Trial of Erythropoietin for Hypoxic-Ischemic Encephalopathy in Newborns.

BACKGROUND: Neonatal hypoxic-ischemic encephalopathy is an important cause of death as well as long-term disability in survivors. Erythropoietin has been hypothesized to have neuroprotective effects in infants with hypoxic-ischemic encephalopathy, but its effects on neurodevelopmental outcomes when given in conjunction with therapeutic hypothermia are unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled trial, we assigned 501 infants born at 36 weeks or more of gestation with moderate or severe hypoxic-ischemic encephalopathy to receive erythropoietin or placebo, in conjunction with standard therapeutic hypothermia. Erythropoietin (1000 U per kilogram of body weight) or saline placebo was administered intravenously within 26 hours after birth, as well as at 2, 3, 4, and 7 days of age. The primary outcome was death or neurodevelopmental impairment at 22 to 36 months of age. Neurodevelopmental impairment was defined as cerebral palsy, a Gross Motor Function Classification System level of at least 1 (on a scale of 0 [normal] to 5 [most impaired]), or a cognitive score of less than 90 (which corresponds to 0.67 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: Of 500 infants in the modified intention-to-treat analysis, 257 received erythropoietin and 243 received placebo. The incidence of death or neurodevelopmental impairment was 52.5% in the erythropoietin group and 49.5% in the placebo group (relative risk, 1.03; 95% confidence interval [CI], 0.86 to 1.24; P = 0.74). The mean number of serious adverse events per child was higher in the erythropoietin group than in the placebo group (0.86 vs. 0.67; relative risk, 1.26; 95% CI, 1.01 to 1.57). CONCLUSIONS: The administration of erythropoietin to newborns undergoing therapeutic hypothermia for hypoxic-ischemic encephalopathy did not result in a lower risk of death or neurodevelopmental impairment than placebo and was associated with a higher rate of serious adverse events. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT02811263.).

Safety of High Dose Erythropoietin Used with Therapeutic Hypothermia as Treatment for Newborn Hypoxic-Ischemic Encephalopathy: Secondary Analysis of the HEAL Randomized Controlled Trial.

OBJECTIVE: To assess whether high dose erythropoietin (Epo) treatment of cooled infants with neonatal hypoxic ischemic encephalopathy results in a higher risk of prespecified serious adverse events (SAEs). STUDY DESIGN: Five hundred infants born at ≥36 weeks of gestation with moderate or severe hypoxic ischemic encephalopathy undergoing therapeutic hypothermia were randomized to Epo or placebo on days 1, 2, 3, 4, and 7. Pretreatment and posttreatment SAEs were compared with adjusted generalized linear models, with posttreatment models adjusted for the presence of a pretreatment SAE. Clinical risk factors and potential mechanisms for SAEs were also examined. RESULTS: The rate of experiencing at least one posttreatment SAE did not significantly differ between groups (adjusted relative risk [aRR], 95% CI: 1.17, 0.92-1.49); however, posttreatment thrombosis was identified more often in the Epo group (n = 6, 2.3%) than the placebo group (n = 1, 0.4%; aRR, 95% CI: 5.09, 1.32-19.64). The rate of posttreatment intracranial hemorrhage identified at the treatment sites by either ultrasound or magnetic resonance imaging was slightly elevated in the Epo group (n = 61, 24%) but not significantly different from the placebo group (n = 46, 19%; aRR, 95% CI: 1.21, 0.85, 1.72). CONCLUSIONS: A small increased risk of major thrombotic events was identified in the Epo treatment group. TRIAL REGISTRATION: NCT02811263.

Isolation of Cells from Glioblastoma Multiforme Grade 4 Tumors for Infection with Zika Virus prME and ME Pseudotyped HIV-1.

This study aimed to isolate cells from grade 4 glioblastoma multiforme tumors for infection experiments with Zika virus (ZIKV) prME or ME enveloped HIV-1 pseudotypes. The cells obtained from tumor tissue were successfully cultured in human cerebrospinal fluid (hCSF) or a mixture of hCSF/DMEM in cell culture flasks with polar and hydrophilic surfaces. The isolated tumor cells as well as the U87, U138, and U343 cells tested positive for ZIKV receptors Axl and Integrin αvß5. Pseudotype entry was detected by the expression of firefly luciferase or green fluorescent protein (gfp). In prME and ME pseudotype infections, luciferase expression in U-cell lines was 2.5 to 3.5 logarithms above the background, but still two logarithms lower than in the VSV-G pseudotype control. Infection of single cells was successfully detected in U-cell lines and isolated tumor cells by gfp detection. Even though prME and ME pseudotypes had low infection rates, pseudotypes with ZIKV envelopes are promising candidates for the treatment of glioblastoma.

