Epidemiologic Analysis of Chilblains Cohorts Before and During the COVID-19 Pandemic.

Importance: Beginning in March 2020, case reports and case series linked the COVID-19 pandemic with an increased occurrence of chilblains, but this association has not been evaluated in an epidemiologic study. Objective: To assess whether a correlation exists between COVID-19 incidence and chilblains incidence. Design, Setting, and Participants: A retrospective cohort study was conducted within the Kaiser Permanente Northern California system from January 1, 2016, to December 31, 2020; health plan members of all ages were included. Exposure: COVID-19 incidence in 207 location-months, representing 23 geographic locations in northern California across 9 months. Main Outcome and Measures: Chilblains incidence was the main outcome. The association of chilblains incidence with COVID-19 incidence across the 207 location-months was measured using the Spearman rank correlation coefficient. Results: Of 780 patients with chilblains reported during the pandemic, 464 were female (59.5%); mean (SD) age was 36.8 (21.8) years. COVID-19 incidence was correlated with chilblains incidence at 207 location-months (Spearman coefficient 0.18; P = .01). However, only 17 of 456 (3.7%) patients with chilblains tested during the pandemic were positive for SARS-CoV-2, and only 9 of 456 (2.0%) were positive for SARS-CoV-2 within 6 weeks of the chilblains diagnosis. Test results of 1 of 97 (1.0%) patients were positive for SARS-CoV-2 IgG antibodies. Latinx patients were disproportionately affected by COVID-19 but not by chilblains. Conclusions and Relevance: This cohort study found that in northern California, the incidence of chilblains increased during the pandemic but was correlated weakly with the incidence of COVID-19 across 207 location-months. These findings may have resulted from a causal role of COVID-19, increased care-seeking by patients with chilblains during the pandemic, or changes in behavior during shelter in place.

Cutaneous manifestations of COVID-19: a systematic review and analysis of individual patient-level data.

Distinctive patterns in the cutaneous manifestations of COVID-19 have been recently reported. We conducted a systematic review to identify case reports and case series characterizing cutaneous manifestations of confirmed COVID-19. Key demographic and clinical data from each case were extracted and analyzed. The primary outcome measure was risk factor analysis of skin related outcomes for severe COVID-19 disease. Seventy-one case reports and series comprising 144 cases of cutaneous involvement in COVID-19 were included. The most frequently occurring morphologies were: morbilliform (30.6%), varicelliform (18.8%), urticarial (13.2%), chilblains-like (12.5%), and acro-ischemic (9%). The median age of patients was 51 years (mean: 45.9, range: 0 to 91). Patients with chilblains-like eruptions had lower frequencies of extracutaneous COVID-19 symptoms (5/18, 27.8%, P<0.05) and were less likely to have severe COVID-19 disease (2/18, 11%, 95% CI 1.4% to 34.7%, P=0.02). Patients with livedoid and acro-ischemic morphologies had severe COVID-19 more frequently than those with other morphologies (17/21, 81%, 95% CI 58.0% to 94.5%, P<0.0001). The most frequently observed cutaneous manifestations of COVID-19 (morbilliform, varicelliform, and urticarial) are well-described patterns of viral exanthems. However, chilblains-like, livedoid, and acro-ischemic morphologies are not traditionally associated with viral infections and were significantly associated with severity of COVID-19 disease.

Generalized fixed drug eruption to piperacillin/tazobactam and review of literature.

Fixed drug eruption (FDE) is an adverse drug reaction characterized by the development of well-circumscribed, round, dusky erythematous macules and plaques on cutaneous or mucosal surfaces. The reaction occurs on the same mucosal or cutaneous site with subsequent exposures to the offending drug. Although FDE usually manifests as a single lesion, in rare instances, more than one lesion may arise and this is referred to as a generalized eruption. Herein, we present a 31year-old man with history of cystic fibrosis who developed a generalized fixed drug eruption to piperacillin/tazobactam (Zosyn, Pfizer). We discuss our patient's course and review causes and outcomes of generalized fixed drug eruptions in the literature.

Ultraviolet Radiation Inhibits Mammary Carcinogenesis in an ER-Negative Murine Model by a Mechanism Independent of Vitamin D3.

