Inhaled Nitric Oxide Therapy for Pulmonary Disorders of the Term and Preterm Infant

The 21st century began with the FDA approval of inhaled nitric oxide therapy for the treatment of neonatal hypoxic respiratory failure associated with pulmonary hypertension in recognition of the two randomized clinical trials demostrating a significant reduction in the need for extracorporeal support in the term and near-term infant. Inhaled nitric oxide is one of only a few therapeutic agents approved for use through clinical investigations primarily in the neonate. This article provides an overview of the pertinent biology and chemistry of nitric oxide, discusses potential toxicities, and reviews the results of pertinent clinical investigations and large randomized clinical trials including neurodevelopmental follow-up in term and preterm neonates. The clinical investigations conducted by the Eunice Kennedy Shriver NICHD Neonatal Research Network will be discussed and placed in context with other pertinent clinical investigations exploring the efficacy of inhaled nitric oxide therapy in neonatal hypoxic respiratory failure

Timing of postnatal steroids for bronchopulmonary dysplasia: association with pulmonary and neurodevelopmental outcomes

Objective: To determine the associations between age at first postnatal corticosteroids (PNS) exposure and risk for severe bronchopulmonary dysplasia (BPD) and neurodevelopmental impairment (NDI). Study Design: Cohort study of 951 infants born <27 weeks gestational age at NICHD Neonatal Research Network sites who received PNS between 8 days of life (DOL) and 36 weeks’ postmenstrual age was used to produce adjusted odds ratios (aOR). Results: Compared to infants in the reference group (22–28 DOL-lowest rate), aOR for severe BPD was similar for children given PNS between DOL 8–49 but higher among infants treated at DOL 50–63 (aOR 1.77, 95% CI 1.03–3.06), and at DOL ≥64 (aOR 3.06, 95% CI 1.44–6.48). The aOR for NDI did not vary significantly by age of PNS exposure. Conclusion: For infants at high risk of BPD, initial PNS should be considered prior to 50 DOL for the lowest associated odds of severe BPD

Global Validation of the AO Spine Upper Cervical Injury Classification.

STUDY DESIGN Global Cross Sectional Survey. OBJECTIVE To determine the classification accuracy, interobserver reliability, and intraobserver reproducibility of the AO Spine Upper Cervical Injury Classification System based on an international group of AO Spine members. SUMMARY OF BACKGROUND DATA Previous upper cervical spine injury classifications have primarily been descriptive without incorporating a hierarchical injury progression within the classification system. Further, upper cervical spine injury classifications have focused on distinct anatomical segments within the upper cervical spine. The AO Spine Upper Cervical Injury Classification System incorporates all injuries of the upper cervical spine into a single classification system focused on a hierarchical progression from isolated bony injuries (type A) to fracture dislocations (type C). METHODS A total of 275 AO Spine members participated in a validation aimed at classifying 25 upper cervical spine injuries via computed tomography (CT) scans according to the AO Spine Upper Cervical Classification System. The validation occurred on two separate occasions, three weeks apart. Descriptive statistics for percent agreement with the gold-standard were calculated and Pearson's chi square test evaluated significance between validation groups. Kappa coefficients (ƙ) determined the interobserver reliability and intraobserver reproducibility. RESULTS The accuracy of AO Spine members to appropriately classify upper cervical spine injuries was 79.7% on assessment 1 (AS1) and 78.7% on assessment 2 (AS2). The overall intraobserver reproducibility was substantial (ƙ=0.70), while the overall interobserver reliability for AS1 and AS2 was substantial (ƙ=0.63 and ƙ=0.61, respectively). Injury location had higher interobserver reliability (AS1: ƙ = 0.85 and AS2: ƙ=0.83) than the injury type (AS1: ƙ=0.59 and AS2: 0.57) on both assessments. CONCLUSION The global validation of the AO Spine Upper Cervical Injury Classification System demonstrated substantial interobserver agreement and intraobserver reproducibility. These results support the universal applicability of the AO Spine Upper Cervical Injury Classification System

COVID-19 is associated with early emergence of preeclampsia: results from a large regional collaborative

