Xylazine is an agonist at kappa opioid receptors and exhibits sex-specific responses to opioid antagonism.

Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions.

Increased reactivity of the paraventricular nucleus of the hypothalamus and decreased threat responding in male rats following psilocin administration.

Psychedelics have experienced renewed interest following positive clinical effects, however the neurobiological mechanisms underlying effects remain unclear. The paraventricular nucleus of the hypothalamus (PVN) plays an integral role in stress response, autonomic function, social behavior, and other affective processes. We investigated the effect of psilocin, the psychoactive metabolite of psilocybin, on PVN reactivity in Sprague Dawley rats. Psilocin increased stimulus-independent PVN activity as measured by c-Fos expression in male and female rats. Psilocin increased PVN reactivity to an aversive air-puff stimulus in males but not females. Reactivity was restored at 2- and 7-days post-injection with no group differences. Additionally, prior psilocin injection did not affect PVN reactivity following acute restraint stress. Experimental groups sub-classified by baseline threat responding indicate that increased male PVN reactivity is driven by active threat responders. These findings identify the PVN as a significant site of psychedelic drug action with implications for threat responding behavior.

A suite of engineered mice for interrogating psychedelic drug actions.

Psychedelic drugs like lysergic acid diethylamide (LSD) and psilocybin have emerged as potentially transformative therapeutics for many neuropsychiatric diseases, including depression, anxiety, post-traumatic stress disorder, migraine, and cluster headaches. LSD and psilocybin exert their psychedelic effects via activation of the 5-hydroxytryptamine 2A receptor (HTR2A). Here we provide a suite of engineered mice useful for clarifying the role of HTR2A and HTR2A-expressing neurons in psychedelic drug actions. We first generated Htr2a-EGFP-CT-IRES-CreERT2 mice (CT:C-terminus) to independently identify both HTR2A-EGFP-CT receptors and HTR2A-containing cells thereby providing a detailed anatomical map of HTR2A and identifying cell types that express HTR2A. We also generated a humanized Htr2a mouse line and an additional constitutive Htr2A-Cre mouse line. Psychedelics induced a variety of known behavioral changes in our mice validating their utility for behavioral studies. Finally, electrophysiology studies revealed that extracellular 5-HT elicited a HTR2A-mediated robust increase in firing of genetically-identified pyramidal neurons--consistent with a plasma membrane localization and mode of action. These mouse lines represent invaluable tools for elucidating the molecular, cellular, pharmacological, physiological, behavioral, and other actions of psychedelic drugs in vivo.

Site-Specific knockdown of microglia in the locus coeruleus regulates hypervigilant responses to social stress in female rats.

BACKGROUND: Women are at increased risk for psychosocial stress-related anxiety disorders, yet mechanisms regulating this risk are unknown. Psychosocial stressors activate microglia, and the resulting neuroimmune responses that females exhibit heightened sensitivity to may serve as an etiological factor in their elevated risk. However, studies examining the role of microglia during stress in females are lacking. METHODS: Microglia were manipulated in the stress-sensitive locus coeruleus (LC) of female rats in the context of social stress in two ways. First, intra-LC lipopolysaccharide (LPS; 0 or 3 µg/side, n = 5-6/group), a potent TLR4 agonist and microglial activator, was administered. One hour later, rats were exposed to control or an aggressive social defeat encounter between two males (WS, 15-min). In a separate study, females were treated with intra-LC or intra-central amygdala mannosylated liposomes containing clodronate (m-CLD; 0 or 25 µg/side, n = 13-14/group), a compound toxic to microglia. WS-evoked burying, cardiovascular responses, and sucrose preference were measured. Brain and plasma cytokines were quantified, and cardiovascular telemetry assessed autonomic balance. RESULTS: Intra-LC LPS augmented the WS-induced burying response and increased plasma corticosterone and interleukin-1ß (IL-1ß). Further, the efficacy and selectivity of microinjected m-CLD was fully characterized. In the context of WS, intra-LC m-CLD attenuated the hypervigilant burying response during WS as well as the accumulation of intra-LC IL-1ß. Intra-central amygdala m-CLD had no effect on WS-evoked behavior. CONCLUSIONS: These studies highlight an innovative method for depleting microglia in a brain region specific manner and indicate that microglia in the LC differentially regulate hypervigilant WS-evoked behavioral and autonomic responses.

ALiEM Connect: Large-Scale, Interactive, Virtual Residency Programming in Response to COVID-19.

