An update on the impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk of bronchopulmonary dysplasia.

Infants at higher risk of bronchopulmonary dysplasia had increased rates of survival free of cerebral palsy after postnatal corticosteroid treatment in a previous metaregression of data from 14 randomized controlled trials. The relationship persists and is stronger in an updated analysis with data from 20 randomized controlled trials.

Changes in circulating red cell volume during the first 6 weeks of life in very-low-birth-weight infants.

BACKGROUND: Little is known about the change in circulating red cell volume (RCV) of very-low-birth-weight (VLBW) infants during the first weeks of life. METHODS: RCV was measured during the first 5 d in 35 VLBW infants using chromium-51 labeling of the infants' red blood cells (RBCs). RCV was measured again at 6 wk of age in 12 infants, and the volumes of RBCs lost by phlebotomy and those gained by transfusion were recorded between the RCV measurements. In six infants, the volume of waste blood on materials contaminated with blood during phlebotomy, which would usually be discarded, was measured by radioactive counting. RESULTS: The mean RCV in the first several days of life was 39.6 ml (35.7 ml/kg; range: 20.1-58.7 ml/kg). Of the 12 infants whose RCV was measured twice, all but one had a decrease in absolute RCV. The mean RCV initially and at 6 wk were 37.3 and 26.6 ml, respectively. The mean volume of RBCs lost through phlebotomy was 29.2 ml, and the mean volume of RBCs given by transfusion was 34.5 ml. CONCLUSION: During the first 6 wk of life, when the anemia of prematurity is evolving, the RCV falls despite complete replacement of RBCs lost by diagnostic phlebotomy with transfused RBCs.

A generalised model for individualising a treatment recommendation based on group-level evidence from randomised clinical trials.

OBJECTIVES: Randomised controlled trials report group-level treatment effects. However, an individual patient confronting a treatment decision needs to know whether that person's expected treatment benefit will exceed the expected treatment harm. We describe a flexible model for individualising a treatment decision. It individualises group-level results from randomised trials using clinical prediction guides. METHODS: We constructed models that estimate the size of individualised absolute risk reduction (ARR) for the target outcome that is required to offset individualised absolute risk increase (ARI) for the treatment harm. Inputs to the model include estimates for the individualised predicted absolute treatment benefit and harm, and the relative value assigned by the patient to harm/benefit. A decision rule recommends treatment when the predicted benefit exceeds the predicted harm, value-adjusted. We also derived expressions for the maximum treatment harm, or the maximum relative value for harm/benefit, above which treatment would not be recommended. RESULTS: For the simpler model, including one kind of benefit and one kind of harm, the individualised ARR required to justify treatment was expressed as required ARRtarget(i)=ARIharm(i) × RVharm/target(i). A complex model was also developed, applicable to treatments causing multiple kinds of benefits and/or harms. We demonstrated the applicability of the models to treatments tested in superiority trials (either placebo or active control, either fixed harm or variable harm) and non-inferiority trials. CONCLUSIONS: Individualised treatment recommendations can be derived using a model that applies clinical prediction guides to the results of randomised trials in order to identify which individual patients are likely to derive a clinically important benefit from the treatment. The resulting individualised prediction-based recommendations require validation by comparison with strategies of treat all or treat none.

Constructing arrays of proteins.

The construction of crystalline arrays allows proteins to be presented in a dense, oriented and functional way that also facilitates determination of their structure. Rational design of these supramolecular structures is becoming increasingly tractable with recent successes exploiting both innate protein symmetry and advances in protein­protein interface design. Pre-existing symmetry minimizes the number of non-native interfaces that must be produced, and the use of symmetric interfaces facilitates protein alignment. Arrays in which metal coordination or peptide binding are responsible for the inter-particle associations show particular promise due to the malleable and reversible nature of these interactions. Cross-pollination of the principles that underlie successful strategies is likely to produce rapid advances in this field and consequent benefits to both nanotechnology and structural biology.

Interventions for treatment of neonatal hyperglycemia in very low birth weight infants.

