Genome-Wide Analysis Identifies Nuclear Factor 1C as a Novel Transcription Factor and Potential Therapeutic Target in SCLC.

INTRODUCTION: Recent insights regarding mechanisms mediating stemness, heterogeneity, and metastatic potential of lung cancers have yet to be fully translated to effective regimens for the treatment of these malignancies. This study sought to identify novel targets for lung cancer therapy. METHODS: Transcriptomes and DNA methylomes of 14 SCLC and 10 NSCLC lines were compared with normal human small airway epithelial cells (SAECs) and induced pluripotent stem cell (iPSC) clones derived from SAEC. SCLC lines, lung iPSC (Lu-iPSC), and SAEC were further evaluated by DNase I hypersensitive site sequencing (DHS-seq). Changes in chromatin accessibility and depths of transcription factor (TF) footprints were quantified using Bivariate analysis of Genomic Footprint. Standard techniques were used to evaluate growth, tumorigenicity, and changes in transcriptomes and glucose metabolism of SCLC cells after NFIC knockdown and to evaluate NFIC expression in SCLC cells after exposure to BET inhibitors. RESULTS: Considerable commonality of transcriptomes and DNA methylomes was observed between Lu-iPSC and SCLC; however, this analysis was uninformative regarding pathways unique to lung cancer. Linking results of DHS-seq to RNA sequencing enabled identification of networks not previously associated with SCLC. When combined with footprint depth, NFIC, a transcription factor not previously associated with SCLC, had the highest score of occupancy at open chromatin sites. Knockdown of NFIC impaired glucose metabolism, decreased stemness, and inhibited growth of SCLC cells in vitro and in vivo. ChIP-seq analysis identified numerous sites occupied by BRD4 in the NFIC promoter region. Knockdown of BRD4 or treatment with Bromodomain and extra-terminal domain (BET) inhibitors (BETis) markedly reduced NFIC expression in SCLC cells and SCLC PDX models. Approximately 8% of genes down-regulated by BETi treatment were repressed by NFIC knockdown in SCLC, whereas 34% of genes repressed after NFIC knockdown were also down-regulated in SCLC cells after BETi treatment. CONCLUSIONS: NFIC is a key TF and possible mediator of transcriptional regulation by BET family proteins in SCLC. Our findings highlight the potential of genome-wide chromatin accessibility analysis for elucidating mechanisms of pulmonary carcinogenesis and identifying novel targets for lung cancer therapy.

Social distancing and extremely preterm births in the initial COVID-19 pandemic period.

HYPOTHESIS: Increased social distancing was associated with a lower incidence of extremely preterm live births (EPLB) during the initial COVID-19 pandemic period. STUDY DESIGN: Prospective study at the NICHD Neonatal Research Network sites comparing EPLB (220/7-286/7 weeks) and extremely preterm intrapartum stillbirths (EPIS) rates during the pandemic period (March-July, weeks 9-30 of 2020) with the reference period (same weeks in 2018 and 2019), correlating with state-specific social distancing index (SDI). RESULTS: EPLB and EPIS percentages did not significantly decrease (1.58-1.45%, p = 0.07, and 0.08-0.06%, p = 0.14, respectively). SDI was not significantly correlated with percent change of EPLB (CC = 0.29, 95% CI = -0.12, 0.71) or EPIS (CC = -0.23, 95% CI = -0.65, 0.18). Percent change in mean gestational age was positively correlated with SDI (CC = 0.49, 95% CI = 0.07, 0.91). CONCLUSIONS: Increased social distancing was not associated with change in incidence of EPLB but was associated with a higher gestational age of extremely preterm births. GOV ID: Generic Database: NCT00063063.

Long-Term Video Electroencephalographic Monitoring in <30-Week Gestational Age Infants With High-Grade Intraventricular Hemorrhage.

