Cluster PEACE observations of electron pressure tensor divergence in the magnetotail

Cluster crossed the magnetotail neutral sheet on four occasions between 16: 38 and 16: 43 UT on 08/17/2003. The four-spacecraft capabilities of Cluster are used to determine spatial gradients from the magnetic field vectors and, for the first time, full electron pressure tensors. We find that the contribution to the electric field from the Hall term (max of similar to 6 mV/m) pointed towards the neutral sheet, whereas that from the electron pressure divergence ( max of similar to 1 mV/m) pointed away from the neutral sheet. The electric field contributions in this direction were closely anti-correlated. During this period Clusters 1 and 4 were sometimes above and below the neutral sheet respectively. This allowed the simultaneous observation of magnetic fields that are interpreted as two quadrants of the Hall magnetic field system. An associated field-aligned current system was detected using the curlometer and moments of the particle distributions

Mathematical Modelling of Arbovirus Outbreak Dynamics in Fiji and the Wider Pacific

Diseases spread by the Aedes genus of mosquitoes are some of the fastest growing and fastest spreading viral pathogens in the world. Large dengue virus (DENV) epidemics have emerged in Fiji since the Second World War and there was widespread transmission of Zika virus (ZIKV) throughout the Pacific between 2013 and 2017. However, very few ZIKV cases were confirmed in Fiji. I conducted a serological survey in Fiji in 2017 and used these serological data, combined with mathematical modelling, to analyse transmission dynamics of arboviruses in Fiji. I found evidence for ZIKV circulation in Fiji between 2013 and 2015 followed by low ZIKV seroprevalence in 2017. I used paired serum samples to analyse the immunological response to ZIKV following outbreaks in Fiji and French Polynesia and found that neutralising antibodies declined in adults within two years of the outbreak in each country. I combined serological data with surveillance and molecular data to model unobserved ZIKV transmission and compare ZIKV and DENV transmission dynamics in Fiji. I found that the introduction time of a virus in Fiji could explain different transmission dynamics and concluded that ZIKV was likely introduced to Fiji in late 2014. I found high seroprevalence for all four DENV serotypes. I used a mathematical model of DENV transmission to analyse a DENV outbreak in 2017 to predict the duration and peak of the outbreak in real-time. I found that jointly fitting the model to a historic outbreak as well as the emerging outbreak improved the accuracy of the predictions from the model. Mathematical Modelling of Arbovirus Outbreak Dynamics in Fiji and the Wider Pacific Overall, I combined multiple data sources with mathematical modelling to reveal a diverse range of outbreak dynamics and serological responses to outbreaks of closely related viruses in the same location. I found that ZIKV and DENV do not necessarily generate a similar immune response in the same population and that both can cause low level multi-year outbreaks as well as large single season epidemics. Despite these challenges, mathematical modelling can improve our understanding of arbovirus outbreak dynamics such that it is possible to accurately forecast outbreak dynamics in real-time

Rapid reserve generation from a Francis Turbine for system frequency control

The increase in contributions from non base load renewables, such as wind and solar,can have adverse effects on the stability of an electrical grid. In this study, the possibility of rapidlyloading a Francis turbine from a tail water depression (TWD) mode for providing additional systemfrequency control is investigated. Based on the analysis of full-scale TWD test results and keyfindings from the transient testing of a micro-hydro scale turbine unit, a detailed description ofthe TWD transition process is given. The formulation of an improved turbine model for use inone-dimensional hydro-electric plant models is presented with simulation results compared tofull-scale data. The analytical model, which calculates output power according to the conservation ofangular momentum and identified sources of loss, is used in parallel with full-scale and model scaletest observations to elucidate the events and mechanisms occurring during this proposed transition.The output response, in terms of active power, was found to be highly dependent on guide vaneopening rate in both full-scale and model tests. For an approximate doubling in opening rate, theduration of the reverse power flow was reduced by 38% and 21%, for full-scale and model units,while the low pressure transient increased by 16% and 8%, respectively. The analytical model wasshown to capture the general response characteristic in all cases tested; however, output powerresponse was over predicted due to two identified model assumptions made, while, for the morerapid opening, the penstock pressure was under predicted by approximately 15%

Therapeutic Myeloperoxidase Inhibition Attenuates Neutrophil Activation, ANCA-Mediated Endothelial Damage, and Crescentic GN

BACKGROUND: Myeloperoxidase released after neutrophil and monocyte activation can generate reactive oxygen species, leading to host tissue damage. Extracellular glomerular myeloperoxidase deposition, seen in ANCA-associated vasculitis, may enhance crescentic GN through antigen-specific T and B cell activation. Myeloperoxidase-deficient animals have attenuated GN early on, but augmented T cell responses. We investigated the effect of myeloperoxidase inhibition, using the myeloperoxidase inhibitor AZM198, to understand its potential role in treating crescentic GN. METHODS: We evaluated renal biopsy samples from patients with various forms of crescentic GN for myeloperoxidase and neutrophils, measured serum myeloperoxidase concentration in patients with ANCA-associated vasculitis and controls, and assessed neutrophil extracellular trap formation, reactive oxygen species production, and neutrophil degranulation in ANCA-stimulated neutrophils in the absence and presence of AZM198. We also tested the effect of AZM198 on ANCA-stimulated neutrophil-mediated endothelial cell damage in vitro, as well as on crescentic GN severity and antigen-specific T cell reactivity in the murine model of nephrotoxic nephritis. RESULTS: All biopsy specimens with crescentic GN had extracellular glomerular myeloperoxidase deposition that correlated significantly with eGFR and crescent formation. In vitro, AZM198 led to a significant reduction in neutrophil extracellular trap formation, reactive oxygen species production, and released human neutrophil peptide levels, and attenuated neutrophil-mediated endothelial cell damage. In vivo, delayed AZM198 treatment significantly reduced proteinuria, glomerular thrombosis, serum creatinine, and glomerular macrophage infiltration, without increasing adaptive T cell responses. CONCLUSIONS: Myeloperoxidase inhibition reduced neutrophil degranulation and neutrophil-mediated endothelial cell damage in patients with ANCA-associated vasculitis. In preclinical crescentic GN, delayed myeloperoxidase inhibition suppressed kidney damage without augmenting adaptive immune responses, suggesting it might offer a novel adjunctive therapeutic approach in crescentic GN

