Value of treatment by comprehensive stroke services for the reduction of critical gaps in acute stroke care in Europe.

Stroke is the second leading cause of death and dependency in Europe and costs the European Union more than €30bn, yet significant gaps in the patient pathway remain and the cost-effectiveness of comprehensive stroke care to meet these needs is unknown. The European Brain Council Value of Treatment Initiative combined patient representatives, stroke experts, neurological societies and literature review to identify unmet needs in the patient pathway according to Rotterdam methodology. The cost-effectiveness of comprehensive stroke services was determined by a Markov model, using UK cost data as an exemplar and efficacy data for prevention of death and dependency from published systematic reviews and trials, expressing effectiveness as quality-adjusted life-years (QALYs). Model outcomes included total costs, total QALYs, incremental costs, incremental QALYs and the incremental cost-effectiveness ratio (ICER). Key unmet needs in the stroke patient pathway included inadequate treatment of atrial fibrillation (AF), access to neurorehabilitation and implementation of comprehensive stroke services. In the Markov model, full implementation of comprehensive stroke services was associated with a 9.8% absolute reduction in risk of death of dependency, at an intervention cost of £9566 versus £6640 for standard care, and long-term care costs of £35 169 per 5.1251 QALYS vs. £32 347.40 per 4.5853 QALYs, resulting in an ICER of £5227.89. Results were robust in one-way and probabilistic sensitivity analyses. Implementation of comprehensive stroke services is a cost-effective approach to meet unmet needs in the stroke patient pathway, to improve acute stroke care and support better treatment of AF and access to neurorehabilitation.

Blood pressure and hypertension in athletes: a systematic review.

OBJECTIVE: Hypertension is reported to be the most prevalent risk factor for cardiovascular disease in elite athletes. We aimed to review blood pressure (BP) and prevalence of hypertension in different elite athletes, and study whether there was an association between high BP and left ventricular hypertrophy (LVH). METHODS: A systematic review of studies reporting BP in athletes using search strategies developed for PubMed and EMBASE, including only studies with ≥100 participants. We collected data on BP, prevalence of hypertension, LVH and methods of BP measurement. RESULTS: Of 3723 records identified, 51 met the inclusion criteria. These included men and women (n=138,390), aged mostly between 18 and 40 years, from varied sports disciplines. Mean systolic BP varied from 109±11 to 138±7 mm Hg and mean diastolic BP from 57±12 to 92±10 mm Hg. Strength-trained athletes had higher BP than endurance-trained athletes (131.3±5.3/77.3±1.4 vs 118.6±2.8/71.8±1.2 mm Hg, p<0.05), and there was a trend towards a higher BP in athletes training ≥10 h compared with others (121.8±3.8/73.8±2.5 vs 117.6±3.3/66.8±6.9, p=0.058), but overall there was no significant difference in BP between athletes and controls. The prevalence of hypertension varied from 0% to 83%. Some studies showed an association between high BP and LVH. Measurement methods were poorly standardised. CONCLUSIONS: BP and prevalence of hypertension in athletes varied considerably partly because of variations in methodology, but type and intensity of training may contribute towards higher BP. High BP may be associated with LVH.

Uncertainties in short term prediction of atmospheric dispersion of radionuclides. A case study of a hypothetical accident in a nuclear floating power plant off the West coast of Norway.

