Evolutionary origins of the lysosome-related organelle sorting machinery reveal ancient homology in post-endosome trafficking pathways.

The major organelles of the endomembrane system were in place by the time of the last eukaryotic common ancestor (LECA) (~1.5 billion years ago). Their acquisitions were defining milestones during eukaryogenesis. Comparative cell biology and evolutionary analyses show multiple instances of homology in the protein machinery controlling distinct interorganelle trafficking routes. Resolving these homologous relationships allows us to explore processes underlying the emergence of additional, distinct cellular compartments, infer ancestral states predating LECA, and explore the process of eukaryogenesis itself. Here, we undertake a molecular evolutionary analysis (including providing a transcriptome of the jakobid flagellate Reclinomonas americana), exploring the origins of the machinery responsible for the biogenesis of lysosome-related organelles (LROs), the Biogenesis of LRO Complexes (BLOCs 1,2, and 3). This pathway has been studied only in animals and is not considered a feature of the basic eukaryotic cell plan. We show that this machinery is present across the eukaryotic tree of life and was likely in place prior to LECA, making it an underappreciated facet of eukaryotic cellular organisation. Moreover, we resolve multiple points of ancient homology between all three BLOCs and other post-endosomal retrograde trafficking machinery (BORC, CCZ1 and MON1 proteins, and an unexpected relationship with the "homotypic fusion and vacuole protein sorting" (HOPS) and "Class C core vacuole/endosomal tethering" (CORVET) complexes), offering a mechanistic and evolutionary unification of these trafficking pathways. Overall, this study provides a comprehensive account of the rise of the LROs biogenesis machinery from before the LECA to current eukaryotic diversity, integrating it into the larger mechanistic framework describing endomembrane evolution.

Comparative efficacy of volume expansion, inotropes and vasopressors in preterm neonates with probable transitional circulatory instability in the first week of life: a systematic review and network meta-analysis.

BACKGROUND: There exists limited agreement on the recommendations for the treatment of transitional circulatory instability (TCI) in preterm neonates OBJECTIVE: To compare the efficacy of various interventions used to treat TCI METHODS: Medline and Embase were searched from inception to 21st July 2023. Two authors extracted the data independently. A Bayesian random effects network meta-analysis was used. Recommendations were formulated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework. INTERVENTIONS: Dopamine, dobutamine, epinephrine, hydrocortisone, vasopressin, milrinone, volume and placebo. MAIN OUTCOME MEASURES: Mortality, major brain injury (MBI) (intraventricular haemorrhage > grade 2 or cystic periventricular leukomalacia), necrotising enterocolitis (NEC) ≥stage 2 and treatment response (as defined by the author). RESULTS: 15 Randomized Controlled Trials (RCTs) were included from the 1365 titles and abstracts screened. Clinical benefit or harm could not be ruled out for the critical outcome of mortality. For the outcome of MBI, epinephrine possibly decreased the risk when compared to dobutamine and milrinone (very low certainty). Epinephrine was possibly associated with a lesser risk of NEC when compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Dopamine was possibly associated with a lesser risk of NEC when compared with dobutamine (very low certainty). Vasopressin possibly decreased the risk of NEC compared with dopamine, dobutamine, hydrocortisone and milrinone (very low certainty). Clinical benefit or harm could not be ruled out for the outcome response to treatment. CONCLUSIONS: Epinephrine may be used as the first-line drug in preterm neonates with TCI, the evidence certainty being very low. We suggest future trials evaluating the management of TCI with an emphasis on objective criteria to define it.

Contractile vacuoles: a rapidly expanding (and occasionally diminishing?) understanding.

Osmoregulation is the homeostatic mechanism essential for the survival of organisms in hypoosmotic and hyperosmotic conditions. In freshwater or soil dwelling protists this is frequently achieved through the action of an osmoregulatory organelle, the contractile vacuole. This endomembrane organelle responds to the osmotic challenges and compensates by collecting and expelling the excess water to maintain the cellular osmolarity. As compared with other endomembrane organelles, this organelle is underappreciated and under-studied. Here we review the reported presence or absence of contractile vacuoles across eukaryotic diversity, as well as the observed variability in the structure, function, and molecular machinery of this organelle. Our findings highlight the challenges and opportunities for constructing cellular and evolutionary models for this intriguing organelle.