Development of Zika Virus E Variants for Pseudotyping Retroviral Vectors Targeting Glioblastoma Cells.

A fundamental idea for targeting glioblastoma cells is to exploit the neurotropic properties of Zika virus (ZIKV) through its two outer envelope proteins, prM and E. This study aimed to develop envelope glycoproteins for pseudotyping retroviral vectors that can be used for efficient tumor cell infection. Firstly, the retroviral vector pNLlucAM was packaged using wild-type ZIKV E to generate an E-HIVluc pseudotype. E-HIVluc infection rates for tumor cells were higher than those of normal prME pseudotyped particles and the traditionally used vesicular stomatitis virus G (VSV-G) pseudotypes, indicating that protein E alone was sufficient for the formation of infectious pseudotyped particles. Secondly, two envelope chimeras, E41.1 and E41.2, with the E wild-type transmembrane domain replaced by the gp41 transmembrane and cytoplasmic domains, were constructed; pNLlucAM or pNLgfpAM packaged with E41.1 or E41.2 constructs showed infectivity for tumor cells, with the highest rates observed for E41.2. This envelope construct can be used not only as a tool to further develop oncolytic pseudotyped viruses for therapy, but also as a new research tool to study changes in tumor cells after the transfer of genes that might have therapeutic potential.

Interdisciplinary Approaches to COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has been a significant concern worldwide. The pandemic has demonstrated that public health issues are not merely a health concern but also affect society as a whole. In this chapter, we address the importance of bringing together the world's scientists to find appropriate solutions for controlling and managing the COVID-19 pandemic. Interdisciplinary cooperation, through modern scientific methods, could help to handle the consequences of the pandemic and to avoid the recurrence of future pandemics.

Feasibility and Outcomes Associated With the Use of 2.6-Fr Double-Lumen PICCs in Neonates.

BACKGROUND: Low birth-weight infants' survival continues to improve and there is increased need to provide secure vascular access. This study examines safety of larger peripherally inserted central catheters (PICCs) that offer greater utility. PURPOSE: To determine feasibility of 2.6-French (Fr) double-lumen PICCs in newborns and compare noninfectious complications such as thrombus formation, catheter breakage, infiltration, and accidental dislodgment and central line-associated bloodstream infection (CLABSI) rate with that of newborn infants treated with 1.9-Fr single- and double-lumen PICCs. METHODS: Infants requiring PICCs were admitted in our 69-bed level IV neonatal intensive care unit from September 2006 to May 2015. Two distinct groups were compared: the 1.9-Fr-(single-lumen [n = 105] and double-lumen [n = 27])-and 2.6-Fr double-lumen PICCs (n = 111). Data obtained included birth weight and weight at insertion, gestational age at birth and corrected gestation age at insertion, indication, catheter days, indication for removal, and complications: noninfectious and infectious. Univariate and multivariate statistical analysis evaluated data. RESULTS: There were no differences regarding gestational age at birth and insertion and indications for placement of 2.6-Fr double-lumen (n =111) and 1.9-Fr both single- and double-lumen (n = 132) PICCs. The same was noted between the groups' complications. Noninfectious complications were more common in PICCs with peripheral tip location in all groups. IMPLICATIONS FOR PRACTICE: Consider use of 2.6-Fr PICCs in a neonatal intensive care unit when the utility of blood administration and sampling is required. IMPLICATIONS FOR RESEARCH: Examine line migration and CLABSI associated with sampling and blood administration.

[Focused Abdominal Ultrasound in Emergency, Perioperative and Intensive Care Medicine]. / Abdominelle Notfallsonografie in der Intensiv- und Akutmedizin.

The rising impact of perioperative sonography is mainly based on mobile high quality ultrasound systems. Relevant bleedings or functional limitations of the abdomen are easy to identify with sonography. The FAST-Concept can be the first access to continue proceedings in ultrasound examination of the abdomen. This paper demonstrates some important ultrasound examinations of the abdomen. The clinical main issues are traumatic and atraumatic bleedings of heart, liver and spleen with haemodynamic instability and functional limitations of abdominal organs like bile cystitis, gastrointestinal passage disability and obstructive uropathy. Just outside of the normal working time the ultrasound experts are often not promptly available. The demonstrated techniques allow in acute medicine to make a diagnosis and to decide fast in critical situations. Perspective in view of the many benefits and possibilities, point-of-care ultrasound will be a high-ranking skill in the field of anaesthesia, emergency medicine or intensive care.

