Postnatal cytomegalovirus infection and pulmonary vascular disease in extremely premature infants: A case series.

BACKGROUND: Pulmonary vascular disease (PVD) is a major determinant of both morbidity and mortality in extremely low birth weight infants. It is biologically plausible that postnatal cytomegalovirus (pCMV) infection may lead to PVD in premature infants secondary to pneumonitis or via derangement of pulmonary vascular development directly through endothelial dysfunction. Uncertainty remains, however, regarding thresholds for intervention in premature infants with cardiorespiratory instability and presumed CMV infection likely secondary to the limited understanding of the natural history of the disease. METHODS/RESULTS: We describe four cases of premature infants with clinical and echocardiography features of PVD, in the setting of postnatally acquired CMV. All patients had atypical PVD trajectories, refractory to vasodilator treatment, which improved after initiation of CMV treatment. CONCLUSION: We highlight the need to consider postnatally acquired CMV infection in patients with PVD non-responsive to standard pulmonary vasodilator therapies or disease severity which is out of proportion of the usual clinical trajectory. Treatment of extremely premature infants with CMV-associated PVD may have positive impact on cardiorespiratory health, although duration of therapy remains uncertain.

Impact of early screening echocardiography and targeted PDA treatment on neonatal outcomes in "22-23" week and "24-26" infants.

The hemodynamically significant patent ductus arteriosus (hsPDA) is a controversial topic in neonatology, particularly among neonates at the earliest gestational ages of 22+0-23+6 weeks. There is little, to no data on the natural history or impact of the PDA in extremely preterm babies. In addition, these high-risk patients have typically been excluded from randomized clinical trials of PDA treatment. In this work, we present the impact of early hemodynamic screening (HS) of a cohort of patients born 22+0-23+6 weeks gestation who either were diagnosed with hsPDA or died in the first postnatal week as compared to a historical control (HC) cohort. We also report a comparator population of 24+0-26+6 weeks gestation. All patients in the HS epoch were evaluated between 12-18h postnatal age and treated based on disease physiology whereas the HC patients underwent echocardiography at the discretion of the clinical team. We demonstrate a two-fold reduction in the composite primary outcome of death prior to 36 weeks or severe BPD and report a lower incidence of severe intraventricular hemorrhage (n=5, 7% vs n=27, 27%), necrotizing enterocolitis (n=1, 1% vs n=11, 11%) and first-week vasopressor use (n=7, 11% vs n=40, 39%) in the HS cohort. HS was also associated with an increase in survival free of severe morbidity from the already high rate of 50% to 73% among neonates <24 weeks gestation. We present a biophysiological rationale behind the potential modulator role of hsPDA on these outcomes and review the physiology relevant to neonates born at these extremely preterm gestations. These data highlight the need for further interrogation of the biological impact of hsPDA and impact of early echocardiography directed therapy in infants born less than 24 weeks gestation.

Arterial pressure is not reflective of right ventricular function in neonates with hypoxic ischemic encephalopathy treated with therapeutic hypothermia.

AIM: to evaluate the correlation of recovery of arterial pressure with physiological recovery among patients with hypoxic ischemic encephalopathy undergoing therapeutic hypothermia. METHODS: At 24 h postnatal age, we compared 53 neonates of whom 22 (41%) were inotrope-treated to those untreated with cardiovascular medications. RESULTS: Inotrope-treated patients had persistent severe right ventricular (RV) dysfunction and evidence of abnormal brain tissue oxygen delivery, despite recovered arterial pressure. CONCLUSION: Arterial pressure is not reflective of RV function and the need for inotropic agents may be reflective of abnormal brain tissue oxygen delivery.

How to diagnose and treat acute pulmonary hypertension when you have no cardiology support.