BACKGROUND: Early neonatal hyperglycemia is common among very low birth weight (VLBW) neonates. Increased risks for death and major morbidities have been observed among VLBW neonates who develop hyperglycemia. It is uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or whether the incidence of adverse outcomes can be reduced by treatment. OBJECTIVES: To assess the effects on clinical outcomes of interventions for treating neonatal hyperglycemia in the VLBW neonate receiving total or partial parenteral nutrition. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 of 12, 2011), MEDLINE (1966 to April 2011), EMBASE (1980 to April 2011) and CINAHL (1982 to July 2008). We searched for abstracts submitted for the annual meetings of Pediatric Academic Societies 2000 to 2011 and The European Society for Pediatric Research  2005 to 2010. SELECTION CRITERIA: Randomized or quasi-randomized trials of interventions for the treatment of hyperglycemia in hyperglycemic VLBW neonates were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility and extracted data on study design, methodology, clinical features, and treatment outcomes. Additional information on study design and outcomes was obtained from the lead investigator of each of the two included trials. The included trials were assessed for blinding of randomization, blinding of caretakers to the intervention, completeness of follow-up, and blinding of outcome measurement. The treatment effect measures for categorical outcomes were relative risk (RR) and risk difference (RD) with their 95% confidence intervals (CI); for continuous outcomes the measure was mean difference and 95% CI. MAIN RESULTS: Only two eligible trials were found (Collins 1991; Meetze 1998). Both were randomized but of very small size (24 and 23 neonates randomized in each trial, respectively).No trial compared reduction versus no reduction of glucose infusion.Collins 1991 compared insulin infusion with standard care. Insulin infusion had no significant effect on death or bacterial sepsis; effects on other major morbidities were not assessed. Insulin infusion resulted in significant increases in non-protein energy intake, glucose intake, and short-term weight gain.Meetze 1998 compared insulin infusion with reduction of glucose infusion. Insulin infusion had no significant effects on death, severe intraventricular hemorrhage, retinopathy of prematurity, bacterial sepsis, fungal sepsis, or necrotizing enterocolitis; effects on other major morbidities were not assessed. Insulin infusion resulted in significant increases in glucose intake and total energy intake. AUTHORS' CONCLUSIONS: Evidence from randomized trials in hyperglycemic VLBW neonates is insufficient to determine the effects of treatment on death or major morbidities. It remains uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or how the hyperglycemia should be treated. Much larger randomized trials in hyperglycemic VLBW neonates that are powered on clinical outcomes are needed in order to determine whether, and how, the hyperglycemia should be treated.

Interventions for prevention of neonatal hyperglycemia in very low birth weight infants.

BACKGROUND: Among very low birth weight (VLBW) infants, early neonatal hyperglycemia is common and is associated with increased risks for death and major morbidities. It is uncertain whether hyperglycemia per se is a cause of adverse clinical outcomes or whether outcomes can be improved by preventing hyperglycemia. OBJECTIVES: To assess effects on clinical outcomes of interventions for preventing hyperglycemia in VLBW neonates receiving full or partial parenteral nutrition. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, issue 4 of 12, 2011; MEDLINE (1966 to April 2011); EMBASE (1980 to April 2011); CINAHL (1982 to Nov 2008); abstracts of Pediatric Academic Societies 2000 to 2011 and European Society for Pediatric Research 2005 to 2010. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of interventions for prevention of hyperglycemia in neonates with birth weight < 1500 g or gestational age < 32 wk. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility and extracted data on study design, methods, clinical features, and treatment outcomes. Included trials were assessed for blinding of randomization, intervention and outcome measurement, and completeness of follow-up. Treatment effect measures for categorical outcomes were relative risk and risk difference, and for continuous outcomes, mean difference, each with their 95% confidence intervals. MAIN RESULTS: We detected four eligible trials. Two trials compared lower versus higher rates of glucose infusion in the early postnatal period. These trials were too small to assess effects on mortality or major morbidities. Two trials, one a moderately large multicentre trial (NIRTURE, Beardsall 2008), compared insulin infusion with standard care. Insulin infusion reduced hyperglycemia but increased death before 28 days and hypoglycemia. Reduction in hyperglycemia was not accompanied by significant effects on major morbidities; effects on neurodevelopment are awaited. AUTHORS' CONCLUSIONS: Glucose infusion rate: There is insufficient evidence from trials comparing lower with higher glucose infusion rates to inform clinical practice. Large randomized trials are needed, powered on clinical outcomes including death, major morbidities and adverse neurodevelopment.Insulin infusion: The evidence reviewed does not support the routine use of insulin infusions to prevent hyperglycemia in VLBW neonates. Further randomized trials of insulin infusion may be justified. They should enrol extremely low birth weight neonates at very high risk for hyperglycemia and neonatal death. They might use real time glucose monitors if these are validated for clinical use. Refinement of algorithms to guide insulin infusion is needed to enable tight control of glucose concentrations within the target range.

