CD4+ T cell cytokine responses to the DAR-901 booster vaccine in BCG-primed adults:A randomized, placebo-controlled trial

<div><p>Background</p><p>DAR-901 is an inactivated whole cell tuberculosis booster vaccine, prepared using a new scalable, broth-grown method from the master cell bank of SRL172, a vaccine previously shown to prevent tuberculosis. This study examined whether DAR-901 (a) induces CD4+ T cell cytokine profiles previously proposed as correlates of protection and (b) has a specific vaccine-induced immunological signature compared to BCG or placebo.</p><p>Methods</p><p>We analysed CD4+ T cell cytokine immune responses from 10 DAR-901 recipients, 9 BCG recipients and 9 placebo recipients from the Phase I DAR-901 MDES trial. In that study, HIV-negative, IGRA-negative participants with prior BCG immunization were randomized (double-blind) to receive three intradermal injections of DAR-901 or saline placebo or two injections of saline placebo followed by an intradermal injection of BCG. Antigen-specific functional and phenotypic CD4+ T cell responses along with effector phenotype of responder cells were measured by intracellular cytokine staining.</p><p>Results</p><p>DAR-901 recipients exhibited increased DAR-901 antigen-specific polyfunctional or bifunctional T cell responses compared to baseline. Vaccine specific CD4+ IFNγ, IL2, TNFα and any cytokine responses peaked at 7 days post-dose 3. Th1 responses predominated, with most responder cells exhibiting a polyfunctional effector memory phenotype. BCG induced greater CD4+ T cell responses than placebo while the more modest DAR-901 responses did not differ from placebo. Neither DAR-901 nor BCG induced substantial or sustained Th17 /Th22 cytokine responses.</p><p>Conclusion</p><p>DAR-901, a TB booster vaccine grown from the master cell bank of SRL 172 which was shown to prevent TB, induced low magnitude polyfunctional effector memory CD4+ T cell responses. DAR-901 responses were lower than those induced by BCG, a vaccine that has been shown ineffective as a booster to prevent tuberculosis disease. These results suggest that induction of higher levels of CD4+ cytokine stimulation may not be a critical or pre-requisite characteristic for candidate TB vaccine boosters.</p><p>Trial registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT02063555" target="_blank">NCT02063555</a>.</p></div

Bioclimatic transect networks: Powerful observatories of ecological change

Transects that traverse substantial climate gradients are important tools for climate change research and allow questions on the extent to which phenotypic variation associates with climate, the link between climate and species distributions, and variation in sensitivity to climate change among biomes to be addressed. However, the potential limitations of individual transect studies have recently been highlighted. Here, we argue that replicating and networking transects, along with the introduction of experimental treatments, addresses these concerns. Transect networks provide cost-effective and robust insights into ecological and evolutionary adaptation and improve forecasting of ecosystem change. We draw on the experience and research facilitated by the Australian Transect Network to demonstrate our case, with examples, to clarify how population- and community-level studies can be integrated with observations from multiple transects, manipulative experiments, genomics, and ecological modeling to gain novel insights into how species and systems respond to climate change. This integration can provide a spatiotemporal understanding of past and future climate-induced changes, which will inform effective management actions for promoting biodiversity resilience

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Elevated protein concentrations in newborn blood and the risks of autism spectrum disorder, and of social impairment, at age 10 years among infants born before the 28th week of gestation

Among the 1 of 10 children who are born preterm annually in the United States, 6% are born before the third trimester. Among children who survive birth before the 28th week of gestation, the risks of autism spectrum disorder (ASD) and non-autistic social impairment are severalfold higher than in the general population. We examined the relationship between top quartile inflammation-related protein concentrations among children born extremely preterm and ASD or, separately, a high score on the Social Responsiveness Scale (SRS total score ≥65) among those who did not meet ASD criteria, using information only from the subset of children whose DAS-II verbal or non-verbal IQ was ≥70, who were assessed for ASD, and who had proteins measured in blood collected on ≥2 days (N = 763). ASD (N = 36) assessed at age 10 years is associated with recurrent top quartile concentrations of inflammation-related proteins during the first post-natal month (e.g., SAA odds ratio (OR); 95% confidence interval (CI): 2.5; 1.2–5.3) and IL-6 (OR; 95% CI: 2.6; 1.03–6.4)). Top quartile concentrations of neurotrophic proteins appear to moderate the increased risk of ASD associated with repeated top quartile concentrations of inflammation-related proteins. High (top quartile) concentrations of SAA are associated with elevated risk of ASD (2.8; 1.2–6.7) when Ang-1 concentrations are below the top quartile, but not when Ang-1 concentrations are high (1.3; 0.3–5.8). Similarly, high concentrations of TNF-α are associated with heightened risk of SRS-defined social impairment (N = 130) (2.0; 1.1–3.8) when ANG-1 concentrations are not high, but not when ANG-1 concentrations are elevated (0.5; 0.1–4.2)

POLICY worst case female only RAMAS model

This is the RAMAS metapopulation model file for estimating the the worst case effect of 'hot and dry' and 'cool and wet' winter and spring conditions on the sleepy lizard study population in the future. The probabilities of extreme conditions are based on regional temperature and rainfall forecasts from an ensemble climate model under policy greenhouse gas emission scenarios

REFERENCE best case female only RAMAS model

This is the RAMAS metapopulation model file for estimating the the best case effect of 'hot and dry' and 'cool and wet' winter and spring conditions on the sleepy lizard study population in the future. The probabilities of extreme conditions are based on regional temperature and rainfall forecasts from an ensemble climate model under reference greenhouse gas emission scenarios

REFERENCE worst case female only RAMAS model

This is the RAMAS metapopulation model file for estimating the the worst case effect of 'hot and dry' and 'cool and wet' winter and spring conditions on the sleepy lizard study population in the future. The probabilities of extreme conditions are based on regional temperature and rainfall forecasts from an ensemble climate model under reference greenhouse gas emission scenarios

BASELINE worst case RAMAS female only model

This is the RAMAS metapopulation model file for estimating the the baseline (current conditions) effect of 'hot and dry' and 'cool and wet' winter and spring conditions on the sleepy lizard study population. The effect of these extreme conditions are based on the largest effect size estimated from the capture-mark-recapture models (i.e. worst case)

POLICY best case female only RAMAS model

This is the RAMAS metapopulation model file for estimating the the best case effect of 'hot and dry' and 'cool and wet' winter and spring conditions on the sleepy lizard study population in the future. The probabilities of extreme conditions are based on regional temperature and rainfall forecasts from an ensemble climate model under policy greenhouse gas emission scenarios

BASELINE best case female only RAMAS model

This is the RAMAS metapopulation model file for estimating the the baseline (current conditions) effect of 'hot and dry' and 'cool and wet' winter and spring conditions on the sleepy lizard study population. The effect of these extreme conditions are based on the smallest effect size estimated from the capture-mark-recapture models (i.e. best case)