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Inhabitants of the northeastern states have to advance their clocks with the early sunrise and avoid the extra consumption of energy after daylight hours.

In the late s, a team of researchers proposed separating the country into two or three time zones to conserve energy.

The binary system that they suggested involved a return to British—era time zones; the recommendations were not adopted. In , the government established a four—member committee under the Ministry of Science and Technology to examine the need for multiple time zones and daylight saving.

Though the government has consistently refused to split the country into multiple time zones, provisions in labour laws such as the Plantations Labour Act, allow the Central and State governments to define and set the local time for a particular industrial area.

The filmmaker Jahnu Barua has been campaigning for a separate time zone daylight saving time for the past 25 years. 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 At 6 months, vital status was known for most patients and there was no evidence of any difference in the number of deaths, despite the excess of deaths within 7 days of stroke mainly due to intracranial haemorrhage.

Since mortality at 6 months was equal in the two groups, and in view of the evidence that the lower the patients' degree of disability at 6 months, the greater their subsequent survival, 31 long-term follow-up beyond 6 months is important.

Follow-up for survival, therefore, continues in the UK, Norway, and Sweden to assess whether an overall survival advantage from rt-PA after 6 months emerges.

Since we sought to recruit older patients and patients who did not strictly meet prevailing licence criteria for thrombolytic therapy with rt-PA, we anticipated a higher risk of adverse events, chiefly symptomatic intracranial haemorrhage.

Reassuringly, despite the different event rates in the control group, for most of the outcomes, there was no clear evidence that the effects of treatment were qualitatively different in IST-3 to those seen in earlier randomised trials, with two exceptions.

We identified significant trends towards larger effects of treatment in patients with more severe strokes.

We also anticipated a reduction in fatal and non-fatal neurological deterioration due to swelling of the initial infarct, 6 so the clear 17 per excess was unexpected, and inconsistent with data from previous trials.

As proposed by Kent and colleagues, 33 we reported the effect of treatment on the primary outcome in several prespecified subgroups and included the effects sub-divided by the result of a prognostic score.

Benefit with treatment was greatest within 3 h, but the analyses did not have sufficient power to define the shape of the relation between benefit and time beyond 3 h.

The effect of treatment in patients older than 80 years of age was at least as large as in patients younger than 80 years of age. A formal test for trend showed a significant difference for greater benefit of rt-PA in patients with increasingly severe strokes.

However, in view of the overall non-significant benefit for the primary outcome, the significant interactions across subgroups in these analyses should be interpreted with caution.

As specified in the statistical analysis plan, we planned additional secondary analyses to explore these apparent effects on the primary outcome and on other outcomes, such as symptomatic intracranial haemorrhage and to decide if these effects were due to chance.

Lyden 34 has identified limitations in these data, chiefly that IST-3 recruited only half the number of patients originally intended and so was underpowered for the primary outcome and more so for the subgroup analyses.

The many changes in the regulatory environment over the course of the trial delayed the approval of the trial in many centres and precluded the participation of several countries and hence was a significant factor in our failing to achieve our original target.

To update the published systematic review of randomised-controlled trials of recombinant tissue plasminogen activator rt-PA in patients with acute ischaemic stroke and incorporate the third International Stroke Trial IST-3 results, 6 we searched for additional randomised trials of intravenous rt-PA versus control within 6 h of onset of acute ischaemic stroke up to March 30, , in the Cochrane Stroke Trials Registry November, , Internet Stroke Trials Centre March, , Medline and Embase search strategy available on request , and references lists in review articles and conference abstracts.

The primary analysis was for all patients treated up to 6 h after stroke. Data were available for patients in 12 trials.

We tested for heterogeneity between the estimates of effect for key outcomes from two strata: The review established that the effects of treatment reported in IST-3—in this wider range of patients generally outside the current approvals —were consistent with those seen in previous trials.

By providing estimates on the benefits and harms of treating patients with acute ischaemic stroke outside the current approvals, IST-3 enables clinicians to consider thrombolytic treatment for a wider range of patients, especially those older than 80 years of age.

The data reinforce the need for further efforts to increase the proportion of all ischaemic strokes treated within 3 h. The additional data from IST-3 give greater confidence that mortality is not increased by treatment.

The absence of masking is most relevant for the assessment of the events within 7 days. However, every possible precaution was taken to ensure masking of the expert panel assessing the scans, and the adjudication committee, who also assessed clinical data on all potential cerebral events.

The proportional effect of treatment on fatal and non-fatal events within 7 days was very similar, which perhaps suggest that masking of the assessors was successful.

The self-assessment at 6 months by patients or their carer by postal questionnaire or masked telephone interview was unmasked and so could be subject to reporting bias.

The subgroup analysis subdivided by trial phase provides some reassurance in that no significant difference was seen in the effect of treatment on the primary outcome in the double-blind phase and the open phase figure 3.

The measurement of outcome with OHS at 6 months is different from previous trials that measured the modified Rankin score at 3 months.

Both are derivatives of the original Rankin scale, developed by members of our group. While the proportion of patients recorded as dependent might be slightly different with each scale, the choice of outcome scale would not bias the assessment of treatment effect between treatment and control groups.

The outcome was recorded at 6 months and 18 months, to assess the effects on survival free of disability after a few months and also in the long term the longer the benefit persists, the greater the cost-effectiveness.

The longer time to follow-up allowed any differential effect of rt-PA on early and late death to become clearer. Outcome other than survival was not recorded at 3 months, although the proportional effects on death and disability seen at 6 months in IST-3 are comparable with those seen at 3 months in previous trials.

Lyden also comments that the sampling approach to monitoring in IST-3 was less intense than in many commercial studies, and is a potential concern, but also states: When the results of IST-3 are incorporated into an updated systematic review, 35 the estimates of relative treatment effect are broadly compatible with the previous rt-PA trials for each of the main outcomes: Our trial was underpowered to reliably detect important subgroup effects, and so a collaborative individual patient data meta-analysis the Stroke Thrombolysis Trialists Collaboration [STTC] has been established, which will include data from all the completed intravenous rt-PA trials and will update the previous pooled analysis.

For the types of patient recruited in IST-3 about three quarters of whom were randomised after 3 h, and half of all patients were older than 80 years of age , by 6 months there was evidence that rt-PA improved functional outcome.

The data add weight to the policy of treating patients as soon as possible, and also justify extending treatment to patients older than 80 years of age.

The data do not support any restriction of treatment on the basis of stroke severity or the presence of early ischaemic change on the baseline brain scan.

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 is an investigator led trial. The start-up phase was supported by a grant from the Stroke Association, UK. The main phase of the trial is funded by the following organisations: 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.

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