***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 Therapeutic hypothermia reduces death and disability after moderate or severe neonatal encephalopathy in high-income countries and is used as st and ard therapy in these setting s. However , the safety and efficacy of cooling therapy in low- and middle-income countries ( LMICs ) , where 99 % of the disease burden occurs , remains unclear . We will examine whether whole body cooling reduces death or neurodisability at 18–22 months after neonatal encephalopathy , in LMICs . Methods We will r and omly allocate 408 term or near-term babies ( aged ≤ 6 h ) with moderate or severe neonatal encephalopathy admitted to public sector neonatal units in LMIC countries ( India , Bangladesh or Sri Lanka ) , to either usual care alone or whole-body cooling with usual care . Babies allocated to the cooling arm will have core body temperature maintained at 33.5 ° C using a servo-controlled cooling device for 72 h , followed by re-warming at 0.5 ° C per hour . All babies will have detailed infection screening at the time of recruitment and 3 Telsa cerebral magnetic resonance imaging and spectroscopy at 1–2 weeks after birth . Our primary endpoint is death or moderate or severe disability at the age of 18 months . Discussion Upon completion , HELIX will be the largest cooling trial in neonatal encephalopathy and will provide a definitive answer regarding the safety and efficacy of cooling therapy for neonatal encephalopathy in LMICs . The trial will also provide important data about the influence of co-existent perinatal infection on the efficacy of hypothermic neuroprotection . Trial registration Clinical Trials.gov , NCT02387385 . Registered on 27 February 2015 Background Exercise training is an integral component of evidence -based management programs for many chronic cardiac and respiratory conditions . Despite this , there are limited high- quality studies available on the significance of exercise training in pulmonary hypertension ( PH ) . The aim of this study is to evaluate the short and long-term effectiveness of exercise training in PH patients in terms of exercise capacity , quality of life , cardiac function and disease progression . Methods This r and omized control trial will aim to recruit 50 medically stable PH patients categorised as New York Heart Association functional classification II-III . Participants will be r and omly allocated to either the supervised exercise training group or usual care group for the 8-week study period . Exercise training will be conducted in an outpatient setting . Measurements at baseline and following the 8-week study period include exercise capacity ( 6 min walk distance and cardiopulmonary exercise test ) , cardiac function ( exercise cardiac magnetic resonance imaging [ CMRI ] and echocardiography ) , health-related quality of life ( Cambridge Pulmonary Hypertension Outcome Review ) , adverse responses to exercise training and time to clinical worsening . In addition , participants will be followed up for a minimum of 2 year period from commencement of the study so as to monitor long-term clinical outcomes i.e. time to clinical worsening . Discussion This study will determine whether an 8-week outpatient based supervised exercise training program is safe and beneficial for medically stable PH patients in the short and long term . This will be the first study to examine the impact of exercise training on right heart function using exercise CMRI . Results from the study will contribute new knowledge in relation to the impact of  exercise training  on cardiac function , long-term prognosis and inform clinical practice guidelines for this patient population . Moreover , the study will add to our underst and ing regarding the efficacy of exercise training in individuals with PH in an outpatient setting .Trial registration Australia and New Zeal and Clinical Trials Registry : ACTRN12616001467426 . Registered 21st October , 2016 OBJECTIVE : To determine if multiple doses of erythropoietin ( Epo ) administered with hypothermia improve neuroradiographic and short-term outcomes of newborns with hypoxic-ischemic encephalopathy . METHODS : In a phase II double-blinded , placebo-controlled trial , we r and omized newborns to receive Epo ( 1000 U/kg intravenously ; n = 24 ) or placebo ( n = 26 ) at 1 , 2 , 3 , 5 , and 7 days of age . All infants had moderate/severe encephalopathy ; perinatal depression ( 10 minute Apgar < 5 , pH < 7.00 or base deficit ≥15 , or resuscitation at 10 minutes ) ; and received hypothermia . Primary outcome was neurodevelopment at 12 months assessed by the Alberta Infant Motor Scale and Warner Initial Developmental Evaluation . Two independent observers rated MRI brain injury severity by using an established scoring system . RESULTS : The mean age at first study drug was 16.5 hours ( SD , 5.9 ) . Neonatal deaths did not significantly differ between Epo and placebo groups ( 8 % vs 19 % , P = .42 ) . Brain MRI at mean 5.1 days ( SD , 2.3 ) showed a lower global brain injury score in Epo-treated infants ( median , 2 vs 11 , P = .01 ) . Moderate/severe brain injury ( 4 % vs 44 % , P = .002 ) , subcortical ( 30 % vs 68 % , P = .02 ) , and cerebellar injury ( 0 % vs 20 % , P = .05 ) were less frequent in the Epo than placebo group . At mean age 12.7 months ( SD , 0.9 ) , motor performance in Epo-treated ( n = 21 ) versus placebo-treated ( n = 20 ) infants were as follows : Alberta Infant Motor Scale ( 53.2 vs 42.8 , P = .03 ) ; Warner Initial Developmental Evaluation ( 28.6 vs 23.8 , P = .05 ) . CONCLUSIONS : High doses of Epo given with hypothermia for hypoxic-ischemic encephalopathy may result in less MRI brain injury and improved 1-year motor function OBJECTIVE : To determine the safety and pharmacokinetics of erythropoietin ( Epo ) given in conjunction with hypothermia for hypoxic-ischemic encephalopathy ( HIE ) . We hypothesized that high dose Epo would produce plasma concentrations that are neuroprotective in animal studies ( ie , maximum concentration = 