Pregnancy-related and Neonatal outcomes during Omicron variant-dominant COVID-19 pandemic among the Black-dominant population.

OBJECTIVE: This study aimed to determine the effect of the Omicron variant on pregnancy-related and neonatal outcomes among the Black-dominant population. STUDY DESIGN: We performed a single-center retrospective cohort study during the prepandemic period from December 1, 2019 to February 29, 2020 and the Omicron surging period from December 1, 2021 to February 28, 2022. A total of 518 pregnant women were admitted for delivery during the study periods. Multiple gestations (n=21) and deliveries at less than 20 weeks of gestation (n=5) were excluded. We analyzed and compared the sociodemographic and clinical data from mothers and their neonates between the two cohorts as well as between SARS-CoV-2 positive and negative mothers during the Omicron surge. Subgroup analyses were also conducted specifically among the Black-only population. RESULTS: The cohorts were predominantly Black (88.6%), with smaller proportions of Hispanic (8.9%), Asian (0.8%), White (0.8%), and other ethnicities (0.8%). Of 492 singleton deliveries, 275 live births, 8 (2.8%) stillbirths, and 31 (11.3%) preterm births (PTB) occurred during the prepandemic period, and 207 live births, 2 (1%) stillbirths, and 33 (15.9%) PTB occurred during the Omicron wave. There was no statistically significant difference in the rates of PTB, stillbirths, medically indicated PTB, and cesarean delivery between the two cohorts. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive mothers were not at an increased risk of adverse outcomes. However, Neonatal Intensive Care Unit (NICU) admission rate significantly increased among neonates born to SARS-CoV-2 positive mothers compared with negative mothers (32.3% vs. 16.5%, p=0.038). In subgroup analyses among Black individuals, this difference was not observed. CONCLUSION: There was no significant difference in pregnancy-related or neonatal outcomes in the Black-dominant population between the two cohorts. SARS-CoV-2 infection did not alter these findings except an increased NICU admission rate among neonates born to SARS-CoV-2 positive mothers.

Enhancing the action of serotonin by three different mechanisms prevents spontaneous seizure-induced mortality in Dravet mice.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome. METHODS: Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined. RESULTS: Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex. SIGNIFICANCE: Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.

Autonomous closed-loop mechanistic investigation of molecular electrochemistry via automation.

Electrochemical research often requires stringent combinations of experimental parameters that are demanding to manually locate. Recent advances in automated instrumentation and machine-learning algorithms unlock the possibility for accelerated studies of electrochemical fundamentals via high-throughput, online decision-making. Here we report an autonomous electrochemical platform that implements an adaptive, closed-loop workflow for mechanistic investigation of molecular electrochemistry. As a proof-of-concept, this platform autonomously identifies and investigates an EC mechanism, an interfacial electron transfer (E step) followed by a solution reaction (C step), for cobalt tetraphenylporphyrin exposed to a library of organohalide electrophiles. The generally applicable workflow accurately discerns the EC mechanism's presence amid negative controls and outliers, adaptively designs desired experimental conditions, and quantitatively extracts kinetic information of the C step spanning over 7 orders of magnitude, from which mechanistic insights into oxidative addition pathways are gained. This work opens opportunities for autonomous mechanistic discoveries in self-driving electrochemistry laboratories without manual intervention.

Interrogating the Mechanistic Features of Ni(I)-Mediated Aryl Iodide Oxidative Addition Using Electroanalytical and Statistical Modeling Techniques.

While the oxidative addition of Ni(I) to aryl iodides has been commonly proposed in catalytic methods, an in-depth mechanistic understanding of this fundamental process is still lacking. Herein, we describe a detailed mechanistic study of the oxidative addition process using electroanalytical and statistical modeling techniques. Electroanalytical techniques allowed rapid measurement of the oxidative addition rates for a diverse set of aryl iodide substrates and four classes of catalytically relevant complexes (Ni(MeBPy), Ni(MePhen), Ni(Terpy), and Ni(BPP)). With >200 experimental rate measurements, we were able to identify essential electronic and steric factors impacting the rate of oxidative addition through multivariate linear regression models. This has led to a classification of oxidative addition mechanisms, either through a three-center concerted or halogen-atom abstraction pathway based on the ligand type. A global heat map of predicted oxidative addition rates was created and shown applicable to a better understanding of the reaction outcome in a case study of a Ni-catalyzed coupling reaction.

Induction of antigen-specific tolerance by hepatic AAV immunotherapy regardless of T cell epitope usage or mouse strain background.

