Neonatal outcomes in preterm infants with severe congenital heart disease: a national cohort analysis.

Background: Prematurity and congenital heart disease (CHD) are the leading causes of neonatal mortality and morbidity. Limited data are available about the outcomes of premature infants with severe CHD. Methods: We queried The National Inpatient Database using ICD-10 codes for premature patients (<37 weeks) with severe CHD from 2016 to 2020. Severe CHDs were grouped into three categories: A. left-sided lesions with impaired systemic output, B. Cyanotic CHD, and C. Shunt lesions with pulmonary overcirculation. Patients with isolated atrial or ventricular septal defects and patent ductus arteriosus were excluded. We also excluded patients with chromosomal abnormalities and major congenital anomalies. Patients' demographics, clinical characteristics, and outcomes were evaluated by comparing premature infants with vs. without CHD adjusting for gestational age (GA), birth weight, and gender. Results: A total of 27710 (1.5%) out of 1,798,245 premature infants had severe CHD. This included 27%, 58%, and 15% in groups A, B, and C respectively. The incidence of severe CHD was highest between 25 and 28 weeks of gestation and decreased significantly with increasing GA up to 36 weeks (p < 0.001). Premature infants with severe CHD had a significantly higher incidence of neonatal morbidities including necrotizing enterocolitis (NEC) [OR = 4.88 (4.51-5.27)], interventricular hemorrhage [OR = 6.22 (5.57-6.95)], periventricular leukomalacia [OR = 3.21 (2.84-3.64)] and bronchopulmonary dysplasia [OR = 8.26 (7.50-10.06) compared to preterm infants of similar GA without CHD. Shunt lesions had the highest incidence of NEC (8.5%) compared to 5.3% in cyanotic CHD and 3.7% in left-sided lesions (p < 0.001). Mortality was significantly higher in premature infants with CHD compared to control [11.6% vs. 2.5%, p < 0.001]. Shunt lesions had significantly higher mortality (11.0%) compared to those with left-sided lesions (8.3%) and cyanotic CHD (6.4%), p < 0.001. Conclusion: Premature infants with severe CHD are at high risk of neonatal morbidity and mortality. Morbidity remains increased across all GA groups and in all CHD categories. This significant risk of adverse outcomes is important to acknowledge when managing this patient population and when counseling their families. Future research is needed to examine the impact of specific rather than categorized congenital heart defects on neonatal outcomes.

Outcomes of atrioventricular septal defects with and without down syndrome: analysis of the national inpatient database.

BACKGROUND: Controversial data exist about the impact of Down syndrome on outcomes after surgical repair of atrioventricular septal defect. AIMS: (A) assess trends and outcomes of atrioventricular septal defect with and without Down syndrome and (B) determine risk factors associated with adverse outcomes after atrioventricular septal defect repair. METHODS: We queried The National Inpatient Sample using International Classification of Disease codes for patients with atrioventricular septal defect < 1 year of age from 2000 to 2018. Patients' characteristics, co-morbidities, mortality, and healthcare utilisation were evaluated by comparing those with versus without Down syndrome. RESULTS: In total, 2,318,706 patients with CHD were examined; of them, 61,101 (2.6%) had atrioventricular septal defect. The incidence of hospitalisation in infants with atrioventricular septal defect ranged from 4.5 to 7.5% of all infants hospitalised with CHD per year. A total of 33,453 (54.7%) patients were associated with Down syndrome. Double outlet right ventricle, coarctation of the aorta, and tetralogy of Fallot were the most commonly associated with CHD in 6.9, 5.7, and 4.3% of patients, respectively. Overall atrioventricular septal defect mortality was 6.3%. Multivariate analysis revealed that prematurity, low birth weight, pulmonary hypertension, and heart block were associated with mortality. Down syndrome was associated with a higher incidence of pulmonary hypertension (4.3 versus 2.8%, p < 0.001), less arrhythmia (6.6 versus 11.2%, p < 0.001), shorter duration for mechanical ventilation, shorter hospital stay, and less perioperative mortality (2.4 versus 11.1%, p < 0.001). CONCLUSION: Trends in atrioventricular septal defect hospitalisation had been stable over time. Perioperative mortality in atrioventricular septal defect was associated with prematurity, low birth weight, pulmonary hypertension, heart block, acute kidney injury, and septicaemia. Down syndrome was present in more than half of atrioventricular septal defect patients and was associated with a higher incidence of pulmonary hypertension but less arrhythmia, lower mortality, shorter hospital stay, and less resource utilisation.

Accumulation of oxysterols in the erythrocytes of COVID-19 patients as a biomarker for case severity.

