Examination of cord blood at birth in women with SARS-CoV-2 exposure and/or vaccination during pregnancy and relationship to fetal complete blood count, cortisol, ferritin, vitamin D, and CRP.

Background: SARS-CoV-2 is known to manifest a robust innate immune response. However, little is known about inflammatory influences from maternal SARS-CoV-2 infection or maternal mRNA vaccination upon the fetus. In addition, it is unknown if Vitamin D deficiency influences fetal homeostasis or if an anti-inflammatory mechanism to the development of possible innate cytokines or acute phase reactants by the maternal/fetal dyad, in the form of cortisol elevations, occur. In addition, effects on Complete Blood Count (CBC) are not known. Objective: To evaluate the neonatal acute phase reactants and anti-inflammatory responses after maternal SARS-CoV-2 disease or mRNA vaccination. Methods: Samples and medical records reviews from mother/baby dyads (n = 97) were collected consecutively, and were categorized into 4 groups; no SARS-CoV-2 or vaccination exposure (Control), Vaccinated mothers, maternal SARS-CoV-2 disease positive/IgG titer positive fetal blood, and maternal SARS-CoV-2 positive/IgG titer negative fetal blood. SARS-CoV-2 IgG/IgM/IgA titers, CBC, CRP, ferritin, cortisol, and Vitamin D were obtained to examine the possible development of an innate immune response and possible anti-inflammatory response. Student's t-test, Wilcoxon rank-sum, and Chi-squared with Bonferroni corrections were used to compare groups. Multiple imputations were performed for missing data. Results: Cortisol was higher in babies of both mothers who were vaccinated (p = 0.001) and SARS-CoV-2 positive/IgG positive (p = 0.009) as compared to the control group suggesting an attempt to maintain homeostasis in these groups. Measurements of ferritin, CRP, and vitamin D did not reach statistical significance. CBC showed no variation, except for the mean platelet volume (MPV), which was elevated in babies whose mothers were vaccinated (p = 0.003) and SARS-CoV-2 positive/IgG positive (p = 0.007) as compared to the control group. Conclusion: Acute phase reactant elevations were not noted in our neonates. Vitamin D levels were unchanged from homeostatic levels. Cord blood at birth, showed Cortisol and MPV higher in vaccinated and SARS-CoV-2 IgG positive mother/baby dyads as compared to the Control group, indicating that possible anti-inflammatory response was generated. The implication of possible inflammatory events and subsequent cortisol and/or MPV elevation effects upon the fetus after SARS-CoV-2 disease or vaccination is unknown and merits further investigation.

Are preterm birth and very low birth weight rates altered in the early COVID (2020) SARS-CoV-2 era?

Objective: We evaluated the prevalence of preterm birth (PTB) and very low birth weight (VLBW) during Jan-Dec 2,020 (early COVID era) at 5 hospitals (2 in West Virginia, 3 in California) compared to Jan 2017-Dec 2019 (pre-COVID) inclusive of 2 regional perinatal centers (1 in Huntington, WV and 1 in San Jose, CA) and 3 community hospitals (1 each in Cabell, Los Angeles and Santa Clara counties). Design/methods: We examined PTB and VLBW rates of live births at 5 US hospitals from Jan 2017-Dec 2020. We compared PTB and VLBW rates in 2020 to 2017-2019 using Poisson regression and rate ratio with a 95% confidence interval. We stratified live births by gestational age (GA) (<37, 33-36, and <33 weeks) and birth weight (≤1,500 g, >1,001 g to ≤1,500 g, ≤1,000 g). We examined PTB rates at 4 of the hospitals during Jan-Dec 2020 and compared them to the prior period of Jan 2017-Dec 2019 using Statistical Process Control (SPC) for quarterly data. Results: We examined PTB and VLBW rates in 34,599 consecutive live births born Jan 2017-Dec 2019 to rates of 9,691 consecutive live births in 2020. There was no significant change in PTB (<37 weeks GA) rate, 10.6% in 2017-2019 vs. 11.0% in 2020 (p = 0.222). Additionally, there was no significant change when comparing VLBW rates in 2017-2019 to 2020, 1.4% in 2017-2019 vs. 1.5% in 2020 (p = 0.832). Conclusion: We found no significant change in the rates of PTB or VLBW when combining the live birth data of 5 US hospitals in 3 different counties.

