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.

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.

Loss of the transforming growth factor-ß effector ß2-Spectrin promotes genomic instability.

Exposure to genotoxins such as ethanol-derived acetaldehyde leads to DNA damage and liver injury and promotes the development of cancer. We report here a major role for the transforming growth factor ß/mothers against decapentaplegic homolog 3 adaptor ß2-Spectrin (ß2SP, gene Sptbn1) in maintaining genomic stability following alcohol-induced DNA damage. ß2SP supports DNA repair through ß2SP-dependent activation of Fanconi anemia complementation group D2 (Fancd2), a core component of the Fanconi anemia complex. Loss of ß2SP leads to decreased Fancd2 levels and sensitizes ß2SP mutants to DNA damage by ethanol treatment, leading to phenotypes that closely resemble those observed in animals lacking both aldehyde dehydrogenase 2 and Fancd2 and resemble human fetal alcohol syndrome. Sptbn1-deficient cells are hypersensitive to DNA crosslinking agents and have defective DNA double-strand break repair that is rescued by ectopic Fancd2 expression. Moreover, Fancd2 transcription in response to DNA damage/transforming growth factor ß stimulation is regulated by the ß2SP/mothers against decapentaplegic homolog 3 complex. CONCLUSION: Dysfunctional transforming growth factor ß/ß2SP signaling impacts the processing of genotoxic metabolites by altering the Fanconi anemia DNA repair pathway. (Hepatology 2017;65:678-693).

Glomerular mitochondrial changes in HIV associated renal injury.

HIV-associated nephropathy (HIVAN) is an AIDs-related disease of the kidney. HIVAN is characterized by severe proteinuria, podocyte hyperplasia, collapse, glomerular, and tubulointerstitial damage. HIV-1 transgenic (Tg26) mouse is the most popular model to study the HIV manifestations that develop similar renal presentations as HIVAN. Viral proteins, including Tat, Nef, and Vpr play a significant role in renal cell damage. It has been shown that mitochondrial changes are involved in several kidney diseases, and therefore, mitochondrial dysfunction may be implicated in the pathology of HIVAN. In the present study, we investigated the changes of mitochondrial homeostasis, biogenesis, dynamics, mitophagy, and examined the role of reactive oxygen species (ROS) generation and apoptosis in the Tg26 mouse model. The Tg26 mice showed significant impairment of kidney function, which was accompanied by increased blood urea nitrogen (BUN), creatinine and protein urea level. In addition, histological, western blot and PCR analysis of the Tg26 mice kidneys showed a downregulation of NAMPT, SIRT1, and SIRT3 expressions levels. Furthermore, the kidney of the Tg26 mice showed a downregulation of PGC1α, MFN2, and PARKIN, which are coupled with decrease of mitochondrial biogenesis, imbalance of mitochondrial dynamics, and downregulation of mitophagy, respectively. Furthermore, our results indicate that mitochondrial dysfunction were associated with ER stress, ROS generation and apoptosis. These results strongly suggest that the impaired mitochondrial morphology, homeostasis, and function associated with HIVAN. These findings indicated that a new insight on pathological mechanism associated with mitochondrial changes in HIVAN and a potential therapeutic target.

Renal aquaporin-4 associated pathology in TG-26 mice.

Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in HIV patients, which is characterized by glomerulosclerosis and renal tubular dysfunction. Aquaporin-4 (AQP-4) is a membrane bound water channel protein that plays a distinct role in water reabsorption from renal tubular fluid. It has been proven that failure of AQP-4 insertion into the renal tubular membrane leads to renal dysfunction. However, the role of AQP-4 in HIVAN is unclear. We hypothesize that impaired water reabsorption leads to renal injury in HIVAN, where AQP-4 plays a crucial role. Renal function is assessed by urinary protein and serum blood urea nitrogen (BUN). Kidneys from HIV Transgenic (TG26) mice (HIVAN animal model) were compared to wild type mice by immunostaining, immunoblotting and quantitative RT-PCR. TG26 mice had increased proteinuria and BUN. We found decreased AQP-4 levels in the renal medulla, increased endothelin-1, endothelin receptor A and reduced Sirtuin1 (SIRT-1) levels in TG26 mice. Also, oxidative and endoplasmic reticulum stress was enhanced in kidneys of TG26 mice. We provide the first evidence that AQP-4 is inhibited due to induction of HIV associated stress in the kidneys of TG26 mice which limits water reabsorption in the kidney which may be one of the cause associated with HIVAN, impairing kidney physiology. AQP-4 dysregulation in TG26 mice suggests that similar changes may occur in HIVAN patients. This work may identify new therapeutic targets to be evaluated in HIVAN.

