Non-invasive high-frequency ventilation in newborn infants with respiratory distress.

BACKGROUND: Respiratory distress occurs in up to 7% of newborns, with respiratory support (RS) provided invasively via an endotracheal (ET) tube or non-invasively via a nasal interface. Invasive ventilation increases the risk of lung injury and chronic lung disease (CLD). Using non-invasive strategies, with or without minimally invasive surfactant, may reduce the need for mechanical ventilation and the risk of lung damage in newborn infants with respiratory distress. OBJECTIVES: To evaluate the benefits and harms of nasal high-frequency ventilation (nHFV) compared to invasive ventilation via an ET tube or other non-invasive ventilation methods on morbidity and mortality in preterm and term infants with or at risk of respiratory distress. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and three trial registries in April 2023. SELECTION CRITERIA: Randomised controlled trials (RCTs), cluster- or quasi-RCTs of nHFV in newborn infants with respiratory distress compared to invasive or non-invasive ventilation. DATA COLLECTION AND ANALYSIS: Two authors independently selected the trials for inclusion, extracted data, assessed the risk of bias, and undertook GRADE assessment. MAIN RESULTS: We identified 33 studies, mostly in low- to middle-income settings, that investigated this therapy in 5068 preterm and 46 term infants. nHFV compared to invasive respiratory therapy for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 0.67, 95% CI 0.20 to 2.18; 1 study, 80 infants) or the incidence of CLD (RR 0.38, 95% CI 0.09 to 1.59; 2 studies, 180 infants), both very low-certainty. ET intubation, death or CLD, severe intraventricular haemorrhage (IVH) and neurodevelopmental disability (ND) were not reported. nHFV vs nasal continuous positive airway pressure (nCPAP) used for initial RS We are very uncertain whether nHFV reduces mortality before hospital discharge (RR 1.00, 95% CI 0.41 to 2.41; 4 studies, 531 infants; very low-certainty). nHFV may reduce ET intubation (RR 0.52, 95% CI 0.33 to 0.82; 5 studies, 571 infants), but there may be little or no difference in CLD (RR 1.35, 95% CI 0.80 to 2.27; 4 studies, 481 infants); death or CLD (RR 2.50, 95% CI 0.52 to 12.01; 1 study, 68 participants); or severe IVH (RR 1.17, 95% CI 0.36 to 3.78; 4 studies, 531 infants), all low-certainty evidence. ND was not reported. nHFV vs nasal intermittent positive-pressure ventilation (nIPPV) used for initial RS nHFV may result in little to no difference in mortality before hospital discharge (RR 1.86, 95% CI 0.90 to 3.83; 2 studies, 84 infants; low-certainty). nHFV may have little or no effect in reducing ET intubation (RR 1.33, 95% CI 0.76 to 2.34; 5 studies, 228 infants; low-certainty). There may be a reduction in CLD (RR 0.63, 95% CI 0.42 to 0.95; 5 studies, 307 infants; low-certainty). A single study (36 infants) reported no events for severe IVH. Death or CLD and ND were not reported. nHFV vs high-flow nasal cannula (HFNC) used for initial RS We are very uncertain whether nHFV reduces ET intubation (RR 2.94, 95% CI 0.65 to 13.27; 1 study, 37 infants) or reduces CLD (RR 1.18, 95% CI 0.46 to 2.98; 1 study, 37 participants), both very low-certainty. There were no mortality events before hospital discharge or severe IVH. Other deaths, CLD and ND, were not reported. nHFV vs nCPAP used for RS following planned extubation nHFV probably results in little or no difference in mortality before hospital discharge (RR 0.92, 95% CI 0.52 to 1.64; 6 studies, 1472 infants; moderate-certainty). nHFV may result in a reduction in ET reintubation (RR 0.42, 95% CI 0.35 to 0.51; 11 studies, 1897 infants) and CLD (RR 0.78, 95% CI 0.67 to 0.91; 10 studies, 1829 infants), both low-certainty. nHFV probably has little or no effect on death or CLD (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 966 infants) and severe IVH (RR 0.80, 95% CI 0.57 to 1.13; 3 studies, 1117 infants), both moderate-certainty. We are very uncertain whether nHFV reduces ND (RR 0.92, 95% CI 0.37 to 2.29; 1 study, 74 infants; very low-certainty). nHFV versus nIPPV used for RS following planned extubation nHFV may have little or no effect on mortality before hospital discharge (RR 1.83, 95% CI 0.70 to 4.79; 2 studies, 984 infants; low-certainty). There is probably a reduction in ET reintubation (RR 0.69, 95% CI 0.54 to 0.89; 6 studies, 1364 infants), but little or no effect on CLD (RR 0.88, 95% CI 0.75 to 1.04; 4 studies, 1236 infants); death or CLD (RR 0.92, 95% CI 0.79 to 1.08; 3 studies, 1070 infants); or severe IVH (RR 0.78, 95% CI 0.55 to 1.10; 4 studies, 1162 infants), all moderate-certainty. One study reported there might be no difference in ND (RR 0.88, 95% CI 0.35 to 2.16; 1 study, 72 infants; low-certainty). nHFV versus nIPPV following initial non-invasive RS failure nHFV may have little or no effect on mortality before hospital discharge (RR 1.44, 95% CI 0.10 to 21.33); or ET intubation (RR 1.23, 95% CI 0.51 to 2.98); or CLD (RR 1.01, 95% CI 0.70 to 1.47); or severe IVH (RR 0.47, 95% CI 0.02 to 10.87); 1 study, 39 participants, all low- or very low-certainty. Other deaths or CLD and ND were not reported. AUTHORS' CONCLUSIONS: For initial RS, we are very uncertain if using nHFV compared to invasive respiratory therapy affects clinical outcomes. However, nHFV may reduce intubation when compared to nCPAP. For planned extubation, nHFV may reduce the risk of reintubation compared to nCPAP and nIPPV. nHFV may reduce the risk of CLD when compared to nCPAP. Following initial non-invasive respiratory support failure, nHFV when compared to nIPPV may result in little to no difference in intubation. Large trials, particularly in high-income settings, are needed to determine the role of nHFV in initial RS and following the failure of other non-invasive respiratory support. Also, the optimal settings of nHVF require further investigation.

