Preoperative plasma growth-differentiation factor-15 for prediction of acute kidney injury in patients undergoing cardiac surgery

Covariate plot of the predictions from the random forest model. Four variables are displayed. Within each box, the x-axis denotes plasma creatinine (Îźmol/l), the y-axis the probability of developing cardiac-surgery-associated acute kidney injury (CSA-AKI). Within each column of plots, the additive Euroscore increases from bottom to top (legend, right). Within each row of plots the growth-differentiation factor-15 (GDF-15) levels increase from left to right. Significant non-linear interaction takes place between GDF-15 and creatinine. Within each additive Euroscore category (row of plots), increases in GDF-15 (plots more to the right within each row) increase the probability of developing CSA-AKI. However, this effect is more prominent in patients with normal creatinine (x-axis label of each plot). (TIFF 3197 kb

StreptomeDB 2.0 - An extended resource of natural products produced by streptomycetes

Over the last decades, the genus Streptomyces has stirred huge interest in the scientific community as a source of bioactive compounds. The majority of all known antibiotics is isolated from these bac-terial strains, as well as a variety of other drugs such as antitumor agents, immunosuppressants and antifungals. To the best of our knowledge, Strep-tomeDB was the first database focusing on com-pounds produced by streptomycetes. The new ver-sion presented herein represents a major step for-ward: its content has been increased to over 4000 compounds and more than 2500 host organisms. In addition, we have extended the background in-formation and included hundreds of new manually curated references to literature. The latest update features a unique scaffold-based navigation system, which enables the exploration of the chemical diver-sity of StreptomeDB on a structural basis. We have included a phylogenetic tree, based on 16S rRNA se-quences, which comprises more than two-thirds of the included host organisms. It enables visualizing the frequency, appearance, and persistence of com-pounds and scaffolds in an evolutionary context. Ad-ditionally, we have included predicted MS- and NMR-spectra of thousands of compounds for assignment of experimental data. The database is freely acces-sible vi

Setting up a pragmatic clinical trial in a lowresource setting: a qualitative assessment of GoLBeT, a trial of podoconiosis management in Northern Ethiopia

Background Clinical trials are often perceived as being expensive, difficult and beyond the capacity of healthcare workers in low-resource settings. However, in order to improve healthcare coverage, the World Health Organization (WHO) World Health Report 2013 stated that all countries need to become generators as well as recipients of data. This study is a methodological examination of the steps and processes involved in setting up the Gojjam Lymphoedema Best Practice Trial (GoLBeT; ISRCTN67805210), a highly pragmatic clinical trial conducted in northern Ethiopia. Challenges to the trial and strategies used to deal with them were explored, together with the reasons for delays. Methodology and principal findings Qualitative research methods were used to analyse emails and reports from the period between trial inception and recruitment. This analysis was complemented by interviews with key informants from the trial operational team. The Global Health Research Process Map was used as a framework against which to compare the steps involved in setting up the trial. A mini-group discussion was conducted with the trial operational team after study completion for reflection and further recommendations. This study showed that the key areas of difficulty in setting up and planning this trial were: the study design, that is, deciding on the study endpoint, where and how best to measure it, and assuring statistical power; recruitment and appropriate training of staff; planning for data quality; and gaining regulatory approvals. Collaboration, for example with statisticians, the trial steering committee, the study monitors, and members of the local community was essential to successfully setting up the trial. Conclusions and significance Lessons learnt from this trial might guide others planning pragmatic trials in settings where research is not common, allowing them to anticipate possible challenges and address them through trial design, planning and operational delivery. We also hope that this example might encourage similar pragmatic studies to be undertaken. Such studies are rarely undertaken or locally led, but are an accessible and efficient way to drive improved outcomes in public health

Harmonized clinical trial methodologies for localized cutaneous leishmaniasis and potential for extensive network with capacities for clinical evaluation

