The role of pre-receptor steroid metabolism in the therapeutic application of glucocorticoids

Glucocorticoids (GCs) are widely used in the treatment of chronic inflammatory diseases such as rheumatoid arthritis (RA). Unfortunately, their application is limited by side effects including GC-induced osteoporosis (GIO). The GC-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been shown to mediate side effects associated with therapeutic GCs, suggesting that 11β-HSD1 inhibition may be effective in managing their deleterious side effect profile. In this thesis, I have examined the contribution of 11β-HSD1 to therapeutic actions and off target bone side effects of therapeutic GCs in the TNF-transgenic (TNF-tg) murine model of chronic polyarthritis. TNF-tg animals receiving the GC corticosterone in drinking water (100 mg/L) demonstrated a significant reduction in markers of inflammation, disease activity, synovitis and inflammatory bone loss. In contrast, TNF-tg animals with transgenic deletion of 11β-HSD1 (TNF11βKO) showed a marked resistance to GC-induced changes showing more severe, persistent inflammation and inflammatory bone loss, despite being protected from GIO driven by suppression of anabolic bone formation. Local and systemic bone loss in TNF11βKO animals receiving GCs, was underpinned by increased inflammatory activation of osteoclasts. This study demonstrates a fundamental role for 11β-HSD1 in mediating the anti-inflammatory and bone protective actions of therapeutic GCs in murine models of chronic polyarthritis

Exploring the interface between inflammatory and therapeutic glucocorticoid induced bone and muscle loss

Due to their potent immunomodulatory anti-inflammatory properties, synthetic glucocorticoids (GCs) are widely utilized in the treatment of chronic inflammatory disease. In this review, we examine our current understanding of how chronic inflammation and commonly used therapeutic GCs interact to regulate bone and muscle metabolism. Whilst both inflammation and therapeutic GCs directly promote systemic osteoporosis and muscle wasting, the mechanisms whereby they achieve this are distinct. Importantly, their interactions in vivo are greatly complicated secondary to the directly opposing actions of GCs on a wide array of pro-inflammatory signalling pathways that underpin catabolic and anti-anabolic metabolism. Several clinical studies have attempted to address the net effects of therapeutic glucocorticoids on inflammatory bone loss and muscle wasting using a range of approaches. These have yielded a wide array of results further complicated by the nature of inflammatory disease, underlying the disease management and regimen of GC therapy. Here, we report the latest findings related to these pathway interactions and explore the latest insights from murine models of disease aimed at modelling these processes and delineating the contribution of pre-receptor steroid metabolism. Understanding these processes remains paramount in the effective management of patients with chronic inflammatory disease

11 beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis

Objective Inandnbsp;rheumatoid arthritis, theandnbsp;enzymeandnbsp;11 beta-hydroxysteroid dehydrogenase type 1(11andbeta;-HSD1) is highly expressed at sites ofandnbsp;inflammation, where it converts inactiveandnbsp;glucocorticoidsandnbsp;(GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator ofandnbsp;muscleandnbsp;wasting andandnbsp;bone loss. Here we examine the contribution of 11andbeta;-HSD1 to the pathology of persistent chronicandnbsp;inflammatory disease. Methods To determine the contribution of 11andbeta;-HSD1 toandnbsp;jointandnbsp;inflammation, destruction and systemicandnbsp;boneandnbsp;loss associated with persistent inflammatory arthritis, we generatedandnbsp;miceandnbsp;with global and mesenchymal specific 11andbeta;-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis.andnbsp;Disease severityandnbsp;was determined by clinical scoring.andnbsp;Histologyandnbsp;was assessed inandnbsp;formalinandnbsp;fixed sections andandnbsp;fluorescence-activated cell sortingandnbsp;(FACS) analysis of synovialandnbsp;tissueandnbsp;was performed. Local and systemicandnbsp;boneandnbsp;loss were measured byandnbsp;micro computed tomography(micro-CT). Measures of inflammation andandnbsp;bone metabolismandnbsp;were assessed inandnbsp;serumandnbsp;and inandnbsp;tibiaandnbsp;mRNA. Results Global deletion of 11andbeta;-HSD1 drove an enhanced inflammatoryandnbsp;phenotype, characterised byandnbsp;floridandnbsp;synovitis,andnbsp;joint destructionandnbsp;and systemic bone loss. This was associated with increasedandnbsp;pannusandnbsp;invasion into subchondral bone, a markedandnbsp;polarisationandnbsp;towards pro-inflammatoryandnbsp;M1 macrophagesandnbsp;at sites of inflammation and increasedandnbsp;osteoclastandnbsp;numbers. Targeted mesenchymal deletion of 11andbeta;-HSD1 failed to recapitulate thisandnbsp;phenotypeandnbsp;suggesting that 11andbeta;-HSD1 withinandnbsp;leukocytesmediate its protective actions in vivo. Conclusions We demonstrate a fundamentalandnbsp;roleandnbsp;for 11andbeta;-HSD1 in the suppression ofandnbsp;synovitis, joint destruction, and systemic bone loss. Whilst aandnbsp;roleandnbsp;for 11andbeta;-HSD1 inhibitors has been proposed for metabolicandnbsp;complicationsandnbsp;in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.</p