Dexmedetomidine for analgesia and sedation in newborn infants receiving mechanical ventilation.

BACKGROUND: Dexmedetomidine is a selective alpha-2 agonist with minimal impact on the haemodynamic profile. It is thought to be safer than morphine or stronger opioids, which are drugs currently used for analgesia and sedation in newborn infants. Dexmedetomidine is increasingly being used in children and infants despite not being licenced for analgesia in this group. OBJECTIVES: To determine the overall effectiveness and safety of dexmedetomidine for sedation and analgesia in newborn infants receiving mechanical ventilation compared with other non-opioids, opioids, or placebo. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and two trial registries in September 2023. SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs) and quasi-RCTs evaluating the effectiveness of dexmedetomidine compared with other non-opioids, opioids, or placebo for sedation and analgesia in neonates (aged under four weeks) requiring mechanical ventilation. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were level of sedation and level of analgesia. Our secondary outcomes included days on mechanical ventilation, number of infants requiring additional medication for sedation or analgesia (or both), hypotension, neonatal mortality, and neurodevelopmental outcomes. We planned to use GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We identified no eligible studies for inclusion. We identified four ongoing studies, two of which appear to be eligible for inclusion; they will compare dexmedetomidine with fentanyl in newborn infants requiring surgery. We listed the other two studies as awaiting classification pending assessment of full reports. One study will compare dexmedetomidine with morphine in asphyxiated newborns undergoing hypothermia, and the other (mixed population, age up to three years) will evaluate dexmedetomidine versus ketamine plus dexmedetomidine for echocardiography. The planned sample size of the four studies ranges from 40 to 200 neonates. Data from these studies may provide some evidence for dexmedetomidine efficacy and safety. AUTHORS' CONCLUSIONS: Despite the increasing use of dexmedetomidine, there is insufficient evidence supporting its routine use for analgesia and sedation in newborn infants on mechanical ventilation. Furthermore, data on dexmedetomidine safety are scarce, and there are no data available on its long-term effects. Future studies should address the efficacy, safety, and long-term effects of dexmedetomidine as a single drug therapy for sedation and analgesia in newborn infants.

Transcutaneous bilirubinometry for detecting jaundice in term or late preterm neonates.

BACKGROUND: The American Academy of Pediatrics and the Canadian Paediatric Society both advise that all newborns should undergo bilirubin screening before leaving the hospital, and this has become the standard practice in both countries. However, the US Preventive Task Force has found no strong evidence to suggest that this practice of universal screening for bilirubin reduces the occurrence of significant outcomes such as bilirubin-induced neurologic dysfunction or kernicterus. OBJECTIVES: To evaluate the effectiveness of transcutaneous screening compared to visual inspection for hyperbilirubinemia to prevent the readmission of newborns (infants greater than 35 weeks' gestation) for phototherapy. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, ClinicalTrials.gov, ICTRP, and ISRCTN in June 2023. We also searched conference proceedings, and the reference lists of included studies. SELECTION CRITERIA: We included randomized controlled trials (RCTs), quasi-randomized, cluster-randomized, or prospective cohort studies with control arm that evaluated the use of transcutaneous bilirubin (TcB) screening for hyperbilirubinemia in newborns before hospital discharge. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. We evaluated treatment effects using a fixed-effect model with risk ratio (RR) and 95% confidence intervals (CI) for categorical data and mean, standard deviation (SD), and mean difference (MD) for continuous data. We used the GRADE approach to evaluate the certainty of evidence. MAIN RESULTS: We identified one RCT (1858 participants) that met our inclusion criteria. The study included 1858 African newborns at 35 weeks' gestation or greater who were receiving routine care at a well-baby nursery, and were randomly recruited prior to discharge to undergo TcB screening. The study had good methodologic quality. TcB screening versus visual assessment of hyperbilirubinemia in newborns: - may reduce readmission to the hospital for hyperbilirubinemia (RR 0.25, 95% CI 0.14 to 0.46; P < 0.0001; moderate-certainty evidence); - probably has little or no effect on the rate of exchange transfusion (RR 0.20, 95% CI 0.01 to 14.16; low-certainty evidence); - may increase the number of newborns who require phototherapy prior to discharge (RR 2.67, 95% CI 1.56 to 4.55; moderate-certainty evidence). - probably has little or no effect on the rate of acute bilirubin encephalopathy (RR 0.33, 95% CI 0.01 to 8.18; low-certainty evidence). The study did not evaluate or report cost of care. AUTHORS' CONCLUSIONS: Moderate-certainty evidence suggests that TcB screening may reduce readmission for hyperbilirubinemia compared to visual inspection. Low-certainty evidence also suggests that TcB screening probably has little or no effect on the rate of exchange transfusion compared to visual inspection. However, moderate-certainty evidence suggests that TcB screening may increase the number of newborns that require phototherapy before discharge compared to visual inspection. Low-certainty evidence suggests that TcB screening probably has little or no effect on the rate of acute bilirubin encephalopathy compared to visual inspection. Given that we have only identified one RCT, further studies are necessary to determine whether TcB screening can help to reduce readmission and complications related to neonatal hyperbilirubinemia. In settings with limited newborn follow-up after hospital discharge, identifying newborns at risk of severe hyperbilirubinemia before hospital discharge will be important to plan targeted follow-up of these infants.

