human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke . The drug has shown some evidence of efficacy in a pooled analysis . We sought to confirm the efficacy of citicoline in a larger trial . METHODS We undertook a r and omised , placebo-controlled , sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany , Portugal , and Spain . Using a central ised minimisation process , patients were r and omly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms ( 1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [ 2 × 500 mg oral tablets given every 12 h ] ) . All study participants were masked . The primary outcome was recovery at 90 days measured by a global test combining three measures of success : National Institutes of Health Stroke Scale ≤1 , modified Rankin score ≤1 , and Barthel Index ≥95 . Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator , neurological deterioration , and mortality . This trial is registered , NCT00331890 . RESULTS 2298 patients were enrolled into the study from Nov 26 , 2006 , to Oct 27 , 2011 . 37 centres in Spain , 11 in Portugal , and 11 in Germany recruited patients . Of the 2298 patients who gave informed consent and underwent r and omisation , 1148 were assigned to citicoline and 1150 to placebo . The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients . The final r and omised analysis was based on data for 2298 patients : 1148 in citicoline group and 1150 in  placebo group . Global recovery was similar in both groups ( odds ratio 1·03 , 95 % CI 0·86 - 1·25 ; p=0·364 ) . No significant differences were reported in the safety variables nor in the rate of adverse events . INTERPRETATION Under the circumstances of the ICTUS trial , citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke . FUNDING Ferrer Grupo The purpose of this study was to evaluate the effects of magnesium sulfate on maternal and fetal blood flow in pregnancy‐induced hypertension . Twelve patients with pregnancy‐induced hypertension were prospect ively studied with transcranial pulsed Doppler and transabdominal color flow Doppler before and after infusion of a 6 gram intravenous loading dose of magnesium sulfate . The maternal vessels studied included the middle cerebral , common carotid , and internal carotid arteries . The fetal vessels studied included the middle cerebral , renal , and umbilical arteries . In addition the maternal circulation in the placental base plate was imaged . The results of this descriptive study suggest that a 6 gram loading dose of magnesium sulfate  significantly vasodilates the vascular bed distal to the maternal middle cerebral artery , and increases blood velocity in this distribution . There was no significant change in pulsatility index or blood velocity in the central large vessels of the head and neck . There were no acute effects noted in the fetal or placental vessels evaluated Background and Purpose — The goal of the Stroke Treatment Academic Industry Roundtable ( STAIR ) meetings is to advance the development of acute and restorative stroke therapies . Summary of Review — At the STAIR VII recommendations for strategies to maximize the use of intravenous thrombolytics through targeting public education , and the refinement of current treatment exclusion criteria were proposed . Increased utilization of mechanical devices for intra-arterial recanalization can be achieved by obtaining more definitive evidence of efficacy in r and omized clinical trials , identification of patient characteristics associated with treatment efficacy , optimization of technical approaches , clarification of effective time windows , and development of approaches to limit complications . Neuroprotective strategies remain viable ; recommendations for further study of these agents include an emphasis on rapid administration , consideration of the systemic effects of ischemic stroke , prevention of complications associated with early reperfusion , a focus on agents with multiple mechanisms of action , and consideration of possible interactions between neuroprotective and thrombolytic therapies . Conclusions — Extending intravenous thrombolysis to a broader patient population , clarifying the risk and benefits of intra-arterial reperfusion therapies , and further development of neuroprotective therapies were the key recommendations from STAIR VII BACKGROUND AND PURPOSE Parenterally administered MgSO4 is neuroprotective in st and ard animal models of focal cerebral ischemia and in many other paradigms of brain injury . Previous small clinical trials in stroke patients have explored the safety and tolerability of different infusion regimens . This study was undertaken to optimize the regimen for a multicenter trial . METHODS Within 24 hours of the onset of clinical ly diagnosed