***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 
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    ***EXAMPLES*** 
    Input: Summary Background Many investigators have suggested that malaria infection predisposes individuals to bacteraemia . We tested this hypothesis with mendelian r and omisation studies of children with the malaria-protective phenotype of sickle-cell trait ( HbAS ) . Methods This study was done in a defined area around Kilifi District Hospital , Kilifi , Kenya . We did a matched case-control study to identify risk factors for invasive bacterial disease , in which cases were children aged 3 months to 13 years who were admitted to hospital with bacteraemia between Sept 16 , 1999 , and July 31 , 2002 . We aim ed to match two controls , by age , sex , location , and time of recruitment , for every case . We then did a longitudinal case-control study to assess the relation between HbAS and invasive bacterial disease as malaria incidence decreased . Cases were children aged 0–13 years who were admitted to hospital with bacteraemia between Jan 1 , 1999 , and Dec 31 , 2007 . Controls were born in the study area between Jan 1 , 2006 , and June 23 , 2009 . Finally , we modelled the annual incidence of bacteraemia against the community prevalence of malaria during 9 years with Poisson regression . Results In the matched case-control study , we recruited 292 cases — we recruited two controls for 236 , and one for the remaining 56 . Sickle-cell disease , HIV , leucocyte haemozoin pigment , and undernutrition were positively associated with bacteraemia and HbAS was strongly negatively associated with bacteraemia ( odds ratio 0·36 ; 95 % CI 0·20–0·65 ) . In the longitudinal case-control study , we assessed data from 1454 cases and 10 749 controls . During the study period , the incidence of admission to hospital with malaria per 1000 child-years decreased from 28·5 to 3·45 , with a reduction in protection afforded by HbAS against bacteraemia occurring in parallel ( p=0·0008 ) . The incidence of hospital admissions for bacteraemia per 1000 child-years also decreased from 2·59 to 1·45 . The bacteraemia incidence rate ratio associated with malaria parasitaemia was 6·69 ( 95 % CI 1·31–34·3 ) and , at a community parasite prevalence of 29 % in 1999 , 62 % ( 8·2–91 ) of bacteraemia cases were attributable to malaria . Interpretation Malaria infection strongly predisposes individuals to bacteraemia and can account for more than half of all cases of bacteraemia in malaria-endemic areas . Interventions to control malaria will have a major additional benefit by reducing the burden of invasive bacterial disease . Funding Wellcome Trust 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 Background The World Health Organization has declared Sickle Cell Anemia ( SCA ) a public health priority . There are 300,000 births/year , over 75 % in Africa , with estimates suggesting that 6 million Africans will be living with SCA if average survival reaches half the African norm . Countries such as United States of America and United Kingdom have reduced SCA mortality from 3 to 0.13 per 100 person years of observation ( PYO ) , with interventions such as newborn screening , prevention of infections and comprehensive care , but implementation of interventions in African countries has been hindered by lack of locally appropriate information . The objective of this study was to determine the incidence and factors associated with death from SCA in Dar-es-Salaam . Methods and Findings A  hospital-based cohort study was conducted , with prospect i ve surveillance of 1,725 SCA patients recruited from 2004 to 2009 , with 209 ( 12 % ) lost to follow up , while 86 died . The mortality rate was 1.9 ( 95%CI 1.5 , 2.9 ) per 100 PYO , highest under 5-years old [ 7.3 ( 4.8–11.0 ) ] , adjusting for date s of birth and study enrollment . Independent risk factors , at enrollment to the cohort , predicting death were low hemoglobin ( < 5 g/dL ) [ 3.8 ( 1.8–8.2 ) ; p = 0.001 ] and high total bilirubin ( ≥102 µmol/L ) [ 1.7 ( 1.0–2.9 ) ; p = 0.044 ] as determined by logistic regression . Conclusions Mortality in SCA in Africa is high , with the most vulnerable period being under 5-years old . This is most likely an underestimate , as this was a hospital cohort and may not have captured SCA individuals with severe disease who died in early childhood , those with mild disease who are undiagnosed or do not utilize services at health facilities . Prompt and effective treatment for anemia in SCA is recommended as it is likely to improve survival . Further research is required to determine the etiology , pathophysiology and the most appropriate strategies for management of anemia in SCA CONTEXT Hydroxyurea increases levels of fetal hemoglobin ( HbF ) and decreases morbidity from vaso-occlusive complications in patients with sickle cell anemia ( SCA ) . High HbF levels reduce morbidity and mortality . OBJECTIVE To determine whether hydroxyurea attenuates mortality in patients with SCA . DESIGN Long-term observational follow-up study of mortality in patients with SCA who originally participated in the r and omized , double-blind , placebo-controlled Multicenter Study of Hydroxyurea in Sickle Cell Anemia ( MSH ) , conducted in 1992 - 1995 , to determine if hydroxyurea reduces vaso-occlusive events . In the MSH Patients ' Follow-up , conducted in 1996 - 2001 , patients could continue , stop , or start hydroxyurea . Data were collected during the trial and in the follow-up period . SETTING In patients and out patients in 21 sickle cell referral centers in the United States and Canada . PATIENTS Two-hundred ninety-nine adult patients with frequent painful episodes enrolled in the follow-up . Follow-up data through May 2001 were complete for 233 patients . INTERVENTION In the MSH , patients were r and omly assigned to receive hydroxyurea ( n = 152 ) or placebo ( n = 147 ) . MAIN OUTCOME