Neonatal brain inflammation enhances methamphetamine-induced reinstated behavioral sensitization in adult rats analyzed with explainable machine learning.

Neonatal brain inflammation produced by intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) results in long-lasting brain dopaminergic injury and motor disturbances in adult rats. The goal of the present work is to investigate the effect of neonatal systemic LPS exposure (1 or 2 mg/kg, i.p. injection in postnatal day 5, P5, male rats)-induced dopaminergic injury to examine methamphetamine (METH)-induced behavioral sensitization as an indicator of drug addiction. On P70, subjects underwent a treatment schedule of 5 once daily subcutaneous (s.c.) administrations of METH (0.5 mg/kg) (P70-P74) to induce behavioral sensitization. Ninety-six hours following the 5th treatment of METH (P78), the rats received one dose of 0.5 mg/kg METH (s.c.) to reintroduce behavioral sensitization. Hyperlocomotion is a critical index caused by drug abuse, and METH administration has been shown to produce remarkable locomotor-enhancing effects. Therefore, a random forest model was used as the detector to extract the feature interaction patterns among the collected high-dimensional locomotor data. Our approaches identified neonatal systemic LPS exposure dose and METH-treated dates as features significantly associated with METH-induced behavioral sensitization, reinstated behavioral sensitization, and perinatal inflammation in this experimental model of drug addiction. Overall, the analysis suggests that the implementation of machine learning strategies is sensitive enough to detect interaction patterns in locomotor activity. Neonatal LPS exposure also enhanced METH-induced reduction of dopamine transporter expression and [3H]dopamine uptake, reduced mitochondrial complex I activity, and elevated interleukin-1ß and cyclooxygenase-2 concentrations in the P78 rat striatum. These results indicate that neonatal systemic LPS exposure produces a persistent dopaminergic lesion leading to a long-lasting change in the brain reward system as indicated by the enhanced METH-induced behavioral sensitization and reinstated behavioral sensitization later in life. These findings indicate that early-life brain inflammation may enhance susceptibility to drug addiction development later in life, which provides new insights for developing potential therapeutic treatments for drug addiction.

Intranasal insulin attenuates hypoxia-ischemia-induced short-term sensorimotor behavioral disturbances, neuronal apoptosis, and brain damage in neonatal rats.

There is a significant need for additional therapy to improve outcomes for newborns with acute Hypoxic-ischemic (HI) encephalopathy (HIE). New evidence suggests that insulin could be neuroprotective. This study aimed to investigate whether intranasal insulin attenuates HI-induced brain damage and neurobehavioral dysfunction in neonatal rats. Postnatal day 10 (P10), Sprague-Dawley rat pups were randomly divided into Sham + Vehicle, Sham + Insulin, HI + Vehicle, and HI + Insulin groups with equal male-to-female ratios. Pups either had HI by permanent ligation of the right common carotid artery followed by 90 min of hypoxia (8% O2) or sham surgery followed by room air exposure. Immediately after HI or Sham, pups were given fluorescence-tagged insulin (Alex-546-insulin)/vehicle, human insulin (25 µg), or vehicle in each nare under anesthesia. Shortly after administration, widespread Alex-546-insulin-binding cells were detected in the brain, primarily co-localized with neuronal nuclei-positive neurons on double-immunostaining. In the hippocampus, phospho-Akt was activated in a subset of Alex-546-insulin double-labeled cells, suggesting activation of the Akt/PI3K pathway in these neurons. Intranasal insulin (InInsulin) reduced HI-induced sensorimotor behavioral disturbances at P11. InInsulin prevented HI-induced increased Fluoro-Jade C+ degenerated neurons, cleaved caspase 3+ neurons, and volume loss in the ipsilateral brain at P11. There was no sex-specific response to HI or insulin. The findings confirm that intranasal insulin provides neuroprotection against HI brain injury in P10 rats associated with activation of intracellular cell survival signaling. If further pre-clinical research shows long-term benefits, intranasal insulin has the potential to be a promising non-invasive therapy to improve outcomes for newborns with HIE.