Short-term predictions for dispersion of radionuclides in the atmosphere following releases from nuclear incidents are associated with uncertainties originating from meteorology, source term and parameterization. Characterization of these uncertainties is of key importance for preparedness, decision making during an accident and for the further uncertainty propagation in the subsequent modelling of human and ecosystem exposures. Increased traffic of nuclear-propulsion vessels in Norwegian territorial waters gives rise to growing concern of a potential nuclear accident along the coast of Norway. In the present study, we have quantified and inter-compared the uncertainties associated with the model outputs for a hypothetical loss of coolant accident with an ensuing fire in a nuclear vessel situated along the Norwegian coastline, applying two different atmospheric dispersion models: the SNAP Lagrangian particle model (SNAP-Severe Nuclear Accident Program) and the DIPCOT Lagrangian puff model (DIPCOT - Dispersion over Complex Terrain). The case highlights a situation with atmospheric transport from the offshore area to the coast of Western Norway, combined with large wet deposition in inland mountainous terrain, i.e. a common weather situation in this region. The meteorological data include an Ensemble Prediction System with nine ensemble members in addition to a deterministic base run. Five different 7 h emission scenarios with the same total released activity were considered. Hourly wind data at 10 m above ground for a 24 h period, showed that 36% of the wind direction and 41% of the wind speed data were outside the spread of the meteorological ensemble. About 55% and 13% of the measured values fell outside the ensemble for hourly 2 m above ground temperatures and 3 hourly accumulated precipitation, respectively, indicating that the ensemble did not cover all uncertainties in the meteorological fields. The maps of accumulated concentrations and depositions were qualitatively similar for the two models, but SNAP predicted higher accumulated concentration levels compared to DIPCOT for quite large areas, while DIPCOT yielded larger total depositions in the same areas. Furthermore, the direction, speed of movement and spatial extension of the radioactive plume from the accident varied considerably from one model to the other. The spread in the dispersion of the radionuclides ranged from a factor of about 1-3 in the source area to a factor of about 2-5 further away. The spreads due to meteorology and emission scenarios were of similar magnitude. Considering the ratio of the 50th percentiles of the two models, the spread varied by a factor of about 1-9, indicating that uncertainties arising from the formulation of the dispersion model could be as important or even larger than those associated with meteorology and emissions. Thus, it is recommended to include the uncertainty originating from the choice of the dispersion model into the overall uncertainty of short-term prediction of the dispersion of radionuclides and to exploit this further by generating an ensemble of several dispersion models.

European Stroke Organisation (ESO) standard operating procedure for the preparation and publishing of guidelines.

The first European Stroke Organization (ESO) standard operating procedure (SOP) published in 2015 aimed at the implementation the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to provide evidence-based guidelines for stroke management. This second ESO-SOP is aiming at further increase of the practicability of ESO guidelines and its technical implications. Authors comprised of the members of the ESO guideline Board and ESO Executive Committee. The final document was agreed on by several internal reviews. The second SOP comprises of the following aspects: rational for the SOP, the introduction of expert consensus statements, types of guideline documents, structures involved and detailed description of the guideline preparation process, handling of financial and intellectual conflicts of interest (CoI), involvement of ESO members in the guideline process, review process, authorship and publication policy, updating of guidelines, cooperation with other societies, and dealing with falsified data. This second SOP supersedes the first SOP published in 2015.

Novel exon 1 mutations in MECP2 implicate isoform MeCP2_e1 in classical Rett syndrome.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. Recently, a new MeCP2 isoform was described, MeCP2_e1, which skips exon 2 and has an alternative N-terminus, translated from exon 1, whereas MeCP2_e2 is translated from a start codon in exon 2. Since the incorporation of exon 1 into standard sequencing protocols for RTT, few exon 1 mutations have been described and are thus assumed to be only rare causes of RTT. Also, studies have suggested that the frameshift mutations identified in exon 1 affect both isoforms. Our aim in this study was to assess the frequency of mutations in exon 1, their relationship to phenotype, and the implications on the etiological role for the isoform MeCP2_e1 in RTT, versus the previously described isoform, MeCP2_e2. We sequenced MECP2 in 51 females with various clinical presentations, including developmental delay, autism, atypical and classical RTT, referred to our laboratories for testing. In patients with identified mutations, X-chromosome inactivation was analyzed. We identified four patients with exon 1 mutations; three were novel (c.1A > T; c.1A > G; c.5C > T), two of which affected the start codon, one a missense change, and one patient had a previously reported splice site mutation, c.62 + 1delGT. The four patients fit criteria for classical RTT, and thus these findings add support to previous reports that exon 1 mutations may be associated with a severe phenotype. Also, these findings add significant weight to the mounting evidence suggesting that the MeCP2_e1 isoform is the etiologically relevant form of the protein.

Thrombolytic treatment for stroke in the Scandinavian countries.