Objective: To examine the relationship between COVID-19 and preeclampsia (PreE) in a large, diverse population. Study Design: The COVID-19 in Pregnancy and The Newborn: State of Michigan Collaborative established a database of pregnant patients admitted to 14 institutions in Southern Michigan. Patients with COVID-19 (cases) were matched to 2 or 3 non-COVID patients (controls) on the same unit within 30 days of each case. Relative Risks (RR) were calculated using robust Poisson regression models with adjustment for covariates. Chi-squared test for trend was used to assess the increase in risk with the severity of disease. Results: 369 cases and 1,090 controls were delivered between March - October 2020. An increased risk of PreE (RR=1.8), driven almost entirely by an increase in preterm PreE (pretermPreE) (RR=2.85) was observed in COVID pregnancies (Table 1), with a dose-response relationship with symptomatology and severity (Table 2). The associations between COVID-19 disease and PreE or pretermPreE were independent of other risk factors, as demonstrated by the minimal changes in RR after adjustment for confounders (Table 1). However, African American (AA) COVID patients experienced pretermPreE 1.9 times more than COVID patients of other races (10.1 vs 5.3), an increase not observed in control patients. The strength of the association for COVID with PreE was comparable to the association of PreE with chronic hypertension and nulliparity (data not shown). Increasing symptoms and severity of COVID-19 were associated with an increased risk for PreE with placental lesions, even after adjustment for relevant covariates (Tables 1 & 2). Non-PreE COVID patients had an increased trend of placental lesions compared to non-COVID patients, reaching significance for intravillous thrombin. Conclusion: COVID-19 is significantly associated with early emergence of PreE, independent of known risk factors other than AA race. Our study shows that among patients predisposed to PreE, COVID-19 impacts PreE severity in that it leads to pretermPreE. Further studies on COVID-19 and PreE, with a focus on racial disparities, is warranted

Racial Disparities and Risk for COVID-19 Among Pregnant Patients: Results from the Michigan Statewide Collaborative

Objective: Previous studies have looked at COVID-19 outcomes in pregnancy and racial disparities among patients with COVID-19, but few have studied racial disparities among pregnant patients with COVID-19. Our goal in this study is to analyze the relationship between race and disparate COVID-19 risk in pregnancy. Study Design: A retrospective cohort analysis was performed on data collected as part of the COVID-19 in Pregnancy and The Newborn: State of Michigan Collaborative, a database of pregnant patients admitted to 14 institutions in Southern Michigan. Cases were defined as patients with a positive SARS-CoV-2 test result. Controls, those with suspicion of COVID-19 prior to universal screening or a negative PCR test, were matched to cases on the same unit within 30 days of each case. For this analysis, the two primary groups of interest were non-Hispanic Black (Black) vs. non-Hispanic White (White) patients. Potential covariates were age, body mass index (BMI), chronic hypertension, diabetes, asthma, substance use, and smoking; the dependent variable was COVID/non-COVID in a robust Poisson regression model. In addition, 18 symptoms and disease severity (mild/moderate/severe) were compared between the Black and White groups using the same statistical method. Results: Of 1,131 gravidas, 42.9%(n=485) were Black. These patients were at two-fold greater risk for COVID-19 compared with their White counterparts [35.9% vs. 18.3%, RR=1.96(1.6-2.4)]. After adjusting for obesity and diabetes, the risk of COVID-19 in Black patients remained higher compared to the risk among White patients (aRR=2.46 [1.87-3.24]). There were no differences in symptoms nor severity of disease presentation between the groups. Conclusion: In our population, Black patients are more likely to be diagnosed with COVID-19 infection during pregnancy. This finding is not explained by a range of covariates. Other factors, such as social determinants of health, may be important to understand this disparity and warrant further examination

Weaning of Moderately Preterm Infants from the Incubator to the Crib: A Randomized Clinical Trial

OBJECTIVE: To assess whether length of hospital stay is decreased among moderately preterm infants weaned from incubator to crib at a lower vs higher weight. STUDY DESIGN: This trial was conducted in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Infants with gestational ages 29-33 weeks, birthweight <1600 g, and in an incubator were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. The infants were weaned to the crib following stable temperature at 36.5°C to 37.4°C for 8 to 12 hours. Clothing and bedcoverings were standardized. The primary outcome was length of hospital stay from birth to discharge; secondary outcomes included length of stay and growth velocity from weaning to discharge. Adverse events were monitored. RESULTS: Of 1565 infants screened, 885 were eligible, and 366 enrolled-187 to the 1600-g and 179 to the 1800-g group. Maternal and neonatal characteristics did not differ among weight groups. Length of hospital stay was a median of 43 days in the lower and 41 days in the higher weight group (P = .12). Growth velocity from completion of weaning to discharge was higher in the lower weight group, 13.7 g/kg/day vs 12.8 g/kg/day (P = .005). Groups did not differ in adverse events. CONCLUSIONS: Among moderately preterm neonates, weaning from incubator to crib at a lower weight did not decrease length of stay, but was safe and was accompanied by higher weight gain after weaning

