***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: Objective Fabry patients have autonomic dysfunction but usually do not present clinical ly overt signs of orthostatic dysregulation . This study evaluated orthostatic regulation and baroreflex sensitivity ( BRS ) in untreated Fabry patients and possible baroreflex improvement with enzyme replacement therapy ( ERT ) . Methods In 22 Fabry patients ( aged 28 ± 8 years ) , we assessed electrocardiographic RR intervals ( RRIs ) , SBP , DBP and respiratory frequency , in supine and st and ing position , before and after 18 ( 11 patients ) or 23 months ( 11 patients ) of biweekly α-galactosidase A infusions ( 1.0 mg/kg agalsidase beta ) . We determined spectral powers of mainly sympathetically mediated low-frequency ( 0.04–0.15 Hz ) and parasympathetically mediated high-frequency ( 0.15–0.5 Hz ) RRI fluctuations , and sympathetic low-frequency powers of blood pressure fluctuations . We normalized RRI powers by relating low-frequency and high-frequency powers to total powers ( low-frequency + high-frequency powers ) , assessed the RRI low-frequency/high-frequency ratio reflecting sympathicovagal balance . As a measure of BRS , we used the α-index , obtained as square root of the ratio between powers of simultaneous spectral analyses of spontaneous low-frequency variabilities in RRIs and SBP ( coherence > 0.5 ) . We compared parameters in supine and st and ing position of untreated and treated patients with those of 15 healthy age-matched ( 27 ± 5 years ) men ( repeated-measure analysis of variance , significance at P < 0.05 ) . Results Supine biosignals were similar in all groups . Upon st and ing , RRIs were lower in controls and patients after ERT than in patients before ERT ( P < 0.05 ) ; normalized RRI high-frequency powers as well as BRS decreased , whereas DBP , low-frequency/high-frequency ratios and sympathetic low-frequency powers of SBP increased in controls and treated patients only ( P < 0.05 ) . Conclusion Reduced increase in heart rate , blood pressure and sympathetic activation , and limited cardiovagal withdrawal and BRS adjustment seen in untreated Fabry patients upon st and ing normalized after 18 and 23 months of ERT demonstrating improved baroreflex function , which , in turn , is an established parameter of improved disease prognosis BACKGROUND Fabry disease ( FD ) is caused by an X-linked deficiency in the activity of alpha-galactosidase A and the result ant accumulation of globotriaosylceramide ( Gb3 ) in multiple tissues . Nearly all classically affected males with FD experience kidney dysfunction , with progression to end-stage renal disease ( ESRD ) in the third decade of life or shortly thereafter . METHODS Twenty-two FD patients ( 20 men and 2 women ) receiving dialysis or who had a history of kidney transplantation were treated with agalsidase alfa in an open label setting using the same dosing regimen given to patients without ESRD  ( 0.2 mg/kg every other week ) . Pharmacokinetics ( PK ) were determined during and following the initial dose , and safety was evaluated during therapy . Change in plasma Gb3 level was used as a surrogate marker of enzyme activity in vivo . RESULTS A typical biphasic plasma elimination profile was seen in both dialysis and transplant patients , similar to that observed in 18 non-ESRD FD patients . Calculated PK parameters were similar to the three patient groups . In the male patients , plasma Gb3 level declined by 43 % after 6 months ( P<0.001 ) . Infusion reactions were experienced by 8 of 21 ( 38 % ) patients , but did not result in any infusions being stopped prematurely . Anti-agalsidase alfa IgG antibodies were detected in 15.8 % of males and 0 % female patients . No anti-agalsidase alfa IgE antibodies were detected . CONCLUSIONS The same dosing regimen of agalsidase alfa may be safely administered to FD patients with ESRD as given to those without ESRD Background Signs and symptoms of the X-linked disorder , Fabry disease ( FD ) , can occur early during childhood with heterogeneous clinical manifestations including potential cardiac and renal dysfunction . Several studies support the efficacy of the enzyme replacement therapy ( ERT ) agalsidase alfa , in adults with FD , though published data on the long-term safety and efficacy of agalsidase alfa in children