Three decades ago, the Garlands postulated that vitamin D3 produced in the skin by ultraviolet radiation (UVR)-induced conversion of 7-dehydrocholesterol to pre-D3 has anticancer effects, thus triggering more than 9,500 publications on D3 and cancer. Here, we report that UVR treatment of transgenic mice of the well-established C3(1)/SV40 Tag mammary cancer model significantly inhibits both autochthonous carcinogenesis and allograft tumor growth, but in contrast neither dietary nor topical D3 influences mammary carcinogenesis in this specific mouse model. Furthermore, UVR's inhibitory effects occur irrespective of whether or not the treatment increases circulating D3 in the mice. The inhibitory effect of UVR on autochthonous tumors occurs at or before the stage of ductal carcinoma in situ. Our studies indicate clearly that UVR can exert D3-independent anticancer effects in C3(1)/SV40 Tag mice. Therefore, supplemental D3 may not mimic all possible beneficial effects of UVR, and uncovering non-D3-mediated mechanisms of UVR tumor inhibition may lead to novel strategies for cancer prevention. Cancer Prev Res; 11(7); 383-92. ©2018 AACR.

Combination therapy of autologous adipose mesenchymal stem cell-enriched, high-density lipoaspirate and topical timolol for healing chronic wounds.

Chronic venous leg ulcers are profoundly debilitating and result in billions in health care expenditure. Thus, there is a quest for engineered and innovative approaches. Herein we present a 63-year-old patient with a 30 year history of venous stasis and left lower extremity ulcers, which have been refractory to standard of care, anticoagulation and venous stripping. The medial ulcer was treated with transplantation of autologous adipose mesenchymal stem cell (AMSC)-enriched, high-density lipoaspirate (HDL) on OASIS wound matrix and compression therapy. The lateral ulcer was treated as a control with standard debridement and compression therapy. Four weeks later, both ulcers received daily topical timolol. Three months later, the test ulcer was completely epithelized and remains healed for over 15 months. However, the control showed minimal signs of improvement. In companion studies in our laboratory, human AMSC were cultured in Minimum Essential Medium Eagle Alpha Modifications (MEMα) with fetal bovine serum (FBS). Timolol was administered to AMSC prior to treatment with epinephrine and 104 bacteria/ml heat-killed Staphylococcus aureus. The MEMα with FBS devoid of AMSC served as a background control. After 24 h, cell culture supernatants and protein lysates were collected to determine cytokine production. There was a statistical significant decrease in pro-inflammatory interleukin-6 and -8 induced by the bacteria (to model the wound environment) in AMSC in the presence of timolol compared with control (p < 0.5). This is the first case of a successful combination of autologous AMSC-enriched, HDL with topical timolol for the healing of chronic venous leg ulcers. Copyright © 2016 John Wiley & Sons, Ltd.

Prehospital hypertonic fluid resuscitation for trauma patients: A systematic review and meta-analysis.

BACKGROUND: Prehospital assessment of a patient's circulation status and appropriate resuscitation with intravenous fluids plays a critical role in patients with obvious hemorrhage or systolic blood pressure below 90 mm Hg. OBJECTIVES: We assessed the efficacy and safety of prehospital administration of crystalloids or colloids to improve the survival rate of trauma patients with acceptable safety profile. DATA SOURCES: We searched SCOPUS, Embase, TRIP database, Cochrane Central Register of Controlled Trials, Ovid MEDLINE, and PubMed as per search protocol from January 1, 1900 to February 12, 2015. STUDY ELIGIBILITY CRITERIA: All randomized controlled trials were considered. PARTICIPANTS AND INTERVENTIONS: All patients had penetrating or blunt trauma, excluding traumatic brain or thermal injuries. At least one of the comparators should be a crystalloid or colloid. STUDY APPRAISAL AND SYNTHESIS METHODS: Detailed search strategy was developed and utilized. Duplicates were removed from the search results. We, the co-first authors (C.d.C. and F.G.), independently reviewed the article titles and abstracts to assess eligibility. Eligible articles were downloaded for full text review to determine inclusion in the review and analysis. We (C.d.C. and F.G.) performed a methodological quality assessment of each included article. The primary outcome was mortality. The secondary outcomes included adverse events, infections, multiple organ dysfunction score, and length of stay at the hospital. Heterogeneity was measured by I value. An I value greater than 50% was considered to be substantial heterogeneity. Fixed effect analysis and random effect analysis were performed when needed. RESULTS: A total of nine trials (3,490 patients) were included in the systematic review, and six trials were included in meta-analyses. There were no significant differences between hypertonic saline with dextran and lactated Ringer's solution in 1 day using two studies (2.91; 95% CI, 0.58-14.54; p = 0.19) and 28- to 30-day survival rates using another two studies (1.47; 95% CI, 0.30-7.18; p = 0.63). Adding dextran to hypertonic saline did not increase the survival rate (0.94; 95% CI, 0.65-1.34; p = 0.71). Overall, complications were comparable between all groups. LIMITATIONS: The quality of some of the included studies is not optimal. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: There is no beneficial effect of hypertonic saline with or without dextran in general traumatic patients. Further trials to evaluate its benefit in patients with penetrating trauma requiring surgery are warranted. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level I.

