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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 Emoticons and emojis have become staple additions to modern-day communication. These graphical icons are now embedded in daily society through the various forms of popular social media and through users’ personal electronic conversations. With ever-increasing use and inclusivity, exploration of the possible health care and dermatology applications of these tools is imperative. Objective The goal of this narrative review was to provide and evaluate an up-to-date literature survey examining the utility of emoticons and emojis in medicine. Special attention was paid to their existing and potential uses in the field of dermatology, especially during the COVID-19 pandemic. Methods A PubMed search of peer-reviewed publications was performed in mid-2021 to collect articles with emoticon or emoji keywords in combination with other health care–relevant or dermatology-relevant keywords. Screening of publications and described studies was performed by the authors with education and research experience in health care, dermatology, social media, and electronic communication trends. Selected articles were grouped based on common subjects for qualitative analysis and presentation for in-depth discussion. Results From this extensive search, researchers were able to identify a wide variety of publications detailing the use of emoticons and emojis in general health care, pediatric health care, public health, and dermatology. Key subject areas that emerged from the investigation included the ability of emoticons and emojis to improve communication within pediatric health care, enhance mood and psychological assessment or mental health screening in adults, develop interventions to improve patient medication adherence, complement novel means of public health and COVID-19 surveillance, and bolster dermatology-specific applications. Conclusions This review illuminated the repurposing of emojis and emoticons for a myriad of advantageous functions in health care and public health, with applications studied in many populations and situations. Dermatology-specific uses were relatively sparse in the literature, highlighting potential opportunities for growth in future studies and practices. The importance of diversity and inclusivity has extended to emojis, with the recent introduction of skin color customization and new emojis better representing the comprehensive spectrum of users’ experiences. A continuously evolving and technology-driven population creates a unique niche for emoticons and emojis to ease worldwide communication and understanding, transcending the barriers of age, language, and background. We encourage future studies and innovations to better understand and expand their utility.

BACKGROUND Emoticons and emojis have become staple additions to modern day communication. These graphical icons are now imbedded into daily society through the various forms of popular social media and through users’ personal electronic conversations. With ever increasing use and inclusivity, exploration of the possible healthcare and dermatology applications of these tools is imperative. OBJECTIVE The goal of this narrative review is to provide and evaluate an up-to-date literature survey examining the utility of emoticons and emojis in medicine. Special attention will be drawn to existing and potential usage in the field of dermatology, especially during the COVID-19 pandemic. METHODS A PubMed search of peer-reviewed publications was performed in mid-2021 to collect articles with emoticon or emoji keywords in combination with other healthcare or dermatology-relevant keywords. Screening of publications and described studies was performed by authors with education and research experience in healthcare, dermatology, social media, and electronic communication trends. Selected articles were grouped by common subjects to be qualitatively analyzed and presented for in-depth discussion. RESULTS From this extensive search, researchers were able to identify a wide variety of publications detailing the use of emoticons and emojis within general healthcare, pediatric healthcare, public health, and dermatology. Key subject areas that emerged from the investigation included the ability of emoticons or emojis to improve communication within pediatric healthcare, enhance mood and psychological assessment or mental health screening in adults, develop interventions to improve patient medication adherence, complement novel means of public health and COVID-19 surveillance, and bolster dermatology-specific applications. CONCLUSIONS This review illuminated the repurposing of emojis or emoticons for a myriad of advantageous functions in the healthcare and public health, with applications studied in many populations and situations. Dermatology-specific uses were relatively sparse in the literature, which highlights a potential opportunity for growth in future studies and practices. The importance of diversity and inclusivity has extended to emojis, with the recent introduction of Skin of Color customization and new emojis better representing the comprehensive spectrum of users’ experiences. A continuously evolving and technology-driven population creates a unique niche for emoticons and emojis to ease worldwide communication and understanding, transcending barriers of age, language, and background. We encourage future studies and innovation to further understand and expand their utility.

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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.