Race Effects of Inhaled Nitric Oxide in Preterm Infants: An Individual Participant Data Meta-Analysis.

OBJECTIVE: To assess whether inhaled nitric oxide (iNO) improves survival without bronchopulmonary dysplasia (BPD) for preterm African American infants. STUDY DESIGN: An individual participant data meta-analysis was conducted, including 3 randomized, placebo-controlled trials that enrolled infants born at <34 weeks of gestation receiving respiratory support, had at least 15% (or a minimum of 10 infants in each trial arm) of African American race, and used a starting iNO of >5 parts per million with the intention to treat for 7 days minimum. The primary outcome was a composite of death or BPD. Secondary outcomes included death before discharge, postnatal steroid use, gross pulmonary air leak, pulmonary hemorrhage, measures of respiratory support, and duration of hospital stay. RESULTS: Compared with other races, African American infants had a significant reduction in the composite outcome of death or BPD with iNO treatment: 49% treated vs 63% controls (relative risk, 0.77; 95% CI, 0.65-0.91; P = .003; interaction P = .016). There were no differences between racial groups for death. There was also a significant difference between races (interaction P = .023) of iNO treatment for BPD in survivors, with the greatest effect in African American infants (P = .005). There was no difference between racial groups in the use of postnatal steroids, pulmonary air leak, pulmonary hemorrhage, or other measures of respiratory support. CONCLUSION: iNO therapy should be considered for preterm African American infants at high risk for BPD. iNO to prevent BPD in African Americans may represent an example of a racially customized therapy for infants.

Single-Particle Mobility Edge in a One-Dimensional Quasiperiodic Optical Lattice.

A single-particle mobility edge (SPME) marks a critical energy separating extended from localized states in a quantum system. In one-dimensional systems with uncorrelated disorder, a SPME cannot exist, since all single-particle states localize for arbitrarily weak disorder strengths. However, in a quasiperiodic system, the localization transition can occur at a finite detuning strength and SPMEs become possible. In this Letter, we find experimental evidence for the existence of such a SPME in a one-dimensional quasiperiodic optical lattice. Specifically, we find a regime where extended and localized single-particle states coexist, in good agreement with theoretical simulations, which predict a SPME in this regime.

The Test of Infant Motor Performance at 3 months predicts language, cognitive, and motor outcomes in infants born preterm at 2 years of age.

AIM: To determine the relationship between the Test of Infant Motor Performance (TIMP) at 3 months and cognitive, language, and motor outcomes on the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) at 2 years of age in high-risk infants born preterm. METHOD: One hundred and six infants (47 females, 59 males) born at earlier than 31 weeks gestational age were prospectively tested with the TIMP at 10 to 15 weeks after term age and were assessed again with the Bayley-III at 2 years corrected age. Sensitivity and specificity were calculated for various cut points of the TIMP z-score and Bayley-III composite scores of no more than 85. RESULTS: The TIMP z-scores at 10 to 15 weeks of age were significantly associated with all three subscales on the Bayley-III at 2 years of age (p<0.001). Using a TIMP z-score cutoff of -0.5, specificity was relatively high for cognitive (87%), language (88%), and motor (89%) outcomes, but sensitivity was low (cognitive 41%, language 49%, motor 57%). INTERPRETATION: This study demonstrates that the TIMP is related to cognitive, language, and motor outcomes on the Bayley-III at 2 years of age in high-risk infants born preterm. WHAT THIS PAPER ADDS: The Test of Infant Motor Performance (TIMP) predicts Bayley Scales of Infant and Toddler Development, Third Edition outcomes at 2 years of age. The TIMP is relatively good at discriminating between children who will and will not have typical development.

Emergence of coherence and the dynamics of quantum phase transitions.

The dynamics of quantum phase transitions pose one of the most challenging problems in modern many-body physics. Here, we study a prototypical example in a clean and well-controlled ultracold atom setup by observing the emergence of coherence when crossing the Mott insulator to superfluid quantum phase transition. In the 1D Bose-Hubbard model, we find perfect agreement between experimental observations and numerical simulations for the resulting coherence length. We, thereby, perform a largely certified analog quantum simulation of this strongly correlated system reaching beyond the regime of free quasiparticles. Experimentally, we additionally explore the emergence of coherence in higher dimensions, where no classical simulations are available, as well as for negative temperatures. For intermediate quench velocities, we observe a power-law behavior of the coherence length, reminiscent of the Kibble-Zurek mechanism. However, we find nonuniversal exponents that cannot be captured by this mechanism or any other known model.

