Sirolimus for vascular anomalies in the first year of life: a systematic review.

Evidence on effectiveness and safety of sirolimus in congenital vascular anomalies in infancy is lacking. We aim to systematically review the efficacy and safety of sirolimus in treating congenital VA in infancy. We searched for and included all studies evaluating sirolimus for VA in the first year of life. The primary outcome was effectiveness. The secondary outcome was safety. We included 84 case series and reports (172 participants). Sirolimus decreased the size of the VA in >50% of participants, most of whom had minor transient side effects, and 27% had no adverse effects at all. When categorized by age (<1 month, 1-5 months and 6-12 months), the effectiveness was similar in all age groups. Available evidence suggests that sirolimus is effective and well tolerated. The effectiveness of sirolimus should be evaluated in a well-designed randomized controlled or observational studies.

Leptin deficiency, a potential mechanism for impaired fetal lung development in uteroplacental insufficiency?

Uteroplacental insufficiency (UPI) is a major cause of fetal growth restriction (FGR). Leptin, an adipokine, has been shown to play a vital role in fetal organogenesis. There is evidence reporting leptin deficiency in preterm and growth-restricted fetuses. In this issue of Pediatric Research, Yuliana et al. report leptin expression and lung development in UPI-induced FGR rats. UPI-induced FGR rats expressed decreased lung leptin and had impaired lung development, as shown by decreased surface area and lung volume. They also found a significant association between lung radial alveolar count, serum leptin, von Willebrand factor, and specific metabolites on metabolomic analyses. Previous studies on leptin supplementation in vivo have been associated with improvement in lung maturation; supporting the evidence, that leptin improves lung growth and development in FGR and may have future therapeutic potential in the improvement of respiratory outcomes in these infants. Future studies to support evidence of this association in humans are warranted.

Do hematological biomarkers predict surgical necrotizing enterocolitis?

Necrotizing enterocolitis (NEC) is a devastating gastrointestinal emergency in preterm infants and the clinical presentation of NEC may vary with gestational age. We lack reliable biomarkers for early diagnosis of NEC limiting timely intervention. Hematological changes in NEC are actively researched for their potential role as biomarkers. The pattern and severity of hematological abnormalities have been correlated with rapid progression, the need for surgery, increased risk of mortality, and morbidity. In this issue of Pediatric Research, Chong et al. report GA-specific hematological biomarkers in preterm infants with NEC that could predict the need for surgery. Thrombocytopenia at NEC onset was an independent predictor of surgical intervention in extremely preterm infants. Persistent thrombocytopenia and lymphopenia at 72 h and elevated C-reactive protein at 48 h after NEC onset, predicted surgery in infants of 28 to <32 weeks GA. Persistent thrombocytopenia at 24 h after the onset of NEC was predictive of mortality in infants who underwent surgery. Well-designed, prospective, multi-center studies are needed to confirm the role of hematological biomarkers in early diagnosis and prognostication in NEC.

Diagnostic Accuracy of Urinary N Terminal pro-B Type Natriuretic Peptides for Hemodynamically Significant-Patent Ductus Arteriosus in Preterm Infants.

BACKGROUND: Echocardiography is the gold standard for the diagnosis hemodynamically significant-patent ductus arteriosus (hs-PDA). It requires trained personnel and is not readily available. Urinary biomarkers can be used as an adjunct. OBJECTIVE: The objective of this study was to systematically review the diagnostic accuracy of urinary N terminal pro-B type natriuretic peptides (NT-proBNP) for hs-PDA in preterm neonates. METHODS: We included studies that evaluated urinary NT-proBNP and urinary NT-proBNP/creatinine ratio (index tests) in preterm neonates with hs-PDA (participants) in comparison with echocardiogram (reference standard). Methodological quality and certainty of evidence were assessed using Quality Assessment of Diagnostic-Accuracy Studies (QUADAS-2) and Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. RESULTS: Low quality of evidence suggests that urinary NT-proBNP has modest sensitivity and specificity for the diagnosis of a hs-PDA, with variation in accuracy based on assay and patient characteristics. CONCLUSION: Urinary NT-proBNP assays must be locally validated for specific patient populations and further studies to support its use must be performed.

