Non-coding RNAs versus protein biomarkers to diagnose and differentiate acute stroke:Systematic review and meta-analysis

BACKGROUND: Stroke diagnosis is dependent on lengthy clinical and neuroimaging assessments, while rapid treatment initiation improves clinical outcome. Currently, more sensitive biomarker assays of both non-coding RNA- and protein biomarkers have improved their detectability, which could accelerate stroke diagnosis. This systematic review and meta-analysis compares non-coding RNA- with protein biomarkers for their potential to diagnose and differentiate acute stroke (subtypes) in (pre-)hospital settings.METHODS: We performed a systematic review and meta-analysis of studies evaluating diagnostic performance of non-coding RNA- and protein biomarkers to differentiate acute ischemic and hemorrhagic stroke, stroke mimics, and (healthy) controls. Quality appraisal of individual studies was assessed using the QUADAS-2 tool while the meta-analysis was performed with the sROC approach and by assessing pooled sensitivity and specificity, diagnostic odds ratios, positive- and negative likelihood ratios, and the Youden Index.SUMMARY OF REVIEW: 112 studies were included in the systematic review and 42 studies in the meta-analysis containing 11627 patients with ischemic strokes, 2110 patients with hemorrhagic strokes, 1393 patients with a stroke mimic, and 5548 healthy controls. Proteins (IL-6 and S100 calcium-binding protein B (S100B)) and microRNAs (miR-30a) have similar performance in ischemic stroke diagnosis. To differentiate between ischemic- or hemorrhagic strokes, glial fibrillary acidic protein (GFAP) levels and autoantibodies to the NR2 peptide (NR2aAb, a cleavage product of NMDA neuroreceptors) were best performing whereas no investigated protein or non-coding RNA biomarkers differentiated stroke from stroke mimics with high diagnostic potential.CONCLUSIONS: Despite sampling time differences, circulating microRNAs (&lt; 24 h) and proteins (&lt; 4,5 h) perform equally well in ischemic stroke diagnosis. GFAP differentiates stroke subtypes, while a biomarker panel of GFAP and UCH-L1 improved the sensitivity and specificity of UCH-L1 alone to differentiate stroke.</p

Experience and Challenges from Clinical Trials with Malaria Vaccines in Africa.

Malaria vaccines are considered amongst the most important modalities for potential elimination of malaria disease and transmission. Research and development in this field has been an area of intense effort by many groups over the last few decades. Despite this, there is currently no licensed malaria vaccine. Researchers, clinical trialists and vaccine developers have been working on many approached to make malaria vaccine available.African research institutions have developed and demonstrated a great capacity to undertake clinical trials in accordance to the International Conference on Harmonization-Good Clinical Practice (ICH-GCP) standards in the last decade; particularly in the field of malaria vaccines and anti-malarial drugs. This capacity is a result of networking among African scientists in collaboration with other partners; this has traversed both clinical trials and malaria control programmes as part of the Global Malaria Action Plan (GMAP). GMAP outlined and support global strategies toward the elimination and eradication of malaria in many areas, translating in reduction in public health burden, especially for African children. In the sub-Saharan region the capacity to undertake more clinical trials remains small in comparison to the actual need.However, sustainability of the already developed capacity is essential and crucial for the evaluation of different interventions and diagnostic tools/strategies for other diseases like TB, HIV, neglected tropical diseases and non-communicable diseases. There is urgent need for innovative mechanisms for the sustainability and expansion of the capacity in clinical trials in sub-Saharan Africa as the catalyst for health improvement and maintained

Health research ethics in malaria vector trials in Africa

Malaria mosquito research in Africa as elsewhere is just over a century old. Early trials for development of mosquito control tools were driven by colonial enterprises and war efforts; they were, therefore, tested in military or colonial settings. The failure of those tools and environmental concerns, coupled with the desperate need for integrated malaria control strategies, has necessitated the development of new malaria mosquito control tools, which are to be tested on humans, their environment and mosquito habitats. Ethical concerns start with phase 2 trials, which pose limited ethical dilemmas. Phase 3 trials, which are undertaken on vulnerable civilian populations, pose ethical dilemmas ranging from individual to community concerns. It is argued that such trials must abide by established ethical principles especially safety, which is mainly enshrined in the principle of non-maleficence. As there is total lack of experience with many of the promising candidate tools (eg genetically modified mosquitoes, entomopathogenic fungi, and biocontrol agents), great caution must be exercised before they are introduced in the field. Since malaria vector trials, especially phase 3 are intrusive and in large populations, individual and community respect is mandatory, and must give great priority to community engagement. It is concluded that new tools must be safe, beneficial, efficacious, effective, and acceptable to large populations in the short and long-term, and that research benefits should be equitably distributed to all who bear the brunt of the research burdens. It is further concluded that individual and institutional capacity strengthening should be provided, in order to undertake essential research, carry out scientific and ethical review, and establish competent regulatory frameworks

