Search

Competing Interests: Competing Interests C Tackaberry is a director and employee of Clinithink and also a shareholder. No other competing interests from any author to disclose.

Physiologic and psychological effects of substance use are common occurrences. They may be the proximate purpose of the exposure or related to an unintended complication. Acute short-term exposure effects may not be the same as long-term effects. These effects are mediated by different receptors they act on and the homeostatic changes that occur due to repeat exposure. We review in this article the physiologic and psychological effects from exposure to commonly encountered drugs, ethanol, sedative hypnotics, cocaine, amphetamines, marijuana, opioids, nicotine, hydrocarbons (halogenated and non-halogenated), and nitrous oxide., (Published by Elsevier Inc.)

Rationale & Objective: Urinary biomarkers of injury, inflammation, and repair may help phenotype acute kidney injury (AKI) observed in clinical trials. We evaluated the differences in biomarkers between participants randomized to monotherapy or to combination renin-angiotensin-aldosterone system (RAAS) blockade in VA NEPHRON-D, where an increased proportion of observed AKI was acknowledged in the combination arm., Study Design: Longitudinal analysis., Setting & Participants: A substudy of the VA NEPHRON-D trial., Predictor: Primary exposure was the treatment arm (combination [RAAS inhibitor] vs monotherapy). AKI is used as a stratifying variable., Outcome: Urinary biomarkers, including albumin, EGF (epidermal growth factor), MCP-1 (monocyte chemoattractant protein-1), YKL-40 (chitinase 3-like protein 1), and KIM-1 (kidney injury molecule-1)., Analytical Approach: Biomarkers measured at baseline and at 12 months in trial participants were compared between treatment groups and by AKI. AKI events occurring during hospitalization were predefined safety end points in the original trial. The results were included in a meta-analysis with other large chronic kidney disease trials to assess global trends in biomarker changes., Results: In 707 participants followed for a median of 2.2 years, AKI incidence was higher in the combination (20.7%) versus the monotherapy group (12.7%; relative risk [RR], 1.64 [95% CI, 1.16-2.30]). Compared with the monotherapy arm, in the combination arm the urine biomarkers at 12 months were either unchanged (MCP-1: RR, -3% [95% CI, -13% to 9%], P adj =0.8; KIM-1: RR, -10% [95% CI, -20% to 1%], P adj =0.2; EGF, RR-7% [95% CI, -12% to-1%], P adj =0.08) or lower (albuminuria: RR, -24% [95% CI, -37% to-8%], P adj =0.02; YKL: RR, -40% to-44% [95% CI, -58% to-25%], P adj <0.001). Pooled meta-analysis demonstrated reduced albuminuria in the intervention arm across 3 trials and similar trajectories in other biomarkers., Limitations: Biomarker measurement was limited to 2 time points independent of AKI events., Conclusions: Despite the increased risk of serum creatinine-defined AKI, combination RAAS inhibitor therapy was associated with unchanged or decreased urinary biomarkers at 12 months. This suggests a possible role for kidney biomarkers to further characterize kidney injury in clinical trials., Plain-Language Summary: The VA NEPHRON-D trial investigated inhibition of the renin-angiotensin-aldosterone system (RAAS) hormonal axis on kidney outcomes in a large population of diabetic chronic kidney disease patients. The trial was stopped early due to increased events of serum creatinine-defined acute kidney injury in the combination therapy arm. Urine biomarkers can serve as an adjunct to serum creatinine in identifying kidney injury. We found that urinary biomarkers in the combination therapy group were not associated with a pattern of harm and damage to the kidney, despite the increased number of kidney injury events in that group. This suggests that serum creatinine alone may be insufficient for defining kidney injury and supports further exploration of how other biomarkers might improve identification of kidney injury in clinical trials., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AR is a co-founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and, until 31 July 2020, was a scientific advisory board member of Thermo Fisher Scientific, Syros Pharmaceuticals, Asimov, and Neogene Therapeutics. From 1 August 2020, AR is an employee of Genentech and has equity in Roche. AR is a named inventor on multiple patents related to single cell and spatial genomics filed by or issued to the Broad Institute., (Copyright: © 2023 Hawrylycz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: The Veratrum genus is composed of plants containing a diverse set of steroidal alkaloids. Veratrum plant material has been utilized for centuries as herbal medicines, however the alkaloids have such a low therapeutic index that they are not used in modern medicine. Here we report an incident of inadvertent ingestion of V. parviflorum by hikers in Georgia that allowed detection, and in several instances identification of alkaloids from the plant, and correlated their presence within patient blood and breast milk specimens., Case History: Eight patients, three male and five female, presented in the spring of 2020 and 2021 with symptoms requiring emergent medical attention after ingestion of Veratrum parviflorum. All patients believed the plants to be a local native species of wild leek, Allium tricoccum , locally known as ramps. Plants were identified using photographs as well as fresh and cooked plant material provided by patients, in consultation with botanists at the University of Georgia Herbarium. Written consent was obtained from all patients for collection of blood and breast milk specimens for laboratory identification of Veratrum alkaloids., Methods: V. parviflorum plant material, and patient serum and breast milk were analyzed by high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (HPLC-QTOF) to identify steroidal alkaloids., Results: The V. parviflorum extract was confirmed to contain cyclopamine, veratramine, jervine, and muldamine. Two out of the eight patients had detectable concentrations of Veratrum alkaloids. Of the alkaloids identified in the plant, cyclopamine and jervine were detected within patient serum, and cyclopamine and veratramine were observed to be present in breast milk., Discussion: Toxicity resulting from Veratrum steroidal alkaloids has primarily been reported from V. album and V. viride . This is the second report of V. parviflorum poisoning. The present work reports for the first time the presence of muldamine and jervine within V. parviflorum . This work provides the first instance of identification of Veratrum alkaloids in breast milk. Thus, the findings presented herein add to literature record causative agents contributing to the toxicity of V. parviflorum when ingested and potential for secondary poisoning through breastfeeding., Conclusion: V. parviflorum toxicity was observed to cause nausea, vomiting, hypotension, bradycardia, abdominal pain, light-headedness, blurred vision, and tingling in the arms. Patients experiencing mild symptoms improved with supportive care, IV fluids, and antiemetics, but hemodynamically unstable patients required atropine and vasopressors. This study demonstrated that more lipophilic Veratrum alkaloids can be passed along in breast milk, which suggests additional precautions may be critical to limit further poisonings.

Background: Historically, the first step in treating cyanide (CN - ) toxicity utilized antidotes to induce methemoglobinemia. This is concerning in patients who are already hypoxemic or have elevated carboxyhemoglobin. Hydroxocobalamin (OHCbl) is now the first-line antidote for CN - toxicity and is not known to induce methemoglobinemia. We observed elevated methemoglobin (MetHb) levels in several patients treated with OHCbl and sought to investigate the incidence of MetHb formation following administration of OHCbl., Methods: Chart review: A single-center, retrospective case series of patients who received 5 or 10 g of hydroxocobalamin from 01/01/2011 through 04/30/2019. Data was analyzed using descriptive statistics. In-vitro study: Discarded blood was separated into whole blood and plasma samples. OHCbl and normal saline was added to reach 0×, 1×, 2×, and 4× peak therapeutic concentrations and analyzed at times 0, 2, and 4 h after administration., Results: Chart review : Twenty-seven cases of OHCbl administration were identified. The median age was 53 years (IQR 38 - 64) and 20 (74.1%) were male. Exposure to a house fire or smoke inhalation was the reason for OHCbl administration in 21 (77.8%) patients. Five (18.5%) patients received 10 g of OHCbl while the rest received 5 g. Six (22.2%) patients developed methemoglobinemia, all after 5 g OHCbl administration; four had been exposed to fire and smoke, two received the medication for severe acidosis of unknown etiology not related to fire or smoke. The median peak level was 7.1% (IQR 2.2 - 16.4%) at a median time of 11.4 h post-administration. Two patients received methylene blue (MB), neither responded. Death occurred in 17 (63%) cases. In-vitro study: We observed a dose dependent elevation in total hemoglobin but did not detect any increase in MetHb., Conclusion: We observed a noteworthy temporal association between the formation of methemoglobinemia and the administration of hydroxocobalamin. This does not appear to be an artifact of the CO-oximeters. This could have profound implications for patients who are already hypoxemic or have impaired oxygen carrying capacity from carboxyhemoglobin.