Caring for the hypertensive newborn: a prospective evaluation of risk factors, clinical profile, management, and predictors of outcome of neonatal hypertension.

With the advancement of neonatal care and routine blood pressure monitoring, neonatal hypertension (NHT) has been increasingly recognised over the past few decades. NHT is known to cause target organ damage and risk of renal dysfunction later in life. However, diagnosis and management of NHT remain challenging, and there is a lack of evidence on the persistence of hypertension beyond the neonatal period and factors predicting its severity. This study aimed to identify risk factors, clinical profiles, predictors of the severity of hypertension, and short-term outcomes of NHT. A cohort of neonates diagnosed with hypertension requiring pharmacotherapy from September 2019 to July 2021 was prospectively enrolled. Demographic data, risk factors, the severity of hypertension, target organ damage, and follow-up for the persistence of hypertension at 3, 6, and 12 months of age were recorded. Of 1682 neonates admitted during this period, 34 had hypertension requiring pharmacotherapy, with a hospital incidence rate of 2%. Of these, 19 (55.9%) were preterm, 14 (41.2%) very low birth weight, and 15 (44.1%) were small for gestational age. Malignant hypertension was seen in 29 (85%) cases, moderate hypertension in 5 (15%) cases, and target organ damage (heart, brain, liver) was seen in 10 (29.4%) cases. On univariate and multivariate regression, an increasing total number of postnatal risk factors was an independent predictor of the occurrence of hypertensive crisis (OR = 3.5, p = 0.04; 95% CI 1.06-11.42). A significant positive correlation (p = 0.004) was observed between total number of postnatal risk factors and the duration of hospital stay. Renal causes of hypertension were identified significantly earlier (day 14 vs. 23, p = 0.01, 95% CI 2.5-17) and had shorter hospital stay (24 vs 45 days, p = 0.002, 95% CI 834). At 3 months follow-up, 7 (20.6%) babies were still requiring antihypertensive therapy, and 1 (3%) required antihypertensives at 6 and 12 months of age.  Conclusion: NHT is a clinically important but underrecognised entity. Hypertension was seen in preterm, low birth weight neonates and associated with certain maternal and postnatal risk factors, with majority responding to a single drug. Neonates with multiple comorbid illnesses need careful monitoring for hypertension as they are at a higher risk of developing hypertensive crisis. Most NHT cases were normotensive at the time of discharge and did not require pharmacotherapy beyond the neonatal period. What is Known: • Neonatal hypertension (NHT) is an under-recognised entity, and the spectrum of clinical presentation varies from asymptomatic to severe target organ damage. • Hypertension is commonly seen in preterm, low birth weight neonates and associated with certain maternal and postnatal risk factor. What is New: • NHT is mostly transient, but intrauterine growth retardation, use of antenatal steroids, renal dysfunction due to congenital anomalies, drugs, and chronic lung disease may lead to the persistence of hypertension beyond the neonatal period. • Neonates with multiple comorbid illnesses need careful monitoring for hypertension as they are at a higher risk of developing hypertensive crisis. Three-fourths of hypertensive neonates respond to a single antihypertensive drug, and only one-fourth of patients required an additional drug to control hypertension. Most neonates respond to short duration of treatment, and only a few patients require long-term therapy.

Comparative Genomics for Evolutionary Cell Biology Using AMOEBAE: Understanding the Golgi and Beyond.

Taking an evolutionary approach to cell biology can yield important new information about how the cell works and how it evolved to do so. This is true of the Golgi apparatus, as it is of all systems within the cell. Comparative genomics is one of the crucial first steps to this line of research, but comes with technical challenges that must be overcome for rigor and robustness. We here introduce AMOEBAE, a workflow for mid-range scale comparative genomic analyses. It allows for customization of parameters, queries, and taxonomic sampling of genomic and transcriptomics data. This protocol article covers the rationale for an evolutionary approach to cell biological study (i.e., when would AMOEBAE be useful), how to use AMOEBAE, and discussion of limitations. It also provides an example dataset, which demonstrates that the Golgi protein AP4 Epsilon is present as the sole retained subunit of the AP4 complex in basidiomycete fungi. AMOEBAE can facilitate comparative genomic studies by balancing reproducibility and speed with user-input and interpretation. It is hoped that AMOEBAE or similar tools will encourage cell biologists to incorporate an evolutionary context into their research.