BACKGROUND: Due to the high risk of COVID-19 patients developing thrombosis in the circulating blood, atherosclerosis, and myocardial infarction, it is necessary to study the lipidome of erythrocytes. Specifically, we examined the pathogenic oxysterols and acylcarnitines in the erythrocyte homogenate of COVID-19 patients. These molecules can damage cells and contribute to the development of these diseases. METHODS: This study included 30 patients and 30 healthy volunteers. The erythrocyte homogenate extract was analyzed using linear ion trap mass spectrometry combined with high-performance liquid chromatography. The concentrations of oxysterols and acylcarnitines in erythrocyte homogenates of healthy individuals and COVID-19 patients were measured. Elevated levels of toxic biomarkers in red blood cells could initiate oxidative stress, leading to a process known as Eryptosis. RESULTS: In COVID-19 patients, the levels of five oxysterols and six acylcarnitines in erythrocyte homogenates were significantly higher than those in healthy individuals, with a p-value of less than 0.05. The mean total concentration of oxysterols in the red blood cells of COVID-19 patients was 23.36 ± 13.47 µg/mL, while in healthy volunteers, the mean total concentration was 4.92 ± 1.61 µg/mL. The 7-ketocholesterol and 4-cholestenone levels were five and ten times higher, respectively, in COVID-19 patients than in healthy individuals. The concentration of acylcarnitines in the red blood cell homogenate of COVID-19 patients was 2 to 4 times higher than that of healthy volunteers on average. This finding suggests that these toxic biomarkers may cause the red blood cell death seen in COVID-19 patients. CONCLUSIONS: The abnormally high levels of oxysterols and acylcarnitines found in the erythrocytes of COVID-19 patients were associated with the severity of the cases, complications, and the substantial risk of thrombosis. The concentration of oxysterols in the erythrocyte homogenate could serve as a diagnostic biomarker for COVID-19 case severity.

Impact of postnatal steroids on peripheral avascular retina and severity of retinopathy of prematurity.

BACKGROUND: We investigated the role of postnatal steroids on the severity of retinopathy of prematurity (ROP) and its impact on peripheral avascular retina (PAR). METHODS: A retrospective cohort study of infants born at ≤32 weeks gestation and/or birth weight ≤1500 g. Demographics, the dose and duration of steroid treatment, and age when full retinal vascularization occurred were collected. The primary outcomes were the severity of ROP and time to full vascularization of the retina. RESULTS: A total of 1695 patients were enrolled, 67% of whom received steroid therapy. Their birth weight was 1142 ± 396 g and gestational age was 28.6 ± 2.7 weeks. The total hydrocortisone-equivalent dose prescribed was 28.5 ± 74.3 mg/kg. The total days of steroid treatment were 8.9 ± 35.1 days. After correction for major demographic differences, infants who received a higher cumulative dose of steroids for a longer duration had a significantly increased incidence of severe ROP and PAR (P < 0.001). For each day of steroid treatment, there was a 3.2% increase in the hazard of the severe form of ROP (95% CI: 1.022-1.043) along with 5.7% delay in achieving full retinal vascularization (95% CI: 1.04-1.08) (P < 0.001). CONCLUSION: Cumulative dose and duration of postnatal steroid use were independently associated with the severity of ROP and PAR. Thus, postnatal steroids should be used very prudently. IMPACT: We report ROP outcomes in a large cohort of infants from two major healthcare systems where we have studied the impact of postnatal steroids on the severity of ROP, growth, and development of retinal vessels. After correcting our data for three major outcome measures, we show that high-dose postnatal steroids used for a prolonged duration of time are independently associated with severe ROP and delay in retinal vascularization. Postnatal steroids impact the visual outcomes of VLBW infants significantly, so their clinical use needs to be moderated.

Epidemiologic evaluation of inhaled nitric oxide use among neonates with gestational age less than 35 weeks.

