Enteral L-citrulline supplementation in preterm infants is safe and effective in increasing plasma arginine and citrulline levels-a pilot randomized trial.

OBJECTIVE: Deficiencies of citrulline and arginine have been associated with adverse outcomes in preterm-infants and data regarding enteral supplementation in preterm infants is limited. STUDY DESIGN: This randomized -trial [NCT03649932] included 42 preterm infants (gestational age ≤33 weeks) randomized to receive enteral L-citrulline in low (100 mg/kg/day), medium (200 mg/kg/day) and high-dose (300 mg/kg/day) groups for 7 days. Plasma citrulline and arginine levels were obtained pre-and-post supplementation and efficacy was determined by a significant increase in levels after supplementation. A p < 0.05 was considered significant. Safety monitoring included blood-pressure-monitoring as well as complications and death during hospitalization. RESULTS: A total of 40/42 (95%) of the recruits completed the 7-day supplementation with no adverse events. Plasma-citrulline levels increased significantly in all three groups while plasma-arginine levels increased significantly in the high-dose group. CONCLUSION: Enteral L-citrulline supplementation in preterm infants is safe and effective in increasing plasma citrulline and arginine levels. CLINICAL TRIAL REGISTRATION: NCT03649932 https://clinicaltrials.gov/ct2/show/NCT03649932 .

Neurodevelopmental Outcomes of Preterm Infants Born <29 Weeks with Bronchopulmonary Dysplasia-Associated Pulmonary Hypertension: A Multicenter Study.

OBJECTIVE: This study aimed to determine neurodevelopmental outcomes of preterm infants born at <29 weeks' gestational age (GA) with bronchopulmonary dysplasia and pulmonary hypertension (BPD-PH) at 18 to 24 months' corrected age (CA). STUDY DESIGN: In this retrospective cohort study, preterm infants born at <29 weeks' GA between January 2016 and December 2019, admitted to level 3 neonatal intensive care units, who developed BPD and were evaluated at 18 to 24 months' CA in the neonatal follow-up clinics were included. We compared demographic characteristics and neurodevelopmental outcomes between the two groups: Group I: BPD with PH and Group II: BPD with no PH, using univariate and multivariate regression models. The primary outcome was a composite of death or neurodevelopmental impairment (NDI). NDI was defined as any Bayley-III score < 85 on one or more of the cognitive, motor, or language composite scores. RESULTS: Of 366 eligible infants, 116 (Group I [BPD-PH] =7, Group II [BPD with no PH] = 109) were lost to follow-up. Of the remaining 250 infants, 51 in Group I and 199 in Group II were followed at 18 to 24 months' CA. Group I and Group II had median (interquartile range [IQR]) birthweights of 705 (325) and 815 g (317; p = 0.003) and median GAs (IQR) were 25 (2) and 26 weeks (2; p = 0.015) respectively. Infants in the BPD-PH group (Group I) were more likely to have mortality or NDI (adjusted odds ratio: 3.82; bootstrap 95% confidence interval; 1.44-40.87). CONCLUSION: BPD-PH in infants born at <29 weeks' GA is associated with increased odds of the composite outcome of death or NDI at 18 to 24 months' CA. KEY POINTS: · Long-term neurodevelopmental follow-up of preterm infants born <29 weeks' GA.. · Association of neurodevelopmental outcomes with BPD-associated PH.. · Need for longitudinal follow-up of children with BPD-associated PH..

The Association between Prolonged Antibiotic Use in Culture Negative Infants and Length of Hospital Stay and Total Hospital Costs.

OBJECTIVE: This study aimed to determine if prolonged antibiotic use at birth in neonates with a negative blood culture increases the total cost of hospital stay. STUDY DESIGN: This was a retrospective study performed at a 60-bed level IV neonatal intensive care unit. Neonates born <30 weeks of gestation or <1,500 g between 2016 and 2018 who received antibiotics were included. A multivariate linear regression analysis was conducted to determine if clinical factors contributed to increased hospital cost or length of stay. RESULTS: In total, 190 patients met inclusion criteria with 94 infants in the prolonged antibiotic group and 96 in the control group. Prolonged antibiotic use was associated with an increase length of hospital stay of approximately 31.87 days, resulting in a $69,946 increase in total cost of hospitalization. CONCLUSION: Prolonged antibiotics in neonates with negative blood culture were associated with significantly longer hospital length of stay and increased total cost of hospitalization. KEY POINTS: · Prolonged antibiotic use at birth is associated with prolonged hospital stay.. · Prolonged antibiotic use at birth is associated with increased cost of hospitalization.. · Prolonged antibiotic use at birth is associated with increased days on total parenteral nutrition.. · Prolonged antibiotic use at birth is associated with increased subsequent courses of antibiotics..

