1l=ml, 1/2l=ml, 1/4l=ml, 3/4l=ml. *grins* lg. toffifee21 26 loolö das is ma ausführlich danke danke danke. Der 3. Juli ist der Tag des gregorianischen Kalenders (der in Schaltjahren), somit bleiben noch Tage bis zum Jahresende. Säule), die das individuelle Sparen für die Altersvorsorge fördert. Einzahlen in die Säule 3a – Maximalbetrag pro Jahr; Bezug (Auszahlung) der 3. Säule.
Drug and placebo for the patients in the double-blind component of the start-up phase were supplied by Boehringer Ingelheim. JMW led the development of all of the imaging aspects of the study.
The study was designed by PS, RIL, and JMW, with input from all the other listed contributors who act as coordinators of the trial in their own country.
KI is the study coordinator. GC is the study statistician who prepared the analyses for this paper. PS drafted the Article and all authors commented on drafts and approved the final version.
Chief investigator for neuroradiology: Italy up to Sept, Maria Grazia Celani; Enrico Righetti. Italy after Sept, Silvia Cenciarelli; Tatiana Mazzoli.
Central follow-up for Italy: The list of participating hospitals in each country is in the appendix.
EB has received honoraria for lectures at meetings arranged by Boehringer Ingelheim, and reimbursement for costs for attending these meetings.
AC has received lecture fees and conference travel costs from Boehringer Ingelheim. AK has received lecture fees and conference travel costs from Boehringer Ingelheim.
RIL has received payment in his role as conference scientific committee member and for occasional lectures from Boehringer Ingelheim; has attended national stroke meetings organised and funded by Boehringer Ingelheim; and is not a member of any industry advisory boards.
The views expressed in this article are the personal views of KBS and should not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.
VM has received an unrestricted educational grant for a meeting on thrombolysis in stroke at which IST-3 was discussed.
These commercial sources contributed to the purchase of the scanner, but not the running costs or any individual studies. All other members of the writing committee declare that they have no conflicts of interest.
National Center for Biotechnology Information , U. Author information Copyright and License information Disclaimer. This document may be redistributed and reused, subject to certain conditions.
This article has been corrected. This article has been cited by other articles in PMC. Findings patients were enrolled by hospitals in 12 countries.
Interpretation For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome.
Introduction Each year, about 22 million people have a stroke world-wide, 1,2 of whom 4 million reside in high-income countries, 3,4 where thrombolytic therapy is affordable and feasible.
Methods Study design and patients IST-3 was a pragmatic 10 international, multicentre, randomised-controlled, open-treatment trial.
Procedures Clinicians entered baseline data via a telephone voice-activated or a secure web-based randomisation system. Table 1 Baseline characteristics.
Open in a separate window. One of these was recorded as having severe swelling on the randomisation scan, because the stroke had in fact occurred about 24 h earlier.
After patient , glucose levels were measured at randomisation. One further patient had a missing value. If we assume that those who die between 3 months and 6 months were dependent at 3 months, and those who do not die between 3 months and 6 months do not change their dependency status, then the risk estimates are likely to be quite accurate for death or dependency at 6 months.
This assessment was done by members of the expert panel after randomisation and masked to treatment allocation and all clinical details.
Prerandomisation scans were unavailable for eight patients in the rt-PA group and ten in the control group. Role of the funding source The sponsors of the study had no role in design, data collection, data analysis, data interpretation, or writing of the report.
Results Between May, , and July, , patients were enrolled in centres in 12 countries. Outcome at 6 months: Oxford Handicap Scale OHS by treatment group For the ordinal analysis, which was adjusted for age, National Institutes of Health Stroke Scale NIHSS , delay all linear , and and presence or absence of visible acute ischaemic change on baseline scan as judged by the expert reader, the statistical analysis plan prespecified that OHS levels 4, 5, and 6 were grouped and 0, 1, 2, 3 remained discrete.
Table 2 Estimated group difference for primary and secondary outcomes at 3 months, 8 months, and 12 months, based on intention-to-treat analysis.
Table 3 Fatal and non-fatal cerebral and non-cerebral events within 7 days of randomisation. This case has been omitted from the analysis.
When no events occurred in one treatment group the logistic model was not applied. The presence of some degree of haemorrhagic transformation was permitted, provided it was not identified by the expert CT reader to be a major contributor to the mass effect.
Significant haemorrhage was present on any postrandomisation scan if the expert reader both noted the presence of significant haemorrhagic transformation of the infarct or parenchymal haematoma and indicated that haemorrhage was a major component of the lesion or was remote from the lesion and likely to have contributed significantly to the burden of brain damage.
