Lack of association between glucocorticoid use and presence of the metabolic syndrome in patients with rheumatoid arthritis: a cross-sectional study

Introduction - Rheumatoid arthritis (RA) associates with excessive cardiovascular morbidity and mortality, attributed to both traditional and novel cardiovascular risk factors. The metabolic syndrome, a cluster of classical cardiovascular risk factors, including hypertension, obesity, glucose intolerance, and dyslipidaemia, is highly prevalent in RA. Reports suggest that long-term glucocorticoid (GC) use may exacerbate individual cardiovascular risk factors, but there have been no studies in RA to assess whether it associates with the metabolic syndrome. We examined whether GC exposure associates with the presence of metabolic syndrome in patients with RA. Methods - RA patients (n = 398) with detailed clinical and laboratory assessments were categorised into three groups according to GC exposure: no/limited (<3 months) exposure (NE), low-dose (<7.5 mg/day) long-term exposure (LE), and medium-dose (greater than or equal to 7.5 mg to 30 mg/day) long-term exposure (ME). The metabolic syndrome was defined using the National Cholesterol Education Programme III guidelines. The association of GC exposure with the metabolic syndrome was evaluated using binary logistic regression. Results - The metabolic syndrome was present in 40.1% of this population and its prevalence did not differ significantly between the GC exposure groups (NE 37.9% versus LE 40.7% versus ME 50%, P = 0.241). Binary logistic regression did not demonstrate any increased odds for the metabolic syndrome when comparing ME with LE (odds ratio = 1.64, 95% confidence interval 0.92 to 2.92, P = 0.094) and remained non significant after adjusting for multiple potential confounders. Conclusions - Long-term GC exposure does not appear to associate with a higher prevalence of the metabolic syndrome in patients with RA. The components of the metabolic syndrome may already be extensively modified by other processes in RA (including chronic inflammation and treatments other than GCs), leaving little scope for additive effects of GCs

CpG-island fragments from the HNRPA2B1/CBX3 genomic locus reduce silencing and enhance transgene expression from the hCMV promoter/enhancer in mammalian cells

BACKGROUND: The hCMV promoter is very commonly used for high level expression of transgenes in mammalian cells, but its utility is hindered by transcriptional silencing. Large genomic fragments incorporating the CpG island region of the HNRPA2B1 locus are resistant to transcriptional silencing. RESULTS: In this report we describe studies on the use of a novel series of vectors combining the HNRPA2B1 CpG island with the hCMV promoter for expression of transgenes in CHO-K1 cells. We show that the CpG island gives at least twenty-fold increases in the levels of EGFP and EPO observed in pools of transfectants, and that transgene expression levels remain high in such pools for more than 100 generations. These novel vectors also allow facile isolation of clonal CHO-K1 cell lines showing stable, high-level transgene expression. CONCLUSION: Vectors incorporating the hnRPA2B1 CpG island give major benefits in transgene expression from the hCMV promoter, including substantial improvements in the level and stability of expression. The utility of these vectors for the improved production of recombinant proteins in CHO cells has been demonstrated

Emergence and spread of predominantly community-onset Clostridium difficile PCR ribotype 244 infection in Australia, 2010 to 2012

We describe an Australia-wide Clostridium difficile outbreak in 2011 and 2012 involving the previously uncommon ribotype 244. In Western Australia, 14 of 25 cases were community-associated, 11 were detected in patients younger than 65 years, 14 presented to emergency/outpatient departments, and 14 to non-tertiary/community hospitals. Using whole genome sequencing, we confirm ribotype 244 is from the same C. difficile clade as the epidemic ribotype 027. Like ribotype 027, it produces toxins A, B, and binary toxin, however it is fluoroquinolone-susceptible and thousands of single nucleotide variants distinct from ribotype 027. Fifteen outbreak isolates from across Australia were sequenced. Despite their geographic separation, all were genetically highly related without evidence of geographic clustering, consistent with a point source, for example affecting the national food chain. Comparison with reference laboratory strains revealed the outbreak clone shared a common ancestor with isolates from the United States and United Kingdom (UK). A strain obtained in the UK was phylogenetically related to our outbreak. Follow-up of that case revealed the patient had recently returned from Australia. Our data demonstrate new C. difficile strains are an on-going threat, with potential for rapid spread. Active surveillance is needed to identify and control emerging lineages