The Role of the School Nurse in Detecting and Preventing Child Abuse During This Age of Online Education.

Due to collaborative relationships fostered with school staff and the ability to form long-term trusting relationships with students, school nurses are uniquely situated to address the issue of child abuse detection and prevention in this age of online education brought about by coronavirus disease 2019 (COVID-19). School nurses can and should champion the cause of child safety in their schools, even during school closures through the implementation of key nursing interventions such as staff education on detecting child abuse in online environments. School nurses can also protect children by supporting parents who are dealing with great stressors due to the current global pandemic. Providing resources for families, encouraging parental self-care, educating families about online safety, and encouraging family discussion about child abuse all help to prevent abuse and maltreatment of children. When child abuse goes unreported because of school closures, school nurses can bridge the gap and advocate for detection and prevention in online education.

Identifying Co-Exposure to Opiates and Gabapentin During Pregnancy.

Neonatal withdrawal can be difficult to treat in infants with co-exposure to opiates and gabapentin. Because maternal self-report can underestimate exposures, we evaluated the effect of universal toxicology screening for gabapentin. Identification of co-exposure to opiates and gabapentin increased after implementation of toxicology screening, with implications for improved neonatal care.

Abnormal Presentation of Hypoxic Ischemic Encephalopathy Attributed to Polysubstance Exposure.

BACKGROUND With the increasing prevalence of substance use in pregnancy, the rates of neonatal abstinence syndrome (NAS) are dramatically increasing. There is little information on the use of multiple substances in adults, even less so of polysubstance abuse during pregnancy and the consequences for the fetus as well as the mother. CASE REPORT A newborn male born at 35 weeks presented post-delivery with hips bilaterally dislocated and hyperflexed. The patient's legs fully extended and their shoulders were bilaterally mid-flexed with arms fully extended. This neonate was also reported to have bilateral hearing and vision loss as well as NAS symptoms of high-pitched crying and respiratory distress. During pregnancy the mother in this case study admitted to using buprenorphine, benzodiazepines, gabapentin, and heroin. The consequences of using this combination has not been well studied in pregnancy. CONCLUSIONS The presented case had severe complications, likely due to maternal polysubstance use and poor prenatal care in pregnancy. Clonidine was used to control the NAS symptoms, ranitidine was used to treat the gastroesophageal reflux, and glycopyrronium bromide was used for the neonate's excessive secretions. After delivery, the patient was placed on a nasal noninvasive cannula for respiratory distress and was transferred to a different hospital for treatment of the more serious comorbid conditions.

Functional comparison of induced pluripotent stem cell- and blood-derived GPIIbIIIa deficient platelets.

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application.

Wildfire risk transmission in the Colorado Front Range, USA.

Wildfires are a global phenomenon that in some circumstances can result in human casualties, economic loss, and ecosystem service degradation. In this article we spatially identify wildfire risk transmission pathways and locate the areas of highest exposure of human populations to wildland fires under severe, but not uncommon, weather events. We quantify varying levels of exposure in terms of population potentially affected and tie the exposure back to the spatial source of the risk for the Front Range of Colorado, USA. We use probabilistic fire simulation modeling to address where fire ignitions are most likely to cause the highest impact to human communities, and to explore the role that various landowners play in that transmission of risk. Our results indicated that, given an ignition and the right fire weather conditions, large areas along the Front Range in Colorado could be exposed to wildfires with high potential to impact human populations, and that overall private ignitions have the potential to impact more people than federal ignitions. These results can be used to identify high-priority areas for wildfire risk mitigation using various mitigation tools.

Direct nkx2-5 transcriptional repression of isl1 controls cardiomyocyte subtype identity.

