SpatialView: an interactive web application for visualization of multiple samples in spatial transcriptomics experiments.

MOTIVATION: Spatial transcriptomics (ST) experiments provide spatially localized measurements of genome-wide gene expression allowing for an unprecedented opportunity to investigate cellular heterogeneity and organization within a tissue. Statistical and computational frameworks exist that implement robust methods for pre-processing and analyzing data in ST experiments. However, the lack of an interactive suite of tools for visualizing ST data and results currently limits the full potential of ST experiments. RESULTS: To fill the gap, we developed SpatialView, an open-source web browser-based interactive application for visualizing data and results from multiple 10× Genomics Visium ST experiments. We anticipate SpatialView will be useful to a broad array of clinical and basic science investigators utilizing ST to study disease. AVAILABILITY AND IMPLEMENTATION: SpatialView is available at https://github.com/kendziorski-lab/SpatialView (and https://doi.org/10.5281/zenodo.10223907); a demo application is available at https://www.biostat.wisc.edu/˜kendzior/spatialviewdemo/.

Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders.

BACKGROUND: Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear. OBJECTIVE: We sought to understand spatial gene expression characteristics in these disorders. METHODS: We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion. RESULTS: CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation. CONCLUSIONS: Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.

Cutaneous granulomas associated with rubella virus: A clinical review.

Since the initial identification of vaccine-derived rubella virus (RuV) in the cutaneous granulomas of pediatric patients with inborn errors of immunity in 2014, more than 80 cases of RuV granulomas have been reported implicating both vaccine-derived and wild type RuV. Previously thought to arise exclusively in patients with significant immunocompromise, the identification of RuV granulomas in clinically immunocompetent patients adds nuance to our understanding of the interplay between host environment, immune dysregulation, and RuV granuloma formation. This review summarizes the literature on RuV granulomas including clinical and histopathologic features, proposed pathomechanisms supporting granuloma development, and potential therapeutic options. There is no standardized algorithm to guide the workup and diagnosis of suspected RuV granulomas. We highlight the importance of contributing RuV granuloma cases to ongoing Centers for Disease Control and Prevention surveillance efforts to monitor wild type and vaccine-derived RuV transmission. Studies advancing our understanding of RuV granulomas may provide insights into the role of viral infectious agents in granulomatous disease pathogenesis and guide the development of improved therapeutic options.

Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

Alpha-gal syndrome: A review for the dermatologist.

Alpha-gal syndrome (AGS) is an allergy to "red meat" and other mammalian products due to immunoglobulin E (IgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal), which is acquired following tick bites. Clinically, AGS presents with urticaria, abdominal pain, nausea, and occasionally anaphylaxis, and has wide inter- and intra-personal variability. Because symptom onset is generally delayed by 2 to 6 hours after meat consumption, AGS can be easily confused with other causes of urticaria and anaphylaxis, such as chronic spontaneous urticaria (CSU) and mast cell activation syndrome (MCAS). Diagnosis relies on a combination of clinical history, positive alpha-gal IgE blood testing and improvement on a mammalian-restricted diet. Management of the syndrome centers primarily on avoidance of mammalian meats (and occasionally dairy and other products) as well as acute management of allergic symptoms. Counseling about tick avoidance measures is also important as AGS will wane over time in many patients.

COVID-19 associated severe mucocutaneous blistering eruptions: A case series.

Mucocutaneous eruptions are associated with numerous infectious processes and can present as erythema multiforme (EM), reactive infectious mucocutaneous eruption (RIME), Stevens Johnson syndrome (SJS), or toxic epidermal necrolysis (TEN). Limited reports have detailed the association of these eruptions with SARS-CoV-2 infection. We present a series of eight cases of severe mucocutaneous blistering eruptions associated with SARS-CoV-2 infection. A retrospective case series was performed at six tertiary medical centers from March 1, 2020 to August 1, 2022. Inclusion criteria were met with a clinical diagnosis of EM, RIME, SJS, or TEN and a positive SARS-CoV-2 test (rapid antigen or polymerase chain reaction) less than 4 weeks prior to onset of dermatologic manifestation. Data was collected at time of each patient encounter. Eight patients met criteria with six pediatric patients (<18 years of age) having a median age of 15 years and two adult patients (>18 years of age) having a median age of 36 years. Patients were found to have a clinical diagnosis of RIME in 85.7% of cases. Oral mucosal involvement was the most common clinical finding (100%), followed by ocular (50.0%), urogenital (50.0%), and skin (37.5%) involvement. Evaluation did not reveal any additional infectious triggers in four patients. Evidence of possible concurrent or previous infectious triggers were identified in four patients. This case series highlights the development of severe mucocutaneous eruptions in association with COVID-19 infection, as well as the potential contributing role of concurrent or prior infections.