Predation Risk Shapes Social Networks in Fission-Fusion Populations

Predation risk is often associated with group formation in prey, but recent advances in methods for analysing the social structure of animal societies make it possible to quantify the effects of risk on the complex dynamics of spatial and temporal organisation. In this paper we use social network analysis to investigate the impact of variation in predation risk on the social structure of guppy shoals and the frequency and duration of shoal splitting (fission) and merging (fusion) events. Our analyses revealed that variation in the level of predation risk was associated with divergent social dynamics, with fish in high-risk populations displaying a greater number of associations with overall greater strength and connectedness than those from low-risk sites. Temporal patterns of organisation also differed according to predation risk, with fission events more likely to occur over two short time periods (5 minutes and 20 minutes) in low-predation fish and over longer time scales (>1.5 hours) in high-predation fish. Our findings suggest that predation risk influences the fine-scale social structure of prey populations and that the temporal aspects of organisation play a key role in defining social systems

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Measurement of the inclusive isolated-photon cross section in pp collisions at √s = 13 TeV using 36 fb−1 of ATLAS data

The differential cross section for isolated-photon production in pp collisions is measured at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC using an integrated luminosity of 36.1 fb. The differential cross section is presented as a function of the photon transverse energy in different regions of photon pseudorapidity. The differential cross section as a function of the absolute value of the photon pseudorapidity is also presented in different regions of photon transverse energy. Next-to-leading-order QCD calculations from Jetphox and Sherpa as well as next-to-next-to-leading-order QCD calculations from Nnlojet are compared with the measurement, using several parameterisations of the proton parton distribution functions. The predictions provide a good description of the data within the experimental and theoretical uncertainties. [Figure not available: see fulltext.

Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study

Background: The SARS-CoV-2 delta (B.1.617.2) variant was first detected in England in March, 2021. It has since rapidly become the predominant lineage, owing to high transmissibility. It is suspected that the delta variant is associated with more severe disease than the previously dominant alpha (B.1.1.7) variant. We aimed to characterise the severity of the delta variant compared with the alpha variant by determining the relative risk of hospital attendance outcomes. Methods: This cohort study was done among all patients with COVID-19 in England between March 29 and May 23, 2021, who were identified as being infected with either the alpha or delta SARS-CoV-2 variant through whole-genome sequencing. Individual-level data on these patients were linked to routine health-care datasets on vaccination, emergency care attendance, hospital admission, and mortality (data from Public Health England's Second Generation Surveillance System and COVID-19-associated deaths dataset; the National Immunisation Management System; and NHS Digital Secondary Uses Services and Emergency Care Data Set). The risk for hospital admission and emergency care attendance were compared between patients with sequencing-confirmed delta and alpha variants for the whole cohort and by vaccination status subgroups. Stratified Cox regression was used to adjust for age, sex, ethnicity, deprivation, recent international travel, area of residence, calendar week, and vaccination status. Findings: Individual-level data on 43 338 COVID-19-positive patients (8682 with the delta variant, 34 656 with the alpha variant; median age 31 years [IQR 17–43]) were included in our analysis. 196 (2·3%) patients with the delta variant versus 764 (2·2%) patients with the alpha variant were admitted to hospital within 14 days after the specimen was taken (adjusted hazard ratio [HR] 2·26 [95% CI 1·32–3·89]). 498 (5·7%) patients with the delta variant versus 1448 (4·2%) patients with the alpha variant were admitted to hospital or attended emergency care within 14 days (adjusted HR 1·45 [1·08–1·95]). Most patients were unvaccinated (32 078 [74·0%] across both groups). The HRs for vaccinated patients with the delta variant versus the alpha variant (adjusted HR for hospital admission 1·94 [95% CI 0·47–8·05] and for hospital admission or emergency care attendance 1·58 [0·69–3·61]) were similar to the HRs for unvaccinated patients (2·32 [1·29–4·16] and 1·43 [1·04–1·97]; p=0·82 for both) but the precision for the vaccinated subgroup was low. Interpretation: This large national study found a higher hospital admission or emergency care attendance risk for patients with COVID-19 infected with the delta variant compared with the alpha variant. Results suggest that outbreaks of the delta variant in unvaccinated populations might lead to a greater burden on health-care services than the alpha variant. Funding: Medical Research Council; UK Research and Innovation; Department of Health and Social Care; and National Institute for Health Research