Multiomic Investigations into Lung Health and Disease.

Diseases of the lung account for more than 5 million deaths worldwide and are a healthcare burden. Improving clinical outcomes, including mortality and quality of life, involves a holistic understanding of the disease, which can be provided by the integration of lung multi-omics data. An enhanced understanding of comprehensive multiomic datasets provides opportunities to leverage those datasets to inform the treatment and prevention of lung diseases by classifying severity, prognostication, and discovery of biomarkers. The main objective of this review is to summarize the use of multiomics investigations in lung disease, including multiomics integration and the use of machine learning computational methods. This review also discusses lung disease models, including animal models, organoids, and single-cell lines, to study multiomics in lung health and disease. We provide examples of lung diseases where multi-omics investigations have provided deeper insight into etiopathogenesis and have resulted in improved preventative and therapeutic interventions.

Current Patterns of Probiotic Use in U.S. Neonatal Intensive Care Units: A Multi-Institution Survey.

OBJECTIVE: Probiotic supplementation is associated with health benefits in preterm infants. The 2021 American Academy of Pediatrics (AAP) statement on probiotic use advised caution, citing heterogeneity and absence of federal regulation. We assessed the impact of the AAP statement and current institution-wide patterns of probiotic use across neonatal intensive care units (NICU) across the United States. STUDY DESIGN: A cross-sectional web-based institutional survey using REDCap was emailed to 430 Children's Hospital Neonatal Consortium (CHNC) and Pediatrix Medical Group institutions. The survey captured data on probiotic formulations, supplementation, initiation and cessation criteria, reasons for discontinuation, interest in initiating, and AAP statement's impact. RESULTS: Ninety-five (22.1%) hospitals, including 42/46 (91%) CHNC and 53/384 (14%) Pediatrix institutions, completed the survey. Thirty-seven (39%) currently use probiotics. Fourteen different probiotic formulations were reported. The common criteria for initiation were birth weight <1,500 g and gestational age <32 weeks. Parental consent or assent was obtained at only 30% of institutions. Five hospitals (11%) with prior probiotic use discontinued solely due to the AAP statement. Overall, 23 (24%) of hospitals indicated that the AAP statement significantly influenced their decision regarding probiotic use. Nineteen of 51 nonusers (37%) are considering initiation. CONCLUSION: Probiotic use in preterm infants is likely increasing in NICUs across the United States, but significant variability exists. The 2021 AAP statement had variable impact on NICUs' decision regarding probiotic use. The growing interest in adopting probiotics and the significant interhospital variability highlight the need for better regulation and consensus guidelines to ensure standardized use. KEY POINTS: · Probiotic use in preterm infants is likely increasing in U.S. NICUs, but clinical variability exists.. · The AAP statement on probiotic use in preterm infants had a modest impact on current practices.. · There's a need for better product regulation and consensus guidelines to ensure standardized use..

Viral Infections and Neonatal Necrotizing Enterocolitis: A Meta-analysis.

CONTEXT: Necrotizing enterocolitis (NEC) is a devastating intestinal disease affecting preterm infants. Studies implicate viral infections in etiopathogenesis. OBJECTIVE: To summarize the association of viral infections with NEC by systematic review and meta-analysis. DATA SOURCES: We searched Ovid-Medline, Embase, Web of Science, and Cochrane databases in November 2022. STUDY SELECTION: We included observational studies that examined the association between viral infections and NEC in newborn infants. DATA EXTRACTION: We extracted data regarding the methodology, participant characteristics, and outcome measures. RESULTS: We included 29 and 24 studies in the qualitative review and meta-analysis, respectively. The meta-analysis demonstrated a significant association between viral infections and NEC (odds ratio [OR], 3.81, 95% confidence interval: 1.99-7.30, 24 studies). The association remained significant after excluding the outliers (OR, 2.89 [1.56-5.36], 22 studies) and studies with poor methodology (OR, 3.33 [1.73-6.43], 22 studies). In subgroup analysis based on participants' birth weight, studies including very low birth weight infants only (OR, 3.62 [1.63-8.03], 8 studies) and non-very low birth weight infants only (OR, 5.28 [1.69-16.54], 6 studies) showed a significant association. In subgroup analysis based on specific viruses, infection with rotavirus (OR, 3.96 [1.12-13.95], 10 studies), cytomegalovirus (OR, 3.50 [1.60-7.65], 5 studies), norovirus (OR, 11.95 [2.05-69.84], 2 studies), and astrovirus (OR, 6.32 [2.49-16.02], 2 studies) was significantly associated with NEC. LIMITATIONS: Heterogeneity of the included studies. CONCLUSIONS: Viral infection is associated with an increased risk of NEC in newborn infants. We need methodologically sound prospective studies to assess the effect of preventing or treating viral infections on NEC incidence.