Common mental health disorders in adults with inflammatory skin conditions: nationwide population-based matched cohort studies in the UK

BACKGROUND: Psoriasis and atopic eczema are common inflammatory skin diseases. Existing research has identified increased risks of common mental disorders (anxiety, depression) in people with eczema and psoriasis; however, explanations for the associations remain unclear. We aimed to establish the risk factors for mental illness in those with eczema or psoriasis and identify the population groups most at risk. METHODS: We used routinely collected data from the UK Clinical Practice Research Datalink (CPRD) GOLD. Adults registered with a general practice in CPRD (1997-2019) were eligible for inclusion. Individuals with eczema/psoriasis were matched (age, sex, practice) to up to five adults without eczema/psoriasis. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for hazards of anxiety or depression in people with eczema/psoriasis compared to people without. We adjusted for known confounders (deprivation, asthma [eczema], psoriatic arthritis [psoriasis], Charlson comorbidity index, calendar period) and potential mediators (harmful alcohol use, body mass index [BMI], smoking status, and, in eczema only, sleep quality [insomnia diagnoses, specific sleep problem medications] and high-dose oral glucocorticoids). RESULTS: We identified two cohorts with and without eczema (1,032,782, matched to 4,990,125 without), and with and without psoriasis (366,884, matched to 1,834,330 without). Sleep quality was imbalanced in the eczema cohorts, twice as many people with eczema had evidence of poor sleep at baseline than those without eczema, including over 20% of those with severe eczema. After adjusting for potential confounders and mediators, eczema and psoriasis were associated with anxiety (adjusted HR [95% CI]: eczema 1.14 [1.13-1.16], psoriasis 1.17 [1.15-1.19]) and depression (adjusted HR [95% CI]: eczema 1.11 [1.1-1.12], psoriasis 1.21 [1.19-1.22]). However, we found evidence that these increased hazards are unlikely to be constant over time and were especially high 1-year after study entry. CONCLUSIONS: Atopic eczema and psoriasis are associated with increased incidence of anxiety and depression in adults. These associations may be mediated through known modifiable risk factors, especially sleep quality in people with eczema. Our findings highlight potential opportunities for the prevention of anxiety and depression in people with eczema/psoriasis through treatment of modifiable risk factors and enhanced eczema/psoriasis management

Prolonged B Cell Depletion with Rituximab is Effective in Treating Refractory Pulmonary Granulomatous Inflammation in Granulomatosis with Polyangiitis

Objective - Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Methods - Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Results - Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22-52) years. Pulmonary nodules (median 4, range 2-6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (< 5 cells/µl) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these three and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (p = <0.0001) and largest nodule diameter (p = <0.0001) in all patients for at least 18 months following B cell depletion. Conclusion - RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion

Severe Mental Illness Among Adults with Atopic Eczema or Psoriasis: Population-Based Matched Cohort Studies within UK Primary Care

BACKGROUND: Existing research exploring associations between atopic eczema (AE) or psoriasis, and severe mental illness (SMI – ie, schizophrenia, bipolar disorder, other psychoses) is limited, with longitudinal evidence particularly scarce. Therefore, temporal directions of associations are unclear. We aimed to investigate associations between AE or psoriasis and incident SMI among adults. METHODS: We conducted matched cohort studies using primary care electronic health records (January 1997 to January 2020) from the UK Clinical Practice Research Datalink GOLD. We identified two cohorts: 1) adults (≥ 18 years) with and without AE and 2) adults with and without psoriasis. We matched (on age, sex, general practice) adults with AE or psoriasis with up to five adults without. We used Cox regression, stratified by matched set, to estimate hazard ratios (HRs) comparing incident SMI among adults with and without AE or psoriasis. RESULTS: We identified 1,023,232 adults with AE and 4,908,059 without, and 363,210 with psoriasis and 1,801,875 without. After adjusting for matching variables (age, sex, general practice) and potential confounders (deprivation, calendar period) both AE and psoriasis were associated with at least a 17% increased hazard of SMI (AE: HR=1.17,95% CI=1.12– 1.22; psoriasis: HR=1.26,95% CI=1.18– 1.35). After additionally adjusting for potential mediators (comorbidity burden, harmful alcohol use, smoking status, body mass index, and, in AE only, sleep problems and high-dose glucocorticoids), associations with SMI did not persist for AE (HR=0.98,95% CI=0.93– 1.04), and were attenuated for psoriasis (HR=1.14,95% CI=1.05– 1.23). CONCLUSION: Our findings suggest adults with AE or psoriasis are at increased risk of SMI compared to matched comparators. After adjusting for potential mediators, associations with SMI did not persist for AE, and were attenuated for psoriasis, suggesting that the increased risk may be explained by mediating factors (eg, sleep problems). Our research highlights the importance of monitoring mental health in adults with AE or psoriasis