OBJECTIVE: We wanted to describe the use of thrombolytic treatment for stroke in Scandinavia, to assess stroke doctors' opinions on this treatment, to identify barriers against treatment, and to suggest improvements to overcome these barriers. METHODS: We sent questionnaires to 493 Scandinavian doctors, who were involved in acute stroke care. RESULTS: We received 453 (92%) completed questionnaires. Overall, 1.9% (range per hospital 0-13.9%) of patients received thrombolytic treatment. A majority (94%) of the respondents was convinced of the beneficial effects of thrombolytic treatment and many (85%) felt that its risks were acceptable. Main barriers were: unawareness of stroke symptoms among patients (82%) and their failure to respond adequately (54%); ambulance services not triaging acute stroke as urgent (23%); and insufficient in-hospital routines (15%). The respondents suggested that the following measures should be prioritized to increase the treatment's use: educational programmes to improve public awareness on stroke and how to respond (96%); education of in-hospital (88%) and prehospital (76%) medical staff. CONCLUSIONS: A large majority of Scandinavian doctors regard thrombolytic treatment for stroke as beneficial, yet its implementation in clinical practice has so far been poor. Our survey identified important barriers and potential measures that could increase its future use.

"Two per cent isn't a lot, but when it comes to death it seems quite a lot anyway": patients' perception of risk and willingness to accept risks associated with thrombolytic drug treatment for acute stroke.

BACKGROUND: Thrombolytic drugs to treat an acute ischaemic stroke reduce the risk of death or major disability. The treatment is, however, also associated with an increased risk of potentially fatal intracranial bleeding. This confronts the patient with the dilemma of whether or not to take a risk of a serious side effect in order to increase the likelihood of a favourable outcome. OBJECTIVE: To explore acute stroke patients' perception of risk and willingness to accept risks associated with thrombolytic drug treatment. DESIGN: Eleven patients who had been informed about thrombolytic drug treatment and had been through the process of deciding whether or not to participate in a thrombolytic drug trial went through repeated qualitative, semistructured interviews. RESULTS: Many patients showed a limited perception of the risks connected with thrombolytic drug treatment. Some perceived the risk as not relevant to them and were reluctant to accept that treatment could cause harm. Others seemed to be aware that treatment would mean exposure to risk. The patients' willingness to take a risk also varied substantially. Several statements revealed ambiguity and confusion about being involved in a decision about treatment. The patients' reasoning about risk was put into the context of their health-related experiences and life histories. Several patients wanted the doctor to be responsible for the decisions. CONCLUSION: Acute stroke patients' difficulties in perceiving and processing information about risk may reduce their ability to be involved in clinical decisions where risks are involved.

I don't like that, it's tricking people too much...: acute informed consent to participation in a trial of thrombolysis for stroke.

BACKGROUND: Informed consent is regarded as a contract between autonomous and equal parties and requires the elements of information disclosure, understanding, voluntariness and consent. The validity of informed consent for critically ill patients has been questioned. Little is known about how these patients experience the process of consent. OBJECTIVE: The aim of this study was to explore critically ill patients' experience with the principle of informed consent in a clinical trial and their ability to give valid informed consent. DESIGN: 11 stroke patients who had been informed about thrombolytic treatment and had been through the process of deciding whether or not to participate in a thrombolysis trial went through repeated qualitative semistructured interviews. RESULTS: None of the patients had any clear understanding of the purpose of the trial. Neither did they understand the principles of randomisation and voluntariness. Reasons for giving or not giving consent were trust, conceptions of benefits and risks and altruism. Several patients found it immoral to involve patients in the consent procedure and argued that this was the doctors' responsibility. Others argued that it is a duty to question patients and perceived it as a sign of being treated with respect and dignity. A majority of the patients found the consent process vague and ambiguous. CONCLUSIONS: The results indicate that the principle of informed consent from critically ill patients cannot be seen as a contract between equal and autonomous parties. Further studies are needed to explore critically ill patients' experiences with the process of informed consent.

A step-wise approach to find a valid and feasible method to detect non-adherence to tuberculosis drugs.

A step-wise approach to identify valid and feasible methods to detect non-adherence to tuberculosis drugs was evaluated in a prospective study among pulmonary tuberculosis patients in an outpatient clinic in Indonesia. First, adherence was measured by self-reporting with the standardized Morisky questionnaire, physician assessment, pill-count, visit attendance, diary and an electronic medication event monitoring system (MEMS). Next, validity of single methods was assessed against MEMS as gold standard. Feasibility of methods was then judged by physicians in the field. Finally, when valid and feasible methods were combined, it appeared that self-reporting by a questionnaire plus physician assessment could identify all non-adherent patients. It is recommended to use a systematic approach to develop a valid and locally feasible combination of methods to detect non-adherence to TB drugs.