Methylxanthine for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Very preterm infants often require respiratory support and are therefore exposed to an increased risk of chronic lung disease and later neurodevelopmental disability. Although methylxanthines are widely used to prevent and treat apnea associated with prematurity and to facilitate extubation, there is uncertainty about the benefits and harms of different types of methylxanthines. OBJECTIVES: To assess the effects of methylxanthines on the incidence of apnea, death, neurodevelopmental disability, and other longer-term outcomes in preterm infants (1) at risk for or with apnea, or (2) undergoing extubation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, two other databases, and three trial registers (November 2022). SELECTION CRITERIA: We included randomized trials in preterm infants, in which methylxanthines (aminophylline, caffeine, or theophylline) were compared to placebo or no treatment for any indication (i.e. prevention of apnea, treatment of apnea, or prevention of re-intubation). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods and GRADE to assess the certainty of evidence. MAIN RESULTS: We included 18 studies (2705 infants), evaluating the use of methylxanthine in preterm infants for: any indication (one study); prevention of apnea (six studies); treatment of apnea (five studies); and to prevent re-intubation (six studies). Death or major neurodevelopmental disability (DMND) at 18 to 24 months. Only the Caffeine for Apnea of Prematurity (CAP) study (enrolling 2006 infants) reported on this outcome. Overall, caffeine probably reduced the risk of DMND in preterm infants treated with caffeine for any indication (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.78 to 0.97; risk difference (RD) -0.06, 95% CI -0.10 to -0.02; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence). No other trials reported DMND. Results from the CAP trial regarding DMND at 18 to 24 months are less precise when analyzed based on treatment indication. Caffeine probably results in little or no difference in DMND in infants treated for prevention of apnea (RR 1.00, 95% CI 0.80 to 1.24; RD -0.00, 95% CI -0.10 to 0.09; 1 study, 423 infants; moderate-certainty evidence) and probably results in a slight reduction in DMND in infants treated for apnea of prematurity (RR 0.85, 95% CI 0.71 to 1.01; RD -0.06, 95% CI -0.13 to 0.00; NNTB 16, 95% CI 7 to > 1000; 1 study, 767 infants; moderate-certainty evidence) or to prevent re-intubation (RR 0.85, 95% CI 0.73 to 0.99; RD -0.08, 95% CI -0.15 to -0.00; NNTB 12, 95% CI 6 to >1000; 1 study, 676 infants; moderate-certainty evidence). Death. In the overall analysis of any methylxanthine treatment for any indication, methylxanthine used for any indication probably results in little or no difference in death at hospital discharge (RR 0.99, 95% CI 0.71 to 1.37; I2 = 0%; RD -0.00, 95% CI -0.02 to 0.02; I2 = 5%; 7 studies, 2289 infants; moderate-certainty evidence). Major neurodevelopmental disability at 18 to 24 months. In the CAP trial, caffeine probably reduced the risk of major neurodevelopmental disability at 18 to 24 months (RR 0.85, 95% CI 0.76 to 0.96; RD -0.06, 95% CI -0.10 to -0.02; NNTB 16, 95% CI 10 to 50; 1 study, 1869 infants; moderate-certainty evidence), including a reduction in the risk of cerebral palsy or gross motor disability (RR 0.60, 95% CI 0.41 to 0.88; RD -0.03, 95% CI -0.05 to -0.01; NNTB 33, 95% CI 20 to 100; 1 study, 1810 infants; moderate-certainty evidence) and a marginal reduction in the risk of developmental delay (RR 0.88, 95% CI 0.78 to 1.00; RD -0.05, 95% CI -0.09 to -0.00; NNTB 20, 95% CI 11 to > 1000; 1 study, 1725 infants; moderate-certainty evidence). Any apneic episodes, failed apnea reduction after two to seven days (< 50% reduction in apnea) (for infants treated with apnea), and need for positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication probably reduces the occurrence of any apneic episodes (RR 0.31, 95% CI 0.18 to 0.52; I2 = 47%; RD -0.38, 95% CI -0.51 to -0.25; I2 = 49%; NNTB 3, 95% CI 2 to 4; 4 studies, 167 infants; moderate-certainty evidence), failed apnea reduction after two to seven days (RR 0.48, 95% CI 0.33 to 0.70; I2 = 0%; RD -0.31, 95% CI -0.44 to -0.17; I2 = 53%; NNTB 3, 95% CI 2 to 6; 4 studies, 174 infants; moderate-certainty evidence), and may reduce receipt of positive-pressure ventilation after institution of treatment (RR 0.61, 95% CI 0.39 to 0.96; I2 = 0%; RD -0.06, 95% CI -0.11 to -0.01; I2 = 49%; NNTB 16, 95% CI 9 to 100; 9 studies, 373 infants; low-certainty evidence). Chronic lung disease. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age) (RR 0.77, 95% CI 0.69 to 0.85; I2 = 0%; RD -0.10, 95% CI -0.14 to -0.06; I2 = 18%; NNTB 10, 95% CI 7 to 16; 4 studies, 2142 infants; high-certainty evidence). Failure to extubate or the need for re-intubation within one week after initiation of therapy. Methylxanthine used for the prevention of re-intubation probably results in a large reduction in failed extubation compared with no treatment (RR 0.48, 95% CI 0.32 to 0.71; I2 = 0%; RD -0.27, 95% CI -0.39 to -0.15; I2 = 69%; NNTB 4, 95% CI 2 to 6; 6 studies, 197 infants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: Caffeine probably reduces the risk of death, major neurodevelopmental disability at 18 to 24 months, and the composite outcome DMND at 18 to 24 months. Administration of any methylxanthine to preterm infants for any indication probably leads to a reduction in the risk of any apneic episodes, failed apnea reduction after two to seven days, cerebral palsy, developmental delay, and may reduce receipt of positive-pressure ventilation after institution of treatment. Methylxanthine used for any indication reduces chronic lung disease (defined as the use of supplemental oxygen at 36 weeks' postmenstrual age).

Doxapram for the prevention and treatment of apnea in preterm infants.