stroke , patients were r and omized to receive placebo or one of three intravenous MgSO4 infusions : a loading infusion of 8 , 12 , or 16 mmol , followed by 65 mmol over 24 hours . Cardiovascular parameters , serum magnesium concentrations , and blood glucose concentrations were determined . Outcome at 30 and 90 days was recorded . RESULTS Twenty-five patients were recruited and treated at a mean time of 20 hours after stroke . No tolerability problems were identified . No effects of magnesium on heart rate , blood pressure , or blood glucose were evident . Serum magnesium concentrations rose to target levels most rapidly in the highest loading infusion group and were maintained in all groups for at least 24 hours . CONCLUSIONS MgSO4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke . The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more A r and omized , placebo-controlled , double-blind study was performed as a pilot study to examine the benefit of the administration of magnesium sulfate given intravenously as a protective substance during the first 24 hours following a stroke . Patients who had cortical infa rct ion in the middle cerebral artery territory with moderate to severe neurologic deficits lasting for more than 15 minutes with onset less than 24 hours were included . The patients were treated with magnesium sulfate or placebo for 5 days and examined by a blinded investigator . Patients had follow-up for 30 days . The primary efficacy variable was the proportion of patients reaching mild to moderate neurologic deficit on the Orgogozo scale ( 80 points ) and relative functional independence on the Barthel index ( 60 points ) . Orgogozo scale and Mathew scale values were obtained on admission and days 2 , 4 , 8 , and 30 after stroke . Barthel activities of daily living index and Rankin disability score were obtained on day 30 . Forty-one patients ( 22 given treatment and 19 given placebo )  demonstrated significant beneficial effects on the Orgogozo scale ( 84 ± 11 vs. 64 ± 10 , p < 0.0001 ) and ( 83 ± 14 vs. 70 ± 15 , p < 0.009 ) , respectively . At the end of 1-month follow-up , the Barthel ADL index was nonsignificantly higher and the Rankin disability score was marginally significantly lower in the magnesium-treated group ( 84 ± 26 vs. 71.8 ± 26 , p < 0.143 ) than in control subjects ( 2.3 ± 1.1 vs. 3 ± 1.3 , p < 0.077 ) . Intravenous magnesium sulfate had significant positive effect on the outcome in patients with acute stroke . Further studies on a larger scale are needed to confirm these findings Background and Purpose — In the Interventional Management of Stroke ( IMS ) III trial , we sought to demonstrate evidence of a differential treatment effect of endovascular treatment of acute ischemic stroke compared with intravenous tissue-type plasminogen activator , according to baseline collateral status measured using computed tomographic angiography . Methods — Of 656 patients enrolled in Interventional Management of Stroke III trial , 306 had baseline computed tomographic angiography .  Of these , 185 patients had M1 middle cerebral artery ± intracranial internal carotid artery occlusion , where baseline collateral status could be measured . Collateral status was assessed by consensus using 3 different ordinal scales and categorized as good , intermediate , and poor . Multivariable modeling was used to assess the effect of collateral status and treatment type on clinical outcome by modified Rankin Scale ( mRS 0–2 , mRS 0–1 , and the ordinal mRS ) . Results — Of 185 patients , 126 r and omized to endovascular therapy ( 87.6 % recanalized , 41.3 % 90-day mRS 0–2 ) and 59 to intravenous tissue-type plasminogen activator only ( 60.5 % recanalized , 30.5 % 90-day mRS 0–2 ) . In multivariable modeling , collateral status was a significant predictor of all clinical outcomes ( P<0.05 ) . Maximal benefit with endovascular treatment across all clinical outcomes was seen in patients with intermediate collaterals , some benefit in patients with good collaterals , and none in patients with poor collaterals , although small sample size limited the power of the analysis to show a statistically significant interaction between collateral status and treatment type ( P>0.05 ) . Conclusion — Using data from a large r and omized controlled trial ( IMS III ) , we show that baseline computed tomographic angiography collaterals are a robust determinant of final clinical outcome and could be used to select patients for endovascular therapy . Clinical Trial Registration — URL : http://www . clinical trials.gov/ct2/show/. Unique identifier : 0020NCT00359424 Background The National Institute of Neurological Disorders and Stroke ( NINDS ) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset . At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale ( NIHSS ) . The authors performed further analyses to characterize the relationship of  onset-to-treatment time ( OTT ) to outcome at 3 months , early improvement at 24 hours , and intracranial hemorrhage within 36 hours . Methods Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT – treatment interaction . Tests for OTT – treatment interactions adjusting for potential masking confounders were performed . An OTT – treatment interaction was considered significant if p ≤ 0.10 , implying that treatment effectiveness was related to OTT . Results For 24-hour improvement , there were no masking confounders identified and there was an OTT – treatment interaction ( p = 0.08 ) . For 3-month favorable outcome , the NIHSS met criteria for a masking confounder . After adjusting for NIHSS as a covariate , an OTT – treatment interaction was detected ( p = 0.09 ) : the adjusted OR ( 95 % CI ) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator ( rt-PA ) was 2.11 ( 1.33 to 3.35 ) in the 0 to 90 minute stratum and 1.69 ( 1.09 to 2.62 ) in the 91 to 180 minute stratum . In the group treated with rt-PA , after adjusting for baseline NIHSS , an effect of OTT on the occurrence of intracranial hemorrhage was not detected . Conclusions If the NINDS rt-PA Stroke Trial treatment protocol is followed , this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes . No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA , possibly due to low power BACKGROUND The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I ( SAINT I ) trial , reducing disability when given to patients who had acute ischemic stroke . We sought confirmation of efficacy in a second , larger trial . METHODS We enrolled 3306 patients with acute ischemic stroke in a r and omized , double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms . Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days . We examined scores on neurologic and activities- 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: BACKGROUND Citicoline is approved in some countries for the treatment of acute ischaemic stroke . The drug has shown some evidence of efficacy in a pooled analysis . We sought to confirm the efficacy of citicoline in a larger trial . METHODS We undertook a r and omised , placebo-controlled , sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany , Portugal , and Spain . Using a central ised minimisation process , patients were r and omly assigned in a 1:1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms ( 1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [ 2 × 500 mg oral tablets given every 12 h ] ) . All study participants were masked . The primary outcome was recovery at 90 days measured by a global test combining three measures of success : National Institutes of Health Stroke Scale ≤1 , modified Rankin score ≤1 , and Barthel Index ≥95 . Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator , neurological deterioration , and mortality . This trial is registered , NCT00331890 . RESULTS 2298 patients were enrolled into the study from Nov 26 , 2006 , to Oct 27 , 2011 . 37 centres in Spain , 11 in Portugal , and 11 in Germany recruited patients . Of the 2298 patients who gave informed consent and underwent r and omisation , 1148 were assigned to citicoline and 1150 to placebo . The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients . The final r and omised analysis was based on data for 2298 patients : 1148 in citicoline group and 1150 in  placebo group . Global recovery was similar in both groups ( odds ratio 1·03 , 95 % CI 0·86 - 1·25 ; p=0·364 ) . No significant differences were reported in the safety variables nor in the rate of adverse events . INTERPRETATION Under the circumstances of the ICTUS trial , citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke . FUNDING Ferrer Grupo The purpose of this study was to evaluate the effects of magnesium sulfate on maternal and fetal blood flow in pregnancy‐induced hypertension . Twelve patients with pregnancy‐induced hypertension were prospect ively studied with transcranial pulsed Doppler and transabdominal color flow Doppler before and after infusion of a 6 gram intravenous loading dose of magnesium sulfate . The maternal vessels studied included the middle cerebral , common carotid , and internal carotid arteries . The fetal vessels studied included the middle cerebral , renal , and umbilical arteries . In addition the maternal circulation in the placental base plate was imaged . The results of this descriptive study suggest that a 6 gram loading dose of magnesium sulfate  significantly vasodilates the vascular bed distal to the maternal middle cerebral artery , and increases blood velocity in this distribution . There was no significant