Acute pulmonary hypertension (aPH) is a complex, physiology-driven disorder that causes critical illness in newborns, the hallmark of which is elevated pressure in the pulmonary vascular bed. Several underlying hemodynamic phenotypes exist, including classic arterial aPH with resistance-driven elevations in pulmonary arterial pressure (PAP), alongside flow-driven aPH from left-to-right shunt lesions, and primary left ventricular dysfunction with pulmonary venous hypertension and elevated left atrial pressure. Targeted neonatal echocardiography (TnECHO) is an important tool for evaluation of hemodynamics in aPH and is highly useful for evaluating modulators of disease and targeting cardiovascular therapy. The diagnostic approach to aPH includes confirmation of elevation of PAP, evaluation of the cause and exclusion of structural cardiac disease, assessment of the response of the myocardium to adverse loading conditions, and appraisal of the adequacy of systemic blood flow. Therapeutic goals include support of right ventricular (RV) function, RV afterload reduction, and selection of cardiotropic agents that support underlying pathophysiology without adverse effects on heart rate or pulmonary vascular resistance in addition to routine supportive intensive care. Training programs for TnECHO exist across multiple jurisdictions and strong correlation with pediatric cardiology assessment has been demonstrated. Future directions include adapting TnECHO training with a greater focus on achieving competency, and further research into the role of the modality in providing individualized cardiovascular care for patients with heterogenous underlying physiology, and its effect on key neonatal outcomes.

Management of cardiac dysfunction in neonates with pulmonary hypertension and the role of the ductus arteriosus.

Pulmonary hypertension in the neonate is associated with cardiopulmonary disturbances and neurodevelopment morbidity. The patent ductus arteriosus is a persistent fetal shunt that can be pathologic vs supportive in the setting of neonatal pulmonary hypertension. Understanding the underlying pathophysiology of pulmonary hypertension and the cardiopulmonary effects of various phenotypes can guide management in this vulnerable population. In this narrative, we will summarize the physiologic principles of pulmonary hypertension, the impact of the patent ductus arteriosus on various phenotypes, and the utility of serial targeted neonatal echocardiography to individualize clinical assessment and management.

Association of hemoglobin and spontaneous closure of the ductus arteriosus during the transitional period in very low birth weight infants.

OBJECTIVES: To determine the association between plasma hemoglobin (HB) at three time-points (birth, postnatal days 0-3 and 0-10) and spontaneous closure of the ductus arteriosus (sDAC). STUDY DESIGN: A retrospective case-control study of preterm infants born (2013-2016) between 24 and 29 weeks of gestational age (GA) was conducted in a level three perinatal center in Switzerland. We collected hemoglobin at birth, between days 0-3 and 0-10 in two distinct groups: (i) patients treated for a PDA and (ii) patients with spontaneous closure of the ductus arteriosus (sDAC). Antenatal and postnatal demographic data and neonatal morbidity were collected. Bivariate analysis was performed and a stepwise logistic regression was done to investigate factors associated with sDAC. RESULTS: We reviewed the medical chart of 184 premature infants of whom 146 (79.3%) satisfied eligibility criteria. Of these, 74 (51%) were classified as sDAC. Patients with sDAC were older (GA: 28 vs 27, p < 0.001), more stable (clinical risk index for babies score (CRIB score): 2 vs 5, p < 0.001) and had better clinical outcomes than patients who received treatment for a PDA. Infants in the sDAC group had a higher level of hemoglobin during the first ten postnatal days. Multiple logistic regression analysis revealed that lower HB level (day 0-10) were associated with failure of sDAC (p < 0.05). CONCLUSIONS: This is one of the first studies to highlight a potential association between hemoglobin during the transitional period and sDAC. The biological nature of this observation requires prospective clarification.

Patent ductus arteriosus and cerebral, cardiac, and gut hemodynamics in premature neonates.