Impact of Intrauterine Growth Restriction and Placental Insufficiency on Nutritional Outcomes of Extremely Low Birth Weight Infants.

Introduction The aim of our study was to assess the impact of intrauterine growth restriction (IUGR) and placental insufficiency (PI) on the nutritional outcomes of extremely low birth weight (ELBW) infants. Methods We conducted a six-year retrospective case-control study that included 117 ELBW infants. Of these, 58 infants had IUGR and 59 were born appropriate-for-gestational age (AGA). Infants with IUGR were further divided based on the presence or absence of PI, as determined by umbilical arterial doppler velocimetry on serial ultrasounds. Results IUGR infants with PI had the lowest enteral calorie intake at 28 days of life (DOL) (median intake- IUGR+PI: 32 vs IUGR-PI: 93 vs AGA: 110 kcal/kg/day; p-value 0.011) and at 36 weeks corrected gestational age (CGA) (median intake- IUGR+PI: 102 vs IUGR-PI: 125 vs AGA: 119 kcal/kg/day; p-value 0.012). These infants also trended towards requiring a longer duration of total parenteral nutrition (TPN) (median duration - IUGR+PI: 35 vs IUGR-PI: 25 vs AGA: 21 days; p-value 0.054) and higher incidence of conjugated hyperbilirubinemia (IUGR+PI: 43% IUGR-PI: 29% vs AGA: 16%; p-value 0.058), but these results did not reach statistical significance. Despite challenges with enteral nutrition, IUGR infants with PI showed good catch-up growth and had higher growth velocities over the first month of life, compared to AGA controls. Conclusion IUGR in the presence of PI is associated with significantly poorer enteral nutritional outcomes in ELBW infants. However, with the support of optimal parenteral nutrition these infants showed good catch-up growth.

Maternal Nutrition and Fetal/Infant Development.

Nutrition in pregnant mothers has long been known to be an important determinant of fetal/maternal outcomes. In general, the typical American diet shows opportunities for improvement. The intake of fruits, vegetables, whole grains, and fiber may be below recommended levels, but the relative proportion of sodium, fats, and carbohydrates seems high. In this review, we present current evidence on how the fetal/neonatal outcomes may be altered by maternal nutrition at the time of conception, fetal nutrition in utero, contribution of maternal dietary factors in fetal outcomes, weight gain during pregnancy, diabetes during pregnancy, fetal growth restriction (FGR), maternal nutritional status during later pregnancy, and pregnancy in adolescent mothers.

Gastroretentive Metformin Loaded Nanoparticles for the Effective Management of Type-2 Diabetes Mellitus.

INTRODUCTION: Metformin, an anti-diabetic drug, has low bioavailability and short biological half-life. Thus, bioavailability enhancement and prolonged release of the drug are highly desirable. In this regard, we aimed to developed gastroretentive nanoparticles made of jackfruit seed starch (JFSS) loaded with metformin. METHODS: Developed nanoparticles were optimized for various process variables and were further characterized. Nanoparticles exhibited good results with respect to particle size (244.3 to 612.4 nm), particle size distribution, shape and drug entrapment efficiency (75.8 to 89.2%) with sustained drug release for 24 h and a high buoyancy (89% for F7; formulation made of highest concentration of Jackfruit seed starch prepared at 1000 RPM stirring speed). RESULTS: The hypoglycemic potential of these nanoparticles was tested in nicotinamide streptozocin induced diabetic model, there was a significant reduction in blood glucose level (50% reduction from 4-8 h; p < 0.01) for prolonged period of time (up to 24 h) in comparison to diabetic control and plain metformin solution. CONCLUSION: The outcome of the study suggested that developed formulations are suitable for gastro- retentive delivery of Metformin in a controlled manner appropriate for a single administration per day.