BACKGROUND: Apnea of prematurity is a common problem in preterm infants that may have significant consequences on their development. Methylxanthines (aminophylline, theophylline, and caffeine) are effective in the treatment of apnea of prematurity. Doxapram is used as a respiratory stimulant in cases refractory to the methylxanthine treatment. OBJECTIVES: To evaluate the benefits and harms of doxapram administration on the incidence of apnea and other short-term and longer-term clinical outcomes in preterm infants. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was March 2023. SELECTION CRITERIA: We included randomized controlled trials (RCTs) assessing the role of doxapram in prevention and treatment of apnea of prematurity and prevention of reintubation in preterm infants (less than 37 weeks' gestation). We included studies comparing doxapram with either placebo or methylxanthines as a control group, or when doxapram was used as an adjunct to methylxanthines and compared to methylxanthines alone as a control group. We included studies of doxapram at any dose and route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were clinical apnea, need for positive pressure ventilation after initiation of treatment, failed apnea reduction after two to seven days, and failed extubation (defined as unable to wean from invasive intermittent positive pressure ventilation [IPPV] and extubate or reintubation for IPPV within one week). We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included eight RCTs enrolling 248 infants. Seven studies (214 participants) provided data for meta-analysis. Five studied doxapram for treatment of apnea in preterm infants. Three studied doxapram to prevent reintubation in preterm infants. None studied doxapram in preventing apnea in preterm infants. All studies administered doxapram intravenously as continuous infusions. Two studies used doxapram as an adjunct to aminophylline compared to aminophylline alone and one study as an adjunct to caffeine compared to caffeine alone. When used to treat apnea, compared to no treatment, doxapram may result in a slight reduction in failed apnea reduction (risk ratio [RR] 0.45, 95% confidence interval [CI] 0.20 to 1.05; 1 study, 21 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 0.31, 95% CI 0.01 to 6.74; 1 study, 21 participants; very low-certainty evidence). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in both groups; risk difference [RD] 0.00, 95% CI -0.17 to 0.17; 1 study, 21 participants; low-certainty evidence). Compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed apnea reduction (RR 1.35, 95% CI 0.53 to 3.45; 4 studies, 84 participants; very low-certainty evidence). The evidence is very uncertain about the effect of doxapram on need for positive pressure ventilation after initiation of treatment (RR 2.40, 95% CI 0.11 to 51.32; 2 studies, 37 participants; very-low certainty evidence; note 1 study recorded 0 events in both groups. Thus, the RR and CIs were calculated from 1 study rather than 2). Doxapram may result in little to no difference in side effects causing cessation of therapy (0 events in all groups; RD 0.00, 95% CI -0.15 to 0.15; 37 participants; 2 studies; low-certainty evidence). As adjunct therapy to methylxanthine, the evidence is very uncertain about the effect of doxapram on failed apnea reduction after two to seven days (RR 0.08, 95% CI 0.01 to 1.17; 1 study, 10 participants; very low-certainty evidence). No studies reported on clinical apnea, chronic lung disease at 36 weeks' postmenstrual age (PMA), death at any time during initial hospitalization, long-term neurodevelopmental outcomes in the three comparisons, and need for positive pressure ventilation and side effects when used as adjunct therapy to methylxanthine. In studies to prevent reintubation, when compared to alternative treatment, the evidence is very uncertain about the effect of doxapram on failed extubation (RR 0.43, 95% CI 0.10 to 1.83; 1 study, 25 participants; very low-certainty evidence). As adjunct therapy to methylxanthine, doxapram may result in a slight reduction in 'clinical apnea' after initiation of treatment (RR 0.36, 95% CI 0.13 to 0.98; 1 study, 56 participants; low-certainty evidence). Doxapram may result in little to no difference in failed extubation (RR 0.92, 95% CI 0.52 to 1.62; 1 study, 56 participants; low-certainty evidence). The evidence is very uncertain about the effect of doxapram on side effects causing cessation of therapy (RR 6.42, 95% CI 0.80 to 51.26; 2 studies, 85 participants; very low-certainty evidence). No studies reported need for positive pressure ventilation, chronic lung disease at 36 weeks' PMA, long-term neurodevelopmental outcomes in the three comparisons; failed extubation when compared to no treatment; and clinical apnea, death at any time during initial hospitalization, and side effects when compared to no treatment or alternative treatment. We identified two ongoing studies, one conducted in Germany and one in multiple centers in the Netherlands and Belgium. AUTHORS' CONCLUSIONS: In treating apnea of prematurity, doxapram may slightly reduce failure in apnea reduction when compared to no treatment and there may be little to no difference in side effects against both no treatment and alternative treatment. The evidence is very uncertain about the need for positive pressure ventilation when compared to no treatment or alternative treatment and about failed apnea reduction when used as alternative or adjunct therapy to methylxanthine. For use to prevent reintubation, doxapram may reduce apnea episodes when administered in adjunct to methylxanthine, but with little to no difference in failed extubation. The evidence is very uncertain about doxapram's effect on death when used as adjunct therapy to methylxanthine and about failed extubation when used as alternative or adjunct therapy to methylxanthine. There is a knowledge gap about the use of doxapram as a therapy to prevent apnea. More studies are needed to clarify the role of doxapram in the treatment of apnea of prematurity, addressing concerns about long-term outcomes. The ongoing studies may provide useful data.

Transcutaneous bilirubinometry versus total serum bilirubin measurement for newborns.

BACKGROUND: Jaundice is a very common condition in newborns, affecting up to 60% of term newborns and 80% of preterm newborns in the first week of life. Jaundice is caused by increased bilirubin in the blood from the breakdown of red blood cells. The gold standard for measuring bilirubin levels is obtaining a blood sample and processing it in a laboratory. However, noninvasive transcutaneous bilirubin (TcB) measurement devices are widely available and used in many settings to estimate total serum bilirubin (TSB) levels. OBJECTIVES: To determine the diagnostic accuracy of transcutaneous bilirubin measurement for detecting hyperbilirubinaemia in newborns. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL and trial registries up to 18 August 2022. We also checked the reference lists of all included studies and relevant systematic reviews for other potentially eligible studies. SELECTION CRITERIA: We included cross-sectional and prospective cohort studies that evaluated the accuracy of any TcB device compared to TSB measurement in term or preterm newborn infants (0 to 28 days postnatal age). All included studies provided sufficient data and information to create a 2 × 2 table for the calculation of measures of diagnostic accuracy, including sensitivities and specificities. We excluded studies that only reported correlation coefficients. DATA COLLECTION AND ANALYSIS: Two review authors independently applied the eligibility criteria to all citations from the search and extracted data from the included studies using a standard data extraction form. We summarised the available results narratively and, where possible, we combined study data in a meta-analysis. MAIN RESULTS: We included 23 studies, involving 5058 participants. All studies had low risk of bias as measured by the QUADAS 2 tool. The studies were conducted in different countries and settings, included newborns of different gestational and postnatal ages, compared various TcB devices (including the JM 101, JM 102, JM 103, BiliChek, Bilitest and JH20-1C) and used different cutoff values for a positive result. In most studies, the TcB measurement was taken from the forehead, sternum, or both. The sensitivity of various TcB cutoff values to detect significant hyperbilirubinaemia ranged from 74% to 100%, and specificity ranged from 18% to 89%. AUTHORS' CONCLUSIONS: The high sensitivity of TcB to detect hyperbilirubinaemia suggests that TcB devices are reliable screening tests for ruling out hyperbilirubinaemia in newborn infants. Positive test results would require confirmation through serum bilirubin measurement.