Bronchopulmonary Dysplasia: Pathogenesis and Pathophysiology.

Bronchopulmonary dysplasia (BPD), also known as chronic lung disease, is the most common respiratory morbidity in preterm infants. "Old" or "classic" BPD, as per the original description, is less common now. "New BPD", which presents with distinct clinical and pathological features, is more frequently observed in the current era of advanced neonatal care, where extremely premature infants are surviving because of medical advancements. The pathogenesis of BPD is complex and multifactorial and involves both genetic and environmental factors. This review provides an overview of the pathology of BPD and discusses the influence of several prenatal and postnatal factors on its pathogenesis, such as maternal factors, genetic susceptibility, ventilator-associated lung injury, oxygen toxicity, sepsis, patent ductus arteriosus (PDA), and nutritional deficiencies. This in-depth review draws on existing literature to explore these factors and their potential contribution to the development of BPD.

Anemia as a Significant Predictor of Adverse Outcomes in Hospitalized Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Analysis of National (Nationwide) Inpatient Sample Database.

BACKGROUND: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has significant health implications. Anemia is usually an unseen comorbidity, which could significantly affect outcomes in AECOPD patients, and there is limited data to support this. We conducted this study to assess the effect of anemia on this patient population. METHODS: We performed a retrospective cohort study using the National (Nationwide) Inpatient Sample (NIS) data from 2008 to 2014. Patients with AECOPD and anemia with age >40 years were identified using appropriate International Classification of Diseases, Ninth Revision (ICD-9) codes, excluding transfer out to other hospitals. We calculated the Charlson Comorbidity Index as a measure of associated comorbidities. We analyzed bivariate group comparisons in patients with and without anemia. Odds ratios were calculated using multivariate logistic and linear regression analysis using SAS version 9.4 (2013; SAS Institute Inc. Cary, North Carolina, United States). RESULTS: Among 3,331,305 patients hospitalized with AECOPD, 567,982 (17.0%) had anemia as a comorbidity. The majority of patients were elderly, women, and white. After adjusting for potential confounders in regression, mortality (adjusted OR (aOR) 1.25, 95%CI: 1.18-1.32), length of hospital stay (ß 0.79, 95%Cl 0.76-0.82), and hospitalization cost (ß 6873, 95%Cl 6437-7308) were significantly higher in patients with anemia. In addition, patients with anemia required significantly higher blood transfusion (aOR 16.9, 95%CI 16.1-17.8), invasive ventilator support (aOR 1.72, 95%CI 1.64-1.79), and non-invasive ventilator support (aOR 1.21, 95%CI 1.17-1.26). CONCLUSION: In this first retrospective largest cohort study on this topic, we find anemia is a significant comorbidity associated with adverse outcomes and healthcare burden in hospitalized AECOPD patients. We should focus on close monitoring and management of anemia to improve the outcomes in this population.

Pediatric Sickle Cell Disease and Stroke: A Literature Review.

Both ischemic and hemorrhagic strokes in children can be a complication of sickle cell disease, which also affects adults. The occurrence is high without any screening or preventative care. This review article found that although transcranial Doppler (TCD) has reduced the prevalence of stroke in pediatric patients, there is still a need for an epidemiological survey to define such screening for adults, the ideal dose of hydroxyurea to reduce the incidence of stroke, and to identify silent cerebral stroke to prevent its complications. Increased hydroxyurea prescription and specific antibiotic and vaccination regimes lowered the occurrence of this condition. In pediatric cases with a time-averaged mean of the maximal velocity greater than 200cm/s, transcranial Doppler screening and preventive chronic transfusion for at least the first year have lowered the occurrence of stroke by up to 10 times. The ideal dose of hydroxyurea is still debatable, but it seems to reduce the risk of the first stroke to a comparable level in the average population. Adult ischemic and hemorrhagic stroke prevention has not yet received the same attention. Though there are fewer studies, sickle cell disease is also more common than age-matched controls in terms of silent cerebral infarction on magnetic resonance imaging (MRI), as well as other neurological problems such as cognitive impairment, seizures, and headaches. Currently, there is no evidence-supported way to prevent ischemic stroke in adults at any age. Also, there is no defined ideal dose of hydroxyurea that can be helpful in preventing strokes. Data also lack a way to identify a silent cerebral infarction, so its complications can be prevented. An additional epidemiological survey may help in the prevention of the condition. The primary aim of this article was to emphasize the importance of information on clinical, neuropsychological, and quantitative MRI assessment of sickle cell patients to understand the epidemiology and etiology of stroke in sickle cell patients to prevent stroke and its related morbidity.

