easily adapted to measure cellular response to COVID-19. A complete evaluation of the vaccine response may be particularly important for individuals living with immunodeficiency. A clinical immunodeficiency score and a validated vaccine response score may be valuable tools in estimating COVID-19 disease risk and identifying individuals living with immunodeficiency who may benefit from enhanced vaccination schedules., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Murray, O’Brien, Alamin, Phelan, Argue, Kiersey, Gardiner, Naughton, Keogh, Holmes, Naughton, Scanlon, Sloan, McCrea, Sui, Dunne and Conlon.)

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Although chronic urticaria (CU) is a common and primarily affects females, there is little data on how pregnancy interacts with the disease., Objective: To analyse the treatment use by CU patients before, during and after pregnancy as well as outcomes of pregnancy., Methods: PREG-CU is an international, multicentre study of the Urticaria Centers of Reference and Excellence network. Data were collected via a 47-item-questionnaire completed by CU patients who became pregnant during their disease course., Results: Questionnaires from 288 CU patients from 13 countries were analysed. During pregnancy, most patients (60%) used urticaria medication including standard-dose second generation H1-antihistamines (35.1%), first generation H1-antihistamines (7.6%), high-dose second-generation H1-antihistamines (5.6%) and omalizumab (5.6%). The preterm birth rate was 10.2%; rates were similar between patients who did and did not receive treatment during pregnancy (11.6% vs. 8.7%, respectively). Emergency referrals for CU and twin birth were risk factors for preterm birth. The caesarean delivery rate was 51.3%. More than 90% of new-borns were healthy at birth. There was no link between any patient or disease characteristics or treatments and medical problems at birth., Conclusion: Most CU patients used treatment during pregnancy especially second-generation antihistamines which seem to be safe during pregnancy regardless of the trimester. The rates of preterm births and medical problems of new-borns in CU patients were similar to population norms and not linked to treatment used during pregnancy. Emergency referrals for CU increased the risk of preterm birth and emphasize the importance of sufficient treatment to keep urticaria under control during pregnancy., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: The PRECISE Study, a multi-phase cross-sectional seroprevalence study of anti-SARS-CoV-2 antibodies in Irish healthcare workers (HCW) investigated: (1) risk factors for SARS-CoV-2 seropositivity, (2) the durability of antibody responses in a highly vaccinated HCW cohort, and (3) the neutralisation capacity of detected antibodies, prior to booster COVID-19 vaccination., Materials and Methods: Serology samples were collected across two hospital sites in November 2021 and analysed using the Roche Elecsys Anti-SARS-CoV-2/Elecsys-S Anti-SARS-CoV-2 assays to detect anti-nucleocapsid (N) and anti-spike (S) antibodies respectively. Paired serology results from prior study phases were used to analyse changes in individual HCW serostatus over time. Risk-factors for SARS-CoV-2 infection were assessed for demographic and work-related factors. Antibody neutralisation capacity was assessed in a subset of samples via an in vitro ACE2 binding enzyme-linked immunosorbent assay., Results: 2,344 HCW samples were analysed. Median age was 43 years (IQR 33-50) with 80.5% ( n = 1,886) female participants. Irish (78.9%, n = 1,850) and Asian (12.3%, n = 288) were the most commonly reported ethnicities. Nursing/midwifery (39.3%, n = 922) was the most common job role. 97.7% of participants were fully vaccinated, with Pfizer (81.1%, n = 1,902) and AstraZeneca (16.1%, n = 377) the most common vaccines received. Seroprevalence for anti-SARS-CoV-2 antibodies indicating prior infection was 23.4%, of these 33.6% represented previously undiagnosed infections. All vaccinated participants demonstrated positive anti-S antibodies and in those with paired serology, no individual demonstrated loss of previously positive anti-S status below assay threshold for positivity. Interval loss of anti-N antibody positivity was demonstrated in 8.8% of previously positive participants with paired results. Risk factors for SARS-CoV-2 seropositivity suggestive of previous infection included age 18-29 years (aRR 1.50, 95% CI 1.19-1.90, p < 0.001), India as country of birth (aRR 1.35, 95% CI 1.01-1.73, p = 0.036), lower education level (aRR 1.35, 95% CI 1.11-1.66, p = 0.004) and HCA job role (aRR 2.12, 95% CI 1.51-2.95, p < 0.001). Antibody neutralisation varied significantly by anti-SARS-CoV-2 antibody status, with highest levels noted in those anti-N positive, in particular those with vaccination plus previous SARS-CoV-2 infection., Conclusion: All vaccinated HCWs maintained anti-S positivity prior to COVID-19 booster vaccination, however anti-N positivity was more dynamic over time. Antibody neutralisation capacity was highest in participants with COVID-19 vaccination plus prior SARS-CoV-2 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 McGrath, Kenny, Nielsen, Domegan, Walsh, Rooney, Walsh, Conlon, Brady, Ibrahim, Dunne, McCormack, Corcoran, Allen, Fleming and Bergin.)