Predictors of Poor Prognosis in Recurrent Hepatitis C After Liver Transplantation.

BACKGROUND: Hepatitis C is a common indication for liver transplantation (LT). Hepatitis C virus (HCV) recurrence is universal in viremic patients. This recurrence is frequently very aggressive, with graft loss in less than 5 years. Our aim is to detect which factors are related to worse fibrosis at 1 year post-LT. PATIENTS AND METHODS: Records of all HCV-positive transplanted patients in Hospital Universitario Nuestra Señora de la Candelaria from 1996 to 2014 were collected. The variables analyzed were donor and recipient age and gender, hypertension, diabetes, viral genotype, viral load at LT, hepatocellular carcinoma in the explant, anticoagulation or antiplatelet treatment, year of transplantation, and mean levels of tacrolimus in the first month. Severe recurrence was defined as fibrosis F3 by biopsy, liver stiffness > 9.5 kPa by transient elastography, or hepatic venous pressure gradient > 5 mm Hg at 1 year post-LT. Univariate and multivariate analyses were performed. RESULTS: From a sample of 112 patients, 88 patients met inclusion criteria. Mean recipient age was 52.8 ± 8.0 years and 70.5% were men. Mean donor age was 46.4 ± 16.1 years and 59.1% were men. Severe recurrence occurred in 23.9%. Univariate analyses showed 3 variables were statistically significant: donor age (P = .03), recipient age (P = .008), and presence of hepatocellular carcinoma (P = .01). Only the 2 first variables remained significant in the multivariate model (P = .009 and P = .044 respectively). Hepatocellular carcinoma was probably related to older recipients becoming a confounding factor. CONCLUSIONS: In our study, donor and recipient age both conferred a worse prognosis in terms of fibrosis progression in patients with liver transplant due to HCV.

ACPA-positive primary Sjögren's syndrome: true primary or rheumatoid arthritis-associated Sjögren's syndrome?

OBJECTIVES: Anticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5-10% of primary Sjögren's syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA. PATIENTS AND METHODS: ACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria. RESULTS: At inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5-10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA. CONCLUSIONS: Median term follow-up of ACPA-positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS.

Thrombolytic therapy with recombinant tissue plasminogen activator for acute ischemic stroke: where do we go from here? A cumulative meta-analysis.

BACKGROUND AND PURPOSE: Recombinant tissue plasminogen activator (rtPA; Actilyse) is not as widely used in clinical practice as it could be. Have new data since 1995 strengthened the evidence sufficiently to justify more widespread use of rtPA? METHODS: We performed a sequential year-to-year cumulative meta-analysis of randomized controlled trials of rtPA in acute ischemic stroke. RESULTS: Although the amount of data has doubled since 1995, effect estimates for key outcomes remain imprecise, and significant between-trial heterogeneity persists. In the most recent analysis, rtPA up to 6 hours after stroke yielded 55 fewer dead or dependent people per 1000 treated (95% CI, 18 to 92) despite some risk (nonsignificant excess of 19 deaths per 1000 patients treated; 95% CI, 6 fewer to 48 more). Severity of stroke, patient age, and aspirin use were possible sources of heterogeneity. CONCLUSIONS: Despite doubling of the data since 1995, the magnitude of risks and benefits with rtPA remains imprecise. This gap in knowledge may be hindering clinical use of rtPA and can be filled only by new trials designed to address these specific issues.

Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial.