The Utility of Serial Echocardiography Parameters in Management of Newborns with Congenital Diaphragmatic Hernia (CDH) and Predictors of Mortality.

Ventricular dysfunction may be found in 40% of newborns with CDH, and is not only a predictor of disease severity, but also mortality and need for ECMO. We conducted this study to assess the utility of serial echocardiography in management of newborns with CDH and their survival outcomes. This is a retrospective study, wherein the demographic, clinical and echocardiographic data from our local CDH registry and hospital clinical database were analyzed to study the correlation of timed echocardiographic findings with mortality and other outcomes. Fourty-two newborns with CDH were admitted during the study period (M/F:19/23), with median gestation of 38 weeks (IQR:36-39) and birth weight of 2.83 kg (IQR 2.45-3.17). Thirty-one were left-sided, seven right, one central, and three bilateral hernias. Twelve infants (28%) died in early infancy. Three infants were excluded from analysis due to either palliation at birth or significant cardiac anomaly. A total of 137 echos from 39 infants were analyzed. Seventy percent of newborns who died and had an echo within the first 72 h, were noted to have suffered from moderate to severe PH. Birth weight < 2.8 kg, RVSP > 45.5 in the first 72 h and postoperative VIS > 23.5 and RSS > 4.3 were good predictors of mortality. Markers of elevated pulmonary pressures and cardiac function were useful in guiding therapy. Serial timed functional echocardiography (f-Echo) monitoring allows targeted therapy of patients with CDH. Birth weight, initial severity of pulmonary hypertension and postoperative RSS and VIS may be useful in predicting mortality.

Antenatal Magnesium Sulfate for Preterm Neuroprotection: A Single-Center Experience from Kuwait Tertiary NICU.

Objectives: The study aimed to evaluate the impact of antenatal exposure of magnesium sulfate (MgSO4) on short- and long-term outcomes in preterm neonates born less than 32 weeks gestation. Methods: Single-center retrospective cohort study of 229 neonates born between 24 and 32 weeks gestation was conducted from January 2018 through December 2018 in a level III neonatal care unit in Kuwait. Antenatal MgSO4 exposure was collected from the medical records, and the indication was for neuroprotection effect. Brain MRI was done on 212 neonates (median gestational age 36 weeks), and brain injury was assessed using the Miller's score. Neurodevelopmental outcome was assessed by Bayley-III scales of infant development at 36 months corrected age (N = 146). The association of exposure to MgSO4 with brain injury and neurodevelopmental outcomes was examined using multivariable regression analysis adjusting for gestational age at MRI and variables with p value <0.05 on univariate analysis. Results: Among the 229 neonates, 47 received antenatal MgSO4. There were no differences between the groups in gestational age and birth weight. MgSO4 exposure was not associated with an increased risk of necrotizing enterocolitis, chronic lung disease, retinopathy of prematurity, and mortality. The incidence of cerebellar hemorrhage was significantly less in the MgSO4 group (0% vs. 16%, p value = 0.002). Neonates who received MgSO4 had lower risks of grade 3-4 intraventricular hemorrhage (IVH) adjusted OR 0.248 (95% CI: 0.092, 0.66), p = 0.006; moderate-severe white matter injury (WMI) adjusted odd ratio 0.208 (95% CI: 0.044, 0.96), p = 0.046; and grade 3-4 IVH and/or moderate-severe WMI adjusted OR 0.23 (95% CI: 0.06, 0.84), p = 0.027. Neurodevelopmental assessment at 36 months corrected age showed better motor (adjusted beta coefficient 1.08 [95% CI: 0.099, 2.06]; p = 0.031) and cognitive composite scores (adjusted beta coefficient 1.29 [95% CI: 0.36, 2.22]; p = 0.007) in the MgSO4 group. Conclusion: Antenatal exposure to MgSO4 in preterm neonates less than 32 weeks was independently associated with lower risks of brain injury and better motor and cognitive outcomes.

The role of bedside functional echocardiography in the assessment and management of pulmonary hypertension.