Background: Bupropion is not known to have direct serotonin agonism or inhibit serotonin reuptake. In spite of this, it has been implicated as a causative agent of serotonin syndrome. We highlight two cases of single-agent bupropion overdose that subsequently met the diagnosis of serotonin syndrome by the Hunter criteria, despite the absence of direct serotonergic agents. CASE 1: A 14-year-old boy intentionally ingested an estimated 30 bupropion 75-mg immediate-release tablets. He presented in status epilepticus, was intubated, and was placed on midazolam and fentanyl infusions. He developed tremor, ankle clonus, and agitation. He was administered cyproheptadine for presumed serotonin syndrome with temporal improvement in his symptoms. CASE 2: A 19-year-old woman intentionally ingested an estimated 53 bupropion 150-mg extended-release tablets. She had a seizure and required sedation and intubation. During her course, she developed hyperthermia, inducible clonus, and hyperreflexia. She was treated with cyproheptadine without temporal improvement of symptoms but improved the following day. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Although bupropion is not known to be directly serotonergic, it has been implicated as the single causative agent after overdose. This may be due to an indirect increase in activity of serotonergic cells. In these cases, bupropion overdose resulted in a clinical presentation consistent with serotonin syndrome, with the first having a temporal improvement after treatment with cyproheptadine. Physicians need to be aware of the potential serotonergic activity of bupropion for accurate assessment and treatment of this dangerous condition., (Published by Elsevier Inc.)

Hypoxia (Hx) is a component of multiple disorders, including stroke and sleep-disordered breathing, which often precede or are comorbid with neurodegenerative diseases. However, little is known about how hypoxia affects the ability of microglia, resident CNS macrophages, to respond to subsequent inflammatory challenges that are often present during neurodegenerative processes. We, therefore, tested the hypothesis that hypoxia would enhance or "prime" microglial pro-inflammatory gene expression in response to a later inflammatory challenge without programmatically increasing basal levels of pro-inflammatory cytokine expression. To test this, we pre-exposed immortalized N9 and primary microglia to hypoxia (1% O 2 ) for 16 h and then challenged them with pro-inflammatory lipopolysaccharide (LPS) either immediately or 3-6 days following hypoxic exposure. We used RNA sequencing coupled with chromatin immunoprecipitation sequencing to analyze primed microglial inflammatory gene expression and modifications to histone H3 lysine 4 trimethylation (H3K4me3) at the promoters of primed genes. We found that microglia exhibited enhanced responses to LPS 3 days and 6 days post-hypoxia. Surprisingly, however, the majority of primed genes were not enriched for H3K4me3 acutely following hypoxia exposure. Using the bioinformatics tool MAGICTRICKS and reversible pharmacological inhibition, we found that primed genes required the transcriptional activities of NF-κB. These findings provide evidence that hypoxia pre-exposure could lead to persistent and aberrant inflammatory responses in the context of CNS disorders., (Copyright © 2020 Kiernan, Ewald, Ouellette, Wang, Agbeh, Knutson, Roopra and Watters.)