Pentoxifylline for treatment of sepsis and necrotising enterocolitis in neonates.

BACKGROUND: Mortality and morbidity due to neonatal sepsis and necrotising enterocolitis (NEC) remain high despite the use of potent antimicrobial agents. Agents that modulate inflammation may improve outcomes. Pentoxifylline (PTX), a phosphodiesterase inhibitor, is one such agent. This is an update of a review first published in 2003 and updated in 2011 and 2015. OBJECTIVES: To assess the effectiveness and safety of intravenous PTX as an adjunct to antibiotic therapy on mortality and morbidity in neonates with suspected or confirmed sepsis and neonates with NEC. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, and trial registries in July 2022. We also searched the reference lists of identified clinical trials and handsearched conference abstracts.   SELECTION CRITERIA: We included randomised controlled trials (RCTs) or quasi-RCTs assessing the efficacy of PTX with antibiotics (any dose or duration) for treatment of suspected or confirmed sepsis or NEC in neonates. We included three comparisons: (1) PTX with antibiotics compared to placebo or no intervention with antibiotics; (2) PTX with antibiotics compared to PTX with antibiotics and adjunct treatments such as immunoglobulin M-enriched intravenous immunoglobulin (IgM-enriched IVIG); (3) PTX with antibiotics compared to adjunct treatments such as IgM-enriched IVIG with antibiotics. DATA COLLECTION AND ANALYSIS: We reported typical risk ratio (RR) and risk difference (RD) with 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes derived from a fixed-effect model of meta-analysis. We calculated the number needed to treat for an additional beneficial outcome (NNTB) if there was a statistically significant reduction in RD. MAIN RESULTS: We identified no new studies for this update. We included six RCTs (416 neonates). All of the included studies examined neonates with sepsis; we identified no studies on neonates with NEC. Four of the six trials had high risk of bias for at least one risk of bias domain. Comparison 1: PTX with antibiotics compared to placebo with antibiotics, or antibiotics alone, in neonates with sepsis may reduce all-cause mortality during hospital stay (typical RR 0.57, 95% CI 0.35 to 0.93; typical RD -0.08, 95% CI -0.14 to -0.01; NNTB 13, 95% CI 7 to 100; 6 studies, 416 participants, low-certainty evidence) and may decrease length of hospital stay (LOS) (MD -7.74, 95% CI -11.72 to -3.76; 2 studies, 157 participants, low-certainty evidence). The evidence is very uncertain that PTX with antibiotics compared to placebo or no intervention results in any change in chronic lung disease (CLD) (RR 1.50, 95% CI 0.45 to 5.05; 1 study, 120 participants, very low-certainty evidence), severe intraventricular haemorrhage (sIVH) (RR 0.75, 95% CI 0.28 to 2.03; 1 study, 120 participants, very low-certainty evidence), periventricular leukomalacia (PVL) (RR 0.50, 95% CI 0.10 to 2.63; 1 study, 120 participants, very low-certainty evidence), NEC (RR 0.56, 95% CI 0.29 to 1.06; 6 studies, 405 participants, very low-certainty evidence), or retinopathy of prematurity (ROP) (RR 0.40, 95% CI 0.08 to 1.98; 1 study, 120 participants, very low-certainty evidence) in neonates with sepsis. Comparison 2: the evidence is very uncertain that PTX with antibiotics compared to PTX with antibiotics and IgM-enriched IVIG has any effect on mortality (RR 0.71, 95% CI 0.24 to 2.10; 102 participants, 1 study, very low-certainty evidence) or development of NEC in neonates with sepsis (RR 1.33, 95% CI 0.31 to 5.66; 1 study, 102 participants, very low-certainty evidence). The outcomes of CLD, sIVH, PVL, LOS, and ROP were not reported. Comparison 3: the evidence is very uncertain that PTX with antibiotics compared to IgM-enriched IVIG with antibiotics has any effect on mortality (RR 1.25, 95% CI 0.36 to 4.39; 102 participants, 1 study, very low-certainty evidence) or development of NEC (RR 1.33, 95% CI 0.31 to 5.66; 102 participants, 1 study, very low-certainty evidence) in neonates with sepsis. The outcomes of CLD, sIVH, PVL, LOS, and ROP were not reported. All of the included studies evaluated adverse effects due to PTX, but none were reported in the intervention group in any of the comparisons. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that adjunct PTX therapy in neonatal sepsis may decrease mortality and length of hospital stay without any adverse effects. The evidence is very uncertain if PTX with antibiotics compared to PTX with antibiotics and IgM-enriched IVIG, or PTX with antibiotics compared to IgM-enriched IVIG with antibiotics, has any effect on mortality or development of NEC. We encourage researchers to undertake well-designed multicentre trials to confirm or refute the effectiveness and safety of pentoxifylline in reducing mortality and morbidity in neonates with sepsis or NEC.

