Paxlovid-Induced Tacrolimus Toxicity in the Treatment of COVID-19: A Case Report.

PaxlovidTM (nirmaltrelvir/ritonavir) received emergency use authorization from the Food and Drug Administration (FDA) in December 2021 to treat coronavirus disease 2019 (COVID-19). Given the actions of Paxlovid on cytochrome P450-3A4 (CYP3A4) enzymes, it is imperative to check for potential drug-drug interactions before prescribing. We describe a case in which the common emergency department presentation of generalized weakness was found to be caused by interactions between Paxlovid and a patient's home medications resulting in tacrolimus toxicity.

Where Have All the FLOWERS Gone? A Multicenter Investigation of Frequent Users of Midwest Emergency Department Services During the COVID-19 Stay-at-home Orders.

INTRODUCTION: In this study we aimed to determine the impact of the mandatory coronavirus disease 2019 (COVID-19) pandemic stay-at-home order on the proportional makeup of emergency department (ED) visits by frequent users and super users. METHODS: We conducted a secondary analysis of existing data using a multisite review of the medical records of 280,053 patients to measure the impact of the COVID-19 pandemic stay-at-home order on ED visits. The primary outcomes included analysis before and during the lockdown in determining ED use and unique characteristics of non-frequent, frequent, and super users of emergency services. RESULTS: During the mandatory COVID-19 stay-at-home order (lockdown), the percentage of frequent users increased from 7.8% (pre-lockdown) to 21.8%. Super users increased from 0.7% to 4.7%, while non-frequent users dropped from 91.5% to 73.4%. Frequent users comprised 23.7% of all visits (4% increase), while super user encounters (4.7%) increased by 53%. Patients who used Medicaid and Medicare increased by 39.3% and 4.6%, respectively, while those who were uninsured increased ED use by 190.3% during the lockdown. CONCLUSION: When barriers to accessing healthcare are implemented as part of a broader measure to reduce the spread of an infectious agent, individuals reliant on these services are more likely to seek out the ED for their medical needs. Policymakers considering future pandemic planning should consider this finding to ensure that vital healthcare resources are allocated appropriately.

Mycotic Aortic Aneurysm: A Rare Etiology of Septic Shock.

Mycotic aneurysm of the aorta is a rare disease with a high mortality rate due to its likelihood of aneurysmal rupture. This syndrome is predominantly seen in patients over age 65 with the most common presenting symptoms being fever and back pain. Our case illustrates a mycotic aneurysm of the aorta presenting in an elderly female with vague abdominal pain, flank pain, and generalized weakness. We review the investigative approach, diagnostic modalities, and treatment options in patient management. This case emphasizes the need for a high index of suspicion of mycotic aneurysms of the aorta in critically ill elderly patients as early antibiotic therapy can be crucial for source control.

Leech Me Alone! Atraumatic Hemarthrosis after Hirudotherapy.

A 58-year-old male presented to the emergency department with a chief complaint of knee pain and swelling after performing hirudotherapy (leech therapy) approximately one week prior. Knee arthrocentesis demonstrated significant hemarthrosis. Hirudotherapy is being used for a broad array of reasons including treatment of osteoarthritis, to plastic and reconstructive surgery. Case reports and journal articles often discuss cutaneous reactions, bleeding, and infection as common adverse events. Intra-articular bleeding is not commonly mentioned. With hirudotherapy being utilized more as alternative therapy for osteoarthritis and joint pain, physicians should be aware of hemarthrosis as a possible adverse reaction.

Doctor, I'm Seeing Two of Everything.