Healthcare educational debt in the united states: unequal economic impact within interprofessional team members.

BACKGROUND: Advancing healthcare access and quality for underserved populations requires a diverse, culturally competent interprofessional workforce. However, high educational debt may influence career choice of healthcare professionals. In the United States, health professions lack insight into the maximum educational debt that can be supported by current entry-level salaries. The purpose of this interprofessional economic analysis was to examine whether average educational debt for US healthcare graduates is supportable by entry-level salaries. Additionally, the study explored whether trainees from minoritized backgrounds graduate with more educational debt than their peers in physical therapy. METHODS: The study modeled maximum educational debt service ratios for 12 healthcare professions and 6 physician specialties, incorporating profession-specific estimates of entry-level salary, salary growth, national average debt, and 4 loan repayment scenarios offered by the US Department of Education Office of Student Financial Aid. Net present value (NPV) provided an estimate for lifetime "economic power" for the modeled careers. The study used a unique data source available from a single profession (physical therapy, N = 4,954) to examine whether educational debt thresholds based on the repayment model varied between minoritized groups and non-minoritized peers. RESULTS: High salary physician specialties (e.g. obstetrics/gynecology, surgery) and professions without graduate debt (e.g. registered nurse) met debt ratio targets under any repayment plan. Professions with strong salary growth and moderate debt (e.g. physician assistant) required extended repayment plans but had high career NPV. Careers with low salary growth and high debt relative to salary (e.g. physical therapy) had career NPV at the lowest range of modeled professions. 29% of physical therapy students graduated with more debt than could be supported by entry-level salaries. Physical therapy students from minoritized groups graduated with 10-30% more debt than their non-minoritized peers. CONCLUSIONS: Graduates from most healthcare professions required extended repayment plans (higher interest) to meet debt ratio benchmarks. For several healthcare professions, low debt relative to salary protected career NPV. Students from minoritized groups incurred higher debt than their peers in physical therapy.

Angiokeratoma-like purpuric palmar nodules following chemotherapy.

We describe a patient with leukemia undergoing chemotherapy who developed painful purpuric nodules of the digits. These findings were concerning for endocarditis (clinically) and angiokeratomas on gross histology. After extensive evaluation, we report the development of painful purpuric nodules as a likely side effect of the patient's therapeutic regimen (hydroxyurea, danorubicin, cytarabine, and methotrexate).

Intralesional corticosteroid-induced hypopigmentation and atrophy.

Intralesional corticosteroids are associated with various, uncommon, local adverse events [1]. Atrophy and hypopigmentation most commonlyremain localized to sites of injection. However, outward radiation in a linear, streaky pattern has been reported and is termed "perilesional/perilymphatic hypopigmentation or atrophy [2]." We report a case of this rare adverse event.

Occipital alopecia in a young man.

Lipedematous alopecia is a rare, non-androgenic form of alopecia that is challenging to diagnose, often requiring clinical-pathological correlation. The condition has been reported predominantly in African-American females, but more recently has been described in a broader demographic [1,2]. We describe a rare case of a young Caucasian man with isolated lipedematous alopecia who presented with a boggy, erythematous plaque with alopecia of the occipital scalp and subcutaneous thickening with lymphocytic dermal infiltrate and decreased anagen hairs on histology.

Angioinvasive fungal infections impacting the skin: Diagnosis, management, and complications.

As discussed in the first article in this continuing medical education series, angioinvasive fungal infections pose a significant risk to immunocompromised and immunocompetent patients alike, with a potential for severe morbidity and high mortality. The first article in this series focused on the epidemiology and clinical presentation of these infections; this article discusses the diagnosis, management, and potential complications of these infections. The mainstay diagnostic tests (positive tissue culture with histologic confirmation) are often supplemented with serum biomarker assays and molecular testing (eg, quantitative polymerase chain reaction analysis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry) to ensure proper speciation. When an angioinvasive fungal infection is suspected or diagnosed, further workup for visceral involvement also is essential and may partially depend on the organism. Different fungal organisms have varied susceptibilities to antifungal agents, and knowledge on optimal treatment regimens is important to avoid the potential complications associated with undertreated or untreated fungal infections.

