The chemical and computational biology of inflammation

Non-communicable diseases (NCD) such as cancer, heart disease and cerebrovascular injury are dependent on or aggravated by inflammation. Their prevention and treatment is arguably one of the greatest challenges to medicine in the 21st century. The pleiotropic, proinflammatory cytokine; interleukin-l beta (IL-l~) is a primary, causative messenger of inflammation. Lipopolysaccharide (LPS) induction ofIL-l~ expression via toll-like receptor 4 (TLR4) in myeloid cells is a robust experimental model of inflammation and is driven in large part via p38-MAPK and NF-KB signaling networks. The control of signaling networks involved in IL-l~ expression is distributed and highly complex, so to perturb intracellular networks effectively it is often necessary to modulate several steps simultaneously. However, the number of possible permutations for intervention leads to a combinatorial explosion in the experiments that would have to be performed in a complete analysis. We used a multi-objective evolutionary algorithm (EA) to optimise reagent combinations from a dynamic chemical library of 33 compounds with established or predicted targets in the regulatory network controlling IL-l ~ expression. The EA converged on excellent solutions within 11 generations during which we studied just 550 combinations out of the potential search space of - 9 billion. The top five reagents with the greatest contribution to combinatorial effects throughout the EA were then optimised pair- wise with respect to their concentrations, using an adaptive, dose matrix search protocol. A p38a MAPK inhibitor (30 ± 10% inhibition alone) with either an inhibitor of IKB kinase (12 ± 9 % inhibition alone) or a chelator of poorly liganded iron (19 ± 8 % inhibition alone) yielded synergistic inhibition (59 ± 5 % and 59 ± 4 % respectively, n=7, p≥O.04 for both combinations, tested by one way ANOVA with Tukey's multiple test correction) of macrophage IL-l~ expression. Utilising the above data, in conjunction with the literature, an LPS-directed transcriptional map of IL-l ~ expression was constructed. Transcription factors (TF) targeted by the signaling networks coalesce at precise nucleotide binding elements within the IL-l~ regulatory DNA. Constitutive binding of PU.l and C/EBr-~ TF's are obligate for IL-l~ expression. The findings in this thesis suggest that PU.l and C/EBP-~ TF's form scaffolds facilitating dynamic control exerted by other TF's, as exemplified by c-Jun. Similarly, evidence is emerging that epigenetic factors, such as the hetero-euchromatin balance, are also important in the relative transcriptional efficacy in different cell types. Evolutionary searches provide a powerful and general approach to the discovery of novel combinations of pharmacological agents with potentially greater therapeutic indices than those of single drugs. Similarly, construction of signaling network maps aid the elucidation of pharmacological mechanism and are mandatory precursors to the development of dynamic models. The symbiosis of both approaches has provided further insight into the mechanisms responsible for IL-lβ expression, and reported here provide a - platform for further developments in understanding NCD's dependent on or aggravated by inflammation.EThOS - Electronic Theses Online ServiceBBSRCEPSRCGBUnited Kingdo

Procalcitonin Is Not a Reliable Biomarker of Bacterial Coinfection in People With Coronavirus Disease 2019 Undergoing Microbiological Investigation at the Time of Hospital Admission

Abstract Admission procalcitonin measurements and microbiology results were available for 1040 hospitalized adults with coronavirus disease 2019 (from 48 902 included in the International Severe Acute Respiratory and Emerging Infections Consortium World Health Organization Clinical Characterisation Protocol UK study). Although procalcitonin was higher in bacterial coinfection, this was neither clinically significant (median [IQR], 0.33 [0.11–1.70] ng/mL vs 0.24 [0.10–0.90] ng/mL) nor diagnostically useful (area under the receiver operating characteristic curve, 0.56 [95% confidence interval, .51–.60]).</jats:p

Implementation of corticosteroids in treating COVID-19 in the ISARIC WHO Clinical Characterisation Protocol UK:prospective observational cohort study

BACKGROUND: Dexamethasone was the first intervention proven to reduce mortality in patients with COVID-19 being treated in hospital. We aimed to evaluate the adoption of corticosteroids in the treatment of COVID-19 in the UK after the RECOVERY trial publication on June 16, 2020, and to identify discrepancies in care. METHODS: We did an audit of clinical implementation of corticosteroids in a prospective, observational, cohort study in 237 UK acute care hospitals between March 16, 2020, and April 14, 2021, restricted to patients aged 18 years or older with proven or high likelihood of COVID-19, who received supplementary oxygen. The primary outcome was administration of dexamethasone, prednisolone, hydrocortisone, or methylprednisolone. This study is registered with ISRCTN, ISRCTN66726260. FINDINGS: Between June 17, 2020, and April 14, 2021, 47 795 (75·2%) of 63 525 of patients on supplementary oxygen received corticosteroids, higher among patients requiring critical care than in those who received ward care (11 185 [86·6%] of 12 909 vs 36 415 [72·4%] of 50 278). Patients 50 years or older were significantly less likely to receive corticosteroids than those younger than 50 years (adjusted odds ratio 0·79 [95% CI 0·70–0·89], p=0·0001, for 70–79 years; 0·52 [0·46–0·58], p80 years), independent of patient demographics and illness severity. 84 (54·2%) of 155 pregnant women received corticosteroids. Rates of corticosteroid administration increased from 27·5% in the week before June 16, 2020, to 75–80% in January, 2021. INTERPRETATION: Implementation of corticosteroids into clinical practice in the UK for patients with COVID-19 has been successful, but not universal. Patients older than 70 years, independent of illness severity, chronic neurological disease, and dementia, were less likely to receive corticosteroids than those who were younger, as were pregnant women. This could reflect appropriate clinical decision making, but the possibility of inequitable access to life-saving care should be considered. FUNDING: UK National Institute for Health Research and UK Medical Research Council