Objective: The disease-modifying therapies (DMT), dimethyl fumarate (DMF) and fingolimod (FTY) improve the outcomes in multiple sclerosis (MS) by reducing relapses and numbers and volume of lesions. They mediate their effects through reduction of immune reactivation, which may potentially lead to lymphopaenia and increased risk of infections. Previous studies have examined the effects of these therapies on lymphocyte subsets; however, the in vivo effects on circulating lymphocyte proliferation require further elucidation. The aim of this study was to determine the effects of DMF and FTY on T-cell proliferation in patients with MS., Method: We examined T-cell lymphocyte proliferation and lymphocyte subsets in ten patients (five on DMF, five on FTY) before starting DMT and again 4 to 11 months after being maintained on DMT., Results: In the FTY-treated group, the mean percentage proliferation was significantly lower using both assays (PHA assay mean percentage change - 51.2 ± 25.97, p < 0.05; anti-CD3/CD28 assay mean percentage change - 39.74 ± 27.85, p < 0.05). There was no statistical difference in T-cell lymphocyte proliferation in the DMF-treated group for either assay (PHA, p = 0.316; anti-CD3/CD28, p = 0.373)., Conclusions: This pilot study suggests that the T-lymphocytes of patients on FTY have an abnormal proliferation response as well as being reduced in the circulation., (© 2022. The Author(s).)

Background: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease. There is a need for interoperable national registries to enable reporting of real-world long-term outcomes and their predictors in AAV. Methods: The Irish National Rare Kidney Disease (RKD) registry was founded in 2012. To date, 842 patients with various forms of vasculitis have been recruited across eight nephrology, rheumatology and immunology centres. We focus here on patient- and disease- characteristics, treatment and outcomes of the 397 prospectively recruited patients with AAV. Results: Median age was 64 years (IQR 55-73), 57.9% were male, 58.9% had microscopic polyangiitis and 85.9% had renal impairment. Cumulative one- and five-year patient survival was 94% and 77% respectively. Median follow-up was 33.5 months (IQR 10.7-52.7). After controlling for age, baseline renal dysfunction (p = 0.04) and the burden of adverse events (p <0.001) were independent predictors of death overall. End-stage-kidney-disease (ESKD) occurred in 73 (18.4%) patients; one- and five-year renal survival was 85% and 79% respectively. Baseline severity of renal insufficiency (p = 0.02), urine soluble CD163 (usCD163) (p = 0.002) and "sclerotic" Berden histological class (p = 0.001) were key determinants of ESKD risk. Conclusions: Long-term outcomes of Irish AAV patients are comparable to other reported series. Our results emphasise the need for personalisation of immunosuppression, to limit treatment toxicity, particularly in those with advanced age and renal insufficiency. Baseline usCD163 is a potential biomarker for ESKD prediction and should be validated in a large independent cohort., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Scott J et al.)

