Management of Critically Ill Pregnant Patients with COVID-19 Infection in a Rural State.

OBJECTIVE: There is limited data on the treatment of coronavirus disease 2019 (COVID-19) in pregnancy. Arkansas saw an increase in COVID-19 cases in June 2020. The first critically ill pregnant patient was admitted to our institution on May 21st, 2020. The objective of this study was to evaluate outcomes in critically ill pregnant women with COVID-19 at a single tertiary care center who received remdesivir and convalescent plasma (CCP). STUDY DESIGN: This is a retrospective observational review of critically ill pregnant women with COVID-19 who received remdesivir and CCP. This study was approved by the institutional review board (#261354). RESULTS: Seven pregnant patients with COVID-19 were admitted to the intensive care unit (ICU). All received remdesivir and CCP. Six received dexamethasone. The median ICU length of stay (LOS) was 8 days (range 3-17). Patient 1 had multi-organ failure requiring vasopressors, renal dialysis, and had an intrauterine fetal demise. Patients 4 and 6 required mechanical ventilation, were delivered for respiratory distress and were extubated at 2 and 1 days postpartum, respectively. The only common risk factor was obesity. There were no adverse events noted with remdesivir or CCP. CONCLUSION: There is little data regarding the use of remdesivir or CCP for the treatment of COVID-19 in pregnant women. In our cohort, these were well tolerated with no adverse events. Previously reported median ICU LOS in critically ill pregnant women with COVID-19 was 8 days (range 4-15).1 Our study found a similar ICU LOS (8 days; range 3-17). Patient 1 did not receive remdesivir or CCP until transport to our facility on hospital day 3. Excluding patient 1, median ICU LOS was 6.5 days (range 3-9). Our institution's treatment of pregnant women with critical illness with remdesivir, CCP and dexamethasone combined with delivery in select cases has thus far had good outcomes. KEY POINTS: · Combined therapy: remdesivir, CCP, dexamethasone.. · Remdesivir, CCP and dexamethasone was effective in treating critically ill pregnant women with COVID-19.. · No adverse events were associated with combined therapy.. · Delivery improved respiratory status..

Specific mesenchymal/epithelial induction of olfactory receptor, vomeronasal, and gonadotropin-releasing hormone (GnRH) neurons.

We asked whether specific mesenchymal/epithelial (M/E) induction generates olfactory receptor neurons (ORNs), vomeronasal neurons (VRNs), and gonadotropin-releasing hormone (GnRH) neurons, the major neuron classes associated with the olfactory epithelium (OE). To assess specificity of M/E-mediated neurogenesis, we compared the influence of frontonasal mesenchyme on frontonasal epithelium, which becomes the OE, with that of the forelimb bud. Despite differences in position, morphogenetic and cytogenic capacity, both mesenchymal tissues support neurogenesis, expression of several signaling molecules and neurogenic transcription factors in the frontonasal epithelium. Only frontonasal mesenchyme, however, supports OE-specific patterning and activity of a subset of signals and factors associated with OE differentiation. Moreover, only appropriate pairing of frontonasal epithelial and mesenchymal partners yields ORNs, VRNs, and GnRH neurons. Accordingly, the position and molecular identity of specialized frontonasal epithelia and mesenchyme early in gestation and subsequent inductive interactions specify the genesis and differentiation of peripheral chemosensory and neuroendocrine neurons.

Two Epidemics and a Pandemic: The Collision of Prescription Drug Misuse and Racism during COVID-19.