BACKGROUND Game-based approaches, or gamification, are popular learning strategies in medical education for health care providers and patients alike. Gamification has taken the form of serious educational games and simulations to enable learners to rehearse skills and knowledge in a safe environment. Dermatology learners in particular may benefit from gamification methods, given the visual and procedural nature of the field. OBJECTIVE This narrative review surveys current applications of gamification within general medical training, in the education of dermatology students, and in dermatology patient outreach. METHODS A literature search was performed using PubMed, Google Scholar, and ResearchGate to access and review relevant medical education- and dermatology-related gamification studies published in peer-reviewed journals. Two independent researchers with education and experience in dermatology screened publications to select studies featuring a diversity of gamification approaches and study subjects for in-depth examination. RESULTS A total of 6 general medical education–related and 7 dermatology-specific gamification studies were selected. Gamification generally increased motivation and engagement, improved reinforcement of learning objectives, and contributed to more enjoyable and positive educational experiences compared to traditional modes of instruction. Enhancing examination scores, building confidence, and developing stronger team dynamics were additional benefits for medical trainees. Despite the abundance of gamification studies in general medical education, comparatively few instances were specific to dermatology learning, although large organizations such as the American Academy of Dermatology have begun to implement these strategies nationally. Gamification may also a provide promising alternative means of diversifying patient education and outreach methods, especially for self-identification of malignant melanoma. CONCLUSIONS Serious games and simulations in general medical education have successfully increased learner motivation, enjoyment, and performance. In limited preliminary studies, gamified approaches to dermatology-specific medical education enhanced diagnostic accuracy and interest in the field. Game-based interventions in patient-focused educational pilot studies surrounding melanoma detection demonstrated similar efficacy and knowledge benefits. However, small study participant numbers and large variability in outcome measures may indicate decreased generalizability of findings regarding the current impact of gamification approaches, and further investigation in this area is warranted. Additionally, some relevant studies may have been omitted by the simplified literature search strategy of this narrative review. This could be expanded upon in a secondary systematic review of gamified educational platforms.

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.

BACKGROUND Google Trends is a powerful online database and analytics tool of popular Google search queries over time and has the potential to inform medical practice and priorities. OBJECTIVE This review aimed to survey Google Trends literature in dermatology and elucidate its current roles and relationships with the field. METHODS A literature search was performed using PubMed to access and review relevant dermatology-related Google Trends studies published within the last 5 years. RESULTS Current research utilizing Google Trends data provides insight related to skin cancer, pruritus, cosmetic procedures, and COVID-19. We also found that dermatology is presently the highest-searched medical specialty—among 15 medical and surgical specialties as well as general practitioners. Google searches related to dermatology demonstrate a seasonal nature for various skin conditions and sun-related topics, depending on a region’s inherent climate and hemi-sphere. In addition, celebrity social media and other viral posts have been found to potentiate Google searches about dermatology and drive public interest. CONCLUSIONS A limited number of relevant studies may have been omitted by the simplified search strategy of this study, as well as by restriction to English language articles and articles indexed in the PubMed database. This could be expanded upon in a secondary systematic review. Future re-search is warranted to better understand how Google Trends can be utilized to improve the quality of clinic visits, drive public health campaigns, and detect disease clusters in real time.

BACKGROUND Cannabis oil is being used topically by patients with skin cancer as a homeopathic remedy, and has been promoted and popularized on social media, including YouTube. Although topical cannabinoids, especially tetrahydrocannabinol (THC), may have antitumor effects, results from a sparse number of clinical trials and peer-reviewed studies detailing safety and efficacy are still under investigation. OBJECTIVE We sought to assess the accuracy, quality, and reliability of THC oil and skin cancer information available on YouTube. METHODS The 10 most-viewed videos on THC oil and skin cancer were analyzed with the Global Quality Scale (GQS), DISCERN score, and useful/misleading criteria based on presentation of erroneous and scientifically unproven information. The videos were also inspected for source, length, and audience likes/dislikes. Top comments were additionally examined based on whether they were favorable, unfavorable, or neutral regarding the video content. RESULTS All analyzed videos (10/10, 100%) received a GQS score of 1, corresponding to poor quality of content, and 9/10 (90%) videos received a DISCERN score of 0, indicating poor reliability of information presented. All 10 videos were also found to be misleading and not useful according to established criteria. Top comments were largely either favorable (13/27, 48%) or neutral (13/27, 48%) toward the content of the videos, compared to unfavorable (1/27, 4%). CONCLUSIONS Dermatologists should be aware that the spread of inaccurate information on skin cancer treatment currently exists on popular social media platforms and may lead to detrimental consequences for patients interested in pursuing alternative or homeopathic approaches.

Type 2 diabetes is increasing in all ancestry groups1. Part of its genetic basis may reside among the rare (minor allele frequency 2. We analyzed high-coverage (mean depth 38.2x) whole genome sequencing from 9,639 individuals with T2D and 34,994 controls in the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program2 to show that rare, non-coding variants that are poorly captured by genotyping arrays or imputation panels contribute h2=53% (P=4.2×10−5) to the genetic component of risk in the largest (European) ancestry subset. We coupled sequence variation with islet epigenomic signatures3 to annotate and group rare variants with respect to gene expression4, chromatin state5 and three-dimensional chromatin architecture6, and show that pancreatic islet regulatory elements contribute to T2D genetic risk (h2=8%, P=2.4×10−3). We used islet annotation to create a non-coding framework for rare variant aggregation testing. This approach identified five loci containing rare alleles in islet regulatory elements that suggest novel biological mechanisms readily linked to hypotheses about variant-to-function. Large scale whole genome sequence analysis reveals the substantial contribution of rare, non-coding variation to the genetic architecture of T2D and highlights the value of tissue-specific regulatory annotation for variant-to-function discovery.