Changes in symptomatology, reinfection, and transmissibility associated with the SARS-CoV-2 variant B.1.1.7: an ecological study

Background The SARS-CoV-2 variant B.1.1.7 was first identified in December, 2020, in England. We aimed to investigate whether increases in the proportion of infections with this variant are associated with differences in symptoms or disease course, reinfection rates, or transmissibility. Methods We did an ecological study to examine the association between the regional proportion of infections with the SARS-CoV-2 B.1.1.7 variant and reported symptoms, disease course, rates of reinfection, and transmissibility. Data on types and duration of symptoms were obtained from longitudinal reports from users of the COVID Symptom Study app who reported a positive test for COVID-19 between Sept 28 and Dec 27, 2020 (during which the prevalence of B.1.1.7 increased most notably in parts of the UK). From this dataset, we also estimated the frequency of possible reinfection, defined as the presence of two reported positive tests separated by more than 90 days with a period of reporting no symptoms for more than 7 days before the second positive test. The proportion of SARS-CoV-2 infections with the B.1.1.7 variant across the UK was estimated with use of genomic data from the COVID-19 Genomics UK Consortium and data from Public Health England on spike-gene target failure (a non-specific indicator of the B.1.1.7 variant) in community cases in England. We used linear regression to examine the association between reported symptoms and proportion of B.1.1.7. We assessed the Spearman correlation between the proportion of B.1.1.7 cases and number of reinfections over time, and between the number of positive tests and reinfections. We estimated incidence for B.1.1.7 and previous variants, and compared the effective reproduction number, Rt, for the two incidence estimates. Findings From Sept 28 to Dec 27, 2020, positive COVID-19 tests were reported by 36 920 COVID Symptom Study app users whose region was known and who reported as healthy on app sign-up. We found no changes in reported symptoms or disease duration associated with B.1.1.7. For the same period, possible reinfections were identified in 249 (0·7% [95% CI 0·6–0·8]) of 36 509 app users who reported a positive swab test before Oct 1, 2020, but there was no evidence that the frequency of reinfections was higher for the B.1.1.7 variant than for pre-existing variants. Reinfection occurrences were more positively correlated with the overall regional rise in cases (Spearman correlation 0·56–0·69 for South East, London, and East of England) than with the regional increase in the proportion of infections with the B.1.1.7 variant (Spearman correlation 0·38–0·56 in the same regions), suggesting B.1.1.7 does not substantially alter the risk of reinfection. We found a multiplicative increase in the Rt of B.1.1.7 by a factor of 1·35 (95% CI 1·02–1·69) relative to pre-existing variants. However, Rt fell below 1 during regional and national lockdowns, even in regions with high proportions of infections with the B.1.1.7 variant. Interpretation The lack of change in symptoms identified in this study indicates that existing testing and surveillance infrastructure do not need to change specifically for the B.1.1.7 variant. In addition, given that there was no apparent increase in the reinfection rate, vaccines are likely to remain effective against the B.1.1.7 variant. Funding Zoe Global, Department of Health (UK), Wellcome Trust, Engineering and Physical Sciences Research Council (UK), National Institute for Health Research (UK), Medical Research Council (UK), Alzheimer's Society

Genomic assessment of quarantine measures to prevent SARS-CoV-2 importation and transmission

Mitigation of SARS-CoV-2 transmission from international travel is a priority. We evaluated the effectiveness of travellers being required to quarantine for 14-days on return to England in Summer 2020. We identified 4,207 travel-related SARS-CoV-2 cases and their contacts, and identified 827 associated SARS-CoV-2 genomes. Overall, quarantine was associated with a lower rate of contacts, and the impact of quarantine was greatest in the 16–20 age-group. 186 SARS-CoV-2 genomes were sufficiently unique to identify travel-related clusters. Fewer genomically-linked cases were observed for index cases who returned from countries with quarantine requirement compared to countries with no quarantine requirement. This difference was explained by fewer importation events per identified genome for these cases, as opposed to fewer onward contacts per case. Overall, our study demonstrates that a 14-day quarantine period reduces, but does not completely eliminate, the onward transmission of imported cases, mainly by dissuading travel to countries with a quarantine requirement