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.

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.

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.

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.

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.

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..

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.

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.

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.

Evidence from systematic reviews of randomized trials on enteral lactoferrin supplementation in preterm neonates.

In this commentary, we summarize the current evidence from randomized controlled trials on enteral lactoferrin supplementation in preterm neonates. Our recently completed systematic review includes 12 randomized controlled trials performed all over the world. Our meta-analysis suggests clinical benefit in decreasing late-onset sepsis, late-onset fungal sepsis, length of stay in the hospital and urinary tract infections. There were no adverse effects. There was no statistically significant decrease in necrotizing enterocolitis, mortality or neurodevelopmental impairment in lactoferrin supplemented preterm infants. There was significant statistical heterogeneity in the effects of lactoferrin on late-onset sepsis between larger and smaller studies, which may reflect either small study biases, differences in the effectiveness, dose or duration of supplemental lactoferrin products, or differences in underlying population risk, or any or all of these.

Two-port, exteriorized uterus, fetoscopic meningomyelocele closure has fewer adverse neonatal outcomes than open hysterotomy closure.

BACKGROUND: In utero closure of meningomyelocele using an open hysterotomy approach is associated with preterm delivery and adverse neonatal outcomes. OBJECTIVE: This study compared the neonatal outcomes in in utero meningomyelocele closure using a 2-port, exteriorized uterus, fetoscopic approach vs the conventional open hysterotomy approach. STUDY DESIGN: This retrospective cohort study included all consecutive patients who underwent in utero meningomyelocele closure using open hysterotomy (n=44) or a 2-port, exteriorized uterus, fetoscopic approach (n=46) at a single institution between 2012 and 2020. The 2-port, exteriorized uterus, fetoscopic closure was composed of the following 3 layers: a bovine collagen patch, a myofascial layer, and a skin. The frequency of respiratory distress syndrome and a composite of other adverse neonatal outcomes, including retinopathy of prematurity, periventricular leukomalacia, and perinatal death, were compared between the study groups. Regression analyses were performed to determine any association between the fetoscopic closure and adverse neonatal outcomes, adjusted for several confounders, including gestational age of <37 weeks at delivery. RESULTS: The fetoscopic closure was associated with a lower rate of respiratory distress syndrome than the open hysterotomy closure (11.5% [5 of 45] vs 29.5% [13 of 44]; P=.037). The proportion of neonates with a composite of other adverse neonatal outcomes in the fetoscopic group was half of that observed patients in the open hysterotomy group; however, this difference did not reach statistical significance (4.3% [2 of 46] vs 9.1% [4 of 44]; P=.429). Here, regression analysis has demonstrated that fetoscopic meningomyelocele closure was associated with a lower risk of respiratory distress syndrome (adjusted odds ratio, 0.23; 95% confidence interval, 0.06-0.84; P=.026) than open hysterotomy closure. CONCLUSION: In utero meningomyelocele closure using a 2-port, exteriorized uterus, fetoscopic approach was associated with a lower risk of respiratory distress syndrome than the conventional open hysterotomy meningomyelocele closure.

Ultrasound for diagnosis of birth weight discordance in twin pregnancies.