Intermittent phototherapy versus continuous phototherapy for neonatal jaundice.

BACKGROUND: Phototherapy is a widely accepted, effective first-line therapy for neonatal jaundice. It is traditionally used continuously but intermittent phototherapy has been proposed as an equally effective alternative with practical advantages of improved maternal feeding and bonding. The effectiveness of intermittent phototherapy compared with continuous phototherapy is unknown. OBJECTIVES: To assess the safety and effectiveness of intermittent phototherapy compared with continuous phototherapy. SEARCH METHODS: Searches were conducted on 31 January 2022 in the following databases: CENTRAL via CRS Web, MEDLINE and Embase via Ovid. We also searched clinical trials databases and the reference lists of retrieved articles for randomised controlled trials (RCTs) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs, cluster-RCTs and quasi-RCTs comparing intermittent phototherapy with continuous phototherapy in jaundiced infants (both term and preterm) up to the age of 30 days. We compared intermittent phototherapy with continuous phototherapy by any method and at any dose and duration as defined by the authors. DATA COLLECTION AND ANALYSIS: Three review authors independently selected trials, assessed trial quality and extracted data from included studies. We performed fixed-effect analyses and expressed treatment effects as mean difference (MD), risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CIs). Our primary outcomes of interest were rate of decline of serum bilirubin, and kernicterus. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 12 RCTs (1600 infants) in the review. There is one ongoing study and four awaiting classification. There was little or no difference between intermittent phototherapy and continuous phototherapy with respect to rate of decline of bilirubin in jaundiced newborn infants (MD -0.09 micromol/L/hr, 95% CI -0.21 to 0.03; I² = 61%; 10 studies; 1225 infants; low-certainty evidence). One study involving 60 infants reported no incidence of bilirubin induced brain dysfunction (BIND). It is uncertain whether either intermittent or continuous phototherapy reduces BIND because the certainty of this evidence is very low. There was little or no difference in treatment failure (RD 0.03, 95% CI 0.08 to 0.15; RR 1.63, 95% CI 0.29 to 9.17; 1 study; 75 infants; very low-certainty evidence) or infant mortality (RD -0.01, 95% CI -0.03 to 0.01; RR 0.69, 95% CI 0.37 to 1.31 I² = 0%; 10 studies, 1470 infants; low-certainty evidence).  AUTHORS' CONCLUSIONS: The available evidence detected little or no difference between intermittent and continuous phototherapy with respect to rate of decline of bilirubin. Continuous phototherapy appears to be more effective in preterm infants, however, the risks of continuous phototherapy and the potential benefits of a slightly lower bilirubin level are unknown. Intermittent phototherapy is associated with a decrease in the total number of hours of phototherapy exposure. There are theoretical benefits to intermittent regimens but there are important safety outcomes that were inadequately addressed. Large, well designed, prospective trials are needed in both preterm and term infants before it can be concluded that intermittent and continuous phototherapy regimens are equally effective.

Effects of oncological care pathways in primary and secondary care on patient, professional and health systems outcomes: a systematic review and meta-analysis.

BACKGROUND: Pathways are frequently used to improve care for cancer patients. However, there is little evidence about the effects of pathways used in oncological care. Therefore, we performed a systematic review and meta-analysis aiming to identify and synthesize existing literature on the effects of pathways in oncological care. METHODS: All patients diagnosed with cancer in primary and secondary/tertiary care whose treatment can be characterized as the strategy "care pathways" are included in this review. A systematic search in seven databases was conducted to gather evidence. Studies were screened by two independent reviewers. Study outcomes regarding patients, professionals, and system level were extracted from each study. RESULTS: Out of 13,847 search results, we selected 158 articles eligible for full text assessment. One hundred fifty studies were excluded and the remaining eight studies represented 4786 patients. Most studies were conducted in secondary/tertiary care. Length of stay (LOS) was the most common used indicator, and was reported in five studies. Meta-analysis based on subgroups showed an overall shorter LOS regarding gastric cancer (weighted mean difference (WMD)): - 2.75, CI: - 4.67 to - 0.83) and gynecological cancer (WMD: - 1.58, CI: - 2.10 to - 1.05). Costs were reported in six studies and most studies reported lower costs for pathway groups. CONCLUSIONS: Despite the differences between the included studies, we were able to present an evidence base for cancer care pathways performed in secondary/tertiary care regarding the positive effects of LOS in favor of cancer care pathways. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017057592.

Mind-Body Therapies for Opioid-Treated Pain: A Systematic Review and Meta-analysis.

