***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: Noninvasive , quantitative , and accurate assessment of liver iron concentration ( LIC ) by MRI is useful for patients receiving transfusions , but R2 and R2 * MRI techniques have not been systematic ally compared in sickle cell anemia ( SCA ) . We report baseline LIC results from the TWiTCH trial , which compares hydroxyurea with blood transfusion treatment for primary stroke prophylaxis assessed by transcranial Doppler sonography in pediatric SCA patients . Liver R2 was collected and processed using a FDA ‐approved commercial process ( FerriScan ® ) , while liver R2 * quality control and processing were performed by a Core Laboratory blinded to clinical site and patient data . Baseline LIC studies using both MRI techniques were available for 120 participants . LICR2 * and LICR2 results were highly correlated ( r2 = 0.93 ) . A proportional bias of LIC(R2*)/LIC(R2 ) , decreasing with average LIC , was observed . Systematic differences between LICR2 * and LICR2 were also observed by MRI manufacturer . Importantly , LICR2 * and LICR2 estimates had broad 95 % limits of agreement with respect to each other . We recommend LICR2 and LICR2 * not be used interchangeably in SCA patients to follow individual patient trends in iron burden . Am . J. Hematol . 90:806–810 , 2015 . © 2015 Wiley Periodicals , Hydroxyurea has hematologic and clinical efficacy in sickle cell anemia ( SCA ) , but its effects on transcranial Doppler ( TCD ) flow velocities remain undefined . Fifty-nine children initiating hydroxyurea therapy for clinical severity had pretreatment baseline TCD measurements ; 37 with increased flow velocities ( > or = 140 cm/s ) were then enrolled in an institutional review board (IRB)-approved prospect i ve phase 2 trial with TCD velocities measured at maximum tolerated dose ( MTD ) and one year later . At hydroxyurea MTD ( mean + /- 1 SD = 27.9 + /- 2.7 mg/kg per day ) , significant decreases were observed in the right middle cerebral artery ( MCA ) ( 166 + /- 27 cm/s to 135 + /- 27 cm/s , P < .001 ) and left ( MCA ) ( 168 + /- 26 cm/s to 142 + /- 27 cm/s , P < .001 ) velocities . The magnitude of TCD velocity decline was significantly correlated with the maximal baseline TCD value . At hydroxyurea MTD , 14 of 15 children with conditional baseline TCD values improved , while 5 of 6 with abnormal TCD velocities whose families refused transfusions became less than 200 cm/s . TCD changes were sustained at follow-up . These prospect i ve data indicate that hydroxyurea can significantly decrease elevated TCD flow velocities , often into the normal range . A multicenter trial is warranted to determine the efficacy of hydroxyurea for the management of increased TCD values , and ultimately for primary stroke prevention in children with SCA The Stroke With Transfusions Changing to Hydroxyurea ( SWiTCH ) trial compared st and ard ( transfusions/chelation ) to alternative ( hydroxyurea/phlebotomy ) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment . St and ardized brain magnetic resonance imaging/magnetic resonance angiography ( MRA ) and transcranial Doppler ( TCD ) exams were performed at entry and exit , with a central blinded review . A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis ( 53%/41 % ≥ Grade 4 ) ; 31 % had no vessel stenosis on either side . Baseline parenchymal injury was prevalent ( 85%/79 % subcortical , 53%/37 % cortical , 50%/35 % subcortical and cortical ) . Most children had low or uninterpretable baseline middle cerebral artery TCD velocities , which were associated with worse stenoses ( incidence risk ratio [ IRR ] = 5.1 , P ≤ .0001 and IRR = 4.1 , P < .0001 ) than normal velocities ; only 2 % to 12 % had any conditional/abnormal velocity . Patients with adjudicated stroke ( 7 ) and transient ischemic attacks ( 19 in 11 st and ard/8 alternative arm subjects ) had substantial parenchymal injury/vessel stenosis . At exit , 1 child ( alternative arm ) had a new silent infa rct , and another had worse stenosis . SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury . The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials . This trial was registered at www . clinical trials.gov as # NCT00122980 The Stroke Prevention Trial in Sickle Cell Anemia ( STOP ) was a r and omized multicenter controlled trial comparing prophylactic blood transfusion with st and ard care in sickle cell anemia ( SCA ) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler ( TCD ) . More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the r and omized trial . A total of 5613 TCD studies from 2324 children were evaluated . We also collected information on stroke . We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort . Risk of stroke was higher with abnormal TCD than with normal or conditional TCD ( P < .001 ) or inadequate TCD ( P = .002 ) , and risk with conditional TCD was higher than with normal TCD ( P < .001 ) . Repeated TCD in 1215 children showed that the condition of 9.4 % of children became abnormal during observation . Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs . Screening in STOP confirmed the predictive value of TCD for stroke . Substantial differences in the probability of conversion to abnormal TCD were observed , with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening BACKGROUND A substantial minority of neurologically normal children with sickle cell disease have lesions consistent with cerebral infa rct ion as seen on magnetic resonance imaging ( MRI ) . OBJECTIVES To determine if transfusion therapy affects the rate at which silent infa rcts develop and to evaluate the contribution of MRI of the brain to stroke prediction by transcranial Doppler ( TCD ) ultrasonography . STUDY DESIGN Children with elevated TCD ultrasonographic velocity were r and omized to receive long-term transfusion therapy or st and ard care .  Magnetic resonance imaging of the brain was obtained at r and omization , annually , and with clinical neurologic events . The risk for new silent lesions and /or stroke was compared for each treatment arm . RESULTS Among the 37 % of subjects with silent infa rcts , those receiving st and ard care were significantly more likely to develop new silent lesions or stroke than were those who received transfusion therapy . For subjects receiving st and ard care , those with lesions at baseline were significantly more likely to develop stroke or new silent lesions than those whose MRI studies showed no abnormality . CONCLUSIONS Transfusion therapy lowers the risk for new silent infa rct or stroke for children having both abnormal TCD ultrasonographic velocity and silent infa rct . However , those with both abnormalities who are not provided transfusion therapy are at higher risk for developing a new silent infa rct or stroke than are those whose initial MRI showed no abnormality . The finding of a silent infa rct reinforces the need for TCD ultrasonographic screening and consideration of transfusion therapy if the abnormalities are seen . Similarly , elevated TCD ultrasonographic velocity warrants MRI of the brain because children with both abnormalities seem to be at increased risk for developing new silent infa rct or stroke The Stroke Prevention Trial in Sickle Cell Anemia ( STOP ) was a r and omized trial to evaluate whether chronic transfusion could prevent initial stroke in children with sickle-cell anemia at high risk as determined by transcranial Doppler ( TCD ) . The trial demonstrated a large benefit of transfusion and was halted early . After termination of the trial , patients participated in a post-trial follow-up study . More patients in the transfusion group ( 70 % ) elected transfusion for primary stroke prevention compared with those on st and ard care ( 45 % ) . Six patients with persistently abnormal TCD results developed stroke . A minority with initially abnormal TCD results remained stroke-free without transfusion . Except for lower baseline and follow-up TCD velocities compared with those with stroke , no predictive features of this apparent lower-risk subgroup could be determined . TCD results at last testing in 108 patients that did not have stroke were : normal ( 44.4 % ) , conditional ( 26.9 % ) , abnormal ( 22.2 % ) , and inadequate ( 6.5 % ) . Patients on transfusion were more likely to have normal TCD results . Transfusion result ed in iron overload and alloimmunization , but no infection . The study provides new information on acceptance rates and long-term effects of transfusion . Persistent TCD elevation signals ongoing stroke risk . Reduction in TCD results over time without transfusion is observed in some patients and requires further study Background : Silent cerebral infa rct ( SCI ) is the most common cause of serious neurological disease in sickle cell anemia ( SCA ) , affecting approximately 22 % of children . The goal of this trial is to determine whether blood transfusion therapy will reduce further neurological morbidity in children with SCI , and if so , the magnitude of this benefit . Procedure : The Silent Cerebral Infa rct Transfusion ( SIT ) Trial includes 29 clinical sites and 3 subsites , a Clinical Coordinating Center , and a Statistical and Data Coordinating Center , to test the following hypothesis : prophylactic blood transfusion therapy in children with SCI will result in at least an 86 % reduction in the rate of subsequent overt strokes or new or progressive cerebral infa rcts as defined by magnetic resonance imaging ( MRI ) of the brain . The intervention is blood transfusion versus observation .  