Role of functional echocardiographic parameters in the diagnosis of bronchopulmonary dysplasia-associated pulmonary hypertension.

Echocardiogram (echo) is a commonly used noninvasive modality for the diagnosis of bronchopulmonary dysplasia associated pulmonary hypertension (BPD-PH). Though not considered the gold standard for the diagnosis of BPD-PH, it is an extremely valuable tool in the neonatal and pediatric population, especially when cardiac catheterization is not feasible. In addition to the traditional echo parameters that are used to assess the presence of BPD-PH, much attention has been recently placed on newer bedside echo measures, the so-called functional echo parameters, to aid and assist in the diagnosis. This review article provides a brief introduction to BPD-PH, describes the pitfalls of traditional echo parameters and details the newer echo modalities currently available for the diagnosis of neonatal PH.

Genotypic and phenotypic variability of 22q11.2 microdeletions - an institutional experience.

Patients with chromosome 22q11.2 deletion syndromes classically present with variable cardiac defects, parathyroid and thyroid gland hypoplasia, immunodeficiency and velopharyngeal insufficiency, developmental delay, intellectual disability, cognitive impairment, and psychiatric disorders. New technologies including chromosome microarray have identified smaller deletions in the 22q11.2 region. An increasing number of studies have reported patients presenting with various features harboring smaller 22q11.2 deletions, suggesting a need to better elucidate 22q11.2 deletions and their phenotypic contributions so that clinicians may better guide prognosis for families. We identified 16 pediatric patients at our institution harboring various 22q11.2 deletions detected by chromosomal microarray and report their clinical presentations. Findings include various neurodevelopmental delays with the most common one being attention deficit hyperactivity disorder (ADHD), one reported case of infant lethality, four cases of preterm birth, one case with dual diagnoses of 22q11.2 microdeletion and Down syndrome. We examined potential genotypic contributions of the deleted regions.

Loop Diuretics in Infants with Heart Failure.

Tremendous advances have been made in the last 5 decades in the surgical management of congenital heart disease (CHD). Most infants affected by clinically significant CHD are at risk for developing heart failure (HF). Adult HF management is mostly evidence-based and our knowledge in this field has expanded significantly in the past decade. However, data on management approaches for HF in infants are limited. The indications and implications for various medications and interventions in patients with HF secondary to CHD are an upcoming area of interest. It is critical that we expand our ability to prevent, detect, and manage HF in the pediatric population.

Repaglinide and Metformin-Loaded Amberlite Resin-Based Floating Microspheres for the Effective Management of Type 2 Diabetes.

BACKGROUND: Low bioavailability of anti-diabetic drugs results in the partial absorption of the drug as they are mainly absorbed from the stomach and the lower part of the GIT. Drug bioavailability of anti-diabetic drugs can be significantly increased by prolonging gastric retention time through gastro-retentive dosage form such as floating microspheres. OBJECTIVE: The study was aimed to develop and characterize resin based floating microspheres of Repaglinide and Metformin for superior and prolonged maintenance of normoglycaemia in type-2 diabetes mellitus. METHODS: Repaglinide and metformin were complexed with amberlite resin; later resin complexed drug was encapsulated in Ethylcellulose floating microspheres. Floating microspheres were characterized for morphology, particle size, IR spectroscopy, DSC, in vitro release and buoyancy studies. Further, floating microspheres were tested for in vivo blood glucose reduction potential in Streptozocin- induced diabetic mice. RESULTS: Floating microspheres had a spherical shape and slightly rough surface with the entrapment efficiency in a range of 49-78% for metformin and 52-73% for repaglinide. DSC studies revealed that no chemical interaction took place between polymer and drugs. Floating microspheres showed good buoyancy behavior (P<0.05) and prolonged drug release as compared to plain drug (P<0.05). The blood glucose lowering effect of floating microspheres on Streptozocin induced diabetic rats was significantly greater (P<0.05) and prolonged (˃12h) and normoglycaemia was maintained for 6hr. CONCLUSION: Floating microspheres containing drug resin complex were able to prolong drug release in an efficient way for a sustained period of time; as a result, profound therapeutic response was obtained.

