High-dose amphotericin: yay or nay? A case series and literature review.

Invasive fungal infections pose significant morbidity and mortality risks, particularly those caused by moulds. Available antifungal classes are limited by toxicities and are increasingly susceptible to resistance, particularly amongst challenging fungal pathogens. The purpose of this case series and literature review was to characterize the use of a high-dose lipid formulation of amphotericin B. A case series is presented including patients who received high-dose lipid formulation amphotericin B (≥7.5 mg/kg/day) between June 2012 and August 2021. Additionally, a systematic literature review was conducted by searching the PubMed database for English-language studies involving individuals who received high-dose amphotericin B therapy (≥7.5 mg/kg) using lipid formulations. Nine patients were included in the case series, receiving an average of 8.9 ± 1.3 mg/kg liposomal amphotericin B over a mean of 11.0 ± 10.8 days predominantly for mould infections including Mucorales, aspergillosis and Fusarium. The patients were primarily cared for in intensive care units, with varying treatment histories and outcomes. A total of 11 studies (n=260 patients) met inclusion criteria for the literature review. Responses to high-dose liposomal amphotericin B ranged from 8% to 100%, often showing favourable outcomes. High doses of liposomal amphotericin B were well tolerated both in the case series and in published literature, with serum creatinine changes being the most commonly reported adverse event. However, multi-patient studies continue to report less than favourable (range 8-62%) response rates. High-dose liposomal amphotericin B, either alone or in combination with other antifungal agents, might be a viable strategy for managing invasive fungal infections when few treatment choices exist. This article is part of the Challenges and strategies in the management of invasive fungal infections Special Issue: https://www.drugsincontext.com/special_issues/challenges-and-strategies-in-the-management-of-invasive-fungal-infections.

Cultivation, chemistry, and genome of Psilocybe zapotecorum.

Psilocybe zapotecorum is a strongly blue-bruising psilocybin mushroom used by indigenous groups in southeastern Mexico and beyond. While this species has a rich history of ceremonial use, research into its chemistry and genetics have been limited. Herein, we detail mushroom morphology and report on cultivation parameters, chemical profile, and the full genome sequence of P. zapotecorum . First, growth and cloning methods are detailed that are simple, and reproducible. In combination with high resolution microscopic analysis, the strain was barcoded, confirming species-level identification. Full genome sequencing reveals the architecture of the psilocybin gene cluster in P. zapotecorum, and can serve as a reference genome for Psilocybe Clade I. Characterization of the tryptamine profile revealed a psilocybin concentration of 17.9±1.7 mg/g, with a range of 10.6-25.7 mg/g (n=7), and similar tryptamines (psilocin, baeocystin, norbaeocystin, norpsilocin, aeruginascin, 4-HO-tryptamine, and tryptamine) in lesser concentrations for a combined tryptamine concentration of 22.5±3.2 mg/g. These results show P. zapotecorum to be a potent - and variable - Psilocybe mushroom. Chemical profiling, genetic analysis, and cultivation assist in demystifying these mushrooms. As clinical studies with psilocybin gain traction, understanding the diversity of psilocybin mushrooms will assure that psilocybin therapy does not become synonymous with psilocybin mushrooms.

Naloxone Accessibility Under the State Standing Order Across Mississippi.

Importance: Naloxone is a life-saving medication for individuals experiencing an opioid overdose. Naloxone standing orders aim to make naloxone more available by allowing patients improved access to this medication at community pharmacies; however, lawful availability does not mean that this life-saving intervention is accessible to patients. Objective: To characterize naloxone availability and out-of-pocket cost under the state standing order in Mississippi. Design, Setting, and Participants: This telephone-based, mystery-shopper census survey study included Mississippi community pharmacies open to the general public in Mississippi at the time of data collection. Community pharmacies were identified using the Hayes Directories April 2022 complete Mississippi pharmacy database. Data were collected from February to August 2022. Exposures: Mississippi House bill 996, the Naloxone Standing Order Act, signed into law in 2017, allowing pharmacists to dispense naloxone under a physician state standing order at a patient's request. Main Outcomes and Measures: The main outcomes were naloxone availability under Mississippi's state standing order and the out-of-pocket cost of available formulations. Results: There were 591 open-door community pharmacies surveyed for this study, with a 100% response rate. The most common pharmacy type was independent (328 [55.50%]), followed by chain (147 [24.87%]) and grocery store (116 [19.63%]). When asked, "Do you have naloxone that I can pick up today?" 216 Mississippi pharmacies (36.55%) had naloxone available for purchase under the state standing order. Of the 591 pharmacies, 242 (40.95%) were unwilling to dispense naloxone under the state standing order. Among the 216 pharmacies with naloxone available, the median out-of-pocket cost for naloxone nasal spray (n = 202) across Mississippi was $100.00 (range, $38.11-$229.39; mean [SD], $105.58 [$35.42]) and the median out-of-pocket cost of naloxone injection (n = 14) was $37.70 (range, $17.00-$208.96; mean [SD], $66.62 [$69.27]). Conclusions and Relevance: In this survey study of open-door Mississippi community pharmacies, availability of naloxone was limited despite standing order implementation. This finding has important implications for the effectiveness of the legislation in preventing opioid overdose deaths in this region. Further studies are needed to understand pharmacists' unwillingness to dispense naloxone and the implications of lack of availability and unwillingness for further naloxone access interventions.