BACKGROUND: Despite recognizing high seizure risk, the current consensus guidelines on evaluating seizures in preterm neonates are based on limited data. We chose to investigate the seizure risk in high-risk preterm (<30 weeks gestation) asymptomatic (without a clinical concern for seizures) infants with high-grade intraventricular hemorrhage who underwent long-term video electroencephalographic monitoring. METHODS: We performed a comprehensive retrospective review on all infants of <30-week gestational age admitted to the University of Alabama at Birmingham Regional Neonatal Intensive Care Unit from June 2018 to October 2022. We selected those patients who underwent electroencephalographic monitoring without a prior clinical concern for seizures. We recorded gender, gestational age, APGAR scores (one and five minutes), intraventricular hemorrhage (grade, age at diagnosis), and electroencephalographic monitoring (timing and duration) data. RESULTS: Among 37 premature infants, six had seizures detected on electroencephalographic monitoring. All six infants had subclinical seizures. Only two of six patients had a clinical correlation (although not identified by the providers) with some of their seizures. Patients with seizures were significantly younger in chronological age (median age 6.5 days vs 9 days, P value 0.009) at the time of the electroencephalographic monitoring initiation and were more likely to have subsequent monitoring studies (P value 0.0418). CONCLUSIONS: Long-term video electroencephalographic monitoring performed after the diagnosis of high-grade intraventricular hemorrhage captured seizures in ∼16% of asymptomatic premature neonates of <30 weeks' gestation. Patients identified to have seizures were significantly younger (chronological age) at the time of the electroencephalographic monitoring initiation and were more likely to be remonitored.

Neonatal Respiratory Support Utilization in Low- and Middle-Income Countries: A Registry-Based Observational Study.

BACKGROUND: Newborns with hypoxemia often require life-saving respiratory support. In low-resource settings, it is unknown if respiratory support is delivered more frequently to term infants or preterm infants. We hypothesized that in a registry-based birth cohort in 105 geographic areas in seven low- and middle-income countries, more term newborns received respiratory support than preterm newborns. METHODS: This is a hypothesis-driven observational study based on prospectively collected data from the Maternal and Newborn Health Registry of the NICHD Global Network for Women's and Children's Health Research. Eligible infants enrolled in the registry were live-born between 22 and 44 weeks gestation with a birth weight ≥400 g and born from January 1, 2015, to December 31, 2018. Frequency data were obtained to report the number of term and preterm infants who received treatment with oxygen only, CPAP, or mechanical ventilation. Test for trends over time were conducted using robust Poisson regression. RESULTS: 177,728 (86.3%) infants included in this study were term, and 28,249 (13.7%) were preterm. A larger number of term infants (n = 5,108) received respiratory support compared to preterm infants (n = 3,287). Receipt of each mode of respiratory support was more frequent in term infants. The proportion of preterm infants who received respiratory support (11.6%) was higher than the proportion of term infants receiving respiratory support (2.9%, p < 0.001). The rate of provision of respiratory support varied between sites. CONCLUSIONS: Respiratory support was more frequently used in term infants expected to be at low risk for respiratory disorders compared to preterm infants.

Early and exclusive enteral nutrition in infants born very preterm.

OBJECTIVE: To characterise the effects of early and exclusive enteral nutrition with either maternal or donor milk in infants born very preterm (280/7-326/7 weeks of gestation). DESIGN: Parallel-group, unmasked randomised controlled trial. SETTING: Regional, tertiary neonatal intensive care unit. PARTICIPANTS: 102 infants born very preterm between 2021 and 2022 (51 in each group). INTERVENTION: Infants randomised to the intervention group received 60-80 mL/kg/day within the first 36 hours after birth. Infants randomised to the control group received 20-30 mL/kg/day (standard trophic feeding volumes). MAIN OUTCOME MEASURES: The primary outcome was the number of full enteral feeding days (>150 mL/kg/day) in the first 28 days after birth. Secondary outcomes included growth and body composition at the end of the first two postnatal weeks, and length of hospitalisation. RESULTS: The mean birth weight was 1477 g (SD: 334). Half of the infants were male, and 44% were black. Early and exclusive enteral nutrition increased the number of full enteral feeding days (+2; 0-2 days; p=0.004), the fat-free mass-for-age z-scores at postnatal day 14 (+0.5; 0.1-1.0; p=0.02) and the length-for-age z-scores at the time of hospital discharge (+0.6; 0.2-1.0; p=0.002). Hospitalisation costs differed between groups (mean difference favouring the intervention group: -$28 754; -$647 to -$56 861; p=0.04). CONCLUSIONS: In infants born very preterm, early and exclusive enteral nutrition increases the number of full enteral feeding days. This feeding practice may also improve fat-free mass accretion, increase length and reduce hospitalisation costs. TRIAL REGISTRATION NUMBER: NCT04337710.