Совершенствование механизмов формирования доходов бюджета АРК

Целью нашей работы является исследование механизмов формирования доходов бюджета Автономной Республики Крым и разработка мероприятий по их совершенствованию

Within-Gender Changes in HIV Prevalence among Adults between 2005/6 and 2010/11 in Zimbabwe

INTRODUCTION: Zimbabwe has reported significant declines in HIV prevalence between 2005/06 and 2010/11 Demography and Health Surveys; a within-gender analysis to identify the magnitude and factors associated with this change, which can be masked, is critical for targeting interventions. METHODS: We analyzed change in HIV prevalence for 6,947 women and 5,848 men in the 2005/06 survey and 7,313 women and 6,250 men in 2010/11 surveys using 2005/06 as referent. The data was analyzed taking into consideration the survey design and therefore the svy, mean command in Stata was used in both linear and logistic regression. RESULTS: There were similar proportional declines in prevalence at national level for males (15% p=0.011) and females (16%,p=0.008). However, there were variations in decline by provincial setting, demographic variables of age, educational level and some sexual risk behaviours. In logistic regression analysis, statistically significant declines were observed among men in Manicaland, Mashonaland East and Harare (p<0.01) and for women in Manicaland, Mashonaland Central and Harare (p<0.01). Although not statistically significant, numerical increases were observed among men in Matebeleland North, Matebeleland South, Midlands and for both men and women in Bulawayo. Young women in the age range 15-34 experienced a decline in prevalence (p<0.01) while older men 30-44 had a statistically significant decline (p<0.01). Having a secondary and above education, regardless of employment status for both men and women recorded a significant decline. For sexual risk behaviours, currently in union for men and women and not in union for women there was a significant decline in prevalence. CONCLUSION: Zimbabwe has reported a significant decline among both men and women but there are important differentials across provinces, demographic characteristics and sexual risk behaviours that suggest that the epidemic in Zimbabwe is heterogeneous and therefore interventions must be targeted in order to achieve epidemic control

Clinical Ethics in Gabon: The Spectrum of Clinical Ethical Issues Based on Findings from In-Depth Interviews at Three Public Hospitals

Introduction Unlike issues in biomedical research ethics, ethical challenges arising in daily clinical care in Sub-Saharan African countries have not yet been studied in a systematic manner. However this has to be seen as a distinct entity as we argue in this paper. Our aim was to give an overview of the spectrum of clinical ethical issues and to understand what influences clinical ethics in the Sub-Saharan country of Gabon. Materials and Methods In-depth interviews with 18 health care professionals were conducted at three hospital sites in Gabon. Interview transcripts were analyzed using a grounded theory approach (open and axial coding),giving a qualitative spectrum of categories for clinical ethical issues. Validity was checked at a meeting with study participants and other health care experts in Gabon after analysis of the data. Results Twelve main categories (with 28 further-specified subcategories) for clinical ethical issues were identified and grouped under three core categories: A) micro level: "confidentiality and information","interpersonal, relational and behavioral issues","psychological strain of individuals",and "scarce resources";B) meso level: "structural issues of medical institutions","issues with private clinics","challenges connected to the family",and "issues of education, training and competence";and C) macro level: "influence of society, culture, religion and superstition","applicability of western medicine","structural issues on the political level",and "legal issues". Discussion Interviewees reported a broad spectrum of clinical ethical issues that go beyond challenges related to scarce financial and human resources. Specific socio-cultural, historical and educational backgrounds also played an important role. In fact these influences are central to an understanding of clinical ethics in the studied local context. Further research in the region is necessary to put our study into perspective. As many participants reported a lack of awareness of ethical issues amongst other health care professionals in daily clinical practice, we suggest that international organizations and national medical schools should consider infrastructure and tools to improve context-sensitive capacity building in clinical ethics for Sub-Saharan African countries like Gabon

Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP): study protocol for a randomised controlled trial

BACKGROUND: Some studies have suggested that transdermal administration of glyceryl trinitrate (GTN; nitroglycerin) in the first few hours after symptom onset increases the chance of a favourable outcome after ischaemic stroke or intracerebral haemorrhage, possibly through an increase in intracranial collateral blood flow and a reduction in blood pressure. The Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch (MR ASAP) aims to assess the effect of transdermal GTN, started within 3 h after stroke onset in the prehospital setting, on functional outcome at 90 days in patients with acute ischaemic stroke or intracerebral haemorrhage. METHODS: MR ASAP is a phase III, multicentre, randomised, open-label clinical trial with a blinded outcome assessment. A total of 1400 adult patients with suspected stroke and a systolic blood pressure ≥ 140 mmHg will be randomised to transdermal GTN (5 mg/day), administered as a transdermal patch by paramedics in the prehospital setting within 3 h of stroke onset and continued for 24 h or to standard care. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days, analysed with ordinal logistic regression. Secondary outcomes include blood pressure and collateral circulation at hospital admission, neurological deficit measured with the National Institutes of Health Stroke Scale at 24 h, and mortality and poor outcome (mRS score 3 to 6) at 90 days. This trial will be conducted in the Netherlands and will use a deferred consent procedure. The trial is part of the Collaboration for New Treatments of Acute Str

