Determining the contribution of IL33 and IL1RL1 polymorphisms to clinical and immunological features of asthma

Rationale: IL33 (9p24.1) and the IL33 receptor (IL1RL, 2q12) have been reproducibly identified as asthma susceptibility genes. However, the variants driving genetic associations are not yet fully defined. Using a population based birth cohort of 1059 children (Manchester Asthma and Allergy Study-(MAAS)) and 2536 adults with asthma (Genetics of Asthma Severity and Phenotypes- (GASP)) cohort we aimed to define genetic variants associated with clinical and immunological features of asthma. Methods: MAAS samples were genotyped using the Illumina 610 Quad array and imputed using 1000G reference panel. GASP samples were genotyped using two custom designed Affymetrix arrays (UK BiLEVE/UK Biobank array). Datasets were quality controlled for gender mismatches, outliers and relatedness. Data was generated for the IL33/IL1RL1 regions consisting of the genes and surrounding regions (chr9:5715785−6757983 & chr2:102427961−103468497) on the following traits: asthma diagnosis (MAAS), atopy, FEV1 (GASP) and FEV1/FVC (MAAS and GASP) as well as total blood eosinophil counts and serum total IgE levels (GASP). Variables for blood eosinophils and total IgE were log10 transformed. Analysis was carried out in PLINK using linear or logistic regression modelling including appropriate covariates for each trait. Results: In the MAAS cohort, we replicated the association of the IL33 locus with asthma diagnosis, identifying potentially two independent novel signals in that locus (rs10975398; P=1.70E-05; B= -1.519; MAF=0.32 and rs2890697; P=1.10E-04; B= -1.573; MAF=0.43). This association survived a Bonferroni correction for multiple testing. Although not surviving correction, an association was also identified for atopy in the IL1RL1 locus for MAAS (P=1.08E-04; MAF=0.48). In GASP we identified modest associations not in known LD with published loci (P-value range: 5.00E-02 – 7.60E-04) for FEV1, FEV1/FVC, atopy, blood eosinophils and total IgE in both the IL33 and IL1RL1 loci. Multiple SNPs presented nominal association (P<0.01) with more than one trait such as atopy & total IgE, providing supporting evidence for association. Conclusion: We replicated the association of IL33 region SNPs with asthma diagnosis in MAAS, highlighting the role of this locus in childhood asthma. Although trait association signals did not survive correction for multiple testing, nominal association across multiple phenotypes in GASP provides suggestive evidence of the role of the IL33/IL1RL1 genetic polymorphisms in determining clinical and immunological features of asthma

A genome wide association study of moderate-severe asthma in subjects from the United Kingdom

Rationale: Genome wide association studies (GWAS) in asthma have been successful in identifying disease susceptibility genes, however to date these have focused on mild disease. The genetic risk factors for moderate-severe asthma remain unclear. Aim: To identify common genetic variants affecting susceptibility to develop moderate-severe asthma. Methods: We identified asthma cases and controls from UK Biobank and additional cases from the Genetics of Asthma Severity & Phenotypes (GASP) cohort. A genome-wide association study was undertaken in 5,135 European ancestry individuals with moderate-severe asthma based on British Thoracic Society criteria 3 or above and 25,675 controls free from lung disease, allergic rhinitis and atopic dermatitis. After imputation (UK10K + 1000 genomes Phase 3) and standard quality control measures, the association of 33,771,858 single nucleotide polymorphisms (SNPs) were tested. A logistic model of association of asthma status with imputed genotype dose was fitted using SNPTEST adjusted for ancestry principal components. Results: We identified 22 loci showing association (P < 5 × 10(-8)) including novel signals in or near D2HGDH, STAT6, HLA-B, CD247, GATA3, PDCD1LG2, ZNF652, RPAP3, MUC5AC and BACH2. Previously described asthma loci where replicated including signals in or near HLA-DQB1, TSLP, IL1RL1/IL18R1, CLEC16A, GATA3, IL33, SMAD3, SLC22A5/IL13, C11orf30, ZBTB10, IKZF3-ORMDL3 and IKZF4. Conclusion: The largest genome-wide association study of moderate-severe asthma to date was carried out and multiple novel loci where identified. These findings may provide new insight into the molecular mechanisms underlying this difficult to treat population

Reimagining the language of engagement in a post-stakeholder world

Language matters in shaping perceptions and guiding behaviour. The term stakeholder is widely used, yet little attention is paid to the possibility that its use may inadvertently perpetuate colonial narratives and reinforce systemic inequities. In this article, we critically examine the limitations of the stakeholder concept and its ambiguity, normativity, and exclusionary implications. We emphasise the importance of using language that gives a voice to marginalised groups, promotes inclusion and equity, and fosters meaningful and reflexive participation in decision-making processes. In critiquing the use of the term and calling for alternative practices, we aim to contribute to the decolonisation of research norms and the creation of more inclusive and equitable societies. Therefore, rather than advocating a single alternative term, we suggest a focus on the people, places, and species affected by decisions, interventions, projects, and issues

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

ISIR: Informed sensitised intelligent response - A PSS conceptual design framework using service characteristics

This paper considers two dominant definitions of services in the service literature and then proposes a set of service characteristics which have been derived from Service Dominant Logic. These characteristics are then used to chart the differences and similarities between products and services and a case study shows how these characteristics could be applied to Product Service Systems conceptual design

Hyperacute changes in blood mRNA expression profiles of rats after middle cerebral artery occlusion: Towards a stroke time signature.

