Increased frequency and mortality in persons with neurological disorders during COVID-19.

Determining the frequency and outcomes of neurological disorders associated with COVID-19 is imperative for understanding risks as well as recognition of emerging neurological disorders. We investigated the susceptibility and impact of SARS-CoV-2 infection among persons with premorbid neurological disorder rs, as well as the post-infection incidence of neurological sequelae in a case-control population-based cohort. Using health service data collected from March 1, 2020, to June 30, 2021, we constructed a cohort of SARS-CoV-2 RNA-positive (n=177,892) and -negative (n=177,800) adults who were age-, sex-, and comorbidity-matched and underwent RT- PCR testing at similar times. COVID-19 associated mortality rates were examined within the cohort. Neurological sequelae were analysed during the acute (less than three months) and the post-acute (three to nine months) phases post-infection. The risk of death was significantly greater in the SARS-CoV-2 RNA-positive (2,140 per 100,000 person years) compared to RNA-negative (922 per 100,000 person years) over a follow-up of 9 months, particularly amongst those with premorbid neurological disorders: adjusted odds ratios (aOR, 95% CI) in persons with a prior history of parkinsonism (1·65, 1·15-2·37), dementia (1·30, 1·11-1·52), seizures (1·91, 1·26-2·87), encephalopathy (1·82, 1·02-3·23), and stroke (1·74, 1·05-2·86). There was also a significantly increased risk for diagnosis of new neurological sequelae during the acute time phase after COVID-19 including encephalopathy (2·0, 1·10-3·64), dementia (1·36, 1·07-1·73), seizure (1·77, 1·22-2·56), and brain fog (1·96, 1·20-3·20). These risks persisted into the post-acute phase after COVID-19 during which inflammatory myopathy (2·57, 1·07-6·15) and coma (1·87, 1·22-2·87) also became significantly increased. Thus, persons with SARS-CoV-2 infection and premorbid neurological disorders are at greater risk of death while SARS-CoV-2 infection was complicated by increased risk of new onset neurological disorders in both the acute and post-acute phases of COVID-19.

Normocomplementemic urticarial vasculitis in a patient with multiple sclerosis on glatiramer acetate.

Glatiramer acetate is one of the oldest and safest disease modifying therapies used to treat relapsing-remitting multiple sclerosis. Urticarial vasculitis is a rare complication of treatment with glatiramer acetate, having been reported by only two others previously. Here, we describe a case of normocomplementemic urticarial vasculitis diagnosed on skin punch biopsy in a patient with multiple sclerosis treated with glatiramer acetate for five years. Upon treatment with steroids and an antihistamine along with discontinuation of glatiramer acetate, the urticaria resolved.

Pregnancy, obstetrical and neonatal outcomes in women exposed to physician-related occupational hazards: a scoping review.

OBJECTIVE: Evidence is needed to guide organisational decision making about workplace accommodations for pregnant physicians. Our objective was to characterise the strengths and limitations of current research examining the association between physician-related occupational hazards with pregnancy, obstetrical and neonatal outcomes. DESIGN: Scoping review. DATA SOURCES: MEDLINE/PubMed, EMBASE, CINAHL/ EBSCO, SciVerse Scopus and Web of Science/Knowledge were searched from inception to 2 April 2020. A grey literature search was performed on 5 April 2020. The references of all included articles were hand searched for additional citations. ELIGIBILITY CRITERIA: English language citations that studied employed pregnant people and any 'physician-related occupational hazards', meaning any relevant physical, infectious, chemical or psychological hazard, were included. Outcomes included any pregnancy, obstetrical or neonatal complication. DATA EXTRACTION AND SYNTHESIS: Physician-related occupational hazards included physician work, healthcare work, long work hours, 'demanding' work, disordered sleep, night shifts and exposure to radiation, chemotherapy, anaesthetic gases or infectious disease. Data were extracted independently in duplicate and reconciled through discussion. RESULTS: Of the 316 included citations, 189 were original research studies. Most were retrospective, observational and included women in any occupation rather than healthcare workers. Methods for exposure and outcome ascertainment varied across studies and most studies had a high risk of bias in data ascertainment. Most exposures and outcomes were defined categorically and results from different studies could not be combined in a meta-analysis due to heterogeneity in how these categories were defined. Overall, some data suggested that healthcare workers may have an increased risk of miscarriage compared with other employed women. Long work hours may be associated with miscarriage and preterm birth. CONCLUSIONS: There are important limitations in the current evidence examining physician-related occupational hazards and adverse pregnancy, obstetrical and neonatal outcomes. It is not clear how the medical workplace should be accommodated to improve outcomes for pregnant physicians. High-quality studies are needed and likely feasible.

A 58-Year-Old Man With Episodic Hypercapnic Respiratory Failure.

CASE PRESENTATION: A 58-year-old man presented to the ED with a 1-week history of progressive weight loss, generalized weakness, unsteadiness, and dizziness. In hospital, he experienced a witnessed episode of loss of consciousness with no observable respirations that lasted for 15 minutes. His arterial blood gas demonstrated hypercapnic respiratory failure, and he required mask ventilation and vasoactive medications. Similar episodes occurred several more times over the course of the night that required the patient to be intubated. The paroxysmal episodes persisted necessitating continued invasive ventilatory support and admission to the ICU. The episodes occurred in both awake and asleep states and required the ventilator settings to dictate a minimum rate, but minimal ventilatory support otherwise. Further history revealed other symptomatic complaints of vertigo, dysphagia, and hypophonia that had progressed over a 2-month period. The patient's medical history was pertinent for a diagnosis of prostatic carcinoma 3 years previously that was found to be castrate resistant. He had metastases to his hip, ribs, and thoracic spine. Previous treatments had included bicalutamide, docetaxel, and abiraterone; he was receiving leuprolide therapy on presentation.

Embryonic Microglia Interact with Hypothalamic Radial Glia during Development and Upregulate the TAM Receptors MERTK and AXL following an Insult.

Despite a growing appreciation for microglial influences on the developing brain, the responsiveness of microglia to insults during gestation remains less well characterized, especially in the embryo when microglia themselves are still maturing. Here, we asked if fetal microglia could coordinate an innate immune response to an exogenous insult. Using time-lapse imaging, we showed that hypothalamic microglia actively surveyed their environment by near-constant "touching" of radial glia projections. However, following an insult (i.e., IUE or AAV transduction), this seemingly passive touching became more intimate and long lasting, ultimately resulting in the retraction of radial glial projections and degeneration into small pieces. Mechanistically, the TAM receptors MERTK and AXL were upregulated in microglia following the insult, and Annexin V treatment inhibited radial glia breakage and engulfment by microglia. These data demonstrate a remarkable responsiveness of embryonic microglia to insults during gestation, a critical window for neurodevelopment.

Embryonic microglia influence developing hypothalamic glial populations.

BACKGROUND: Although historically microglia were thought to be immature in the fetal brain, evidence of purposeful interactions between these immune cells and nearby neural progenitors is becoming established. Here, we examined the influence of embryonic microglia on gliogenesis within the developing tuberal hypothalamus, a region later important for energy balance, reproduction, and thermoregulation. METHODS: We used immunohistochemistry to quantify the location and numbers of glial cells in the embryonic brain (E13.5-E17.5), as well as a pharmacological approach (i.e., PLX5622) to knock down fetal microglia. We also conducted cytokine and chemokine analyses on embryonic brains in the presence or absence of microglia, and a neurosphere assay to test the effects of the altered cytokines on hypothalamic progenitor behaviors. RESULTS: We identified a subpopulation of activated microglia that congregated adjacent to the third ventricle alongside embryonic Olig2+ neural progenitor cells (NPCs) that are destined to give rise to oligodendrocyte and astrocyte populations. In the absence of microglia, we observed an increase in Olig2+ glial progenitor cells that remained at the ventricle by E17.5 and a concomitant decrease of these Olig2+ cells in the mantle zone, indicative of a delay in migration of these precursor cells. A further examination of maturing oligodendrocytes in the hypothalamic grey and white matter area in the absence of microglia revealed migrating oligodendrocyte progenitor cells (OPCs) within the grey matter at E17.5, a time point when OPCs begin to slow their migration. Finally, quantification of cytokine and chemokine signaling in ex vivo E15.5 hypothalamic cultures +/- microglia revealed decreases in the protein levels of several cytokines in the absence of microglia. We assayed the influence of two downregulated cytokines (CCL2 and CXCL10) on neurosphere-forming capacity and lineage commitment of hypothalamic NPCs in culture and showed an increase in NPC proliferation as well as neuronal and oligodendrocyte differentiation. CONCLUSION: These data demonstrate that microglia influence gliogenesis in the developing tuberal hypothalamus.

Granulocyte-colony-stimulating factor (G-CSF) signaling in spinal microglia drives visceral sensitization following colitis.