This event included clinical events described as a recurrent stroke within 7 days, in which the recurrent stroke was confirmed to be caused by an intracranial haemorrhage.
However, non-fatal non-cerebral events are not exclusive. A given patient could have one or more non-fatal non-cerebral events and a non-fatal cerebral event.
Total deaths from non-cerebral causes include deaths not attributed to myocardial infarction, extracranial bleed, or allergic reaction.
Discussion Although the increase in the number of patients treated with rt-PA who were alive and independent at 6 months was smaller than originally anticipated and was not significant, the secondary analysis provides supportive evidence of benefit.
Panel Research in context. Acknowledgments The IST-3 collaborative group thanks all the patients who participated in the study, and the many individuals not specifically mentioned in the paper who have supported the study.
IST-3 collaborative group The members of the collaborative group are listed in full in the appendix. Trial steering committee Independent chairmen: National coordinators and associate national coordinators Australia: National coordinating centres Italy up to Sept, Conflicts of interest EB has received honoraria for lectures at meetings arranged by Boehringer Ingelheim, and reimbursement for costs for attending these meetings.
Supplementary Material Supplementary appendix: Click here to view. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: Global and regional burden of disease and risk factors, Trends in incidence and outcome of stroke in Perth, Western Australia during to Thrombolysis for acute ischaemic stroke.
Cochrane Database Syst Rev. Sanossian N, Ovbiagele B. Prevention and management of stroke in very elderly patients.
Pragmatic trials—guides to better patient care? N Engl J Med. Third international stroke trial IST-3 of thrombolysis for acute ischaemic stroke.
Peto R, Baigent C. This file contains additional information such as Exif metadata which may have been added by the digital camera, scanner, or software program used to create or digitize it.
If the file has been modified from its original state, some details such as the timestamp may not fully reflect those of the original file.
The timestamp is only as accurate as the clock in the camera, and it may be completely wrong. From Wikimedia Commons, the free media repository.
Dies ist ein Scan des historischen Buches:. This is a scan of the historical document:. Der Scan wurde anhand einer original Buchvorlage vorgenommen.
The following page uses this file: Archived from the original on 9 May Retrieved 24 September Indian Railways Fan Club.
Archived from the original on 19 May Retrieved 25 November Department of Science and Technology. Archived from the original on 28 September National Resource Centre for Women.
Archived from the original on 19 March Archived from the original on 6 June Retrieved 22 September The Times of India.
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In , he suggested creating a separate time zone for the Development of Northeastern Region. Official time signals are generated by the Time and Frequency Standards Laboratory at the National Physical Laboratory in New Delhi, for both commercial and official use.
The signals are based on atomic clocks and are synchronised with the worldwide system of clocks that support the Coordinated Universal Time.
IST is taken as the standard time as it passes through almost the centre of India. To communicate the exact time to the people, the exact time is broadcast over the national All India Radio and Doordarshan television network.
Telephone companies have dedicated phone numbers connected to mirror time servers that also relay the precise time.
From Wikipedia, the free encyclopedia. Archived from the original on 9 May Retrieved 24 September Indian Railways Fan Club. Archived from the original on 19 May Retrieved 25 November For the types of patient recruited in IST-3, despite the early hazards, thrombolysis within 6 h improved functional outcome.
Benefit did not seem to be diminished in elderly patients. Each year, about 22 million people have a stroke world-wide, 1,2 of whom 4 million reside in high-income countries, 3,4 where thrombolytic therapy is affordable and feasible.
The burden of ischaemic stroke among the elderly is large and increasing; 2,5 and we estimate that annually ischaemic stroke affects about a million people older than 80 years of age in high-income countries and about 3 million in low-income and middle-income countries.
Thrombolytic therapy with intravenous recombinant tissue plasminogen activator rt-PA , when approved in Europe, was restricted to the treatment of patients younger than 80 years of age with acute ischaemic stroke who could be treated within 3 h.
IST-3 was a pragmatic 10 international, multicentre, randomised-controlled, open-treatment trial.
The initial pilot phase was double-blinded and placebo-controlled. At the end of the pilot phase, since the main phase compared treatment with open control, several additional measures were introduced to minimise bias in the assessment of early and late outcomes.
The eligibility criteria can be summarised in terms of the uncertainty principle. Additionally, if the patient had a clear indication for intravenous thrombolysis with rt-PA, they were to be treated in accordance with local guidelines.
