Exercise training improves activity in adolescents with congenital heart disease Design and rationale for the PREVAIL study: effect of e-Health individually tailored encouragements to physical exercise on aerobic fitness among adolescents with congenital heart disease--a randomized clinical trial. Clinical assessment of cardiac performance in infants and children following cardiac surgery Six-minute walking test to assess exercise tolerance and cardiorespiratory responses during training program in children with congenital heart disease. Prediction of preschool functional abilities after early complex cardiac surgery. A new look at outcomes of infants with congenital heart disease. Cardiac rehabilitation improves functional capacity and patient-reported health status in patients with continuous-flow left ventricular assist devices: the Rehab-VAD randomized controlled trial. Patterns of Developmental Dysfunction After Surgery During Infancy to Correct Transposition of the Great Arteries Cardiopulmonary exercise parameters in children with atrial septal defect and increased pulmonary blood flow: short‐term effects of defect closure Reproducibility of Maximal and Submaximal Exercise Testing in “Normal Ambulatory” and “Community Ambulatory” Children and Adolescents With Spina Bifida: Which Is Best for the Evaluation and Application of Exercise Training? Performance of 2-year-old children after early surgery for congenital heart disease on the Bayley Scales of Infant and Toddler Development, Third Edition. Effects of group-based high-intensity aerobic interval training in patients with chronic heart failure. Neurologic status of newborns with congenital heart defects before open heart surgery. Neurodevelopment in children with hypoplastic left heart syndrome. Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease. Relationship between Social-Emotional and Neurodevelopment of 2-Year-Old Children with Congenital Heart Disease. Severe Congenital Heart Defects Are Associated with Global Reduction of Neonatal Brain Volumes.
Objectives To ascertain if motivational techniques and a structured exercise programme can increase activity in adolescents afflicted with congenital heart disease ( CHD ) . Design Prospect i ve r and omised controlled trial . Setting One hundred and forty-three patients aged 12–20 years attending the tertiary centre for paediatric cardiology in Northern Irel and . Main outcome measures Increase in exercise capacity as assessed by duration of exercise stress test , and number of minutes spent in moderate to vigorous physical activity ( MVPA ) per day . Results Eighty-six patients were men ( 60 % ) , mean age was 15.60±2.27 years . Seventy-three percent were considered to have major CHD . Seventy-two participants were r and omised to the intervention group . Following intervention , duration of exercise test increased by 1 min 5 s for the intervention group ( p value 0.02 ) along with increase in predicted VO2Max ( p value 0.02 ) . There was a significant increase in minutes of MVPA per day for the intervention group from baseline to re assessment ( p value < 0.001 ) while MVPA remained much the same for the control group . Fourteen patients met the current recommendation for more than 60 min MVPA per day at baseline . This doubled to 29 participants at re assessment . There were no adverse effects or mortalities reported . Conclusions Exercise training  is safe , feasible and beneficial in adolescents with CHD . Psychological techniques can be employed to maximise the impact of interventions . Trial Registration Number IS RCT N27986270 Intensive exercise may be an important part of rehabilitation in patients with congenital heart disease ( CHD ) . However , performing regular physical exercise is challenging for many adolescent patients . Consequently , effective exercise encouragements may be needed . Little is known on the effect of e-Health encouragements on physical fitness , physical activity , and health-related quality of life in adolescents . This trial is a nationwide interactive e-Health rehabilitation study lasting 1 year , centered on interactive use of mobile phone and Internet technology . We hypothesize that e-Health encouragements and interactive monitoring of intensive exercise for 1 year can improve physical fitness , physical activity , and health-related quality of life .  