BACKGROUND AND PURPOSE: We sought to investigate the apparently high risk of early death after an ischemic stroke among patients with atrial fibrillation (AF), identify the main factors associated with early death, and assess the effect of treatment with different doses of subcutaneous unfractionated heparin (UFH) given within 48 hours. METHODS: We studied the occurrence of major clinical events within 14 days among 18 451 patients from the International Stroke Trial, first for all treatment groups combined. Then, among patients with AF, we examined the effects of treatment with subcutaneous UFH started within 48 hours and continued until 14 days after stroke onset. RESULTS: A total of 3169 patients (17%) had AF. Seven hundred eighty-four patients were allocated to UFH 12 500 IU SC BID, 773 to UFH 5000 IU SC BID, and 1612 to no heparin. Within each of these groups, half of the patients were randomly assigned to aspirin 300 mg once daily. Compared with patients without AF, patients with AF were more likely to be female (56% versus 45%), to be old (mean age, 78 versus 71 years), to have an infarct on prerandomization CT (57% versus 47%), and to have impaired consciousness (37% versus 20%). The initial ischemic stroke type was more often a large-artery infarct (36% versus 21%). A lacunar stroke syndrome was less common (13% versus 26%). Death within 14 days was more common in patients with AF (17% versus 8%) and more often attributed to neurological damage from the initial stroke (10% versus 4%). The frequency of recurrent ischemic or undefined stroke was not significantly different (3.9% versus 3.3%). The proportion of AF patients with further events within 14 days allocated to UFH 12 500 IU (n=784), UFH 5000 IU (n=773), and to no-heparin (n=1612) groups were as follows: ischemic stroke, 2.3%, 3.4%, 4.9% (P=0.001); hemorrhagic stroke, 2.8%, 1.3%, 0.4% (P<0.0001); and any stroke or death, 18.8%, 19.4% and 20.7% (P=0.3), respectively. No effect of heparin on the proportion of patients dead or dependent at 6 months was apparent. CONCLUSIONS: Acute ischemic stroke patients with AF have a higher risk of early death, which can be explained by older age and larger infarcts but not by a higher risk of early recurrent ischemic stroke, although slightly more patients with AF died from a fatal recurrent stroke of ischemic or unknown type (1.3% versus 0.9%). In patients with AF the absolute risk of early recurrent stroke is low, and there is no net advantage to treatment with heparin. These data do not support the widespread use of intensive heparin regimens in the acute phase of ischemic stroke associated with AF.

Hemostatic activation in acute ischemic stroke.

BACKGROUND AND PURPOSE: The purpose of this study was to examine the association between hemostatic activation and stroke severity, and to provide data on hemostatic variables in acute ischemic stroke. METHODS: The patient material comprised 76 consecutive patients with acute ischemic stroke (median 16 h, interquartile range 3-48). Levels of hemostatic variables were determined in blood samples collected on the day of hospitalization. Stroke severity was assessed on admission by the Oxfordshire Community Stroke Project (OCSP) classification, and on discharge (median 9 days, interquartile range 6-14) by Barthel Index (BI, scores 0-50, 55-90, or 95-100) and modified Rankin Scale (mRS, scores 0-1 or 2-6). Associations were assessed by multiple linear regression analyses. RESULTS: Levels of the fibrin degradation product D-Dimer and the activation peptide prothrombin fragment 1 + 2 (F1 + 2) were linearly related to stroke severity, whether assessed on admission (P = .001 and.03, respectively, for the OCSP classification), or on discharge (P = .009 and.43, respectively, for BI; and.001 and.05, respectively, for mRS). High levels of D-Dimer and F(1 + 2), as well as low levels of antithrombin and protein C were also present in patients with a presumed embolic source, and low antithrombin or protein C was borderline significantly associated with atrial fibrillation (P = .072 and.058, respectively). Low levels of protein C or protein S, and the presence of antiphospholipid antibodies, including lupus anticoagulant (LA), was detected in 13/73 (18%) and 15/70 (21%) of the patients, respectively. CONCLUSION: Activation of the hemostatic system is independently related to acute stroke severity and short-term outcome. Low levels of coagulation inhibitors or presence of antiphospholipid antibodies is a relatively frequent finding in unselected patients with acute ischemic stroke, but a causative role cannot be inferred from our study.

Anticoagulants versus antiplatelet agents for acute ischaemic stroke.

