of the lower extremity are often misdiagnosed as cellulitis (aka "pseudocellulitis") and treated with antibiotics and/or hospitalization. There is limited data on the cost and complications from misdiagnosed cellulitis. OBJECTIVE To characterize the national health care burden of misdiagnosed cellulitis in patients admitted for treatment of lower extremity cellulitis. DESIGN, SETTING, AND PARTICIPANTSCross-sectional study using patients admitted from the emergency department (ED) of a large urban hospital with a diagnosis of lower extremity cellulitis between June 2010 and December 2012. Patients who were discharged with a diagnosis of cellulitis were categorized as having cellulitis, while those who were given an alternative diagnosis during the hospital course, on discharge, or within 30 days of discharge were considered to have pseudocellulitis. A literature review was conducted for calculation of large-scale costs and complication rates. We obtained national cost figures from the Medical Expenditure Panel Survey (MEPS), provided by the Agency for Healthcare Research and Quality (AHRQ) for 2010 to calculate the hospitalization costs per year attributed to misdiagnosed lower extremity pseudocellulitis.EXPOSURES The exposed group was composed of patients who presented to and were admitted from the ED with a diagnosis of lower extremity cellulitis. MAIN OUTCOMES AND MEASURESPatient characteristics, hospital course, and complications during and after hospitalization were reviewed for each patient, and estimates of annual costs of misdiagnosed cellulitis in the United States. RESULTSOf 259 patients, 79 (30.5%) were misdiagnosed with cellulitis, and 52 of these misdiagnosed patients were admitted primarily for the treatment of cellulitis. Forty-four of the 52 (84.6%) did not require hospitalization based on ultimate diagnosis, and 48 (92.3%) received unnecessary antibiotics. We estimate cellulitis misdiagnosis leads to 50 000 to 130 000 unnecessary hospitalizations and $195 million to $515 million in avoidable health care spending. Unnecessary antibiotics and hospitalization for misdiagnosed cellulitis are projected to cause more than 9000 nosocomial infections, 1000 to 5000 Clostridium difficile infections, and 2 to 6 cases of anaphylaxis annually.CONCLUSIONS AND RELEVANCE Misdiagnosis of lower extremity cellulitis is common and may lead to unnecessary patient morbidity and considerable health care spending.

The effects of UVR on the skin include tanning, carcinogenesis, immunomodulation, and synthesis of vitamin D, among others. Melanocortin 1 receptor polymorphisms correlate with skin pigmentation, UV sensitivity, and skin cancer risk. This article reviews pathways through which UVR induces cutaneous stress and the pigmentation response. Modulators of the UV tanning pathway include sunscreen agents, MC1R activators, adenylate cyclase activators, phosphodiesterase 4D3 inhibitors, T oligos, and MITF regulators such as histone deacetylase (HDAC)-inhibitors. UVR, as one of the most ubiquitous carcinogens, represents both a challenge and enormous opportunity in skin cancer prevention.

SUMMARYThe presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.