Two hundred sixteen adolescents ( age , 13 - 16 years ) with surgically corrected complex CHD but without significant hemodynamic residual defects and no restrictions to participate in physical activity are in the process of being enrolled by invitation after informed consent . Physical fitness is measured as the maximal oxygen uptake ( Vo(2 ) ) at baseline and after 12 months by an assessor blinded to the r and omization group . After baseline testing , the patients are 1:1 r and omized to an intervention group or a control group . Individually fully automated tailored e-Health encouragements -- SMS , Internet , and mobile applications--  aim ed at increasing physical activity  are delivered to the participants in the intervention group once a week . The B and ura 's Social Cognitive Theory inspires the behavioral theoretical background . The e-Health intervention and the Godfrey cycle ergometer protocol have been feasibility tested and seem applicable to adolescents with CHD . The trial is expected to contribute with new knowledge regarding how physical activity in adolescents with CHD can be increased and , possibly , comorbidity be reduced Objective To compare clinical assessment of cardiac performance with an invasive method of haemodynamic monitoring . Design and setting Prospect i ve observational study in a 16-bed tertiary paediatric intensive care unit . Patients and participants Infants and children undergoing cardiopulmonary bypass and surgical repair of congenital heart lesions . Interventions Based on physical examination and routinely available haemodynamic monitoring in the paediatric intensive care unit , medical and nursing staff assessed cardiac index , systemic vascular resistance index and volume status . Clinical assessment was compared with cardiac index , systemic vascular resistance index and global end diastolic volume index  , obtained by femoral artery thermodilution . Measurements and results A total of 76 clinical estimations of the three parameters were made in 16 infants and children undergoing biventricular repair of congenital heart lesions . Agreement was poor between clinical and invasive methods of determining all three studied parameters of cardiac performance . Cardiac index was significantly underestimated clinical ly ; mean difference was 0.71 l min−1 m−2 ( 95 % range of agreement ±2.7 ) . Clinical estimates of systemic vascular resistance ( weighted κ=0.15 ) and volume status ( weighted κ=0.04 ) showed poor levels of agreement with measured values and were overestimated clinical ly . There was one complication related to a femoral arterial catheter and one device failure . Conclusions Routine clinical assessment of parameters of cardiac performance agreed poorly with invasive determinations of these indices . Management decisions based on inaccurate clinical assessment s may be detrimental to patients . Invasive haemodynamic monitoring using femoral artery thermodilution warrants cautious further evaluation as there is little agreement with clinical assessment which is presently st and ard accepted care in this patient population This study assessed the exercise tolerance and the cardiorespiratory responses to a training program by the six-minute walk test ( 6'WT ) in children with congenital heart disease ( CHD ) . Seventeen cardiac and 14 healthy children performed maximal cardiopulmonary exercise test ( CPET ) and 6'WT . Reliability of 6'WT was assessed in all subjects ( test-retest ) by Bl and -Altman plots . Cardiac subjects were r and omly divided in training ( T-CHD ) and control groups ( C-CHD ) . T-CHD underwent an individualized training exercise at the ventilatory threshold ( VT ) intensity during 12 weeks . We found that the 6'WT is a reliable and reproducible test . CHD children  walked a lower distance than healthy children before training ( 472.5 + /- 18.1 vs. 548.8 + /- 7.7 m , respectively , p < 0.001 ) . Likewise , power output , oxygen uptake ( V.O ( 2 ) ) , and heart rate ( HR ) at the maximum and the VT levels , were significantly lower in patients ( p < 0.001 ) . After training , a significant improvement of walking distance ( WD ) was shown in T-CHD ( 529.6 + /- 15.3 vs. 467.7 + /- 17.1 m , p < 0.001 ) . The power output , VO2 , HR , and V.E increased slightly ( 6 to 10 % , p > 0.05 ) at peak exercise and significantly at ventilatory threshold level ( p < 0.05 ) in T-CHD . Significant relationships between WD and VO2max as well as VO2 at VT were founded ( p < 0.05 ) . We concluded that the 6'WT is a useful and reliable tool in the assessment and follow-up of functional capacity during rehabilitation program in children with CHD BACKGROUND It is important to identify early predictors of functional limitations in children after congenital heart surgery to optimise their independence as they prepare for school . The purpose of this study is to determine potentially modifiable predictor variables of functional abilities in pre-school children who underwent complex cardiac surgery at 6 weeks of age or earlier . METHODS This prospect i ve inception cohort study comprised a sample of 165 survivors ( 63 % boys ) who had complex cardiac surgery ( 75 % biventricular repairs ) at Stollery Children 's Hospital , Edmonton , Alberta . We excluded children with chromosomal abnormalities . When children were 4 - 5 years of age , the parents completed the Adaptive Behavioral Assessment System II . Regression analysis was used to assess