Infant isolation and cohorting for preventing or reducing transmission of healthcare-associated infections in neonatal units.

BACKGROUND: Neonatal healthcare-associated infections (HAIs) result in increased morbidity and mortality, as well as increased healthcare costs. Patient isolation measures, i.e. single-room isolation or the cohorting of patients with similar infections, remain a recommended and commonly used practice for preventing horizontal spread of infections in the neonatal intensive care unit (NICU).  OBJECTIVES: Our primary objective was to assess the effect of single-room isolation or cohorting, or both for preventing transmission of HAIs or colonization with HAI-causing pathogens in newborn infants less than six months of age admitted to the neonatal intensive care unit (NICU). Our secondary objective was to assess the effect of single-room isolation or cohorting, or both on neonatal mortality and perceived or documented adverse effects in newborn infants admitted to the NICU.  SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, CINAHL, the WHO ICTRP and ClinicalTrials.gov trials registries. There were no restrictions to date, language or publication type. We also checked the reference lists of studies identified for full-text review.  SELECTION CRITERIA: Types of studies: cluster-randomized or quasi-randomized trials at the level of the cluster (where clusters may be defined by NICU, hospital, ward, or other subunits of the hospital). We also included cross-over trials with a washout period of more than four months (arbitrarily defined). TYPES OF PARTICIPANTS: newborn infants less than six months of age in neonatal units that implemented patient isolation or cohorting as infection control measures to prevent HAIs. Types of interventions: patient isolation measures (single-room isolation or cohorting, or both of infants with similar colonization or infections) compared to routine isolation measures. TYPES OF OUTCOME MEASURES: the primary outcome was the rate of transmission of HAIs as estimated by the infection and colonization rates in the NICU. Secondary outcomes included all-cause mortality during hospital stay at 28 days of age, length of hospital stay, as well as potential adverse effects of isolation or cohorting measures, or both. DATA COLLECTION AND ANALYSIS: The standard methods of Cochrane Neonatal were used to identify studies and assess the methodological quality of eligible cluster-randomized trials. The certainty of the evidence was to be assessed by the GRADE method as evidence of high, moderate, low, or very low certainty. Infection and colonization rates were to be expressed as rate ratios for each trial and if appropriate for meta-analysis, the generic inverse variance method in RevMan was to be used. MAIN RESULTS: We did not identify any published or ongoing trials to include in the review. AUTHORS' CONCLUSIONS: The review found no evidence from randomized trials to either support or refute the use of patient isolation measures (single-room isolation or cohorting) in neonates with HAIs. Risks secondary to infection control measures need to be balanced against the benefits of decreasing horizontal transmission in the neonatal unit for optimal neonatal outcomes. There is an urgent need to research the effectiveness of patient isolation measures for preventing the transmission of HAIs in neonatal units. Well-designed trials randomizing clusters of units or hospitals to a type of patient isolation method intervention are warranted.

