The effects of soil moisture, soil texture, and host orientation on the ability of Heterorhabditis bacteriophora (Rhabditida: Heterorhabditidae) to infect Galleria mellonella (Lepidoptera: Pyralidae)

Abstract Entomopathogenic nematodes (EPN) demonstrate potential as a biological control for soil dwelling insects. However, edaphic factors, such as soil moisture and texture impact the efficacy of EPN on a host. The objectives were to examine the effects of soil texture and moisture on 1) the infection rate of Galleria mellonella L. by EPN and; 2) the ability of H. bacteriophora (Poinar) to move through the soil to find a host at different orientations. Soil textures consisted of sand, a sand/silt/peat mixture, and a silt/peat mixture at 50% and 100% moisture. A general linear model was used to evaluate infection rates and EPN movement. Both soil moisture (p \u3c 0.05) and texture (p \u3c 0.05) had significant effects on nematodes infection rates of G. mellonella. Texture, moisture, and host orientation did not significantly affect (p \u3e 0.05) the ability of EPN to find a host. While EPN were able to find a host within a variety of soil types, soils that held more water had higher infection rates than soils that held less water, suggesting that moisture may be a key component in facilitating infection by EPN. By understanding the factors that influence the ability of EPN to find and infect a host, improved bio-control programs using EPN can be developed

The effects of soil moisture, soil texture, and host orientation on the ability of Heterorhabditis bacteriophora (Rhabditida: Heterorhabditidae) to infect Galleria mellonella (Lepidoptera: Pyralidae)

Abstract Entomopathogenic nematodes (EPN) demonstrate potential as a biological control for soil dwelling insects. However, edaphic factors, such as soil moisture and texture impact the efficacy of EPN on a host. The objectives were to examine the effects of soil texture and moisture on 1) the infection rate of Galleria mellonella L. by EPN and; 2) the ability of H. bacteriophora (Poinar) to move through the soil to find a host at different orientations. Soil textures consisted of sand, a sand/silt/peat mixture, and a silt/peat mixture at 50% and 100% moisture. A general linear model was used to evaluate infection rates and EPN movement. Both soil moisture (p \u3c 0.05) and texture (p \u3c 0.05) had significant effects on nematodes infection rates of G. mellonella. Texture, moisture, and host orientation did not significantly affect (p \u3e 0.05) the ability of EPN to find a host. While EPN were able to find a host within a variety of soil types, soils that held more water had higher infection rates than soils that held less water, suggesting that moisture may be a key component in facilitating infection by EPN. By understanding the factors that influence the ability of EPN to find and infect a host, improved bio-control programs using EPN can be developed

Where do we go from here? - Opportunities and barriers to the career development of trial managers: a survey of UK-based trial management professionals

BackgroundClinical trials commonly have a dedicated trial manager and effective trial management is essential to the successful delivery of high-quality trials. Trial managers have diverse experience and currently there is no standardised structured career pathway. The UK Trial Managers’ Network (UKTMN) surveyed its members to understand what is important to them with respect to career development since this would be important in the development of any initiative intended to develop a skilled workforce.MethodsWe conducted an online survey of UKTMN members, who are trial management professionals, working on academic-led trials in the UK. Members were asked what they perceive as opportunities and barriers to career development. Two reminders were sent to facilitate completion of the survey, and responders were offered the opportunity to enter a prize draw for waived fees at the UKTMN annual meeting. Data were analysed descriptively by using Stata (version 15.1), and free-text responses were reviewed for themes.ResultsThe survey was sent to 819 UKTMN members; 433 responses were received, although 13 were from non-UKTMN members; thus 420 respondents' data were included in analyses. Respondents were representative of UKTMN membership; however, more responses were received by trial managers based in registered clinical trials units (CTUs). The top three opportunities for career development were (i) training, (ii) helping design trials and (iii) undertaking relevant qualifications. The top three barriers were (i) funding, (ii) few opportunities to get involved in development activities aside from managing a trial and (iii) unclear organisational career pathway. Almost all respondents (401/420, 95.4%) considered career development either very or quite important. Although all respondents had a day-to-day role in managing trials, there was huge disparity between job titles.ConclusionCareer development is important to trial managers yet there is a lack of a structured pathway. The enablers and disablers to career development for trial managers should be clearly considered by the clinical trial community and, in particular, employers, sponsors and funders in order to develop a highly skilled workforce of trial managers, who are key to the delivery of trials

Leishmaniavirus-dependent metastatic leishmaniasis is prevented by blocking IL-17A