the association between multiple risk factors and each of the four continuous composite scores . RESULTS The mean scores for the practical domain and general adaptive composite score of the Adaptive Behavioural Assessment System were lower than the conceptual and social domains , with 13.3 % of the children having a delay in the practical domain . There was a significant association between the general adaptive ( p=0.003 ; 0.012 ) , conceptual ( p=0.0004 ; 0.042 ) , social ( p=0.0007 ; 0.028 ) , and the practical ( p=0.046 ; 0.003 ) domain composite scores with the mother 's education and preoperative plasma lactate , respectively . CONCLUSION Maternal education may be a marker for the social context of children , and warrants societal attention to improve functional outcomes . Preoperative lactate as a potentially modifiable variable may warrant increased attention to early diagnosis and aggressive resuscitation of young infants with congenital heart disease This article provides an overview of a longitudinal study on a cohort of 131 newborns and young infants with congenital heart defects who required open heart surgery .  The rationale for the study design is provided as well as a summary of the procedures used to evaluate these children prior to surgery , at discharge after surgery , 12 - 18 months later , and at 5 years of age . Results demonstrate that a substantial proportion of these infants had neurologic and developmental abnormalities prior to surgical repair . Developmental delays were common in children with both cyanotic and acyanotic heart defects , and these deficits persisted to school entry . A number of medical , surgical , demographic and environmental factors were significantly associated with developmental outcomes suggesting a multifactorial etiology to brain injury . Limited educational and rehabilitation re sources for this cohort at early school age suggests that service needs may need to be more carefully planned for this high-risk population . Lessons learnt from this prospect i ve study are highlighted as well as future directions for research and clinical practice OBJECTIVES This study examined the effects of a cardiac rehabilitation ( CR ) program on functional capacity and health status ( HS ) in patients with newly implanted left ventricular assist devices ( LVADs ) . BACKGROUND Reduced functional capacity and HS are independent predictors of mortality in patients with heart failure .  CR improves both , and is related to improved outcomes in patients with heart failure ; however , there is a paucity of data that describe the effects of CR in patients with LVADs . METHODS Enrolled subjects ( n = 26 ; 7 women ; age 55 ± 13 years ; ejection fraction 21 ± 8 % ) completed a symptom-limited cardiopulmonary exercise test , the Kansas City Cardiomyopathy Question naire ( KCCQ ) , a 6-min walk test ( 6MW ) , and single-leg isokinetic strength test before 2:1 r and omization to CR versus usual care . Subjects in the CR group underwent 18 visits of aerobic exercise at 60 % to 80 % of heart rate reserve . Within-group changes from baseline to follow-up were analyzed with a paired t-test , whereas an independent t-test was used to determine differences in the change between groups . RESULTS Within-group improvements were observed in the CR group for peak oxygen uptake ( 10 % ) , treadmill time ( 3.1 min ) , KCCQ score ( 14.4 points ) , 6MW distance ( 52.3 m ) , and leg strength ( 17 % ) . Significant differences among groups were observed for KCCQ , leg strength , and total treadmill time . CONCLUSIONS Indicators of functional capacity and HS are improved in patients with continuous-flow LVADs who attend CR . Future trials should examine the mechanisms responsible for these improvements , and if such improvements translate into improved clinical outcomes . ( Cardiac Rehabilitation in Patients With Continuous Flow Left Ventricular Assist Devices : Rehab VAD Trial [ RehabVAD ] ; NCT01584895 ) A r and omized clinical trial was conducted to compare the early development of children with d-transposition of the great arteries ( N=171 ) repaired by an arterial switch operation that used either  predominantly total circulatory arrest or predominantly continuous low-flow cardiopulmonary bypass . The children assigned to the circulatory arrest group scored lower than those assigned to low-flow bypass on the Bayley Scales of Infant Development at 1 year of age . Responses to parental question naires completed when the children were 2.5 years old indicated that the children in the circulatory arrest group , especially those with a ventricular septal defect , also manifested poorer expressive language and were considered to display more internalizing and externalizing problem behaviors . The use of circulatory arrest to protect vital organs during open heart surgery might place children at increased risk of early developmental difficulties , especially in the domains of motor and language function Markedly increased pulmonary blood flow because of a relevant atrial septal defect ( ASD ) leads to impaired cardiopulmonary function during maximum exercise in adults . No comparative preoperative and postoperative data are available on the short‐term effects of shunt closure on cardiorespiratory function at peak exercise in children .  