Generation of protein lattices by fusing proteins with matching rotational symmetry.

The self-assembly of supramolecular structures that are ordered on the nanometre scale is a key objective in nanotechnology. DNA and peptide nanotechnologies have produced various two- and three-dimensional structures, but protein molecules have been underexploited in this area of research. Here we show that the genetic fusion of subunits from protein assemblies that have matching rotational symmetry generates species that can self-assemble into well-ordered, pre-determined one- and two-dimensional arrays that are stabilized by extensive intermolecular interactions. This new class of supramolecular structure provides a way to manufacture biomaterials with diverse structural and functional properties.

Selecting participants that raise a clinical trial's population attributable fraction can increase the treatment effect within the trial and reduce the required sample size.

BACKGROUND: Detection of modest but worthwhile treatment effects in randomized controlled trials (RCTs) demands trials of large sample size. Approaches to decreasing required size of RCTs while maintaining power are needed. OBJECTIVE: The epidemiological concept of population attributable fraction (AF(p)) was applied to the population selected for an RCT to assess its role in determining the size of treatment effect and the required sample size. The additional effect of efficacy of treatment specifically among participants at risk for attributable target events (relative risk reduction(at risk) [RRR(at risk)]) was also examined. RESULTS: A model is described which accounts for size of treatment effect in an RCT based on AF(p) and RRR(at risk): RRR(trial) = (AF(p)) (RRR(at risk)). The increase in RRR(trial) resulting from raising AF(p) exceeds that possible under the traditional high risk/high response approach to trial design and allows a reduction in required trial sample size. AF(p) can be estimated from studies of causation that determine both risk and attributable risk (AR) associated with specific risk factors. CONCLUSION: Larger treatment effects within RCTs are enabled by choosing a target outcome having a specific cause and selecting participants at specific risk for that outcome. Using information about phenotypic and genetic predictors of AR may increase our capacity to select trial populations having high AF(p).

Interventions for prevention of neonatal hyperglycemia in very low birth weight infants.

BACKGROUND: Among very low birth weight (VLBW) infants, early neonatal hyperglycemia is common and is associated with increased risks for death and major morbidities. It is uncertain whether hyperglycemia per se is a cause of adverse clinical outcomes or whether outcomes can be improved by preventing hyperglycemia. OBJECTIVES: To assess effects on clinical outcomes of interventions for preventing hyperglycemia in VLBW neonates receiving full or partial parenteral nutrition. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, issue 4 2008; MEDLINE (1966 - Nov 2008); EMBASE (1980 - Nov 2008); CINAHL (1982 - Nov 2008); abstracts of Pediatric Academic Societies 2000 - 2008 and European Society for Paediatric Research 2005 - 2008. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of interventions for prevention of hyperglycemia in neonates with birth weight < 1500 g or gestational age < 32 wk DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility and extracted data on study design, methods, clinical features, and treatment outcomes. Included trials were assessed for blinding of randomization, intervention and outcome measurement, and completeness of follow-up. Treatment effect measures for categorical outcomes were relative risk and risk difference, and for continuous outcomes, mean difference, each with their 95% confidence intervals. MAIN RESULTS: We detected four eligible trials. Two trials compared lower vs. higher rates of glucose infusion in the early postnatal period. These trials were too small to assess effects on mortality or major morbidities. Two trials, one a moderately large multicentre trial (NIRTURE, Beardsall 2008), compared insulin infusion with standard care. Insulin infusion reduced hyperglycemia but increased death before 28 days and hypoglycemia. Reduction in hyperglycemia was not accompanied by significant effects on major morbidities; effects on neurodevelopment are awaited. AUTHORS' CONCLUSIONS: Glucose infusion rate: There is insufficient evidence from trials comparing lower with higher glucose infusion rates to inform clinical practice. Large randomized trials are needed, powered on clinical outcomes including death, major morbidities and adverse neurodevelopment.Insulin infusion: The evidence reviewed does not support the routine use of insulin infusions to prevent hyperglycemia in VLBW neonates. Further randomized trials of insulin infusion may be justified. They should enrol extremely low birth weight neonates at very high risk for hyperglycemia and neonatal death. They might use real time glucose monitors if these are validated for clinical use. Refinement of algorithms to guide insulin infusion is needed to enable tight control of glucose concentrations within the target range.

