***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: For centuries in Europe , population movements have contributed to ethnic groups , cultures , and consequently , inheritance mixing . There are certain genetic diseases such as hereditary hemochromatosis whose distribution is directly related to the population movements . The objective of the present investigation was to determine the C282Y and H63D mutation frequency of the HFE gene in a cohort study of 1,000 neonates in the Community of Madrid ( Spain ) , thus contributing to the HFE gene mutations distribution research in Europe and establishing the origin of the mutations in Spain . The allelic frequency of C282Y mutation was 1.7 % ( CI 95 % 1.1–2.3 ) and the H63D allele was present in 16.4 % of chromosomes ( CI 95 % 14.8–18 ) . In Spain , the presence of C282Y mutation and its distribution could be due more to Celtic than to Viking legacy , whereas it is assumed that the one in relation to the H63D variant occurred in the Basque Country during the Paleolithic Period This open-label , prospect i ve , phase 2 study evaluated the safety and efficacy of deferasirox ( 10 ± 5 mg/kg/d ) in patients with hereditary hemochromatosis ( HH ) and iron overload refractory to or intolerant of phlebotomy . Ten patients were enrolled and all completed the 12-month treatment period . There were significant decreases from baseline to end of study ( i.e. , 12 months ) in median serum ferritin ( P < 0.001 ) , mean transferrin saturation ( P < 0.05 ) , median liver iron concentration ( P < 0.001 ) , and mean alanine aminotransferase ( P < 0.05 ) . The median time to achieve serum ferritin reduction ≥50 % compared to baseline was 7.53 months . The most common adverse events were mild , transient diarrhea ( n = 5 ) and nausea ( n = 2 ) . No patient experienced an increase in serum creatinine that exceeded the upper limit of normal . These data confirm that deferasirox was well tolerated and effective in reducing iron burden in patients with hereditary hemochromatosis and could be a safe alternative to phlebotomy in selected patients OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials Deferasirox is a once‐daily , oral iron chelator developed for treating transfusional iron overload . Pre clinical studies indicated that the kidney was a potential target organ of toxicity . As patients with sickle cell disease often have abnormal baseline renal function , the primary objective of this r and omised , open‐label , phase II trial was to evaluate the safety and tolerability of deferasirox in comparison with deferoxamine in this population . Assessment of efficacy , as measured by change in liver iron concentration ( LIC ) using biosusceptometry , was a secondary objective . A total of 195 adult and paediatric patients received deferasirox  ( n = 132 ) or deferoxamine ( n = 63 ) . Adverse events most commonly associated with deferasirox were mild , including transient nausea , vomiting , diarrhoea , abdominal pain and skin rash . Abnormal laboratory studies with deferasirox were occasionally associated with mild non‐progressive increases in serum creatinine and reversible elevations in liver function tests . Discontinuation rates  from deferasirox ( 11·4 % ) and deferoxamine ( 11·1 % ) were similar . Over 1 year , similar dose‐dependent LIC reductions were observed with deferasirox and deferoxamine . Once‐daily oral deferasirox has acceptable tolerability and appears to have similar efficacy  to deferoxamine in reducing iron burden in transfused patients with sickle cell disease Introduction HFE p . C282Y homozygosity is the most common cause of hereditary haemochromatosis . There is currently insufficient evidence to assess whether non-specific symptoms or hepatic injury in homozygotes with moderately elevated iron defined as a serum ferritin ( SF ) of 300–1000 µg/L are related to iron overload . As such the evidence for intervention in this group is lacking . We present here methods for a study that aims to evaluate whether non-specific symptoms and hepatic fibrosis markers improve with short-term normalisation of SF in p . C282Y homozygotes with moderate elevation of SF . Methods and analysis Mi-iron is a prospect i ve , multicentre , r and omised patient-blinded trial conducted in three centres in Victoria and Queensl and , Australia . Participants who are HFE p . C282Y homozygotes with SF levels between 300 and 1000 μg/L are recruited and r and omised to either the treatment group or to the sham treatment group . Those in the treatment group have normalisation of SF by 3-weekly erythrocytapheresis while those in the sham treatment group have 3-weekly plasmapheresis and thus do not have normalisation of SF . Patients are blinded to all procedures . All outcome measures are administered prior to and following the course of treatment/sham treatment . Patient reported outcome measures are the Modified Fatigue Impact Scale ( MFIS- primary outcome ) , Hospital Anxiety and Depression Scale ( HADS ) , Medical Outcomes Study 36-item short form V.2 ( SF36v2 ) and Arthritis Impact Measurement Scale 2 short form ( AIMS 2-SF ) . Liver injury and hepatic fibrosis are assessed with transient elastography ( TE ) , Fibrometer and Hepascore , while oxidative stress is assessed by measurement of urine and serum F2-isoprostanes . Ethics and dissemination This study has been approved by the Human Research Ethics Committees of Austin Health , Royal Melbourne Hospital and Royal Brisbane and Women 's Hospital . Study findings will be disseminated through peer- review ed publications and conference presentations . Trial registration Trial identifier : NCT01631708 ; Registry : Clinical Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . BACKGROUND Hereditary haemochromatosis may result in severe organ damage which can be prevented by therapy . We studied the possible advantages and disadvantages of erythrocytapheresis as compared with phlebotomy in patients with hereditary haemochromatosis . MATERIAL S AND METHODS In a prospect i ve , r and omised , open-label study , patients with hereditary haemochromatosis were r and omised to bi-weekly apheresis or weekly whole blood phlebotomy . Primary end-points were decrease in ferritin levels and transferrin saturation . Secondary endpoints were decrease in haemoglobin levels , discomfort during the therapeutic procedure , costs and technicians ' working time . RESULTS Sixty-two patients were included . Thirty patients were r and omised to apheresis and 32 to whole blood phlebotomy .  