Pulmonary function testing at rest and cardiopulmonary exercise testing together with haemodynamic assessment was done prospect ively in children with an ASD preoperatively and again after full recovery at 3–4 mo postoperatively and compared with a matched normal population . Sixteen children , aged 6.8–16.1 y , with a defect of 8–23 mm ( median 15 mm ) and a pulmonary/systemic flow ratio of 1.5–3.5 ( median 2.2 ) were tested and compared with 15 healthy children . Preoperatively , baseline pulmonary function parameters and exercise capacity were no different from normals . At peak exercise , patients with a shunt had increased pulmonary resistance , especially of the distal airways ( p= 0.04 ) , with a significantly larger proportion of children having a paradoxical increase in total airway resistance during exercise ( p < 0.05 ) . Maximum serum lactate at peak exercise was elevated ( p < 0.05 ) in patients . In patients , maximum oxygen uptake was impaired ( p= 0.03 ) and remained so at repeat evaluation postoperatively . The same observation was made for chronotropic response to exercise Background With emerging interest in exercise and lifestyle interventions for children and adolescents with spina bifida , there is a need for appropriate measurements in exercise testing . Objective The purpose of this study was to assess both reliability and agreement of maximal and submaximal exercise measures in “ normal ambulatory ” and “ community ambulatory ” children and adolescents with spina bifida . Design This was a reproducibility study . Methods Twenty-three children and adolescents with spina bifida ( 10 normal ambulatory and 13 community ambulatory ) participated in the study . Maximal exercise outcomes were measured using a grade d treadmill test .  Peak measures ( peak oxygen uptake [ V̇o2peak ] , peak heart rate [ HRpeak ] , heart rate response [ HRR ] , and oxygen pulse ) were recorded . For submaximal measures , heart rate ( HR ) and oxygen uptake ( V̇o2 ) at the ventilatory threshold and oxygen uptake efficiency slope ( OUES ) were derived from the maximal measures . Functional performance was measured as the 6-minute walking distance and the maximal speed during the treadmill test . After checking for normality and heteroscedasticity , paired t tests , intraclass correlation coefficients ( ICCs ) , and the smallest detectable difference ( SDD ) or the coefficient of variation ( CV ) were calculated . Results Performance measures showed good reliability and agreement . For maximal measures , acceptable ICCs were found for all measures . For submaximal measures , only HR at the ventilatory threshold showed an ICC of less than .80 . Agreement showed a CV of less than 10 % for all measures , except for V̇o2 at the ventilatory threshold , HRR , and OUES . Limitations Limitations of the study include missing data due to equipment failure . Furthermore , the outcomes were limited to normal ambulatory and community ambulatory children and adolescents with spina bifida . Conclusions Both maximal and submaximal measures of exercise testing can be used for discriminative purpose s in ambulatory children and adolescents with spina bifida . For evaluative purpose s , HR measures are superior to V̇o2 measures , while taking into account the individual variation of 5 % to 8 % . The SDD was 0.5 km/h for peak speed and 36.3 m for 6-minute walking distance . Heart rate response , oxygen pulse , and OUES are not recommended in the evaluation of exercise testing in this population BACKGROUND Previous research on developmental outcomes of infants with congenital heart disease ( CHD ) has shown delays in both cognitive and motor skills . AIMS To describe outcomes on the Bayley Scales of Infant and Toddler Development , 3rd edition ( Bayley-III ) for infants with CHD and to compare those findings to published results for similar sample s of infants assessed on the 2nd edition of the Bayley Scales ( BSID-II ) . STUDY DESIGN Prospect i ve cohort . PARTICIPANTS AND OUTCOME MEASURES Of 50 infants with CHD who participated in this longitudinal study ( 2006 - 2008 ) at the Royal Children 's Hospital in Melbourne , Australia , 47 were assessed on the Bayley-III ( median age=24.5 months ) ,  administered by a psychologist or neonatologist . Although neither assessor was blind to the CHD diagnosis , they were unaware of results of previous developmental assessment s conducted in this longitudinal study . RESULTS For the Bayley-III cognitive composite score , 17.0 % of