Prehospital Stroke Triage:A Modeling Study on the Impact of Triage Tools in Different Regions

Background and purpose: Direct transportation to a thrombectomy-capable intervention center is beneficial for patients with ischemic stroke due to large vessel occlusion (LVO), but can delay intravenous thrombolytics (IVT). The aim of this modeling study was to estimate the effect of prehospital triage strategies on treatment delays and overtriage in different regions. Methods: We used data from two prospective cohort studies in the Netherlands: the Leiden Prehospital Stroke Study and the PRESTO study. We included stroke code patients within 6 h from symptom onset. We modeled outcomes of Rapid Arterial oCclusion Evaluation (RACE) scale triage and triage with a personalized decision tool, using drip-and-ship as reference. Main outcomes were overtriage (stroke code patients incorrectly triaged to an intervention center), reduced delay to endovascular thrombectomy (EVT), and delay to IVT. Results: We included 1798 stroke code patients from four ambulance regions. Per region, overtriage ranged from 1-13% (RACE triage) and 3-15% (personalized tool). Reduction of delay to EVT varied by region between 24 ± 5 min (n = 6) to 78 ± 3 (n = 2), while IVT delay increased with 5 (n = 5) to 15 min (n = 21) for non-LVO patients. The personalized tool reduced delay to EVT for more patients (25 ± 4 min [n = 8] to 49 ± 13 [n = 5]), while delaying IVT with 3-14 min (8-24 patients). In region C, most EVT patients were treated faster (reduction of delay to EVT 31 ± 6 min (n = 35), with RACE triage and the personalized tool. Conclusions: In this modeling study, we showed that prehospital triage reduced time to EVT without disproportionate IVT delay, compared to a drip-and-ship strategy. The effect of triage strategies and the associated overtriage varied between regions. Implementation of prehospital triage should therefore be considered on a regional level.</p

Dexamethasone therapy versus surgery for chronic subdural haematoma (DECSA trial):study protocol for a randomised controlled trial

BACKGROUND: Chronic subdural haematoma (CSDH) is a common neurological disease with a rapidly rising incidence due to increasing age and widespread use of anticoagulants. Surgical intervention by burr-hole craniotomy (BHC) is the current standard practice for symptomatic patients, but associated with complications, a recurrence rate of up to 30% and increased mortality. Dexamethasone (DXM) therapy is, therefore, used as a non-surgical alternative but considered to achieve a lower success rate. Furthermore, the benefit of DXM therapy appears much more deliberate than the immediate relief from BHC. Lack of evidence and clinical equipoise among caregivers prompts the need for a head-to-head randomised controlled trial. The objective of this study is to compare the effect of primary DXM therapy versus primary BHC on functional outcome and cost-effectiveness in symptomatic patients with CSDH. METHODS/DESIGN: This study is a prospective, multicentre, randomised controlled trial (RCT). Consecutive patients with a CSDH with a Markwalder Grading Scale (MGS) grade 1 to 3 will be randomised to treatment with DXM or BHC. The DXM treatment scheme will be 16 mg DXM per day (8 mg twice daily, days 1 to 4) which is then halved every 3 days until a dosage of 0.5 mg a day on day 19 and stopped on day 20. If the treatment response is insufficient (i.e. persistent or progressive symptomatology due to insufficient haematoma resolution), additional surgery can be performed. The primary outcomes are the functional outcome by means of the modified Rankin Scale (mRS) score at 3 months and cost-effectiveness at 12 months. Secondary outcomes are quality of life at 3 and 12 months using the Short Form Health Survey (SF-36) and Quality of Life after Brain Injury Overall Scale (QOLIBRI), haematoma thickness after 2 weeks on follow-up computed tomography (CT), haematoma recurrence during the first 12 months, complications and drug-related adverse events, failure of therapy within 12 months after randomisation and requiring intervention, mortality during the first 3 and 12 months, duration of hospital stay and overall healthcare and productivity costs. To test non-inferiority of DXM therapy compared to BHC, 210 patients in each treatment arm are required (assumed adjusted common odds ratio DXM compared to BHC 1.15, limit for inferiority < 0.9). The aim is to include a total of 420 patients in 3 years with an enrolment rate of 60%. DISCUSSION: The present study should demonstrate whether treatment with DXM is as effective as BHC on functional outcome, at lower costs. TRIAL REGISTRATION: EUCTR 2015-001563-39 . Date of registration: 29 March 2015