In vivo induction of antigen (Ag)-specific regulatory T cells (Treg) is considered the holy grail of therapeutic strategies for restoring tolerance in autoimmunity. Unfortunately, in the autoimmune disease multiple sclerosis, an effective and durable therapy targeting the diverse repertoire of emerging Ags without compromising the patient's natural immunity has remained elusive. To address this deficiency, we have developed an Ag-specific adeno-associated virus (AAV) immunotherapy that will restore tolerance in a Treg-dependent manner. Using multiple strains of mice with different genetic and immunological backgrounds, we demonstrate that a liver directed AAV vector expressing a single transgene can prevent experimental autoimmune encephalomyelitis from developing and effectively mitigate pre-existing or established disease that was induced by one or more auto-reactive myelin oligodendrocyte glycoprotein-derived peptides. Overall, the results suggests that AAV can efficiently restore Ag-specific immune tolerance to an immunogenic protein that is neither restricted by the major histocompatibility complex haplotype, nor by the specific antigenic epitope(s) presented. These findings may pave the way for developing a comprehensive Ag-specific immunotherapy that does not require prior knowledge of the specific immunogenic epitopes and that may prove to be universally applicable to all MS patients, and adaptable for other autoimmune diseases.

Identification and characterization of a novel peptide from rainbow trout (Oncorhynchus mykiss) with antimicrobial activity against Streptococcus iniae.

The overuse and misuse of antibiotics has led to the emergence of antibiotic-resistant bacterial species which remain a challenge to treat therapeutically. Novel and efficacious drugs are desperately needed to combat pathogens. One method to facilitate these discoveries is the use of in silico methods. Computational biology has the power to scan large data sets and screen for potential molecules with antibacterial function. In the current study, an in silico approach was used to identify an antimicrobial peptide (AMP) derived from rainbow trout von Willebrand Factor. The AMP was tested against a panel of aquatic bacterial pathogens and was found to possess antibacterial activity against Streptococcus iniae (S. iniae). Since S. iniae is a zoonotic pathogen, this may be useful in other species as well. The peptide was non-hemolytic and non-cytotoxic at the concentrations tested in rainbow trout cells. Pre-treatment of rainbow trout cells with the peptide did not result in an upregulation of immune genes but stimulating the rainbow trout macrophage/monocyte-like cell line, RTS11, with heat-killed S. iniae, did result in a significant upregulation of the tumor necrosis factor alpha (tnfa) gene. In this study, a new AMP has been identified but its expression, synthesis and role in vivo remains unknown. Nevertheless, the findings presented improve our understanding of fish gill and macrophage responses towards this important zoonotic pathogen.

Genistein, a Natural Isoflavone, Alleviates Seizure-Induced Respiratory Arrest in DBA/1 Mice.

Objective: Sudden unexpected death in epilepsy (SUDEP) is a fatal event that ranks second in years of potential life lost among neurological disorders. Seizure-induced respiratory arrest (S-IRA) is the primary instigator leading to death in many SUDEP cases. However, there are currently no effective preventive strategies against S-IRA other than the seizure control. Therefore, it is critical to develop new avenues to prevent SUDEP by investigating the pharmacological interventions of S-IRA. In the present study, we examined the effect of genistein, an isoflavone found in various dietary vegetables, on the incidence of S-IRA in DBA/1 mice. Methods: DBA/1 mice exhibited generalized seizures and S-IRA when subjected to acoustic stimulation. Genistein was intraperitoneally administered alone or in combination with an adrenoceptor antagonist and a serotonin (5-HT) receptor antagonist, respectively. The effects of drug treatments on S-IRA incidence and seizure behaviors were examined. Results: The incidence of S-IRA in DBA/1 mice was significantly reduced 2 h after injection of genistein at 1-90 mg/kg as compared with that in the vehicle control. Genistein could block S-IRA without interfering with any component of seizures, especially at relatively lower dosages. The S-IRA-suppressing effect of genistein was reversed by an α2 adrenoceptor antagonist but was not altered by an α1 antagonist. The inhibitory effect of genistein on S-IRA was not affected by a 5-HT3 or 5-HT2A receptor antagonist. Significance: Our data show that genistein reduces S-IRA incidence and can specifically block S-IRA in DBA/1 mice. Its suppressing effect on S-IRA is dependent on activating α2 adrenoceptors. Our study suggests that genistein, a dietary supplement, is potentially useful to prevent SUDEP in at-risk patients.

AXIOME3: Automation, eXtension, and Integration Of Microbial Ecology.