infants showed mild delays ( 1 - 2 SD below the mean ) , 2.1 % had moderate delays ( 2 - 3 SD below the mean ) , and none had severe delays ( greater than 3 SD below the mean ) . Motor composite scores showed mild delays in 10.9 % of infants and moderate delays in 2.2 % ; none had severe motor delays . These findings differ from study results using the BSID-II in similar infants . CONCLUSIONS The Bayley-III may underestimate developmental delay in 2-year-old children with CHD when compared to results of similar children tested at 12 - 36 months of age on the BSID-II The aim of this study was to evaluate the effectiveness of a novel group-based aerobic interval training of high intensity on functional capacity and quality of life in patients with chronic heart failure ( CHF ) and examine the relation between changes in functional capacity and quality of life .  Eighty patients with stable CHF ( 63 men , 17 women ; mean age 70.1 + /- 7.9 [ SD ] years ; left ventricular ejection fraction 30 + /- 8.5 % ) on optimal medical treatment were r and omly assigned to either a 16-week group-based aerobic high-intensity interval training model twice weekly for 65 to 80 minutes/day ( n = 40 ) or a control group ( n = 40 ) that received st and ard care .  Functional capacity was measured using the 6-minute walk test and cycle ergometer test . Quality of life was measured using the Minnesota Living with Heart Failure Question naire . After 16 weeks , functional capacity improved significantly in the exercise group compared with the control group measured using the 6-minute walk test ( + 58 vs -15 meters ; p < 0.001 ) and for both workload and time measured using the bicycle ergometer test ( + 10 vs -1 W ; p < 0.001 ; + 57 vs -8 seconds ; p < 0.001 ) . Quality of life improved significantly in the exercise group compared with the control group ( p = 0.03 ) , and a significant inverse correlation was found between quality of life and functional capacity ( r = -0.49 , p < 0.05 ) . In conclusion , our exercise model significantly improved functional capacity and quality of life compared with the control group in patients with CHF . Improvements in quality of life were significantly related to functional capacity UNLABELLED Controversy exists regarding the integrity of the nervous system in the newborn with a congenital heart defect who must undergo corrective or palliative open heart surgery .  Neurodevelopmental sequelae have been primarily attributed to surgical procedures without st and ardized evaluation of the preoperative neurologic status . OBJECTIVE To determine whether newborns with congenital heart defects demonstrate abnormalities in neurobehavioral status before surgery . STUDY DESIGN In this prospect i ve study , a st and ardized neonatal neurobehavioral assessment and a neurologic examination  were conducted independently in a consecutive series of 56 neonates referred to our hospital for investigation of open heart surgery . RESULTS Neurobehavioral and neurologic abnormalities were documented in greater than half of the cohort and included hypotonia , hypertonia , jitteriness , motor asymmetries , and absent suck . Poor state regulation ( 62 % ) and feeding difficulties ( 34 % ) also were commonly observed . Furthermore , 3 subjects had seizures , 35.7 % were microcephalic , and 12.5 % were macrocephalic . The overall likelihood of neurobehavioral abnormalities was not enhanced by indicators of cardiorespiratory compromise . Interestingly , newborns with acyanotic congenital heart defects were more likely to demonstrate neurologic compromise than were those with cyanotic defects . CONCLUSIONS Findings suggest that the prevalence of neurobehavioral abnormalities before surgery in newborns with congenital heart defects has been underappreciated and would indicate that factors other than intraoperative procedures should be considered in the genesis of brain injury in this population .congenital heart defects , neurologic examination , newborn OBJECTIVE To assess neurodevelopment in children with hypoplastic left heart syndrome ( HLHS ) or other types of functionally single ventricle ( univentricular heart , UVH ) and to estimate the effect of possible clinical predictors on outcome . STUDY DESIGN A total of 22 patients with HLHS and 14 with UVH , surviving after palliative surgery performed in the same center , and 42 healthy control subjects were examined at a median age of 30.2 months neurologically and according to the Bayley Scales of Infant Development  in a population based prospect i ve neurodevelopmental follow-up study . RESULTS The mean Mental Developmental Index was significantly lower ( 89.9 ) in patients with HLHS than in control subjects ( 105.5 , P<.001 ) , whereas there was no difference between patients with UVH ( 98.5 ) and control subjects . The mean Psychomotor Developmental Index in patients with HLHS ( 80.7 , P<.001 ) as well as in