Importance: Mind-body therapies (MBTs) are emerging as potential tools for addressing the opioid crisis. Knowing whether mind-body therapies may benefit patients treated with opioids for acute, procedural, and chronic pain conditions may be useful for prescribers, payers, policy makers, and patients. Objective: To evaluate the association of MBTs with pain and opioid dose reduction in a diverse adult population with clinical pain. Data Sources: For this systematic review and meta-analysis, the MEDLINE, Embase, Emcare, CINAHL, PsycINFO, and Cochrane Library databases were searched for English-language randomized clinical trials and systematic reviews from date of inception to March 2018. Search logic included (pain OR analgesia OR opioids) AND mind-body therapies. The gray literature, ClinicalTrials.gov, and relevant bibliographies were also searched. Study Selection: Randomized clinical trials that evaluated the use of MBTs for symptom management in adults also prescribed opioids for clinical pain. Data Extraction and Synthesis: Independent reviewers screened citations, extracted data, and assessed risk of bias. Meta-analyses were conducted using standardized mean differences in pain and opioid dose to obtain aggregate estimates of effect size with 95% CIs. Main Outcomes and Measures: The primary outcome was pain intensity. The secondary outcomes were opioid dose, opioid misuse, opioid craving, disability, or function. Results: Of 4212 citations reviewed, 60 reports with 6404 participants were included in the meta-analysis. Overall, MBTs were associated with pain reduction (Cohen d = -0.51; 95% CI, -0.76 to -0.26) and reduced opioid dose (Cohen d = -0.26; 95% CI, -0.44 to -0.08). Studies tested meditation (n = 5), hypnosis (n = 25), relaxation (n = 14), guided imagery (n = 7), therapeutic suggestion (n = 6), and cognitive behavioral therapy (n = 7) interventions. Moderate to large effect size improvements in pain outcomes were found for meditation (Cohen d = -0.70), hypnosis (Cohen d = -0.54), suggestion (Cohen d = -0.68), and cognitive behavioral therapy (Cohen d = -0.43) but not for other MBTs. Although most meditation (n = 4 [80%]), cognitive-behavioral therapy (n = 4 [57%]), and hypnosis (n = 12 [63%]) studies found improved opioid-related outcomes, fewer studies of suggestion, guided imagery, and relaxation reported such improvements. Most MBT studies used active or placebo controls and were judged to be at low risk of bias. Conclusions and Relevance: The findings suggest that MBTs are associated with moderate improvements in pain and small reductions in opioid dose and may be associated with therapeutic benefits for opioid-related problems, such as opioid craving and misuse. Future studies should carefully quantify opioid dosing variables to determine the association of mind-body therapies with opioid-related outcomes.

Tumor mutational burden in lung cancer: a systematic literature review.

Purpose: To assess the association of tumor mutational burden (TMB) with clinical outcomes, other biomarkers and patient/disease characteristics in patients receiving therapy for lung cancer. Results: In total, 4,303 publications were identified; 81 publications were included. The majority of publications assessing clinical efficacy of immunotherapy reported an association with high TMB, particularly when assessing progression-free survival and objective response rate. High TMB was consistently associated with TP53 alterations, and negatively associated with EGFR mutations. High TMB was also associated with smoking, squamous cell non-small cell lung carcinoma, and being male. Methods: A systematic literature review based upon an a priori protocol was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Cochrane methodologies. Searches were conducted in EMBASE, SCOPUS, Ovid MEDLINE®, and Emcare (from January 2012 until April 2018) and in two clinical trial registries. Conference abstracts were identified in EMBASE, and in targeted searches of recent major conference proceedings (from January 2016 until April 2018). Publications reporting data in patients receiving therapy for lung cancer that reported TMB and its association with clinical efficacy, or with other biomarkers or patient/disease characteristics, were included. Results are presented descriptively. Conclusion: This systematic literature review identified several clinical outcomes, biomarkers, and patient/disease characteristics associated with high TMB, and highlights the need for standardized definitions and testing practices. Further studies using standardized methodology are required to inform treatment decisions.

Cross-Leg Flaps for Lower Extremity Salvage: A Scoping Review.

BACKGROUND: Lower extremity trauma with soft tissue loss presents a challenge to the reconstructive surgeon. Cross-leg flaps, first described by Hamilton in 1854, are still used to salvage traumatized lower extremities in patients not suitable for free tissue transfer, or those who are receiving care in locations with limited resources. METHODS: A scoping review methodology was used to examine the evidence supporting the use of cross-leg flaps in modern healthcare. RESULTS: There have been 409 cases of cross-leg flaps reported in the modern literature, with the majority of flap cases occurring outside the United States in Turkey, India, and Japan. The most common indication was trauma, mentioned in 93.2% of patients (n = 353 of 379), and anatomic limitation, including inadequate vasculature, was the main reason for not performing free tissue transfer (52.8% of patients; n = 170 of 322). The majority are cross-leg fasciocutaneous flaps (85.8%, n = 273 of 318), based off the posterior tibial artery (27.5%, n = 50 of 182) and peroneal artery (26.9%, n = 49 of 182) and, covering defects of the distal third of the leg (55.5%, n = 151 of 272), or the foot (27.9%, n = 76 of 272). The pedicles are typically divided at 3 weeks (mean 20.9 days) after external fixation is used as the immobilization method (57.7%, n = 184 of 319). Flap survival was 100% across all publications except one (n = 349 of 350 patients), making cross-leg flaps a robust and reliable reconstructive option. CONCLUSION: In resource-limited environments or in patients who are unsuitable for microvascular free tissue transfer, the cross-leg flap remains an impactful and reliable option for limb salvage.

What Is Lean Management in Health Care? Development of an Operational Definition for a Cochrane Systematic Review.

Industrial improvement approaches such as Lean management are increasingly being adopted in health care. Synthesis is necessary to ensure these approaches are evidence based and requires operationalization of concepts to ensure all relevant studies are included. This article outlines the process utilized to develop an operational definition of Lean in health care. The literature search, screening, data extraction, and data synthesis processes followed the recommendations outlined by the Cochrane Collaboration. Development of the operational definition utilized the methods prescribed by Kinsman et al. and Wieland et al. This involved extracting characteristics of Lean, synthesizing similar components to establish an operational definition, applying this definition, and updating the definition to address shortcomings. We identified two defining characteristics of Lean health-care management: (1) Lean philosophy, consisting of Lean principles and continuous improvement, and (2) Lean activities, which include Lean assessment activities and Lean improvement activities. The resulting operational definition requires that an organization or subunit of an organization had integrated Lean philosophy into the organization's mandate, guidelines, or policies and utilized at least one Lean assessment activity or Lean improvement activity. This operational definition of Lean management in health care will act as an objective screening criterion for our systematic review. To our knowledge, this is the first evidence-based operational definition of Lean management in health care.

A scoping review of Advanced Practice Registered Nurses Consensus Model outcomes: Part four of a four-part series on critical topics identified by the 2015 Nurse Practitioner Research Agenda.