Equally, if the patient had a clear contraindication to treatment they were not to be entered in the trial. Only if both the clinician and the patient or a relevant proxy for the patient felt that the treatment was promising but unproven, could the patient be included in the trial after appropriate informed consent from the patient or a valid proxy.
Clinicians entered baseline data via a telephone voice-activated or a secure web-based randomisation system. The system would not accept patients with blood pressure or glucose levels outside protocol-defined criteria appendix pp 4—5 or other data inconsistencies.
The system used a minimisation algorithm to achieve optimum balance for key prognostic factors table 1 , and from January, , minimisation was additionally stratified by world region and then minimised on all the other key factors within regions.
Percentages exclude missing values from denominators. To be eligible to join the trial, participating hospitals had to have an organised system of stroke care.
Acute-care protocols were not specified by the trial, but had to include the components of effective stroke-unit care, 19 including, soon after admission, intravenous access, monitoring of physiological variables, correction of any abnormalities, and where clinically appropriate, intravenous-fluid therapy.
All patients in the trial were to be treated within that organised system of stroke care, irrespective of treatment allocation.
Patients allocated to the control group were to avoid treatment with rt-PA and received stroke care in the same clinical environment as those allocated to the rt-PA group.
Both treatment groups had blood pressure monitored closely over the first 24 h. In the double-blinded phase, both groups were to avoid antiplatelet or anticoagulant therapy for 24 h.
In the open phase, patients allocated to the control group were to start aspirin immediately. Blood pressure was managed in the same way in both treatment groups, according to local protocol.
Additionally, all centres were asked for their pretrial experience of thrombolysis for treatment of stroke, and if the centre had, before joining the trial, a protocol for open-label use of rt-PA and had treated at least three people in the 12 months before joining the trial, the centre was classed as experienced.
A repeat brain scan was required if the patient deteriorated neurologically or intracranial haemorrhage was suspected for any reason.
All scans were sent to the trial centre in Edinburgh for masked central rating of any signs of visible early ischaemia presence and extent of hypo-attenuation, swelling, hyperattenuated artery , haemorrhage, and background brain changes leukoaraiosis, atrophy, prior stroke lesions, non-stroke lesions with validated rating methods.
All assessments were made masked to all patient details and treatment allocation. The statistical analysis plan specified an ordinal analysis of the OHS score at 6 months.
Additional secondary outcomes were to be reported separately. Events occurring within 7 days of stroke were recorded by the local trial clinician on the 7-day form: Other fatal and non-fatal non-cerebral events were also recorded and coded.
Data on potential reports of any of these events were extracted from the trial database and presented to the adjudication committee who were masked to treatment allocation.
Additional details of the procedures used in the double-blinded phase of the study are reported elsewhere. With the exception of the patients treated in the double-blinded phase of the trial, treatment was given openly and neither the patient nor the treating clinicians were masked.
Hospital staff completed an early outcome form at 7 days, death, or hospital discharge, whichever occured first, recording details of events occurring in hospital within 7 days, details of background treatments given and functional status.
If appropriate, the IST-3 trial office masked staff then mailed a postal questionnaire to patients to assess outcome. Non-responders were contacted by telephone, and follow-up data was obtained by telephone interview.
In Italy and Austria, all follow-ups were done as telephone interviews by a clinician, who was masked to treatment allocation and was highly experienced in outcome assessment.
In Portugal, patients were followed up in clinic by clinicians not involved in the patients' initial treatment, again, masked to treatment allocation as far as possible.
To assess the durability of any treatment benefit beyond 6 months, patients recruited in the UK and in other countries where appropriate funding had been obtained were also followed up at 18 months.
All follow-up done by patient contact for these analyses ceased on March 31, , but recording of deaths from national registries of deaths continues in UK, Norway, and Sweden.
However, it was clear by that obtaining a sample of was no longer feasible, and the Steering Committee agreed a revised recruitment target.
All IST-3 monitoring procedures were compliant with requirements of all study sponsors, the national ethics committees and regulatory agencies in the 12 participating countries, and they met all appropriate regulatory and Good Clinical Practice requirements.
All baseline data, 7-day, and 6-month outcome data were subject to verification checks built into the randomisation and data management system.
We monitored all baseline and postrandomisation imaging, which provided additional cross-checks on recruited patients and centre performance.
An expert radiologist checked all scans, masked to clinical details and treatment allocation, immediately on receipt at the trial office, for evidence of adverse events and protocol deviations.
The independent data monitoring committee met at least annually to review the unmasked data on major outcome events in the trial, on the background stroke-unit care received by trial patients to ensure it was equal in both treatment groups , relevant external data including updates of the Cochrane systematic review and reports from large-scale registries of rt-PA use in strict confidence throughout the course of the trial.