99mTc-labelled and pH-awakened microbeads entrapping surface-modified lipid nanoparticles for the augmented effect of oxaliplatin in the therapy of colorectal cancer.

AIM: This study was aimed to develop Eudragit S100-coated, pH-awakened microbeads (MBs) encapsulating folic acid (FA)-modified tristearin solid lipid nanoparticles (SLNs) loaded with oxaliplatin (OP). Afterward, these formulations were evaluated (in vitro and in vivo) for their potential against colorectal cancer (CRC). METHODS: The SLNs were synthesised by employing the solvent diffusion technique and then they were entrapped in the MBs. The prepared uncoupled and coupled SLNs (SLN-OP and FA-SLN-OP, respectively) were examined for in vitro cytotoxicity effect against COLO-205. Gamma-scintigraphy study was used for determining biodistribution (in vivo) of drug in different organs through MBs. RESULTS: Outcomes for FA-SLN-OP revealed more cytotoxicity (50% inhibitory concentration [IC50] = 6.8 µg/ml) against COLO-205 cells (in vitro) than OP solution (IC50 = 8.0 µg/ml) and SLN-OP (IC50= 7.5 µg/ml). MBs were also investigated in vivo using Gamma-scintigraphy study. After 48 h study, 99mTc-EuB-FA-SLN-OP confirmed an elevated level of drug in the colonic tumour, which was found significantly (p< 0.0001) higher than that of 99mTc-EuB-SLN-OP. CONCLUSIONS: In conclusion, developed MBs formulation (99mTc-EuB-FA-SLN-OP) suggested promising results against therapy of CRC using dual targeting (i.e. ligand-directed and pH-awakened) approach.

Targeted inhibition of thrombin attenuates murine neonatal necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is an inflammatory bowel necrosis of premature infants and an orphan disease with no specific treatment. Most patients with confirmed NEC develop moderate-severe thrombocytopenia requiring one or more platelet transfusions. Here we used our neonatal murine model of NEC-related thrombocytopenia to investigate mechanisms of platelet depletion associated with this disease [K. Namachivayam, K. MohanKumar, L. Garg, B. A. Torres, A. Maheshwari, Pediatr. Res. 81, 817-824 (2017)]. In this model, enteral administration of immunogen trinitrobenzene sulfonate (TNBS) in 10-d-old mouse pups produces an acute necrotizing ileocolitis resembling human NEC within 24 h, and these mice developed thrombocytopenia at 12 to 15 h. We hypothesized that platelet activation and depletion occur during intestinal injury following exposure to bacterial products translocated across the damaged mucosa. Surprisingly, platelet activation began in our model 3 h after TNBS administration, antedating mucosal injury or endotoxinemia. Platelet activation was triggered by thrombin, which, in turn, was activated by tissue factor released from intestinal macrophages. Compared to adults, neonatal platelets showed enhanced sensitivity to thrombin due to higher expression of several downstream signaling mediators and the deficiency of endogenous thrombin antagonists. The expression of tissue factor in intestinal macrophages was also unique to the neonate. Targeted inhibition of thrombin by a nanomedicine-based approach was protective without increasing interstitial hemorrhages in the inflamed bowel or other organs. In support of these data, we detected increased circulating tissue factor and thrombin-antithrombin complexes in patients with NEC. Our findings show that platelet activation is an important pathophysiological event and a potential therapeutic target in NEC.

Milrinone Use in Persistent Pulmonary Hypertension of the Newborn.

Failure of the normal transition from in utero to ex utero physiology leads to "persistent" pulmonary hypertension of the newborn (PPHN). PPHN is frequently associated with low systemic blood pressure and low cardiac output because of increased right ventricular afterload and myocardial dysfunction. The general management of newborns with PPHN is geared toward maintenance of normothermia, normal serum electrolytes, normal intravascular volume, correction of acidosis, adequate sedation/analgesia, adequate ventilation and oxygenation with optimal lung recruitment, and avoidance of hyperoxia. Inotropic and vasoactive agents are commonly initiated early to increase cardiac output, maintain adequate systemic blood pressure, and enhance oxygen delivery to the tissue. Unfortunately, there is not much evidence on the choice, timing of initiation, dosing, monitoring, and titrating of vasoactive agents in this patient population. In this review, we will discuss the pathophysiology of PPHN and review the use of inotropic, lusitropic, and vasoactive agents in the management of PPHN, with particular attention to milrinone.