The neural control system underlying breathing is sexually dimorphic with males being more vulnerable to dysfunction. Microglia also display sex differences, and their role in the architecture of brainstem respiratory rhythm circuitry and modulation of cervical spinal cord respiratory plasticity is becoming better appreciated. To further understand the molecular underpinnings of these sex differences, we performed RNA sequencing of immunomagnetically isolated microglia from brainstem and cervical spinal cord of adult male and female rats. We used various bioinformatics tools (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Reactome, STRING, MAGICTRICKS) to functionally categorize identified gene sets, as well as to pinpoint common transcriptional gene drivers that may be responsible for the observed transcriptomic differences. We found few sex differences in the microglial transcriptomes derived from the brainstem, but several hundred genes were differentially expressed by sex in cervical spinal microglia. Comparing brainstem and spinal microglia within and between sexes, we found that the major factor guiding transcriptomic differences was central nervous system (CNS) location rather than sex. We further identified key transcriptional drivers that may be responsible for the transcriptomic differences observed between sexes and CNS regions; enhancer of zeste homolog 2 emerged as the predominant driver of the differentially downregulated genes. We suggest that functional gene alterations identified in metabolism, transcription, and intercellular communication underlie critical microglial heterogeneity and sex differences in CNS regions that contribute to respiratory disorders categorized by dysfunction in neural control. These data will also serve as an important resource data base to advance our understanding of innate immune cell contributions to sex differences and the field of respiratory neural control. SIGNIFICANCE STATEMENT: The contributions of central nervous system (CNS) innate immune cells to sexually dimorphic differences in the neural circuitry controlling breathing are poorly understood. We identify key transcriptomic differences, and their transcriptional drivers, in microglia derived from the brainstem and the C3-C6 cervical spinal cord of healthy adult male and female rats. Gene alterations identified in metabolism, gene transcription, and intercellular communication likely underlie critical microglial heterogeneity and sex differences in these key CNS regions that contribute to the neural control of breathing., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: As of January 7, 2020, a total of 2558 hospitalized patients with nonfatal cases and 60 patients with fatal cases of e-cigarette, or vaping, product use-associated lung injury (EVALI) had been reported to the Centers for Disease Control and Prevention (CDC)., Methods: In a national study, we compared the characteristics of patients with fatal cases of EVALI with those of patients with nonfatal cases to improve the ability of clinicians to identify patients at increased risk for death from the condition. Health departments reported cases of EVALI to the CDC and included, when available, data from medical-record abstractions and patient interviews. Analyses included all the patients with fatal or nonfatal cases of EVALI that were reported to the CDC as of January 7, 2020. We also present three case reports of patients who died from EVALI to illustrate the clinical characteristics common among such patients., Results: Most of the patients with fatal or nonfatal cases of EVALI were male (32 of 60 [53%] and 1666 of 2498 [67%], respectively). The proportion of patients with fatal or nonfatal cases was higher among those who were non-Hispanic white (39 of 49 [80%] and 1104 of 1818 [61%], respectively) than among those in other race or ethnic groups. The proportion of patients with fatal cases was higher among those 35 years of age or older (44 of 60 [73%]) than among those younger than 35 years, but the proportion with nonfatal cases was lower among those 35 years of age or older (551 of 2514 [22%]). Among the patients who had an available medical history, a higher proportion of those with fatal cases than those with nonfatal cases had a history of asthma (13 of 57 [23%] vs. 102 of 1297 [8%]), cardiac disease (26 of 55 [47%] vs. 115 of 1169 [10%]), or a mental health condition (32 of 49 [65%] vs. 575 of 1398 [41%]). A total of 26 of 50 patients (52%) with fatal cases had obesity. Half the patients with fatal cases (25 of 54 [46%]) were seen in an outpatient setting before hospitalization or death., Conclusions: Chronic conditions, including cardiac and respiratory diseases and mental health conditions, were common among hospitalized patients with EVALI., (Copyright © 2020 Massachusetts Medical Society.)

Introduction: Bupropion is the only Food and Drug Administration-approved synthetic cathinone. It increases the release of norepinephrine in the locus coeruleus and dorsal raphe nucleus, causing an increase in the frequency of serotonergic neuron firing. The diagnosis of serotonin toxicity (ST) from bupropion poisoning is controversial due to the lack of direct serotonergic activity. Nonetheless, there is one documented report of ST after single-agent bupropion overdose and multiple reports describing polypharmacy overdoses where bupropion may have contributed to ST., Methods: This is a retrospective analysis of data collected by the Toxicology Investigators Consortium (ToxIC), a prospective multi-center toxico-surveillance and research network registry, from 2014 to 2017. Cases were identified if ST was a clinical effect and bupropion was the single agent listed. Data is presented descriptively., Results: Of the 266 recorded single bupropion overdoses, the most common symptoms were seizures (47.1%), tachycardia (greater than 140 bpm) (33.9%), agitation (31.7%), toxic psychosis (20.4%), and myoclonus/tremor/hyperreflexia (19%). Benzodiazepines were the most common therapy (69.2%). Thirteen patients (5.9%) were diagnosed with ST by a medical toxicologist., Conclusion: Bupropion overdose is primarily associated with seizures, tachycardia, and agitation; bupropion may be an atypical cause of serotonin toxicity.