Patent ductus arteriosus is associated with multiple comorbidities in premature infants, however a causal link or strategy to decrease these morbidities has not been found. The association between the patent ductus arteriosus and morbidities has biologic plausibility as, like any cardiac mixing lesion, a significant systemic to pulmonic shunt may lead to pulmonary over-circulation and systemic hypoperfusion. Understanding the underlying pathophysiology of associated morbidities in the setting of a patent ductus arteriosus may aid in risk stratifying infants and offer a patient targeted approach to infants with a pathological ductal shunt. While the deleterious impact of increased pulmonary blood flow maybe easier to identify, the impact on end-organ perfusion is more challenging. In this review, we will discuss the pathophysiology of a hemodynamically significant patent ductus arteriosus in premature infants, impact on end-organ perfusion and associated morbidities, and novel modalities to assess shunt volume and effect on end-organ perfusion.

Analysis of the accuracy of actuation electronics in the laser interferometer space antenna pathfinder.

The Laser Interferometer Space Antenna Pathfinder (LPF) main observable, labeled Δg, is the differential force per unit mass acting on the two test masses under free fall conditions after the contribution of all non-gravitational forces has been compensated. At low frequencies, the differential force is compensated by an applied electrostatic actuation force, which then must be subtracted from the measured acceleration to obtain Δg. Any inaccuracy in the actuation force contaminates the residual acceleration. This study investigates the accuracy of the electrostatic actuation system and its impact on the LPF main observable. It is shown that the inaccuracy is mainly caused by the rounding errors in the waveform processing and also by the random error caused by the analog to digital converter random noise in the control loop. Both errors are one order of magnitude smaller than the resolution of the commanded voltages. We developed a simulator based on the LPF design to compute the close-to-reality actuation voltages and, consequently, the resulting actuation forces. The simulator is applied during post-processing the LPF data.

The changing landscape of SARS-CoV-2: Implications for the maternal-infant dyad.

The COVID-19 pandemic represents the greatest challenge to date faced by the medical community in the 21st century. The rate of rapid dissemination, magnitude of viral contagiousness, person to person transmission at an asymptomatic phase of illness pose a unique and dangerous challenge for all patients, including neonatal and obstetric patients. Although scientific understanding of the pathophysiology of the disease, nature of transmission, and efficacy of mitigation strategies is growing, neither a cure or vaccine have been developed. While COVID-19 is primarily a disease of older patients, infection is now seen across all age demographics with reports of illness in pregnant patients and infants. Altered hormone status and predominance of Th-2 immune helper cells may result in increased predisposition to SARS-CoV-2. Case reports of pregnant patients demonstrate a clinical presentation comparable to non-pregnant adults, but evidence of vertical transmission to the fetus is controversial. Neonatal reports demonstrate an inconsistent and non-specific phenotype, and it is often difficult to separate COVID-19 from the underlying conditions of prematurity or bacterial infection. The development of international registries to enable risk profiling of COVID-19 positive pregnant mothers and/or their offspring may facilitate the development of enhanced mitigation strategies, medical treatments and effective vaccinations.

Targeted Neonatal Echocardiography-Guided Therapy in Vein of Galen Aneurysmal Malformation: A Report of Two Cases with a Review of Physiology and Approach to Management.

Vein of Galen malformation results in predictable changes in physiology which exist on a continuum. Severe pulmonary hypertension may present as hypoxemia; however, excessive reduction in pulmonary vascular resistance may precipitate progressive pulmonary overcirculation and impaired systemic blood flow. Right ventricular performance and the patency and direction of the ductus arteriosus may play a crucial role in postductal organ perfusion. Physiological stabilization may be complex and variable over time. The utilization of targeted neonatal echocardiography to guide treatment decisions may improve the ability to provide therapy tailored to the specific disease pathophysiology and monitor serially as conditions change. An enhanced approach to physiological stabilization may reduce the risk of unexpected decompensation and allow for thoughtful, controlled endovascular embolization in appropriate candidates.

Evidence-based use of acetaminophen for hemodynamically significant ductus arteriosus in preterm infants.