Uncertainty in the minimum event risk to justify treatment was evaluated.

OBJECTIVE: To derive expressions for the standard errors (SEs) and coefficients of variation (CV) of the threshold number needed to treat (NNT(t)) and the minimum target event risk for treatment (MERT). STUDY DESIGN AND SETTING: NNT(t) reflects the point at which the risks and costs of a clinical intervention balance the benefit. MERT defines the minimum target event risk at which the intervention is justified. Uncertainty in these measures has not previously been investigated. RESULTS: SEs for NNT(t) and MERT were derived. The corresponding CVs are particularly useful, because they decompose the variability of NNT(t) and MERT into the uncertainty in their components (the values of target and adverse events, and the adverse event risk [AER]). The precision required for these components to formulate treatment recommendations is, thereby, highlighted. These ideas were illustrated with data concerning warfarin treatment for atrial fibrillation. CONCLUSION: Our expressions for uncertainty in NNT(t) and MERT inform the confidence one has in initiating a clinical intervention. In our example, a recommendation for treatment could be made for groups of patients whose risk exceeded the range of uncertainty in MERT. However, for lower-risk patients, a recommendation for or against treatment could not be made, mainly because of the limited data on AERs. Our methods can also be used to estimate how much additional data would be required to provide a firmer recommendation for such patient groups.

Interventions for treatment of neonatal hyperglycemia in very low birth weight infants.

BACKGROUND: Early neonatal hyperglycemia is common among very low birth weight (VLBW) neonates. Increased risks for death and major morbidities have been observed among VLBW neonates who develop hyperglycemia. It is uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or whether the incidence of adverse outcomes can be reduced by treatment. OBJECTIVES: To assess the effects on clinical outcomes of interventions for treating neonatal hyperglycemia in the VLBW neonate receiving total or partial parenteral nutrition. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL), The Cochrane Library, Issue 3, 2008; MEDLINE (1966 - July 2008); EMBASE (1980 - July 2008); and CINAHL (1982 - July 2008). We searched for abstracts submitted for the annual meetings of The Society for Pediatric Research 2000 - 2008 and The European Society for Paediatric Research 2005-2007. SELECTION CRITERIA: Randomized or quasi-randomized trials of interventions for the treatment of hyperglycemia in hyperglycemic VLBW neonates were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for eligibility and extracted data on study design, methodology, clinical features, and treatment outcomes. Additional information on study design and outcomes was obtained from the lead investigator of each of the two included trials. The included trials were assessed for blinding of randomization, blinding of caretakers to the intervention, completeness of follow-up, and blinding of outcome measurement. The treatment effect measures for categorical outcomes were relative risk (RR) and risk difference (RD) with their 95% confidence intervals (CI); for continuous outcomes the measure was mean difference and 95% CI. MAIN RESULTS: Only two eligible trials were found (Collins 1991; Meetze 1998). Both were randomized but of very small size (24 and 23 neonates randomized in each trial, respectively).No trial compared reduction vs. no reduction of glucose infusion.Collins 1991 compared insulin infusion with standard care. Insulin infusion had no significant effect on death or bacterial sepsis; effects on other major morbidities were not assessed. Insulin infusion resulted in significant increases in non-protein energy intake, glucose intake, and short-term weight gain.Meetze 1998 compared insulin infusion with reduction of glucose infusion. Insulin infusion had no significant effects on death, severe intraventricular hemorrhage, retinopathy of prematurity, bacterial sepsis, fungal sepsis, or necrotizing enterocolitis; effects on other major morbidities were not assessed. Insulin infusion resulted in significant increases in glucose intake and total energy intake. AUTHORS' CONCLUSIONS: Evidence from randomized trials in hyperglycemic VLBW neonates is insufficient to determine the effects of treatment on death or major morbidities. It remains uncertain whether the hyperglycemia per se is a cause of adverse clinical outcomes or how the hyperglycemia should be treated. Much larger randomized trials in hyperglycemic VLBW neonates that are powered on clinical outcomes are needed in order to determine whether, and how, the hyperglycemia should be treated.