Physiological and environmental factors impacting respiratory homeostasis vary throughout the course of an animal's lifespan from embryo to adult and can shape respiratory development. The developmental emergence of complex neural networks for aerial breathing dates back to ancestral vertebrates, and represents the most important process for respiratory development in extant taxa ranging from fish to mammals. While substantial progress has been made towards elucidating the anatomical and physiological underpinnings of functional respiratory control networks for air-breathing, much less is known about the mechanisms establishing these networks during early neurodevelopment. This is especially true of the complex neurochemical ensembles key to the development of air-breathing. One approach to this issue has been to utilize comparative models such as anuran amphibians, which offer a unique perspective into early neurodevelopment. Here, we review the developmental emergence of respiratory behaviours in anuran amphibians with emphasis on contributions of neurochemicals to this process and highlight opportunities for future research., (Copyright © 2019 Elsevier B.V. All rights reserved.)

CDC, the Food and Drug Administration (FDA), state and local health departments, and public health and clinical stakeholders are investigating a nationwide outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) (1). CDC has published recommendations for health care providers regarding EVALI (2-4). Recently, researchers from Utah and New York published proposed diagnosis and treatment algorithms for EVALI (5,6). EVALI remains a diagnosis of exclusion because, at present, no specific test or marker exists for its diagnosis, and evaluation should be guided by clinical judgment. Because patients with EVALI can experience symptoms similar to those associated with influenza or other respiratory infections (e.g., fever, cough, headache, myalgias, or fatigue), it might be difficult to differentiate EVALI from influenza or community-acquired pneumonia on initial assessment; EVALI might also co-occur with respiratory infections. This report summarizes recommendations for health care providers managing patients with suspected or known EVALI when respiratory infections such as influenza are more prevalent in the community than they have been in recent months (7). Recommendations include 1) asking patients with respiratory, gastrointestinal, or constitutional symptoms about the use of e-cigarette, or vaping, products; 2) evaluating those suspected to have EVALI with pulse oximetry and obtaining chest imaging, as clinically indicated; 3) considering outpatient management for clinically stable EVALI patients who meet certain criteria; 4) testing patients for influenza, particularly during influenza season, and administering antimicrobials, including antivirals, in accordance with established guidelines; 5) using caution when considering prescribing corticosteroids for outpatients, because this treatment modality has not been well studied among outpatients, and corticosteroids could worsen respiratory infections; 6) recommending evidence-based treatment strategies, including behavioral counseling, to help patients discontinue using e-cigarette, or vaping, products; and 7) emphasizing the importance of annual influenza vaccination for all persons aged ≥6 months, including patients who use e-cigarette, or vaping products., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

CDC, the Food and Drug Administration (FDA), state and local health departments, and public health and clinical partners are investigating a multistate outbreak of lung injury associated with the use of electronic cigarette (e-cigarette), or vaping, products. In late August, CDC released recommendations for health care providers regarding e-cigarette, or vaping, product use associated lung injury (EVALI) based on limited data from the first reported cases (1,2). This report summarizes national surveillance data describing clinical features of more recently reported cases and interim recommendations based on these data for U.S. health care providers caring for patients with suspected or known EVALI. It provides interim guidance for 1) initial clinical evaluation; 2) suggested criteria for hospital admission and treatment; 3) patient follow-up; 4) special considerations for groups at high risk; and 5) clinical and public health recommendations. Health care providers evaluating patients suspected to have EVALI should ask about the use of e-cigarette, or vaping, products in a nonjudgmental and thorough manner. Patients suspected to have EVALI should have a chest radiograph (CXR), and hospital admission is recommended for patients who have decreased blood oxygen (O 2 ) saturation (<95%) on room air or who are in respiratory distress. Health care providers should consider empiric use of a combination of antibiotics, antivirals, or steroids based upon clinical context. Evidence-based tobacco product cessation strategies, including behavioral counseling, are recommended to help patients discontinue use of e-cigarette, or vaping, products. To reduce the risk of recurrence, patients who have been treated for EVALI should not use e-cigarette, or vaping, products. CDC recommends that persons should not use e-cigarette, or vaping, products that contain tetrahydrocannabinol (THC). At present, CDC recommends persons consider refraining from using e-cigarette, or vaping, products that contain nicotine. Irrespective of the ongoing investigation, e-cigarette, or vaping, products should never be used by youths, young adults, or women who are pregnant. Persons who do not currently use tobacco products should not start using e-cigarette, or vaping, products., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed. All members of the Lung Injury Response Clinical Working Group have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Carolyn S. Calfee reports a grant from the FDA/NIH (Tobacco Center of Regulatory Science [TCORS]) for a project entitled Impact of Different E-cigarette Characteristics on Acute Lung Injury; a grant from GlaxoSmithKline for an observational study on sepsis and ARDS biomarkers; a grant and personal fees from Bayer for an observational study on pulmonary hypertension in ARDS and for medical consultation; and personal fees from Roche/Genentech for consultation on potential therapies for ARDS, and personal fees from Prometic, CSL Behring, and Quark for serving on medical advisory boards for ARDS. No other potential conflicts of interest were disclosed.

On September 6, 2019, this report was posted as an MMWR Early Release on the MMWR website (https://www.cdc.gov/mmwr). As of August 27, 2019, 215 possible cases of severe pulmonary disease associated with the use of electronic cigarette (e-cigarette) products (e.g., devices, liquids, refill pods, and cartridges) had been reported to CDC by 25 state health departments. E-cigarettes are devices that produce an aerosol by heating a liquid containing various chemicals, including nicotine, flavorings, and other additives (e.g., propellants, solvents, and oils). Users inhale the aerosol, including any additives, into their lungs. Aerosols produced by e-cigarettes can contain harmful or potentially harmful substances, including heavy metals such as lead, volatile organic compounds, ultrafine particles, cancer-causing chemicals, or other agents such as chemicals used for cleaning the device (1). E-cigarettes also can be used to deliver tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, or other drugs; for example, "dabbing" involves superheating substances that contain high concentrations of THC and other plant compounds (e.g., cannabidiol) with the intent of inhaling the aerosol. E-cigarette users could potentially add other substances to the devices. This report summarizes available information and provides interim case definitions and guidance for reporting possible cases of severe pulmonary disease. The guidance in this report reflects data available as of September 6, 2019; guidance will be updated as additional information becomes available., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. No potential conflicts of interest were disclosed.

Sleep disordered breathing (SDB) affects 3-5% of the pediatric population, including neonates who are highly susceptible due to an underdeveloped ventilatory control system, and REM-dominated sleep. Although pediatric SDB is associated with poor cognitive outcomes, very little research has focused on models of pediatric SDB, particularly in neonates. In adults and neonates, intermittent hypoxia (IH), a hallmark of SDB, recapitulates multiple physiological aspects of severe SDB, including neuronal apoptosis, sex-specific cognitive deficits, and neuroinflammation. Microglia, resident CNS immune cells, are important mediators of neurodevelopment and neuroinflammation, but to date, no studies have examined the molecular properties of microglia in the context of neonatal IH. Here, we tested the hypothesis that neonatal IH will enhance microglial inflammation and sex-specifically lead to long-term changes in working memory. To test this hypothesis, we exposed post-natal day (P1) neonates with dams to an established adult model of pathological IH consisting of 2 min cycles of 10.5% O 2 followed by 21% O 2 , 8 h/day for 8 days. We then challenged the offspring with bacterial lipopolysaccharide (LPS) at P9 or at 6-8 weeks of age and immunomagnetically isolated microglia for gene expression analyses and RNA-sequencing. We also characterized neonatal CNS myeloid cell populations by flow cytometry analyses. Lastly, we examined working memory performance using a Y-maze in the young adults. Contrary to our hypothesis, we found that neonatal IH acutely augmented basal levels of microglial anti-inflammatory cytokines, attenuated microglial responses to LPS, and sex-specifically altered CNS myeloid populations. We identified multiple sex differences in basal neonatal microglial expression of genes related to chemotaxis, cognition, and aging. Lastly, we found that basal, but not LPS-induced, anti-inflammatory cytokines were augmented sex-specifically in the young adults, and that there was a significant interaction between sex and IH on basal working memory. Our results support the idea that neonates may be able to adapt to IH exposures that are pathological in adults. Further, they suggest that male and female microglial responses to IH are sex-specific, and that these sex differences in basal microglial gene expression may contribute to sexual dimorphisms in vulnerability to IH-induced cognitive disruption.

