Baseline skin cytokine profiles determined by RNA in situ hybridization correlate with response to dupilumab in patients with eczematous dermatitis.

BACKGROUND: Dupilumab has revolutionized the treatment of atopic dermatitis. However, not all patients respond optimally, and this may relate to underlying molecular heterogeneity. Nevertheless, clinically useful and accessible methods to assess such heterogeneity have not been developed. OBJECTIVE: We assessed whether cytokine staining and/or histologic features correlate with clinical response to dupilumab in patients with eczematous dermatitis. METHODS: We retrospectively analyzed biopsies from 61 patients with eczematous dermatitis treated with dupilumab (90.2% met Hanifin-Rajka criteria for atopic dermatitis). RNA in situ hybridization was used to measure markers of type 2 (interleukin [IL]4, IL13), type 1 (interferon gamma) and type 3 (IL17A, IL17F, IL22) inflammation. Histologic features were also assessed. Patterns were compared among complete (n = 16), partial (n = 37), and nonresponders (n = 8) to dupilumab. RESULTS: We found that increased IL13 expression was associated with optimal response to dupilumab. In contrast, nonresponders tended to express less IL13 and relatively greater levels of type 1 and 3 cytokines. In addition, certain histologic features tended to correlate with improved response to dupilumab. LIMITATIONS: Retrospective approach and small size of the nonresponder group. CONCLUSION: Cytokine RNA in situ hybridization may aid in treatment selection for eczematous disorders. Moreover, personalization of treatment selection for inflammatory skin diseases may be possible.

Middle school meets MedEd: Five K-12 teaching strategies medical educators should know.

While the COVID-19 pandemic has challenged the way medical educators develop and deliver content, it has also presented an opportunity for innovation. As students, trainees, and faculty design new curricula and employ new learning modalities, primary and secondary school offer a wealth of teaching strategies and ideas for medical education. In this Personal View, the authors share their experience as former middle school teachers and current medical students to offer five valuable teaching strategies - backwards planning, the 5E model, setting norms, scaffoldings, and checks for understanding (CFUs) - for medical educators to incorporate into their practice.

Peer-Assisted Learning in a Longitudinal Hybrid Physical Exam Course.

Peer-assisted learning (PAL) improves teaching skills and self-confidence for instructors and creates a supportive learning climate for learners. We developed a PAL hybrid teaching structure for our physical exam course by partnering upper-level peer instructors with faculty co-instructors and evaluated its impact on upper-level student peer instructors and first-year student learners using quantitative and qualitative methods. The PAL component of the hybrid teaching structure was perceived to have important benefits for all and salient limitations for student learners. The hybrid nature of the course provided a unique vantage point for evaluation of PAL and we theorize that faculty co-instructors may balance some of the perceived limitations of PAL.

Vascular oxidative stress causes neutrophil arrest in brain capillaries, leading to decreased cerebral blood flow and contributing to memory impairment in a mouse model of Alzheimer’s disease.

INTRODUCTION: In this study, we explore the role of oxidative stress produced by NOX2-containing NADPH oxidase as a molecular mechanism causing capillary stalling and cerebral blood flow deficits in the APP/PS1 mouse model of AD. METHODS: We inhibited NOX2 in APP/PS1 mice by administering a 10 mg/kg dose of the peptide inhibitor gp91-ds-tat i.p., for two weeks. We used in vivo two-photon imaging to measure capillary stalling, penetrating arteriole flow, and vascular inflammation. We also characterized short-term memory function and gene expression changes in cerebral microvessels. RESULTS: We found that after NOX2 inhibition capillary stalling, as well as parenchymal and vascular inflammation, were significantly reduced. In addition, we found a significant increase in penetrating arteriole flow, followed by an improvement in short-term memory, and downregulation of inflammatory gene expression pathways. DISCUSSION: Oxidative stress is a major mechanism leading to microvascular dysfunction in AD, and represents an important therapeutic target.

Antibiotic Resistance Risk with Oral Tetracycline Treatment of Acne Vulgaris.

Almost 1 billion people worldwide have acne, and oral tetracyclines, including doxycycline and minocycline, are effective and frequently prescribed treatments for acne. However, there is growing concern for the development of antibiotic resistance with such widespread utilization by dermatologists. Additionally, tetracyclines are known to have various potential side effects, including gut dysbiosis, gastrointestinal upset, photosensitivity, dizziness, and vertigo. However, in 2018 a novel narrow-spectrum tetracycline, sarecycline, was Food and Drug Administration-approved to treat moderate-to-severe acne vulgaris in patients 9-years-old and above. Sarecycline was designed to target Cutibacterium acnes, the pathogenic bacterium in acne vulgaris, which may reduce the risk of resistance. This paper examines the growing concerns of antibiotic resistance due to oral tetracycline usage in the treatment of acne vulgaris, with a focus on the promising third-generation, narrow-spectrum tetracycline, sarecycline.

The pipeline starts in medical school: characterizing clinician-educator training programs for U.S. medical students.

In the past forty years, clinician-educators have become indispensable to academic medicine. Numerous clinician-educator-training programs exist within graduate medical education (GME) as clinician-educator tracks (CETs). However, there is a call for the clinician-educator pipeline to begin earlier. This work aims to identify and characterize clinician-educator track-like programs (CETLs) available in undergraduate medical education (UME). We developed an algorithm of 20 individual keyword queries to search the website of each U.S. allopathic medical school for CETLs. We performed the web search between March to April 2021 and repeated the search between July and September 2021. The search identified CETLs for 79 (51%) of the 155 U.S. allopathic medical schools. The identified CETLs commonly address the clinician-educator competency of educational theory (86%, 68/79), are formally organized as concentrations or analogous structures (52%, 41/79), and span all four years of medical school (37%, 29/79). The prevalence of CETLs varies with geography and medical school ranking. We provide an overview of the current state of CETLs as assessed from institutional websites. To create a future with a sustainable output of skilled clinician-educators, UME must continue to increase the number and quality of CETLs.

Increasing cerebral blood flow improves cognition into late stages in Alzheimer's disease mice.

Alzheimer's disease is associated with a 20-30% reduction in cerebral blood flow. In the APP/PS1 mouse model of Alzheimer's disease, inhibiting neutrophil adhesion using an antibody against the neutrophil specific protein Ly6G was recently shown to drive rapid improvements in cerebral blood flow that was accompanied by an improvement in performance on short-term memory tasks. Here, in a longitudinal aging study, we assessed how far into disease development a single injection of anti-Ly6G treatment can acutely improve short-term memory function. We found that APP/PS1 mice as old as 15-16 months had improved performance on the object replacement and Y-maze tests of spatial and working short-term memory, measured at one day after anti-Ly6G treatment. APP/PS1 mice at 17-18 months of age or older did not show acute improvements in cognitive performance, although we did find that capillary stalls were still reduced and cerebral blood flow was still increased by 17% in 21-22-months-old APP/PS1 mice given anti-Ly6G antibody. These data add to the growing body of evidence suggesting that cerebral blood flow reductions are an important contributing factor to the cognitive dysfunction associated with neurodegenerative disease. Thus, interfering with neutrophil adhesion could be a new therapeutic approach for Alzheimer's disease.

High fat diet worsens Alzheimer's disease-related behavioral abnormalities and neuropathology in APP/PS1 mice, but not by synergistically decreasing cerebral blood flow.

Obesity is linked to increased risk for and severity of Alzheimer's disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We recently showed that non-flowing capillaries, caused by adhered neutrophils, contribute to CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensory-motor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd on capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting that capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd.