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High perioperative patient anxiety is predictive of worse postoperative pain and quality of life. Several Mohs micrographic surgery (MMS) patient characteristics influence anxiety; however, the contributions of certain factors remain uncertain.Investigate factors influencing perioperative MMS patient anxiety, especially those with debated impact or unclear data.The authors surveyed 145 adult patients receiving MMS performed by a single MMS surgeon from 2018 to 2020. Patients self-reported demographics, history, and 10-point visual analog scale anxiety assessments at multiple stages. Health care provider (HCP)-perceived anxiety assessments were queried. A stepwise multiple regression modeling approach was used to explore potential factors.Younger age, female sex, and a self-reported history of anxiety confirmed by prior HCP diagnosis were significant predictors of pre-MMS anxiety. Postoperative anxiety increased with more layers removed and higher pre-MMS anxiety. HCP-perceived patient anxiety increased with younger patient age, more layers removed, prior skin cancer removal, and HCP-perceived pre-MMS patient anxiety.Anxiety-reducing interventions should target young female patients with a history of HCP-diagnosed anxiety, and patients with more layers removed. Prior skin cancer removal is associated with increased HCP-perceived intraoperative patient anxiety; however, it is not significant for patient-reported anxiety. Pre-MMS consultation may not be effective for anxiety reduction.

Objective: To explore mortality outcome usage in Cochrane systematic reviews and Core Outcome Sets for research.Study Design and Setting: Cochrane PICO searches identified Cochrane reviews (published January 2015-March 2021) including mortality outcomes. These outcomes were categorized according to terminology used: all-cause mortality, cause-specific mortality, infant mortality, maternal mortality, survival.Mortality outcomes in Core Outcome Sets (published until 2019 on the Core Outcome Measures in Effectiveness Trials (COMET) database) were also extracted and categorized.Results: In total, 2454 mortality outcomes were reported in 49% (1978/3999) of Cochrane reviews published January 2015-March 2021: all-cause (37%), infant (23%), maternal (11%), survival (10%), cause-specific (9%). Due to reviews not specifying mortality outcome type or including studies reporting no data, 11% (273/2208) remained uncategorized. Infant mortality and maternal mortality were frequently used together in reviews reporting two mortality outcomes.In total, 226 mortality outcomes were reported in 37% (165/449) of Core Outcome Sets: all-cause (48%), survival (27%), cause-specific (12%), infant (9%), maternal (4%). Mortality measurement timing varied.Conclusion: Mortality outcome usage varies in Cochrane reviews and Core Outcome Sets. This is problematic for evidence-based decision-making. Greater standardization is necessary for effective utilization of health research.

Background The prioritisation of updating published systematic reviews of interventions is vital to prevent research waste and ensure relevance to stakeholders. The consideration of health equity in reviews is also important to ensure interventions will not exacerbate the existing inequities of the disadvantaged if universally implemented. This study aimed to pilot a priority setting exercise based on systematic reviews of interventions published in the Cochrane Library, to identify and prioritise reviews to be updated with a focus on health equity. Methods We conducted a priority setting exercise with a group of 13 international stakeholders. We identified Cochrane reviews of interventions that showed a reduction in mortality, had at least one Summary of Findings table and that focused on one of 42 conditions with a high global burden of disease from the 2019 WHO Global Burden of Disease report. This included 21 conditions used as indicators of success of the United Nations Universal Health Coverage in attaining the Sustainable Development Goals. Stakeholders prioritised reviews that were relevant to disadvantaged populations, or to characteristics of potential disadvantage within the general population. Results After searching for Cochrane reviews of interventions within 42 conditions, we identified 359 reviews that assessed mortality and included at least one Summary of Findings table. These pertained to 29 of the 42 conditions; 13 priority conditions had no reviews with the outcome mortality. Reducing the list to only reviews showing a clinically important reduction in mortality left 33 reviews. Stakeholders ranked these reviews in order of priority to be updated with a focus on health equity. Conclusions This project developed and implemented a methodology to set priorities for updating systematic reviews spanning multiple health topics with a health equity focus. It prioritised reviews that reduce overall mortality, are relevant to disadvantaged populations, and focus on conditions with a high global burden of disease. This approach to the prioritisation of systematic reviews of interventions that reduce mortality provides a template that can be extended to reducing morbidity, and the combination of mortality and morbidity as represented in Disability-Adjusted Life Years and Quality-Adjusted Life Years.

