Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection. METHODS: In this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants. FINDINGS: Between Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18-45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference -1·4%, 95% CI -7·0 to 4·3; hazard ratio 0·96, 0·68-1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3-4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment

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

A global horizon scan of the future impacts of robotics and autonomous systems on urban ecosystems

Technology is transforming societies worldwide. A major innovation is the emergence of robotics and autonomous systems (RAS), which have the potential to revolutionize cities for both people and nature. Nonetheless, the opportunities and challenges associated with RAS for urban ecosystems have yet to be considered systematically. Here, we report the findings of an online horizon scan involving 170 expert participants from 35 countries. We conclude that RAS are likely to transform land use, transport systems and human–nature interactions. The prioritized opportunities were primarily centred on the deployment of RAS for the monitoring and management of biodiversity and ecosystems. Fewer challenges were prioritized. Those that were emphasized concerns surrounding waste from unrecovered RAS, and the quality and interpretation of RAS-collected data. Although the future impacts of RAS for urban ecosystems are difficult to predict, examining potentially important developments early is essential if we are to avoid detrimental consequences but fully realize the benefits

Early ovule development following self- and cross-pollinations in Eucalyptus globulus Labill. ssp globulus

Copyright © 2002 Annals of Botany CompanyL. M. Pound, M. A. B. Wallwork, B. M. Potts and M. Sedgle

Self-incompatibility in Eucalyptus globulus ssp. globulus (Myrtaceae)

Copyright © 2002 CSIROControlled pollinations with self- and cross-pollen were applied to individual flowers of five mature Eucalyptus globulus Labill. ssp. globulus trees to investigate the site of action of the self-incompatibility mechanism. Growth of pollen tubes in styles at 2 weeks after pollination and ovule penetration by pollen tubes at 2 and 4 weeks after pollination were investigated by fluorescence microscopy. Some pollinated flowers were left to develop to seed maturity, then harvested to quantify the level of self-incompatibility of each tree. Trees ranged from 76 to 100% self-incompatible. There was no significant difference in the number of pollen tubes in the style between treatments although variation was present between trees. The number of pollen tubes present was similar to the number of ovules present within flowers. Penetration of ovules by pollen tubes over all five trees combined revealed no difference between treatments at 2 weeks after pollination; however, there was slightly greater penetration by cross-pollen tubes at 4 weeks after pollination. This difference was not large enough to account for the near complete lack of selfed-seed production, suggesting late pre- or post-zygotic arrest of selfed ovules.L. M. Pound, M. A. B. Wallwork, B. M. Potts and M. Sedgle

Medication adherence in adults listed for kidney transplant

"Medication non-adherence is 40 percent in pre-transplant adult heart, lung, and liver patients (Dobbels et al., 2009) Pre-transplant medication non-adherence predicts poor post-transplant outcomes in adult heart, lung, and liver patients (Dobbels et al, 2009) Medication non-adherence in those awaiting a kidney transplant has been under-investigated Purpose is to describe rates and correlates of medication adherence on those on the wait list for kidney transplant. "--Introduction