Pulmonary hypertension is an emergency in neonatal intensive care units with high morbidity and mortality. Its timely assessment and management is crucial for intact survival. Over the last couple of decades, there have been significant advances in management and techniques, which have resulted in improved survival. The use of neonatologist-performed echocardiography (NPE) is now increasingly utilized on neonatal intensive care units to understand the pathophysiology of the disease and to direct the treatment to the underlying cause. Its use is now established not only in cases of congenital diaphragmatic hernia and in the newborn with refractory hypoxemia, but also in other conditions such as bronchopulmonary dysplasia and the premature infant with difficulty in oxygenation. The use of NPE, however, requires the availability of trained personnel, equipment, and a close working relationship with pediatric cardiology.

Neurodevelopmental outcomes of infants born to mothers with SARS-CoV-2 infections during pregnancy: a national prospective study in Kuwait.

BACKGROUND: An increasing proportion of women are infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during pregnancy. Intrauterine viral infections induce an increase in the levels of proinflammatory cytokines, which inhibit the proliferation of neuronal precursor cells and stimulate oligodendrocyte cell death, leading to abnormal neurodevelopment. Whether a maternal cytokine storm can affect neonatal brain development is unclear. The objective of the present study was to assess neurodevelopmental outcomes in neonates born to mothers with SARS-CoV-2 infections during pregnancy. METHODS: In this prospective cohort study, the neurodevelopmental status of infants (N = 298) born to women with SARS-CoV-2 infections during pregnancy was assessed at 10-12 months post-discharge using the Ages and Stages Questionnaire, 3rd edition (ASQ-3). The ASQ-3 scores were classified into developmental delays (cutoff scores ≤ 2 standard deviations (SDs) below the population mean) and no delays (scores > 2 SDs above the population mean). RESULTS: The majority (90%) of the infants born to mothers with SARS-CoV-2 infections during pregnancy had favorable outcomes and only 10% showed developmental delays. Two of the 298 infants tested positive for SARS-CoV-2, and both had normal ASQ-3 scores. The majority of the pregnant women had SARS-CoV-2 infections during their third trimester. The risk of developmental delays among infants was higher in those whose mothers had SARS-CoV-2 infections during the first (P = 0.039) and second trimesters (P = 0.001) than in those whose mothers had SARS-CoV-2 infections during the third trimester. CONCLUSION: The neurodevelopmental outcomes of infants born to mothers with SARS-CoV-2 infections seem favorable. However, more studies with larger sample sizes and longer follow-up periods are required.

Multisystemic Inflammatory Syndrome in Neonates: A Systematic Review.

INTRODUCTION: Multisystem inflammatory syndrome in neonates (MIS-N) related to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has increasingly been reported worldwide amid the spread of the SARS-CoV-2 pandemic. METHODS: We searched PubMed, EMBASE, and CINAHL and preprint servers (BioRxiv.org and MedRxiv.org) using a specified strategy integrating Medical Subject Headings terms and keywords until October 20, 2021. Our aim was to systematically review demographic profiles, clinical features, laboratory parameters, complications, treatments, and outcomes of neonates with MIS-N. Studies were selected when fulfilling the inclusion criteria. Articles were included if they fulfilled the World Health Organization (WHO), Centers for Disease Control (CDC) definitions of MIS-C, or our proposed definition. RESULTS: Sixteen reports of MIS-N including 47 neonates meeting MIS-N criteria were identified. Presentation included cardiovascular compromise (77%), respiratory involvement (55%), and fever in (36%). Eighty-three percent of patients received steroids, and 76% received immunoglobulin. Respiratory support was provided to 60% of patients and inotropes to 45% of patients. Five (11%) neonates died. CONCLUSION: The common presentation of MIS-N included cardiorespiratory compromise with the possibility of high mortality. Neonates with MIS-N related to SARS-CoV-2 may be at higher risk of adverse outcomes.

Multisystem inflammatory syndrome in neonates (MIS-N) associated with SARS-CoV2 infection: a case series.