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.

Cardiovascular disease (CVD) is the leading cause of death in the U.S. and disproportionately affects African Americans (AAs). Routinely measured circulating red blood cell traits, which are highly heritable and differ by ethnicity, are independent predictors for CVD-related traits including hypertension, stroke, coronary heart disease, and CVD mortality. Many genetic loci associated with red blood cell count (RBC), hemoglobin (HGB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red cell distribution width (RDW) have been identified. However, identified genetic variants do not fully explain the heritability of these traits. Epigenetic alterations in DNA methylation likely also explain a portion of red cell trait variance, and detecting methylation quantitative trait loci (meQTLs) can provide critical insight into the development of CVD and CVD health disparities. We performed an epigenome-wide association analysis to identify CpG sites at which DNA methylation levels are associated with red blood cell traits in 1753 participants from the Jackson Heart Study, a population-based cohort of AAs. DNA methylation was measured by the Illumina MethylationEPIC array, interrogating approximately 850,000 CpG sites in peripheral blood mononuclear cells at the baseline exam. Associations were assessed using linear mixed models adjusted for age, sex, cell proportions, genetic ancestry, and experimental batch effects. A Bonferroni-corrected p-value of 9x10 -8 was used to assess statistical significance. We identified many significant differentially methylated CpG sites associated with red blood cell traits. Analysis of RBC, HGB, MCV, MCH, and MCHC revealed a novel highly significant association with a CpG annotated to a non-coding RNA (cg11703701; RBC P = 5.19x10 -22 , HGB P = 1.19x10 -11 , MCV P = 4.69x10 -59 , MCH P = 2.68x10 -67 , MCHC P = 2.32x10 -31 ), as well as a strong signal for a reprogramming-specific differentially methylated region (cg04321267; RBC P = 1.67x10 -16 , HGB P = 3.58x10 -12 , MCV P = 2.12x10 -49 , MCH P = 1.74x10 -57 , MCHC P = 5.91x10 -30 ). Multiple CpGs annotated to genes HBA1 and HBA2 were associated with RBC, MCV, MCH, and MCHC, while ITPKB (cg23740281; HGB P = 4.88x10 -10 , HCT P = 6.20x10 -11 ) and ALDH2 (cg17969951; HGB P = 3.03x10 -11 , HCT P = 8.31x10 -9 ) were significantly associated with both HGB and HCT. Additional CpG sites were significantly associated with HCT ( PLXND1 cg22902177; P = 7.54x10 -11 and ARL1 cg23903357; P = 9.86x10 -11 ) and RDW ( CPNE2 cg09018739; P = 3.03x10 -22 ). These findings shed light on potential hematologic and CVD mechanisms in understudied populations. Future work will explore the role of neighboring SNPs in mediating observed methylation-trait associations, and replicate results in an additional multi-ethnic cohort.

Age is the dominant risk factor for most chronic human diseases; yet the mechanisms by which aging confers this risk are largely unknown.1 Recently, the age-related acquisition of somatic mutations in regenerating hematopoietic stem cell populations was associated with both hematologic cancer incidence2–4 and coronary heart disease prevalence.5 Somatic mutations with leukemogenic potential may confer selective cellular advantages leading to clonal expansion, a phenomenon termed ‘Clonal Hematopoiesis of Indeterminate Potential’ (CHIP).6 Simultaneous germline and somatic whole genome sequence analysis now provides the opportunity to identify root causes of CHIP. Here, we analyze high-coverage whole genome sequences from 97,691 participants of diverse ancestries in the NHLBI TOPMed program and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid, and inflammatory traits specific to different CHIP genes. Association of a genome-wide set of germline genetic variants identified three genetic loci associated with CHIP status, including one locus at TET2 that was African ancestry specific. In silico-informed in vitro evaluation of the TET2 germline locus identified a causal variant that disrupts a TET2 distal enhancer. Aggregates of rare germline loss-of-function variants in CHEK2, a DNA damage repair gene, predisposed to CHIP acquisition. Overall, we observe that germline genetic variation altering hematopoietic stem cell function and the fidelity of DNA-damage repair increase the likelihood of somatic mutations leading to CHIP.

© 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.