Impact of postnatal systemic corticosteroids on mortality and cerebral palsy in preterm infants: effect modification by risk for chronic lung disease.

OBJECTIVE: In preterm infants, chronic lung disease (CLD) is associated with an increased risk for cerebral palsy (CP). However, systemic postnatal corticosteroid therapy to prevent or treat CLD, although effective in improving lung function, may cause CP. The objective of this study was to determine the effect of systemic postnatal corticosteroid treatment on death and CP and to assess any modification of effect arising from risk for CLD. METHODS: Randomized, controlled trials of postnatal corticosteroid therapy for prevention or treatment of CLD in preterm infants that reported rates of both mortality and CP were reviewed and their data were synthesized. Twenty studies with data on 1721 randomized infants met eligibility criteria. The relationship between the corticosteroid effect on the combined outcome, death or CP, and the risk for CLD in control groups was analyzed by weighted meta-regression. RESULTS: Among all infants who were randomized, a significantly higher rate of CP after corticosteroid treatment (typical risk difference [RD]: 0.05; 95% confidence interval [CI]: 0.02, 0.08) was partly offset by a nonsignificant reduction in mortality (typical RD: -0.02; 95% CI: -0.06 to 0.02). Consequently, there was no significant effect of corticosteroid treatment on the combined rate of mortality or CP (typical RD: 0.03; 95% CI: -0.01 to 0.08). However, on meta-regression, there was a significant negative relationship between the treatment effect on death or CP and the risk for CLD in control groups. With risks for CLD below 35%, corticosteroid treatment significantly increased the chance of death or CP, whereas with risks for CLD exceeding 65%, it reduced this chance. CONCLUSIONS: The effect of postnatal corticosteroids on the combined outcome of death or CP varies with the level of risk for CLD.

Collaborative quality improvement to promote evidence based surfactant for preterm infants: a cluster randomised trial.

OBJECTIVE: To test a multifaceted collaborative quality improvement intervention designed to promote evidence based surfactant treatment for preterm infants of 23-29 weeks' gestation. DESIGN: Cluster randomised controlled trial. SETTING AND PARTICIPANTS: 114 neonatal intensive care units (which treated 6039 infants of 23-29 weeks gestation born in 2001). MAIN OUTCOME MEASURES: Process of care measures: proportion of infants receiving first surfactant in the delivery room, proportion receiving first surfactant more than two hours after birth, and median time from birth to first dose of surfactant. Clinical outcomes: death before discharge home, and pneumothorax. INTERVENTION: Multifaceted collaborative quality improvement advice including audit and feedback, evidence reviews, an interactive training workshop, and ongoing faculty support via conference calls and email. RESULTS: Compared with those in control hospitals, infants in intervention hospitals were more likely to receive surfactant in the delivery room (adjusted odds ratio 5.38 (95% confidence interval 2.84 to 10.20)), were less likely to receive the first dose more than two hours after birth (adjusted odds ratio 0.35 (0.24 to 0.53)), and received the first dose of surfactant sooner after birth (median of 21 minutes v 78 minutes, P < 0.001). The intervention effect on timing of surfactant was larger for infants born in the participating hospitals than for infants transferred to a participating hospital after birth. There were no significant differences in mortality or pneumothorax. CONCLUSION: A multifaceted intervention including audit and feedback, evidence reviews, quality improvement training, and follow up support changed the behaviour of health professionals and promoted evidence based practice.

Timing of initial surfactant treatment for infants 23 to 29 weeks' gestation: is routine practice evidence based?