Initially , ferritin levels declined more rapidly in the apheresis group , and the difference became statistically highly significant at 11 weeks ; however , time to normalisation of ferritin level was equal in the two groups . We observed no significant differences in decline of transferrin saturation , haemoglobin levels or discomfort . The mean cumulative technician time consumption until the ferritin level reached 50 μg/L was longer in the apheresis group , but the difference was not statistically significant . The cumulative costs for material s until achievement of the desired ferritin levels were three-fold higher in the apheresis group . CONCLUSION Treatment of hereditary haemochromatosis with erythrocytapheresis instead of whole blood phlebotomy results in a more rapid initial decline in ferritin levels and a reduced number of procedures per patient , but not in earlier achievement of target ferritin level . The frequency of discomfort was equally low with the two methods . The costs and , probably , technician time consumption were higher in the apheresis group BACKGROUND St and ard treatment of newly diagnosed HFE hemochromatosis patients is phlebotomy . Erythrocytapheresis provides a new therapeutic modality that can remove up to three times more red blood cells per single procedure and could thus have a clinical and economic benefit . STUDY DESIGN AND METHODS To compare the number of treatment procedures between erythrocytapheresis and phlebotomy needed to reach the serum ferritin ( SF ) target level of 50 µg/L , a two-treatment-arms , r and omized trial was conducted in which 38 newly diagnosed patients homozygous for C282Y were r and omly assigned in a 1:1 ratio to undergo either erythrocytapheresis or phlebotomy . A 50 % decrease in the number of treatment procedures  for erythrocytapheresis compared to phlebotomy was chosen as the relevant difference to detect . RESULTS Univariate analysis showed a significantly lower mean number of treatment procedures in the erythrocytapheresis group ( 9 vs. 27 ; ratio , 0.33 ; 95 % confidence interval [ CI ] , 0.25 - 0.45 ; Mann-Whitney p < 0.001 ) . After adjustments for the two important influential factors initial SF level and body weight , the reduction ratio was still significant ( 0.43 ; 95 % CI , 0.35 - 0.52 ; p < 0.001 ) . Cost analysis showed no significant difference in treatment costs between both procedures . The costs result ing from productivity loss were significantly lower for the erythrocytapheresis group . CONCLUSION Erythrocytapheresis is highly effective treatment to reduce iron overload and from a societal perspective might potentially also be a cost-saving therapy BACKGROUND Phlebotomy is st and ard maintenance treatment of patients with hereditary hemochromatosis ( HH ) .  Erythrocytapheresis , which selectively removes red blood cells , provides a new , potentially more effective treatment option . Our aim was to evaluate the effectiveness of erythrocytapheresis over phlebotomy for maintenance therapy in patients with HH . STUDY DESIGN AND METHODS We conducted a two-treatment-arms , r and omized , crossover clinical trial , involving 46 patients , treated for 1 year with either erythrocytapheresis or phlebotomy to keep the ferritin level at not more than 50 µg/L. After 1 year , patients were switched to the other treatment modality . Primary endpoint was the number of treatment procedures per treatment year . Secondary endpoints were intertreatment intervals , several aspects of health-related quality of life , costs , and patient discomfort as well as preference for one of both treatments . RESULTS The mean number of required treatment procedures per treatment year was significantly higher using phlebotomy versus erythrocytapheresis ( 3.3 vs. 1.9 ; mean difference , 1.4 ; 95 % confidence interval , 1.1 - 1.7 ) . The median intertreatment time was 2.3 times longer for erythrocytapheresis . There was no significant difference in overall health assessed by SF-36 and EQ-5D , respectively , between both treatments arms . The number of self-reported swollen joints was significantly higher during phlebotomy treatment . The mean treatment costs of one treatment year were 235 € for phlebotomy versus 511 € for erythrocytapheresis . Eighty percent of patients preferred erythrocytapheresis as treatment method . CONCLUSION Erythrocytapheresis significantly reduced the number of treatment procedures per treatment year , although the mean treatment costs per year are higher in our health care system . It is the preferred treatment for the majority of patients The CONSORT statement is used worldwide to improve the reporting 
    Output:
    
There is currently insufficient evidence to determine whether erythrocytapheresis is beneficial or harmful compared with phlebotomy .
Phlebotomy has less equipment requirements and remains the treatment of choice in people with hereditary haemochromatosis who require blood letting in some form .
However , it should be noted that there is no evidence from r and omised clinical trials that blood letting in any form is beneficial in people with hereditary haemochromatosis .