Systematic review and stratified meta-analysis of the efficacy of RhoA and Rho kinase inhibitors in animal models of ischaemic stroke

There is currently only one clinically approved drug, tissue plasminogen activator (tPA), for the treatment of acute ischaemic stroke. The RhoA pathway, including RhoA and its downstream effector Rho kinase (ROCK), has been identified as a possible therapeutic target. Our aim was to assess the impact of study design characteristics and study quality on reported measures of efficacy and to assess for the presence and impact of publication bias. We conducted a systematic review and meta-analysis on publications describing the efficacy of RhoA and ROCK inhibitors in animal models of focal cerebral ischaemia where outcome was assessed as a change in lesion size or neurobehavioural score, or both. We identified 25 published papers which met our inclusion criteria. RhoA and ROCK inhibitors reduced lesion size by 37.3% in models of focal cerebral ischaemia (95% CI, 28.6% to 46.0%, 41 comparisons), and reduced neurobehavioural data by 40.5% (33.4% to 47.7%, 30 comparisons). Overall study quality was low (median=4, interquartile range 3-5) and measures to reduce bias were seldom reported. Publication bias was prevalent and associated with a substantial overstatement of efficacy for lesion size. RhoA and ROCK inhibitors appear to be effective in animal models of stroke. However the low quality score, publication bias and limited number of studies are areas which need attention prior to conducting clinical trials

Some salt with your statin, professor?

We know that clinical trials sponsored by the pharmaceutical industry are likely to exaggerate benefit and minimise harms. But do these biases extend to their sponsorship of non-human animal research? Using systematic review and meta-analysis Bero and colleagues show that, in the case of statins, things are a little more complicated. While the conclusions of industry-sponsored studies were indeed more enthusiastic than warranted by their data, the data themselves painted a picture more conservative than was seen in non-industry-sponsored studies. This behaviour is consistent with maximising the return on investment, seeking robust data before embarking on a clinical trial, and, once that investment has been made, making every effort to “prove” that the drug is safe and effective if this is at all credible. The findings suggest that there is something different about industry-sponsored non-human animal research, perhaps reflecting higher standards than is the case elsewhere. Perhaps the academic community can learn something from our colleagues in the commercial sector

Improving STD testing behavior among high-risk young adults by offering STD testing at a vocational school

<p>Abstract</p> <p>Background</p> <p>Chlamydia trachomatis infection (CT) is the most prevalent bacterial STD. Sexually active adolescents and young adults are the main risk group for CT. However, STD testing rates in this group are low since exposed individuals may not feel at risk, owing-at least in part-to the infection's largely asymptomatic nature. Designing new testing environments that are more appealing to young people who are most at risk of acquiring chlamydia can be an important strategy to improve overall testing rates. Here we evaluate the effect of a school-based sexual health program conducted among vocational school students, aiming to obtain better access for counseling and enhance students' STD testing behavior.</p> <p>Methods</p> <p>Adolescents (median age 19 years) attending a large vocational school were provided with sexual health education. Students filled in a questionnaire measuring CT risk and were offered STD testing. Using univariate and multivariate analysis, we assessed differences between men and women in STD-related risk behavior, sexual problems, CT testing behavior and determinants of CT testing behavior.</p> <p>Results</p> <p>Of 345 participants, 70% were female. Of the 287 sexually active students, 75% were at high risk for CT; one third of women reported sexual problems. Of sexually active participants, 61% provided a self-administered specimen for STD testing. Independent determinants for testing included STD related symptoms and no condom use. All CT diagnoses were in the high-CT-risk group. In the high-risk group, STD testing showed an increased uptake, from 27% (previous self-reported test) to 65% (current test). CT prevalence was 5.7%.</p> <p>Conclusions</p> <p>Vocational school students are a target population for versatile sexual health prevention. When provided with CT testing facilities and education, self selection mechanisms seemed to increase CT testing rate dramatically in this high-CT-risk population expressing sexual problems. Considering the relative ease of testing and treating large numbers of young adults, offering tests at a vocational school is feasible in reaching adolescents for STD screening. Although cost-effectiveness remains an issue counseling is effective in increasing test rates.</p

Systematic review and meta-analysis of the efficacy of interleukin-1 receptor antagonist in animal models of stroke: an update