While cyclooxygenase inhibitors have been the most common medications used to facilitate earlier closure of patent ductus arteriosus in preterm infants, adverse effects and variable efficacy have highlighted a need for alternative options. Acetaminophen facilitates ductal closure via an alternate pathway of prostaglandin inhibition. Despite treatment with high doses, toxicity is uncommon in preterm infants, possibly due to immature hepatic metabolism. Pooled data from randomized clinical trials of early treatment demonstrate that acetaminophen has similar efficacy as cyclooxygenase inhibitors for PDA closure with a favorable side effect profile and without any apparent increase in adverse neonatal outcomes. Acetaminophen may therefore be an ideal first-line agent among moderately and extremely preterm infants, though there is a paucity of data from controlled trials regarding its use in infants at the border of viability (gestation age ≤25 weeks). Evidence from clinical studies of limited quality supports acetaminophen treatment as rescue therapy for infants with persistent PDA after unsuccessful cyclooxygenase inhibitor treatment, including those being considered for surgical ligation.

Role of neonatologist-performed echocardiography in the assessment and management of patent ductus arteriosus physiology in the newborn.

Neonatologist-performed echocardiography (NPE) is an indispensable tool in the haemodynamic management of critically ill newborn infants. NPE is used to facilitate timely diagnosis of a patent ductus arteriosus (PDA) in preterm infants and to assess its haemodynamic significance. Before treatment is considered, it is obligatory to confirm structural cardiac normality. Importantly, NPE offers the ability to guide therapeutic interventions, allowing an individualised haemodynamic management approach to the PDA. After discussing PDA pathophysiology, an overview is provided on the role of NPE in the assessment and management of PDA in preterm infants.

Synthesis of 3 H, 13 C2 , 2 H414 C-SCH 430765 and 35 S-SCH 500946, potent and selective inhibitors of the NPY5 receptor.

SCH 430765 and SCH 500496 are potent and selective antagonists of the NPY5 receptor. NPY5 receptor antagonists have the potential for the treatment of obesity. [35 S]SCH 500946 was prepared for a competition binding assay which led to the identification of SCH 430765. Three distinct isotopically labelled forms of SCH 430765 were synthesized. [3 H]SCH 430765 was prepared for a preliminary absorption, distribution, metabolism and excretion data evaluation of the compound and [14 C]SCH 430765 for more definitive absorption, distribution, metabolism and excretion data work. In addition, [13 C2 ,2 H4 ]SCH 430765 was prepared as an internal standard for a LC-MS bioanalytical method. The paper discusses the synthesis of 3 isotopically labelled forms of SCH 430765 and [35 S]SCH 500946.

Non-pharmacological management of a hemodynamically significant patent ductus arteriosus.

The association between the patent ductus arteriosus (PDA) and neonatal morbidity, mortality and poor neurodevelopmental outcome in later childhood has been the focus of intense debate for decades. The lack of evidence supporting therapeutic strategies aimed at achieving PDA closure has led to the widespread adoption of conservative management aimed at mitigating the impact of shunt volume without achieving ductal closure. In this article, we review this management approach, describe the supportive evidence and potential complications associated with this strategy.

The newborn rat gastric emptying rate is volume and not developmentally dependent.

BACKGROUND: Gastric residuals are a common finding in enterally fed preterm neonates and traditionally thought to reflect immaturity-related delayed gastric emptying. Adult human data suggest that the meal volume regulate the gastric emptying rate, but early in life, this has not been adequately evaluated. The goal of this study was to study the rat postnatal changes in gastric emptying rate and the strain-induced effect on muscle contraction. We hypothesized that the stomach content volume and not developmental factors determines the newborn gastric emptying rate, via the Rho-kinase 2 (ROCK-2) pathway. METHODS: Gastric volume and emptying rate measurements were obtained by ultrasound at different postprandial times and the wall strain-dependent changes in muscle contraction were evaluated ex vivo. KEY RESULTS: The newborn rat gastric emptying rate was unrelated to postnatal age, maximal 30 min postprandial, and directly proportional to content volume. In vitro measurements showed that the agonist-induced gastric muscle contraction was directly proportional to the stomach wall strain. These changes were mediated via upregulation of ROCK-2 activity. CONCLUSIONS & INFERENCES: The newborn rat gastric emptying rate is not developmentally regulated, but dependent on the content volume via wall strain-induced ROCK-2 activation. Further clinical studies addressing the content volume effect on the rate of gastric emptying are warranted, to enhance feeding tolerance in preterm neonates.