The present study investigated the relationship between perceived racial discrimination and prescription drug misuse (PDM) among Asian, Black, and Latinx Americans during the COVID-19 crisis. U.S. racial/ethnic minorities may have been uniquely affected by two national and one global pandemic: the opioid crisis, racism, and COVID-19. Opioid death rates increased among many groups prior to the pandemic. This country witnessed an increase in racialized acts against people of color across the spectrum in the spring and summer months of the world's COVID-19 outbreak. While studies have shown a clear link between perceived racial discrimination and substance abuse outside of the global pandemic, no identified studies have done so against the backdrop of a global health pandemic. Separate hierarchical regressions revealed a significant association between perceived racial discrimination and PDM for Black Americans, Asian Americans, and Latinx individuals. Findings build on the scant literature on PDM in diverse samples and establish a relationship between perceived racial discrimination and PDM, as previously identified for other abused substances. Future post-pandemic substance misuse interventions should consider the influence of perceived racial discrimination as they help individuals recover from the aftermath of this stressful trifecta.

Development of Coagulation Factor XII Antibodies for Inhibiting Vascular Device-Related Thrombosis.

INTRODUCTION: Vascular devices such as stents, hemodialyzers, and membrane oxygenators can activate blood coagulation and often require the use of systemic anticoagulants to selectively prevent intravascular thrombotic/embolic events or extracorporeal device failure. Coagulation factor (F)XII of the contact activation system has been shown to play an important role in initiating vascular device surface-initiated thrombus formation. As FXII is dispensable for hemostasis, targeting the contact activation system holds promise as a significantly safer strategy than traditional antithrombotics for preventing vascular device-associated thrombosis. OBJECTIVE: Generate and characterize anti-FXII monoclonal antibodies that inhibit FXII activation or activity. METHODS: Monoclonal antibodies against FXII were generated in FXII-deficient mice and evaluated for their binding and anticoagulant properties in purified and plasma systems, in whole blood flow-based assays, and in an in vivo non-human primate model of vascular device-initiated thrombus formation. RESULTS: A FXII antibody screen identified over 400 candidates, which were evaluated in binding studies and clotting assays. One non-inhibitor and six inhibitor antibodies were selected for characterization in functional assays. The most potent inhibitory antibody, 1B2, was found to prolong clotting times, inhibit fibrin generation on collagen under shear, and inhibit platelet deposition and fibrin formation in an extracorporeal membrane oxygenator deployed in a non-human primate. CONCLUSION: Selective contact activation inhibitors hold potential as useful tools for research applications as well as safe and effective inhibitors of vascular device-related thrombosis.

Spontaneous Renal Rupture During Pregnancy: A Contemporary Literature Review and Guide to Management.

IMPORTANCE: Spontaneous renal rupture is a rare pregnancy complication, which requires a high index of suspicion for a timely diagnosis to prevent a poor maternal or fetal outcome. OBJECTIVE: This review highlights risk factors, pathophysiology, symptoms, diagnosis, management, and complications of spontaneous renal rupture in pregnancy. EVIDENCE ACQUISITION: A literature search was carried out by research librarians using the PubMed and Web of Science search engines at 2 universities. Fifty cases of spontaneous renal rupture in pregnancy were identified and are the basis of this review. RESULTS: The first case of spontaneous renal rupture in pregnancy was reported in 1947. Rupture occurs more commonly on the right side and during the third trimester. Pain was a reported symptom in every case reviewed. Treatment usually consists of stent or nephrostomy tube placement. Conservative management has been reported. CONCLUSIONS: When diagnosed early and managed appropriately, maternal and fetal outcomes are favorable. Preterm delivery is the most common complication. RELEVANCE: Our aim is to increase the awareness of spontaneous renal rupture in pregnancy and its associated complications in order to improve an accurate diagnosis and maternal and fetal outcomes.

Progesterone inhibits cytokine/TNF-α production by porcine CL macrophages via the genomic progesterone receptor.