A critical review of personal statements submitted by dermatology residency applicants.

Background. A strong personal statement is deemed favorable in the overall application review process. However, research on the role of personal statements in the application process is lacking. Objective. To determine if personal statements from matched applicants differ from unmatched applicants. Methods. All dermatology residency applications (n = 332) submitted to UC Davis Dermatology in the year of 2012 were evaluated. Two investigators identified the characteristics and recurring themes of content present in the personal statements. Then, both investigators individually evaluated the content of these personal statements in order to determine if any of the defined themes was present. Chi-square, Fisher's exact, and reliability tests were used. Results. The following themes were emphasized more often by the matched applicants than the unmatched applicants as their reasons for going into dermatology are to study the cutaneous manifestations of systemic disease (33.8% versus 22.8%), to contribute to the literature gap (8.3% versus 1.1%), and to study the pathophysiology of skin diseases (8.3% versus 2.2%; P ≤ 0.05 for all). Conclusion. The prevalence of certain themes in personal statements of dermatology applicants differs according to match status; nevertheless, whether certain themes impact match outcome needs to be further elucidated.

Dermatology residency selection criteria with an emphasis on program characteristics: a national program director survey.

Background. Dermatology residency programs are relatively diverse in their resident selection process. The authors investigated the importance of 25 dermatology residency selection criteria focusing on differences in program directors' (PDs') perception based on specific program demographics. Methods. This cross-sectional nationwide observational survey utilized a 41-item questionnaire that was developed by literature search, brainstorming sessions, and online expert reviews. The data were analyzed utilizing the reliability test, two-step clustering, and K-means methods as well as other methods. The main purpose of this study was to investigate the differences in PDs' perception regarding the importance of the selection criteria based on program demographics. Results. Ninety-five out of 114 PDs (83.3%) responded to the survey. The top five criteria for dermatology residency selection were interview, letters of recommendation, United States Medical Licensing Examination Step I scores, medical school transcripts, and clinical rotations. The following criteria were preferentially ranked based on different program characteristics: "advanced degrees," "interest in academics," "reputation of undergraduate and medical school," "prior unsuccessful attempts to match," and "number of publications." Conclusions. Our survey provides up-to-date factual data on dermatology PDs' perception in this regard. Dermatology residency programs may find the reported data useful in further optimizing their residency selection process.

Crosstalk between adrenergic and toll-like receptors in human mesenchymal stem cells and keratinocytes: a recipe for impaired wound healing.

Previous studies demonstrate that skin wounds generate epinephrine (EPI) that can activate local adrenergic receptors (ARs), impairing healing. Bacterially derived activators of Toll-like receptors (TLRs) within the wound initiate inflammatory responses and can also impair healing. In this study, we examined the hypothesis that these two pathways crosstalk to one another, using EPI and macrophage-activating lipopeptide-2 (MALP2) to activate ARs and TLR2, respectively, in human bone marrow-derived mesenchymal stem cells (BM-MSCs) and neonatal keratinocytes (NHKs). BM-MSCs exposed to EPI significantly (p < .05) increased TLR2 message (sevenfold BM-MSCs), TLR2 protein (twofold), and myeloid differentiation factor 88 (MyD88) (fourfold). Conversely, activation of TLR2 by MALP2 in these cells increased ß2-AR message (twofold in BM-MSCs, 2.7-fold in NHKs), ß2-AR protein (2.5-fold), phosphorylation of ß-AR-activated kinase (p-BARK, twofold), and induced release of EPI from both cell types (twofold). Treating cells with EPI and MALP2 together, as would be encountered in a wound, increased ß2-AR and p-BARK protein expression (sixfold), impaired cell migration (BM-MSCs- 21%↓ and NHKs- 60%↓, p < .002), and resulted in a 10-fold (BM-MSCs) and 51-fold (NHKs) increase in release of IL-6 (p < .001) responses that were remarkably reduced by pretreatment with ß2-AR antagonists. In vivo, EPI-stressed animals exhibited impaired healing, with elevated levels of TLR2, MyD88, and IL-6 in the wounds (p < .05) relative to nonstressed controls. Thus, our data describe a recipe for decreasing cell migration and exacerbating inflammation via novel crosstalk between the adrenergic and Toll-like receptor pathways in BM-MSCs and NHKs.

Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis.

Lichen planus (LP) is a chronic inflammatory disorder that most often affects middle-aged adults. LP can involve the skin or mucous membranes including the oral, vulvovaginal, esophageal, laryngeal, and conjunctival mucosa. It has different variants based on the morphology of the lesions and the site of involvement. The literature suggests that certain presentations of the disease such as esophageal or ophthalmological involvement are underdiagnosed. The burden of the disease is higher in some variants including hypertrophic LP and erosive oral LP, which may have a more chronic pattern. LP can significantly affect the quality of life of patients as well. Drugs or contact allergens can cause lichenoid reactions as the main differential diagnosis of LP. LP is a T-cell mediated immunologic disease but the responsible antigen remains unidentified. In this paper, we review the history, epidemiology, and clinical subtypes of LP. We also review the histopathologic aspects of the disease, differential diagnoses, immunopathogenesis, and the clinical and genetic correlations.

Catecholamine stress alters neutrophil trafficking and impairs wound healing by ß2-adrenergic receptor-mediated upregulation of IL-6.

Stress-induced hormones can alter the inflammatory response to tissue injury; however, the precise mechanism by which epinephrine influences inflammatory response and wound healing is not well defined. Here we demonstrate that epinephrine alters the neutrophil (polymorphonuclear leukocyte (PMN))-dependent inflammatory response to a cutaneous wound. Using noninvasive real-time imaging of genetically tagged PMNs in a murine skin wound, chronic, epinephrine-mediated stress was modeled by sustained delivery of epinephrine. Prolonged systemic exposure of epinephrine resulted in persistent PMN trafficking to the wound site via an IL-6-mediated mechanism, and this in turn impaired wound repair. Further, we demonstrate that ß2-adrenergic receptor-dependent activation of proinflammatory macrophages is critical for epinephrine-mediated IL-6 production. This study expands our current understanding of stress hormone-mediated impairment of wound healing and provides an important mechanistic link to explain how epinephrine stress exacerbates inflammation via increased number and lifetime of PMNs.

Allergic contact dermatitis to metal allergens in Iran.

BACKGROUND: Metallic allergens such as nickel are among the most common causes of allergic contact dermatitis (ACD), but frequencies of contact dermatitis to these allergens may vary in different areas. OBJECTIVES: This study aimed to determine the frequencies of ACD caused by three common metallic allergens: nickel sulfate; potassium dichromate; and cobalt chloride. METHODS: Data for 1137 patients with clinical diagnoses of contact dermatitis and/or atopic dermatitis evaluated by patch testing in Iran during a 5-year period were retrospectively studied to establish the frequencies of hypersensitivity to these metallic allergens. RESULTS: A total of 313 patients (27.5%) gave positive patch test results for at least one metallic allergen. Allergy to nickel (229 cases, 20.0%) was the most commonly observed, followed by allergy to cobalt (90 cases, 8.0%) and allergy to chromium (70 cases, 6.2%). Nickel allergy was significantly more frequent in females and in subjects aged <40 years, whereas chromium hypersensitivity was more common in males and in subjects aged >40 years. Sensitivity to nickel or chromium was a risk factor for cobalt allergy. CONCLUSIONS: Nickel was most commonly identified as a metallic allergen in Iran and tended to affect women aged <40 years. Regulations pertaining to nickel release may decrease the frequency of nickel hypersensitivity in Iran.

Treatment of female pattern hair loss.

Female pattern hair loss (FPHL) as a distinctive entity was first described about 30 years ago. The objective of this study was to perform a systematic review of all randomized controlled trials for treatment of FPHL. A preliminary search was carried out in several databases up to August 2008 to identify all randomized controlled trials on nonsurgical interventions for treatment of FPHL. Studies reporting fewer than 10 patients and non-English articles were excluded. Additionally, references of relevant articles and reviews were checked manually in search for additional sources. Among 238 citations found in the preliminary search, 12 fulfilled all criteria to be included in the systematic review. Topical minoxidil 1% to 5% for 24 to 48 weeks was shown to be effective in FPHL and its effect was not related to age or androgen level of patients. In addition, it may be effective in women with FPHL, both with and without hyperandrogenism, and in young and old premenopausal or postmenopausal. In patients with increased serum androgens, oral flutamide but not finasteride or cyproterone acetate was more effective than no treatment. Topical minoxidil is effective in patients with FPHL, with or without hyperandrogenism, but there is limited evidence for the efficacy of antiandrogens.