BACKGROUND AND OBJECTIVES: The use of inhaled nitric oxide (iNO) in +late preterm and term infants with pulmonary hypertension is Food and Drug Administration (FDA) approved and has improved outcomes and survival. iNO use is not FDA approved for preterm infants and previous studies show no mortality benefit. The objectives were 1) to determine the usage of iNO among preterm neonates <35 weeks before and after the 2010 National Institutes of Health consensus statement and 2) to evaluate characteristics and outcomes among preterm neonates who received iNO. METHODS: This is a population-based cross-sectional study. Billing and procedure codes were used to determine iNO usage. Data were queried from the National Inpatient Sample from 2004 to 2016. Neonates were included if gestational age was <35 weeks. The epochs were spilt into 2004-2010 (Epoch 1) and 2011-2016 (Epoch 2). Prevalence of iNO use, mortality, bronchopulmonary dysplasia (BPD), intraventricular hemorrhage, length of stay, mechanical ventilation, and cost of hospitalization. RESULTS: There were 4865 preterm neonates <35 weeks who received iNO. There was a significant increase in iNO use during Epoch 2 (p < 0.001). There was significantly higher use in Epoch 2 among neonates small for gestational age (SGA) 2.3% versus 7.2%, congenital heart disease (CHD) 11.1% versus 18.6%, and BPD 35.2% versus 46.8%. Mortality was significantly lower in Epoch 2 19.8% versus 22.7%. CONCLUSION: Usage of iNO was higher after the release of the consensus statement. The increased use of iNO among preterm neonates may be targeted at specific high-risk populations such as SGA and CHD neonates. There was lower mortality in Epoch 2; however, the cost was doubled.

Design, synthesis and biological evaluation of novel 5-((substituted quinolin-3-yl/1-naphthyl) methylene)-3-substituted imidazolidin-2,4-dione as HIV-1 fusion inhibitors.

A series of novel 5-(substituted quinolin-3-yl or 1-naphthyl)methylene)-3-substituted imidazolidin-2,4-dione 9-26 was designed and synthesized. The prepared compounds were identified using 1H NMR, 13C NMR as well as elemental analyses. The inhibitory activity of 9-26 on HIV-1IIIB replication in MT-2 cells was evaluated. Some derivatives showed good to excellent anti-HIV activities as compounds 13, 18, 19, 20, 22 and 23. They showed EC50 of 0.148, 0.460, 0.332, 0.50, 0.271 and 0.420 µM respectively being more potent than compound I (EC50 = 0.70 µM) and II ( EC50 = 2.40 µM) as standards. The inhibitory activity of 9-26 on infected primary HIV-1 domain, 92US657 (clade B, R5) was investigated. All the tested compounds consistently inhibited infection of this virus with EC50 from 0.520 to 11.857 µM. Results from SAR studies showed that substitution on ring A with 6/7/8-methyl group resulted in significant increase in the inhibitory activity against HIV-1IIIB infection (5- >300 times) compared to the unsubstituted analog 9. The cytotoxicity of these compounds on MT-2 cells was tested and their CC50 values ranged from 11 to 85 µM with selectivity indexes ranged from 0.53 to 166. The docking study revealed nice fitting of the new compounds into the hydrophobic pocket of HIV-1 gp41 and higher affinity than NB-64. Compound 13, the most active in preventing HIV-1IIIB infection, adopted a similar orientation to compound IV. Molecular docking analysis of the new compounds revealed hydrogen bonding interactions between the imidazolidine-2,4-dione ring and LYS574 which were missed in the weakly active derivatives.

Validation of the Hamilton Depression Rating Scale (HDRS) and sociodemographic factors associated with Lebanese depressed patients.

OBJECTIVES: The Hamilton Depression Rating Scale (HDRS) is the most commonly used scale for the evaluation of patients' treatments for depression. Since the HDRS has never been validated in Lebanon to our knowledge, our primary objective, therefore, is to investigate the correlation, sensitivity, specificity, as well as the reliability and the validity of the Hamilton Depression Rating Scale (HDRS) among Lebanese depressed patients. The secondary objective is to identify sociodemographic factors that would be correlated to depression among our sample. METHODS: This case-control study, performed between January till May 2017, included 400 patients (200 patients, 200 controls). RESULTS: The HDRS scale items converged over a solution of four factors, explaining a total of 58.88% of the variance. A high Cronbach's alpha was found for the full scale (0.862). A stepwise linear regression, using the total HDRS score as continuous variable, showed that a low socioeconomic level, divorced participants and a family history of mental disorders would significantly increase the HDRS total score (Beta=4.278; Beta=5.405; and Beta=3.922) respectively. However, having a university level of education would significantly decrease the HDRS total score (Beta=-4.248, P<0.001). CONCLUSION: This study shows that the Arabic version of the HDRS has promising psychometric properties, making it a good tool to use for the diagnosis of patients with depression. Depression recognition and treatment in general practice with the aim of improving patient outcome and reducing health care expenditure, is definitely warranted.

Cytotoxic effects of three new metabolites from Red Sea marine sponge, Petrosia sp.