BACKGROUND: Advances in high-throughput sequencing accessibility have democratized small subunit ribosomal RNA gene sequence data collection, coincident with an increasing availability of computational tools for sequence data processing, multivariate statistics, and data visualization. However, existing tools often require programming ability and frequent user intervention that may not be suitable for fast-paced and large-scale data analysis by end user microbiologists who are unfamiliar with the Linux command line environment or who prefer interactions with a GUI. Here we present AXIOME3, which is a completely redeveloped AXIOME pipeline that streamlines small subunit ribosomal RNA data analysis by managing QIIME2, R, and Python-associated analyses through an interactive web interface. FINDINGS: AXIOME3 comes with web GUI to improve usability by simplifying configuration processes and task status tracking. Internally, it uses an automated pipeline that is wrapped around QIIME2 to generate a range of outputs including amplicon sequence variant tables, taxonomic classifications, phylogenetic trees, biodiversity metrics, and ordinations. The extension module for AXIOME3 provides advanced data visualization tools such as principal coordinate analysis, bubble plots, and triplot ordinations that can be used to visualize interactions between a distance matrix, amplicon sequence variant taxonomy, and sample metadata. CONCLUSIONS: Because repeat analysis of small subunit ribosomal RNA amplicon sequence data is challenging for those who have limited experience in command line environments, AXIOME3 now offers rapid and user-friendly options within an automated pipeline, with advanced data visualization tools and the ability for users to incorporate additional analyses easily through extension. AXIOME3 is completely open source (https://github.com/neufeld/AXIOME3, https://github.com/neufeld/AXIOME3-GUI), and researchers are encouraged to modify and redistribute the package.

EpigenCentral: Portal for DNA methylation data analysis and classification in rare diseases.

Epigenetic processes play a key role in regulating gene expression. Genetic variants that disrupt chromatin-modifying proteins are associated with a broad range of diseases, some of which have specific epigenetic patterns, such as aberrant DNA methylation (DNAm), which may be used as disease biomarkers. While much of the epigenetic research has focused on cancer, there is a paucity of resources devoted to neurodevelopmental disorders (NDDs), which include autism spectrum disorder and many rare, clinically overlapping syndromes. To address this challenge, we created EpigenCentral, a free web resource for biomedical researchers, molecular diagnostic laboratories, and clinical practitioners to perform the interactive classification and analysis of DNAm data related to NDDs. It allows users to search for known disease-associated patterns in their DNAm data, classify genetic variants as pathogenic or benign to assist in molecular diagnostics, or analyze patterns of differential methylation in their data through a simple web form. EpigenCentral is freely available at http://epigen.ccm.sickkids.ca/.

Catastrophic catecholamine-induced cardiomyopathy rescued by extracorporeal membrane oxygenation in recurrent malignant pheochromocytoma.

Pheochromocytoma (PCC) is a rare catecholamine-producing tumor with the incidence in hypertension of 0.1-0.6%. PCC crisis is an endocrine emergency that can lead to hemodynamic disturbance and organ failure such as catecholamine-induced cardiomyopathy. The circulatory collapse caused by it often requires mechanical support. The author reports an unusual case in which a patient who previously underwent surgery for malignant PCC developed catecholamine-induced cardiomyopathy, and successfully recovered using extracorporeal membrane oxygenation.

Serial measurements of neutrophil gelatinase-associated lipocalin: prognostic value in patients with ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention.

BACKGROUND: There are no previous data on serial changes in neutrophil gelatinase-associated lipocalin (NGAL) levels in ST-segment elevation myocardial infarction (STEMI) patients before and after a primary percutaneous coronary intervention (pPCI). The aim of the present study was to evaluate the prognostic value of serial NGAL measurements in patients with STEMI treated by pPCI. MATERIALS AND METHODS: We identified 169 STEMI patients who underwent pPCI within 12 h of symptom onset and had plasma NGAL measurements before (pre-NGAL) and 6 h after (post-NGAL) pPCI. The primary endpoint was 30-day all-cause mortality, including cardiac death, whereas the secondary endpoint was the change in NGAL levels from before to after pPCI. RESULTS: The mean pre-NGAL and post-NGAL levels were 109.2±76.1 and 93.3±83.8 ng/ml, respectively. Thirty-day mortality occurred in 12 (7.1%) patients. In terms of changes in serial NGAL levels, post-NGAL levels were decreased in 132 (79%) patients. Patients with elevated post-NGAL levels showed increased mortality compared with patients with decreased post-NGAL levels (P=0.005). Multivariate analyses indicated that old age and high post-NGAL levels were independent risk factors for 30-day mortality. CONCLUSION: In a large percentage of STEMI patients, plasma post-pPCI NGAL levels were decreased compared with pre-pPCI NGAL levels, even with the administration of potentially nephrotoxic contrast medium. Post-NGAL levels seemed to be superior to pre-NGAL levels for the prediction of 30-day mortality outcome.