Transcriptomic profiling and quantitative high-throughput (qHTS) drug screening of CDH1 deficient hereditary diffuse gastric cancer (HDGC) cells identify treatment leads for familial gastric cancer.

BACKGROUND: Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease. METHODS: In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells. RESULTS: Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function. CONCLUSION: Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer.

Enhanced hydrogen sorption in a Li-Mg-N-H system by the synergistic role of Li4(NH2)3BH4 and ZrFe2.

The present investigation describes the synergistic role of Li4(BH4)(NH2)3 and ZrFe2 in the hydrogen storage behaviour of a Li-Mg-N-H hydride system. The onset desorption temperature of ZrFe2-catalysed Mg(NH2)2-LiH-Li4(BH4)(NH2)3 is ∼122 °C, which is 83 °C, 63 °C, and 28 °C lower than that of thermally treated 2LiNH2-1MgH2, 2LiNH2-1MgH2-4 wt%ZrFe2, and 2LiNH2-1MgH2-0.1LiBH4 composites, respectively. Native Mg(NH2)2-LiH-Li4(BH4)(NH2)3 absorbed only 2.78 wt% of H2 within 30 min. On the other hand, the ZrFe2-catalysed Mg(NH2)2-LiH-Li4(BH4)(NH2)3 sample absorbed 3.70 wt% of hydrogen within 30 min and 5 wt% of H2 in 6 h at 180 °C and 7 MPa H2 pressure. Mg(NH2)2-LiH-Li4(BH4)(NH2)3 catalyzed with ZrFe2 shows negligible degradation of the storage capacity even after repeated cycles of de/rehydrogenation. The effect of ZrFe2 and Li4(BH4)(NH2)3 on a Mg(NH2)2/LiH composite has been described and discussed with the help of structural (X-ray diffraction), microstructural (electron microscopy), and vibrational modes of molecules through FTIR studies. The present results suggest that an optimum catalysis may originate from the synergistic action of an in situ formed quaternary hydride (Li4(BH4)(NH2)3) and an intermetallic-like ZrFe2, which acts as a pulverizer cum catalyst.

Determinants of broiler chicken meat quality and factors affecting them: a review.

Broiler production at mass level has already been achieved and now emphasis is being laid on increasing meat quality by altering various characteristics of broiler meat. Appearance, texture, juiciness, wateriness, firmness, tenderness, odor and flavor are the most important and perceptible meat features that influence the initial and final quality judgment by consumers before and after purchasing a meat product. The quantifiable properties of meat such as water holding capacity, shear force, drip loss, cook loss, pH, shelf life, collagen content, protein solubility, cohesiveness, and fat binding capacity are indispensable for processors involved in the manufacture of value added meat products. Nutrition of birds has a significant impact on poultry meat quality and safety. It is well known that dietary fatty acid profiles are reflected in tissue fatty acid. Management of poultry meat production is reflected mostly on consumption features (juiciness, tenderness, flavour) of meat. After slaughter, biochemical changes, causing the conversion of muscle to meat, determine final meat quality. Postmortem carcass temperature has profound effect on rigor mortis and the physicochemical changes observed in PSE muscles are attributed to postmortem glycolysis, temperature, and pH. Primary processing and further processing have become a matter of concern with respect to nutritional quality of broiler meat. Genetic variation among birds could contribute to large differences in the rate of rigor mortis completion and meat quality. Heritability estimates for meat quality traits in broilers are amazingly high (0.35-0.81), making genetic selection a best tool for improvement of broiler meat quality.