Marine sponges represent an affluent source of biogenetically unprecedented array of biologically active compounds. This study revealed the isolation of ten compounds from marine sponge of Petrosia sp. Their chemical structures were determined by using 1D and 2D NMR, UV, IR and MS measurements. A polyoxygenated steroid (3ß,7ß,9α-trihydroxycholest-5-en (1), a purine-derivative (3,7-dimethyl-2-(methylamino)-3H-purin-6(7H)-one (2) and a sphingolipid (N-((3S,E)-1,3-dihydroxytetracos-4-en-2-yl)stearamide (3) proved to be new compounds. Meanwhile, seven known compounds; (4-10) were also identified. The cytotoxicity of the total extract and the isolated compounds were subjected to cytotoxicity evaluation employing two cancer cell lines; HepG2 and MCF-7. All tested compounds exhibited cytotoxic effect on both cancer cell lines with IC(50) in range of 20-500 µM. The proposed mechanism of cytotoxic activities was examined through its molecular affinity to the DNA. Compound 5 showed the highest affinity to the DNA with IC(50) 30 µg/mL.

Effect of ketamine pretreatment on cocaine-mediated hepatotoxicity in rats.

Cocaine (COC) produces hepatotoxicity by a mechanism, which remains undefined, but has been linked to its oxidative metabolism. Ketamine (KET) is also a potentially hepatotoxic agent. The abuse of KET with COC is currently popular among young abusers therefore; this study was conducted to investigate the possible potentiation of COC-mediated hepatotoxicity (CMH) by KET. Male Sprague Dawley (SD) rats were administered oral KET hydrochloride for three consecutive days at a dose of 100 mg/kg with and without a single dose of COC (5 mg/kg, i.v.) administered 18 h after the last KET dose. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured as markers of liver injury. Liver reduced glutathione (GSH) levels were determined as well as the activities of glutathione peroxidase (GPx) and catalase (CAT). In addition, the activity of liver glutathione reductase (GRx) was measured. The results demonstrate that KET pretreatment potentiated the hepatotoxicity of COC. Serum ALT and AST were significantly elevated with the combined KET and COC treatment versus all other treatments. While COC alone resulted in focal inflammatory cell infiltration, COC administration after KET pretreatment produced sub-massive hepatic necrosis. Hepatic GSH content was significantly reduced in KET-pretreated COC group compared to the other treatment groups, rendering the liver more susceptible to oxidative stress. Moreover, there was a significant decrease in the activities of hepatic GPx and CAT, particularly with the KET-pretreated COC group. In addition, norcocaine (NC) was only detected in the plasma of rats received COC after KET pretreatment. In conclusion, this study demonstrates that KET pretreatment potentiates the hepatotoxicity of COC as revealed by an array of biochemical and morphological markers most probably due to increase in COC oxidative metabolism.

Does elevated peak bilirubin protect from retinopathy of prematurity in very low birthweight infants.

OBJECTIVE: Bilirubin is a potent in vitro antioxidant. Despite repeated study, its in vivo significance has yet to be defined. Bilirubin is universally elevated in very low birthweight (VLBW) infants. Retinopathy of prematurity (ROP) is a disease thought to be associated with exposure to oxygen free radicals in VLBW infants. The objective of this study was to determine whether there was an association between peak bilirubin levels and ROP. METHODS: The risk for ROP, stages III and IV was measured as a function of increasing peak bilirubin levels in VLBW infants admitted to the neonatal ICU. A similar analysis was performed on a subgroup of VLBW infants with prolonged (> or =28 days) oxygen requirement. The relation between peak bilirubin level and the duration of oxygen requirement was tested by logistic regression analysis. All analyses were conducted after controlling for birthweight and presence of intraventricular hemorrhage (IVH). RESULTS: There was an increased risk for ROP, stages III and IV (OR 1.187; 95% CI 1.013 to 1.390; p=0.034) with elevated peak serum bilirubin levels in the entire population. Duration of oxygen requirement was not related to peak bilirubin (p>0.1). In the subgroup of infants with prolonged oxygen requirement (> or =28 days), there was no association between peak serum bilirubin levels and ROP III and IV (p>0.1); however, there was an association with further increased duration of oxygen requirement (p=0.034). CONCLUSION: Elevated peak bilirubin does not protect from and may be a risk for ROP in VLBW infants.

Immunomodulation by cocaine and ketamine in postnatal rats.