Host immunity to infection with SARS-CoV-2 is highly variable, dictating diverse clinical outcomes ranging from asymptomatic to severe disease and death. We previously reported reduced type I interferon in severe COVID-19 patients preceded clinical worsening. Further studies identified genetic mutations in loci of the TLR3- or TLR7-dependent interferon-I pathways, or neutralizing interferon-I autoantibodies as risk factors for development of COVID-19 pneumonia. Here we show in patient cohorts with different severities of COVID-19, that baseline plasma interferon α measures differ according to the immunoassay used, timing of sampling, the interferon α subtype measured, and the presence of autoantibodies. We also show a consistently reduced induction of interferon-I proteins in hospitalized COVID-19 patients upon immune stimulation, that is not associated with detectable neutralizing autoantibodies against interferon α or interferon ω. Intracellular proteomic analysis shows increased monocyte numbers in hospitalized COVID-19 patients but impaired interferon-I response after stimulation. We confirm this by ex vivo whole blood stimulation with interferon-I which induces transcriptomic responses associated with inflammation in hospitalized COVID-19 patients, that is not seen in controls or non-hospitalized moderate cases. These results may explain the dichotomy of the poor clinical response to interferon-I based treatments in late stage COVID-19, despite the importance of interferon-I in early acute infection and may guide alternative therapeutic strategies., (© 2022. The Author(s).)

Background: Non-islet cell tumour hypoglycemia (NICTH) is rarely encountered in clinical practice. Insulin-like growth factor 2 (IGF2) is the most common cause of NICTH observed in the setting of mesenchymal and epithelial neoplasia. This is a paraneoplastic syndrome caused by IGF2 activation of the insulin receptor., Case Presentation: An 80 year old female presented with a short history of recurrent episodes of confusion with laboratory confirmed hypoglycemia with a plasma glucose of 2.7 mmol/L on fasting which fulfilled Whipple's triad. Diagnostic clues to the aetiology at presentation include the fasting pattern of hypoglycemia, hypokalaemia and the absence of weight gain. A 72 hour fast with results showed early hypoglycemia and suppression of serum insulin, c-peptide, and proinsulin. Serum insulin antibody was not detected. Subsequent measurement of the serum IGF2:IGF1 ratio was elevated at 22.3 and consistent with IGF-2 mediated hypoglycemia and imaging studies demonstrated a pelvic mass. Dietary intervention and oral prednisolone abated hypoglycemia prior to surgery. Ultimately, hypoglycemia resolved following operative intervention and steroid therapy was successfully withdrawn. Histopathology was remarkable for dual neoplastic processes with uterine solitary fibrous tumour (SFT) confirmed as the source of IGF2 hypersecretion on IGF-2 immunohistochemistry and a coincidental invasive high grade serous carcinoma involving the fimbria of the right fallopian tube., Conclusion: The paradox in this case is that the benign solitary fibrous tumour accounted for patient morbidity through secretion of IGF2 and without treatment, posed a mortality risk. This is despite the synchronous presence of a highly malignant fallopian tube neoplasm. This case reinforces the need for thorough clinical evaluation of hypoglycemia to allow prompt and definitive management., (© 2022. The Author(s).)

With an ever-growing market and continual financial pressures associated with the prohibition of antibiotic growth promoters, the poultry industry has had to rapidly develop non-antibiotic alternatives to increase production yields. A possible alternative is yeast and its derivatives, such as the yeast cell wall (YCW), which have been proposed to confer selected beneficial effects on the host animal. Here, the effect of YCW supplementation on the broiler chicken was investigated using a quantitative proteomic strategy, whereby serum was obtained from three groups of broilers fed with distinct YCW-based Gut Health Products (GHP) or a control basal diet. Development of a novel reagent enabled application of ProteoMiner™ technology for sample preparation and subsequent comparative quantitative proteomic analysis revealed proteins which showed a significant change in abundance (n = 167 individual proteins; p < 0.05); as well as proteins which were uniquely identified (n = 52) in, or absent (n = 37) from, GHP-fed treatment groups versus controls. An average of 7.1% of proteins showed changes in abundance with GHP supplementation. Several effects of these GHPs including immunostimulation (via elevated complement protein detection), potential alterations in the oxidative status of the animal (e.g., glutathione peroxidase and catalase), stimulation of metabolic processes (e.g., differential abundance of glyceraldehyde-3-phosphate dehydrogenase), as well as evidence of a possible hepatoprotective effect (attenuated levels of serum α-glutathione s-transferase) by one GHP feed supplement, were observed. It is proposed that specific protein detection may be indicative of GHP efficacy to stimulate broiler immune status, i.e., may be biomarkers of GHP efficacy. In summary, this work has developed a novel technology for the preparation of high dynamic range proteomic samples for LC-MS/MS analysis, is part of the growing area of livestock proteomics and, importantly, provides evidential support for beneficial effects that GHP supplementation has on the broiler chicken.