Cutaneous leishmaniasis has various outcomes, ranging from self-healing reddened papules to extensive open ulcerations that metastasise to secondary sites and are often resistant to standard therapies. In the case of L. guyanensis (L.g), about 5-10% of all infections result in metastatic complications. We recently showed that a cytoplasmic virus within L.g parasites (LRV1) is able to act as a potent innate immunogen, worsening disease outcome in a murine model. In this study, we investigated the immunophenotype of human patients infected by L.g and found a significant association between the inflammatory cytokine IL-17A, the presence of LRV1 and disease chronicity. Further, IL-17A was inversely correlated to the protective cytokine IFN-γ. These findings were experimentally corroborated in our murine model, where IL-17A produced in LRV1+ L.g infection contributed to parasite virulence and dissemination in the absence of IFN-γ. Additionally, IL-17A inhibition in mice using digoxin or SR1001, showed therapeutic promise in limiting parasite virulence. Thus, this murine model of LRV1-dependent infectious metastasis validated markers of disease chronicity in humans and elucidated the immunologic mechanism for the dissemination of Leishmania parasites to secondary sites. Moreover, it confirms the prognostic value of LRV1 and IL-17A detection to prevent metastatic leishmaniasis in human patients

Efficacy and safety of co-careldopa as an add-on therapy to occupational and physical therapy in patients after stroke (DARS): a randomised, double-blind, placebo controlled trial

Background Dopamine is a key modulator of striatal function and learning and might improve motor recovery after stroke. Previous small trials of dopamine agonists after stroke provide equivocal evidence of effectiveness on improving motor recovery. We aimed to assess the safety and efficacy of co-careldopa plus routine occupational and physical therapy during early rehabilitation after stroke. Methods This double-blind, multicentre, randomised controlled trial of co-careldopa versus placebo in addition to routine NHS occupational and physical therapy was done at 51 UK NHS acute inpatient stroke rehabilitation services. We recruited patients with new or recurrent clinically diagnosed ischaemic or haemorrhagic (excluding subarachnoid haemorrhage) stroke 5–42 days before randomisation, who were unable to walk 10 m or more, had a score of less than 7 points on the Rivermead Mobility Index, were expected to need rehabilitation, and were able to access rehabilitation after discharge from hospital. Participants were assigned (1:1) using stratified random blocks to receive 6 weeks of oral co-careldopa or matched placebo in addition to routine NHS physiotherapy and occupational therapy. The initial two doses of co-careldopa were 62·5 mg (50 mg of levodopa and 12·5 mg of carbidopa) and the remaining doses were 125 mg (100 mg of levodopa and 25 mg of carbidopa). Participants were required to take a single oral tablet 45–60 min before physiotherapy or occupational therapy session. The primary outcome was ability to walk independently, defined as a Rivermead Mobility Index score of 7 or more, at 8 weeks. Primary and safety analyses were done in the intention-to-treat population. The trial is registered on the ISRCTN registry, number ISRCTN99643613.Findings Between May 30, 2011, and March 28, 2014, of 1574 patients found eligible, 593 (mean age 68·5 years) were randomly assigned to either the co-careldopa group (n=308) or to the placebo group (n=285), on an average 18 days after stroke onset. Primary outcome data were available for all 593 patients. We found no evidence that the ability to walk independently improved with co-careldopa (125 [41%] of 308 patients) compared with placebo (127 [45%] of 285 patients; odds ratio 0·78 [95% CI 0·53–1·15]) at 8 weeks. Mortality at 12 months did not differ between the two groups (22 [7%] vs 17 [6%]). Serious adverse events were largely similar between groups. Vomiting during therapy sessions, after taking the study drug, was the most frequent adverse event and was more frequent in the co-careldopa group than the placebo group (19 [6·2%] vs 9 [3·2%]).Interpretation Co-careldopa in addition to routine occupational and physical therapy does not seem to improve walking after stroke. Further research might identify subgroups of patients with stroke who could benefit from dopaminergic therapy at different doses or times after stroke with more intensive motor therap

Enhanced feedback interventions to promote evidence-based blood transfusion guidance and reduce unnecessary use of blood components:The AFFINITIE research programme including two cluster factorial RCTs