A combined network model for membrane fouling

Membrane fouling during particle filtration occurs through a variety of mechanisms, including internal pore clogging by contaminants, coverage of pore entrances, and deposition on the membrane surface. Each of these fouling mechanisms results in a decline in the observed flow rate over time, and the decrease in filtration efficiency can be characterized by a unique signature formed by plotting the volumetric flux, bQ , as a function of the total volume of fluid processed, bV . When membrane fouling takes place via any one of these mechanisms independently the bQ bV signature is always convex downwards for filtration under a constant transmembrane pressure. However, in many such filtration scenarios, the fouling mechanisms are inherently coupled and the resulting signature is more difficult to interpret. For instance, blocking of a pore entrance will be exacerbated by the internal clogging of a pore, while the deposition of a layer of contaminants is more likely once the pores have been covered by particulates. As a result, the experimentally observed bQ bV signature can vary dramatically from the canonical convex-downwards graph, revealing features that are not captured by existing continuum models. In a range of industrially relevant cases we observe a concave downwards bQ bV signature, indicative of a fouling rate that becomes more severe with time. We derive a network model for membrane fouling that accounts for the inter-relation between fouling mechanisms and demonstrate the impact on the bQ bV signature. Our formulation recovers the behaviour of existing models when the mechanisms are treated independently, but also elucidates the concave-downward bQ bV signature for multiple interactive fouling mechanisms. The resulting model enables post-experiment analysis to identify the dominant fouling modality at each stage, and is able to provide insight into selecting appropriate operating regimes

Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury.

BACKGROUND: Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine with both injurious and protective functions, which are thought to diverge at the level of its two cell surface receptors, TNFR1 and TNFR2. In the setting of acute injury, selective inhibition of TNFR1 is predicted to attenuate the cell death and inflammation associated with TNF-α, while sparing or potentiating the protective effects of TNFR2 signalling. We developed a potent and selective antagonist of TNFR1 (GSK1995057) using a novel domain antibody (dAb) therapeutic and assessed its efficacy in vitro, in vivo and in a clinical trial involving healthy human subjects. METHODS: We investigated the in vitro effects of GSK1995057 on human pulmonary microvascular endothelial cells (HMVEC-L) and then assessed the effects of pretreatment with nebulised GSK1995057 in a non-human primate model of acute lung injury. We then tested translation to humans by investigating the effects of a single nebulised dose of GSK1995057 in healthy humans (n=37) in a randomised controlled clinical trial in which subjects were subsequently exposed to inhaled endotoxin. RESULTS: Selective inhibition of TNFR1 signalling potently inhibited cytokine and neutrophil adhesion molecule expression in activated HMVEC-L monolayers in vitro (P<0.01 and P<0.001, respectively), and also significantly attenuated inflammation and signs of lung injury in non-human primates (P<0.01 in all cases). In a randomised, placebo-controlled trial of nebulised GSK1995057 in 37 healthy humans challenged with a low dose of inhaled endotoxin, treatment with GSK1995057 attenuated pulmonary neutrophilia, inflammatory cytokine release (P<0.01 in all cases) and signs of endothelial injury (P<0.05) in bronchoalveolar lavage and serum samples. CONCLUSION: These data support the potential for pulmonary delivery of a selective TNFR1 dAb as a novel therapeutic approach for the prevention of acute respiratory distress syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01587807

Improving programme-led and focused interventions for eating disorders: An experts' consensus statement-A UK perspective