ß-CATENIN stabilizes HIF2 through lncRNA and inhibits intravenous immunoglobulin immunotherapy.

Introduction: Tumor-initiating cells (TICs) are rare, stem-like, and highly malignant. Although intravenous hepatitis B and C immunoglobulins have been used for HBV and HCV neutralization in patients, their tumor-inhibitory effects have not yet been examined. Hepatitis B immunoglobulin (HBIG) therapy is employed to reduce hepatocellular carcinoma (HCC) recurrence in patients after living donor liver transplantations (LDLT). Hypothesis: We hypothesized that patient-derived intravenous immunoglobulin (IVIG) binding to HCC associated TICs will reduce self-renewal and cell viability driven by ß-CATENIN-downstream pathways. ß-CATENIN activity protected TICs from IVIG effects. Methods: The effects of HBIG and HCIG binding to TICs were evaluated for cell viability and self-renewal. Results: Inhibition of ß-CATENIN pathway(s) augmented TIC susceptibility to HBIG- and HCIG-immunotherapy. HBV X protein (HBx) upregulates both ß-CATENIN and NANOG expression. The co-expression of constitutively active ß-CATENIN with NANOG promotes self-renewal ability and tumor-initiating ability of hepatoblasts. HBIG bound to HBV+ cells led to growth inhibition in a TIC subset that expressed hepatitis B surface antigen. The HBx protein transformed cells through ß-CATENIN-inducible lncRNAs EGLN3-AS1 and lnc-ß-CatM. Co-expression of constitutively active ß-CATENIN with NANOG promoted self-renewal ability of TICs through EGLN3 induction. ß-CATENIN-induced lncRNAs stabilized HIF2 to maintain self-renewal of TICs. Targeting of EGLN3-AS1 resulted in destabilization of EZH2-dependent ß-CATENIN activity and synergized cell-killing of TICs by HBIG or HCIG immunotherapy. Discussion: Taken together, WNT and stemness pathways induced HIF2 of TICs via cooperating lncRNAs resulting in resistance to cancer immunotherapy. Therefore, therapeutic use of IVIG may suppress tumor recurrence through inhibition of TICs.

Trends in fetal and neonatal outcomes during the COVID-19 pandemic in Alabama.

BACKGROUND: The current study evaluated the hypothesis that the COVID-19 pandemic is associated with higher stillbirth but lower neonatal mortality rates. METHODS: We compared three epochs: baseline (2016-2019, January-December, weeks 1-52, and 2020, January-February, weeks 1-8), initial pandemic (2020, March-December, weeks 9-52, and 2021, January-June, weeks 1-26), and delta pandemic (2021, July-September, weeks 27-39) periods, using Alabama Department of Public Health database including deliveries with stillbirths ≥20 weeks or live births ≥22 weeks gestation. The primary outcomes were stillbirth and neonatal mortality rates. RESULTS: A total of 325,036 deliveries were included (236,481 from baseline, 74,076 from initial pandemic, and 14,479 from delta pandemic period). The neonatal mortality rate was lower in the pandemic periods (4.4 to 3.5 and 3.6/1000 live births, in the baseline, initial, and delta pandemic periods, respectively, p < 0.01), but the stillbirth rate did not differ (9 to 8.5 and 8.6/1000 births, p = 0.41). On interrupted time-series analyses, there were no significant changes in either stillbirth (p = 0.11 for baseline vs. initial pandemic period, and p = 0.67 for baseline vs. delta pandemic period) or neonatal mortality rates (p = 0.28 and 0.89, respectively). CONCLUSIONS: The COVID-19 pandemic periods were not associated with a significant change in stillbirth and neonatal mortality rates compared to the baseline period. IMPACT: The COVID-19 pandemic could have resulted in changes in fetal and neonatal outcomes. However, only a few population-based studies have compared the risk of fetal and neonatal mortality in the pandemic period to the baseline period. This population-based study identifies the changes in fetal and neonatal outcomes during the initial and delta COVID-19 pandemic period as compared to the baseline period. The current study shows that stillbirth and neonatal mortality rates were not significantly different in the initial and delta COVID-19 pandemic periods as compared to the baseline period.