BACKGROUND: Antiplatelet agents produce a small, but worthwhile benefit in long-term functional outcome and survival, and have become standard treatment for acute ischaemic stroke. Anticoagulants are often used as an alternative treatment, despite evidence that they are ineffective in producing long-term benefits. We wanted to review trials which have directly compared anticoagulants and antiplatelet agents, to assess whether any anticoagulant regimen offers net advantages over antiplatelet agents, overall or in some particular category of patients (e.g. patients with atrial fibrillation). OBJECTIVES: a) To assess the effectiveness of anticoagulants compared with antiplatelet agents in acute ischaemic stroke b) To assess whether the addition of anticoagulants to antiplatelet agents offers any net advantage over antiplatelet agents alone. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register, the Cochrane Controlled Trials Register (Central/CCTR), the trials register held by the Antithrombotic Therapy Trialists' Collaboration, MEDLINE (1966-2000), and EMBASE (1980-2000). All searches were performed during April and May 2001. SELECTION CRITERIA: Truly unconfounded, randomised-controlled trials comparing anticoagulants with antiplatelet agents, or anticoagulants and antiplatelet agents with antiplatelet agents alone, given within 14 days of onset of presumed or confirmed ischaemic stroke. DATA COLLECTION AND ANALYSIS: Both reviewers independently selected trials for inclusion in the review, assessed trial quality and extracted data. MAIN RESULTS: A total of 16,558 patients from four trials contributed to the analyses. The methodological quality was high in all four trials. The anticoagulants tested were unfractionated heparin (UFH) and low molecular-weight heparin. Aspirin was used as control in all trials. Overall, there was no evidence that anticoagulants were superior to aspirin in reducing 'death or dependency' at long-term follow-up (odds ratio [OR] 1.07, 95% confidence interval [95% CI] 0.98-1.15). Compared with aspirin, anticoagulants were associated with a small but significant increase in the number of deaths at the end of follow-up (OR 1.10, 95% CI 1.01-1.29), equivalent to 20 more deaths (95% CI 0-30) per 1000 patients treated; a significant increased risk of symptomatic intracranial haemorrhage (OR 2.35, 95% CI 1.49-3.46); and a non-significant increased risk of 'any recurrent stroke' during treatment (OR 1.20, 95% CI 0.99-1.46). These neutral or adverse effects outweighed a small, but significant effect on symptomatic deep vein thrombosis (OR 1.20, 95% CI 0.07-0.58), equivalent to 10 fewer (95% CI 0-30) DVTs by 14 days per 1000 patients treated with anticoagulants instead of aspirin. Subgroup analysis could not identify any type, dose, or route of administration of anticoagulants associated with net benefit, or any benefit in patients with atrial fibrillation. Overall, the combination of UFH and aspirin did not appear to be associated with a net advantage over aspirin alone. A subgroup analysis showed that, compared with aspirin, the combination of low-dose UFH and aspirin was associated with a marginally significant reduced risk of 'any recurrent stroke' (OR 0.75, 95% CI 0.56-1.03) and a marginally significant reduced risk of death at 14 days (OR 0.84, 95% CI 0.69-1.01), and with no clear adverse effect on death at end of follow-up (OR 0.98, 95% CI 0.85-1.12). REVIEWER'S CONCLUSIONS: Anticoagulants offered no net advantages over antiplatelet agents in acute ischaemic stroke. The combination of low-dose UFH and aspirin appeared in a subgroup analysis to be associated with net benefits compared with aspirin alone, and this merits further research.

Thrombolysis for acute ischaemic stroke.