BACKGROUND: There is a need to standardize monitoring in obstetric research of twin pregnancies. Identification of birth weight discordance (BWD), defined as a difference in the birth weights of twins, is a well-documented phenomenon in twin pregnancies. Ultrasound for the diagnosis of BWD informs complex decision making including whether to intervene medically (via laser photo coagulation) or deliver the twins to avoid fetal morbidities or even death. The question is, how accurate is this measurement? OBJECTIVES: To determine the diagnostic accuracy (sensitivity and specificity) of ultrasound estimated fetal weight discordance (EFWD) of 20% and 25% using different estimated biometric ultrasound measurements compared with the actual BWD as the reference standard in twin pregnancies. SEARCH METHODS: The search for this review was performed on 15 March 2019. We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), seven other databases, conference proceedings, reference lists and contacted experts. There were no language or date restrictions applied to the electronic searches, and no methodological filters to maximize sensitivity. SELECTION CRITERIA: We selected cohort-type studies with delayed verification that evaluated the accuracy of biometric measurements at ultrasound scanning of twin pregnancies that had been proposed for the diagnosis of estimated BWD, compared to BWD measurements after birth as a reference standard. In addition, we only selected studies that considered twin pregnancies and applied a reference standard for EFWD for the target condition of BWD. DATA COLLECTION AND ANALYSIS: We screened all titles generated by electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility, and extracted data to create 2 × 2 tables. Two review authors independently performed quality assessment using the 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 assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 39 eligible studies with a median study sample size of 140. In terms of risk of bias, there were many unclear statements regarding patient selection, index test and use of proper reference standard. Twenty-one studies (53%) were of methodological concern due to flow and timing. In terms of applicability, most studies were of low concern. Ultrasound for diagnosis of BWD in twin pregnancies at 20% cut-off Twenty-two studies provided data for a BWD of 20% and the summary estimate of sensitivity was 0.51 (95% CI 0.42 to 0.60), and the summary estimate of specificity was 0.91 (95% CI 0.89 to 0.93) (8005 twin pregnancies; very low-certainty evidence). Ultrasound for diagnosis of BWD in twin pregnancies at 25% cut-off Eighteen studies provided data using a BWD discordance of 25%. The summary estimate of sensitivity was 0.46 (95% CI 0.26 to 0.66), and the summary estimate of specificity was 0.93 (95% CI 0.89 to 0.96) (6471 twin pregnancies; very low-certainty evidence). Subgroup analyses were possible for both BWD of 20% and 25%. The diagnostic accuracy did not differ substantially between estimation by abdominal circumference and femur length but femur length had a trend towards higher sensitivity and specificity. Subgroup analyses were not possible by sex of twins, chorionicity or gestational age due to insufficient data. AUTHORS' CONCLUSIONS: Very low-certainty evidence suggests that EFWD identified by ultrasound has low sensitivity but good specificity in detecting BWD in twin pregnancies. There is uncertain diagnostic value of EFWD; this review suggests there is insufficient evidence to support this index as the sole measure for clinical decision making to evaluate the prognosis of twins with growth discordance. The diagnostic accuracy of other measures including amniotic fluid index and umbilical artery Doppler resistive indices in combination with ultrasound for clinical intervention requires evaluation. Future well-designed studies could also evaluate the impact of chorionicity, sex and gestational age in the diagnostic accuracy of ultrasound for EFWD.

Music therapy for preterm neonates in the neonatal intensive care unit: An overview of systematic reviews.

AIM: To summarise the quantity and quality of evidence for using music therapy for preterm infants in the neonatal intensive care unit (NICU). METHODS: We performed an overview of evidence for the effectiveness and safety of MT for preterm infants in the NICU. We performed a random-effects meta-analysis of data from studies that fit the definition of MT. RESULTS: We identified 12 eligible systematic reviews and the methodological quality by AMSTAR-2 ranged from moderate to critically low. We identified 14 eligible randomised trials and 7 observational studies where the intervention fits the definition of MT. Meta-analysis of the RCTs showed that MT significantly decreases heart rate, mean difference (MD) (95% CI), -3.21 [-5.22, -1.19], respiratory rate, MD -2.93 [-5.65, -0.22], and maternal anxiety, MD -17.50 [-20.10, -14.90], and increases feeding volume, MD 29.59 [12.79, 46.38]. Long-term neurodevelopmental or safety outcomes were not reported. GRADE assessment of outcomes ranged from low to very low, downgraded for high risk of bias in the included studies, inconsistency and imprecision. CONCLUSION: Low to very low certainty evidence suggests that MT in preterm infants improves short-term physiological parameters, feeding and maternal anxiety but safety and long-term outcomes were not reported.

An update on developments in medical education in response to the COVID-19 pandemic: A BEME scoping review: BEME Guide No. 64.