Association of Active Postnatal Care With Infant Survival Among Periviable Infants in the US.

Importance: Active postnatal care has been associated with center differences in survival among periviable infants. Regional differences in outcomes among periviable infants in the US may be associated with differences in active postnatal care. Objective: To determine if regions with higher rates of active postnatal care will have higher gestational age-specific survival rates among periviable infants. Design, Setting, and Participants: This cohort study included live births from 22 to 25 weeks' gestation weighing 400 to 999 g in the US Centers for Disease Control and Prevention (CDC) WONDER 2017 to 2020 (expanded) database. Infants with congenital anomalies were excluded. Active postnatal care was defined using the CDC definition of abnormal conditions of newborn as presence of any of the following: neonatal intensive care unit (NICU) admission, surfactant, assisted ventilation, antibiotics, and seizures. Data were analyzed from August to November 2022. Main Outcomes and Measures: Regional gestational age-specific survival rates were compared with rates of active postnatal care in the 10 US Health and Human Services regions using Kendall τ test. Results: We included 41 707 periviable infants, of whom 32 674 (78%) were singletons and 19 467 (46.7%) were female. Among those studied 34 983 (83.9%) had evidence of active care, and 26 009 (62.6%) survived. Regional rates of active postnatal care were positively correlated with regional survival rates at 22 weeks' gestation (rτ[8] = 0.56; r2 = 0.31; P = .03) but the correlation was not significant at 23 weeks' gestation (rτ[8] = 0.47; r2 = 0.22; P = .07). There was no correlation between active care and survival at 24 or 25 weeks' gestation. Regional rates of both NICU admission and assisted ventilation following delivery were positively correlated with regional rates of survival at 22 weeks' gestation (both P < .05). Regional rates of antenatal corticosteroids exposure were also positively correlated with regional rates of survival at 22 weeks' gestation (rτ[8] = 0.60; r2 = 0.36; P = .02). Conclusions and Relevance: In this cohort study of 41 707 periviable infants, regional differences in rates of active postnatal care, neonatal intensive care unit admission, provision of assisted ventilation and antenatal corticosteroid exposure were moderately correlated with survival at 22 weeks' gestation. Further studies focused on individual-level factors associated with active periviable care are warranted.

Total Fluid Administration and Weight Loss during the First 2 Weeks in Infants Randomized to Early Enteral Feeding after Extremely Preterm Birth.

BACKGROUND: Randomized trials have not reported the effects of the early progression of feeding volumes on fluid balance and neurodevelopment among infants born extremely preterm (≤28 weeks). METHOD: Fluid, electrolyte, and neurodevelopment data of 60 extremely preterm infants randomly assigned to receive either 1 (early feeding group) or 4 days (late feeding group) of trophic feeding volumes at 20-24 mL/kg/day were analyzed. RESULTS: Infants randomized to the early feeding group received less parenteral fluids, generated lower urine volumes, and had less excessive weight loss during the first 14 days after birth. The 7-point difference in cognitive scores and the 0.5 difference in weight-for-age z-scores favoring the early feeding group did not reach statistical significance. CONCLUSIONS: In extremely preterm infants, early enteral feeding is associated with less total fluid administration and with less excessive weight loss during the first 2 weeks after birth. These short-term effects could have long-lasting benefits.

Risk Prediction for Stillbirth and Neonatal Mortality in Low-resource Settings.