BACKGROUND: The majority of strokes are due to blockage of an artery in the brain by a blood clot. Prompt treatment with thrombolytic drugs can restore blood flow before major brain damage has occurred. Successful treatment could mean that the patient is more likely to make a good recovery from their stroke. Thrombolytic drugs however, can also cause serious bleeding in the brain which can be fatal. Thrombolytic therapy has now been evaluated in several randomised trials in acute ischaemic stroke. OBJECTIVES: The objective of this review was to assess the safety and efficacy of thrombolytic agents in patients with acute ischaemic stroke. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched January 2003), MEDLINE (1966- January 2003) and EMBASE (1980-January 2003). In addition we contacted researchers and pharmaceutical companies, attended relevant conferences and handsearched four Japanese journals. SELECTION CRITERIA: Randomised trials of any thrombolytic agent compared with control in patients with definite ischaemic stroke. DATA COLLECTION AND ANALYSIS: One reviewer applied the inclusion criteria and extracted the data. Trial quality was assessed. The extracted data were verified by the principal investigators of all major trials. Thus published and unpublished data were obtained where available. MAIN RESULTS: Eighteen trials including 5727 patients were included, but not all trials contributed data to each outcome examined in this review. Sixteen trials were double-blind. The trials tested urokinase, streptokinase, recombinant tissue plasminogen activator or recombinant pro-urokinase. Two trials used intra-arterial administration but the rest used the intravenous route. About 50% of the data (patients and trials) come from trials testing intravenous tissue plasminogen activator. There are few data from patients aged over 80 years. Much of the data comes from trials conducted in the first half of the 1990s when, in an effort to reduce delays to trial drug administration, on site randomisation methods were used that, in consequence, limited the ability to stratify randomisation on key prognostic variables. Several trials, because of the biological effects of thrombolysis combined with the follow-up methods used, did not have complete blinding of outcome assessment. Thrombolytic therapy, administered up to six hours after ischaemic stroke, significantly reduced the proportion of patients who were dead or dependent (modified Rankin 3 to 6) at the end of follow-up at three to six months (OR 0.84, 95% CI 0.75 to 0.95). This was in spite of a significant increase in : the odds of death within the first ten days (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.46 to 2.24), the main cause of which was fatal intracranial haemorrhage (OR 4.34, 95% CI 3.14 to 5.99). Symptomatic intracranial haemorrhage was increased following thrombolysis (OR 3.37, 95% CI 2.68 to 4.22). Thrombolytic therapy also increased the odds of death at the end of follow-up at three to six months (OR 1.33, 95% CI 1.15 to 1.53). For patients treated within three hours of stroke, thrombolytic therapy appeared more effective in reducing death or dependency (OR 0.66, 95% CI 0.53 to 0.83) with no statistically significant adverse effect on death (OR 1.13, 95% CI 0.86 to 1.48). There was heterogeneity between the trials that could have been due to many trial features including : thrombolytic drug used, variation in the use of aspirin and heparin, severity of the stroke (both between trials and between treatment groups within trials), and time to treatment. Trials testing intravenous recombinant tissue plasminogen activator suggested that it may be associated with slightly less hazard and more benefit than other drugs when given up to six hours after stroke but these are non-random comparisons - death within the first ten days OR 1.24, 95% CI 0.85 to 1.81, death at the end of follow-up OR 1.17, 95% CI 0.95 to 1.45, dead or dependent at the end of follow-up OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly comparedup OR 0.80, 95% CI 0.69 to 0.93. However, no trial has directly compared rt-PA with any other thrombolytic agent. There is some evidence that antithrombotic drugs given soon after thrombolysis may increase the risk of death. REVIEWER'S CONCLUSIONS: Overall, thrombolytic therapy appears to result in a significant net reduction in the proportion of patients dead or dependent in activities of daily living. However, this appears to be net of an increase in deaths within the first seven to ten days, symptomatic intracranial haemorrhage, and deaths at follow-up at three to six months. The data from trials using intravenous recombinant tissue plasminogen activator, from which there are the most evidence on thrombolytic therapy so far, suggest that it may be associated with less hazard and more benefit. There was heterogeneity between the trials for some outcomes and the optimum criteria to identify the patients most likely to benefit and least likely to be harmed, the latest time window, the agent, dose, and route of administration, are not clear. The data are promising and may justify the use of thrombolytic therapy with intravenous recombinant tissue plasminogen activator in experienced centres in highly selected patients where a licence exists. However, the data do not support the widespread use of thrombolytic therapy in routine clinical practice at this time, but suggest that further trials are needed to identify which patients are most likely to benefit from treatment and the environment in which it may best be given. To avoid the problem of data missing from some trials for some key outcomes encountered in this review to date, and to assist future metaanalyses, future trialists should try to collect data in such a way as to be compatible with the basic outcome assessments reviewed here (eg early death, fatal intracranial haemorrhage, poor functional outcome).

Surgical decompression for cerebral oedema in acute ischaemic stroke.