Background: Prolonged recovery is common after acute SARS-CoV-2 infection; however, the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF/ADAMTS-13 imbalance, dysregulated angiogenesis, and immunothrombosis are hallmarks of acute COVID-19. We hypothesized that VWF/ADAMTS-13 imbalance persists in convalescence together with endothelial cell (EC) activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation., Patients and Methods: Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS-13, Weibel Palade Body (WPB) proteins, and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n = 20) and acute COVID-19 patients (n = 36)., Results: ADAMTS-13 levels were reduced (p = 0.009) and the VWF-ADAMTS-13 ratio was increased in convalescence (p = 0.0004). Levels of platelet factor 4 (PF4), a putative protector of VWF, were also elevated (p = 0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively., Conclusion: Our data provide insights into sustained EC activation, dysregulated angiogenesis, and VWF/ADAMTS-13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immunothrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

The naturally occurring sulphur-containing histidine derivative, ergothioneine (EGT), exhibits potent antioxidant properties and has been proposed to confer human health benefits. Although it is only produced by select fungi and prokaryotes, likely to protect against environmental stress, the GRAS organism Saccharomyces cerevisiae does not produce EGT naturally. Herein, it is demonstrated that the recombinant expression of a single gene, Aspergillus fumigatus egtA, in S. cerevisiae results in EgtA protein presence which unexpectedly confers complete EGT biosynthetic capacity. Both High Performance Liquid Chromatography (HPLC) and LC−mass spectrometry (MS) analysis were deployed to detect and confirm EGT production in S. cerevisiae. The localisation and quantification of the resultant EGT revealed a significantly (p < 0.0001) larger quantity of EGT was extracellularly present in culture supernatants than intracellularly accumulated in 96 h yeast cultures. Methionine addition to cultures improved EGT production. The additional expression of two candidate cysteine desulfurases from A. fumigatus was thought to be required to complete EGT biosynthesis, namely AFUA&#95;2G13295 and AFUA&#95;3G14240, termed egt2a and egt2b in this study. However, the co-expression of egtA and egt2a in S. cerevisiae resulted in a significant decrease in the observed EGT levels (p < 0.05). The AlphaFold prediction of A. fumigatus EgtA 3-Dimensional structure illuminates the bidomain structure of the enzyme and the opposing locations of both active sites. Overall, we clearly show that recombinant S. cerevisiae can biosynthesise and secrete EGT in an EgtA-dependent manner which presents a facile means of producing EGT for biotechnological and biomedical use.