High stillbirth and neonatal mortality are major public health problems, particularly in low-resource settings in low- and middle-income countries (LMIC). Despite sustained efforts by national and international organizations over the last several decades, quality intrapartum and neonatal care is not universally available, especially in these low-resource settings. A few studies identify risk factors for adverse perinatal outcomes in low-resource settings in LMICs. This review highlights the evidence of risk prediction for stillbirth and neonatal death. Evidence using advanced machine-learning statistical models built on data from low-resource settings in LMICs suggests that the predictive accuracy for intrapartum stillbirth and neonatal mortality using prenatal and pre-delivery data is low. Models with delivery and post-delivery data have good predictive accuracy of the risk for neonatal mortality. Birth weight is the most important predictor of neonatal mortality. Further validation and testing of the models in other low-resource settings and subsequent development and testing of possible interventions could advance the field.

Hospital and Neurodevelopmental Outcomes in Nano-Preterm Infants Receiving Invasive vs Noninvasive Ventilation at Birth.

Importance: Infants with gestational age between 22 0/7 and 23 6/7 weeks (referred to as nano-preterm infants) are at very high risk of adverse outcomes. Noninvasive respiratory support at birth improves outcomes in infants born at 24 0/7 to 27 6/7 weeks' gestational age. Evidence is limited on whether similar benefits of non-invasive respiratory support at birth extend to nano-preterm infants. Objective: To evaluate the hypothesis that intubation at 10 minutes or earlier after birth is associated with a higher incidence of bronchopulmonary dysplasia (BPD) or death by 36 weeks' postmenstrual age (PMA) in nano-preterm infants. Design, Setting, and Participants: This observational cohort study included all nano-preterm infants at a level IV neonatal intensive care unit who were delivered from January 1, 2014, to June 30, 2021. Infants receiving palliative or comfort care at birth were excluded. Exposures: Infants were grouped based on first intubation attempt timing after birth (>10 minutes after birth and ≤10 minutes as noninvasive and invasive respiratory support at birth groups, respectively). Main Outcomes and Measures: The primary outcome was the composite outcome of BPD (physiological definition) or death by 36 weeks' PMA. Results: All 230 consecutively born, eligible nano-preterm infants were included, of whom 88 (median [IQR] gestational age, 23.6 [23.4-23.7] weeks; 45 [51.1%] female; 54 [62.1%] Black) were in the noninvasive respiratory support at birth group and 142 (median [IQR] gestational age, 23.0 [22.4-23.3] weeks; 71 [50.0%] female; 94 [66.2%] Black) were in the invasive respiratory support at birth group. The incidence of BPD or death by 36 weeks' PMA did not differ between the noninvasive and invasive respiratory support groups (83 of 88 [94.3%] in the noninvasive group vs 129 of 142 [90.9%] in the invasive group; adjusted odds ratio, 2.09; 95% CI, 0.60-7.25; P = .24). Severe intraventricular hemorrhage or death by 36 weeks' PMA was lower in the invasive respiratory support at birth group (adjusted odds ratio, 2.20; 95% CI, 1.07-4.51; P = .03). Conclusions and Relevance: This cohort study's findings suggest that noninvasive respiratory support in the first 10 minutes after birth is feasible but is not associated with a decrease in the risk of BPD or death compared with intubation and early surfactant delivery in nano-preterm infants.

Prevention of severe brain injury in very preterm neonates: A quality improvement initiative.

OBJECTIVE: To determine the impact of neuroprotection interventions bundle on the incidence of severe brain injury or early death (intraventricular hemorrhage grade 3/4 or death by 7 days or ventriculomegaly or cystic periventricular leukomalacia on 1-month head ultrasound, primary composite outcome) in very preterm (270/7 to ≤ 296/7 weeks gestational age) infants. STUDY DESIGN: Prospective quality improvement initiative, from April 2017-September 2019, with neuroprotection interventions bundle including cerebral NIRS, TcCO2, and HeRO monitoring-based management algorithm, indomethacin prophylaxis, protocolized bicarbonate and inotropes use, noise reduction, and neutral positioning. RESULT: There was a decrease in the incidence of the primary composite outcome in the intervention period on unadjusted (N = 11/99, pre-intervention to N = 0/127, intervention period, p < 0.001) and adjusted analysis (adjusted for birthweight and Apgar score <5 at 5 min, aOR = 0.042, 95% CI = 0.003-0.670, p = 0.024). CONCLUSIONS: Neuroprotection interventions bundle was associated with significant decrease in severe brain injury or early death in very preterm infants.