BACKGROUND: The high mortality that follows a large cerebral infarction is in part due to brain oedema. Oedema causes mass-effect with raised intracranial pressure and herniation. Medical therapies are used to reduce intracranial pressure but outcome is poor in spite of treatment. Decompressive surgical techniques that attempt to relieve high intracranial pressure due to oedema have been described, but their efficacy in reducing case fatality and disability is uncertain. OBJECTIVES: To compare medical therapy plus decompressive surgery with medical therapy alone on the outcomes death and 'death or dependency' in patients with an acute ischaemic stroke complicated by clinical and radiologically confirmed cerebral oedema. SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (4 October 2001). In addition, we searched the following electronic databases: the Cochrane Controlled Trials Register (Cochrane Library, issue 3, 2001), MEDLINE (1966 - April 2002), EMBASE (1980 - April 2002), and SCISEARCH (to April 2002). We also searched the reference lists of all relevant articles retrieved and contacted individual investigators and experts in the field. SELECTION CRITERIA: Randomised controlled studies comparing the outcome of treatment with decompressive surgical intervention with treatment not involving surgery. We aimed to include only those studies with low or moderate risk of bias. DATA COLLECTION AND ANALYSIS: Titles retrieved by searching were assessed for relevance by one author. Data were extracted independently by two authors with discussion to resolve differences. Relevant sub-group analyses were planned and we planned to calculate Peto odds ratios with 95% confidence intervals. MAIN RESULTS: Over 9000 citations were retrieved and inspected for relevance. We identified no randomised-controlled trials to include in a meta-analysis. Five observational studies reporting comparative data were found along with a number of small series and single case reports. Two ongoing randomised-controlled trials were identified. REVIEWER'S CONCLUSIONS: There is no evidence from randomised-controlled trials to support the use of decompressive surgery for the treatment of cerebral oedema in acute ischaemic stroke. Evidence from randomised-controlled trials is needed to accurately assess the effect of decompressive surgery.

The therapeutic approach to intrathoracic metastases of non-seminomatous testicular tumour.

Before the era of chemotherapy an extensively metastasized non-seminomatous testicular tumour was nearly always fatal. Only 10 cases of spontaneous regression of thoracic metastasis have been reported. With chemotherapy, a much better outlook has been achieved, however, in 10% of the cases, chemotherapy resistant thoracic masses remain after treatment. In 70 to 80% of those cases with normal tumour markers, mature teratoma is found. In this paper, three patients with non-seminomatous testicular tumour and thoracic opacities resistant to conservative treatment are reported. One patient showed a complete disappearance of 9 out of 10 thoracic opacities 6 months after a short chemotherapy course, which had seemed to be ineffective. After a short period of reduction, the remaining opacity demonstrated continued tumour growth with a significantly longer tumour doubling time. The other two patients showed enlarged thoracic opacities despite combination chemotherapy and normal tumour marker levels. At the time of thoracotomy and complete surgical resection of the tumours all patients had normal tumour marker levels. Mature teratoma without genuine malignant cells was found microscopically. At this time all patients are free of metastases, 18, 3.5 and 2 year post thoracotomy. We suggest complete extirpation of the chemotherapy resistant lesions because, mature teratoma may give rise to compression and because in the cases with notwithstanding normalization of tumour markers and active tumour histology has to be obtained to restart combination chemotherapy.

[French validation of a disability rating scale for the evaluation of low back pain (EIFEL questionnaire)]. / Validation française d'une échelle d'incapacité fonctionnelle pour l'évaluation des lombalgies (EIFEL).

Functional disability is one of the main components of low back pain (LBP)-associated morbidity and should be taken into account in the evaluation and care of patients. This article describes the French-language adaptation and validation of the Roland and Morris Disability Questionnaire. This self-administered questionnaire proved rapid, simple to use, reliable, valid, and sensitive to changes in clinical status, suggesting that its widespread use may be possible in settings ranging from epidemiological or clinical research to individual LBP patient evaluation in daily clinical practice.

Cochrane Stroke Group: twenty years of evidence-based stroke medicine.

The Cochrane Stroke Group was one of the first specialist review groups set up within The Cochrane Collaboration and has been in existence for 20 years. Its key outputs include a number of high profile reviews in the area of the management of stroke, which have become one of the most important sources of information for clinical practice guidelines. The work of the group is only possible through a collaborative network of staff, editors, and authors.