Equity in medical education: Addressing microaggressions and discrimination on the wards.

PURPOSE: Existing frameworks to address instances of microaggressions and discrimination in the clinical environment have largely been developed for faculty and resident physicians, creating a lack of resources for medical students. METHODS: We implemented a workshop to prepare pre-clinical medical/dental students to recognize and respond to microaggressions. Participants in three cohorts from 2018 to 2020 completed pre- and post-workshop surveys assessing the prevalence of exposure to clinical microaggressions and the workshop's effect on mitigating commonly perceived barriers to addressing microaggressions. RESULTS: Of 461 first-year medical and dental students who participated, 321 (69.6%) provided survey responses. Over 80% of students reported experiencing microaggressions, with women and URM students over-represented. After the workshop, participants reported significant reductions in barriers to addressing microaggressions and discrimination, including recognizing incidents, uncertainty of what to say or do, lack of allies, lack of familiarity with institutional policies, and uncertainty of clinical relevance. The workshop was similarly effective in-person and virtual formats. CONCLUSIONS: Most medical/dental student respondents reported experiencing microaggressions in the clinical setting, particularly female and URM students. Our workshop mitigated most perceived challenges to responding to microaggressions. Future interventions across institutions should continue to equip students with the tools they need to address and respond to microaggressions.

Student-Led Efforts to Advance Anti-Racist Medical Education.

Over the past decade, medical schools across the United States have increasingly dedicated resources to advancing racial and social justice, such as by supporting diversity and inclusion efforts and by incorporating social medicine into the traditional medical curricula. While these changes are promising, the academic medicine community must apply an anti-racist lens to every aspect of medical education to equip trainees to recognize and address structural inequities. Notably, organizing and scholarly work led by medical students has been critical in advancing anti-racist curricula. In this article, the authors illustrate how student activism has reshaped medical education by highlighting examples of student-led efforts to advance anti-racist curricula at Harvard Medical School (HMS) and at the University of California, San Francisco (UCSF) School of Medicine. HMS students collaborated with faculty to address aspects of existing clinical practice that perpetuate racism, such as the racial correction factor in determining kidney function. They also responded to the existing curricula by noting missed opportunities to discuss structural racism, and they planned supplemental sessions to address these gaps. At UCSF, students identified specific avenues to improve the rigor of social medicine courses and developed new curricula to equip students with skills to confront and work to dismantle racism. The authors describe how HMS students, in an effort to improve the learning environment, developed a workshop to assist students in navigating microaggressions and discrimination in the clinical setting. At UCSF, students partnered with faculty and administration to advocate pass/fail grading for clerkships after university data revealed racial disparities in students' clerkship assessments. In reviewing these examples of students' advocacy to improve their own curricula and learning environments, the authors aim to provide support for students and faculty pursuing anti-racist curricular changes at their own institutions.

Transmission, infectivity, and antibody neutralization of an emerging SARS-CoV-2 variant in California carrying a L452R spike protein mutation

We identified a novel SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California. Named B.1.427/B.1.429 to denote its 2 lineages, the variant emerged around May 2020 and increased from 0% to >50% of sequenced cases from September 1, 2020 to January 29, 2021, exhibiting an 18.6-24% increase in transmissibility relative to wild-type circulating strains. The variant carries 3 mutations in the spike protein, including an L452R substitution. Our analyses revealed 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation found in the B.1.1.7, B.1.351, and P.1 variants. Antibody neutralization assays showed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California associated with decreased antibody neutralization warrants further investigation.

Remote Medical Education: Adapting Kern's Curriculum Design to Tele-teaching.

COVID-19 has necessitated a rapid shift to the remote delivery of medical education. We present a timely collection of tips, techniques, and strategies for the facilitation of remote teaching sessions and modification of curriculum design, assessment, and evaluation. We step through Kern's six-step curriculum design, recommending to (1) consider session necessity and a variety of teaching models; (2) inform your session with surveys and polls; (3) keep session endpoints consistent; (4) make the most of technology and translate in-person strategies to virtual forms; (5) engage with individual learners and eliminate distractions; and (6) consider online methods of assessment and evaluation methods.

Ontogeny of hepatic methionine catabolic enzyme activities (Transmethylation and Transsulphuration) and associated physiological amino acids in E10-21 chick embryos and D1-49 broilers.