Association of Infantile Hemangiomas and Retinopathy of Prematurity: Analysis of the Multicenter KID.

INTRODUCTION: Retinopathy of prematurity (ROP) and infantile hemangiomas (IHs) both have similar proposed pathophysiological mechanisms. IH is more common in preterm than term infants. Hypoxia-induced mediators like vascular endothelial growth factor have been found elevated in children with hemangiomas. The aim of our study was to determine if there is an association between ROP and IH in preterm infants and to investigate racial/ethnic and gender differences of ROP and IHs in this cohort. METHODS: We accessed the national multicenter Kids' Inpatient Database (KID) Healthcare Cost and Utilization Project (HCUP) including admissions at age ≤28 days. Eligible infants were identified by using ICD-9 codes of ROP and IH in infants with gestational age (GA) ≤32 weeks and/or birth weight ≤1,500 g during the years 2003, 2006, 2009, and 2012. A weight-based analysis was performed using SAS Enterprise Guide 7.1 for complex sample design. RESULTS: In the cohort of 1,068,502 eligible infants, the prevalence of IH was 4.7 per 1,000 preterm admissions (<32 weeks). ROP prevalence was 16% for GA ≤26 weeks, 12.5% for GA 27-30 weeks, and 2.7% for GA 31-32 weeks. IH was significantly higher in infants with ROP; this relationship was consistent among all stages of ROP. Regression analysis showed that females are at increased risk of IH with ROP compared to males (adjusted odds ratio [aOR]: 2.00 [1.85-2.56]). White non-Hispanic premature infants had an increased risk of IH with concomitant ROP compared to both African American (aOR: 3.9 [2.63-4.76]) and Hispanic (aOR: 1.2 [1.14-1.38]) infants. However, African American infants had an increased risk of ROP compared to white non-Hispanic infants (aOR: 1.16 [1.07-1.14]). These genders and racial/ethnic disparities were consistent among GA categories. CONCLUSIONS: To our knowledge, this is the largest cohort based on a national multicenter database comparing an association between ROP and IH. A strong association between ROP and IH may suggest similar risk factors and/or pathophysiology. A further role of genetic factors could explain racial/ethnic differences in both conditions despite similar pathogenesis. These findings may open up new bases of research for management and prevention strategies.

Outcomes of multiple gestation births compared to singleton: analysis of multicenter KID database.