6000–10 000 U/L ; area under the curve = 117 000–140 000 U*h/L ) . METHODS : In this multicenter , open-label , dose-escalation , phase I study , we enrolled 24 newborns undergoing hypothermia for HIE . All patients had decreased consciousness and acidosis ( pH < 7.00 or base deficit ≥ 12 ) , 10-minute Apgar score ≤ 5 , or ongoing resuscitation at 10 minutes . Patients received 1 of 4 Epo doses intravenously : 250 ( N = 3 ) , 500 ( N = 6 ) , 1000 ( N = 7 ) , or 2500 U/kg per dose ( N = 8) . We gave up to 6 doses every 48 hours starting at < 24 hours of age and performed pharmacokinetic and safety analyses . RESULTS : Patients received mean 4.8 ± 1.2 Epo doses . Although Epo followed nonlinear pharmacokinetics , excessive accumulation did not occur during multiple dosing . At 500 , 1000 , and 2500 U/kg Epo , half-life was 7.2 , 15.0 , and 18.7 hours ; maximum concentration was 7046 , 13 780 , and 33 316 U/L , and total Epo exposure ( area under the curve ) was 50 306 , 131 054 , and 328 002 U*h/L , respectively . Drug clearance at a given dose was slower than reported in uncooled preterm infants . No deaths or serious adverse effects were seen . CONCLUSIONS : Epo 1000 U/kg per dose intravenously given in conjunction with hypothermia is well tolerated and produces plasma concentrations that are neuroprotective in animals . A large efficacy trial is needed to determine whether Epo add-on therapy further improves outcome in infants undergoing hypothermia for HIE OBJECTIVE Our aim was to compare the effectiveness of a one-month treatment with recombinant human erythropoietine ( rHuEpo ) according to the administration route . METHODS Retrospective study based on the data collection from medical files of 64 preterm infant hospitalized in the " institut de puériculture et de périnatalogie " ( Paris ) between January 13th , 2002 and April 13th , 2002 . The first group ( N = 33 ) was treated by subcutaneous rHuEpo 750 IU/kg per week , in three injections by week , for one month . The second group ( N = 15 ) was treated by continuous infusion of rHuEpo in total parenteral nutrition 1050 IU/kg per week ( 30 % augmentation to compensate the amount absorbed by the filter ) . The third group ( N = 16 ) received 750 IU/kg per week of rHuEpo in three direct intravenous injections . The effectiveness of rHuEpo was evaluated by the absolute reticulocyte count , the level of hemoglobin and the incidence of blood transfusion ( multiple logistic analysis of variant and regression ) . RESULTS The absolute reticulocyte count and hemoglobin level were significantly reduced after one month of treatment by continuous infusion of rHuEpo in total parenteral nutrition and direct intravenous injections compared with a one-month treatment by subcutaneous rHuEpo .  Hemoglobine level were at 8.8 and 9.6 g/dl vs 10.3 g/dl ( P = 0.02 ) and absolute reticulocyte count at 123,000/mm3 and 190,000/mm3 vs 216,000/mm3 ( p = 0.001 ) . The number of transfused infants was significantly increased with utilization of continuous ( 40 % ) and direct intravenous ( 75 % ) compared with those treated by subcutaneous route ( 21.2 % ) while the ferritin level and phlebotomy losses were not significantly different in the three groups . The number of blood transfusion was significantly linked to phlebotomy losses and administration route of rHuEpo . CONCLUSION Our study tends to demonstrate that rHuEpo administered subcutaneously reduces significantly the number of transfusion in contrary to intravenous routes . Waiting for pilot study and new molecules , we recommend subcutaneous administration of rHuEpo to preterm infants 250 IU/kg three times weekly in the treatment of anemia of prematurity OBJECTIVE : The purpose of this study was to evaluate the efficacy and safety of erythropoietin in neonatal hypoxic-ischemic encephalopathy ( HIE ) , by using a r and omized , prospect i ve study design . METHODS : A total of 167 term infants with moderate/severe HIE were assigned r and omly to receive either erythropoietin ( N = 83 ) or conventional treatment ( N = 84 ) . Recombinant human erythropoietin , at either 300 U/kg ( N = 52 ) or 500 U/kg ( N = 31 ) , was administered every other day for 2 weeks , starting < 48 hours after birth . The primary outcome was death or disability . Neurodevelopmental outcomes were assessed at 18 months of age . RESULTS : Complete outcome data were available for 153 infants . Nine patients dropped out during treatment , and 5 patients were lost to follow-up monitoring . Death or moderate/severe disability occurred for 35 ( 43.8 % ) of 80 infants in the control group and 18 ( 24.6 % ) of 73 infants in the erythropoietin group ( P = .017 ) at 18 months . The primary outcomes were not different between the 2 erythropoietin doses . Subgroup analyses indicated that erythropoietin improved long-term outcomes only for infants with moderate HIE ( P = .001 ) and not those with severe HIE ( P = .227 ) . No negative hematopoietic side effects were observed . CONCLUSION : Repeated , low-dose , recombinant human erythropoietin treatment reduced the risk of disability for infants with moderate HIE , without apparent side effects Abstract Objective : To determine the safety and efficacy of single dose systemic recombinant human erythropoietin ( rEPO ) in neonates with perinatal hypoxic Ischemic Encephalopathy ( HIE ) , and its effect on serum brain-derived neurotrophic factor ( BDNF ) and neuron-specific enolase ( NSE ) . Methods : Forty-five full-term neonates ; 30 with perinatal HIE and 15 controls were studied . HIE neonates were r and omized into three intervention groups ( first 6 h of life ) : 10 received single subcutaneous 1500 U/kg rEPO at day-1 , 10 subjected to hypothermia for 72 h and 10 received supportive care .  BDNF and NSE measured during first 6 h and day  
    Output:
    
Conclusion EPO administration in neonates with perinatal HIE  reduces the risk of brain injury , cerebral palsy and cognitive impairment .
The evidence is limited to suggest its role as an adjuvant to hypothermia .