Multisystem inflammatory syndrome in neonates (MIS-N) is hypothesised to be caused either following transplacental transfer of SARS-CoV2 antibodies or antibodies developed in the neonate after infection with SARS-CoV-2. In this paper, we aim to discuss the clinical manifestations, laboratory features, and management of neonates diagnosed with MIS-N. We collated information from five participating hospitals in western India. A cohort of newborn infants presenting with multi-system involvement, along with the presence of SARS-CoV2 antibodies, was identified. Current proposed international diagnostic criteria for MIS-N were used to group the cases into three categories of Most likely, Possible, and Unlikely MIS-N. A total of 20 cases were reported with a diagnosis of MIS-N, all having high titres of SARS CoV2 IgG antibodies and negative for SARS CoV2 antigens. Most likely MIS (n = 5) cases presented with respiratory distress (4/5), hypotension and shock (4/5), and encephalopathy (2/5). Inflammatory markers like CRP (1/5), Procalcitonin (1/5), Ferritin (3/5), D-dimer (4/5), and LDH (2/5) were found to be elevated, and four of them had significantly high levels of proBNP. The majority of them (4/5) responded to immunomodulators, three neonates were discharged home, and two died. Possible MIS infants (n = 9) presented with fever (7/9), respiratory distress (4/9), refusal to feed (6/9), lethargy (5/9), and tachycardia (3/9). ProBNP as a marker of cardiac dysfunction was noted to be elevated in four (4/9) infants, correlating with abnormal echocardiography findings in two. In the Unlikely MIS (n = 6) category, three (3/6) infants presented with respiratory distress, one (1/6) with shock and cardiac dysfunction, and only one (1/6) with fever. All of them had elevated inflammatory markers. However, there were other potential diagnoses that could have been responsible for the clinical scenarios in these six cases.   Conclusion: MIS-N requires a high index of suspicion and should be considered in a neonate presenting with two or more systems involvement, in the presence of SARS-CoV2 antibodies, along with elevated inflammatory markers, once other common neonatal conditions have been ruled out. What is Known: • Severe acute respiratory syndrome coronavirus-2 (SARS-CoV2) associated multisystem inflammatory syndrome in children (MIS-C) is  widely reported in paediatric population, however only few reports of newborn affection. • MIS-C is known to cause by virus-induced post-infective antibody mediated immune dysregulation with severe multi-system affection. What is New: • MIS-N may present with varied clinical manifestations with multi-system involvement of variable severity with milder disease in term and severe disease with cardiac dysfunction in preterm newborns. • Multisystem inflammatory syndrome in newborns (MIS-N) is postulated to occur following immune dysregulation associated with transplacental transfer of SARS-CoV2 antibodies or antibodies developed in the neonate after infection with SARS-CoV-2.

Cardiac structure and function in very preterm-born adolescents compared to term-born controls: A longitudinal cohort study.

BACKGROUND: There is emerging evidence of differences in cardiac structure and function in preterm-born adults and increased risk of heart failure. However, there is a paucity of data in populations who have been exposed to modern intensive care and the impact of perinatal factors is unclear. AIMS: To compare echocardiographic measures of cardiac structure and function in a regional cohort of 17-year-olds born very preterm compared to term-born peers and the influence of perinatal factors. STUDY DESIGN: Observational longitudinal cohort study. SUBJECTS: A regional cohort of ninety-one 17-year-olds born at <32 weeks gestation compared to sixty-two term-born controls. OUTCOME MEASURES: Echocardiographic measures of cardiac structure and function. RESULTS: Left ventricular and right atrial volume and left ventricular mass, indexed to body surface area, were significantly smaller in preterm-born adolescents compared to term-born controls even when adjusted for sex. There were no between group differences in cardiac function. Within those born preterm we found a significant association between gestational age and birthweight z-score and measures of cardiac function at 17 years. Within the preterm group, those with a diagnosis of bronchopulmonary dysplasia had higher left ventricular posterior wall thickness, higher mitral deceleration time and lower left atrial area and tricuspid annular plane of systolic excursion. CONCLUSIONS: Adolescents born very prematurely, who have received modern intensive care, have measurable differences in heart structure compared to their term-born peers but heart function is preserved. For those born preterm, gestational age, birthweight and bronchopulmonary dysplasia are associated with differences in cardiac function.

Less Invasive Surfactant Administration (LISA) vs. Intubation Surfactant Extubation (InSurE) in Preterm Infants with Respiratory Distress Syndrome: A Pilot Randomized Controlled Trial.

