Quantification of mast cells in central centrifugal cicatricial alopecia.

Background: Mast cells (MCs) have recently been implicated in lymphocytic scarring alopecias, which may share a common pathogenesis. MCs in central centrifugal cicatricial alopecia (CCCA) have not been studied. Objective: We looked for the presence of MCs in CCCA using 2 different stains to see if their numbers correlated with the number of hair follicles, the degree of inflammation and perifollicular fibrosis, disease duration and severity, and patient symptoms. Methods: We performed a retrospective review of biopsies of patients diagnosed with CCCA, tabulated MC counts and correlated them with histopathologic and clinical findings. Results: MC counts were significantly greater using immunoperoxidase staining with CD117 than Giemsa stain, and more were present when the isthmus level was included with the infundibulum. MC counts with CD117 immunostain significantly correlated with the degree of inflammation. MC counts with both stains were significantly associated with the degree of fibrosis independently and after controlling for other factors. Limitations: The study was limited by insufficient tissue remaining in a small number of the transversely cut blocks. Conclusion: Our findings may have therapeutic implications for CCCA and other types of lymphocytic scarring alopecia.

Biogeographic and disease-specific alterations in epidermal lipid composition and single-cell analysis of acral keratinocytes.

The epidermis is the outermost layer of skin. Here, we used targeted lipid profiling to characterize the biogeographic alterations of human epidermal lipids across 12 anatomically distinct body sites, and we used single-cell RNA-Seq to compare keratinocyte gene expression at acral and nonacral sites. We demonstrate that acral skin has low expression of EOS acyl-ceramides and the genes involved in their synthesis, as well as low expression of genes involved in filaggrin and keratin citrullination (PADI1 and PADI3) and corneodesmosome degradation, changes that are consistent with increased corneocyte retention. Several overarching principles governing epidermal lipid expression were also noted. For example, there was a strong negative correlation between the expression of 18-carbon and 22-carbon sphingoid base ceramides. Disease-specific alterations in epidermal lipid gene expression and their corresponding alterations to the epidermal lipidome were characterized. Lipid biomarkers with diagnostic utility for inflammatory and precancerous conditions were identified, and a 2-analyte diagnostic model of psoriasis was constructed using a step-forward algorithm. Finally, gene coexpression analysis revealed a strong connection between lipid and immune gene expression. This work highlights (a) mechanisms by which the epidermis is uniquely adapted for the specific environmental insults encountered at different body surfaces and (b) how inflammation-associated alterations in gene expression affect the epidermal lipidome.

Feasibility and integration of an intensive emergency pediatric care curriculum in Armenia.

BACKGROUND: Emergency pediatric care curriculum (EPCC) was developed to address the need for pediatric rapid assessment and resuscitation skills among out-of-hospital emergency providers in Armenia. This study was designed to evaluate the effectiveness of EPCC in increasing physicians' knowledge when instruction transitioned to local instructors. We hypothesize that (1) EPCC will have a positive impact on post-test knowledge, (2) this effect will be maintained when local trainers teach the course, and (3) curriculum will satisfy participants. METHODS: This is a quasi-experimental, pre-test/post-test study over a 4-year period from October 2014­November 2017. Train-the-trainer model was used. Primary outcomes are immediate knowledge acquisition each year and comparison of knowledge acquisition between two cohorts based on North American vs local instructors. Descriptive statistics was used to summarize results. Pre-post change and differences across years were analyzed using repeated measures mixed models. RESULTS: Test scores improved from pretest mean of 51% (95% CI 49.6 to 53.0%) to post-test mean of 78% (95% CI 77.0 to 79.6%, p < 0.001). Average increase from pre- to post-test each year was 27% (95% CI 25.3 to 28.7%). Improvement was sustained when local instructors taught the course (p = 0.74). There was no difference in improvement when experience in critical care, EMS, and other specialties were compared (p = 0.23). Participants reported satisfaction and wanted the course repeated. In 2017, EPCC was integrated within the Emergency Medicine residency program in Armenia. DISCUSSION: This program was effective at impacting immediate knowledge as well as participant satisfaction and intentions to change practice. This knowledge acquisition and reported satisfaction remained constant even when the instruction was transitioned to the local instructors after 2 years. Through a partnership between the USA and Armenia, we provided OH-EPs in Armenia with an intensive educational experience to attain knowledge and skills necessary to manage acutely ill or injured children in the out-of-hospital setting. CONCLUSIONS: EPCC resulted in significant improvement in knowledge and was well received by participants. This is a viable and sustainable model to train providers who have otherwise not had formal education in this field.

Eosinophilic fasciitis presenting as a unilateral, solitary plaque.

Eosinophilic fasciitis is a rare connective tissue disorder characterized by inflammation of the fascia that leads to painful, indurated skin. Because of its variable clinical presentation and overlap with conditions, such as morphea, the diagnosis of eosinophilic fasciitis can be challenging and relies on clinical presentation, histopathologic and laboratory analysis, and response to therapy. Herein, we present an unusual, solitary, isolated plaque with pathologic features and response to therapy most consistent with eosinophilic fasciitis.

Alteration of medical therapy in patients with heart failure relative to change in symptom severity.