Efficacy of inhaled nitric oxide in neonates with hypoxic respiratory failure and pulmonary hypertension: the Japanese experience.

OBJECTIVE: To analyze data from a registry of Japanese neonates with hypoxic respiratory failure associated with pulmonary hypertension (PH) to compare the effectiveness of inhaled nitric oxide (iNO) in neonates born <34 weeks vs. ≥34 weeks gestational age (GA). MATERIALS AND METHODS: iNO was administered according to approved Japanese product labeling. Study data were collected before iNO administration and at predefined intervals until discontinuation. RESULTS: A total of 1,114 neonates were included (n=431, <34 weeks GA; n=675, ≥34 weeks GA; n=8, missing age data). Mean decrease from baseline oxygenation index (OI) was similar in both age groups. OI reduction was more pronounced in the <34 weeks subgroups with baseline OI ≥25. Survival rates were similar in the <34 weeks GA and ≥34 weeks GA groups stratified by baseline OI (OI<15, 89% vs. 93%; 15≤OI<25, 85% vs. 91%; 25≤OI≤40, 73% vs. 79%; OI>40, 64% vs. 66%). CONCLUSION: iNO improved oxygenation in preterm neonates as effectively as in late preterm and term neonates, without negative impact on survival. If clinically significant PH is present, as measured by pulse oximetry or echocardiography, a therapeutic trial of iNO might be indicated for preterm neonates.

Coupling Identical one-dimensional Many-Body Localized Systems.

We experimentally study the effects of coupling one-dimensional many-body localized systems with identical disorder. Using a gas of ultracold fermions in an optical lattice, we artificially prepare an initial charge density wave in an array of 1D tubes with quasirandom on-site disorder and monitor the subsequent dynamics over several thousand tunneling times. We find a strikingly different behavior between many-body localization and Anderson localization. While the noninteracting Anderson case remains localized, in the interacting case any coupling between the tubes leads to a delocalization of the entire system.

Multicenter randomized controlled trial of inhaled nitric oxide for pediatric acute respiratory distress syndrome.

OBJECTIVES: To test the hypothesis that inhaled nitric oxide (iNO) would lead to improved oxygenation and a decrease in duration of mechanical ventilation in pediatric patients with acute respiratory distress syndrome. STUDY DESIGN: A total of 55 children with acute respiratory distress syndrome were enrolled from 9 centers. Patients were randomized to iNO or placebo and remained on the study drug until death, they were free of ventilator support, or day 28 after the initiation of therapy. RESULTS: Mean baseline oxygenation indexes (OIs) were 22.0 ± 18.4 and 25.6 ± 14.9 (iNO and placebo groups, respectively, P = .27). There was a trend toward an improved OI in the iNO group compared with the placebo group at 4 hours that became significant at 12 hours. There was no difference in the OI between groups at 24 hours. Days alive and ventilator free at 28 days was greater in the iNO group, 14.2 ± 8.1 and 9.1 ± 9.5 days (iNO and placebo groups, respectively, P = .05). Although overall survival at 28 days failed to reach statistical significance, 92% (22 of 24) in the iNO group and 72% (21 of 29) in the placebo group (P = .07), the rate of extracorporeal membrane oxygenation-free survival was significantly greater in those randomized to iNO 92% (22 of 24) vs 52% (15 of 29) for those receiving placebo (P < .01). CONCLUSION: The use of iNO was associated with a significantly reduced duration of mechanical ventilation and significantly greater rate of extracorporeal membrane oxygenation-free survival.

Stigma, American military personnel and mental health care: challenges from Iraq and Afghanistan.

BACKGROUND: Since 2001, more than 2.5 million United States military personnel have been deployed for combat. Over one million have served multiple deployments. Combat generally involved repeated exposure to highly traumatic events. Personnel were also victims of military sexual trauma (MST), a major risk factor for psychiatric illness. Most survivors do not seek or receive mental health care. Stigma is one of the main barriers to that care. AIMS: To explore the impact of stigma on personnel with psychiatric illness, and suggest some innovative ways to potentially reduce stigma and improve care. METHODS: Cinahl and PubMed databases were searched from 2001 to 2014. RESULTS: Anonymity, the use of non-stigmatizing language, peer-to-peer, and stigma-reduction programs help military personnel receive mental health care. Technology offers the opportunity for effective and appropriate education and treatment. CONCLUSIONS: Although stigma is formidable, several innovative services are available or being developed for military victims of trauma. Commitment of resources for program development and further research to explore which interventions offer the best clinical outcomes are needed to increase efforts to combat stigma and ensure quality care.