Type 2 diabetes (T2D) risk is highly heritable, and although many associated loci have been identified, analyses of regulatory regions in most whole-genome sequencing (WGS) studies have not been specific to relevant tissues. The availability of tissue-specific expression quantitative trait (eQTL) information can further elucidate the functional role of non-coding regulatory variants. A WGS (>38x sequencing depth) association study was performed for variants in 9,663 cases and 35,050 controls from the NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program. eQTL data from 48 different tissues was obtained from the Genotype-Tissue Expression (GTEx) Portal. To generate loci of interest, 200-kb windows were considered upstream and downstream of each variant found to be genome-wide significant (p < 5x10^-8) in both the TOPMed and GTEx datasets. A total of 11 regions in different tissues were significantly associated with T2D status, centered around variants such as rs6585201 in the ascending aorta (TCF7L2, TOPMed p = 1.18x10^-9, GTEx p = 1.12x10^-10, but did not localize to the strongest signal in the region), rs76895963 in the cerebellum (CCND2, TOPMed p = 3.51x10^-9, GTEx p = 4.40x10^-17), and rs4898431 in ovarian tissue (DUSP9, TOPMed p = 1.88x10^-8, GTEx p = 4.39x10^-8). We plan to implement eCAVIAR to examine causal variant colocalization, with the advantages of leveraging summary statistics and accounting for the possibility of more than one causal variant per locus. These results confirm previously published studies, but provide validation of methods we will extend to larger samples and diabetes-related outcomes. Disclosure M.D. Szeto: None. H.M. Highland: None. A. Manning: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (U01DK078616, K01DK107836)

BackgroundGoogle Trends is a powerful online database and analytics tool of popular Google search queries over time and has the potential to inform medical practice and priorities.ObjectiveThis review aimed to survey Google Trends literature in dermatology and elucidate its current roles and relationships with the field.MethodsA literature search was performed using PubMed to access and review relevant dermatology-related Google Trends studies published within the last 5 years.ResultsCurrent research utilizing Google Trends data provides insight related to skin cancer, pruritus, cosmetic procedures, and COVID-19. We also found that dermatology is presently the highest-searched medical specialty—among 15 medical and surgical specialties as well as general practitioners. Google searches related to dermatology demonstrate a seasonal nature for various skin conditions and sun-related topics, depending on a region’s inherent climate and hemi-sphere. In addition, celebrity social media and other viral posts have been found to potentiate Google searches about dermatology and drive public interest.ConclusionsA limited number of relevant studies may have been omitted by the simplified search strategy of this study, as well as by restriction to English language articles and articles indexed in the PubMed database. This could be expanded upon in a secondary systematic review. Future re-search is warranted to better understand how Google Trends can be utilized to improve the quality of clinic visits, drive public health campaigns, and detect disease clusters in real time.

Background Cannabis oil is being used topically by patients with skin cancer as a homeopathic remedy, and has been promoted and popularized on social media, including YouTube. Although topical cannabinoids, especially tetrahydrocannabinol (THC), may have antitumor effects, results from a sparse number of clinical trials and peer-reviewed studies detailing safety and efficacy are still under investigation. Objective We sought to assess the accuracy, quality, and reliability of THC oil and skin cancer information available on YouTube. Methods The 10 most-viewed videos on THC oil and skin cancer were analyzed with the Global Quality Scale (GQS), DISCERN score, and useful/misleading criteria based on presentation of erroneous and scientifically unproven information. The videos were also inspected for source, length, and audience likes/dislikes. Top comments were additionally examined based on whether they were favorable, unfavorable, or neutral regarding the video content. Results All analyzed videos (10/10, 100%) received a GQS score of 1, corresponding to poor quality of content, and 9/10 (90%) videos received a DISCERN score of 0, indicating poor reliability of information presented. All 10 videos were also found to be misleading and not useful according to established criteria. Top comments were largely either favorable (13/27, 48%) or neutral (13/27, 48%) toward the content of the videos, compared to unfavorable (1/27, 4%). Conclusions Dermatologists should be aware that the spread of inaccurate information on skin cancer treatment currently exists on popular social media platforms and may lead to detrimental consequences for patients interested in pursuing alternative or homeopathic approaches.

We describe the identification and characterization of novel homing endonucleases using genome database mining to identify putative target sites, followed by high throughput activity screening in a bacterial selection system. We characterized the substrate specificity and kinetics of these endonucleases by monitoring DNA cleavage events with deep sequencing. The endonuclease specificities revealed by these experiments can be partially recapitulated using 3D structure-based computational models. Analysis of these models together with genome sequence data provide insights into how alternative endonuclease specificities were generated during natural evolution.

Homing endonucleases have great potential as tools for targeted gene therapy and gene correction, but identifying variants of these enzymes capable of cleaving specific DNA targets of interest is necessary before the widespread use of such technologies is possible. We identified homologues of the LAGLIDADG homing endonuclease I-AniI and their putative target insertion sites by BLAST searches followed by examination of the sequences of the flanking genomic regions. Amino acid substitutions in these homologues that were located close to the target site DNA, and thus potentially conferring differences in target specificity, were grafted onto the I-AniI scaffold. Many of these grafts exhibited novel and unexpected specificities. These findings show that the information present in genomic data can be exploited for endonuclease specificity redesign.

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.