Melatonin as a potential therapy for sepsis : a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis

This article is protected by copyright. All rights reserved. This study was funded by the Chief Scientist Office, NHS Scotland. We would like to thank all the volunteers who gave up their time and blood to take part in the study and the data monitoring committee and staff of the intensive care unit for their support. In addition, thanks to Dr Malachy Columb for performing Page's trend test for us and to Annette Fearnley at Nu-Pharm Ltd for her advice.Peer reviewedPublisher PD

Views of Specialist Clinicians and People With Multiple Sclerosis on Upper Limb Impairment and the Potential Role of Virtual Reality in the Rehabilitation of the Upper Limb in Multiple Sclerosis: Focus Group Study

Background: Finding enjoyable and effective long-term approaches to rehabilitation for improving the upper limb (UL) function of people with multiple sclerosis (MS) is challenging. Using virtual reality (VR) could be a solution to this challenge; however, there is a lack of reporting on the views of people with MS and clinicians on VR-based approaches and recommendations for games for rehabilitation. Objective: This study aims to identify common UL problems and their related current therapeutic approaches for people with MS and to explore the opinions of people with MS and specialist clinicians on VR and obtain suggestions for the development and design of VR games. Methods: Separate focus groups were conducted with people with MS, recruited through the MS Society UK’s research network, and clinicians, recruited through the United Kingdom’s Therapists in MS network. A total of 10 people with MS (2 focus groups) and 8 clinicians (5 physiotherapists, 2 occupational therapists, and 1 MS nurse in 2 focus groups) were involved. The focus groups were recorded and transcriptions were analyzed using theme-based content analysis. Results: People with MS commonly reported that their UL problems interfered with activities of daily living and resulted in the loss of meaningful hobbies such as writing. Many people with MS neglected UL exercise and found strategies for adapting to the UL impairments. Similarly, clinicians stated UL rehabilitation was neglected within their service and that it was challenging to find interesting treatment strategies. VR was suggested by both participant groups as a solution, as it was convenient for people with MS to access and it could provide a more engaging and disguised approach to exercise. There were shared concerns with cybersickness and disengagement with using VR approaches. Both groups agreed games should be meaningful and adaptable for users but suggested different VR activities, with clinicians suggesting games directly reflecting activities of daily living and people with MS suggesting more abstract activities. Conclusions: VR was well received by both people with MS and clinicians for UL rehabilitation. Recommendations were made for the development of VR rehabilitation games which are personalized and customizable for the varying abilities of people with M

Upper Limb Impairment and the potential role of Virtual Reality in the Rehabilitation of the Upper Limb in Multiple Sclerosis: views of specialist clinicians and people with MS

Background: Finding enjoyable and effective long-term approaches to rehabilitation for improving upper limb (UL) function for people with multiple sclerosis (pwMS) is challenging. Using virtual reality (VR) could be a solution to this challenge however; there is a lack of reporting on pwMS’ and clinicians’ views on VR-based approaches and recommendations for games for rehabilitation. Objective: To identify common UL problems and their related current therapeutic approaches in pwMS and 2) to explore the opinions of pwMS and specialist clinicians’ on VR and suggestions for development and design of VR games. Methods: Separate focus groups were conducted with pwMS, recruited through the MS Society UK’s research network, and clinicians, recruited through the UK’s Therapists in MS network. Ten pwMS (two focus groups) and eight clinicians (five physiotherapists, two occupational therapists and one MS-nurse, two focus groups) were involved. Focus groups were recorded and transcriptions analyzed using theme-based content analysis (TBCA). Results: People with MS commonly reported their UL problems interfered with activities of daily living (ADL) and resulted in the loss of meaningful hobbies such as writing. Many pwMS neglected UL exercise and found strategies for adapting to the UL impairments. Similarly, clinicians stated UL rehabilitation was neglected within their service and that it was challenging to find interesting treatment strategies. VR was suggested by both participant groups as a solution, being convenient for pwMS to access and could provide a more engaging and disguised approach to exercise. There were shared concerns with cybersickness and disengagement with using VR approaches. Both groups agreed games should be meaningful and adaptable for users, but suggested different VR activities, with clinicians suggesting games directly reflecting ADL and pwMS more abstract activity. Conclusions: VR was well received by both pwMS and clinicians for UL rehabilitation. Recommendations are made for the development of VR rehabilitation games which are personalized and customizable for the varying ability of pwMS

"Other patients are really in need of medical attention" - the quality of health services for rape survivors in South Africa

Objective: To investigate in the South African public health sector where the best services for rape survivors were provided, who provided them, what the providers’ attitudes were towards women who had been raped and whether there were problems in delivering care for rape survivors. Methods: A cross-sectional study of facilities was carried out. Two district hospitals, a regional hospital and a tertiary hospital (where available) were randomly sampled in each of the nine provinces in South Africa. At each hospital, senior staff identified two doctors and two nurses who regularly provided care for women who had been raped. These doctors and nurses were interviewed using a questionnaire with both open-ended and closed questions. We interviewed 124 providers in 31 hospitals. A checklist that indicated what facilities were available for rape survivors was also completed for each hospital. Findings A total of 32.6% of health workers in hospitals did not consider rape to be a serious medical condition. The mean number of rape survivors seen in the previous six months at each hospital was 27.9 (range = 9.3–46.5). A total of 30.3% of providers had received training in caring for rape survivors. More than three-quarters of regional hospitals (76.9%) had a private exam room designated for use in caring for rape survivors. Multiple regression analysis of practitioner factors associated with better quality of clinical care found these to be a practitioner being older than 40 years (parameter estimate = 2.4; 95% confidence interval (CI) = 0.7–5), having cared for a higher number of rape survivors before (parameter estimate = 0.02; 95% CI = 0.001–0.03), working in a facility that had a clinical management protocol for caring for rape survivors (parameter estimate = 2; 95% CI = 0.12–3.94), having worked for less time in the facility (parameter estimate = -0.2; 95% CI = -0.3 to -0.04) and perceiving rape to be a serious medical problem (parameter estimate = 2.8; 95% CI = 1.9–3.8). Conclusion: There are many weaknesses in services for rape survivors in South Africa. Our findings suggest that care can be improved by disseminating clinical management guidelines and ensuring that care is provided by motivated providers who are designated to care for survivors