A case of a resected benign myxoma-like hemorrhagic cyst, which later recurred as undifferentiated pleomorphic sarcoma in the left atrium.

RATIONALE: An intracardiac cystic mass is a rare type of mass found in the left atrium. The differential diagnosis of an intracardiac cystic mass includes hydatid cysts, bronchogenic cysts, intracardiac varices, and hemorrhages in some tumor types, including myxoma. PATIENT CONCERNS: We present the case of a 68-year-old woman who presented with episodic dyspnea. DIAGNOSES-INTERVENTIONS-OUTCOMES: Transthoracic echocardiography (TTE) revealed the presence of a left atrial mass mimicking myxoma. However, in postoperative findings, it was determined that the mass was actually a hemorrhagic cyst. Eighteen months later, the patient presented with recurrent exertional dyspnea and TTE revealed the recurrence of a left atrial mass. Computed tomography showed that the mass extended into the right atrium, inferior vena cava, and coronary sinus. After re-operation, the final histological diagnosis was determined to be an undifferentiated pleomorphic sarcoma in the left atrium. LESSONS: An intracardiac hemorrhagic cyst was suspected during the operation of a benign-looking LA mass. As such, we recommend that other rare etiologies be considered and more biopsies be performed when possible.

Computed Tomography Diagnosis of Nonspecific Acute Chest Pain in the Emergency Department: From Typical Acute Coronary Syndrome to Various Unusual Mimics.

It is a challenging task for emergency department physicians to establish a precise and rapid diagnosis based only on clinical and laboratory findings in patients who present with nonspecific acute chest pain. In this circumstance, CT angiography can provide important clues to the diagnosis. To provide a rapid diagnosis of acute coronary syndrome (ACS) and its various mimics, the physician should enumerate each possible cause of acute chest pain on the basis of an objective assessment of pretest probability. On the basis of clinical suspicion, the appropriate CT protocol should then be performed. Moreover, radiologists should be familiar with typical CT findings of ACS and its various mimics to assist the emergency department physician in diagnosing patients with nonspecific acute chest pain. This review article presents an overview on choosing an appropriate CT protocol in patients with nonspecific acute chest pain and provides specific CT findings of ACS and various mimics of ACS.

Comprehensive metabolic profiles of mulberry fruit (Morus alba Linnaeus) according to maturation stage.

In this study, comprehensive metabolic profiles of mulberry fruits (Morus alba Linnaeus) at various maturation stages were determined using GC-MS and HPLC. In total, 48 compounds, including 3 alcohols, 16 amino acids, 7 organic acids, 2 sugars, 4 phenolics, 2 terpenes, 3 vitamins, 9 fatty acids, and 2 cyanidins were identified in the mulberry samples. Levels of chlorogenic acid, cryptochlorogenic acid, neochlorogenic acid, ascorbic acid, and δ-tocopherol, and total fatty acid content were significantly higher in the semi-matured mulberry fruits. Furthermore, levels of glycerol, citrate, fructose, glucose, 3-O-glucoside, and cyanidin-3-O-rutinoside were significantly higher at the fully matured stage than at the other stages. Twelve biosynthetic pathways were suggested as major pathways involved in mulberry fruit maturation. The information obtained in this study will provide a basis for future investigations toward quality control or metabolic engineering for development of mulberry fruits possessing commercially valuable characteristics.

A case of catamenial hemoptysis treated by bronchial artery embolization.

Catamenial hemoptysis is a rare condition, characterized by recurrent hemoptysis associated with the presence of intrapulmonary or endobronchial endometrial tissue. Therapeutic strategies proposed for intrapulmonary endometriosis with catamenial hemoptysis consist of medical treatments and surgery. Bronchial artery embolization is a well-established modality in the management of massive or recurrent hemoptysis, but has seldom been used for the treatment of catamenial hemoptysis. We report a case of catamenial hemoptysis associated with pulmonary parenchymal endometriosis, which was successfully treated by a bronchial artery embolization.

A case of pulmonary artery sarcoma presented as cavitary pulmonary lesions.