Background: Blood transfusion is a common but costly treatment. Repeated national audits in the UK suggest that up to one-fifth of transfusions are unnecessary when judged against recommendations for good clinical practice. Audit and feedback seeks to improve patient care and outcomes by comparing clinical care against explicit standards. It is widely used internationally in quality improvement. Audit and feedback generally has modest but variable effects on patient care. A considerable scope exists to improve the impact that audit and feedback has, particularly through head-to-head trials comparing different ways of delivering feedback. Objectives: The AFFINITIE (Development & Evaluation of Audit and Feedback INterventions to Increase evidence-based Transfusion practIcE) programme aimed to design and evaluate enhanced feedback interventions, within a national blood transfusion audit programme, to promote evidence-based guidance and reduce the unnecessary use of blood components. We developed, piloted and refined two feedback interventions, ‘enhanced content’ and ‘enhanced follow-on’ (workstream 1), evaluated the effectiveness and cost-effectiveness of the two feedback interventions compared with standard feedback practice (workstream 2), examined intervention fidelity and contextual influences (workstream 3) and developed general implementation recommendations and tools for other audit and feedback programmes (workstream 4). Design: Interviews, observations and documentary analysis in four purposively sampled hospitals explored contemporary practice and opportunities for strengthening feedback. We developed two interventions: ‘enhanced content’, to improve the clarity and utility of feedback reports, and ‘enhanced follow-on’, to help hospital staff with action-planning (workstream 1). We conducted two linked 2 × 2 factorial cross-sectional cluster-randomised trials within transfusion audits for major surgery and haematological oncology, respectively (workstream 2). We randomised hospital clusters (the organisational level at which hospital transfusion teams operate) to enhanced or standard content or enhanced or standard follow-on. Outcome assessment was masked to assignment. Decision-analytic modelling evaluated the costs, benefits and cost-effectiveness of the feedback interventions in both trials from the perspective of the NHS. A parallel process evaluation used semistructured interviews, documentary analyses and web analytics to assess the fidelity of delivery, receipt and enactment and to identify contextual influences (workstream 3). We explored ways of improving the impact of national audits with their representatives (workstream 4). Setting and participants: All NHS hospital trusts and health boards participating in the National Comparative Audit of Blood Transfusions were invited to take part. Among 189 hospital trusts and health boards screened, 152 hospital clusters participated in the surgical audit. Among 187 hospital trusts and health boards screened, 141 hospital clusters participated in the haematology audit. Interventions: ‘Enhanced content’ aimed to ensure that the content and format of feedback reports were consistent with behaviour change theory and evidence. ‘Enhanced follow-on’ comprised a web-based toolkit and telephone support to facilitate local dissemination, planning and response to feedback. Main outcome measures: Proportions of acceptable transfusions, based on existing evidence and guidance and algorithmically derived from national audit data. Data sources: Trial primary outcomes were derived from manually collected, patient-level audit data. Secondary outcomes included routinely collected data for blood transfusion. Results: With regard to the transfusions in the major surgery audit, 135 (89%) hospital clusters participated from 152 invited. We randomised 69 and 66 clusters to enhanced and standard content, respectively, and 68 and 67 clusters to enhanced and standard follow-on, respectively. We analysed a total of 2222 patient outcomes at 12 months in 54 and 58 (enhanced and standard content, respectively) and 54 and 58 (enhanced and standard follow-on, respectively) hospital clusters. With regard to the haematology audit, 134 hospital clusters (95%) participated from 141 invited. We randomised 66 and 68 clusters to enhanced and standard content, respectively, and 67 clusters to both enhanced and standard follow-on. We analysed a total of 3859 patient outcomes at 12 months in 61 and 61 (enhanced and standard content, respectively) and 63 and 59 (enhanced and standard follow-on) hospital clusters. We found no effect of either of the enhanced feedback interventions in either trial across all outcomes. Incremental enhanced intervention costs ranged from £18 to £248 per site. The enhanced feedback interventions were dominated by the standard intervention in cost-effectiveness analyses. The interventions were delivered as designed and intended, but subsequent local engagement was low. Although the enhancements were generally acceptable, doubts about the credibility of the blood transfusion audits undermined the case for change. Limitations: Limitations included the number of participating clusters; loss to follow-up of trial clusters, reducing statistical power and validity; incomplete audit and cost data contributing to outcome measures; participant self-selection; reporting; missing data related to additional staff activity generated in response to receiving feedback; and recall biases in the process evaluation interviews. Conclusions: The enhanced feedback interventions were acceptable to recipients but were more costly and no more effective than standard feedback in reducing unnecessary use of blood components, and, therefore, should not be recommended on economic grounds. Future work: We have demonstrated the feasibility of embedding ambitious large-scale rigorous research within national audit programmes. Further head-to-head comparisons of different feedback interventions are needed in these programmes to identify cost-effective ways of increasing the impact of the interventions

The DARS (Dopamine Augmented Rehabilitation in Stroke) trial: protocol for a randomised controlled trial of Co-careldopa treatment in addition to routine NHS occupational and physical therapy after stroke

Background: Stroke has a huge impact, leaving more than a third of affected people with lasting disability and rehabilitation remains a cornerstone treatment in the National Health Service (NHS). Recovery of mobility and arm function post-stroke occurs through re-learning to use the affected body parts and/or learning to compensate with the lesser affected side. Promising evidence suggests that the addition of Co-careldopa to physical therapy and occupational therapy may improve the recovery of arm and leg movement and lead to improved function. Methods/design: Dopamine Augmented Rehabilitation in Stroke (DARS) is a multi-centre double-blind, randomised, placebo, controlled clinical trial of Co-careldopa in addition to routine NHS occupational therapy and physical therapy as part of early stroke rehabilitation. Participants will be randomised on a 1:1 basis to either Co-careldopa or placebo. The primary objective of the trial is to determine whether the addition of six weeks of Co-careldopa treatment to rehabilitation therapy can improve the proportion of patients who can walk independently eight weeks post-randomisation. Discussion: The DARS trial will provide evidence as to whether Co-careldopa, in addition to routine NHS occupational and physical therapy, leads to a greater recovery of motor function, a reduction in carer dependency and advance rehabilitation treatments for people with stroke. Trial registration: ISRCTN99643613 assigned on 4 December 2009