BACKGROUND: COVID-19 has fundamentally altered how education is delivered. Gordon et al. previously conducted a review of medical education developments in response to COVID-19; however, the field has rapidly evolved in the ensuing months. This scoping review aims to map the extent, range and nature of subsequent developments, summarizing the expanding evidence base and identifying areas for future research. METHODS: The authors followed the five stages of a scoping review outlined by Arskey and O'Malley. Four online databases and MedEdPublish were searched. Two authors independently screened titles, abstracts and full texts. Included articles described developments in medical education deployed in response to COVID-19 and reported outcomes. Data extraction was completed by two authors and synthesized into a variety of maps and charts. RESULTS: One hundred twenty-seven articles were included: 104 were from North America, Asia and Europe; 51 were undergraduate, 41 graduate, 22 continuing medical education, and 13 mixed; 35 were implemented by universities, 75 by academic hospitals, and 17 by organizations or collaborations. The focus of developments included pivoting to online learning (n = 58), simulation (n = 24), assessment (n = 11), well-being (n = 8), telehealth (n = 5), clinical service reconfigurations (n = 4), interviews (n = 4), service provision (n = 2), faculty development (n = 2) and other (n = 9). The most common Kirkpatrick outcome reported was Level 1, however, a number of studies reported 2a or 2b. A few described Levels 3, 4a, 4b or other outcomes (e.g. quality improvement). CONCLUSIONS: This scoping review mapped the available literature on developments in medical education in response to COVID-19, summarizing developments and outcomes to serve as a guide for future work. The review highlighted areas of relative strength, as well as several gaps. Numerous articles have been written about remote learning and simulation and these areas are ripe for full systematic reviews. Telehealth, interviews and faculty development were lacking and need urgent attention.

Delayed versus Immediate Cord Clamping in Preterm Infants.

BACKGROUND: The preferred timing of umbilical-cord clamping in preterm infants is unclear. METHODS: We randomly assigned fetuses from women who were expected to deliver before 30 weeks of gestation to either immediate clamping of the umbilical cord (≤10 seconds after delivery) or delayed clamping (≥60 seconds after delivery). The primary composite outcome was death or major morbidity (defined as severe brain injury on postnatal ultrasonography, severe retinopathy of prematurity, necrotizing enterocolitis, or late-onset sepsis) by 36 weeks of postmenstrual age. Analyses were performed on an intention-to-treat basis, accounting for multiple births. RESULTS: Of 1634 fetuses that underwent randomization, 1566 were born alive before 30 weeks of gestation; of these, 782 were assigned to immediate cord clamping and 784 to delayed cord clamping. The median time between delivery and cord clamping was 5 seconds and 60 seconds in the respective groups. Complete data on the primary outcome were available for 1497 infants (95.6%). There was no significant difference in the incidence of the primary outcome between infants assigned to delayed clamping (37.0%) and those assigned to immediate clamping (37.2%) (relative risk, 1.00; 95% confidence interval, 0.88 to 1.13; P=0.96). The mortality was 6.4% in the delayed-clamping group and 9.0% in the immediate-clamping group (P=0.03 in unadjusted analyses; P=0.39 after post hoc adjustment for multiple secondary outcomes). There were no significant differences between the two groups in the incidences of chronic lung disease or other major morbidities. CONCLUSIONS: Among preterm infants, delayed cord clamping did not result in a lower incidence of the combined outcome of death or major morbidity at 36 weeks of gestation than immediate cord clamping. (Funded by the Australian National Health and Medical Research Council [NHMRC] and the NHMRC Clinical Trials Centre; APTS Australian and New Zealand Clinical Trials Registry number, ACTRN12610000633088 .).

Intestinal dysbiosis and necrotizing enterocolitis: assessment for causality using Bradford Hill criteria.