Stroke evolution is a highly dynamic but variable disease which makes clinical decision making difficult. Biomarker discovery programs intended to aid clinical decision making have however largely ignored the rapidity of stroke evolution. We have used gene array technology to determine blood mRNA expression changes over the first day after stroke in rats. Blood samples were collected from 8 male spontaneously hypertensive rats at 0, 1, 2, 3, 6 and 24h post stroke induction by middle cerebral artery occlusion. RNA was extracted from whole blood stabilized in PAXgene tubes and mRNA expression was detected by oligonucleotide Affymetrix microarray. Using a pairwise comparison model, 1932 genes were identified to vary significantly over time (p≤0.5x10(-7)) within 24h after stroke. Some of the top20 most changed genes are already known to be relevant to the ischemic stroke physiopathology (e.g. Il-1R, Nos2, Prok2). Cluster analysis showed multiple stereotyped and time dependent profiles of gene expression. Direction and rate of change of expression for some profiles varied dramatically during these 24h. Profiles with potential clinical utility including hyper acute or acute transient upregulation (with expression peaking from 2 to 6h after stroke and normalisation by 24h) were identified. We found that blood gene expression varies rapidly and stereotypically after stroke in rats. Previous researchers have often missed the optimum time for biomarker measurement. Temporally overlapping profiles have the potential to provide a biological "stroke clock" able to tell the clinician how far an individual stroke has evolved

Reducing the efficiency–stability–cost gap of organic photovoltaics with highly efficient and stable small molecule acceptor ternary solar cells

Technological deployment of organic photovoltaic modules requires improvements in device light-conversion efficiency and stability while keeping material costs low. Here we demonstrate highly efficient and stable solar cells using a ternary approach, wherein two non-fullerene acceptors are combined with both a scalable and affordable donor polymer, poly(3-hexylthiophene) (P3HT), and a high-efficiency, low-bandgap polymer in a single-layer bulk-heterojunction device. The addition of a strongly absorbing small molecule acceptor into a P3HT-based non-fullerene blend increases the device efficiency up to 7.7 ± 0.1% without any solvent additives. The improvement is assigned to changes in microstructure that reduce charge recombination and increase the photovoltage, and to improved light harvesting across the visible region. The stability of P3HT-based devices in ambient conditions is also significantly improved relative to polymer:fullerene devices. Combined with a low-bandgap donor polymer (PBDTTT-EFT, also known as PCE10), the two mixed acceptors also lead to solar cells with 11.0 ± 0.4% efficiency and a high open-circuit voltage of 1.03 ± 0.01 V

Systemic Nos2 Depletion and Cox inhibition limits TNBC disease progression and alters lymphoid cell spatial orientation and density

Antitumor immune polarization is a key predictor of clinical outcomes to cancer therapy. An emerging concept influencing clinical outcome involves the spatial location of CD8+ T cells, within the tumor. Our earlier work demonstrated immunosuppressive effects of NOS2 and COX2 tumor expression. Here, we show that NOS2/COX2 levels influence both the polarization and spatial location of lymphoid cells including CD8+ T cells. Importantly, elevated tumor NOS2/COX2 correlated with exclusion of CD8+ T cells from the tumor epithelium. In contrast, tumors expressing low NOS2/COX2 had increased CD8+ T cell penetration into the tumor epithelium. Consistent with a causative relationship between these observations, pharmacological inhibition of COX2 with indomethacin dramatically reduced tumor growth of the 4T1 model of TNBC in both WT and Nos2- mice. This regimen led to complete tumor regression in ∼20–25% of tumor-bearing Nos2- mice, and these animals were resistant to tumor rechallenge. Th1 cytokines were elevated in the blood of treated mice and intratumoral CD4+ and CD8+ T cells were higher in mice that received indomethacin when compared to control untreated mice. Multiplex immunofluorescence imaging confirmed our phenotyping results and demonstrated that targeted Nos2/Cox2 blockade improved CD8+ T cell penetration into the 4T1 tumor core. These findings are consistent with our observations in low NOS2/COX2 expressing breast tumors proving that COX2 activity is responsible for limiting the spatial distribution of effector T cells in TNBC. Together these results suggest that clinically available NSAID’s may provide a cost-effective, novel immunotherapeutic approach for treatment of aggressive tumors including triple negative breast cancer