Comparative transcriptomics and host-specific parasite gene expression profiles inform on drivers of proliferative kidney disease

Acknowledgements: This study was supported financially by the Biotechnology and Biological Sciences Research Council (BBSRC-1087-CS), a Swiss National Science Foundation Sinergia Project (CRS113 986 147649), a Ph.D. studentship to Marc Faber from the EU H2020 (H2020-SFS-10a-2014) program (ParaFishControl; 634429) and the Natural History Museum, London. We would like to thank Christopher Saunders-Davies of Test Valley Trout Ltd and Oliver Robinson of the British Trout Association for provision of fish and sampling facilities. Dr Daniel MacQueen of the Roslin Institute, University of Edinburgh, for provision of rainbow trout transcriptome assemblies. This publication reflects the views only of the authors, and the European Commission cannot be held responsible for any use which may be made of the information contained therein.Peer reviewedPublisher PD

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Recommended sleep duration is associated with higher consumption of fruits and vegetables; cross-sectional and prospective analyses from the UK Women’s Cohort Study

Background: High intakes of fruit and vegetable has been shown to protect against diseases and all-cause mortality however, the associations between sleep and fruit and vegetable consumption are not well characterized. This study aims to explore both cross-sectional and prospective associations between sleep duration and fruit and vegetable intakes in UK women. This is the first study to demonstrate the prospective association between sleep duration and fruit and vegetable consumption. Methods: Cross–sectional and prospective data were obtained from the UK Women’s Cohort Study. Sleep duration was assessed by self-report of average hours slept on weekdays and weekends and diet was assessed by a 4-day food diary at baseline and follow-up (~ 4 years later). Sleep duration was categorized as short (≤6 h/d), recommended (7–9 h/d) and long (≥9 h/d). Regression analyses adjusting for age, socio-economic status, smoking, ethnicity and total energy intake were used and restricted cubic spline models were developed to explore potential non-linear associations between sleep duration and fruit and vegetable intakes. Results: In adjusted cross-sectional analyses, short sleepers had on average 17 g/d (95% CI -30 to-4, p = 0.01) and long sleepers had 25 g/d (95% CI -39 to − 12, p < 0.001) less total fruits and vegetables compared to Recommended Sleepers (RS). In adjusted prospective analyses, short sleepers had on average 85 g/d (95% CI -144 to − 26, p = 0.005) less total fruits and vegetables in comparison to RS. Restricted cubic spline models showed that the cross-sectional (p < 0.001) and prospective (p = 0.001) associations between sleep duration and fruit and vegetable intakes were non-linear with women sleeping 7–9 h/d having the highest intakes. Conclusions: Fruit and vegetable consumption differed between sleep duration categories with UK women sleeping the recommended 7–9 h/day having the highest intake of fruits and vegetables in cross-sectional and prospective analyses. These findings suggest that sleeping the recommended duration is associated with higher consumption of fruits and vegetables. Sleep is an overlooked lifestyle factor in relation to fruit and vegetable consumption and more notice is vital. Further studies are required to clarify the underlying mechanisms for these associations

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A Systematic Review of the Audiological Efficacy of Cartilage Conduction Hearing Aids and the Factors Influencing Their Clinical Application

This systematic review evaluates the efficacy and benefit of cartilage conduction hearing aids (CC-HAs) and that factors that influence purchasing decisions. The hearing thresholds and functional gain following CC-HA wear were synthesised. A one-way analysis of variance compared the differences in the hearing thresholds and functional gain at individual frequencies and in patients with a variety of pathological changes. The synchronised aided hearing threshold and functional gain at 2.0 kHz were significantly better than at 0.5, 1.0, and 4.0 kHz. There was no significant difference in the synchronised unaided hearing thresholds across individual frequencies between 0.5 and 4.0 kHz. The synchronised functional gain in patients with atresia was significantly greater than in patients with aural atresia or stenosis and middle ear pathologies with normal ear canals. The acceptability of CC-HAs in terms of purchase decision is influenced by the condition of the external auditory meatus and severity of hearing loss, with the highest purchase rate seen in patients with aural atresia or stenosis. CC-HAs’ fitting procedure advantages and cosmetic considerations make these devices a viable and preferred choice for individuals with microtia and aural atresia. Additional research to evaluate the benefits towards emotional well-being is crucial to gain insights into the psychological impact of CC-HA use