OBJECTIVE: To describe the timing of initial surfactant treatment for high-risk preterm infants in routine practice and compare these findings with evidence from randomized trials and published guidelines. METHODS: Data from the Vermont Oxford Network Database for infants who were born from 1998 to 2000 and had birth weights 401 to 1500 g and gestational ages of 23 to 29 weeks were analyzed to determine the time after birth at which the initial dose of surfactant was administered. Multivariate models adjusting for clustering of cases within hospitals identified factors associated with surfactant administration and its timing. Evidence on surfactant timing from systematic reviews of randomized trials and from published guidelines was reviewed. RESULTS: A total of 47 608 eligible infants were cared for at 341 hospitals in North America that participated in the Vermont Oxford Network Database from 1998 to 2000. Seventy-nine percent of infants received surfactant treatment (77.6% in 1998, 79.4% in 1999, and 79.6% in 2000). Factors that increased the likelihood of surfactant treatment were outborn birth, lower gestational age, lower 1-minute Apgar score, male gender, white race, cesarean delivery, multiple birth, or birth later in the study period. The first dose of surfactant was administered at a median time after birth of 50 minutes (60 minutes in 1998, 51 minutes in 1999, and 42 minutes in 2000). Over the 3-year study period, inborn infants received their initial dose of surfactant earlier than outborn infants (median time: 43 minutes vs 79 minutes). Other factors associated with earlier administration of the initial surfactant dose were gestational age, lower 1-minute Apgar score, cesarean delivery, antenatal steroid treatment, multiple birth, and small size for gestational age. In 2000, 27% of infants received surfactant in the delivery room. There was wide variation among hospitals in the proportion of infants who received surfactant treatment in the delivery room (interquartile range: 0%-75%), in the median time of the initial surfactant dose (interquartile range: 20-90 minutes), and in the proportion of infants who received the first dose >2 hours after birth (interquartile range: 7%-34%). Six systematic reviews of randomized trials of surfactant timing were identified. No national guidelines addressing the timing of surfactant therapy were found. CONCLUSION: Although the time after birth at which the first dose of surfactant is administered to infants 23 to 29 weeks' gestation decreased from 1998 to 2000, in 2000 many infants still received delayed treatment, and delivery room surfactant administration was not routinely practiced at most units. We conclude that there is a gap between evidence from randomized controlled trials that supports prophylactic or early surfactant administration and what is actually done in routine practice at many units.

Weighing risks and benefits in treating the individual patient.

Treatments may cause both benefits and harms. In such cases, the size of the benefit (indicated by the NNT to prevent one target event) needs to be weighed against the harms. One way of doing this is to estimate a threshold NNT, based on the attributable risks of the adverse events and their RVs compared with the importance of the target event prevented. By comparing the NNT at a given baseline risk with the threshold NNT, a critical baseline risk is identified above which treatment benefits are expected to outweigh harms. The assignment of RVs to benefits and harms of treatment is a necessary and crucial step in making a treatment recommendation. Consideration of the determinants of the threshold NNT may assist clinicians and parents in the explicit use of underlying values when making treatment decisions.

Cochrane neonatal systematic reviews: a survey of the evidence for neonatal therapies.

A survey is reported of 113 systematic reviews of therapies in neonatology, based on 559 eligible randomized trials in total. These reviews were prepared by the CNRG and were published in the Cochrane Library, Issue 3,2001. The median number of included trials per review was 3 (range 0 to 32) and participants 207 (range 0 to 5460). Among 90 reviews with a categorical primary outcome, the median number of outcome events per review was 54 (range 1 to 1284). Among reviews finding a statistically significant benefit of treatment, the effect size was large (median relative risk 0.55, range 0.09 to 0.93). Reviews of surfactant for prevention and treatment of respiratory distress syndrome were able to detect moderate-sized treatment effects (median relative risk 0.85) because of the large number and size of trials in this field. Among many reviews finding no evidence of treatment effect, large and potentially important benefits or harms could not be excluded. Most CNRG reviews were current. There is a continuing need to prepare systematic review of therapies not yet covered and to keep an increasing number of reviews up-to-date.