Videolaryngoscopy versus direct laryngoscopy for tracheal intubation in neonates.

BACKGROUND: Establishment of a secure airway is a critical part of neonatal resuscitation in the delivery room and the neonatal intensive care unit. Videolaryngoscopy has the potential to facilitate successful endotracheal intubation, and decrease adverse consequences of a delay in airway stabilization. Videolaryngoscopy may enhance visualization of the glottis and intubation success in neonates. This is an update of a review first published in 2015, and updated in 2018. OBJECTIVES: To determine the effectiveness and safety of videolaryngoscopy compared to direct laryngoscopy in decreasing the time and attempts required for endotracheal intubation and increasing the success rate on first intubation attempt in neonates (0 to 28 days of age). SEARCH METHODS: In November 2022, we updated the search for trials evaluating videolaryngoscopy for neonatal endotracheal intubation in CENTRAL, MEDLINE, Embase, CINAHL, and BIOSIS. We also searched abstracts of the Pediatric Academic Societies, clinical trials registries (www. CLINICALTRIALS: gov; www.controlled-trials.com), and reference lists of relevant studies. SELECTION CRITERIA: Randomized controlled trials (RCTs), quasi-RCTs, cluster-RCTs, or cross-over trials, in neonates (0 to 28 days of age), evaluating videolaryngoscopy with any device used for endotracheal intubation compared with direct laryngoscopy. DATA COLLECTION AND ANALYSIS: Three review authors performed data collection and analysis, as recommended by Cochrane Neonatal. Two review authors independently assessed studies identified by the search strategy for inclusion. We used the GRADE approach to assess the certainty of the evidence. MAIN RESULTS: The updated search yielded 7786 references, from which we identified five additional RCTs for inclusion, seven ongoing trials, and five studies awaiting classification. Three studies were included in the previous version of the review. For this update, we included eight studies, which provided data on 759 intubation attempts in neonates. We included neonates of either sex, who were undergoing endotracheal intubation in international hospitals. Different videolaryngoscopy devices (including C-MAC, Airtraq, and Glidescope) were used in the studies. For the primary outcomes; videolaryngoscopy may not reduce the time required for successful intubation when compared with direct laryngoscopy (mean difference [MD] 0.74, 95% confidence interval [CI] -0.19 to 1.67; 5 studies; 505 intubations; low-certainty evidence). Videolaryngoscopy may result in fewer intubation attempts (MD -0.08, 95% CI -0.15 to 0.00; 6 studies; 659 intubations; low-certainty evidence). Videolaryngoscopy may increase the success of intubation at the first attempt (risk ratio [RR] 1.24, 95% CI 1.13 to 1.37; risk difference [RD] 0.14, 95% CI 0.08 to 0.20; number needed to treat for an additional beneficial outcome [NNTB] 7, 95% CI 5 to 13; 8 studies; 759 intubation attempts; low-certainty evidence).  For the secondary outcomes; the evidence is very uncertain about the effect of videolaryngoscopy on desaturation or bradycardia episodes, or both, during intubation (RR 0.94, 95% CI 0.38 to 2.30; 3 studies; 343 intubations; very-low certainty evidence). Videolaryngoscopy may result in little to no difference in the lowest oxygen saturations during intubation compared with direct laryngoscopy (MD -0.76, 95% CI -5.74 to 4.23; 2 studies; 359 intubations; low-certainty evidence). Videolaryngoscopy likely results in a slight reduction in the incidence of airway trauma during intubation attempts compared with direct laryngoscopy (RR 0.21, 95% CI 0.05 to 0.79; RD -0.04, 95% CI -0.07 to -0.01; NNTB 25, 95% CI 14 to 100; 5 studies; 467 intubations; moderate-certainty evidence). There were no data available on other adverse effects of videolaryngoscopy. We found a high risk of bias in areas of allocation concealment and performance bias in the included studies. AUTHORS' CONCLUSIONS: Videolaryngoscopy may increase the success of intubation on the first attempt and may result in fewer intubation attempts, but may not reduce the time required for successful intubation (low-certainty evidence). Videolaryngoscopy likely results in a reduced incidence of airway-related adverse effects (moderate-certainty evidence). These results suggest that videolaryngoscopy may be more effective and potentially reduce harm when compared to direct laryngoscopy for endotracheal intubation in neonates. Well-designed, adequately powered RCTS are necessary to confirm the efficacy and safety of videolaryngoscopy in neonatal intubation.