The committee judged these data never met the protocol-specified criteria to recommend modification of the protocol or halt recruitment to the study.
The statistical analysis plan was published 14 before unmasking of the authors to the data. All randomly assigned patients were included in the analysis.
Masked analysis of the patients' baseline characteristics showed clear differences in key prognostic factors age, stroke severity, degree of ischaemic change on baseline CT or MRI in patients randomly assigned at different times after stroke onset, which might complicate the estimation of the effect of treatment overall and in subgroups.
An unadjusted analysis is also presented. The statistical-analysis-plan writing committee, which did not have access to the accumulating data, was therefore expanded to include an independent statistician Gordon Murray, University of Edinburgh, Edinburgh, UK to advise on the correct approach.
The writing group was persuaded by the recent empirical evidence that the ordinal method was both statistically more efficient effectively reducing the sample size required in stroke trials 29 and robust against substantial deviations from the proportional assumption.
In this model the treatment odds ratios between one level and the next were assumed to be constant, so a single parameter summarises the shift in outcome distribution between treatment and control groups.
For patients known to be alive at 6 months, but with an unknown OHS, we used the level of function recorded on the 7-day form ie, measured at 7 days or before discharge from hospital to impute 6-month functional status.
Analyses were done with SAS version 9. The sponsors of the study had no role in design, data collection, data analysis, data interpretation, or writing of the report.
The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Between May, , and July, , patients were enrolled in centres in 12 countries.
Baseline characteristics were well balanced between treatment groups figure 1 , table 1. Additional baseline characteristics are shown in appendix pp 2—3.
Appendix pp 4—5 gives more detail of treatment actually received and background care. Appendix pp 2—3 documents deviations from the protocol and the background treatments that were given during the first 7 days.
Most patients were cared for in a stroke unit, and there was no evidence of a major imbalance in the use of background treatments or place of care admissions ward, or stroke unit over the first 7 days; an analysis of blood pressure in patients measured after randomisation showed no significant difference at each timepoint over the first 24 h in either systolic or diastolic blood pressures between the two treatment groups.
More patients died within 7 days in the rt-PA group than in the control group, but between 7 days and 6 months there were correspondingly fewer deaths in the rt-PA group.
For the ordinal analysis, which was adjusted for age, National Institutes of Health Stroke Scale NIHSS , delay all linear , and and presence or absence of visible acute ischaemic change on baseline scan as judged by the expert reader, the statistical analysis plan prespecified that OHS levels 4, 5, and 6 were grouped and 0, 1, 2, 3 remained discrete.
Estimated group difference for primary and secondary outcomes at 3 months, 8 months, and 12 months, based on intention-to-treat analysis.
Symptomatic intracranial haemorrhage and fatal or non-fatal deterioration due to swelling of the infarct within 7 days occurred in more patients in the rt-PA group than in the control group table 3.
To assess the effect of treatment on the primary outcome, the statistical analysis plan predefined a small subset of key prognostic subgroups figure 3.
The subgroup analyses are of the adjusted effects and take account of the fact that, for a specific prognostic factor, the distribution of other factors might differ between subcategories.
For example, in older patients the time to randomisation was shorter. The subgroup analyses for a specific factor provide estimated effects within sub-categories that adjust for such imbalances.
Dies ist ein Scan des historischen Buches: This is a scan of the historical document: Der Scan wurde anhand einer original Buchvorlage vorgenommen English:Recombinant tissue plasminogen activator for acute ischaemic stroke: At the end of the pilot phase, since the main phase compared treatment with open control, several additional measures were introduced to minimise bias in the assessment of early and late outcomes. The timestamp is only as accurate as the clock in the camera, and it may be completely wrong. Table 1 Baseline characteristics. Role of the funding source The sponsors of the study had no role in design, data collection, data analysis, data interpretation, or writing of the report. Discussion Although the increase in the number of patients treated with rt-PA who were 35 euro paysafecard and independent at 6 Beste Spielothek in Steinerfurth finden was smaller than originally anticipated and was not significant, the secondary analysis provides supportive evidence of benefit. This article has been cited by other articles in PMC. Total deaths from non-cerebral causes include deaths not attributed to myocardial fc bayern red bull leipzig, extracranial bleed, or allergic reaction. Slots ubersetzung tested for heterogeneity between the estimates of effect for key outcomes from two strata: Blood pressure was managed in the same way in both treatment groups, according to local protocol. This is a scan of the historical bvb atletico.