BACKGROUND AND PURPOSE: The Advanced Practice Registered Nurses (APRN) Consensus Model was produced by the APRN Joint Dialogue Group in 2008. The aim of the Consensus Model is to guide state boards on the implementation of APRN practice components, including licensure, accreditation, certification, and education and to clarify the legal scope of practice and APRN roles. The purpose of this scoping review and gap analysis was to appraise the evidence related to patient, nurse practitioner (NP) and organizational outcomes resulting from the Consensus Model. METHODS: A scoping review of research studies and grey literature reports was conducted and focused on the outcomes and key concepts related to the Consensus Model. Areas of foci included patients, NPs, and organizations. A subsequent gap analysis was conducted. CONCLUSIONS: Several positive findings related to the Consensus Model, or components thereof, were identified for patient, NP, and organizational outcomes on various levels. Research gaps exist. Additional research is needed to fully evaluate the health outcomes on a broader scale. IMPLICATIONS FOR PRACTICE: Existing evidence may support NPs and supporting organizations to further legislative efforts to more fully implement the Consensus Model nationwide.

The sustainability of Lean in pediatric healthcare: a realist review.

BACKGROUND: Lean is a quality improvement management system from the Toyota manufacturing industry. Since the early 2000's, Lean has been used as an intervention for healthcare improvement. Lean is intended to reduce costs and improve customer value through continuous improvement. Despite its extensive use, the contextual factors and mechanisms that influence the sustainability of Lean in healthcare have not been well studied. Realist synthesis is one approach to "unpack" the causal explanations of how and why Lean is sustained or not in healthcare. We conducted a realist synthesis using the context (C) + mechanim (M) = outcome (O) heuristic, to further develop and refine an initial program theory with seven CMO hypotheses, on the sustainability of Lean efforts across pediatric healthcare. METHODS: Our search strategy was multi-pronged, iterative, and purposeful in nature, consisting of database, gray literature, and contact with three healthcare organizations known for Lean implementation. We included primary research studies, published and unpublished case studies or reports, if they included Lean implementation with a pediatric focus and sustainability outcome. We used the Normalization Process Theory and the National Health Services Sustainability Model, an operational definition for Lean and a comprehensive definition for sustainability as guidance for data extraction and analysis. Our initial program theory with was refined using a blend of abductive and retroductive analytical processes. RESULTS: We identified six published primary research studies, two published quality improvement case studies, and three unpublished quality improvement case reports. Five CMO hypotheses from our initial program theory were substantially supported after synthesis, "sense-making and value congruency," "staff engagement and empowerment," and the "ripple effect" or causal pathway between Lean implementation outcomes that served as facilitating or hindering contexts for sustainability. Overall, there was variation with the conceptualization and measurement of sustainability. CONCLUSIONS: This study is the first to examine Lean sustainability in pediatric healthcare using realist methods. Future research should examine whether the predictors of implementation are the same or different to sustainability and evaluate the underlying mechanisms that influence the sustainability of Lean. There is also a need for research to develop and test conceptual models and frameworks on sustainability. SYSTEMATIC REVIEW REGISTRATION: PROSPERO-CRD42015032252 .

Incidence of urinary extravasation and rate of ureteral stenting after high-grade renal trauma in adults: a meta-analysis.

BACKGROUND: Collecting system injury and urinary extravasation is an important yet understudied aspect of renal trauma. We aimed to examine the incidence of urinary extravasation and also the rates of ureteral stenting after high-grade renal trauma (HGRT) in adults. METHODS: A search strategy was developed to search Ovid Medline, Embase, CINAHL, and Cochrane Library. Two reviewers screened titles and abstracts, followed by full-text review of the relevant publications. Studies were included if they indicated the number of patients with HGRT [the American Association for the Surgery of Trauma (AAST) grades III-IV or equivalents] and number of patients with urinary extravasation. A descriptive meta-analysis of binary proportions was performed with random-effects model to calculate the incidence of urinary extravasation and rates of ureteral stenting. RESULTS: After screening, 24 and 20 studies were included for calculating urinary extravasation and stenting rates, respectively. Most studies involved blunt injury and were retrospective single-center case series. Incidence of urinary extravasation was 29% (95% CI: 17-42%) after HGRT (grade III-V), and 51% (95% CI: 38-64%) when only grade IV-V injuries were combined. Overall, 29% (95% CI: 22-36%) of patients with urinary extravasation underwent ureteral stenting. CONCLUSIONS: Approximately 30% of patients with HGRT are diagnosed with urinary extravasation and 29% of those with urinary extravasation undergo ureteral stenting. Understanding the rate of urinary extravasation and interventions is the first step in creating a prospective trial designed to demonstrate when ureteral stenting and aggressive management of urinary extravasation is needed.

Effects of oncological care pathways in primary and secondary care on patient, professional, and health systems outcomes: protocol for a systematic review and meta-analysis.

BACKGROUND: The high impact of a cancer diagnosis on patients and their families and the increasing costs of cancer treatment call for optimal and efficient oncological care. To improve the quality of care and to minimize healthcare costs and its economic burden, many healthcare organizations introduce care pathways to improve efficiency across the continuum of cancer care. However, there is limited research on the effects of cancer care pathways in different settings. METHODS: The aim of this systematic review and meta-analysis described in this protocol is to synthesize existing literature on the effects of oncological care pathways. We will conduct a systematic search strategy to identify all relevant literature in several biomedical databases, including Cochrane library, MEDLINE, Embase, and CINAHL. We will follow the methodology of Cochrane Effective Practice and Organisation of Care (EPOC), and we will include randomized trials, non-randomized trials, controlled before-after studies, and interrupted time series studies. In addition, we will include full economic evaluations (cost-effectiveness analyses, cost-utility analyses, and cost-benefit analyses), cost analyses, and comparative resource utilization studies, if available. Two reviewers will independently screen all studies and evaluate those included for risk of bias. From these studies, we will extract data regarding patient, professional, and health systems outcomes. Our systematic review will follow the PRISMA set of items for reporting in systematic reviews and meta-analyses. DISCUSSION: Following the protocol outlined in this article, we aim to identify, assess, and synthesize all available evidence in order to provide an evidence base on the effects of oncological care pathways as reported in the literature. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017057592 .