During cardiogenesis, most myocytes arise from cardiac progenitors expressing the transcription factors Isl1 and Nkx2-5. Here, we show that a direct repression of Isl1 by Nkx2-5 is necessary for proper development of the ventricular myocardial lineage. Overexpression of Nkx2-5 in mouse embryonic stem cells (ESCs) delayed specification of cardiac progenitors and inhibited expression of Isl1 and its downstream targets in Isl1(+) precursors. Embryos deficient for Nkx2-5 in the Isl1(+) lineage failed to downregulate Isl1 protein in cardiomyocytes of the heart tube. We demonstrated that Nkx2-5 directly binds to an Isl1 enhancer and represses Isl1 transcriptional activity. Furthermore, we showed that overexpression of Isl1 does not prevent cardiac differentiation of ESCs and in Xenopus laevis embryos. Instead, it leads to enhanced specification of cardiac progenitors, earlier cardiac differentiation, and increased cardiomyocyte number. Functional and molecular characterization of Isl1-overexpressing cardiomyocytes revealed higher beating frequencies in both ESC-derived contracting areas and Xenopus Isl1-gain-of-function hearts, which associated with upregulation of nodal-specific genes and downregulation of transcripts of working myocardium. Immunocytochemistry of cardiomyocyte lineage-specific markers demonstrated a reduction of ventricular cells and an increase of cells expressing the pacemaker channel Hcn4. Finally, optical action potential imaging of single cardiomyocytes combined with pharmacological approaches proved that Isl1 overexpression in ESCs resulted in normally electrophysiologically functional cells, highly enriched in the nodal subtype at the expense of the ventricular lineage. Our findings provide an Isl1/Nkx2-5-mediated mechanism that coordinately regulates the specification of cardiac progenitors toward the different myocardial lineages and ensures proper acquisition of myocyte subtype identity.

Exposure of U.S. National Parks to land use and climate change 1900-2100.

Many protected areas may not be adequately safeguarding biodiversity from human activities on surrounding lands and global change. The magnitude of such change agents and the sensitivity of ecosystems to these agents vary among protected areas. Thus, there is a need to assess vulnerability across networks of protected areas to determine those most at risk and to lay the basis for developing effective adaptation strategies. We conducted an assessment of exposure of U.S. National Parks to climate and land use change and consequences for vegetation communities. We first defined park protected-area centered ecosystems (PACEs) based on ecological principles. We then drew on existing land use, invasive species, climate, and biome data sets and models to quantify exposure of PACEs from 1900 through 2100. Most PACEs experienced substantial change over the 20th century (> 740% average increase in housing density since 1940, 13% of vascular plants are presently nonnative, temperature increase of 1 degree C/100 yr since 1895 in 80% of PACEs), and projections suggest that many of these trends will continue at similar or increasingly greater rates (255% increase in housing density by 2100, temperature increase of 2.5 degrees-4.5 degrees C/100 yr, 30% of PACE areas may lose their current biomes by 2030). In the coming century, housing densities are projected to increase in PACEs at about 82% of the rate of since 1940. The rate of climate warming in the coming century is projected to be 2.5-5.8 times higher than that measured in the past century. Underlying these averages, exposure of individual park PACEs to change agents differ in important ways. For example, parks such as Great Smoky Mountains exhibit high land use and low climate exposure, others such as Great Sand Dunes exhibit low land use and high climate exposure, and a few such as Point Reyes exhibit high exposure on both axes. The cumulative and synergistic effects of such changes in land use, invasives, and climate are expected to dramatically impact ecosystem function and biodiversity in national parks. These results are foundational to developing effective adaptation strategies and suggest policies to better safeguard parks under broad-scale environmental change.

Isogenic human pluripotent stem cell pairs reveal the role of a KCNH2 mutation in long-QT syndrome.