change in pulsatility index or blood velocity in the central large vessels of the head and neck . There were no acute effects noted in the fetal or placental vessels evaluated Background and Purpose — The goal of the Stroke Treatment Academic Industry Roundtable ( STAIR ) meetings is to advance the development of acute and restorative stroke therapies . Summary of Review — At the STAIR VII recommendations for strategies to maximize the use of intravenous thrombolytics through targeting public education , and the refinement of current treatment exclusion criteria were proposed . Increased utilization of mechanical devices for intra-arterial recanalization can be achieved by obtaining more definitive evidence of efficacy in r and omized clinical trials , identification of patient characteristics associated with treatment efficacy , optimization of technical approaches , clarification of effective time windows , and development of approaches to limit complications . Neuroprotective strategies remain viable ; recommendations for further study of these agents include an emphasis on rapid administration , consideration of the systemic effects of ischemic stroke , prevention of complications associated with early reperfusion , a focus on agents with multiple mechanisms of action , and consideration of possible interactions between neuroprotective and thrombolytic therapies . Conclusions — Extending intravenous thrombolysis to a broader patient population , clarifying the risk and benefits of intra-arterial reperfusion therapies , and further development of neuroprotective therapies were the key recommendations from STAIR VII BACKGROUND AND PURPOSE Parenterally administered MgSO4 is neuroprotective in st and ard animal models of focal cerebral ischemia and in many other paradigms of brain injury . Previous small clinical trials in stroke patients have explored the safety and tolerability of different infusion regimens . This study was undertaken to optimize the regimen for a multicenter trial . METHODS Within 24 hours of the onset of clinical ly diagnosed stroke , patients were r and omized to receive placebo or one of three intravenous MgSO4 infusions : a loading infusion of 8 , 12 , or 16 mmol , followed by 65 mmol over 24 hours . Cardiovascular parameters , serum magnesium concentrations , and blood glucose concentrations were determined . Outcome at 30 and 90 days was recorded . RESULTS Twenty-five patients were recruited and treated at a mean time of 20 hours after stroke . No tolerability problems were identified . No effects of magnesium on heart rate , blood pressure , or blood glucose were evident . Serum magnesium concentrations rose to target levels most rapidly in the highest loading infusion group and were maintained in all groups for at least 24 hours . CONCLUSIONS MgSO4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke . The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more A r and omized , placebo-controlled , double-blind study was performed as a pilot study to examine the benefit of the administration of magnesium sulfate given intravenously as a protective substance during the first 24 hours following a stroke . Patients who had cortical infa rct ion in the middle cerebral artery territory with moderate to severe neurologic deficits lasting for more than 15 minutes with onset less than 24 hours were included . The patients were treated with magnesium sulfate or placebo for 5 days and examined by a blinded investigator . Patients had follow-up for 30 days . The primary efficacy variable was the proportion of patients reaching mild to moderate neurologic deficit on the Orgogozo scale ( 80 points ) and relative functional independence on the Barthel index ( 60 points ) . Orgogozo scale and Mathew scale values were obtained on admission and days 2 , 4 , 8 , and 30 after stroke . Barthel activities of daily living index and Rankin disability score were obtained on day 30 . Forty-one patients ( 22 given treatment and 19 given placebo )  demonstrated significant beneficial effects on the Orgogozo scale ( 84 ± 11 vs. 64 ± 10 , p < 0.0001 ) and ( 83 ± 14 vs. 70 ± 15 , p < 0.009 ) , respectively . At the end of 1-month follow-up , the Barthel ADL index was nonsignificantly higher and the Rankin disability score was marginally significantly lower in the magnesium-treated group ( 84 ± 26 vs. 71.8 ± 26 , p < 0.143 ) than in control subjects ( 2.3 ± 1.1 vs. 3 ± 1.3 , p < 0.077 ) . Intravenous magnesium sulfate had significant positive effect on the outcome in patients with acute stroke . Further studies on a larger scale are needed to confirm these findings Background and Purpose — In the Interventional Management of Stroke ( IMS ) III trial , we sought to demonstrate evidence of a differential treatment effect of endovascular treatment of acute ischemic stroke compared with intravenous tissue-type plasminogen activator , according to baseline collateral status measured using computed tomographic angiography . Methods — Of 656 patients enrolled in Interventional Management of Stroke III trial , 306 had baseline computed tomographic angiography .  