Anaphylaxis is a rare side-effect of COVID-19 vaccines. To (a) provide direct advice and reassurance to certain persons with a history of anaphylaxis/complex allergy, in addition to that available in national guidelines, and (b) to provide a medically supervised vaccination, a specialist regional vaccine allergy clinic was established. The main objective was to determine if risk stratification through history can lead to safe COVID-19 vaccination for maximum population coverage. A focused history was taken to establish contraindications to giving COVID-19 vaccines. People who reported a high-risk allergy history were given a vaccine not containing the excipient thought to have directly caused previous anaphylaxis. All vaccines were monitored for 30 min after administration. A total of 206 people were vaccinated between 6 July 2021 and 31 August 2021; Comirnaty (Pfizer-BioNTech) (n = 34), and Janssen (n = 172). In total, 78% were women. Ninety-two people (45%) reported a high-risk allergy history. There were no cases of anaphylaxis. Three people developed urticaria and one of these also developed transient tachycardia. One vaccinee developed a pseudoseizure. Two of 208 people (<1%) referred during this time declined vaccination based on personal preference, despite the assessment of low clinical risk. In our experience, all vaccines with high-risk allergy histories were administered Pfizer BioNTech or Janssen Covid-19 vaccines uneventfully following screening based on allergy-focussed history. Our data support that drug allergy is not associated with a higher risk of vaccine-related anaphylaxis but may act to guide the administration of alternate vaccines to people with polyethylene glycol/polysorbate 80/trometamol allergies or anaphylaxis after the first dose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The interleukin-12 (IL-12) family comprises the only heterodimeric cytokines mediating diverse functional effects. We previously reported a striking bimodal IL-12p70 response to lipopolysaccharide (LPS) stimulation in healthy donors. Herein, we demonstrate that interferon β (IFNβ) is a major upstream determinant of IL-12p70 production, which is also associated with numbers and activation of circulating monocytes. Integrative modeling of proteomic, genetic, epigenomic, and cellular data confirms IFNβ as key for LPS-induced IL-12p70 and allowed us to compare the relative effects of each of these parameters on variable cytokine responses. Clinical relevance of our findings is supported by reduced IFNβ-IL-12p70 responses in patients hospitalized with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or chronically infected with hepatitis C (HCV). Importantly, these responses are resolved after viral clearance. Our systems immunology approach defines a better understanding of IL-12p70 and IFNβ in healthy and infected persons, providing insights into how common genetic and epigenetic variation may impact immune responses to bacterial infection., Competing Interests: Declaration of interests M.L.A. is a current employee of Hibio, who had no influence on the study design or reporting. D.D. declares previous grant support from Rules Based Medicine that was not implicated in this study. The other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Unusually for a viral infection, the immunological phenotype of severe COVID-19 is characterised by a depleted lymphocyte and elevated neutrophil count, with the neutrophil-to-lymphocyte ratio correlating with disease severity. Neutrophils are the most abundant immune cell in the bloodstream and comprise different subpopulations with pleiotropic actions that are vital for host immunity. Unique neutrophil subpopulations vary in their capacity to mount antimicrobial responses, including NETosis (the generation of neutrophil extracellular traps), degranulation and de novo production of cytokines and chemokines. These processes play a role in antiviral immunity, but may also contribute to the local and systemic tissue damage seen in acute SARS-CoV-2 infection. Neutrophils also contribute to complications of COVID-19 such as thrombosis, acute respiratory distress syndrome and multisystem inflammatory disease in children. In this Progress review, we discuss the anti-viral and pathological roles of neutrophils in SARS-CoV-2 infection, and potential therapeutic strategies for COVID-19 that target neutrophil-mediated inflammatory responses., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 McKenna, Wubben, Isaza-Correa, Melo, Mhaonaigh, Conlon, O’Donnell, Ní Cheallaigh, Hurley, Stevenson, Little and Molloy.)

Introduction: Serological SARS-CoV-2 assays have an important role in guiding the pandemic response. This research aimed to compare the performance of 2 antinucleocapsid assays., Methods: Serum from 49 HCWs was analysed at baseline and 6 months using the Abbott diagnostics SARS-CoV-2 IgG assay and the Roche Diagnostics Elecsys Anti-SARS-CoV-2 total antibody assay., Results: At baseline, 14/49 participants (29%) demonstrated antibody reactivity using the Abbott assay. At 6 months, 4/14 participants (29%) continued to demonstrate reactivity. A total of 14/49 (29%) participants had detectable antibodies at baseline using the Roche assay. In total, 13/14 (93%) of participants demonstrated antibody reactivity at 6 months. The Abbott assay showed a statistically significant difference in the signal-to-threshold values of baseline reactive samples when repeated at 6 months (p = 0.001). This was not seen with the Roche assay (p = 0.51)., Conclusion: In this small study, the Roche Diagnostics Elecsys Anti-SARS-CoV-2 total antibody assay appears superior in performance to the Abbott diagnostics SARS-CoV-2 IgG assay in accurately detecting participants with a history of confirmed COVID-19 disease at 6 months follow-up. This finding should be born in mind in the planning of future seroprevalence studies, especially when considering the use of anti-nucleocapsid assays., (© 2021. The Author(s).)