those with UVH ( 94.5 , P=.016 ) was significantly inferior to that in control subjects ( 105.3 ) . CONCLUSIONS In patients with HLHS , mean Mental Developmental Index lags behind control subjects . Psychomotor Developmental Index is impaired in patients with both HLHS and UVH . Routine neurodevelopmental follow-up is recommended for this seriously ill patient group BACKGROUND The objective of this prospect i ve study was to assess the efficacy of exercise training as add-on to medical therapy in patients with congenital heart disease associated pulmonary arterial hypertension ( CHD-APAH ) . METHODS Patients with invasively confirmed CHD-APAH received in-hospital exercise training for 3 weeks and continued at home . Efficacy parameters were evaluated at baseline , after 3 and 15 weeks . Medical treatment remained unchanged . Worsening events and survival rate were assessed in a follow-up period of 21 ± 14 months . RESULTS Twenty consecutive CHD-APAH patients ( 16 female , 4 male , mean pulmonary arterial pressure 60 ± 23 mm Hg ) were included . Patients significantly improved the mean distance walked in 6 min compared to baseline by 63 ± 47 m after 3 weeks ( p<0.001 ) and by 67 ± 59 m after 15 weeks ( p=0.001 ) . Quality of life-score ( p=0.05 ) , peak oxygen consumption ( p=0.002 ) and maximal workload ( p=0.003 ) improved significantly by exercise training after 15 weeks . The 1- and 2-year survival rates were 100 % , the transplantation-free survival rate was 100 % after 1 year and 93 % after 2 years . CONCLUSION Exercise training as add-on to medical therapy may be effective in patients with CHD-APAH and improved work capacity , quality of life and further prognostic relevant parameters . It was associated with an excellent long-term survival . Further r and omized controlled studies are needed to confirm these results OBJECTIVE The purpose of this study was to describe social-emotional outcomes and the relationship with neurodevelopmental outcomes in a cohort of 2-year-old children who underwent surgery for congenital heart disease ( CHD ) in infancy , and explore the relationship between the outcomes and parental and surgical factors . DESIGN A two-center prospect i ve cross-sectional cohort study . PATIENTS A cohort of 105 2-year-olds who underwent surgery in infancy for severe CHD MEASURES : Social-emotional and neurodevelopment was evaluated with the  Infant and Toddler Social and Emotional Assessment tool ( ITSEA ) , and the Bayley Scales of Infant Toddler Development , Third Edition . RESULTS Neurodevelopment was delayed in the CHD cohort with significantly worse results compared to published Australian-based norms in all domains ( P < .001 ) and in the Cognitive ( P < .001 ) and Language ( P < .001 ) domains with respect to the reported American norms . Social-emotional outcome was similar to Australian norms in all domains but better than the American based norms in the Internalizing domain ( P < .05 ) . Higher maternal education was associated to better neurodevelopmental outcome in all domains and better scores in the internalizing and externalizing domains of the ITSEA . There was a moderate correlation ( r = 0.43 , P < .001 ) between Language and social-emotional competence . Motor development was influenced by the need for a significant cardiac reoperation . CONCLUSIONS The influences of social factors may be underestimated in the outcome of children with CHD .  Language development in those with CHD may be improved with intervention targeting social-emotional competence ; further research is needed in this area OBJECTIVES To determine neonatal global and regional brain volumes in infants with congenital heart disease ( CHD ) in comparison with healthy controls and to determine brain growth . STUDY DESIGN Prospect i ve cohort study in infants undergoing open-heart surgery for complex CHD . Global and regional volumetric measurements on preoperative cerebral magnetic resonance imaging were manually segmented in children without overt brain lesions . RESULTS Preoperative brain volumetry of 19 patients demonstrates reduction in total and regional brain volumes , without any specific regional predilection compared with 19 healthy control infants ( total brain volume reduction : 21 % , regional brain volume reduction 8%-28 % , all P < .001 ) . CONCLUSIONS Infants with CHD undergoing bypass surgery  have smaller brain volumes prior to surgery without a specific regional predilection . This suggests a fetal origin of reduced brain growth
Children and adolescents with CHD have lower VO2max and HR compared to controls
BACKGROUND Children and adolescents with congenital heart disease often have alterations in their exercise capacity that can be evaluated by various functional testing .
OBJECTIVE To evaluate the functional capacity of children and adolescents with congenital heart disease ( CHD ) with systematic review and meta-analyses .