Outcome prediction in newborn infants: Past, present, and future.

The perinatal and neonatal periods are the periods of considerable organ development and maturation. Perinatal and neonatal illnesses can result in mortality and morbidities that burden families and the healthcare system. Outcome prediction is essential for informing perinatal and intensive care management, prognosis, and post-discharge interventions. The Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network (NRN) research databases include hospital and neurodevelopment follow-up outcomes of infants with various underlying diseases and conditions receiving intensive care, providing a unique opportunity to assess outcome risk prediction. The NRN has developed outcome risk prediction tools for use in infants with various diseases and conditions that allow data-driven, transparent discussions to inform family-focused communications and clinical management. This review presents the published neonatal outcome risk prediction research from the NRN, their present clinical utility, and possible future directions for advanced individualized risk prediction.

Neonatal resuscitation from a global perspective.

The majority of perinatal and neonatal mortality occurs in low-resource settings in low- and middle-income countries. Access and quality of care at delivery are major determinants of the health and survival of newborn infants. Availability of basic neonatal resuscitation care at birth has improved, but basic neonatal resuscitation at birth or high-quality care continues to be inaccessible in some settings, leading to persistently high perinatal and neonatal mortality. Low-resource settings of high-income countries and socially disadvantaged communities also suffer from inadequate access to quality perinatal healthcare. Quality improvement, implementation research, and innovation should focus on improving the quality of perinatal healthcare and perinatal and neonatal outcomes in low-resource settings. The current review presents an update on issues confronting universal availability of optimal resuscitation care at birth and provides an update on ongoing efforts to address them.

Efficacy of Skin-to-Skin Care versus Swaddling for Pain Control Associated with Vitamin K Administration in Full-Term Neonates: A Randomized Controlled Trial.

OBJECTIVE: The objective of the study was to assess the efficacy of immediate skin-to-skin care (SSC) versus swaddling in pain response to intramuscular injection of vitamin K at 30 min of birth in neonates. METHODS: Healthy full-term newborns were enrolled immediately after normal vaginal delivery and randomized in two groups, SSC and swaddling. Neonatal Infant Pain Scale (NIPS) was measured before, immediately after and at 2 min after the injection. RESULTS: Total 100 newborns were enrolled in the study (50 in each group). The mean (SD) birth weight of newborns in the SSC and swaddling group was 2668 (256) and 2730 (348) g, respectively. NIPS was comparable between the SSC and swaddling at before [1.78 (0.58) vs. 1.96 (0.83), p = 0.21], and immediately after the injection [4.82 (0.72) vs. 5.08 (0.75), p = 0.08]. NIPS at 2 min after the injection was significantly low in the SSC group compared to the swaddling group [1.38 (0.70) vs. 2.88 (1.00), p < 0.001]. At 2 min after injection, the NIPS score was significantly lower than baseline in the SSC group (p = 0.002), while it was significantly higher in the swaddling group (p < 0.001). A significantly higher proportion of newborns had a NIPS score of more than three at 2 min after injection in the swaddling group as compared to the SSC group (22% vs. 2%, p < 0.001). CONCLUSION: Immediate SSC was more efficacious as compared to swaddling as a pain control intervention while giving vitamin K injection. CLINICAL TRIAL REGISTRATION: The trial is registered with the Clinical Trial Registry of India with Registration number: CTRI/2020/01/022984.

Skin-to-skin care and swaddling are commonly used non-pharmacological measures to reduce pain perception in neonates for invasive procedures like heel prick, venipuncture and vaccination. We did this randomized control trial to compare the efficacy of immediate skin-to-skin care after birth vs. swaddling for reducing neonatal pain associated with intramuscular injection of vitamin K at 30 min after birth. We observed that the immediate skin-to-skin care, a standard of care, is more efficacious in controlling pain compared to swaddling for giving routine intramuscular vitamin K injection within one hour of birth.