In pigs, luteolytic sensitivity to PGF-2α (=LS) is delayed until d 13 of the estrous cycle. While the control of LS is unknown, it is temporally associated with macrophage (MAC; which secretes tumor necrosis factor [TNF]-α) infiltration into the corpora lutea (CL), and previous studies have shown that TNF-α induces LS in porcine luteal cells (LCs) in culture. This study was designed to explore the control of LS by CL macrophage (CL MAC)/TNF-α by progesterone (P4), and to examine the hypothesis that P4 acting via the genomic P4 receptor (PGR) inhibits CL MAC TNF-α and thus plays a key role in regulating LS during the pig estrous cycle. In experiment 1, the effects of LCs on CL MAC cytokine/TNF-α mRNA expression in co-culture were examined (MID cycle; ~d 7-12; no LS); results showed that LC was inhibitory to cytokine/TNF-α. In experiment 2, the effects of P4 or R5020 (PGR-agonist) on CL MAC cytokine/TNF-α mRNA expression were examined (MID cycle; ~d 7-12; no LS); results showed that both P4 and R5020 dose-dependently inhibited TNF-α. In experiment 3, CL MACs were isolated from CL at MID (~d 7-12; no LS) and LATE (~d 13-18; + LS) cycle, and TNF-α/PGR mRNA measured. Results indicated that while TNF-α mRNA was 4.2-fold greater in CL MACs from LATE vs MID cycle, PGR mRNA was 4.5-fold greater in CL MACs from MID vs LATE cycle. These data support our hypothesis and suggest that progesterone, acting via PGR, plays a critical physiological role in the control of TNF-α production by CL MACs and LS during the pig estrous cycle.

Preclinical tools for the evaluation of tuberculosis treatment regimens for children.

Tuberculosis (TB) treatment regimens have been extrapolated from adults to children. However, pediatric disease merits different treatment strategies to avoid under- or over-treatment. While animal models have been pivotal in identifying effective regimens for adult disease, pediatric TB is heterogeneous and cannot be represented by a single preclinical model. Infants and young children most commonly have disseminated disease or tuberculous meningitis (TBM), school-aged children have paucibacillary disease, and adolescents have adult-like cavitary lung disease. Models simulating these forms of pediatric TB have been developed, but their utility in assessing treatment regimens is in the early stages. Disseminated, intracellular disease can be partly reproduced by an in vitro pharmacodynamic system, TBM by a pediatric rabbit model of TBM, paucibacillary TB by the balbC mouse model, and cavitary disease by a rabbit model and a C3HeB/FeJ mouse model of pulmonary TB. Although there is no one-size-fits-all preclinical 'pediatric TB model', these models can be employed to study drug distribution to the sites of disease and, coupled with translational modeling, used to help select and optimize regimens for testing in children. Use of these models may accelerate the development of regimens for rare or hard-to-treat TB, namely drug-resistant TB and TBM.

Clinical assessment of gastric emptying and sensory function utilizing gamma scintigraphy: Establishment of reference intervals for the liquid and solid components of the Nottingham test meal in healthy subjects.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study presents the reference intervals of the modular "Nottingham test meal" (NTM) for assessment of gastric function by gamma scintigraphy (GSc) in a representative population of healthy volunteers (HVs) stratified for age and sex. METHODS: The NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and an optional solid component (12 solid agar-beads (0 kcal). Filling and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gamma scintigraphy parameters that describe early and late phase Gastric emptying (GE) were calculated from validated models. KEY RESULTS: Gastric emptying (GE) of the liquid component was measured in 73 HVs (male 34; aged 45±20). The NTM produced normal postprandial fullness (VAS ≥30 in 41/74 subjects). Dyspeptic symptoms were rare (VAS ≥30 in 2/74 subjects). Gastric emptying half-time with the Liquid- and Solid-component -NTM was median 44 (95% reference interval 28-78) minutes and 162 (144-193) minutes, respectively. Gastric accommodation was assessed by the ratio of the liquid-NTM retained in the proximal:total stomach and by Early phase emptying assessed by gastric volume after completing the meal (GCV0). No consistent effect of anthropometric measures on GE parameters was present. CONCLUSIONS AND INFERENCES: Reference intervals are presented for GSc measurements of gastric motor and sensory function assessed by the NTM. Studies involving patients are required to determine whether the reference interval range offers optimal diagnostic sensitivity and specificity.