The abuse of cocaine (COC) in combination with ketamine (KET) among pregnant women was shown to be high. Transplacental exposure is not the only route by which a newborn may be exposed to these agents, but they can also distribute into breast milk. Chronic COC exposure is associated with immunological modulation in human and animal models. The effect of sub-chronic exposure to COC and KET alone and in combination on the developing immune system was assessed in neonatal male Sprague-Dawley (SD) rats. To simulate the route of exposure during lactation, newborn male rats were treated orally with saline, COC alone (20 mg/kg), KET alone (50 mg/kg), or KET (50 mg/kg) followed 15 min later by COC (20 mg/kg) from days 1 to 21 of life. Pups were sacrificed 30 min following the last treatment. Total circulating leukocyte and lymphocyte counts were decreased with relative neutrophilia, while spleen/body weight ratio and IgM antibody response to sheep red blood cells (SRBCs) were increased in animals treated with COC. Moreover, treatment with COC alone increased serum interleukin 10 (IL-10) concentration; however, it did not affect serum interferon gamma (IFN-gamma) concentration. On the other hand, KET treatment did not produce any significant change of any of these parameters. However, when co-administered with COC, the immunomodulatory effects of COC were prevented. COC caused a significant increase in serum corticosterone concentration that KET effectively prevented. Lack of significant change of plasma and tissue concentrations of norcocaine (NC) suggested no role for COC metabolism in COC-induced immunomodulation. However, the results of this study indicate that COC-induced immunomodulatory reactions and their prevention by KET most likely occurred through neuroendocrinal mechanisms.

Reduction of tissue concentration of cocaine in rat by ketamine.

The coabuse of cocaine and ketamine occurs with high frequency. The presence of another active substance with cocaine allows for the potential of various drug-drug interactions to occur. This study investigated the tissue distribution after the administration of cocaine or ketamine alone and their combination in rat. Cocaine (5 mg/kg iv), ketamine (100 mg/kg by gavage), or ketamine followed by cocaine (same doses and routes of administration) was utilized. Tissue contents of cocaine and norcocaine were significantly lowered at 5, 15, and 30 min following ketamine administration versus cocaine alone. However, tissue contents of benzoylecgonine were significantly higher in the combination group compared to cocaine alone. On the other hand, cocaine administration did not affect the tissue disposition of ketamine. The results suggest that ketamine decreased cocaine tissue content, which may affect its pharmacological and toxicological profiles.

The role of ketamine on plasma cocaine pharmacokinetics in rat.

Ketamine has gained attention recently because of re-emergence of its abuse especially in combination with cocaine. When more than one drug is present simultaneously, the potential for drug--drug interaction exists, which can be pharmacokinetic, pharmacodynamic or both in nature. The objective of this study was to investigate the effect of ketamine on plasma cocaine pharmacokinetics to assess the role that the kinetic component may play in the interaction of these agents. Moreover, the effect of repetitive administration of ketamine pretreatment on the pharmacokinetics of cocaine was addressed. Male Sprague-Dawley rats were treated with cocaine alone (5 mg/kg i.v.), ketamine alone (100 mg/kg by gavage), or ketamine followed by cocaine (the same routes and doses). Blood samples were withdrawn at different time points post-injection and analyzed for determination of cocaine, its metabolites (benzoylecgonine and norcocaine) and ketamine. The results demonstrated that ketamine caused a significant decrease in cocaine's area under the curve (AUC) and elimination half-life while its total clearance was increased. The AUC of benzoylecgonine was increased by 1.5-fold after the combination compared with cocaine alone. However, cocaine did not affect ketamine's pharmacokinetic parameters. In the pretreatment study, ketamine was given orally for 3 days, followed 18 h later by a single i.v. of cocaine. Further enhancement of cocaine metabolism occurred with the appearance of norcocaine. This investigation revealed that ketamine enhances cocaine metabolism and may affect its toxicological profile.

Development and validation of a high-performance liquid chromatography method for the determination of cocaine, its metabolites and ketamine.

Cocaine abuse is an extensive problem in the USA. During the past decade, ketamine abuse also has emerged as a public health concern and is now considered a controlled substance. The prevalence of the simultaneous use of cocaine and ketamine has been shown to be high. Previous research indicates that ketamine affects the enzymes that metabolize cocaine. In order to investigate this pharmacokinetic interaction, it was necessary to identify and quantitate each compound. The aim of this study is to develop a method of detecting and resolving cocaine, its metabolites and ketamine. A new precise, accurate and sensitive reversed-phase high-performance liquid chromatography method has been developed and validated. This assay employed a phosphate-buffered aqueous mobile phase (pH 6.9) with an organic component consisting of acetonitrile and methanol and a C-18 column as stationary phase at 225 nm wavelength. Minimum detection limits were 5 ng ml(-1) for cocaine and 10 ng ml(-1) for benzoylecgonine, norcocaine and ketamine. Linearity was demonstrated over a broad range of concentration in plasma, with good sensitivity for ketamine, cocaine and cocaine metabolites.