Prognostic value of echocardiographic parameters in congenital diaphragmatic hernia: a systematic review and meta-analysis.

BACKGROUND: Prognostication of mortality and decision to offer extracorporeal membrane oxygenation (ECMO) treatment in infants with congenital diaphragmatic hernia (CDH) can inform clinical management. OBJECTIVE: To summarise the prognostic value of echocardiography in infants with CDH. METHODS: Electronic databases Ovid MEDLINE, Embase, Scopus, CINAHL, the Cochrane Library and conference proceedings up to July 2022 were searched. Studies evaluating the prognostic performance of echocardiographic parameters in newborn infants were included. Risk of bias and applicability were assessed using the Quality Assessment of Prognostic Studies tool. We used a random-effect model for meta-analysis to compute mean differences (MDs) for continuous outcomes and relative risk (RR) for binary outcomes with 95% CIs. Our primary outcome was mortality; secondary outcomes were need for ECMO, duration of ventilation, length of stay, and need for oxygen and/or inhaled nitric oxide. RESULTS: Twenty-six studies were included that were of acceptable methodological quality. Increased diameters of the right and left pulmonary arteries at birth (mm), MD 0.95 (95% CI 0.45 and 1.46) and MD 0.79 (95% CI 0.58 to 0.99), respectively) were associated with survival. Left ventricular (LV) dysfunction, RR 2.40, (95% CI 1.98 to 2.91), right ventricular (RV) dysfunction, RR 1.83 (95% CI 1.29 to 2.60) and severe pulmonary hypertension (PH), RR 1.69, (95% CI 1.53 to 1.86) were associated with mortality. Left and RV dysfunctions, RR 3.30 (95% CI 2.19 to 4.98) and RR 2.16 (95% CI 1.85 to 2.52), respectively, significantly predicted decision to offer ECMO treatment. Limitations are lack of consensus on what parameter is optimal and standardisation of echo assessments. CONCLUSIONS: LV and RV dysfunctions, PH and pulmonary artery diameter are useful prognostic factors among patients with CDH.

Multiomics, artificial intelligence, and precision medicine in perinatology.

Technological advances in omics evaluation, bioinformatics, and artificial intelligence have made us rethink ways to improve patient outcomes. Collective quantification and characterization of biological data including genomics, epigenomics, metabolomics, and proteomics is now feasible at low cost with rapid turnover. Significant advances in the integration methods of these multiomics data sets by machine learning promise us a holistic view of disease pathogenesis and yield biomarkers for disease diagnosis and prognosis. Using machine learning tools and algorithms, it is possible to integrate multiomics data with clinical information to develop predictive models that identify risk before the condition is clinically apparent, thus facilitating early interventions to improve the health trajectories of the patients. In this review, we intend to update the readers on the recent developments related to the use of artificial intelligence in integrating multiomic and clinical data sets in the field of perinatology, focusing on neonatal intensive care and the opportunities for precision medicine. We intend to briefly discuss the potential negative societal and ethical consequences of using artificial intelligence in healthcare. We are poised for a new era in medicine where computational analysis of biological and clinical data sets will make precision medicine a reality. IMPACT: Biotechnological advances have made multiomic evaluations feasible and integration of multiomics data may provide a holistic view of disease pathophysiology. Artificial Intelligence and machine learning tools are being increasingly used in healthcare for diagnosis, prognostication, and outcome predictions. Leveraging artificial intelligence and machine learning tools for integration of multiomics and clinical data will pave the way for precision medicine in perinatology.

Brain natriuretic peptide and N-terminal brain natriuretic peptide for the diagnosis of haemodynamically significant patent ductus arteriosus in preterm neonates.

