Intravenous sildenafil citrate and post-cardiac surgery acute kidney injury: a double-blind, randomised, placebo-controlled trial

Clinical trial registration ISRCTN18386427. open access articleBackground This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass. Methods In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg−1 i.v. over 150 min or dextrose 5% at the commencement of surgery. The primary outcome was serum creatinine measured at six post-randomisation time points. The primary analysis used a linear mixed-effects model adjusted for the stratification variables, baseline estimated glomerular filtration rate, and surgical procedure. Secondary outcomes considered clinical events and potential disease mechanisms. Effect estimates were expressed as mean differences (MDs) or odds ratios with 95% confidence intervals. Results The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 μmol L−1 [–5.82, 7.59]). There was a statistically significant increase in multiple organ dysfunction scores in the sildenafil group (MD: 0.54 [0.02, 1.07]; P=0.044). Secondary outcomes, and biomarkers of kidney injury, endothelial function, and inflammatory cell activation, were not significantly different between the groups. Conclusions These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery

Are ethnic disparities in HbA1c levels explained by mental wellbeing? Analysis of population-based data from the Health Survey for England

Aims: It is unclear how ethnic differences in HbA1c levels are affected by individual variations in mental wellbeing. Thus, the aim of this study was to assess the extent to which HbA1c disparities between Caucasian and South Asian adults are mediated by various aspects of positive psychological functioning. Methods: Data from the 2014 Health Survey for England was analysed using bootstrapping methods. A total of 3894 UK residents with HbA1c data were eligible to participate. Mental wellbeing was assessed using the Warwick-Edinburgh Mental Well-Being Scale. To reduce bias BMI, blood pressure, diabetes status, and other factors were treated as covariates. Results: Ethnicity directly predicted blood sugar control (unadjusted coefficient -2.15; 95% CI -3.64, -0.67), with Caucasians generating lower average HbA1c levels (37.68 mmol/mol (5.6%)) compared to South Asians (39.87 mmol/mol (5.8%)). This association was mediated by positive mental wellbeing, specifically concerning perceived vigour (unadjusted effect 0.30; 95% CI 0.13, 0.58): South Asians felt more energetic than Caucasians (unadjusted coefficient -0.32; 95% CI -0.49, -0.16), and greater perceived energy predicted lower HbA1c levels (unadjusted coefficient -0.92; 95% CI -1.29, -0.55). This mediator effect accounted for just over 14% of the HbA1c variance, and was negated after adjusting for BMI. Conclusions: Caucasian experience better HbA1c levels compared with their South Asian counterparts. However, this association is partly confounded by individual differences in perceived energy levels, which is implicated in better glycaemic control, and appears to serve a protective function in South Asians

Subjective wellbeing among young dancers with disabilities

Little is known about the subjective wellbeing (SWB) of young dancers with disabilities and whether it changes over time. The aim of this study was to assess the SWB of young dancers with disabilities enrolled on an extracurricular inclusive talent development programme in the UK at two time points. Twenty-two young dancers completed the Personal Wellbeing Index for people with intellectual disability at the beginning of the academic year. Thirteen dancers completed the questionnaire a second time towards the end of the academic year. Scores were compared with normative values, and a Wilcoxon Signed Rank test was conducted to assess change over time. The participants reported high levels of SWB at both time points in comparison with normative values. There was no significant change in wellbeing scores over time. The study contributes to a growing body of literature suggesting that people with disabilities have high levels of SWB. Although causality cannot be assumed, inclusive dance programmes may contribute to SWB and allow young people with disabilities to overcome the barriers associated with physical activity

Do individual versus illness belief schema differ in the prediction of post-stroke recovery?

This longitudinal observational study examined how individual versus illness belief schema compare as predictors of post-stroke recovery. Forty-two stroke survivors (mean age=66.9 years/range=29-96 years; 68% male), were involved. The primary outcome, Health-Related Quality of Life (HRQL) was measured using EQ-5D-5L; mood using Patient Health Questionnaire-9; and disability using Nottingham Extended Activities of Daily Living Scale. Stroke Illness Perception Questionnaire-Revised measured illness beliefs. Linear regressions showed that individual illness beliefs significantly explained more of the variance in three-month post-stroke recovery than schema (7.4-22.5% versus 1.9-9.9%). Individual versus illness belief schema predict outcomes differently, but which approach predicts outcomes better remains unclear

Evaluating a stroke-specific version of the Illness Perception Questionnaire-Revised, using the Think-Aloud method

The main purpose was to evaluate, using the Think-Aloud method, a version of the Illness Perception Questionnaire-Revised (IPQ-R) for stroke survivors (the Stroke IPQ-R). Six stroke survivors (mean age=58.8 years, range=31 to 78 years, SD=18.9 years) took part in Think-Aloud interviews, analysed according to established guidelines. Overall, 179 problems emerged. The most noteworthy was missing or insufficient Think-Aloud data generated, where participants did not think out loud. Others included complex and negative item wording, and items on the treatment control sub-scale. Questionnaire length, simpler wording and verbal probing are important considerations in further development of an IPQ-R for stroke

IL-17RA Is Required for CCL2 Expression, Macrophage Recruitment, and Emphysema in Response to Cigarette Smoke

Chronic Obstructive Pulmonary Disease (COPD) is characterized by airspace enlargement and peribronchial lymphoid follicles; however, the immunological mechanisms leading to these pathologic changes remain undefined. Here we show that cigarette smoke is a selective adjuvant that augments in vitro and in vivo Th17, but not Th1, cell differentiation via the aryl hydrocarbon receptor. Smoke exposed IL-17RA−/− mice failed to induce CCL2 and MMP12 compared to WT mice. Remarkably, in contrast to WT mice, IL-17RA−/− mice failed to develop emphysema after 6 months of cigarette smoke exposure. Taken together, these data demonstrate that cigarette smoke is a potent Th17 adjuvant and that IL-17RA signaling is required for chemokine expression necessary for MMP12 induction and tissue emphysema

Th17 cells are more protective than Th1 cells against the intracellular parasite Trypanosoma cruzi

Th17 cells are a subset of CD4+ T cells known to play a central role in the pathogenesis of many autoimmune diseases, as well as in the defense against some extracellular bacteria and fungi. However, Th17 cells are not believed to have a significant function against intracellular infections. In contrast to this paradigm, we have discovered that Th17 cells provide robust protection against Trypanosoma cruzi, the intracellular protozoan parasite that causes Chagas disease. Th17 cells confer significantly stronger protection against T. cruzi-related mortality than even Th1 cells, traditionally thought to be the CD4+ T cell subset most important for immunity to T. cruzi and other intracellular microorganisms. Mechanistically, Th17 cells can directly protect infected cells through the IL-17A-dependent induction of NADPH oxidase, involved in the phagocyte respiratory burst response, and provide indirect help through IL-21-dependent activation of CD8+ T cells. The discovery of these novel Th17 cell-mediated direct protective and indirect helper effects important for intracellular immunity highlights the diversity of Th17 cell roles, and increases understanding of protective T. cruzi immunity, aiding the development of therapeutics and vaccines for Chagas disease

Early Production of IL-22 but Not IL-17 by Peripheral Blood Mononuclear Cells Exposed to live Borrelia burgdorferi: The Role of Monocytes and Interleukin-1

If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-γ but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1β as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularly when opsonized by antibodies. Since neutrophilic inflammation, indicative of IL-17 bioactivity, is scarcely observed in Erythema migrans, a manifestation of skin inflammation after infection, protective and antibacterial properties of IL-22 may close this gap and serve essential functions in the initial phase of spirochete infection