Rapid Drink Challenge in high-resolution manometry: an adjunctive test for detection of esophageal motility disorders.

BACKGROUND/AIMS: The Chicago Classification for diagnosis of esophageal motility disorders by high-resolution manometry (HRM) is based on single water swallows (SWS). Emerging data suggest that a "Rapid Drink Challenge" (RDC) increases sensitivity for motility disorders. This study establishes normal values and diagnostic thresholds for RDC in clinical practice. METHODS: Two cohort studies were performed in patients with dysphagia or reflux symptoms (development and validation sets). Healthy subjects and patient controls provided reference values. Ten SWS and two 200-mL RDC were performed. Primary diagnosis for SWS was established by the Chicago Classification. Abnormal RDC was defined by impaired esophagogastric junction (EGJ) function (elevated integrated relaxation pressure during RDC [IRP-RDC]); incomplete inhibition of contractility during and ineffective contraction after RDC. Diagnostic thresholds identified in the development set were prospectively tested in the validation set. RESULTS: Normal values were determined in healthy (n=95; age 37.8 ± 12) and patient controls (n=44; age 46.4 ± 15). Development and validation sets included 178 (54 ± 17 years) and 226 (53 ± 16 years) patients, respectively. Integrated relaxation pressure during RDC was higher for SWS than RDC in all groups (overall P<.001), except achalasia. Rapid Drink Challenge suppressed contractility, except in achalasia type III, spasm, and hypercontractile motility disorders (P<.001). An effective after-contraction was present more often in health than disease (P<.001). Optimal diagnostic thresholds identified in the development set (IRP-RDC ≥12 mmHg achalasia, IRP-RDC ≥ 8mmHg "all cause" EGJ dysfunction), were confirmed in the validation set (both, sensitivity ~85%, specificity >95%). CONCLUSIONS: Rapid Drink Challenge contributes clinically relevant information to routine HRM studies, especially in patients with EGJ dysfunction.

Limited influence of olanzapine on adult forebrain neural precursors in vitro.

We evaluated the activity of the atypical antipsychotic drug olanzapine on differentiation and gene expression in adult neural precursor cells in vitro. Neural precursors obtained from forebrain subventricular zone (SVZ)-derived neurospheres express a subset (13/24) of receptors known to bind olanzapine at high to intermediate affinities; in contrast, all 24 are expressed in the SVZ. In the presence of 10 nM, 100 nM or 1 microM olanzapine, there is no significant change in the frequency of oligodendrocytes, neurons, GABAergic neurons and astrocytes generated from neurosphere precursors. In parallel, there is no apparent change in cell proliferation in response to olanzapine, based upon bromodeoxyuridine incorporation. There are no major changes in cytological differentiation in response to the drug; however, at one concentration (10 nM) there is a small but statistically significant increase in the size of glial fibrillary acidic protein-labeled astrocytes derived from neurosphere precursors. In addition, olanzapine apparently modulates expression of one serotonin receptor -- 5HT2A -- in differentiating neurosphere cultures; however, it does not modify expression of several other receptors or schizophrenia vulnerability genes. Thus, olanzapine has a limited influence on differentiation and gene expression in adult neural precursor cells in vitro.

Antioxidant and modified atmosphere packaging prevention of discoloration in pork bones during retail display.

The objective of this study was to evaluate the ability of antioxidants to prevent discoloration in pork rib bones. Pork rib bones were removed from carcasses, frozen (-20°C, 24h), split lengthwise, exposed to antioxidant solutions (ascorbic acid, citric acid, propyl gallate or ascorbic/EDTA mix), packaged (modified atmosphere [80% O(2) and 20% CO(2)] or air), then displayed in a retail case at 4°C for 8days. Dark pigment formation was visually evaluated during the display period. Instrumental color was determined at the end of the 8-day display period. Visual bone discoloration increased over time for all treatments. After 2days of display, samples treated with propyl gallate were visually redder, less discolored and less green/black than samples treated with other antioxidants. After 8days of display, propyl gallate-treated samples had higher a* and b* values, as well as chroma (intensity). However, this difference was no longer large enough to be visually detected.