Treatment for lupus nephritis

BackgroundCyclophosphamide, in combination with corticosteroids has been used to induce remission in proliferative lupus nephritis, the most common kidney manifestation of the multisystem disease, systemic lupus erythematosus. Cyclophosphamide therapy has reduced mortality from over 70% in the 1950s and 1960s to less than 10% in recent years. Cyclophosphamide combined with corticosteroids preserves kidney function but is only partially effective and may cause ovarian failure, infection and bladder toxicity. Several new agents, including mycophenolate mofetil (MMF), suggest reduced toxicity with equivalent rates of remission. This is an update of a Cochrane review first published in 2004.ObjectivesTo assess the benefits and harms of different immunosuppressive treatments in biopsy-proven proliferative lupus nephritis.Search methodsFor this update, we searched the Cochrane Renal Group's Specialised Register (up to 15 April 2012) through contact with the Trials' Search Coordinator using search terms relevant to this review.Selection criteriaRandomised controlled trials (RCTs) and quasi-RCTs comparing any treatments for biopsy-proven lupus nephritis in both adult and paediatric patients with class III, IV, V + III and V + IV lupus nephritis were included. All immunosuppressive treatments were considered.Data collection and analysisData were abstracted and quality assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes were reported as risk ratio (RR) and measurements on continuous scales reported as mean differences (MD) with 95% confidence intervals (CI).Main resultsWe identified 50 RCTs involving 2846 participants. Of these, 45 studies (2559 participants) investigated induction therapy, and six studies (514 participants), considered maintenance therapy.Compared with intravenous (IV) cyclophosphamide, MMF was as effective in achieving stable kidney function (5 studies, 523 participants: RR 1.05, 95% CI 0.94 to 1.18) and complete remission of proteinuria (6 studies, 686 participants: RR 1.16, 95% CI 0.85 to 1.58). No differences in mortality (7 studies, 710 participants: RR 1.02, 95% CI 0.52 to 1.98) or major infection (6 studies, 683 participants: RR 1.11, 95% CI 0.74 to 1.68) were observed. A significant reduction in ovarian failure (2 studies, 498 participants: RR 0.15, 95% CI 0.03 to 0.80) and alopecia (2 studies, 522 participants: RR 0.22, 95% CI 0.06 to 0.86) was observed with MMF. In maintenance therapy, the risk of renal relapse (3 studies, 371 participants: RR 1.83, 95% CI 1.24 to 2.71) was significantly higher with azathioprine compared with MMF. Multiple other interventions were compared but outcome data were relatively sparse. Overall study quality was variable. The internal validity of the design, conduct and analysis of the included RCTs was difficult to assess in some studies because of the omission of important methodological details. No study adequately reported all domains of the risk of bias assessment so that elements of internal bias may be present.Authors' conclusionsMMF is as effective as cyclophosphamide in inducing remission in lupus nephritis, but is safer with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse with no increase in clinically important side effects. Adequately powered trials with long term follow-up are required to more accurately define the risks and eventual harms of specific treatment regimens

Identification of a potent and selective LAPTc inhibitor by RapidFire-Mass Spectrometry, with antichagasic activity

Background: Chagas disease is caused by the protozoan parasite Trypanosoma cruzi and leads to ~10,000 deaths each year. Nifurtimox and benznidazole are the only two drugs available but have significant adverse effects and limited efficacy. New chemotherapeutic agents are urgently required. Here we identified inhibitors of the acidic M17 leucyl-aminopeptidase from T. cruzi (LAPTc) that show promise as novel starting points for Chagas disease drug discovery.Methodology/Principal findings: A RapidFire-MS screen with a protease-focused compound library identified novel LAPTc inhibitors. Twenty-eight hits were progressed to the dose-response studies, from which 12 molecules inhibited LAPTc with IC50 &lt; 34 μM. Of these, compound 4 was the most potent hit and mode of inhibition studies indicate that compound 4 is a competitive LAPTc inhibitor, with Ki 0.27 μM. Compound 4 is selective with respect to human LAP3, showing a selectivity index of &gt;500. Compound 4 exhibited sub-micromolar activity against intracellular T. cruzi amastigotes, and while the selectivity-window against the host cells was narrow, no toxicity was observed for un-infected HepG2 cells. In silico modelling of the LAPTc-compound 4 interaction is consistent with the competitive mode of inhibition. Molecular dynamics simulations reproduce the experimental binding strength (-8.95 kcal/mol), and indicate a binding mode based mainly on hydrophobic interactions with active site residues without metal cation coordination.Conclusions/Significance: Our data indicates that these new LAPTc inhibitors should be considered for further development as antiparasitic agents for the treatment of Chagas disease.</p

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe