Epinephrine autoinjector prescribing following anaphylaxis presentation to the emergency department.

Background: Guidelines recommend patients with anaphylaxis are prescribed epinephrine autoinjectors (EAI), carry the EAI with them, and are referred to an allergist. There also are barriers to EAI administration, such as acquiring the medication, having it available, recognizing when to use it, and administering it appropriately. Objective: The objective was to describe how often patients with anaphylaxis discharged from the emergency department (ED) receive an EAI prescription and allergist referral; also, to assess the frequency of EAI pick-up by the patient from the outpatient pharmacy, out-of-pocket cost, change in EAI device during dispensing, and if patient training on EAI use and allergist follow-up occurred. Patient-specific factors associated with the occurrence of these variables were investigated. Methods: This was a retrospective, observational study of adult and pediatric ED patients who presented with anaphylaxis between July and December 2020. Data were collected from medical records and telephone calls to outpatient pharmacies and included patient demographics; ED treatment; EAI prescribing, EAI pick-up from the outpatient pharmacy, and cost; device changes; EAI training; and allergist referral and follow-up. Data are presented descriptively, and bivariate analyses were used for comparisons between patient-specific factors and incidence of EAI prescribing, patient pick-up, and allergist referral. Results: A total of 102 patients were included; mean age ± standard deviation 34 ± 7 years, 52% were < 18 years of age; and 54% had a history of allergy and/or anaphylaxis. EAI prescribing occurred in 79% of the patients. Of these, 71% picked up the EAI from the outpatient pharmacy, the median cost to the patient was $5 (range, $0-$379), 18% had an EAI device change at dispensing, and 23% received EAI training. Allergist referral occurred in 22%, and 28% followed up with an allergist within 60 days. Presenting symptoms of mucosal edema and respiratory stridor were associated with the occurrence of EAI prescribing. Presenting symptoms of respiratory wheezing, hoarseness, throat itching, skin flushing and allergist referral from the ED were associated with the occurrence of EAI pick-up from the outpatient pharmacy. Conclusion: Overall, 79% of ED patients with anaphylaxis had an EAI prescribed and 22% had an allergist referral; 71% picked up the EAI from the outpatient pharmacy, EAI dispensing changes occurred, and training was infrequent. Collaboration between emergency medicine clinicians, allergists, and pharmacists is needed to streamline treatment and follow-up.

Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases.

The molecular chaperone endoplasmic reticulum protein 29 (ERp29) plays a critical role in protein folding, trafficking, and secretion. Though ubiquitously expressed, ERp29 is upregulated in response to ER stress and is found at higher levels in certain cell types such as secretory epithelial cells and neurons. As an ER resident protein, ERp29 shares many structural and functional similarities with protein disulfide isomerases, but is not regarded as part of this family due to several key differences. The broad expression and myriad roles of ERp29 coupled with its upregulation via the unfolded protein response (UPR) upon ER stress have implicated ERp29 in a range of cellular processes and diseases. We summarize the diverse activities of ERp29 in protein trafficking, cell survival and apoptosis, and ER homeostasis and highlight a potential role of ERp29 in neuroprotection in retinal and neurodegenerative diseases.

Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration.

BACKGROUND: Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses. Herein, we investigate the role of XBP1 in maintaining morphological and functional integrity in retinal neurons during adulthood and the early stages of aging. METHODS: The basal and induced levels of XBP1 activation in the retina were measured in young adult and aged mice. Conditional knockout (cKO) of XBP1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina specific Cre-recombinase line (Chx10-Cre). Retinal morphology, neuronal populations including photoreceptors, bipolar cells, and retinal ganglion cells (RGCs), synaptic structure, and microglial activation were examined with immunohistochemistry and staining of retinal sections. Retinal function was evaluated with light-adapted (photopic) and dark adapted (scotopic) electroretinograms. Retinal mitochondrial function and metabolism was assessed by Seahorse XFe24 Extracellular Flux Analyzer. RESULTS: The retinas of aged wild type (WT) mice display a significantly reduced basal level of Xbp1s and compromised activation of ER stress response. In XBP1 cKO mice, significant structural degeneration of the retina, evidenced by thinning of retinal layers and a loss of RGCs, and functional defects indicated by diminished photopic and scotopic ERG b-waves are observed at the age of 12-14 months. Furthermore, discontinuous and disorganized synaptic laminae, colocalized with activated microglia, in the inner plexiform layer is found in the XBP1 cKO retinas. In addition, cKO mice demonstrate a significant increase in ectopic synapses between bipolar cells and photoreceptors, which is strikingly similar to WT mice at 20-24 months of age. These changes are associated with defective retinal glycolysis while mitochondrial respiratory function appears normal in the cKO retina. CONCLUSIONS: XBP1 cKO mice at 12-14 months of age show significant structural, functional, and metabolic deficits that closely resemble WT mice twice that age. Our findings suggest that the absence of XBP1, a critical component of the UPR, accelerates age-related retinal neurodegeneration.

Erp29 Attenuates Cigarette Smoke Extract-Induced Endoplasmic Reticulum Stress and Mitigates Tight Junction Damage in Retinal Pigment Epithelial Cells.

PURPOSE: Endoplasmic reticulum protein 29 (ERp29) is a novel chaperone that was recently found decreased in human retinas with AMD. Herein, we examined the effect of ERp29 on cigarette smoke-induced RPE apoptosis and tight junction disruption. METHODS: Cultured human RPE (HRPE) cells (ARPE-19) or mouse RPE eyecup explants were exposed to cigarette smoke extract (CSE) for short (up to 24 hours) or long (up to 3 weeks) periods. Expression of ERp29 was up- and downregulated by adenovirus and siRNA, respectively. Endoplasmic reticulum stress markers, apoptosis, and cell death, the expression and distribution of tight junction protein ZO-1, transepithelial electrical resistance (TEER), and F-actin expression were examined. RESULTS: Endoplasmic reticulum protein 29 was significantly increased by short-term exposure to CSE in ARPE-19 cells or eyecup explants but was reduced after 3-week exposure. Overexpression of ERp29 increased the levels of GRP78, p58(IPK), and Nrf-2, while reducing p-eIF2α and C/EBP homologous protein (CHOP), and protected RPE cells from CSE-induced apoptosis. In contrast, knockdown of ERp29 decreased the levels of p58(IPK) and Nrf2, but increased p-eIF2α and CHOP and exacerbated CSE-triggered cell death. In addition, overexpression of ERp29 attenuated CSE-induced reduction in ZO-1 and enhanced the RPE barrier function, as measured by TEER. Knockdown of ERp29 decreased the level of ZO-1 protein. These effects were associated with changes in the expression of cytoskeleton F-actin. CONCLUSIONS: Endoplasmic reticulum protein 29 attenuates CSE-induced ER stress and enhances cell viability and barrier integrity of RPE cells, and therefore may act as a protective mechanism for RPE survival and activity.