Acute diplopia is a rare chief complaint with a broad differential diagnosis; key historical and physical characteristics aid with emergency management. This case report discusses the important findings, imaging, and multidisciplinary interaction between emergency medicine, ophthalmology, and neurology regarding the approach to addressing acute painless vertical diplopia. A 51-year-old male presented to the emergency department (ED), reporting that he was seeing 'two of everything,' since awakening. Although the patient had a history of ischemic stroke, he had never experienced this sensation of diplopia. His ED workup was essentially unremarkable; he was admitted for evaluation of the possibilities of a fourth cranial nerve (CN IV) palsy, acute Parinaud syndrome, or ischemic stroke. Ultimately the patient was sent home one day after admission with the diagnosis of CN IV neuropathy. Highlighted is an approach to undifferentiated diplopia with an included discussion of the pathophysiology of a CN IV palsy and Parinaud syndrome. Understanding basic pathophysiology and anatomy allows for a proper history, physical exam, and appropriate consultation. With these tools, emergency physicians can improve their approach to patients with acute diplopia when arriving at the ED.

Light or Dark Pigmentation of Engineered Skin Substitutes Containing Melanocytes Protects Against Ultraviolet Light-Induced DNA Damage In Vivo.

Engineered skin substitutes (ESS) containing autologous fibroblasts and keratinocytes provide stable wound closure in patients with large, full-thickness burns, but are limited by hypopigmentation due to absence of added melanocytes. DNA damage caused by ultraviolet radiation (UV) increases risk for skin cancer development. In human skin, melanocytes provide pigmentation that protects skin from UV-induced DNA damage. This study investigated whether inclusion of human melanocytes (hM) affects the response of ESS to UV in vivo. Specifically, pigmentation and formation of cyclobutane pyrimidine dimers (CPDs), the most prevalent UV-induced DNA photoproduct, were analyzed. Three groups of ESS were prepared with fibroblasts and keratinocytes, ± melanocytes, and grafted orthotopically to immunodeficient mice: ESS without melanocytes (ESS-hM), ESS with light skin-derived (Caucasian) melanocytes (ESS+hM-L), and ESS with dark skin-derived (African-American) melanocytes (ESS+hM-D). Pigmentation of ESS+hM-L and ESS+hM-D increased significantly after grafting; pigmentation levels were significantly different among groups. Mean melanocyte densities in ESS+hM-L and ESS+hM-D were similar to each other and to densities in normal human skin. After 8 weeks in vivo, grafts were irradiated with 135 mJ/cm2 UV; non-UV-treated mice served as controls. UV modestly increased pigmentation in the ESS+hM groups. UV significantly increased CPD levels in ESS-hM, and levels in ESS-hM were significantly greater than in ESS+hM-L or ESS+hM-D. The results demonstrate that light or dark melanocytes in ESS decreased UV-induced DNA damage. Therefore, melanocytes in ESS play a photoprotective role. Protection against UV-induced DNA damage is expected to reduce skin cancer risk in patients grafted with ESS containing autologous melanocytes.

Exogenous Keratinocyte Growth Factor Is Not Required for Pigmentation of Skin Substitutes with Three Isogeneic Cell Types.