Effect of carbon monoxide and high oxygen modified atmosphere packaging and phosphate enhanced, case-ready pork chops.

The objective of this study was to evaluate the effects of CO-MAP compared to traditional high oxygen MAP (HiOx-MAP) packaging and enhanced with different phosphate on enhanced pork quality. Pork loins were enhanced to 10.5% over initial weight to contain 0.3% salt and 0.4% phosphate (either sodium tripolyphosphate [STP] or a blend of STP and sodium hexametaphosphate) on a finished weight basis. Chops were cut, packaged in atmospheres containing 0.4% CO/30.0% CO(2)/69.6% N(2) (CO-MAP) or 80% O(2)/20% CO(2) (HiOx-MAP), aged in the dark, then placed in a lighted retail display case for 48h. Chops packaged in CO-MAP were redder (higher Minolta a(∗) values) and darker (lower Minolta b(∗) values) than chops packaged in HiOx-MAP. Based on sensory scores, the CO-MAP chops were pinker than the HiOx chops after cooking. CO-MAP chops also experienced less purge loss than chops in HiOx-MAP. Results indicate that CO-MAP had no effect on flavor or consumer acceptability and only minimal effects on other characteristics.

Development and validation of a large, modular test meal with liquid and solid components for assessment of gastric motor and sensory function by non-invasive imaging.

BACKGROUND: Current investigations of stomach function are based on small test meals that do not reliably induce symptoms and analysis techniques that rarely detect clinically relevant dysfunction. This study introduces the large 'Nottingham Test Meal' (NTM) for assessment of gastric motor and sensory function by non-invasive imaging. METHODS: NTM comprises 400 mL liquid nutrient (0.75 kcal/mL) and 12 solid agar-beads (0 kcal) with known breaking strength. Gastric fullness and dyspeptic sensations were documented by 100 mm visual analogue scale (VAS). Gastric emptying (GE) were measured in 24 healthy volunteers (HVs) by gastric scintigraphy (GS) and magnetic resonance imaging (MRI). The contribution of secretion to gastric volume was assessed. Parameters that describe GE were calculated from validated models. Inter-observer agreement and reproducibility were assessed. KEY RESULTS: NTM produced moderate fullness (VAS ≥30) but no more than mild dyspeptic symptoms (VAS <30) in 24 HVs. Stable binding of meal components to labels in gastric conditions was confirmed. Distinct early and late-phase GE were detected by both modalities. Liquid GE half-time was median 49 (95% CI: 36-62) min and 68 (57-71) min for GS and MRI, respectively. Differences between GS and MRI measurements were explained by the contribution of gastric secretion. Breaking strength for agar-beads was 0.8 N/m(2) such that median 25 (8-50) % intact agar-beads and 65 (47-74) % solid material remained at 120 min on MRI and GS, respectively. Good reproducibility for liquid GE parameters was present and GE was not altered by agar-beads. CONCLUSIONS & INFERENCES: The NTM provided an objective assessment of gastric motor and sensory function. The results were reproducible and liquid emptying was not affected by non-nutrient agar-beads. The method is potentially suitable for clinical practice.

The ALK inhibitor PF-06463922 is effective as a single agent in neuroblastoma driven by expression of ALK and MYCN.