Patient-specific induced pluripotent stem cells (iPSCs) will assist research on genetic cardiac maladies if the disease phenotype is recapitulated in vitro. However, genetic background variations may confound disease traits, especially for disorders with incomplete penetrance, such as long-QT syndromes (LQTS). To study the LQT2-associated c.A2987T (N996I) KCNH2 mutation under genetically defined conditions, we derived iPSCs from a patient carrying this mutation and corrected it. Furthermore, we introduced the same point mutation in human embryonic stem cells (hESCs), generating two genetically distinct isogenic pairs of LQTS and control lines. Correction of the mutation normalized the current (IKr) conducted by the HERG channel and the action potential (AP) duration in iPSC-derived cardiomyocytes (CMs). Introduction of the same mutation reduced IKr and prolonged the AP duration in hESC-derived CMs. Further characterization of N996I-HERG pathogenesis revealed a trafficking defect. Our results demonstrated that the c.A2987T KCNH2 mutation is the primary cause of the LQTS phenotype. Precise genetic modification of pluripotent stem cells provided a physiologically and functionally relevant human cellular context to reveal the pathogenic mechanism underlying this specific disease phenotype.

Shortened night sleep impairs facial responsiveness to emotional stimuli.

Sleep deprivation deteriorates mood, impairs the recognition of facial expressions, and affects the ability to regulate emotions. The present study investigated the effect of partial sleep deprivation on facial responses to emotional stimuli. Thirty-three healthy undergraduates were tested twice: after a night with (i) 8h and (ii) 4h sleep. Self-reported sleepiness and sustained attention (Psychomotor Vigilance Task) were assessed. Emotional reactivity was measured with facial Electromyogram (EMG) while participants were asked to respond with either compatible or incompatible facial muscles to emotional stimuli in order to study whether partial sleep deprivation caused slower reactions mainly in response to incompatible stimuli (due to an additional effort to suppress the compatible reaction caused by decreased inhibitory control) or in response to both compatible and incompatible stimuli. Self-reported sleepiness and reaction times in a sustained attention task significantly increased after one night of partial sleep deprivation. Facial reactions to emotional stimuli were decelerated. No significant interaction between sleep restriction and compatibility of the muscle to the picture valence could be observed. Hence, volitional facial reactions in response to emotional stimuli were slower after one night of reduced sleep, but affective inhibitory control was not significantly impaired. However, slowed facial responding to emotional stimuli may affect social interaction after sleep restriction.

1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines as mGluR2 positive allosteric modulators for the treatment of psychosis.

A novel series of mGluR2 positive allosteric modulators (PAMs), 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidines, is herein disclosed. Structure-activity relationship studies led to potent, selective mGluR2 PAMs with excellent pharmacokinetic profiles. A representative lead compound (+)-17e demonstrated dose-dependent inhibition of methamphetamine-induced hyperactivity and mescaline-induced scratching in mice, providing support for potential efficacy in treating psychosis.

3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization.

The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.

Role of glutaredoxin-mediated protein S-glutathionylation in cellular nitroglycerin tolerance.

We hypothesize that nitroglycerin (NTG) causes direct oxidation of multiple cellular sulfhydryl (SH) proteins and that manipulation of SH redox status affects NTG tolerance. In LLC-PK1 cells, we found that nitrate tolerance, as indicated by cGMP accumulation toward NTG, was accompanied by increased protein [(35)S]cysteine incorporation, significant S-glutathionylation of multiple proteins, and decreased metabolic activity of several SH-sensitive enzymes, including creatine kinase, xanthine oxidoreductase, and glutaredoxin (GRX). Cells overexpressing GRX exhibited reduced cellular protein S-glutathionylation (PSSG) and absence of NTG tolerance, whereas those with silenced GRX showed increased extent of NTG-induced tolerance. Incubation of LLC-PK1 cells with oxidized glutathione led to several major observations associated with nitrate tolerance, namely, reduced cGMP accumulation, PSSG formation, superoxide accumulation, and the attenuation of these events by vitamin C. Aortic S-glutathionylated proteins increased approximately 3-fold in rats made tolerant in vivo to NTG and showed significant negative correlation with vascular responsiveness ex vivo. NTG incubation in EA.hy926 endothelial cells and LLC-PK1 cells led to increased S-glutathionylation and activity of p21(ras), a known mediator of cellular signaling. These results indicate that the hallmark events of NTG tolerance, such as reduced bioactivation and redox signaling, are associated with GRX-dependent protein deglutathionylation.