In recent years, several studies have shown that premature infants who develop NEC frequently display enteric dysbiosis with increased Gram-negative bacteria for several days to weeks prior to NEC onset. The importance of these findings, for the possibility of a causal role of these bacteria in NEC pathogenesis, and for potential value of gut dysbiosis as a biomarker of NEC, is well-recognized. In this review, we present current evidence supporting the association between NEC in premature infants and enteric dysbiosis, and its evaluation using the Bradford Hill criteria for causality. To provide an objective appraisal, we developed a novel scoring system for causal inference. Despite important methodological and statistical limitations, there is support for the association from several large studies and a meta-analysis. The association draws strength from strong biological plausibility of a role of Gram-negative bacteria in NEC and from evidence for temporality, that dysbiosis may antedate NEC onset. The weakness of the association is in the low level of consistency across studies, and the lack of specificity of effect. There is a need for an improved definition of dysbiosis, either based on a critical threshold of relative abundances or at higher levels of taxonomic resolution.

Fungal cutaneous microbiome and host determinants in preterm and term neonates.

BACKGROUND: The neonatal cutaneous mycobiome has not been characterized in preterm infants. Invasive fungal infections in preterm neonates are associated with high mortality. The immaturity of the preterm skin predisposes neonates to invasive infection by skin colonizers. We report the clinical and host determinants that influence the skin mycobiome. METHODS: Skin swabs from the antecubital fossa, forehead, and gluteal region of 15 preterm and 15 term neonates were obtained during the first 5 weeks of life. The mycobiome was sequenced using the conserved pan-fungal ITS2 region. Blood samples were used to genotype immune modulating genes. Clinical metadata was collected to determine the clinical predictors of the abundance and diversity of the skin mycobiome. RESULTS: The neonatal mycobiome is characterized by few taxa. Alpha diversity of the mycobiome is influenced by antibiotic exposure, the forehead body site, and the neonatal intensive care unit (NICU) environment. Beta diversity varies with mode of delivery, diet, and body site. The host determinants of the cutaneous microbiome include single-nucleotide polymorphisms in TLR4, NLRP3,CARD8, and NOD2. CONCLUSION: The neonatal cutaneous mycobiome is composed of few genera and is influenced by clinical factors and host genetics, the understanding of which will inform preventive strategies against invasive fungal infections.

Enteral lactoferrin supplementation for prevention of sepsis and necrotizing enterocolitis in preterm infants.