The first-in-class inhibitor of ALK, c-MET and ROS1, crizotinib (Xalkori), has shown remarkable clinical efficacy in treatment of ALK-positive non-small cell lung cancer. However, in neuroblastoma, activating mutations in the ALK kinase domain are typically refractory to crizotinib treatment, highlighting the need for more potent inhibitors. The next-generation ALK inhibitor PF-06463922 is predicted to exhibit increased affinity for ALK mutants prevalent in neuroblastoma. We examined PF-06463922 activity in ALK-driven neuroblastoma models in vitro and in vivo In vitro kinase assays and cell-based experiments examining ALK mutations of increasing potency show that PF-06463922 is an effective inhibitor of ALK with greater activity towards ALK neuroblastoma mutants. In contrast to crizotinib, single agent administration of PF-06463922 caused dramatic tumor inhibition in both subcutaneous and orthotopic xenografts as well as a mouse model of high-risk neuroblastoma driven by Th-ALK(F1174L)/MYCN Taken together, our results suggest PF-06463922 is a potent inhibitor of crizotinib-resistant ALK mutations, and highlights an important new treatment option for neuroblastoma patients.

Properties of a goat anti-L antibody: further evidence for heterogeneity of the L antigen.

The preparation and properties of an antibody (anti-L) against low potassium type (LK) goat red cells raised in a high potassium type (HK) goat are described. This reagent stimulated active potassium transport, but showed only weak serological activity against low potassium type (LK) sheep and goat red cells. The results are discussed in relation to the hypothesis that anti-L antibody has two specificities--a sodium pump-stimulating activity (anti-Lp) and a serological activity (anti-L1y).

The effect of sodium periodate treatment on the modulation of the sodium pump in low-potassium type (LK) sheep red cells by the L antigen.

1. The action of sodium periodate and neuraminidase on active and passive K+ transport in low-potassium type (LK) sheep red cells was investigated in relation to the contribution of the Lp and Ll antigens. 2. Active K+ transport in LK sheep red cells was not affected by treatment with sodium periodate (2 mM), or with neuraminidase. 3. Passive K+ transport in LK sheep red cells was increased by sodium periodate treatment in a concentration-dependent manner. The increase was not Cl- dependent, and so differed from the increased passive K+ uptake resulting from N-ethylmaleimide treatment. 4. HK sheep red cells treated with sodium periodate showed small increases in passive K+ uptake, and N-ethylmaleimide treatment used sequentially with sodium periodate resulted in further small increases in passive K+ uptake. 5. In LK sheep red cells the stimulation of active K+ transport by anti-L was impaired by 50% in cells treated with sodium periodate (2 mM) and was slightly lowered in cells treated with neuraminidase. 6. In LK sheep red cells inhibition of passive K+ transport by anti-L was not impaired by sodium periodate treatment (2 mM), or by neuraminidase treatment.

Relationship between cell age, glutathione and cation concentrations in sheep erythrocytes with a normal and a defective transport system for amino acids.

Percoll density gradients were used to separate sheep erythrocytes according to cell age. Erythrocytes with low intracellular levels of glutathione (GSH) caused by an inherited deficiency of the System C amino acid transporter exhibited large age-related decreases in GSH and K+ content. In contrast, there was no age-related loss of intracellular GSH in normal sheep erythrocytes or in sheep erythrocytes with low GSH resulting from a diminished activity of gamma-glutamylcysteine synthetase. Loss of GSH from amino acid transport-deficient erythrocytes was paralleled by the progressive appearance of Heinz bodies in the cells, indicating an increased susceptibility to oxidative damage.

The solubilization of the L and M antigens from sheep red cell membranes.

The Lp, L1 and M antigens from sheep red cells were solubilized using the non-ionic detergent Triton X-100 in the presence of dithiothreitol. Recovery rates were improved when membranes were sonicated at 4 degrees C in the presence of the detergent; values in the range 16-25% (M) and 9-17% (Lp and L1) were achieved for recovery.

Identification of a 25 kDa polypeptide associated with the L antigen in low potassium-type sheep red cells.

Antisera to the L blood group antigen have been used, following radioiodination of low potassium-type sheep red cells and subsequent immunoprecipitation, to identify a polypeptide of the L antigen. Only LK, and not HK, cells express this 25 kDa component which is present in very low copy number.