Interleukin-1 receptor antagonist (IL-1 RA) is an anti-inflammatory protein used clinically to treat rheumatoid arthritis and is considered a promising candidate therapy for stroke. Here, we sought to update the existing systematic review and meta-analysis of IL-1 RA in models of ischaemic stroke, published in 2009, to assess efficacy, the range of circumstances in which efficacy has been tested and whether the data appear to be confounded due to reported study quality and publication bias. We included 25 sources of data, 11 of which were additional to the original review. Overall, IL-1 RA reduced infarct volume by 36.2 % (95 % confidence interval 31.6–40.7, n = 76 comparisons from 1283 animals). Assessments for publication bias suggest 30 theoretically missing studies which reduce efficacy to 21.9 % (17.3–26.4). Efficacy was higher where IL-1 RA was administered directly into the ventricles rather than peripherally, and studies not reporting allocation concealment during the induction of ischaemia reported larger treatment effects. The preclinical data supporting IL-1 RA as a candidate therapy for ischaemic stroke have improved. The reporting of measures to reduce the risk of bias has improved substantially in this update, and studies now include the use of animals with relevant co-morbidities. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12975-016-0489-z) contains supplementary material, which is available to authorized users

Prospective multi-center trial utilizing electronic brachytherapy for the treatment of endometrial cancer

<p>Abstract</p> <p>Background</p> <p>A modified form of high dose rate (HDR) brachytherapy has been developed called Axxent Electronic Brachytherapy (EBT). EBT uses a kilovolt X-ray source and does not require treatment in a shielded vault or a HDR afterloader unit. A multi-center clinical study was carried out to evaluate the success of treatment delivery, safety and toxicity of EBT in patients with endometrial cancer.</p> <p>Methods</p> <p>A total of 15 patients with stage I or II endometrial cancer were enrolled at 5 sites. Patients were treated with vaginal EBT alone or in combination with external beam radiation.</p> <p>Results</p> <p>The prescribed doses of EBT were successfully delivered in all 15 patients. From the first fraction through 3 months follow-up, there were 4 CTC Grade 1 adverse events and 2 CTC Grade II adverse events reported that were EBT related. The mild events reported were dysuria, vaginal dryness, mucosal atrophy, and rectal bleeding. The moderate treatment related adverse events included dysuria, and vaginal pain. No Grade III or IV adverse events were reported. The EBT system performed well and was associated with limited acute toxicities.</p> <p>Conclusions</p> <p>EBT shows acute results similar to HDR brachytherapy. Additional research is needed to further assess the clinical efficacy and safety of EBT in the treatment of endometrial cancer.</p

D-galactose-induced brain ageing model:A systematic review and meta-analysis on cognitive outcomes and oxidative stress indices

Animal models are commonly used in brain ageing research. Amongst these, models where rodents are exposed to d-galactose are held to recapitulate a number of features of ageing including neurobehavioral and neurochemical changes. However, results from animal studies are often inconsistent. To better understand the characteristics of the model and effects of d-galactose on neurobehavioral and neurochemical outcomes in rodents we performed a systematic review and meta-analysis. We applied random-effects meta-analysis to evaluate the effect of study features. Our results give an overview of the characteristics of the d-galactose rodent ageing model, including neurobehavioral and neurochemical outcomes. We found that few studies took measures to reduce risks of bias, and substantial heterogeneity in the reported effects of d-galactose in included studies. This highlights the need for improvements in the use of the d-galactose rodent ageing model if it is to provide useful in the development of drugs to treat human ageing

General Principles of Preclinical Study Design

Publisher PD

Drug Repurposing: A Systematic Approach to Evaluate Candidate Oral Neuroprotective Interventions for Secondary Progressive Multiple Sclerosis