BACKGROUND: Echocardiogram is the reference standard for the diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. A simple blood assay for brain natriuretic peptide (BNP) or amino-terminal pro-B-type natriuretic peptide (NT-proBNP) may be useful in the diagnosis and management of hsPDA, but a summary of the diagnostic accuracy has not been reviewed recently. OBJECTIVES: Primary objective: To determine the diagnostic accuracy of the cardiac biomarkers BNP and NT-proBNP for diagnosis of haemodynamically significant patent ductus arteriosus (hsPDA) in preterm neonates. Our secondary objectives were: to compare the accuracy of BNP and NT-proBNP; and to explore possible sources of heterogeneity among studies evaluating BNP and NT-proBNP, including type of commercial assay, chronological age of the infant at testing, gestational age at birth, whether used to initiate medical or surgical treatment, test threshold, and criteria of the reference standard (type of echocardiographic parameter used for diagnosis, clinical symptoms or physical signs if data were available). SEARCH METHODS: We searched the following databases in September 2021: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science. We also searched clinical trial registries and conference abstracts. We checked references of included studies and conducted cited reference searches of included studies. We did not apply any language or date restrictions to the electronic searches or use methodological filters, so as to maximise sensitivity. SELECTION CRITERIA: We included prospective or retrospective, cohort or cross-sectional studies, which evaluated BNP or NT-proBNP (index tests) in preterm infants (participants) with suspected hsPDA (target condition) in comparison with echocardiogram (reference standard). DATA COLLECTION AND ANALYSIS: Two authors independently screened title/abstracts and full-texts, resolving any inclusion disagreements through discussion or with a third reviewer. We extracted data from included studies to create 2 × 2 tables. Two independent assessors performed quality assessment using the Quality Assessment of Diagnostic-Accuracy Studies-2 (QUADAS 2) tool. We excluded studies that did not report data in sufficient detail to construct 2 × 2 tables, and where this information was not available from the primary investigators. We used bivariate and hierarchical summary receiver operating characteristic (HSROC) random-effects models for meta-analysis and generated summary receiver operating characteristic space (ROC) curves. Since both BNP and NTproBNP are continuous variables, sensitivity and specificity were reported at multiple thresholds. We dealt with the threshold effect by reporting summary ROC curves without summary points. MAIN RESULTS: We included 34 studies: 13 evaluated BNP and 21 evaluated NT-proBNP in the diagnosis of hsPDA. Studies varied by methodological quality, type of commercial assay, thresholds, age at testing, gestational age and whether the assay was used to initiate medical or surgical therapy. We noted some variability in the definition of hsPDA among the included studies. For BNP, the summary curve is reported in the ROC space (13 studies, 768 infants, low-certainty evidence). The estimated specificities from the ROC curve at fixed values of sensitivities at median (83%), lower and upper quartiles (79% and 92%) were 93.6% (95% confidence interval (CI) 77.8 to 98.4), 95.5% (95% CI 83.6 to 98.9) and 81.1% (95% CI 50.6 to 94.7), respectively. Subgroup comparisons revealed differences by type of assay and better diagnostic accuracy at lower threshold cut-offs (< 250 pg/ml compared to ≥ 250 pg/ml), testing at gestational age < 30 weeks and chronological age at testing at one to three days. Data were insufficient for subgroup analysis of whether the BNP testing was indicated for medical or surgical management of PDA. For NT-proBNP, the summary ROC curve is reported in the ROC space (21 studies, 1459 infants, low-certainty evidence). The estimated specificities from the ROC curve at fixed values of sensitivities at median (92%), lower and upper quartiles (85% and 94%) were 83.6% (95% CI 73.3 to 90.5), 90.6% (95% CI 83.8 to 94.7) and 79.4% (95% CI 67.5 to 87.8), respectively. Subgroup analyses by threshold (< 6000 pg/ml and ≥ 6000 pg/ml) did not reveal any differences. Subgroup analysis by mean gestational age (< 30 weeks vs 30 weeks and above) showed better accuracy with < 30 weeks, and chronological age at testing (days one to three vs over three) showed testing at days one to three had better diagnostic accuracy. Data were insufficient for subgroup analysis of whether the NTproBNP testing was indicated for medical or surgical management of PDA. We performed meta-regression for BNP and NT-proBNP using the covariates: assay type, threshold, mean gestational age and chronological age; none of the covariates significantly affected summary sensitivity and specificity. AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that BNP and NT-proBNP have moderate accuracy in diagnosing hsPDA and may work best as a triage test to select infants for echocardiography. The studies evaluating the diagnostic accuracy of BNP and NT-proBNP for hsPDA varied considerably by assay characteristics (assay kit and threshold) and infant characteristics (gestational and chronological age); hence, generalisability between centres is not possible. We recommend that BNP or NT-proBNP assays be locally validated for specific populations and outcomes, to initiate therapy or follow response to therapy.