Angioinvasive fungal infections impacting the skin: Background, epidemiology, and clinical presentation.

Angioinvasive fungal infections cause significant morbidity and mortality because of their propensity to invade blood vessel walls, resulting in catastrophic tissue ischemia, infarct, and necrosis. While occasionally seen in immunocompetent hosts, opportunistic fungi are emerging in immunosuppressed hosts, including patients with hematologic malignancy, AIDS, organ transplant, and poorly controlled diabetes mellitus. The widespread use of antifungal prophylaxis has led to an "arms race" of emerging fungal resistance patterns. As the at-risk population expands and new antifungal resistance patterns develop, it is critical for dermatologists to understand and recognize angioinvasive fungal pathogens, because they are often the first to encounter the cutaneous manifestations of these diseases. Rapid clinical recognition, histopathologic, and culture confirmation can help render a timely, accurate diagnosis to ensure immediate medical and surgical intervention. Superficial dermatophyte infections and deep fungal infections, such as blastomycosis and histoplasmosis, have been well characterized within the dermatologic literature, and therefore this article will focus on the severe infections acquired by angioinvasive fungal species, including an update on new and emerging pathogens. In the first article in this continuing medical education series, we review the epidemiology and cutaneous manifestations. The second article in the series focuses on diagnosis, treatment, and complications of these infections.

Increasing Access to High Value Care: Preventing Complications in Common Disorders.

Most infantile hemangiomas (IHs), the most common vascular tumors of childhood, evolve without complications; however 10% to 12% require specialty referral for treatment. To emphasize the complications of late referral, we present a case of necrotizing infection within a segmental IH leading to sepsis. Early evaluation by a pediatric dermatologist could have prevented this life-threatening and disfiguring complication. We discuss how teledermatology would enable rapid triage of such critical cases in underserved areas, increasing access to high-value care and optimizing outcomes for our most vulnerable patients.

The effect of smoking on DNA methylation of peripheral blood mononuclear cells from African American women.

BACKGROUND: Regular smoking is associated with a wide variety of syndromes with prominent inflammatory components such as cancer, obesity and type 2 diabetes. Heavy regular smoking is also associated with changes in the DNA methylation of peripheral mononuclear cells. However, in younger smokers, inflammatory epigenetic findings are largely absent which suggests the inflammatory response(s) to smoking may be dose dependent. To help understand whether peripheral mononuclear cells have a role in mediating these responses in older smokers with higher cumulative smoke exposure, we examined genome-wide DNA methylation in a group of well characterized adult African American subjects informative for smoking, as well as serum C-reactive protein (CRP) and interleukin-6 receptor (IL6R) levels. In addition, complementary bioinformatic analyses were conducted to delineate possible pathways affected by long-term smoking. RESULTS: Genome-wide DNA methylation analysis with respect to smoking status yielded 910 significant loci after Benjamini-Hochberg correction. In particular, two loci from the AHRR gene (cg05575921 and cg23576855) and one locus from the GPR15 gene (cg19859270) were identified as highly significantly differentially methylated between smokers and non-smokers. The bioinformatic analyses showed that long-term chronic smoking is associated with altered promoter DNA methylation of genes coding for proteins mapping to critical sub-networks moderating inflammation, immune function, and coagulation. CONCLUSIONS: We conclude that chronic regular smoking is associated with changes in peripheral mononuclear cell methylation signature which perturb inflammatory and immune function pathways and may contribute to increased vulnerability for complex illnesses with inflammatory components.

Micronutrient Deficiencies in Patients With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) can cause micronutrient deficiencies that have cutaneous manifestations. Dermatologists may be the first to identify an undiagnosed micronutrient deficiency in the affected population. The approach to monitoring and repleting a micronutrient deficiency may be impacted by factors such as IBD activity and potential interactions between supplements and medications used to treat IBD. In this article, we review the most common micronutrient deficiencies observed in patients with IBD and their associated cutaneous manifestations. We also provide guidance for monitoring and supplementing each micronutrient discussed.

Culprits of Medication-Induced Telogen Effluvium, Part 2.

Telogen effluvium (TE) is a common mechanism underlying medication-related alopecia. The inciting cause of TE may be difficult to identify due to delays in clinically apparent hair loss. Because medication-induced TE is a nonscarring alopecia that typically is reversible, appropriate management requires identification of the underlying trigger and cessation of potential culprit medications. In part 2 of this 2-part series on medication-induced TE, we focus on anticoagulant and antihypertensive medications.