Pain is a main symptom of inflammatory diseases and often persists beyond clinical remission. Although we have a good understanding of the mechanisms of sensitization at the periphery during inflammation, little is known about the mediators that drive central sensitization. Recent reports have identified hematopoietic colony-stimulating factors as important regulators of tumor- and nerve injury-associated pain. Using a mouse model of colitis, we identify the proinflammatory cytokine granulocyte-colony-stimulating factor (G-CSF or Csf-3) as a key mediator of visceral sensitization. We report that G-CSF is specifically up-regulated in the thoracolumbar spinal cord of colitis-affected mice. Our results show that resident spinal microglia express the G-CSF receptor and that G-CSF signaling mediates microglial activation following colitis. Furthermore, healthy mice subjected to intrathecal injection of G-CSF exhibit pronounced visceral hypersensitivity, an effect that is abolished by microglial depletion. Mechanistically, we demonstrate that G-CSF injection increases Cathepsin S activity in spinal cord tissues. When cocultured with microglia BV-2 cells exposed to G-CSF, dorsal root ganglion (DRG) nociceptors become hyperexcitable. Blocking CX3CR1 or nitric oxide production during G-CSF treatment reduces excitability and G-CSF-induced visceral pain in vivo. Finally, administration of G-CSF-neutralizing antibody can prevent the establishment of persistent visceral pain postcolitis. Overall, our work uncovers a DRG neuron-microglia interaction that responds to G-CSF by engaging Cathepsin S-CX3CR1-inducible NOS signaling. This interaction represents a central step in visceral sensitization following colonic inflammation, thereby identifying spinal G-CSF as a target for treating chronic abdominal pain.

Oligodendrocyte development in the embryonic tuberal hypothalamus and the influence of Ascl1.

BACKGROUND: Although the vast majority of cells in our brains are glia, we are only beginning to understand programs governing their development, especially within the embryonic hypothalamus. In mice, gliogenesis is a protracted process that begins during embryonic stages and continues into the early postnatal period, with glial progenitors first producing oligodendrocyte precursor cells, which then differentiate into pro-oligodendrocytes, pro-myelinating oligodendrocytes, and finally, mature myelinating oligodendrocytes. The exact timing of the transition from neurogenesis to gliogenesis and the subsequent differentiation of glial lineages remains unknown for most of the Central Nervous System (CNS), and is especially true for the hypothalamus. METHODS: Here we used mouse embryonic brain samples to determine the onset of gliogenesis and expansion of glial populations in the tuberal hypothalamus using glial markers Sox9, Sox10, Olig2, PdgfRα, Aldh1L1, and MBP. We further employed Ascl1 and Neurog2 mutant mice to probe the influence of these proneual genes on developing embryonic gliogenic populations. RESULTS: Using marker analyses for glial precursors, we found that gliogenesis commences just prior to E13.5 in the tuberal hypothalamus, beginning with the detection of glioblast and oligodendrocyte precursor cell markers in a restricted domain adjacent to the third ventricle. Sox9+ and Olig2+ glioblasts are also observed in the mantle region from E13.5 onwards, many of which are Ki67+ proliferating cells, and peaks at E17.5. Using Ascl1 and Neurog2 mutant mice to investigate the influence of these bHLH transcription factors on the progression of gliogenesis in the tuberal hypothalamus, we found that the elimination of Ascl1 resulted in an increase in oligodendrocyte cells throughout the expansive period of oligodendrogenesis. CONCLUSION: Our results are the first to define the timing of gliogenesis in the tuberal hypothalamus and indicate that Ascl1 is required to repress oligodendrocyte differentiation within this brain region.

Structural and functional analysis of fucose-processing enzymes from Streptococcus pneumoniae.

Fucose metabolism pathways are present in many bacterial species and typically contain the central fucose-processing enzymes fucose isomerase (FcsI), fuculose kinase (FcsK), and fuculose-1-phosphate aldolase (FcsA). Fucose initially undergoes isomerization by FcsI producing fuculose, which is then phosphorylated by FcsK. FcsA cleaves the fuculose-1-phosphate product into lactaldehyde and dihydroxyacetone phosphate, which can be incorporated into central metabolism allowing the bacterium to use fucose as an energy source. Streptococcus pneumoniae has fucose-processing operons containing homologs of FcsI, FcsK, and FcsA; however, this bacterium appears unable to utilize fucose as an energy source. To investigate this contradiction, we performed biochemical and structural studies of the S. pneumoniae fucose-processing enzymes SpFcsI, SpFcsK, and SpFcsA. These enzymes are demonstrated to act in a sequential manner to ultimately produce dihydroxyacetone phosphate and have structural features entirely consistent with their observed biochemical activities. Analogous to the regulation of the Escherichia coli fucose utilization operon, fuculose-1-phosphate appears to act as an inducing molecule for activation of the S. pneumoniae fucose operon. Despite our evidence that S. pneumoniae appears to have the appropriate regulatory and biochemical machinery for fucose metabolism, we confirmed the inability of the S. pneumoniae TIGR4 strain to grow on fucose or on the H-disaccharide, which is the probable substrate of the transporter for the pathway. On the basis of these observations, we postulate that the S. pneumoniae fucose-processing pathway has a non-metabolic role in the interaction of this bacterium with its human host.