Background: The innate immune system is recognized as an essential aspect of COVID-19 pathogenesis. Toll-like receptors (TLRs) are important in inducing antiviral response, triggering downstream production of interferons (IFNs). Certain loss-of-function variants in TLR7 are associated with increased COVID-19 disease severity, and imiquimod (ImiQ) is known to have immunomodulating effects as an agonist of TLR7. Given that topical imiquimod (topImiQ) is indicated for various dermatologic conditions, it is necessary for dermatologists to understand the interplay between innate immunity mechanisms and the potential role of ImiQ in COVID-19, with a particular focus on TLR7. Summary: Our objective was to survey recent peer-reviewed scientific literature in the PubMed database, examine relevant evidence, and elucidate the relationships between IFNs, TLR7, the innate immune system, and topImiQ in the context of COVID-19. Despite limited studies on this topic, current evidence supports the critical role of TLRs in mounting a strong immune response against COVID-19. Of particular interest to dermatologists, topImiQ can result in systemic upregulation of the immune system via activation of TLR7. Key Message: Given the role of TLR7 in the systemic activation of the immune system, ImiQ, as a ligand of the TLR7 receptor, may have potential therapeutic benefit as a topical immunomodulatory treatment for COVID-19.

Background Prospective studies have suggested higher factor VIII (FVIII) levels are an independent risk factor for coronary heart disease (CHD) and stroke. However, limited information, including on genetic and epigenetic contributors to FVIII variation, is available specifically among African Americans (AAs), who have higher FVIII levels than Europeans. Objectives We measured FVIII levels in ~3400 AAs from the community-based Jackson Heart Study and assessed genetic, epigenetic, and epidemiological correlates of FVIII, as well as incident cardiovascular disease (CVD) associations. Methods We assessed cross-sectional associations of FVIII with CVD risk factors as well as incident CHD, stroke, heart failure, and mortality associations. We additionally assessed associations with TOPMed whole genome sequencing data and an epigenome-wide methylation array. Results Our results confirmed associations between FVIII and risk of incident CHD events and total mortality in AAs; mortality associations were largely independent of traditional risk factors. We also demonstrate an association of FVIII with incident heart failure, independent of B-type natriuretic peptide. Two genomic regions were strongly associated with FVIII (ABO and VWF). The index variant at VWF is specific to individuals of African descent and is distinct from the previously reported European VWF association signal. Epigenome-wide association analysis showed significant FVIII associations with several CpG sites in the ABO region. However, after adjusting for ABO genetic variants, ABO CpG sites were not significant. Conclusions Larger sample sizes of AAs will be required to discover additional genetic and epigenetic contributors to FVIII phenotypic variation, which may have consequences for CVD health disparities.

Dermatologists serve a vast array of patients with unique backgrounds. The National Institutes of Health (NIH) designated members of sexual and gender minorities as underrepresented in scholarly literature. Our study examines the past 10 years of studies published in highly-cited dermatologic journals, surveying each study for common data collection of sexual orientation and gender identity (SOGI) in dermatological studies. We found representation of sexual and gender minorities to be increasing in dermatological studies but recommend that SOGI data be collected regularly just as any other common variable in dermatological patient studies.

Infantile myofibromatosis is a rare myofibroblastic proliferative disorder characterized by firm, skin-colored to red-purple cutaneous and subcutaneous nodules; these are the most prevalent fibrous tumors observed in infancy. A premature male infant presented at birth with multiple subcutaneous firm skin-colored nodules measuring about 1-2cm each. Full body MRI and excisional biopsy of the right chest nodule confirmed the diagnosis. We review the case of infantile myofibromatosis and discuss its highly heterogeneous presentation and clinical course, as well as histopathology, genetic testing, and approaches to management.