Engineered skin substitutes (ESS) containing human fibroblasts (hF) and human keratinocytes (hK) provide significant medical benefits for treatment of acute and chronic skin wounds, including, but not limited to, burns, burn scars, congenital skin lesions, and cutaneous ulcers. However, anatomic deficiencies, such as lack of pigment, can contribute to long-term morbidity, including hypopigmentation and reduced solar protection. To address the deficiency of hypopigmentation, ESS were populated sequentially with cultured hF, human melanocytes (hM), and hK to generate ESS with pigment (ESS-P). Constructs were incubated in media containing 0.0, 1.5, or 5.0 ng/mL keratinocyte growth factor (KGF), which promotes survival and differentiation of hM in ESS-P, and had media changed at 24 or 48 h intervals. ESS-P were evaluated in vitro for surface hydration, surface color, and distribution of hM. Proliferation was assessed by measuring incorporation of 5-bromo-2'-deoxyuridine into replicating DNA in basal epidermal cells. ESS-P from test conditions were grafted to immunodeficient mice, and were assessed over 12 weeks for pigmented area, pigment density, and distribution of hM in healed human grafts. The in vitro data showed differences among test groups, including increase in hydration of the epidermal surface with higher KGF, increase of surface pigmentation with 24 h media changes, increase of hM density with higher KGF and 24 h media changes, and time-dependent decrease of proliferation. At 12 weeks after grafting, differences among groups were found for pigment density, but not for distribution of hM or percentage of pigmented area. These differences demonstrate that a higher concentration of KGF (5 ng/mL) in the maturation medium of ESS-P and more frequent media changes (24 h interval) promote higher viability and hM differentiation of ESS-P before grafting, but are not required for full pigmentation (pigmented area, pigment density, hM distribution) of grafted wounds. Based on these results, reductions of the concentration of KGF (i.e., 1.5 ng/mL) in the maturation medium, and of the frequency of medium changes (48 h intervals) would be expected to support survival, continued replication, and restoration of skin color by hM in therapeutic transplantation of ESS-P. Impact Statement Restoration of skin color after traumatic injury affects personal identity and provides protection from exposure to solar radiation. Keratinocyte growth factor (KGF) and nutrient supply are known to regulate survival of melanocytes before transplantation in engineered skin substitutes with pigment (ESS-P). This report demonstrates that exogenous KGF is not required to restore skin color and that replacement of the nutrient medium at lower frequency (48 versus 24 h) does not inhibit development of skin color after melanocyte transplantation. These results offer new alternatives to conserve resources in fabrication of ESS-P and to maintain efficacy for restoration of skin color.

Curated Collections for Clinician Educators: Five Key Papers on Graduated Responsibility in Residency Education.

Introduction The Accreditation Council for Graduate Medical Education calls graduated responsibility "one of the core tenets of American graduate medical education." However, there is no clear set of resources for programs to implement a system of progressively increasing responsibilities for trainees. This project aimed to identify a set of high-yield papers on graduated responsibility for junior faculty members. Methods A study group of Academic Life in Emergency Medicine Faculty Incubator participants identified relevant literature on graduated responsibility via a comprehensive literature search and a call to the online medical education community; 59 total papers were identified. The most relevant and applicable were selected by the study group via a three-round modified Delphi process. Results Five key articles for junior faculty interested in implementing more robust graduated responsibility at their residency training program were selected and described here. Summaries of key points, along with considerations for faculty developers and relevance to junior faculty, are presented for each article. Conclusions The articles presented here provide a solid theoretical and practical basis for junior faculty to explore graduated responsibility. The five articles presented here provide the junior faculty with a toolkit to examine and improve their systems for assigning responsibilities in a graded fashion at their own institutions.

Identification of Merkel cells associated with neurons in engineered skin substitutes after grafting to full thickness wounds.

Engineered skin substitutes (ESS), prepared using primary human fibroblasts and keratinocytes with a biopolymer scaffold, were shown to provide stable closure of excised burns, but relatively little is known about innervation of ESS after grafting. This study investigated innervation of ESS and, specifically, whether Merkel cells are present in healed grafts. Merkel cells are specialized neuroendocrine cells required for fine touch sensation in skin. We discovered cells positive for keratin 20 (KRT20), a general marker for Merkel cells, in the basal epidermis of ESS after transplantation to mice, suggesting the presence of Merkel cells. Cells expressing KRT20 were not observed in ESS in vitro. However, widely separated KRT20-positive cells were observed in basal epidermis of ESS by 2 weeks after grafting. By 4 weeks, these cells increased in number and expressed keratins 18 and 19, additional Merkel cells markers. Putative Merkel cell numbers increased further between weeks 6 and 14; their densities varied widely and no specific pattern of organization was observed, similar to Merkel cell localization in human skin. KRT20-positive cells co-expressed epidermal markers E-cadherin and keratin 15, suggesting derivation from the epidermal lineage, and neuroendocrine markers synaptophysin and chromogranin A, consistent with their identification as Merkel cells. By 4 weeks after grafting, some Merkel cells in engineered skin were associated with immature afferents expressing neurofilament-medium. By 8 weeks, Merkel cells were complexed with more mature neurons expressing neurofilament-heavy. Positive staining for human leukocyte antigen demonstrated that the Merkel cells in ESS were derived from grafted human cells. The results identify, for the first time, Merkel cell-neurite complexes in engineered skin in vivo. This suggests that fine touch sensation may be restored in ESS after grafting, although this must be confirmed with future functional studies.