Purpose: The purpose of this study was to investigate potential differences by sex in the demographic and clinical characteristics of patients treated utilizing a sepsis electronic bundle order set. Risk factors for in-hospital mortality were also assessed., Methods: Data on patients in whom the sepsis order set was initiated in the emergency department over a 16-month period were entered into the hospital database. Data were analyzed for differences by sex in demographic and clinical factors, treatment modalities, and in-hospital mortality. The Bonferroni correction was applied to account for multiple comparisons; α was set at 0.006 for sex differences., Findings: A total of 2204 patients were included. Male and female cohorts were similar with regard to a variety of demographic and clinical factors, including age, Emergency Severity Index (ESI) levels 1 and 2, time to disposition, appropriateness of antibiotics, and total fluids given by weight. The ESI is an assessment score ranging from 1 to 5 (1 is emergent). There were modest differences in the source of infection (genitourinary was 4% more common in women; P = 0.03) and mode of arrival (men were 4% more likely to arrive by ambulance; P = 0.03). These differences did not achieve our predefined α of 0.006 when the Bonferroni correction was applied. Factors associated with in-hospital mortality were advanced age, arrival by ambulance, and an ESI level of 1 or 2 (all, P < 0.01)., Implications: Women were more likely to have a genitourinary cause of sepsis and less likely to arrive by ambulance. Risk factors of in-hospital mortality were older age, arrival by ambulance, and an ESI level of 1 or 2, but not sex., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: This study aimed to determine the current attitudes, perceptions, and practices of emergency medicine providers and nurses (RNs) regarding the discharge of adult patients from the emergency department (ED) after administration of opioid analgesics., Methods: A cross-sectional survey was administered at 3 hospital sites with a combined annual ED census of >180,000 visits per year. All 59 attending emergency physicians (EPs), 233 RNs, and 23 advanced practice clinicians (APCs) who worked at these sites were eligible to participate., Findings: Thirty-five EPs (59.3%), 88 RNs (37.8%), and 14 APCs (60.9%) completed the survey for an overall response rate of 51.75%. Most respondents were female (95 [69.9%]). The factor ranked most important to consider when discharging a patient from the ED after administration of opioids was the patient's functional status and vital signs (median, 2.00; interquartile range, 2.00-3.50). More RNs (84 [96.6%]) than EPs (29 [82.9%]) reported that developing an ED policy or guideline for safe discharge after administration of opioids is important to clinical practice (P = 0.02). Only 8 physicians (23.5%) reported that they did not prescribe intramuscular morphine, and 15 (42.9%) reported that they did not prescribe intramuscular hydromorphone. EPs (7 [20.0%]) and RNs (3 [3.4%]) differed in regard to whether they were aware if any patients to whom they administered an opioid had experienced an adverse drug-related event (P = 0.01). Most EPs (24 [68.6%]) and RNs (54 [61.4%]) believed that the decision for patient discharge should be left to both the emergency medicine provider and the RN., Implications: Most study participants believed that developing a policy or guideline for safe discharge after administration opioids in the ED is important to clinical practice. Only a few physicians reported that they did not prescribe intramuscular hydromorphone or morphine. Most participants believed the discharge decision after administration of opioids in the ED should be primarily determined by both the emergency medicine provider and the RN., (Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.)