Background DNA methylation (DNAm) is associated with gene regulation and estimated glomerular filtration rate (eGFR), a measure of kidney function. Decreased eGFR is more common among US Hispanics and African Americans. The causes for this are poorly understood. We aimed to identify trans-ethnic and ethnic-specific differentially methylated positions (DMPs) associated with eGFR using an agnostic, genome-wide approach. Methods The study included up to 5428 participants from multi-ethnic studies for discovery and 8109 participants for replication. We tested the associations between whole blood DNAm and eGFR using beta values from Illumina 450K or EPIC arrays. Ethnicity-stratified analyses were performed using linear mixed models adjusting for age, sex, smoking, and study-specific and technical variables. Summary results were meta-analyzed within and across ethnicities. Findings were assessed using integrative epigenomics methods and pathway analyses. Results We identified 93 DMPs associated with eGFR at an FDR of 0.05 and replicated 13 and 1 DMPs across independent samples in trans-ethnic and African American meta-analyses, respectively. The study also validated 6 previously published DMPs. Identified DMPs showed significant overlap enrichment with DNase I hypersensitive sites in kidney tissue, sites associated with the expression of proximal genes, and transcription factor motifs and pathways associated with kidney tissue and kidney development. Conclusions We uncovered trans-ethnic and ethnic-specific DMPs associated with eGFR, including DMPs enriched in regulatory elements in kidney tissue and pathways related to kidney development. These findings shed light on epigenetic mechanisms associated with kidney function, bridging the gap between population-specific eGFR-associated DNAm and tissue-specific regulatory context.

BACKGROUND: Psychological and educational interventions have been used as an adjunct to conventional therapy for children with atopic eczema to enhance the effectiveness of topical therapy. This is an update of the original Cochrane review. OBJECTIVES: To assess the effect of psychological and educational interventions for atopic eczema in children. SEARCH METHODS: We updated our searches of the following databases to January 2013: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2012, Issue 12), MEDLINE (from 1946), EMBASE (from 1974), OpenGrey, and PsycINFO (from 1806). We also searched six trials registers and checked the reference lists of included and excluded studies for further references to relevant randomised controlled trials (RCTs). SELECTION CRITERIA: Randomised controlled trials of psychological or educational interventions, or both, used to assist children and their carers in managing atopic eczema. DATA COLLECTION AND ANALYSIS: Three authors independently applied eligibility criteria, assessed trial quality, and extracted data. A lack of comparable data prevented data synthesis, and we were unable to conduct meta‐analysis because there were insufficient data. MAIN RESULTS: We included 10 RCTs, of which 5 were new to this update; all interventions were adjuncts to conventional therapy and were delivered in primary‐ and secondary‐care settings. There were 2003 participants in the 9 educational interventions and 44 participants in the 1 psychological study. Some included studies had methodological weaknesses; for example, we judged four studies to have high risk of detection bias, attrition bias, or other bias. Our primary outcomes were participant‐rated global assessment, reduction in disease severity (reported as objective SCORAD (SCORing Atopic Dermatitis)), and improvement in sleep and quality of life. No study reported participant‐rated global assessment or improvement of sleep. The largest and most robust study (n = 992) demonstrated significant reduction in disease severity and improvement in quality of life, in both nurse‐ and dermatologist‐led intervention groups. It provided six standardised, age‐appropriate group education sessions. Statistically significant improvements in objective severity using the SCORAD clinical tool were recorded for all intervention groups when compared with controls. Improvements in objective severity (intervention minus no intervention) by age group were as follows: age 3 months to 7 years = 4.2, 95% confidence interval (CI) 1.7 to 6.8; age 8 to 12 years = 6.7, 95% CI 2.1 to 11.2; and age 13 to 18 years = 9.9, 95% CI 4.3 to 15.5. In three of five studies, which could not be combined because of their heterogeneity, the objective SCORAD measure was statistically significantly better in the intervention group compared with the usual care groups. However, in all of the above studies, the confidence interval limits do not exceed the minimum clinically important difference of 8.2 for objective SCORAD. The largest study measured quality of life using the German 'Quality of life in parents of children with atopic dermatitis' questionnaire, a validated tool with five subscales. Parents of children under seven years had significantly better improvements in the intervention group on all five subscales. Parents of children aged 8 to 12 years experienced significantly better improvements in the intervention group on 3 of the 5 subscales. AUTHORS' CONCLUSIONS: This update has incorporated five new RCTs using educational interventions as an adjunct to conventional treatment for children with atopic eczema. We did not identify any further studies using psychological interventions. The inclusion of new studies has not substantially altered the conclusions from the original review. The educational studies in both the original review and this update lack detail about intervention design and do not use a complex interventions framework. Few use an explicit theoretical base, and the components of each intervention are not sufficiently well described to allow replication. A relative lack of rigorously designed trials provides limited evidence of the effectiveness of educational and psychological interventions in helping to manage the condition of atopic eczema in children. However, there is some evidence from included paediatric studies using different educational intervention delivery models (multiprofessional eczema interventions and nurse‐led clinics) that these may lead to improvements in disease severity and quality of life. Educational and psychological interventions require further development using a complex interventions framework. Comparative evaluation is needed to examine their impact on eczema severity, quality of life, psychological distress, and cost‐effectiveness. There is also a need for comparison of educational interventions with stand‐alone psychosocial self‐help.