Developmental changes in hepatic methionine adenosyltransferase, cystathionine ß-synthase, cystathionase, and glycine N-methyltransferase were determined in broiler chick embryos and hatched chicks by using radiometric and spectrometric methods. Hepatic free methionine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, cystathionine, and cysteine levels were also investigated. Results showed an increase in hepatic MAT activity from E10 to E21 during embryogenesis, suggesting greater transmethylation rates throughout the rapid embryonic growth and development period. A strong positive correlation between embryo BW and MAT activity also supports this idea. The MAT specific activity continued to increase after hatching, but there was a negative correlation between chick BW and MAT activities from D1 to D49. This may indicate different MAT isozymes exist for chick embryo hepatic tissue compared to hepatic tissue of hatched chick and growing broilers. The developmental pattern of MAT isozymes could be critical for methionine metabolism to cope with the demand imposed on the embryo, chicks, and growing broilers. Additionally, the specific activity of hepatic CBS in chick embryos was determined to be lower compared to that observed in older broilers (35 and 49 days). Since liver CBS specific activity is at the lowest point from D1-7 in young chicks, the ability to convert adequate homocysteine to cysteine through transsulphuration may be limiting for cysteine synthesis at this time. Steady-state hepatic homocysteine levels in chick embryos and chicks may be a function of the rates of homocysteine formation, remethylation, and catabolism via the transsulphuration pathway. The present study indicates young chicks from D1 to D7 may have a limited ability for adequate transsulphuration; therefore, dietary cystine may be needed for optimum performance.

L-Carnitine metabolism, protein turnover and energy expenditure in supplemented and exercised Labrador Retrievers.

L-Carnitine is critical for protection against bioaccumulation, long-chain fatty acid transportation and energy production. Energy production becomes important as the body maintains lean mass, repairs muscles and recovers from oxidative stress. The aim was to investigate the effects of supplemented L-carnitine on protein turnover (PT), energy expenditure (EE) and carnitine metabolism in muscle/serum of Labrador Retrievers. In a series of experiments, all dogs were fed a low-carnitine diet and sorted into one of two groups: L-carnitine (LC) supplemented daily with 125 mg L-carnitine and 3.75 g sucrose or placebo (P) supplemented with 4 g sucrose daily. The experiments consisted of analyses of muscle/serum for L-carnitine content (EXP1), a protein turnover experiment (EXP2) and analysis of substrate utilization via indirect calorimetry (EXP3). EXP1: 20 Labradors (10 M/10 F) performed a 13 week running regimen. L-Carnitine content was analysed in the serum and biceps femoris muscle before/after a 24.1 km run. LC serum had higher total (p < .001; p = .001), free (p < .001; p = .001) and esterified (p = .001; p = .003) L-carnitine pre- and post-run respectively. LC muscle had significantly higher free L-carnitine post-run (p = .034). EXP2: 26 Labs (13 M/13 F) performed a 60-day running regimen. For the final run, half of the Labradors from each treatment rested and half ran 24.1 km. Twenty-four Labradors received isotope infusion, and then, a biopsy of the biceps femoris of all 26 Labradors was taken to determine PT. Resting/exercised LC had a lower fractional breakdown rate (FBR) versus P group (p = .042). LC females had a lower FBR v. P females (p = .046). EXP3: Respiration of 16 Labradors (8 M/8 F) was measured via indirect calorimetry over 15 week. All dogs ran on a treadmill for 30 min at 30% VO2 max (6.5 kph), resulting in higher maximum and mean EE in LC females v. P females (p = .021; p = .035). Implications for theory, practice and future research are discussed.

SnapShot: COVID-19.

Coronavirus disease 2019 (COVID-19) is a novel respiratory illness caused by SARS-CoV-2. Viral entry is mediated through viral spike protein and host ACE2 enzyme interaction. Most cases are mild; severe disease often involves cytokine storm and organ failure. Therapeutics including antivirals, immunomodulators, and vaccines are in development. To view this SnapShot, open or download the PDF.

The utility of iPhone oximetry apps: A comparison with standard pulse oximetry measurement in the emergency department.

OBJECTIVES: To determine if a correlation exists between 3 iphone pulse ox applications' measurements and the standard pulse oximetry (SpO2) and whether these applications can accurately determine hypoxia. METHODS: Three applications reportedly measuring SpO2 were downloaded onto an iPhone 5s. Two of these applications used the onboard light and camera lens "Pulse Oximeter" (Pox) and "Heart Rate and Pulse Oximeter" (Ox) and one used an external device that plugged into the iphone (iOx). Patients in the ED were enrolled with chief complaints of cardiac/pulmonary origin or a SpO2 ≤ 94%. All measurements were compared to controls. Concordance correlation coefficients, sensitivity, and specificity were calculated. RESULTS: A total of 191 patients were enrolled. The concordance correlation of iOx with control was 0.55 (CI 0.46, 0.63), POx was 0.01 (CI -0.09, 0.11), and Ox was 0.07 (CI -0.02, 0.15). 68/191 patients (35%) were found to have hypoxemia. Sensitivities for detecting hypoxia were 69%, 0%, and 7% for iOx, POx, and Ox, respectively. Specificities were 89%, 100%, and 89%. Even iOx (the most accurate) 21 (11%) were incorrectly classified nonhypoxic, and 22 (12%) were incorrectly classified hypoxic. CONCLUSIONS: While iOx has modest concordance with control, Ox and POx showed almost none. The iOx device was best in correctly identifying hypoxia patients, but almost 1/4 of patients were incorrectly classified. The three apps provided inaccurate SpO2 measurements and had limited to no ability to accurately detect hypoxia. These apps should not be relied upon to provide accurate SpO2 measurements in emergent, even austere conditions.