are limited . As early treatment with ERT has the potential to reduce complications arising from disease progression , children in particular could benefit . The objective of this study was to evaluate the safety and efficacy of long-term agalsidase alfa ERT in children with FD . Methods TKT029 was a 6.5-year open-label , multicenter , extension study of children who completed TKT023 ( 26-week , open-label , every-other-week ,  intravenous 0.2 mg/kg agalsidase alfa )  . TKT029 was divided into two phases ( before and after an agalsidase alfa manufacturing process change ) ; only patients who participated in both phases were included in the analysis . Primary endpoints included safety , tolerability , and heart rate variability ( HRV ) . Additional efficacy parameters included left ventricular mass index ( LVMI ) , estimated glomerular filtration rate ( eGFR ) , and plasma/urine globotriaosylceramide ( Gb3 ) . Results Eleven patients participated ( phase 1 baseline median [ range ] age : 10.8 [ 8.6–17.3 ] years ; 10 [ 90.9 % ] males ) . During TKT029 ( 6.5 years ) , all patients experienced ≥1 treatment-emergent adverse event ( AE ) ; eight patients had ≥1 possibly/probably drug-related AE . Six patients experienced infusion-related AEs , but none discontinued due to AEs . Eight serious AEs arose ( two patients ) ; none were deemed drug-related . No deaths occurred . Three patients developed anti-agalsidase alfa antibodies , with IgG antibodies in one patient that were agalsidase alfa neutralizing , but without apparent clinical impact . Renal ( eGFR ) endpoints remained generally in normal range . Cardiac endpoints remained stable within normal range for LVMI and a trend towards improved HRV , although some patients experienced a reduction in heart rate . Plasma and urinary Gb3 reductions were maintained . Conclusions TKT029 represents the longest assessment of ERT in children with FD in a clinical trial setting . Overall , agalsidase alfa was well tolerated and demonstrated a stabilizing clinical effect . Agalsidase alfa may be a useful clinical therapeutic option for long-term treatment initiated during childhood in patients with FD.Trial registration http:// Clinical Trials.gov identifier http:// clinical trials.gov/show/NCT00084084 Background Fabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal , cardiac , cerebrovascular disease and premature death . Treatment with α-galactosidase A ( enzyme replacement therapy , ERT ) stabilises disease in some patients , but long term effectiveness is unclear . Methods Renal , cardiac , and cerebral outcomes were prospect ively studied in males and females with Fabry disease treated with ERT .  Additionally , the occurrence of major cardiac events , stroke , end-stage renal disease and death was compared to a natural history ( NH ) cohort meeting treatment criteria . Results Of 75 patients on ERT ( median treatment duration 5.2 years , range 0.05 - 11.0 ) , prospect i ve follow-up was available for 57 adult patients ( 30 males ) and 6 adolescents . Renal function declined in males ( -3.4 ml/min/1.73 m2 per year , SE 0.2 ; p < 0.001 ) despite ERT , but followed the normal course in females ( -0.8 ml/min/1.73 m2 per year , SE 0.3 ; p = 0.001 ) . Cardiac mass increased during ERT in males ( + 1.2 gram/m2.7 , SE 0.3 ; p < 0.001 ) , but remained stable in females ( -0.3 gram/m2.7 per year , SE 0.4 ; p = 0.52 ) . ERT did not prevent the occurrence of cerebral white matter lesions . Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age ( OR 1.05 ( 95 % CI : 1.0 - 1.1 ) per year , p = 0.012 ) . For development of a first or second complication the odds declined with longer treatment duration ( OR 0.81 ( 95 % CI : 0.68 - 0.96 ) per year of ERT , p = 0.015;OR 0.52 ( 0.31 - 0.88 ) , p = 0.014 respectively ) . Conclusions Long term ERT does not prevent disease progression , but the risk of developing a first or second complication declines with increasing treatment duration . ERT in advanced Fabry disease seems of doubtful benefit Aim : To assess the effects of enzyme replacement therapy ( ERT ) in children with Fabry disease RATIONALE AND AIM The aims of the Cochrane systematic review s are to make readily available and up-to- date information for clinical practice , offering consistent evidence and straightforward recommendations . In 