Restoration of cutaneous pigmentation by transplantation to mice of isogeneic human melanocytes in dermal-epidermal engineered skin substitutes.

Autologous engineered skin substitutes (ESS) containing melanocytes (hM) may restore pigmentation and photoprotection after grafting to full-thickness skin wounds. In this study, normal hM were isolated from discard skin, propagated with or without tyrosinase inhibitors, cryopreserved, recovered into culture, and added to ESS (ESS-P) before transplantation. ESS-P were incubated in either UCMC160/161 or UCDM1 medium, scored for hM densities, and grafted to mice. The results showed that sufficient hM can be propagated to expand donor tissue by 100-fold; incubation of hM in tyrosinase inhibitors reduced pigment levels but did not change hM recovery after cryopreservation; hM densities in ESS-P were greater after incubation in UCDM1 than UCMC160 medium; hM were localized to the dermal-epidermal junction of ESS-P; and UCDM1 medium promoted earlier pigment distribution and density. These results indicate that hM can be incorporated into ESS-P efficiently to restore cutaneous pigmentation and UV photoprotection after full-thickness skin loss conditions.

State Emergency Department Opioid Guidelines: Current Status.

INTRODUCTION: The purpose of this study was to evaluate and categorize current state-sponsored opioid guidelines for the practice of emergency medicine (EM). METHODS: We conducted a comprehensive search of EM-specific opioid prescribing guidelines and/or policies in each state to determine current state involvement in EM opioid prescribing, as well as to evaluate some of the specifics of each guideline or policy. The search was conducted using an online query and a follow-up email request to each state chapter of ACEP. RESULTS: We found that 17 states had emergency department-specific guidelines. We further organized the guidelines into four categories: limiting prescriptions for opioids with 67 total recommendations; preventing/diverting abuse with 56 total recommendations; addiction-related guidelines with 29 total recommendations; and a community resources section with 24 total recommendations. Our results showed that current state guidelines focus on providers limiting opioid pain prescriptions and vetting patients for possible abuse/diversion. CONCLUSION: This study highlights the 17 states that have addressed opioid prescribing guidelines and categorizes their efforts to date. It is hoped that this study will provide the basis for similar efforts in other states.

PSGL-1 derived from human neutrophils is a high-efficiency ligand for endothelium-expressed E-selectin under flow.

P-selectin glycoprotein ligand-1 (PSGL-1) has been proposed as an important tethering ligand for E-selectin and is expressed at a modest level on human leukocytes. Sialyl Lewis x (sLe(x))-like glycans bind to E-selectin and are expressed at a relatively high level on circulating leukocytes. It is unclear whether PSGL-1 has unique biochemical attributes that contribute to its role as an E-selectin ligand. To probe this issue, we conjugated microspheres with either sLe(x) or PSGL-1 purified from myeloid cells (neutrophils and HL-60) and compared their adhesion to endothelial expressed E-selectin under defined shear conditions. We found that both sLe(x) and PSGL-1 microspheres adhere to 4 h of IL-1beta-activated human umbilical vein endothelial cells predominantly through E-selectin. Analysis of the adhesion revealed that the rate of initial tethering of the PSGL-1 microspheres to E-selectin was significantly greater than the rate of initial tethering of the sLe(x) microspheres despite the fact that the sLe(x) microspheres tested had higher ligand densities than the PSGL-1 microspheres. We also found that pretreatment of the PSGL-1 or sLe(x) microspheres with HECA-452 had no significant effect on initial tethering to E-selectin. These results support the hypotheses that 1) PSGL-1 is a high-efficiency tethering ligand for E-selectin, 2) ligand biochemistry can significantly influence initial tethering to E-selectin, and 3) PSGL-1 tethering to E-selectin can occur via non-HECA-452 reactive epitopes.