BACKGROUND: The available data regarding morbidity and mortality associated with multiple gestation births is conflicting and contradicting. OBJECTIVE: To compare morbidity, mortality, and length of stay (LOS) outcomes between multiple gestation (twin, triplet and higher-order) and singleton births. METHODS: Data from the national multicenter Kids' Inpatient Database of the Healthcare Cost and Utilization Project from the years 2000, 2003, 2006, 2009, 2012, and 2016 were analyzed using a complex survey design using Statistical Analysis System (SAS) 9.4 (SAS Institute, Cary NC). Neonates with ICD9 and ICD10 codes indicating singletons, twins or triplets, and higher-order multiples were included. Mortality was compared between these groups after excluding transfer outs to avoid duplicate inclusion. To analyze LOS, we included inborn neonates and excluded transfers; who died inpatient and any neonates who appear to have been discharged less than 33 weeks PMA. The LOS was compared by gestational age groups. RESULTS: A total of 22,853,125 neonates were analyzed for mortality after applying inclusion-exclusion criteria; 2.96% were twins, and 0.13% were triplets or more. A total of 22,690,082 neonates were analyzed for LOS. Mean GA, expressed as mean (SD), for singleton, twins and triplets, were 38.30 (2.21), 36.39 (4.21), and 32.72 (4.14), respectively. The adjusted odds for mortality were similar for twin births compared to singleton (aOR: 1.004, 95% CI:0.960-1.051, p = 0.8521). The adjusted odds of mortality for triplet or higher-order gestation births were higher (aOR: 1.33, 95% CI: 1.128-1.575, p = 0.0008) when compared to the singleton births. Median LOS (days) was significantly longer in multiple gestation compared to singleton births overall (singletons: 1.59 [1.13, 2.19] vs. twins 3.29 [2.17, 9.59] vs. triplets or higher-order multiples 19.15 [8.80, 36.38], p < .0001), and this difference remained significant within each GA category. CONCLUSION: Multiple gestation births have higher mortality and longer LOS when compared to singleton births. This population data from multiple centers across the country could be useful in counseling parents when caring for multiple gestation pregnancies.

Hypochloremia Secondary to Diuretics in Preterm Infants: Should Clinicians Pay Close Attention?

Diuretic therapy, commonly used in the newborn intensive care unit, is associated with a variety of electrolyte abnormalities such as hyponatremia, hypokalemia, and hypochloremia. Hypochloremia, often ignored, is associated with significant morbidities and increased mortality in infants and adults. Clinicians respond in a reflex manner to hyponatremia than to hypochloremia. Hypochloremia is associated with nephrocalcinosis, hypochloremic alkalosis, and poor growth. Besides, the diuretic resistance associated with hypochloremia makes maintaining chloride levels in the physiological range even more logical. Since sodium supplementation counters the renal absorption of calcium and lack of evidence for spironolactone role in diuretic therapy for bronchopulmonary dysplasia (BPD), alternate chloride supplements such as potassium or arginine chloride may need to be considered in the management of hypochloremia due to diuretic therapy. In this review, we have summarized the current literature on hypochloremia secondary to diuretics and suggested a pragmatic approach to hypochloremia in preterm infants.

Predictors of neonatal abstinence syndrome in buprenorphine exposed newborn: can cord blood buprenorphine metabolite levels help?

BACKGROUND: Buprenorphine is a semi-synthetic opioid used for the treatment of opioid dependence. Opioid use, including buprenorphine, has been increasing in recent years, in the general population and in pregnant women. Consequently, there has been a rise in frequency of neonatal abstinence syndrome (NAS), associated with buprenorphine use during pregnancy. The purpose of this study was to investigate correlations between buprenorphine and buprenorphine-metabolite concentrations in cord blood and onset of NAS in buprenorphine exposed newborns. METHODS: Nineteen (19) newborns who met inclusion criteria were followed after birth until discharge in a double-blind non-intervention study, after maternal consent. Cord blood and tissue samples were collected and analyzed by liquid chromatography-mass spectrometry (LC-MS) for buprenorphine and metabolites. Simple and multiple logistic regressions were used to examine relationships between buprenorphine and buprenorphine metabolite concentrations in cord blood and onset of NAS, need for morphine therapy, and length of stay. RESULTS: Each increase in 5 ng/ml level of norbuprenorphine in cord blood increases odds of requiring treatment by morphine 2.5 times. Each increase in 5 ng/ml of buprenorphine-glucuronide decreases odds of receiving morphine by 57.7 %. Along with concentration of buprenorphine metabolites, birth weight and gestational age also play important roles, but not maternal buprenorphine dose. CONCLUSIONS: LC-MS analysis of cord blood concentrations of buprenorphine and metabolites is an effective way to examine drug and metabolite levels in the infant at birth. Cord blood concentrations of the active norbuprenorphine metabolite and the inactive buprenorphine-glucuronide metabolite show promise in predicting necessity of treatment of NAS. These finding have implications in improving patient care and reducing healthcare costs if confirmed in a larger sample.