Of these , 185 patients had M1 middle cerebral artery ± intracranial internal carotid artery occlusion , where baseline collateral status could be measured . Collateral status was assessed by consensus using 3 different ordinal scales and categorized as good , intermediate , and poor . Multivariable modeling was used to assess the effect of collateral status and treatment type on clinical outcome by modified Rankin Scale ( mRS 0–2 , mRS 0–1 , and the ordinal mRS ) . Results — Of 185 patients , 126 r and omized to endovascular therapy ( 87.6 % recanalized , 41.3 % 90-day mRS 0–2 ) and 59 to intravenous tissue-type plasminogen activator only ( 60.5 % recanalized , 30.5 % 90-day mRS 0–2 ) . In multivariable modeling , collateral status was a significant predictor of all clinical outcomes ( P<0.05 ) . Maximal benefit with endovascular treatment across all clinical outcomes was seen in patients with intermediate collaterals , some benefit in patients with good collaterals , and none in patients with poor collaterals , although small sample size limited the power of the analysis to show a statistically significant interaction between collateral status and treatment type ( P>0.05 ) . Conclusion — Using data from a large r and omized controlled trial ( IMS III ) , we show that baseline computed tomographic angiography collaterals are a robust determinant of final clinical outcome and could be used to select patients for endovascular therapy . Clinical Trial Registration — URL : http://www . clinical trials.gov/ct2/show/. Unique identifier : 0020NCT00359424 Background The National Institute of Neurological Disorders and Stroke ( NINDS ) rt-PA Stroke Study showed a similar percentage of intracranial hemorrhage and good outcome in patients 3 months after stroke treatment given 0 to 90 minutes and 91 to 180 minutes after stroke onset . At 24 hours after stroke onset more patients treated 0 to 90 compared to 91 to 180 minutes after stroke onset had improved by four or more points on the NIH Stroke Scale ( NIHSS ) . The authors performed further analyses to characterize the relationship of  onset-to-treatment time ( OTT ) to outcome at 3 months , early improvement at 24 hours , and intracranial hemorrhage within 36 hours . Methods Univariate analyses identified potentially confounding variables associated with OTT that could mask an OTT – treatment interaction . Tests for OTT – treatment interactions adjusting for potential masking confounders were performed . An OTT – treatment interaction was considered significant if p ≤ 0.10 , implying that treatment effectiveness was related to OTT . Results For 24-hour improvement , there were no masking confounders identified and there was an OTT – treatment interaction ( p = 0.08 ) . For 3-month favorable outcome , the NIHSS met criteria for a masking confounder . After adjusting for NIHSS as a covariate , an OTT – treatment interaction was detected ( p = 0.09 ) : the adjusted OR ( 95 % CI ) for a favorable 3-month outcome associated with recombinant tissue-type plasminogen activator ( rt-PA ) was 2.11 ( 1.33 to 3.35 ) in the 0 to 90 minute stratum and 1.69 ( 1.09 to 2.62 ) in the 91 to 180 minute stratum . In the group treated with rt-PA , after adjusting for baseline NIHSS , an effect of OTT on the occurrence of intracranial hemorrhage was not detected . Conclusions If the NINDS rt-PA Stroke Trial treatment protocol is followed , this analysis suggests that patients treated 0 to 90 minutes from stroke onset with rt-PA have an increased odds of improvement at 24 hours and favorable 3-month outcome compared to patients treated later than 90 minutes . No effect of OTT on intracranial hemorrhage was detected within the group treated with rt-PA , possibly due to low power BACKGROUND The free-radical-trapping agent NXY-059 showed promise as a neuroprotectant in the Stroke-Acute Ischemic NXY Treatment I ( SAINT I ) trial , reducing disability when given to patients who had acute ischemic stroke . We sought confirmation of efficacy in a second , larger trial . METHODS We enrolled 3306 patients with acute ischemic stroke in a r and omized , double-blind trial to receive a 72-hour infusion of intravenous NXY-059 or placebo within 6 hours after the onset of stroke symptoms . Our primary end point was the distribution of disability scores on the modified Rankin scale at 90 days . We examined scores on neurologic and activities- 
    Output:
    