Nonnutritive sweeteners and cardiometabolic health: a systematic review and meta-analysis of randomized controlled trials and prospective cohort studies.

BACKGROUND: Nonnutritive sweeteners, such as aspartame, sucralose and stevioside, are widely consumed, yet their long-term health impact is uncertain. We synthesized evidence from prospective studies to determine whether routine consumption of non-nutritive sweeteners was associated with long-term adverse cardiometabolic effects. METHODS: We searched MEDLINE, Embase and Cochrane Library (inception to January 2016) for randomized controlled trials (RCTs) that evaluated interventions for nonnutritive sweeteners and prospective cohort studies that reported on consumption of non-nutritive sweeteners among adults and adolescents. The primary outcome was body mass index (BMI). Secondary outcomes included weight, obesity and other cardiometabolic end points. RESULTS: From 11 774 citations, we included 7 trials (1003 participants; median follow-up 6 mo) and 30 cohort studies (405 907 participants; median follow-up 10 yr). In the included RCTs, nonnutritive sweeteners had no significant effect on BMI (mean difference -0.37 kg/m2; 95% confidence interval [CI] -1.10 to 0.36; I2 9%; 242 participants). In the included cohort studies, consumption of nonnutritive sweeteners was associated with a modest increase in BMI (mean correlation 0.05, 95% CI 0.03 to 0.06; I2 0%; 21 256 participants). Data from RCTs showed no consistent effects of nonnutritive sweeteners on other measures of body composition and reported no further secondary outcomes. In the cohort studies, consumption of nonnutritive sweeteners was associated with increases in weight and waist circumference, and higher incidence of obesity, hypertension, metabolic syndrome, type 2 diabetes and cardiovascular events. Publication bias was indicated for studies with diabetes as an outcome. INTERPRETATION: Evidence from RCTs does not clearly support the intended benefits of nonnutritive sweeteners for weight management, and observational data suggest that routine intake of nonnutritive sweeteners may be associated with increased BMI and cardiometabolic risk. Further research is needed to fully characterize the long-term risks and benefits of nonnutritive sweeteners. Protocol registration: PROSPERO-CRD42015019749.

Prehospital notification for major trauma patients requiring emergency hospital transport: A systematic review.

OBJECTIVE: This systematic review aimed to determine the effect of prehospital notification systems for major trauma patients on overall (<30 days) and early (<24 hours) mortality, hospital reception, and trauma team presence (or equivalent) on arrival, time to critical interventions, and length of hospital stay. METHODS: Experimental and observational studies of prehospital notification compared with no notification or another type of notification in major trauma patients requiring emergency transport were included. Risk of bias was assessed using the Cochrane ACROBAT-NRSI tool. A narrative synthesis was conducted and evidence quality rated using the GRADE criteria. RESULTS: Three observational studies of 72,423 major trauma patients were included. All were conducted in high-income countries in hospitals with established trauma services, with two studies undertaking retrospective analysis of registry data. Two studies reported overall mortality, one demonstrating a reduction in mortality; (adjusted odds ratio (OR) 0.61, 95% confidence interval (CI) 0.39 to 0.94, 72,073 participants); and the other demonstrating a nonsignificant change (OR 0.61, 95% CI 0.23 to 1.64, 81 participants). The quality of this evidence was rated as very low. CONCLUSION: Limited research on the topic constrains conclusive evidence on the effect of prehospital notification on patient-centered outcomes after severe trauma. Composite interventions that combine prehospital notification with effective actions on arrival to hospital such as trauma bay availability, trauma team presence, and early access to definitive management may provide more robust evidence towards benefits of early interventions during trauma reception and resuscitation.

Quasi-experimental study designs series-paper 8: identifying quasi-experimental studies to inform systematic reviews.

OBJECTIVE: This article reviews the available evidence and guidance on methods to identify reports of quasi-experimental (QE) studies to inform systematic reviews of health care, public health, international development, education, crime and justice, and social welfare. STUDY DESIGN AND SETTING: Research, guidance, and examples of search strategies were identified by searching a range of databases, key guidance documents, selected reviews, conference proceedings, and personal communication. Current practice and research evidence were summarized. RESULTS: Four thousand nine hundred twenty-four records were retrieved by database searches, and additional documents were obtained by other searches. QE studies are challenging to identify efficiently because they have no standardized nomenclature and may be indexed in various ways. Reliable search filters are not available. There is a lack of specific resources devoted to collecting QE studies and little evidence on where best to search. CONCLUSION: Searches to identify QE studies should search a range of resources and, until indexing improves, use strategies that focus on the topic rather than the study design. Better definitions, better indexing in databases, prospective registers, and reporting guidance are required to improve the retrieval of QE studies and promote systematic reviews of what works based on the evidence from such studies.

A systematic review of interventions to increase the use of standardized outcome measures by rehabilitation professionals.

OBJECTIVE: To determine the types and effectiveness of interventions to increase the knowledge about, attitudes towards, and use of standardized outcome measures in rehabilitation professionals. DATA SOURCES: An electronic search using Medline, EMBASE, PsycINFO, CINAHL, Ergonomics Abstracts, Sports Discus. The search is current to February 2016. STUDY SELECTION: All study designs testing interventions were included as were all provider and patient types. Two reviewers independently conducted a title and abstract review, followed by a full-text review. DATA EXTRACTION: Two reviewers independently extracted a priori variables and used consensus for disagreements. Quality assessment was conducted using the Assessment of Quantitative Studies published by the Effective Public Health Practice Group. DATA SYNTHESIS: We identified 11 studies involving at least 1200 providers. Nine of the studies showed improvements in outcome measure use rates but only three of these studies used an experimental or quasi-experimental design. Eight of the studies used an educational approach in the intervention and three used audit and feedback. Poor intervention description and quality of studies limited recommendations. CONCLUSIONS: Increased attention to testing interventions focused on known barriers, matched to behavior change techniques, and with stronger designs is warranted.