Objective: sCD14 (soluble CD14) is a circulating pattern recognition receptor involved in inflammatory signaling. Although it is known that sCD14 levels vary by race, information on the genetic and cardiovascular disease (CVD) risk relationships of sCD14 in Black participants is limited. Approach and Results: We measured sCD14 in plasma at the baseline exam from n=3492 Black participants from the JHS (Jackson Heart Study). We evaluated associations between sCD14 and subclinical CVD measures, incident CVD events, and mortality under 3 levels of covariate adjustment. We used whole-genome sequence data from the Trans-Omics for Personalized Medicine program to identify genetic associations with sCD14. Adjusting for CVD risk factors and C-reactive protein, higher sCD14 was significantly associated with increased risk of mortality (hazard ratio, 1.25 [95% CI, 1.17–1.32]), incident coronary heart disease (hazard ratio, 1.28 [95% CI, 1.11–1.47]), and incident heart failure (hazard ratio, 1.27 [95% CI, 1.15–1.41]), but not stroke (hazard ratio, 0.96 [95% CI, 0.84–1.09]). Some of these relationships differed by age or sex: the association between sCD14 and heart failure was only observed in females; there was an association between sCD14 and stroke only at younger ages (in the lowest tertile of age, CD14 region of chromosome 5q31. We additionally identified 2 novel statistically distinct genetic associations with sCD14 represented by index variants rs770147646 and rs57599368, also in the chromosome 5q31 region. Conclusions: sCD14 independently predicts CVD-related outcomes and mortality in Black participants.

BACKGROUND An increasing number of studies have investigated the adverse effect profile of oral cannabinoids; however, few studies have provided sufficient data on the tolerability of topical cannabinoids in human participants. AIM To assess the tolerability profile of several commercial topical formulations containing cannabidiol (CBD) and palmitoylethanolamide (PEA) on the skin of healthy human participants. METHODS Three human clinical trials and one in vitro study were conducted. The potential for skin irritation, sensitization and phototoxicity of several products, were assessed via patch testing on healthy human skin. The products assessed included two formulations containing CBD and PEA, one containing hemp seed oil and four concentrations of CBD alone. Ocular toxicity was tested using a traditional hen's egg chorioallantoic membrane model with three CBD, PEA and hemp seed oil formulations. RESULTS There was no irritation or sensitization of the products evident via patch testing on healthy participants. Additionally, mild phototoxicity of a hemp seed oil product was found at the 48-h time point compared with the negative control. The in vitro experiment demonstrated comparable effects of cannabinoid products with historically nonirritating products. CONCLUSION These specific formulations of CBD- and PEA-containing products are nonirritating and nonsensitizing in healthy adults, and further encourage similar research assessing their long-term safety and efficacy in human participants with dermatological diseases. There are some limitations to the study: (i) external validity may be limited as formulations from a single manufacturer were used for this study, while vast heterogeneity exists across unregulated, commercial CBD products on the market; and (ii) products were assessed only on normal, nondiseased human skin, and therefore extrapolation to those with dermatological diseases cannot be assumed.

Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA‐methylation modifying enzymes DNMT3A or TET2. We used DNA‐methylation array and whole‐genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31 years (GrimAge, p 0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all‐cause mortality (hazard ratio 2.90, p, Clonal hematopoiesis of indeterminate potential (CHIP) and epigenetic age acceleration are the two important aging phenomenon associated with adverse clinical outcomes. We found that mutations in most CHIP genes were associated with increased age acceleration in multiple epigenetic clocks. Individuals with CHIP and age acceleration had a greatly increased risk of mortality and coronary heart disease compared to individuals with only CHIP or age acceleration.