Transduction Efficiency of Zika Virus E Protein Pseudotyped HIV-1gfp and Its Oncolytic Activity Tested in Primary Glioblastoma Cell Cultures.

The development of new tools against glioblastoma multiforme (GBM), the most aggressive and common cancer originating in the brain, remains of utmost importance. Lentiviral vectors (LVs) are among the tools of future concepts, and pseudotyping offers the possibility of tailoring LVs to efficiently transduce and inactivate GBM tumor cells. Zika virus (ZIKV) has a specificity for GBM cells, leaving healthy brain cells unharmed, which makes it a prime candidate for the development of LVs with a ZIKV coat. Here, primary GBM cell cultures were transduced with different LVs encased with ZIKV envelope variants. LVs were generated by using the pNLgfpAM plasmid, which produces the lentiviral, HIV-1-based, core particle with GFP (green fluorescent protein) as a reporter (HIVgfp). Using five different GBM primary cell cultures and three laboratory-adapted GBM cell lines, we showed that ZIKV/HIVgfp achieved a 4-6 times higher transduction efficiency compared to the commonly used VSV/HIVgfp. Transduced GBM cell cultures were monitored over a period of 9 days to identify GFP+ cells to study the oncolytic effect due to ZIKV/HIVgfp entry. Tests of GBM tumor specificity by transduction of GBM tumor and normal brain cells showed a high specificity for GBM cells.

Genetic shift of env V3 loop viral sequences in patients with HIV-associated neurocognitive disorder during antiretroviral therapy.

The development of human immunodeficiency virus type 1 (HIV)-associated neurocognitive disorder (HAND) involves the adaptation of viral sequences coding for the V3 loop of the env protein. The plasma and cerebrospinal fluid (CSF) may contain viral populations from various cellular sources and with differing pathogenicity. Combination antiretroviral therapy (cART) may alter the relative abundance of these viral populations, leading to a genetic shift. We characterized plasma and CNS viral populations prior to and during cART and relate the findings to viral elimination kinetics and the clinical phenotype. Longitudinal plasma and CSF samples of five chronically infected HIV patients, four of whom had HAND, and one seroconverter were analyzed for V3 sequences by RT-PCR and sequence analysis. In the chronically infected patients, pre-cART plasma and CSF viral sequences were different irrespective of viral elimination kinetics and clinical phenotype. cART induced replacement of plasma viral populations in all subjects. CSF viral populations underwent a clear genetic shift in some patients but remained stable in others. This was not dependent on the presence of HAND. The genetic shift of CSF V3 sequences was absent in the two subjects whose CSF viral load initially increased during cART. In one patient, pre- and post-treatment CSF sequences were closely related to the post-treatment plasma sequences, suggesting a common cellular source. We found heterogeneous patterns of genetic compartmentalization and genetic shift over time. Although these did not closely match viral elimination kinetics and clinical phenotype, the results imply different patterns of the dynamics and relative contribution of compartment-specific virus populations in chronic HIV infection.

Clinical prediction models for bronchopulmonary dysplasia: a systematic review and external validation study.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Very different models using clinical parameters at an early postnatal age to predict BPD have been developed with little extensive quantitative validation. The objective of this study is to review and validate clinical prediction models for BPD. METHODS: We searched the main electronic databases and abstracts from annual meetings. The STROBE instrument was used to assess the methodological quality. External validation of the retrieved models was performed using an individual patient dataset of 3229 patients at risk for BPD. Receiver operating characteristic curves were used to assess discrimination for each model by calculating the area under the curve (AUC). Calibration was assessed for the best discriminating models by visually comparing predicted and observed BPD probabilities. RESULTS: We identified 26 clinical prediction models for BPD. Although the STROBE instrument judged the quality from moderate to excellent, only four models utilised external validation and none presented calibration of the predictive value. For 19 prediction models with variables matched to our dataset, the AUCs ranged from 0.50 to 0.76 for the outcome BPD. Only two of the five best discriminating models showed good calibration. CONCLUSIONS: External validation demonstrates that, except for two promising models, most existing clinical prediction models are poor to moderate predictors for BPD. To improve the predictive accuracy and identify preterm infants for future intervention studies aiming to reduce the risk of BPD, additional variables are required. Subsequently, that model should be externally validated using a proper impact analysis before its clinical implementation.