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Forging connections: anthologies, arts collectives, and the politics of inclusion

The changing social and political landscape of twentieth-century Britain catalysed a remarkable rise in collaborative activity by artists and activists of black and Asian heritage. Creative communities began to gather in both local and regional contexts, with the aim of sharing resources and securing an audience. This chapter records some of these many activities, tracing the groups’ genesis, manifest objectives, and key contributions. It argues that anthologising should be understood as a specifically motivated activity. Literary anthologies of poetry and fiction served to showcase the diversity of contemporary writing, while also suggesting its coherence. Drawing on the concept of “strategic essentialism” elucidated by Gayatri Chakravorty Spivak, I show that the anthology acts to ensure the visibility of a group, bannered as a unified and singly-titled selection of texts, while also insisting on the differences within: the heterogeneous multiplicity of black and Asian British experiences and creative practices

'Vernacular Voices: Black British Poetry'

ABSTRACT Black British poetry is the province of experimenting with voice and recording rhythms beyond the iambic pentameter. Not only in performance poetry and through the spoken word, but also on the page, black British poetry constitutes and preserves a sound archive of distinct linguistic varieties. In Slave Song (1984) and Coolie Odyssey (1988), David Dabydeen employs a form of Guyanese Creole in order to linguistically render and thus commemorate the experience of slaves and indentured labourers, respectively, with the earlier collection providing annotated translations into Standard English. James Berry, Louise Bennett, and Valerie Bloom adapt Jamaican Patois to celebrate Jamaican folk culture and at times to represent and record experiences and linguistic interactions in the postcolonial metropolis. Grace Nichols and John Agard use modified forms of Guyanese Creole, with Nichols frequently constructing gendered voices whilst Agard often celebrates linguistic playfulness. The borders between linguistic varieties are by no means absolute or static, as the emergence and marked growth of ‘London Jamaican’ (Mark Sebba) indicates. Asian British writer Daljit Nagra takes liberties with English for different reasons. Rather than having recourse to established Creole languages, and blending them with Standard English, his heteroglot poems frequently emulate ‘Punglish’, the English of migrants whose first language is Punjabi. Whilst it is the language prestige of London Jamaican that has been significantly enhanced since the 1990s, a fact not only confirmed by linguistic research but also by its transethnic uses both in the streets and on the page, Nagra’s substantial success and the mainstream attention he receives also indicate the clout of vernacular voices in poetry. They have the potential to connect with oral traditions and cultural memories, to record linguistic varieties, and to endow ‘street cred’ to authors and texts. In this chapter, these double-voiced poetic languages are also read as signs of resistance against residual monologic ideologies of Englishness. © Book proposal (02/2016): The Cambridge History of Black and Asian British Writing p. 27 of 4

Non-steroidal anti-inflammatory drug use and outcomes of COVID-19 in the ISARIC Clinical Characterisation Protocol UK cohort: a matched, prospective cohort study.

Background: Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods: This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results: Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84–1·07; p=0·35), critical care admission (1·01, 0·87–1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80–1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96–1·32; p=0·14), requirement for oxygen (1·00, 0·89–1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92–1·26; p=0·33). Interpretation: NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity. Funding: National Institute for Health Research and Medical Research Council

Vitamin D insufficiency in COVID-19 and influenza A, and critical illness survivors: a cross-sectional study

Objectives: The steroid hormone vitamin D has roles in immunomodulation and bone health. Insufficiency is associated with susceptibility to respiratory infections. We report 25-hydroxy vitamin D (25(OH)D) measurements in hospitalised people with COVID-19 and influenza A and in survivors of critical illness to test the hypotheses that vitamin D insufficiency scales with illness severity and persists in survivors. Design: Cross-sectional study. Setting and participants: Plasma was obtained from 295 hospitalised people with COVID-19 (International Severe Acute Respiratory and emerging Infections Consortium (ISARIC)/WHO Clinical Characterization Protocol for Severe Emerging Infections UK study), 93 with influenza A (Mechanisms of Severe Acute Influenza Consortium (MOSAIC) study, during the 2009–2010 H1N1 pandemic) and 139 survivors of non-selected critical illness (prior to the COVID-19 pandemic). Total 25(OH)D was measured by liquid chromatography-tandem mass spectrometry. Free 25(OH)D was measured by ELISA in COVID-19 samples. Outcome measures: Receipt of invasive mechanical ventilation (IMV) and in-hospital mortality. Results: Vitamin D insufficiency (total 25(OH)D 25–50 nmol/L) and deficiency (<25 nmol/L) were prevalent in COVID-19 (29.3% and 44.4%, respectively), influenza A (47.3% and 37.6%) and critical illness survivors (30.2% and 56.8%). In COVID-19 and influenza A, total 25(OH)D measured early in illness was lower in patients who received IMV (19.6 vs 31.9 nmol/L (p<0.0001) and 22.9 vs 31.1 nmol/L (p=0.0009), respectively). In COVID-19, biologically active free 25(OH)D correlated with total 25(OH)D and was lower in patients who received IMV, but was not associated with selected circulating inflammatory mediators. Conclusions: Vitamin D deficiency/insufficiency was present in majority of hospitalised patients with COVID-19 or influenza A and correlated with severity and persisted in critical illness survivors at concentrations expected to disrupt bone metabolism. These findings support early supplementation trials to determine if insufficiency is causal in progression to severe disease, and investigation of longer-term bone health outcomes

Co-infections, secondary infections, and antimicrobial use in patients hospitalised with COVID-19 during the first pandemic wave from the ISARIC WHO CCP-UK study: a multicentre, prospective cohort study

Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19. Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded. Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives. Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist. Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill &amp; Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London