Chronic intermittent hypoxia (CIH) is a hallmark of sleep apnoea, a condition associated with diverse clinical disorders. CIH and sleep apnoea are characterized by increased reactive oxygen species formation, peripheral and CNS inflammation, neuronal death and neurocognitive deficits. Few studies have examined the role of microglia, the resident CNS immune cells, in models of CIH. Thus, little is known concerning their direct contributions to neuropathology or the cellular mechanisms regulating their activities during or following pathological CIH. In this review, we identify gaps in knowledge regarding CIH-induced microglial activation, and propose mechanisms based on data from related models of hypoxia and/or hypoxia-reoxygenation. CIH may directly affect microglia, or may have indirect effects via the periphery or other CNS cells. Peripheral inflammation may indirectly activate microglia via entry of pro-inflammatory molecules into the CNS, and/or activation of vagal afferents that trigger CNS inflammation. CIH-induced release of damage-associated molecular patterns from injured CNS cells may also activate microglia via interactions with pattern recognition receptors expressed on microglia. For example, Toll-like receptors activate mitogen-activated protein kinase/transcription factor pathways required for microglial inflammatory gene expression. Although epigenetic effects from CIH have not yet been studied in microglia, potential epigenetic mechanisms in microglial regulation are discussed, including microRNAs, histone modifications and DNA methylation. Epigenetic effects can occur during CIH, or long after it has ended. A better understanding of CIH effects on microglial activities may be important to reverse CIH-induced neuropathology in patients with sleep disordered breathing., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Neural optogenetic applications over the past decade have steadily increased; however the effects of commonly used blue light paradigms on surrounding, non-optogenetic protein-expressing CNS cells are rarely considered, despite their simultaneous exposure. Here we report that blue light (450 nm) repetitively delivered in both long-duration boluses and rapid optogenetic bursts gene-specifically altered basal expression of inflammatory and neurotrophic genes in immortalized and primary murine wild type microglial cultures. In addition, blue light reduced pro-inflammatory gene expression in microglia activated with lipopolysaccharide. These results demonstrate previously unreported, off-target effects of blue light in cells not expressing optogenetic constructs. The unexpected gene modulatory effects of blue light on wild type CNS resident immune cells have novel and important implications for the neuro-optogenetic field. Further studies are needed to elucidate the molecular mechanisms and potential therapeutic utility of blue light modulation of the wild type CNS.

Context: Past research has revealed that having a sister who gave birth as a teenager is associated with increases in young people's likelihood of engaging in risky sexual behavior. To date, however, no study has determined if having several sisters who were adolescent mothers further raises youths' chances of engaging in risky activities., Methods: Data were collected from 1,510 predominantly Hispanic and black 11-17-year-olds in a California program for youths who have at least one pregnant or parenting sister. Correlational analyses, analyses of variance and regression analyses were conducted to assess the effects of having multiple teenage parenting sisters on a variety of outcomes that are known risk factors for teenage pregnancy, Results: Twenty-four percent of participants had two or more sisters who had given birth as teenagers. The likelihood of having multiple adolescent parenting sisters was greatest in large families, but was unrelated to youths' other background characteristics. In analyses controlling for background factors, females with many parenting sisters had increased levels of behavioral problems (school problems, drug or alcohol use, and delinquent behavior) and an elevated likelihood of being sexually experienced. Having lived with two or more parenting sisters (as opposed to having lived with only one) was related to more permissive sexual and childbearing attitudes among young women and to earlier first intercourse among young men. Males with a sister who gave birth at a young age had elevated levels of delinquent behavior and promiscuous sexual behavior., Conclusions: As the number of teenage parenting sisters rises, youths'--particularly females'--risk of pregnancy involvement increases beyond the level associated with having only one teenage parenting sister. Screening for the number, living situation and age at first birth of parenting sisters is likely to be useful for programs seeking to identify youths at high risk of an early pregnancy.