Importance: Social media is making information about skin of color more readily available to those unfamiliar with ethnic skin and hair. Objectives: To answer: 1) what skin of color-related dermatology content is being posted on Instagram? And 2) who is producing this content? Design: Cross-sectional epidemiologic study analyzing the content of posts associated with 31 Instagram skin of color dermatology-related topics (hashtags). Setting: Population-based Participants: The Instagram accounts linked with the top 9 posts as generated by the Instagram algorithm associated with each search term. Exposures: Instagram account holders. Main Outcomes and Measures: [1] The number of posts associated with each skin of color dermatology hashtag search term. [2] Classification of posts as either educational or promotional. [3] Classification of posts as a photo or video. [4] Classification of Instagram accounts that produced the posts (American board-certified dermatologists, dermatology residents, foreign dermatologists, patients, medical interest groups, or other). [5] Quantification of the number of post likes and comments. [6] Comparison of number of educational and promotional posts between board-certified dermatologists and other Instagram users. Results: The 31 sampled hashtags were associated with a total of 9,087,589 posts as of January 16, 2020. 219 of the 288 top posts generated from these queries met inclusion criteria. Board-certified dermatologists (26 posts) only generated 12% of top posts, whereas individuals not certified in dermatology produced 88% of top content. Of this group, social media influencers were the largest subcategory (37 posts). A majority of the top posts were promotional (135 posts, 61.6%) and formatted as photos (181 posts, 82.6%). While there was a significant difference in the number of likes for content posted by board-certified dermatologists vs non-dermatologists (P=0.027), these differences became non-significant after stratifying by the intention of the post (promotional P=0.13, educational P=0.17). Conclusions and Relevance: Board-certified dermatologists are underrepresented among people generating top skin of color dermatology-related content on Instagram. Board-certified dermatologists should establish a more prominent presence on social media platforms so that patients have greater access to accurate, evidenced-based educational resources regarding dermatologic conditions, treatment options, and treatment risks from reliable sources. J Drugs Dermatol. 2020;19(7): doi:10.36849/JDD.2020.5142.

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown1. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer2–4 and coronary heart disease5—this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP)6. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

Glioblastoma multiforme (GBM) are aggressive and uniformly fatal primary brain tumors characterized by their diffuse invasion of the normal-appearing parenchyma peripheral to the clinical imaging abnormality. Hypoxia, a hallmark of aggressive tumor behavior often noted in GBMs, has been associated with resistance to therapy, poorer survival, and more malignant tumor phenotypes. Based on the existence of a set of novel imaging techniques and modeling tools, our objective was to assess a hypothesized quantitative link between tumor growth kinetics [assessed via mathematical models and routine magnetic resonance imaging (MRI)] and the hypoxic burden of the tumor [assessed via positron emission tomography (PET) imaging]. Our biomathematical model for glioma kinetics describes the spatial and temporal evolution of a glioma in terms of concentration of malignant tumor cells. This model has already been proven useful as a novel tool to dynamically quantify the net rates of proliferation (ρ) and invasion (D) of the glioma cells in individual patients. Estimates of these kinetic rates can be calculated from routinely available pretreatment MRI in vivo. Eleven adults with GBM were imaged preoperatively with 18F-fluoromisonidazole (FMISO)–PET and serial gadolinium-enhanced T1- and T2-weighted MRIs to allow the estimation of patient-specific net rates of proliferation (ρ) and invasion (D). Hypoxic volumes were quantified from each FMISO-PET scan following standard techniques. To control for tumor size variability, two measures of hypoxic burden were considered: relative hypoxia (RH), defined as the ratio of the hypoxic volume to the T2-defined tumor volume, and the mean intensity on FMISO-PET scaled to the blood activity of the tracer (mean T/B). Pearson correlations between RH and the net rate of cell proliferation (ρ) reached significance (P < 0.04). Moreover, highly significant positive correlations were found between biological aggressiveness ratio (ρ/D) and both RH (P < 0.00003) and the mean T/B (P < 0.0007). [Cancer Res 2009;69(10):4502–9] Major Findings Overall, biological aggressiveness assessed by serial MRI is linked with hypoxic burden assessed on FMISO-PET using a novel biomathematical model for glioma growth and invasion. This study suggests that patient-specific modeling of growth kinetics can provide novel and valuable insight into the quantitative connections between disparate information provided by multimodality imaging.