Background: Mucosal-associated invariant T (MAIT) cells promote inflammation in obesity and are implicated in the progression of non-alcoholic fatty liver disease (NAFLD). However, as the intrahepatic MAIT cell response to lifestyle intervention in NAFLD has not been investigated, this work aimed to examine circulating and intrahepatic MAIT cell populations in patients with NAFLD, after either 12 weeks of dietary intervention (DI) or aerobic exercise intervention (EI)., Methods: Multicolour flow cytometry was used to immunophenotype circulating and intrahepatic MAIT cells and measure MAIT cell expression (median fluorescence intensity, MFI) of the activation marker CD69 and apoptotic marker CD95. Liver histology, clinical parameters, and MAIT cell populations were assessed at baseline (T0) and following completion (T1) of DI or EI., Results: Forty-five patients completed the study. DI participants showed decreased median (interquartile range) expression of the activation marker CD69 on circulating MAIT cells (T0: 104 (134) versus T1 27 (114) MFI; p = 0.0353) and improvements in histological steatosis grade post-intervention. EI participants showed increased expression of the apoptotic marker CD95, both in circulating (T0: 1549 (888) versus T1: 2563 (1371) MFI; p = 0.0043) and intrahepatic MAIT cells (T0: 2724 (862) versus T1: 3117 (1622) MFI; p = 0.0269). Moreover, the percentage of intrahepatic MAIT cells significantly decreased after EI (T0: 11.1 (14.4) versus T1: 5.3 (9.3)%; p = 0.0029), in conjunction with significant improvements in fibrosis stage and hepatocyte ballooning., Conclusions: These data demonstrate independent benefits from dietary and exercise intervention and suggest a role for intrahepatic MAIT cells in the observed histological improvements in NAFLD.

A decline in NAD+ is a feature of ageing and may play a causal role in the process. NAD+ plays a pivotal role in myriad processes important in cellular metabolism and is a cosubstrate for enzymes that play key roles in pathways that modify ageing. Thus, interventions that increase NAD+ may slow aspects of the ageing trajectory and there is great interest in pharmacological NAD+ restoration. Dietary supplementation with NAD+ precursors, particularly nicotinamide riboside, has increased NAD+ levels in several human intervention studies and arguably been the most robust approach to date. However, consistency and reliability of such approaches to increase NAD+, and also impact on markers of efficacy to slow or reverse features of ageing, has been inconsistent. We argue that a major element of this variability may arise from the use of single-target approaches that do not consider the underlying biological complexity leading to NAD+ decline. Thus, a systems approach - targeting multiple key nodes in the NAD+ interactome - is likely to be more efficacious and reliable., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

SARS-CoV-2 infection causes a wide spectrum of disease severity. Identifying the immunological characteristics of severe disease and the risk factors for their development are important in the management of COVID-19. This study aimed to identify and rank clinical and immunological features associated with progression to severe COVID-19 in order to investigate an immunological signature of severe disease. One hundred and eight patients with positive SARS-CoV-2 PCR were recruited. Routine clinical and laboratory markers were measured, as well as myeloid and lymphoid whole-blood immunophenotyping and measurement of the pro-inflammatory cytokines IL-6 and soluble CD25. All analysis was carried out in a routine hospital diagnostic laboratory. Univariate analysis demonstrated that severe disease was most strongly associated with elevated CRP and IL-6, loss of DLA-DR expression on monocytes and CD10 expression on neutrophils. Unbiased machine learning demonstrated that these four features were strongly associated with severe disease, with an average prediction score for severe disease of 0.925. These results demonstrate that these four markers could be used to identify patients developing severe COVID-19 and allow timely delivery of therapeutics., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s).)