Synthesis of 3 H, 2 H4 , and 14 C-MK 3814 (preladenant).

MK 3814 is a potent and selective antagonist of the A2a receptor. A2a receptor antagonists have the potential for the treatment of Parkinson disease. Three distinct isotopically labelled forms of MK 3814 were synthesized. [3 H]MK 3814 was prepared for a preliminary absorption, distribution, metabolism, and excretion data (ADME) evaluation of the compound and [14 C]MK 3814 for more definitive ADME work, including an absorption, metabolism, and excretion study in man. In addition, [2 H4 ]MK 3814 was prepared as an internal standard for a liquid chromatography mass spectrometry bioanalytical method. This paper discusses the synthesis of 3 isotopically labelled forms of MK 3814.

Weakly acidic pH reduces inflammatory cytokine expression in airway epithelial cells.

BACKGROUND: Aspiration lung disease (ALD) is a common cause of respiratory morbidity in children and adults with severe neurodisability (sND). Recent studies suggest that chronic microaspiration of gastric contents is associated with mild rather than low, airway acidification. We investigated inflammatory responses to infection by airway epithelial cells (AECs) exposed to weakly acidic media. METHODS: Using pH measurements from children with sND at high risk of ALD as a guide, we incubated AECs in weakly acidic (pH5.5-7.4) media alone; in combination with lipopolysaccharide (LPS); or prior to LPS stimulation at normal pH. Interleukin (IL) -6 and IL-8 expression were measured. RESULTS: IL-6/8 expression in AECs simultaneously exposed to weakly acidic media and LPS for 4 h was reduced with no effect on cell viability. Pre-incubation of AECs at weakly acidic pH also reduced subsequent LPS-induced cytokine expression. Suppression of inflammation was greatest at lower pHs (pH 5.5-6.0) for prolonged periods (16/24 h), but this also adversely affected cell viability. CONCLUSION: AEC inflammatory responses to bacterial stimuli is markedly reduced in a mildly acidic environment.

Pyrolysis of wastewater biosolids significantly reduces estrogenicity.

Most wastewater treatment processes are not specifically designed to remove micropollutants. Many micropollutants are hydrophobic so they remain in the biosolids and are discharged to the environment through land-application of biosolids. Micropollutants encompass a broad range of organic chemicals, including estrogenic compounds (natural and synthetic) that reside in the environment, a.k.a. environmental estrogens. Public concern over land application of biosolids stemming from the occurrence of micropollutants hampers the value of biosolids which are important to wastewater treatment plants as a valuable by-product. This research evaluated pyrolysis, the partial decomposition of organic material in an oxygen-deprived system under high temperatures, as a biosolids treatment process that could remove estrogenic compounds from solids while producing a less hormonally active biochar for soil amendment. The estrogenicity, measured in estradiol equivalents (EEQ) by the yeast estrogen screen (YES) assay, of pyrolyzed biosolids was compared to primary and anaerobically digested biosolids. The estrogenic responses from primary solids and anaerobically digested solids were not statistically significantly different, but pyrolysis of anaerobically digested solids resulted in a significant reduction in EEQ; increasing pyrolysis temperature from 100°C to 500°C increased the removal of EEQ with greater than 95% removal occurring at or above 400°C. This research demonstrates that biosolids treatment with pyrolysis would substantially decrease (removal>95%) the estrogens associated with this biosolids product. Thus, pyrolysis of biosolids can be used to produce a valuable soil amendment product, biochar, that minimizes discharge of estrogens to the environment.