Two hundred and four participants ( 102 in each treatment assignment ) will ensure 85 % power to detect the effect necessary to recommend transfusion therapy ( 86 % reduction ) , after accounting for 10 % drop out and 19 % crossover rates . MRI examination of the brain is done at screening , immediately before r and omization and study exit . Each r and omly assigned participant receives a cognitive test battery at study entry , 12–18 months later , and study exit and an annual neurological examination . Blood is obtained from all screened participants for a biologic repository containing serum and a renewable source of DNA . Conclusion : The SIT Trial could lead to a change in st and ard care practice s for children affected with SCA and SCI , with a consequent reduction in neurological morbidity The Silent Cerebral Infa rct Multicenter Transfusion ( SIT ) Trial is a multi-institutional intervention trial in which children with silent cerebral infa rcts are r and omized to receive either blood transfusion therapy or observation ( st  and ard care )  for 36 months . The SIT Trial is scheduled to enroll approximately 1,880 children with sickle cell disease from 29 clinical sites in the United States , Canada , UK , and France . Each child undergoes a screening magnetic resonance imaging ( MRI ) of the brain to detect the presence of silent cerebral infa rct -like lesions , a pre-r and omization ( baseline ) MRI and exit MRI to determine if there are new or enlarged cerebral infa rcts , using a design ated , prospect i ve imaging protocol . The objective of this manuscript is to describe the innovative method used to process and adjudicate imaging studies for an international trial with a primary endpoint that includes neuroimaging . Institution investigators at each site were provided with computer hardware and software for transmission of MRI images that allow them to strip the scans of all personal information and add unique study identifiers . Three neuroradiologists at separate academic centers review MRI studies and determine the presence or absence of silent cerebral infa rct -like lesions . Their findings are subsequently placed on web-based case report forms and sent to the Statistical Coordinating Center . The average time from imaging center receipt of the MRI study to the radiology committee report back to the local site is less than two working days . This novel strategy was design ed to maximize efficiency and minimize cost of a complex large multicenter trial that depends heavily on neuroimaging for entry criteria and assessment for the primary outcome measures . The technology , process , and expertise used in the SIT Trial can be adapted to virtually any clinical research trial with digital imaging requirements BACKGROUND Prophylactic transfusion prevents strokes in children with sickle cell anemia who have abnormalities on transcranial Doppler ultrasonographic examination . However , it is not known how long transfusion should be continued in these children . METHODS We studied children with sickle cell disease who had a high risk of stroke on the basis of a transcranial Doppler screening examination and who had received transfusions for 30 months or longer , during which time the Doppler readings became normal . The children were r and omly assigned to continued transfusion or no continued transfusion .  Children with severe stenotic les 
    Output:
    
There is no evidence for managing adults , or children who do not have HbSS sickle cell disease .
In children who are at higher risk of stroke and have not had previous long-term transfusions , there is moderate quality evidence that long-term red cell transfusions reduce the risk of stroke , and low quality evidence they also reduce the risk of other sickle cell disease-related complications .
In primary and secondary prevention of stroke there is low quality evidence that switching to hydroxyurea with phlebotomy has little or no effect on the liver iron concentration .
In secondary prevention of stroke there is low- quality evidence that switching to hydroxyurea with phlebotomy increases the risk of sickle cell disease-related events .