BACKGROUND: Lactoferrin, a normal component of human colostrum and milk, can enhance host defenses and may be effective for prevention of sepsis and necrotizing enterocolitis (NEC) in preterm neonates. OBJECTIVES: To assess the safety and effectiveness of lactoferrin supplementation to enteral feeds for prevention of sepsis and NEC in preterm neonates. Secondarily, we assessed the effects of lactoferrin supplementation to enteral feeds on the duration of positive-pressure ventilation, development of chronic lung disease (CLD) or periventricular leukomalacia (PVL), length of hospital stay to discharge among survivors, and adverse neurological outcomes at two years of age or later. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to update our search. We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2019, Issue 9), MEDLINE via PubMed (1966 to 20 January 2020), PREMEDLINE (1996 to 20 January 2020), Embase (1980 to 20 January 2020), and CINAHL (1982 to 20 January 2020). We also searched clinical trials databases, conference proceedings, and the reference lists of retrieved articles for randomized controlled trials and quasi-randomized trials. SELECTION CRITERIA: In our search, we included randomized controlled trials (RCTs) evaluating enteral lactoferrin supplementation at any dose or duration to prevent sepsis or NEC in preterm neonates. DATA COLLECTION AND ANALYSIS: We used the standard methods of Cochrane Neonatal and the GRADE approach to assess the certainty of evidence. MAIN RESULTS: Meta-analysis of data from twelve randomized controlled trials showed that lactoferrin supplementation to enteral feeds decreased late-onset sepsis (typical RR 0.82, 95% CI 0.74 to 0.91; typical RD -0.04, 95% CI, -0.06, -0.02; NNTB 25, 95% CI 17 to 50; 12 studies, 5425 participants, low-certainty evidence) and decreased length of hospital stay (MD -2.38, 95% CI, -4.67, -0.09; 3 studies, 1079 participants, low-certainty evidence). Sensitivity analysis including only good methodological certainty studies suggested a decrease in late-onset sepsis with enteral lactoferrin supplementation (typical RR 0.87, 95% CI, 0.78, 0.97; typical RD -0.03, 95% CI, -0.05, -0.0; 9 studies, 4702 participants, low-certainty evidence). There were no differences in NEC stage II or III (typical RR 1.10, 95% CI, 0.86, 1.41; typical RD -0.00, 95% CI, -0.02, 0.01; 7 studies, 4874 participants; low-certainty evidence) or 'all-cause mortality' (typical RR 0.90, 95% CI 0.69, 1.17; typical RD -0.00, 95% CI, -0.01, 0.01; 11 studies, 5510 participants; moderate-certainty evidence). One study reported no differences in neurodevelopmental testing by Mullen's or Bayley III at 24 months of age after enteral lactoferrin supplementation (one study, 292 participants, low-certainty evidence). Lactoferrin supplementation to enteral feeds with probiotics decreased late-onset sepsis (RR 0.25, 95% CI 0.14 to 0.46; RD -0.13, 95% CI -0.18 to -0.08; NNTB 8, 95% CI 6 to 13; 3 studies, 564 participants; low-certainty evidence) and NEC stage II or III (RR 0.04, 95% CI 0.00 to 0.62; RD -0.05, 95% CI -0.08 to -0.03; NNTB 20, 95% CI 12.5 to 33.3; 1 study, 496 participants; very low-certainty evidence), but not 'all-cause mortality' (very low-certainty evidence). Lactoferrin supplementation to enteral feeds with or without probiotics had no effect on CLD, duration of mechanical ventilation or threshold retinopathy of prematurity (low-certainty evidence). Investigators reported no adverse effects in the included studies. AUTHORS' CONCLUSIONS: We found low-certainty evidence from studies of good methodological quality that lactoferrin supplementation of enteral feeds decreases late-onset sepsis but not NEC ≥ stage II or 'all cause mortality' or neurodevelopmental outcomes at 24 months of age in preterm infants without adverse effects. Low- to very low-certainty evidence suggests that lactoferrin supplementation of enteral feeds in combination with probiotics decreases late-onset sepsis and NEC ≥ stage II in preterm infants without adverse effects, however, there were few included studies of poor methodological quality. The presence of publication bias and small studies of poor methodology that may inflate the effect size make recommendations for clinical practice difficult.

Developments in medical education in response to the COVID-19 pandemic: A rapid BEME systematic review: BEME Guide No. 63.

BACKGROUND: The novel coronavirus disease (COVID-19) was declared a pandemic in March 2020. This rapid systematic review synthesised published reports of medical educational developments in response to the pandemic, considering descriptions of interventions, evaluation data and lessons learned. METHODS: The authors systematically searched four online databases and hand searched MedEdPublish up to 24 May 2020. Two authors independently screened titles, abstracts and full texts, performed data extraction and assessed risk of bias for included articles. Discrepancies were resolved by a third author. A descriptive synthesis and outcomes were reported. RESULTS: Forty-nine articles were included. The majority were from North America, Asia and Europe. Sixteen studies described Kirkpatrick's outcomes, with one study describing levels 1-3. A few papers were of exceptional quality, though the risk of bias framework generally revealed capricious reporting of underpinning theory, resources, setting, educational methods, and content. Key developments were pivoting educational delivery from classroom-based learning to virtual spaces, replacing clinical placement based learning with alternate approaches, and supporting direct patient contact with mitigated risk. Training for treating patients with COVID-19, service reconfiguration, assessment, well-being, faculty development, and admissions were all addressed, with the latter categories receiving the least attention. CONCLUSIONS: This review highlights several areas of educational response in the immediate aftermath of the COVID-19 pandemic and identifies a few articles of exceptional quality that can serve as models for future developments and educational reporting. There was often a lack of practical detail to support the educational community in enactment of novel interventions, as well as limited evaluation data. However, the range of options deployed offers much guidance for the medical education community moving forward and there was an indication that outcome data and greater detail will be reported in the future.