Objective: To develop and implement an evidence based framework to select, from drugs already licenced, candidate oral neuroprotective drugs to be tested in secondary progressive multiple sclerosis. Design: Systematic review of clinical studies of oral putative neuroprotective therapies in MS and four other neurodegenerative diseases with shared pathological features, followed by systematic review and meta-analyses of the in vivo experimental data for those interventions. We presented summary data to an international multi-disciplinary committee, which assessed each drug in turn using pre-specified criteria including consideration of mechanism of action. Results: We identified a short list of fifty-two candidate interventions. After review of all clinical and pre-clinical evidence we identified ibudilast, riluzole, amiloride, pirfenidone, fluoxetine, oxcarbazepine, and the polyunsaturated fatty-acid class (Linoleic Acid, Lipoic acid; Omega-3 fatty acid, Max EPA oil) as lead candidates for clinical evaluation. Conclusions: We demonstrate a standardised and systematic approach to candidate identification for drug rescue and repurposing trials that can be applied widely to neurodegenerative disorders

Usability of a barcode scanning system as a means of data entry on a PDA for self-report health outcome questionnaires: a pilot study in individuals over 60 years of age

BACKGROUND: Throughout the medical and paramedical professions, self-report health status questionnaires are used to gather patient-reported outcome measures. The objective of this pilot study was to evaluate in individuals over 60 years of age the usability of a PDA-based barcode scanning system with a text-to-speech synthesizer to collect data electronically from self-report health outcome questionnaires. METHODS: Usability of the system was tested on a sample of 24 community-living older adults (7 men, 17 women) ranging in age from 63 to 93 years. After receiving a brief demonstration on the use of the barcode scanner, participants were randomly assigned to complete two sets of 16 questions using the bar code wand scanner for one set and a pen for the other. Usability was assessed using directed interviews with a usability questionnaire and performance-based metrics (task times, errors, sources of errors). RESULTS: Overall, participants found barcode scanning easy to learn, easy to use, and pleasant. Participants were marginally faster in completing the 16 survey questions when using pen entry (20/24 participants). The mean response time with the barcode scanner was 31 seconds longer than traditional pen entry for a subset of 16 questions (p = 0.001). The responsiveness of the scanning system, expressed as first scan success rate, was less than perfect, with approximately one-third of first scans requiring a rescan to successfully capture the data entry. The responsiveness of the system can be explained by a combination of factors such as the location of the scanning errors, the type of barcode used as an answer field in the paper version, and the optical characteristics of the barcode scanner. CONCLUSION: The results presented in this study offer insights regarding the feasibility, usability and effectiveness of using a barcode scanner with older adults as an electronic data entry method on a PDA. While participants in this study found their experience with the barcode scanning system enjoyable and learned to become proficient in its use, the responsiveness of the system constitutes a barrier to wide-scale use of such a system. Optimizing the graphical presentation of the information on paper should significantly increase the system's responsiveness

Evaluation design of a systematic, selective, internet-based, Chlamydia screening implementation in the Netherlands, 2008-2010: implications of first results for the analysis

A selective, systematic, Internet-based, Chlamydia Screening Implementation for 16 to 29-year-old residents started in three regions in the Netherlands in April 2008: in the cities of Amsterdam and Rotterdam and a more rural region, South Limburg. This paper describes the evaluation design and discusses the implications of the findings from the first screening round for the analysis. The evaluation aims to determine the effects of screening on the population prevalence of Chlamydia trachomatis after multiple screening rounds. A phased implementation or 'stepped wedge design' was applied by grouping neighbourhoods (hereafter: clusters) into three random, risk-stratified blocks (A, B and C) to allow for impact analyses over time and comparison of prevalences before and after one or two screening rounds. Repeated simulation of pre- and postscreening Chlamydia prevalences was used to predict the minimum detectable decline in prevalence. Real participation and positivity rates per region, block, and risk stratum (high, medium, and low community risk) from the 1st year of screening were used to substantiate predictions. The results of the 1st year show an overall participation rate of 16% of 261,025 invitees and a positivity rate of 4.2%, with significant differences between regions and blocks. Prediction by simulation methods adjusted with the first-round results indicate that the effect of screening (minimal detectable difference in prevalence) may reach significance levels only if at least a 15% decrease in the Chlamydia positivity rate in the cities and a 25% decrease in the rural region after screening can be reached, and pre- and postscreening differences between blocks need to be larger. With the current participation rates, the minimal detectable decline of Chlamydia prevalence may reach our defined significance levels at the regional level after the second screening round, but will probably not be significant between blocks of the stepped wedge design. Evaluation will also include other aspects and prediction models to obtain rational advice about future Chlamydia screening in the Netherland