In this observational analysis from the Practice Innovation and Clinical Excellence Registry®, we examined changes in guideline-directed medical therapies relative to changes in symptom severity in ambulatory patients with heart failure with reduced ejection fraction, finding change in medication more often occurring when patients were changing their New York Heart Association symptom severity, rather than during periods of stable symptoms. Additionally, despite being available for a year during the time of our analysis, the use of sacubitril/valsartan was extremely low, and most often added in the context of worsening symptoms, not how this drug was studied and not how the guidelines articulate its use.

Heart failure with mid-range ejection fraction: characterization of patients from the PINNACLE Registry®.

AIMS: Guidelines for management of patients with heart failure with mid-range ejection fraction [HFmrEF; left ventricular EF (LVEF) 41-49%] do not exist. Disagreement exists whether HFmrEF should be considered a distinct group. The aim of this study is to examine characteristics of patients with HFmrEF with HF with reduced EF (HFrEF; LVEF ≤ 40%) or preserved EF (HFpEF; LVEF ≥ 50%). METHODS AND RESULTS: We examined data collected in the American College of Cardiology's National Cardiovascular Data Registry (NCDR) Practice Innovation and Clinical Excellence (PINNACLE) Registry® for first HF patient visits between 1 May 2008 and 30 June 2016. Analysis was performed using ANOVA F-tests (or Kruskal-Wallis tests for non-normally distributed variables) for continuous parameters and χ2 tests for nominal covariates at the first diagnosed HF visit. Given the NCDR PINNACLE Registry® is a US-based registry, we opted to define HFmrEF as per the US guidelines, which define HFmrEF as LVEF 41-49% in contrast to European guidelines, which define HFmrEF as LVEF 40-49%. Among 1 103 386 patients with available data, 36.1% (N = 398 228) had HFrEF, 7.5% (N = 82 292) had HFmrEF, and 56.5% (N = 622 866) had HFpEF. Compared with patients with HFrEF or HFpEF, patients with HFmrEF had more prevalent coronary and peripheral artery disease and more history of myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery (all P < 0.001). Patients with HFmrEF were also more likely to have atrial fibrillation/flutter, diabetes, and chronic kidney disease and to have a history of tobacco use (both P < 0.001). Among those with EF assessment prior to this analysis, only 4.8% (N = 1032) previously had HFrEF that improved to HFmrEF; 32.9% (N = 7072) had HFpEF previously and progressed to HFmrEF. Those patients who transitioned from HFpEF to HFmrEF had considerably more complex profiles and were less aggressively managed compared with those who remained with HFmrEF (all P < 0.001). CONCLUSIONS: In this large descriptive analysis, patients with HFmrEF had an atherothrombotic phenotype distinct from other forms of HF. Interventions aimed at treating coronary ischaemia and addressing prevalent risk factors may play a particularly important role in the management of patients with HFmrEF.

End stage scurvy in the developed world: A diagnostic conundrum but not to be mistaken for pyoderma gangrenosum.

Scurvy is a clinical syndrome, resulting from ascorbic acid deficiency. Prevalence of the condition is now extremely low in the Western population and its diagnosis can be challenging without a high index of suspicion. When cases do present, they are often misdiagnosed initially. Therefore, a thorough history, physical exam, and laboratory evaluation are key to showing this now rare but extremely well-known disease. We report a case of scurvy manifesting as persistent non-healing lower-extremity ulcerations, initially mistaken for pyoderma gangrenosum. The patient responded to appropriate replacement therapy, but ulcers were slow to heal. As was the case in our patient, symptom reversal may require additional nutritional replacement. We encourage physicians to consider nutritional deficiencies in their differential diagnoses and highlight the incidence of malnutrition in the proper clinical setting to avoid diagnostic delay.

2D Visualization of the Psoriasis Transcriptome Fails to Support the Existence of Dual-Secreting IL-17A/IL-22 Th17 T Cells.

The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.

Umbilical condyloma lata.

Condyloma lata, a cutaneous manifestation of secondary syphilis, usually appear as verrucous papules and plaques in the anogenital area. Involvement of the umbilicus is very uncommon. Thus, awareness of this presentation, along with appropriate history, physical exam, and laboratory testing may aid clinicians in prompt and accurate diagnosis. We describe a patient with an unusual presentation of condyloma lata on the umbilicus.

No Causal Link between Phosphodiesterase Type 5 Inhibition and Melanoma.

PURPOSE: To examine the association between phosphodiesterase type 5 (PDE5) inhibitor use and melanoma by 1) conducting a systematic review of observational studies; and 2) determining if low PDE5A gene expression in human melanoma correlated with decreased overall survival. MATERIALS AND METHODS: A systematic search of observational studies examining the association between PDE5 inhibitor use and melanoma was performed through ClinicalTrials.gov, the Cochrane Library, EMBASE, PubMed, and Web of Science databases, and seven eligible studies were identified. PDE5A gene expression was analyzed with RNA sequencing data from 471 human melanoma samples obtained from The Cancer Genome Atlas. RESULTS: Four studies reported a positive association between PDE5 inhibitor use and melanoma, and three studies found no correlation. RNA sequencing data analysis revealed that under-expression of the PDE5A gene did not impact clinical outcomes in melanoma. CONCLUSIONS: There is currently no evidence to suggest that PDE5 inhibition in patients causes increased risk for melanoma. The few observational studies that demonstrated a positive association between PDE5 inhibitor use and melanoma often failed to account for major confounders. Nonetheless, the substantial evidence implicating PDE5 inhibition in the cyclic guanosine monophosphate (cGMP)-mediated melanoma pathway warrants further investigation in the clinical setting.