2004 , we evaluated the conclusions from Cochrane systematic review s of r and omized controlled trials in terms of their recommendations for clinical practice and found that 47.83 % of them had insufficient evidence for use in clinical practice . We proposed to reanalyze the review s to evaluate whether this percentage had significantly decreased . METHODS A cross-sectional study of systematic review s published in the Cochrane Library ( Issue 7 , 2011 ) was conducted . We r and omly selected review s across all 52 Cochrane Collaborative Review Groups . RESULTS We analyzed 1128 completed systematic review s. Of these , 45.30 % concluded that the interventions studied were likely to be beneficial , of which only 2.04 % recommended no further research . In total , 45.04 % of the review s reported that the evidence did not support either benefit or harm , of which 0.8 % did not recommend further studies and 44.24 % recommended additional studies ; the latter has decreased from our previous study with a difference of 3.59 % . CONCLUSION Only a small number of the Cochrane collaboration 's systematic review s support clinical interventions with no need for additional research . A larger number of high- quality r and omized clinical trials are necessary to change the ' insufficient evidence ' scenario for clinical practice illustrated by the Cochrane data base . It is recommended that we should produce higher- quality primary studies in active collaboration and consultation with global scholars and societies so that this can represent a major component of method ological advance in this context OBJECTIVE To evaluate the safety and explore the efficacy of enzyme replacement therapy with agalsidase beta ( recombinant human alpha-galactosidase A ; Fabrazyme [ Genzyme Corporation , Cambridge , MA ] ) in pediatric patients with Fabry disease , a genetic disorder in which deficient endogenous enzyme causes pathogenic tissue accumulation of globotriaosylceramide ( GL-3 ) . STUDY DESIGN Fourteen male and 2 female patients , 8 to 16 years old , were treated in this open-label study . A 12-week observation period to collect baseline data preceded the 48-week treatment period when agalsidase beta ( 1 mg/kg ) was infused intravenously every 2 weeks . No primary efficacy end point was specified . RESULTS Before treatment , results of skin biopsies from 12 male patients showed moderate or severe GL-3 accumulation in superficial dermal capillary endothelial cells ; with treatment , these cells were completely cleared of GL-3 in week-24 biopsies from all 12 male patients and in all available week-48 biopsies . With treatment , reports of gastrointestinal symptoms declined steadily . Patient diaries documented significant reductions in school absences due to sickness .  Agalsidase beta was generally well tolerated ; most treatment-related adverse events were mild or moderate infusion-associated reactions involving rigors , fever , or rhinitis . CONCLUSIONS Agalsidase beta safely and effectively reduced the GL-3 accumulation in dermal endothelium already evident in children with Fabry disease . Early intervention may prevent irreversible end-organ damage from chronic GL-3 deposition This study was performed to determine whether adult male patients with Fabry disease who demonstrate a continuing decline in renal function despite 2 to 4 yr of conventionally dosed agalsidase alfa therapy ( 0.2 mg/kg every other week [ EOW ] ) show an improved slope of decline with weekly administration using the same dosage . Eleven ( 27 % ) of 41 adult male patients with Fabry disease who participated in long-term agalsidase alfa clinical trials and who had demonstrated a slope of decline in estimated GFR ( eGFR ) of > or = 5 ml/min per 1.73 m(2)/yr while receiving long-term treatment with agalsidase alfa at the currently recommended dosage of 0.2 mg/kg , infused EOW , were enrolled in this open-label , prospect i ve study . Patients were switched from EOW to weekly infusions and followed for an additional 24 mo . Before switching to weekly dosing , eGFR was 53.7 + /- 6.3 ml/min per 1. 
    Output:
    
Agalsidase beta is associated to a significantly lower incidence of renal , cardiovascular and cerebrovascular events than no ERT , and to a significantly lower incidence of cerebrovascular events than agalsidase alfa .