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.

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.

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.