OBJECTIVE: There has been an endeavor in recent years, to administer surfactant by minimally invasive techniques to neonates with surfactant deficiency. The objective of this study was to compare the need for intubation and mechanical ventilation after surfactant delivery, using Less Invasive Surfactant Administration (LISA) technique and Intubation SURfactant Extubation (InSurE), in preterm infants with respiratory distress syndrome (RDS). METHODS: We conducted a pilot randomized control trial (RCT) at a tertiary care center over a period of 18 months. Preterm neonates with RDS (gestational age 28-36 weeks) were randomized to receive surfactant within 6 h of birth by InSurE or LISA. The primary outcome was need for intubation and mechanical ventilation within 72 h of birth. Infants were followed until discharge for adverse events and complications. RESULTS: A total of 40 infants were analyzed (20 in each group). There was no difference in the need for intubation and mechanical ventilation within 72 h of birth between the two groups [InSurE, 6 (30%) and LISA, 6 (30%), relative risk 1.0, 95% confidence interval 0.51-1.97]. About 15% of infants in both groups had adverse events during the procedure. There was no statistically significant difference in the rates of major complications or duration of respiratory support, hospital stay and mortality. CONCLUSION: We found LISA to be feasible and equally effective as InSurE for surfactant administration in the treatment of RDS in preterm infants. Future larger RCTs are required to compare the efficacy and long-term outcomes of LISA with the standard invasive methods of surfactant administration.

Description of the marine predator Sericomyxa perlucida gen. et sp. nov., a cultivated representative of the deepest branching lineage of vampyrellid amoebae (Vampyrellida, Rhizaria).

The vampyrellids (Vampyrellida, Rhizaria) are naked amoebae of considerable genetic diversity. Three families have been well-defined (Vampyrellidae, Leptophryidae, and Placopodidae), but most vampyrellid lineages detected by environmental sequencing are poorly known or completely uncharacterized. In the brackish sediment of Lake Bras D'Or, Nova Scotia, Canada, we discovered an amoeba with a vampyrellid-like life history that was morphologically dissimilar from previously known vampyrellid taxa. We established a culture of this amoeba, studied its feeding behavior and prey range specificity, and characterized it with molecular phylogenetic methods and light and electron microscopy. The amoeba was a generalist predator (i.e. eukaryotroph), devouring a range of marine microalgae, with a strong affinity for some benthic diatoms and Chroomonas. Interestingly, the amoeba varied its feeding strategy depending on the prey species. Small diatoms were engulfed whole, while larger species were fed on through extraction with an invading pseudopodium. The SSU rRNA gene phylogenies robustly placed the amoeba in the most basal, poorly described lineage ("clade C") of the Vampyrellida. Based on the phylogenetic position and the distinct morphology of the studied amoeba, we here describe it as Sericomyxa perlucida gen. et sp. nov., and establish the new vampyrellid family Sericomyxidae for "clade C."

Outcomes of Neonates Born to Mothers With Coronavirus Disease 2019 (COVID-19) - National Neonatology Forum (NNF) India COVID-19 Registry.

BACKGROUND: Limited evidence exists on perinatal transmission and outcomes of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in neonates. OBJECTIVE: To describe clinical outcomes and risk factors for transmission in neonates born to mothers with perinatal SARS-CoV-2 infection. DESIGN: Prospective cohort of suspected and confirmed SARS-CoV-2 infected neonates entered in National Neonatology Forum (NNF) of India registry. SUBJECTS: Neonates born to women with SARS-CoV-2 infection within two weeks before or two days after birth and neonates with SARS-CoV-2 infection. OUTCOMES: Incidence and risk factors of perinatal transmission. RESULTS: Among 1713 neonates, SARS-CoV-2 infection status was available for 1330 intramural and 104 extramural neonates. SARS-CoV-2 positivity was reported in 144 intramural and 39 extramural neonates. Perinatal transmission occurred in 106 (8%) and horizontal transmission in 21 (1.5%) intramural neo-nates. Neonates roomed-in with mother had higher transmission risk (RR1.16, 95% CI 1.1 to 2.4; P=0.01). No association was noted with the mode of delivery or type of feeding. The majority of neonates positive for SARS-CoV2 were asymptomatic. Intra-mural SARS-CoV-2 positive neonates were more likely to be symptomatic (RR 5, 95%CI 3.3 to 7.7; P<0.0001) and need resuscitation (RR 2, 95%CI 1.0 to 3.9; P=0.05) compared to SARS-CoV-2 negative neonates. Amongst symptomatic neonates, most morbidities were related to prematurity and perinatal events. CONCLUSIONS: Data from a large cohort suggests perinatal transmission of SARS-CoV-2 infection and increased morbidity in infected infants.

Melatonin for neuroprotection in neonatal encephalopathy: A systematic review & meta-analysis of clinical trials.

OBJECTIVE: Melatonin has shown neuroprotective properties in pre-clinical studies of perinatal asphyxia through antioxidant, anti-apoptotic and anti-inflammatory actions. Studies have also demonstrated its safety and efficacy in neonatal encephalopathy (NE). However, its role in the current era of therapeutic hypothermia (HT) is unclear. The review aims to describe the currently available clinical evidence for Melatonin as a potential therapy for NE. METHODS: Data Sources: We searched Medline, EMBASE, CINAHL, LILACS, and Cochrane central databases, published journals, and conference proceedings from inception to May 31, 2020. STUDY SELECTION: Randomized controlled trials (RCTs) of Melatonin for NE in term or late preterm infants reporting neurodevelopmental outcomes, death, or both. The evidence quality was evaluated using the GRADE system, while the recommendations were taken according to the quality. RESULTS: We included five RCTs involving 215 neonates. Long-term development outcome data is lacking in all except in one small study, reporting significantly higher composite cognition scores at 18 months. One study reported intermediate 6-month favorable development on follow-up. Meta-analysis of mortality in combined HT + Melatonin group vs HT alone (Studies = 2, participants = 54) demonstrated no significant reduction with relative risk (RR) 0.42; 95%CI, 0.99-1.12). The overall GRADE evidence quality was very low for a very small sample size. We did not meta-analyze the data for Melatonin alone therapy without HT, as the included studies were of very low quality. CONCLUSIONS: Despite strong experimental data supporting the role of Melatonin as a neuroprotective agent in NE (both alone and as an adjunct with therapeutic hypothermia), the clinical data supporting the neuroprotective effects in neonates is limited. Larger well designed, adequately powered multicentre clinical trials are urgently needed to define the neuroprotective role of Melatonin in optimizing outcomes of NE.

Reverse-phase chiral high-performance liquid chromatography for separation of a diastereomer in alalevonadifloxacin: A novel antibacterial agent.

Alalevonadifloxacin (ALA) is a novel antibacterial drug, recently launched in India to treat infections caused by Gram-positive bacteria. In present work, a chiral high-performance liquid chromatographic method was developed and validated for the quantification of a diastereomeric impurity (DI) in ALA. The separation was achieved on Pirkle type (R,R) Whelk-O1 chiral stationary phase, using ammonium formate buffer and acetonitrile in gradient fashion at a flow rate of 1.5 ml/min. The method was extensively validated for the quantification of DI in ALA. The detector response for DI was linear over the concentration range of 0.24-4.78 µg/ml. Limit of quantitation and limit of detection for DI were 0.24 and 0.07 µg/ml respectively. The mean recovery of the DI was 103.47 ± 5.14%. The impact of column temperature on the chiral separation was evaluated. The method was employed for controlling diastereomeric impurity in the batches of ALA used in preclinical studies.

Enantiomeric Separation and Thermodynamic Investigation of (R)-N-Tert-Butoxy Carbonyl-Piperidine-3-Carboxylic Acid Hydrazide, a Key Starting Material of Zidebactam.

A new selective, accurate and precise chiral high-performance liquid chromatography method for the separation of (R)-N-tert-butoxy carbonyl-piperidine-3-carboxylic acid hydrazide (RE) and its enantiomer was developed. RE is a key starting material of novel ß-lactam enhancer drug Zidebactam. Chiral resolution of more than 10 was achieved on Chiralpak IA column using mobile phase consisting of n-hexane, ethanol in the ratio of 70:30, v/v. The flow rate of the mobile phase was 1.0 mL min-1 and the column oven temperature was 30°C. Detection was carried out at 225 nm. The developed method was validated as per the International Conference on Harmonization guideline. Limit of detection and limit of quantification of the enantiomeric impurity (S)-N-tert-butoxy carbonyl-piperidine-3-carboxylic acid hydrazide (SE) was 2.5 and 7.5 µg mL-1, respectively. Mean recovery of the SE was 96.83 ± 1.4%. The effect of thermodynamic parameters on the chiral separation was evaluated.