Pulmonary artery sarcoma (PAS) is a rare, poorly differentiated malignancy arising from the intimal layer of the pulmonary artery. Contrast-enhanced chest computed tomography (CT) is a good diagnostic modality that shows a low-attenuation filling defect of the pulmonary artery in PAS patients. An 18-year-old man was referred to our hospital for the evaluation and management of cavitary pulmonary lesions that did not respond to treatment. A contrast-enhanced CT of the chest was performed, which showed a filling defect within the right interlobar pulmonary artery. The patient underwent a curative right pneumonectomy after confirmation of PAS. Although lung parenchymal lesions of PAS are generally nonspecific, it can be presented as cavities indicate pulmonary infarcts. Clinicians must consider the possibility of PAS as well as pulmonary thromboembolism in patients with pulmonary infarcts. So, we report the case with PAS that was diagnosed during the evaluation of cavitary pulmonary lesions and reviewed the literatures.

Loss of syndecan-1 induces a pro-inflammatory phenotype in endothelial cells with a dysregulated response to atheroprotective flow.

Fluid shear stresses are potent regulators of vascular homeostasis and powerful determinants of vascular disease progression. The glycocalyx is a layer of glycoaminoglycans, proteoglycans, and glycoproteins that lines the luminal surface of arteries. The glycocalyx interacts directly with hemodynamic forces from blood flow and, consequently, is a prime candidate for the mechanosensing of fluidic shear stresses. Here, we investigated the role of the glycocalyx component syndecan-1 (sdc-1) in controlling the shear stress-induced signaling and flow-mediated phenotypic modulation in endothelial cells. We found that knock-out of sdc-1 abolished several key early signaling events of endothelial cells in response to shear stress including the phosphorylation of Akt, the formation of a spatial gradient in paxillin phosphorylation, and the activation of RhoA. After exposure to atheroprotective flow, we found that sdc-1 knock-out endothelial cells had a phenotypic shift to an inflammatory/pro-atherosclerotic phenotype in contrast to the atheroprotective phenotype of wild type cells. Consistent with these findings, we found increased leukocyte adhesion to sdc-1 knock-out endothelial cells in vitro that was reduced by re-expression of sdc-1. In vivo, we found increased leukocyte recruitment and vascular permeability/inflammation in sdc-1 knock-out mice. Taken together, our studies support a key role for sdc-1 in endothelial mechanosensing and regulation of endothelial phenotype.

Endobronchial metastases from extrathoracic malignancies: recent 10 years' experience in a single university hospital.

BACKGROUND: Although the lung is a common site of metastasis, endobronchial metastases (EBM) from extrathoracic malignancies are rare. Previous studies were retrospective reviews of the cases from each single institute, and the last one was performed between 1992 and 2002. We evaluated the characteristics of patients with EBM who had been diagnosed in recent 10 years in our hospital. METHODS: We retrospectively reviewed 1,275 patients who had undergone diagnostic bronchoscopic procedures between 2001 and 2011. An EBM was defined as bronchoscopically notable lesion, which was histopathologically identical to the primary tumor. RESULTS: A total of 18 cases of EBM were identified. The mean age was 53 years, and 12 cases of the 18 patients were female. The most common primary malignancies were colorectal cancer and breast cancer (4 cases each), followed by cervix cancer (3 cases) and renal cell carcinoma (2 cases). Cough was the most common symptom. The most common radiologic finding was atelectasis, which was identified in 27.7% of the cases. The median interval from the diagnosis of primary malignancy to the diagnosis of EBM was 14 months (range, 0-112 months). The median survival time from the diagnosis of EBM was 10 months (range, 1-39 months). CONCLUSION: EBM from extrathoracic malignancies were rare. Colorectal cancer and breast cancer were common as primary malignancies. Fiberoptic bronchoscopy should be performed in all patients, who are suspected of having EBM. If atypical clinical and pathological features are present, appropriate diagnostic studies should be undertaken.

A multichannel dampened flow system for studies on shear stress-mediated mechanotransduction.

Shear stresses are powerful regulators of cellular function and potent mediators of the development of vascular disease. We have designed and optimized a system allowing the application of flow to cultured cells in a multichannel format. By using a multichannel peristaltic pump, flow can be driven continuously in the system for long-term studies in multiple isolated flow loops. A key component of the system is a dual-chamber pulse dampener that removes the pulsatility of the flow without the need for having an open system or elevated reservoir. We optimized the design parameters of the pulse dampening chambers for the maximum reduction in flow pulsation while minimizing the fluid needed for each isolated flow channel. Human umbilical vein endothelial cells (HUVECs) were exposed to steady and pulsatile shear stress using the system. We found that cells under steady flow had a marked increased production of eNOS and formation of actin stress fibers in comparison to those under pulsatile flow conditions. Overall, the results confirm the utility of the device as a practical means to apply shear stress to cultured cells in the multichannel format and provide steady, long term flow to microfluidic devices.