Effect of Therapeutic Hypothermia Initiated After 6 Hours of Age on Death or Disability Among Newborns With Hypoxic-Ischemic Encephalopathy: A Randomized Clinical Trial

Importance: Hypothermia initiated at less than 6 hours after birth reduces death or disability for infants with hypoxic-ischemic encephalopathy at 36 weeks' or later gestation. To our knowledge, hypothermia trials have not been performed in infants presenting after 6 hours. Objective: To estimate the probability that hypothermia initiated at 6 to 24 hours after birth reduces the risk of death or disability at 18 months among infants with hypoxic-ischemic encephalopathy. Design, Setting, and Participants: A randomized clinical trial was conducted between April 2008 and June 2016 among infants at 36 weeks' or later gestation with moderate or severe hypoxic-ischemic encephalopathy enrolled at 6 to 24 hours after birth. Twenty-one US Neonatal Research Network centers participated. Bayesian analyses were prespecified given the anticipated limited sample size. Interventions: Targeted esophageal temperature was used in 168 infants. Eighty-three hypothermic infants were maintained at 33.5°C (acceptable range, 33°C-34°C) for 96 hours and then rewarmed. Eighty-five noncooled infants were maintained at 37.0°C (acceptable range, 36.5°C-37.3°C). Main Outcomes and Measures: The composite of death or disability (moderate or severe) at 18 to 22 months adjusted for level of encephalopathy and age at randomization. Results: Hypothermic and noncooled infants were term (mean [SD], 39 [2] and 39 [1] weeks' gestation, respectively), and 47 of 83 (57%) and 55 of 85 (65%) were male, respectively. Both groups were acidemic at birth, predominantly transferred to the treating center with moderate encephalopathy, and were randomized at a mean (SD) of 16 (5) and 15 (5) hours for hypothermic and noncooled groups, respectively. The primary outcome occurred in 19 of 78 hypothermic infants (24.4%) and 22 of 79 noncooled infants (27.9%) (absolute difference, 3.5%; 95% CI, -1% to 17%). Bayesian analysis using a neutral prior indicated a 76% posterior probability of reduced death or disability with hypothermia relative to the noncooled group (adjusted posterior risk ratio, 0.86; 95% credible interval, 0.58-1.29). The probability that death or disability in cooled infants was at least 1%, 2%, or 3% less than noncooled infants was 71%, 64%, and 56%, respectively. Conclusions and Relevance: Among term infants with hypoxic-ischemic encephalopathy, hypothermia initiated at 6 to 24 hours after birth compared with noncooling resulted in a 76% probability of any reduction in death or disability, and a 64% probability of at least 2% less death or disability at 18 to 22 months. Hypothermia initiated at 6 to 24 hours after birth may have benefit but there is uncertainty in its effectiveness

A Helminth Immunomodulator Exploits Host Signaling Events to Regulate Cytokine Production in Macrophages

Parasitic worms alter their host's immune system to diminish the inflammatory responses directed against them, using very efficient immunomodulating molecules. We have previously shown that the helminth immunomodulator cystatin (AvCystatin) profoundly reduces the progression of inflammatory diseases via modulation of macrophages. Here we elucidate the signaling events in macrophages triggered by AvCystatin. Labeled AvCystatin was predominantly taken up by macrophages and subsequently induced the phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2 and p38. IL-10 expression induced by AvCystatin in macrophages was tyrosine kinase sensitive and dependent on activation of both MAP kinases, in clear contrast to expression of IL-12/23p40. In addition, phosphorylation of the transcription factors CREB and STAT3 was induced by AvCystatin and regulated by phospho-ERK. Chemical inhibition of phosphoinositide 3-kinase (PI3K) reduced AvCystatin-induced cytokine release; however, AKT, the downstream target of PI3K, was not activated following AvCystatin exposure. To characterize signaling elements involved in alteration of the macrophage phenotype we applied mathematical modeling. Experimental testing of the in silico generated hypotheses identified dual specificity phosphatase (DUSP) 1 and 2, as regulators in AvCystatin triggered macrophages in vitro and in vivo. In particular, DUSP1 was subsequently found to be responsible for regulation of ERK- and p38-phosphorylation and controlled the IL-10 expression in macrophages by AvCystatin. Thus, we show that AvCystatin exploits activation and deactivation pathways of MAP kinases to induce regulatory macrophages. This study provides insights into molecular mechanisms of macrophage manipulation by parasites and highlights the utility of mathematical modeling for the elucidation of regulatory circuits of immune cells