OBJECTIVE: Eating disorders are associated with significant illness burden and costs, yet access to evidence-based care is limited. Greater use of programme-led and focused interventions that are less resource-intensive might be part of the solution to this demand-capacity mismatch. METHOD: In October 2022, a group of predominantly UK-based clinical and academic researchers, charity representatives and people with lived experience convened to consider ways to improve access to, and efficacy of, programme-led and focused interventions for eating disorders in an attempt to bridge the demand-capacity gap. RESULTS: Several key recommendations were made across areas of research, policy, and practice. Of particular importance is the view that programme-led and focused interventions are suitable for a range of different eating disorder presentations across all ages, providing medical and psychiatric risk are closely monitored. The terminology used for these interventions should be carefully considered, so as not to imply that the treatment is suboptimal. CONCLUSIONS: Programme-led and focused interventions are a viable option to close the demand-capacity gap for eating disorder treatment and are particularly needed for children and young people. Work is urgently needed across sectors to evaluate and implement such interventions as a clinical and research priority

Effect of γ-irradiation on the physicochemical properties, and microbial and sensory qualities of cold-stored onion puree.

The present study was conducted to evaluate the effect of different doses (0, 1, 2, 3, 5 and 7 kGy) of γ-irradiation on the physicochemical properties (pH, titratable acidity, total soluble solid, color, organic acid content), and also the microbial and sensory qualities of onion puree during cold storage at 4C for 28 days. The different doses of γ-irradiation were found to not have any negative effect on titratable acidity, pH, total soluble solid and organic acid contents of onion puree immediately after irradiation and also during cold storage. Irradiation at 3 kGy and above was able to control the development of yeasts and molds in the onion puree, but had negative effects on the color and sensory quality of the onion puree. This study indicates that irradiation at 2 kGy reduced microbial counts with minimum adverse effects on color and sensory qualities

Spironolactone for adult female acne (SAFA): protocol for a double-blind, placebo-controlled, phase III randomised study of spironolactone as systemic therapy for acne in adult women

Introduction: Acne is one of the most common inflammatory skin diseases worldwide and can have significant psychosocial impact and cause permanent scarring. Spironolactone, a potassium-sparing diuretic, has antiandrogenic properties, potentially reducing sebum production and hyperkeratinisation in acne-prone follicles. Dermatologists have prescribed spironolactone for acne in women for over 30 years, but robust clinical study data are lacking. This study seeks to evaluate whether spironolactone is clinically effective and cost-effective in treating acne in women. Methods and analysis: Women (≥18 years) with persistent facial acne requiring systemic therapy are randomised to receive one tablet per day of 50 mg spironolactone or a matched placebo until week 6, increasing to up to two tablets per day (total of 100 mg spironolactone or matched placebo) until week 24, along with usual topical therapy if desired. Study treatment stops at week 24; participants are informed of their treatment allocation and enter an unblinded observational follow-up period for up to 6 months (up to week 52 after baseline). Primary outcome is the Acne-specific Quality of Life (Acne-QoL) symptom subscale score at week 12. Secondary outcomes include Acne-QoL total and subscales; participant acne self-assessment recorded on a 6-point Likert scale at 6, 12, 24 weeks and up to 52 weeks; Investigator’s Global Assessment at weeks 6 and 12; cost and cost effectiveness are assessed over 24 weeks. Aiming to detect a group difference of 2 points on the Acne-QoL symptom subscale (SD 5.8, effect size 0.35), allowing for 20% loss to follow-up, gives a sample size of 398 participants. Ethics and dissemination: This protocol was approved by Wales Research Ethics Committee (18/WA/0420). Follow-up to be completed in early 2022. Findings will be disseminated to participants, peer-reviewed journals, networks and patient groups, on social media, on the study website and the Southampton Clinical Trials Unit website to maximise impact. Trial registration number ISRCTN12892056;Pre-results