Nutritional Supplements to Improve Outcomes in Preterm Neonates.

Preterm infants are at higher risk of mortality and morbidity compared with those born at term. Nutrition-related morbidities include poor growth, immune deficiency, nutritional deficiencies, and adverse long-term neurodevelopment. In addition to macronutrients, many nutritional supplements have been used to enhance growth and development, and decrease infections. Nutrients can enhance preterm infants' immune status, optimize the microbiome, improve growth and development, and influence the risk of necrotizing enterocolitis, sepsis, and other outcomes.

Metabolome and microbiome multi-omics integration from a murine lung inflammation model of bronchopulmonary dysplasia.

BACKGROUND: Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence. METHODS: C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group). RESULTS: Microbiome alpha and beta diversity were similar between groups. Metabolic changes included hyperoxia 31 up/18 down, LPS 7 up/4 down, exposure interaction 8. Hyperoxia increased Intestinimonas abundance, whereas LPS decreased Clostridiales, Dorea, and Intestinimonas; exposure interaction affected Blautia. Differential co-expression analysis on multi-omics data identified exposure-altered modules. Hyperoxia metabolomics response was integrated with a published matching transcriptome, identifying four induced genes (ALDOA, GAA, NEU1, RENBP), which positively correlated with BPD severity in a published human newborn cohort. CONCLUSIONS: We report hyperoxia and LPS lung microbiome and metabolome signatures in a clinically relevant BPD model. We identified four genes correlating with BPD status in preterm infants that are promising targets for therapy and prevention. IMPACT: Using multi-omics, we identified and correlated key biomarkers of hyperoxia and LPS on murine lung micro-landscape and examined their potential clinical implication, which shows strong clinical relevance for future research. Using a double-hit model of clinical relevance to bronchopulmonary dysplasia, we are the first to report integrated metabolomic/microbiome landscape changes and identify novel disease biomarker candidates.

Pivot to online learning for adapting or continuing workplace-based clinical learning in medical education following the COVID-19 pandemic: A BEME systematic review: BEME Guide No. 70.

BACKGROUND: The novel coronavirus disease was declared a pandemic in March 2020, which necessitated adaptations to medical education. This systematic review synthesises published reports of medical educational developments and innovations that pivot to online learning from workplace-based clinical learning in response to the pandemic. The objectives were to synthesise what adaptations/innovation were implemented (description), their impact (justification), and 'how' and 'why' these were selected (explanation and rationale). METHODS: The authors systematically searched four online databases up to December 21, 2020. Two authors independently screened titles, abstracts and full-texts, performed data extraction, and assessed the risk of bias. Our findings are reported in alignment with the STORIES (STructured apprOach to the Reporting in healthcare education of Evidence Synthesis) statement and BEME guidance. RESULTS: Fifty-five articles were included. Most were from North America (n = 40), and nearly 70% focused on undergraduate medical education (UGME). Key developments were rapid shifts from workplace-based learning to virtual spaces, including online electives, telesimulation, telehealth, radiology, and pathology image repositories, live-streaming or pre-recorded videos of surgical procedures, stepping up of medical students to support clinical services, remote adaptations for clinical visits, multidisciplinary team meetings and ward rounds. Challenges included lack of personal interactions, lack of standardised telemedicine curricula and need for faculty time, technical resources, and devices. Assessment of risk of bias revealed poor reporting of underpinning theory, resources, setting, educational methods, and content. CONCLUSIONS: This review highlights the response of medical educators in deploying adaptations and innovations. Whilst few are new, the complexity, concomitant use of multiple methods and the specific pragmatic choices of educators offers useful insight to clinical teachers who wish to deploy such methods within their own practice. Future works that offer more specific details to allow replication and understanding of conceptual underpinnings are likely to justify an update to this review.