PROBLEM: The COVID-19 pandemic restricted in-person gatherings, including residency conferences. The pressure to quickly reorganize educational conferences and convert content to a remote format overwhelmed many programs. This article describes the pilot event of a large-scale, interactive, virtual educational conference modeled, designed, and implemented by Academic Life in Emergency Medicine (ALiEM), called ALiEM Connect. APPROACH: The pilot ALiEM Connect event was conceptualized and implemented within a 2-week period in March 2020. The pilot was livestreamed via a combination of Zoom and YouTube and was archived by YouTube. Slack was used as a backchannel to allow interaction with other participants and engagement with the speakers (via moderators who posed questions from the backchannel to the speakers live during the videoconference). OUTCOMES: The RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework was used for program evaluation, showing that 64 U.S. Accreditation Council for Graduate Medical Education-accredited emergency medicine residency programs participated in the pilot event, with 1,178 unique users during the event (reach). For effectiveness, 93% (139/149) of trainees reported the pilot as enjoyable and 85% (126/149) reported it was equivalent to or better than their usual academic proceedings. Adoption for ALiEM Connect was fairly good with 64/237 (27%) of invited residency programs registering and participating in the pilot event. Implementation was demonstrated by nearly half of the livestream viewers (47%, 553/1,178) interacting in the backchannel discussion, sending a total of 4,128 messages in the first 4 hours. NEXT STEPS: The final component of the RE-AIM framework, maintenance, will take more time to evaluate. Further study is required to measure the educational impact of events like the ALiEM Connect pilot. The ALiEM Connect model could potentially be used to replace educational conferences that have been canceled or to implement and/or augment a large-scale, shared curriculum among residency programs in the future.

High Prevalence of Burnout Among US Emergency Medicine Residents: Results From the 2017 National Emergency Medicine Wellness Survey.

STUDY OBJECTIVE: Previous work shows that emergency medicine attending physicians have higher-than-average rates of burnout. Preliminary data suggest that emergency medicine residents are also at risk for burnout. The objective of this study was to conduct the first national survey assessment of US emergency medicine residents to determine the prevalence of burnout. METHODS: This prospective 2017 National Emergency Medicine Resident Wellness Survey study was conducted through the Wellness Think Tank, whereby emergency medicine residents from 247 residencies across the United States were invited to participate in a national survey. The primary measure of burnout was the Maslach Burnout Inventory-Human Services Survey. In accordance with others' work, "burnout" was defined as a dichotomous variable represented by high levels of emotional exhaustion or depersonalization. Because of interpretative variability with the survey tool, we also calculated burnout rates by using a more restrictive definition and a more inclusive definition that have been reported in the literature. RESULTS: Surveys were completed by 1,522 residents (21.1% of all US emergency medicine residents), representing 193 of 247 US emergency medicine residency programs (78.1%). Within this sample, the prevalence of burnout was 76.1% (95% confidence interval 74.0% to 78.3%). With alternative definitions applied, burnout prevalence rates for this same sample were 18.2% (95% confidence interval 16.3% to 20.1%) with the more restrictive definition and 80.9% (95% confidence interval 78.9% to 82.9%) with the more inclusive definition. CONCLUSION: The majority of US emergency medicine residents responding to this survey reported symptoms consistent with burnout, highlighting that physician burnout in the emergency medicine profession seems to begin as early as residency training. These findings may provide a baseline against which future work can be compared.

Approach to management of giant basal cell carcinomas.

Basal cell carcinoma (BCC) is a common nonmelanoma skin cancer with increasing incidence in the United States and worldwide. It is strongly linked to UV radiation exposure and typically is slow growing. Malignancy in BCCs is due to local growth and invasion rather than metastasis, and the prognosis is generally favorable. We report the case of a 60-year-old man with a large, locally destructive giant BCC on the right side of the upper back that was successfully treated via complete surgical excision (SE) and did not recur in the subsequent 36 months. We review the indications, evidence, advantages, and disadvantages associated with multiple surgical and nonsurgical treatment modalities available for the management of giant BCCs.

Nicolau syndrome and localized panniculitis: a report of dual diagnoses with an emphasis on morphea profunda-like changes following injection with glatiramer acetate.

Glatiramer acetate, given as a 40 mg subcutaneous injection thrice weekly, was recently approved by the FDA based on data suggesting better compliance and a more favorable side effect profile compared to lower dose, daily dosing. The most commonly reported adverse events are transient injection site reactions involving redness and pain at the site; however, more pronounced panniculitis and lipoatrophy have also been reported. Here, we present the case of a 51-year-old female treated with higher dose glatiramer acetate who presented with a cutaneous injection site reaction consistent with Nicolau syndrome. The excised specimen revealed typical glatiramer acetate-associated panniculitis, alongside subcutaneous sclerosis. This case shows the spectrum of cutaneous complications possible with glatiramer acetate injections, the finding of sclerosis being relatively infrequently reported. Given the relatively short duration of trials leading to FDA approval of thrice weekly dosing of glatiramer acetate, clinicians should perform careful clinical and histopathological evaluation and reporting of patients who experience injection site reactions.