Oral delivery of pH-responsive alginate microbeads incorporating folic acid-grafted solid lipid nanoparticles exhibits enhanced targeting effect against colorectal cancer: A dual-targeted approach.

To achieve an enhanced anticancer effect of drug to treat colorectal cancer, a dual-targeted (i.e., ligand-tailored and pH-triggered) multiparticulate system has been designed to deliver drug directly into the colon domain. In this regard, folic acid-grafted solid lipid nanoparticles (SLNs) bearing irinotecan were encapsulated in microbeads of alginates. Afterward, these microbeads were coated with enteric polymer (i.e., Eudragit S100) to make them pH-responsive. COLO-205 cells were used to determine in vitro cytotoxicity potential of various formulations. Findings for IHT loaded FA-coupled SLNs suggested significantly (p < 0.05) higher cytotoxic effect against COLO-205 cells (in vitro) as compared to drug solution and uncoupled SLNs. Further, the microbeads incorporating SLNs were evaluated for drug release in various simulated gastrointestinal fluids (i.e., pH, 1.2, 4.5, 7.4, and 6.8). Findings confirmed the release of the drug in the intestinal region only (i.e., pH > 7.0). In therapeutic experiments (in vivo), the optimized radiolabeled microbeads (99mTc-EuBIRSLN3 and 99mTc-EuBIRSLNF3) were administered via oral route to Balb/c mice. The results suggested that FA-coupled microbeads (99mTc-EuBIRSLNF3) distributed higher (19.62 ± 0.78%) amount of drug (i.e., 99mTc-IHT/g of tissue) as compared to uncoupled microbeads (99mTc-EuBIRSLN3, 7.63 ± 0.49%) in the colon tumor after 48 h, which confirmed its targeting ability to the tumor in the colon region. Further, 99mTc-EuBIRSLNF3 showed significantly (p < 0.01) higher antitumor effect against HT-29 cells bearing Balb/c mice over uncoupled microbeads and advocated their potential for enhanced antitumor efficacy for the treatment of colorectal cancer.

Urinary NT-proBNP as a potential noninvasive biomarker for screening of pulmonary hypertension in preterm infants: a pilot study.

OBJECTIVE: This pilot study aimed to determine the feasibility of urinary NT-proBNP (NT-proBNP) as a potential noninvasive screening marker for pulmonary hypertension (PH). STUDY DESIGN: A prospective cross-sectional study was conducted. Preterm infants (PI) (birthweight <1500 gm and <30 weeks gestational age (GA)) were enrolled. Serial urinary NT-proBNP measurements and echocardiograms (ECHO) were performed at 28, 32, and 36 weeks. RESULTS: Thirty-six patients were included in the final analysis (BPD-PH group = 6, BPD group = 20, control = 10). Urinary NT-proBNP levels were higher in the BPD-PH group compared with BPD and control groups at all study intervals. A urine NT-proBNP cutoff level of 2345 pg/ml at 28 weeks of GA had a sensitivity and specificity of 83.3% and 84.2%, respectively, for detection of BPD-PH (AUC 0.816, p = 0.022). CONCLUSION: Urinary NT-proBNP measurement is feasible in preterm infants and appears to be a good noninvasive screening tool for PH.

Lyophilization of human amniotic fluid is feasible without affecting biological activity.

BACKGROUND: Fetal swallowing of human amniotic fluid (hAF) containing trophic factors (TFs) promotes gastrointestinal tract (GIT) development. Preterm birth interrupts hAF swallowing, which may increase the risk of necrotizing enterocolitis (NEC). Postnatally, it is difficult to replicate fetal swallowing of hAF due to volume. We aimed to evaluate whether hAF lyophilization is feasible and its effect on hAF-borne TFs. METHODS: We collected hAF (n = 16) from uncomplicated pregnancies. hAF was divided into three groups: unprocessed control (C), concentration by microfiltration (F), and by dialysis and lyophilization (L). EGF, HGF, GM-CSF, and TGF-α were measured in each group by multiplex assay. Bioavailability of TFs was measured by proliferation and LPS-induced IL-8 production by intestinal epithelial cells FHs74. RESULTS: After dialysis/lyophilization, GM-CSF and TGF-α were preserved with partial loss of EGF and HGF. hAF increased cell proliferation and reduced LPS-induced IL-8 production compared to medium alone. Compared to control, dialysis/lyophilization and filtration of hAF increased FHs74 cell proliferation (p < 0.001) and decreased LPS-induced IL-8 production (p < 0.01). CONCLUSIONS: Lyophilization and filtration of hAF is feasible with partial loss of TFs but maintains and even improves bioavailability of TFs measured by proliferation and LPS-induced IL-8 production by FHs74.