MEASURE Mortality , HbF levels , painful episodes , acute chest syndrome , and blood cell counts . The r and omized trial was not design ed to detect specified differences in mortality . RESULTS Seventy-five of the original 299 patients died , 28 % from pulmonary disease . Patients with reticulocyte counts less than 250 000/mm3 and hemoglobin levels lower than 9 g/dL had increased mortality ( P = .002 ) . Cumulative mortality at 9 years was 28 % when HbF levels were lower than 0.5 g/dL after the trial was completed compared with 15 % when HbF levels were 0.5 g/dL or higher ( P = .03 ) . Individuals who had acute chest syndrome during the trial had 32 % mortality compared with 18 % of individuals without acute chest syndrome ( P = .02 ) . Patients with 3 or more painful episodes per year during the trial had 27 % mortality compared with 17 % of patients with less frequent episodes ( P = .06 ) . Taking hydroxyurea was associated with a 40 % reduction in mortality ( P = .04 ) in this observational follow-up with self-selected treatment . There were 3 cases of cancer , 1 fatal . CONCLUSIONS Adult patients taking hydroxyurea for frequent painful sickle cell episodes appear to have reduced mortality after 9 of years follow-up . Survival was related to HbF levels and frequency of vaso-occlusive events . Whether indications for hydroxyurea treatment should be exp and ed is unknown OBJECTIVES To assess adherence to hydroxyurea therapy in children with sickle cell anemia ( SCA ) , evaluate the association between adherence and hematologic profile , and identify barriers and facilitators of adherence . STUDY DESIGN Children with SCA ( n=75 ) receiving hydroxyurea were recruited for a single-institution cross-sectional study . The primary outcome was association between treatment adherence and percent fetal hemoglobin ( HbF ) . RESULTS Good adherence was estimated at 82 % with visual analog scale , 84 % with Morisky score , 85 % with medical provider report , 77 % with clinic visits , and 49 % on the basis of pharmacy refills . Increase in HbF was moderately associated with good adherence as measured with the parent/proxy Morisky score ( r=-0.39 ; 95 % CI , -0.58 - 0.17 ; P < .01 ) and prescription refills ( r=0.39 ; 95 % CI , 0.16 - 0.57 ; P < .01 ) . The number of pharmacy refills and the Morisky score explained 23 % of the variation in HbF response . CONCLUSIONS Adherence was > or = 75 % with 4 of 5 measures . Pharmacy refills and the Modified Morisky Scale may be used to identify children at high risk for poor response because of non-adherence and children with good adherence with poor response because of individual pharmacodynamics . Future research should prospect ively compare adherence measures and evaluate methods to improve treatment adherence BACKGROUND Hydroxyurea improves laboratory parameters and prevents acute clinical complications of sickle cell anemia ( SCA ) in children and adults , but its effects on organ function remain incompletely defined . METHODS To assess the safety and efficacy of hydroxyurea in young children with SCA and to prospect ively assess kidney and brain function , 14 young children ( mean age 35 months ) received hydroxyurea at a mean maximum tolerated dose ( MTD ) of 28 mg/kg/day . RESULTS After a mean of 25 months , expected laboratory effects included significant increases in hemoglobin , MCV and % HbF along with significant decreases in reticulocytes , absolute neutrophil count , and bilirubin . There was no significant increase in glomerular filtration rate by DTPA clearance or Schwartz estimate . Mean transcranial Doppler ( TCD ) velocity changes were -25.6 cm/sec ( P < 0.01 ) and -26.8 cm/sec ( P < 0.05 ) in the right and left MCA vessels , respectively . At study exit , no child had conditional or abnormal TCD values , and none developed brain ischemic lesions or vasculopathy progression by MRI/MRA . Growth and neurocognitive scores were preserved and Impact-on-Family scores improved . CONCLUSIONS These pilot data indicate hydroxyurea at MTD is well-tolerated by both children and families , and may prevent chronic organ damage in young children with SCA There is clinical variability in the presentation of sickle cell disease among Indians . Vaso-occlusive crisis is common among non-tribal patients . Hydroxyurea , induces fetal hemoglobin ( HbF ) synthesis and reduces the clinical severity of sickle cell disease but individual patients have a variable response . This study was undertaken to investigate the efficacy and safety of hydroxyurea in Indians with severe manifestations where the beta(s ) gene is linked to the Arab-Indian haplotype and is associated with higher HbF levels . Seventy-seven patients ( 29 adult sickle homozygous , 25 pediatric sickle homozygous , 23 adult sickle beta-thalassemia ) selected for hydroxyurea therapy  were evaluated for clinical , hematological , biochemical and genetic parameters and were followed for 24 months . Ninety-eight point seven percent of the sickle chromosomes were linked to the Arab-Indian haplotype , 27 % of patients 
    Output:
    
Overall , available evidence from 1 systematic review ( n=26 studies ) , 2 r and omised controlled trials ( n=354 children ) , 14 observational studies and 2 National Institute of Health reports suggest that hydroxyurea may be associated with improved fetal haemoglobin levels , reduced rates of hospitalisation , reduced episodes of acute chest syndrome and decreased frequency of pain events in children with SCD .
However , it is associated with adverse events ( eg , neutropenia ) when high to maximum tolerated doses are used .
Evidence is lacking on whether hydroxyurea improves survival if given to young children .
Overall , available limited evidence suggests that hydroxyurea may improve morbidity and haematological outcomes in SCD in children aged below 5 years and appears safe in setting s able to provide consistent haematological monitoring