Detection of ALDH1 activity in rabbit hepatic VX2 tumors and isolation of ALDH1 positive cancer stem cells.

BACKGROUND: Aldehyde dehydrogenase 1 (ALDH1) activity has been implicated in the therapeutic drug resistance of many malignancies and has been widely used as a marker to identify stem-like cells, including in primary liver cancer. Cancer stem cells (CSCs) are thought to play a crucial role in cancer progression and metastasis. In order to clarify the validity of the rabbit VX2 liver cancer model, we questioned if it expresses ALDH1 as a potential marker of CSCs. Hepatocellular carcinoma is a common malignancy worldwide and has poor prognosis. Most of the animal models used to study hepatocellular carcinoma are rodent models which lack clinical relevance. The rabbit VX2 model is a large animal model useful for preclinical and for developing drugs targeting cancer stem cells. MATERIALS AND METHODS: We used flow cytometry to identify rabbit VX2 liver tumor cells that express ALDH1A1 activity at a high level and confirmed the results with RT-PCR, immunohistochemical and western blot analyses. Further, mRNA and protein expression analysis of tumor samples also express the markers for stemness like klf4, oct3/4, CD44 and nanog as well as the differentiation marker α-fetoprotein. RESULTS: We used Aldefluor flow cytometry-based assay to identify cells with high ALDH1 activity in the rabbit VX2 liver cancer model. We used the brightest 4.39 % of the total cancer cell population in our study. We performed semi-quantitative as well as real time PCR to characterize the stemness derived from VX2 tumors and tissues from normal rabbit liver. We demonstrated that VX2 tumors have higher expression of cancer stem cell markers such as AlDH1A1 and CD44 in comparison to normal rabbit liver cells. Additionally, real time PCR analysis of the same samples using syber-green demonstrated the significant change (p > 0.05) in the expression of genes. We validated the gene expression of the stemness markers by performing western blot and immunofluorescence. We showed that cancer stem cell markers (AlDH1A1, CD44) and the differentiation marker α-fetoprotein were upregulated in VX2 tumor cells. The same extent of upregulation was observed in stemness markers (klf4, oct3/4 and nanog) in VX2 tumors in comparison to normal rabbit liver. CONCLUSION: The overall results of this study indicate that ALDH1 is a valid CSC marker for VX2 cancer. This finding suggests that the rabbit VX2 liver cancer model is useful in studying drug resistance in hepatocellular carcinoma and may be useful for basic and preclinical studies of other types of human cancer.

RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis.

Premature fusion of one or more of the cranial sutures (craniosynostosis) in humans causes over 100 skeletal diseases, which occur in 1 of approximately 2,500 live births. Among them is Apert syndrome, one of the most severe forms of craniosynostosis, primarily caused by missense mutations leading to amino acid changes S252W or P253R in fibroblast growth factor receptor 2 (FGFR2). Here we show that a small hairpin RNA targeting the dominant mutant form of Fgfr2 (Fgfr2(S252W)) completely prevents Apert-like syndrome in mice. Restoration of normal FGFR2 signaling is manifested by an alteration of the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2), implicating the gene encoding ERK and the genes downstream of it in disease expressivity. Furthermore, treatment of the mutant mice with U0126, an inhibitor of mitogen-activated protein (MAP) kinase kinase 1 and 2 (MEK1/2) that blocks phosphorylation and activation of ERK1/2, significantly inhibits craniosynostosis. These results illustrate a pathogenic role for ERK activation in craniosynostosis resulting from FGFR2 with the S252W substitution and introduce a new concept of small-molecule inhibitor-mediated prevention and therapy for diseases caused by gain-of-function mutations in the human genome.

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.

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.

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.

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.

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.

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.

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.

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.