Antenatal Magnesium Sulfate Exposure and Hemodynamically Significant Patent Ductus Arteriosus in Premature Infants.

Objective The use of antenatal magnesium sulfate (MgSO 4 ) has been associated with neuroprotective effects. One of its' proposed mechanisms of action includes antagonism of calcium channels. Calcium influx is important for closure of ductus arteriosus. We hypothesized that antenatal MgSO 4 exposure may be associated with an increased risk of hemodynamically significant patent ductus arteriosus (HsPDA) in premature infants (PI). Study Design A prospective cohort study conducted in two parts. PI (< 32 weeks and < 1,500 g) were recruited ( n = 105). All infants had Echocardiograph (ECHO; within 3 days) and blood samples drawn at the same time for B-type natriuretic peptide (BNP; part 1) and NTproBNP (N-terminal pro BNP; part 2) measurements. HsPDA was defined as a PDA diameter > 1.5 mm and BNP levels > 40 pg/mL or NTproBNP > 10,200 pg/mL. Infants were divided into two groups based on antenatal MgSO 4 exposure. Data were analyzed using SPSS 23. Difference in baseline characteristics and antenatal steroid use in the two groups was analyzed. A matched group analysis was performed to adjust for the difference in the numbers between the two groups. A p -value < 0.05 was considered significant. Results There was no significant difference seen in baseline characteristics or use of antenatal steroids in exposed versus unexposed ( n = 95 vs. n = 10). There was a significant negative correlation between antenatal MgSO 4 exposure and HsPDA in PI ( p ≤ 0.05). However, this association was not significant after matched group analysis. Conclusion Antenatal MgSO 4 exposure is not associated with an increased risk of HsPDA. It may be associated with a decreased likelihood of HsPDA.

Irinotecan hydrochloride trihydrate loaded folic acid-tailored solid lipid nanoparticles for targeting colorectal cancer: development, characterization, and in vitro cytotoxicity study using HT-29 cells.

Aim: The aim of this investigation was to evaluate the potential of folic acid-tailored solid lipid nanoparticles (SLNs) for encapsulation as well as for in vitro cytotoxicity study of irinotecan hydrochloride trihydrate (IHT) against colorectal cancer (CRC) by using HT-29 cells. Methods: Solvent diffusion technique was employed for the preparation of SLNs. Further, the formulations were optimised via three-level, three-factor Box-Behnken design (BBD). Results: The uncoupled SLNs (IRSLNs) and folic acid-coupled SLNs (IRSLNFs) formulations revealed not only high %entrapment efficiency but also small particle size. Moreover, in vitro drug release results from IRSLNs and IRSLNFs confirmed that they followed sustained-release effect for up to 144 h. Whereas, in vitro cell viability study against HT-29 cell line suggested significantly (p < 0.05) higher cytotoxicity (IC50 = 15 µg/ml) of IRSLNFs over IRSLNs and IHT solution. Conclusions: Outcomes suggested that the engineered IRSLNFs hold great potential for targeting CRC for an extended period of time.

Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience.

Duplications in the 22q11.2 region can cause 22q11.2 duplication syndrome and encompass a variety of phenotypes including developmental delays, facial abnormalities, cardiovascular defects, central nervous system delays, and other congenital abnormalities. However, the contribution of these contiguous duplicated regions to the clinical phenotypes has not been fully elucidated. In this study, we identified nine patients carrying different 22q11.2 microduplications detected by chromosomal microarray. Of these patients, seven pediatric patients presented with various clinical features including two neonate cases died shortly after birth, and two healthy adults. We examined region specific genotype-phenotype associations and found unpredictability associated with 22q11.2 duplications in these nine patients.