International audienceINTRODUCTION: Progress with the treatment of cutaneous leishmaniasis (CL) has been hampered by inconsistent methodologies used to assess treatment effects. A sizable number of trials conducted over the years has generated only weak evidence backing current treatment recommendations, as shown by systematic reviews on old-world and new-world CL (OWCL and NWCL).MATERIALS AND METHODS: Using a previously published guidance paper on CL treatment trial methodology as the reference, consensus was sought on key parameters including core eligibility and outcome measures, among OWCL (7 countries, 10 trial sites) and NWCL (7 countries, 11 trial sites) during two separate meetings.RESULTS: Findings and level of consensus within and between OWCL and NWCL sites are presented and discussed. In addition, CL trial site characteristics and capacities are summarized.CONCLUSIONS: The consensus reached allows standardization of future clinical research across OWCL and NWCL sites. We encourage CL researchers to adopt and adapt as required the proposed parameters and outcomes in their future trials and provide feedback on their experience. The expertise afforded between the two sets of clinical sites provides the basis for a powerful consortium with potential for extensive, standardized assessment of interventions for CL and faster approval of candidate treatments

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Methodology research in clinical studies for Neglected Tropical Diseases (NTDs) of the skin: Addressing design, conduct and relevance for context and target population

Buruli Ulcer (BU) and Cutaneous Leishmaniasis (CL) are two Neglected Tropical Diseases (NTDs) of the skin. Both are âdiseases of povertyâ and can cause long-term disabilities. This work comprises two research methodology studies, suggesting novel approaches to design and conduct of clinical studies in order to make research more relevant for their context, and for patients. The first is a study evaluating a diagnostic test for BU at a point-of-care (PoC) setting in rural Ghana, complemented by interviews and focus group discussions (FGDs) with relevant stakeholders. It reports results from the diagnostics trial and points out roles for a Bayesian statistical framework using existing data on the one hand, and qualitative research in diagnostics development on the other hand, addressing challenges such as those related to the context or small sample sizes. The second, qualitative, study sought to address methodological issues of clinical trials for CL interventions. Semi-structured interviews were conducted with 74 CL patients from seven endemic countries about their disease experiences, and analysed for their preferred outcomes. Patients reported a number of treatment outcomes as important; the majority had only been insufficiently or not included in trials so far. Recommendations made include consideration of a group of outcomes into future trials via suitable outcome measures, and suggest information and/or psychological support for patients to address their fears related to other, undesired ones. The thesis shows a role for qualitative research to enrich clinical studies for skin NTDs. It emphasizes the importance of consulting appropriate stakeholders via suitable methods in order to make trials more relevant and suitable for the context and the intended target population. It also identifies areas that could be addressed with targeted capacity development or further operational research, and seeks to facilitate the conduct of pragmatic trials in low-resource areas.</p

Treatment of Pregnant Women with Ivermectin during Mass Drug Distribution: Time to Investigate Its Safety and Potential Benefits

To date, pregnant women are excluded from programmes delivering community-directed treatment of ivermectin (CDTI) for onchocerciasis and preventive chemotherapy of other helminthiases because of concerns over ivermectin safety during pregnancy. This systematic exclusion sustains an infection reservoir at the community level and deprives a vulnerable population from known benefits&mdash;there are indications that treating O. volvulus infected women may improve pregnancy outcomes and reduce the risk that their children develop onchocerciasis-associated morbidities. Furthermore, teratogenic effects are seen in non-clinical experiments at doses that far exceed those used in CDTI. Lastly, early, undetected and undeclared pregnancies are being systematically exposed to ivermectin in practice. Treatment of this population requires appropriate supporting evidence, for which we propose a three-pronged approach. First, to develop a roadmap defining the key steps needed to obtain regulatory clearance for the safe and effective use of ivermectin in all pregnant women who need it. Second, to conduct a randomised placebo-controlled double-blind clinical trial to evaluate the safety and benefits of ivermectin treatment in O. volvulus infected pregnant women. Such a trial should evaluate the possible effects of ivermectin in reducing adverse pregnancy outcomes and neonatal mortality, as well as in reducing the incidence of onchocerciasis-associated epilepsy. Third, to establish a pregnancy registry for women who inadvertently received ivermectin during pregnancy. This situation is not unique to ivermectin. Access to valuable therapies is often limited, delayed, or denied to pregnant women due to a lack of evidence. Concerns over protecting vulnerable people may result in harming them. We need to find acceptable ways to build robust evidence towards providing essential interventions during pregnancy