Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

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.

Prioritising Cochrane reviews to be updated with health equity focus.

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.

Tocilizumab Treatment in COVID-19 Patients: Comparing Cutaneous Disease and Adverse Drug Effects.

Actemra (tocilizumab) received emergency use authorization for the treatment of coronavirus disease 2019 (COVID-19) in June 2021. Literature has linked numerous cutaneous adverse effects to tocilizumab. In this current survey, investigators reviewed and compared these adverse effects to the common cutaneous manifestations of COVID-19. While similarities in patient presentation exist, important distinctions are made to aid dermatologists in their clinical diagnosis.  J Drugs Dermatol. 2023;22(12):e42-e43.     doi:10.36849/JDD.6532e.

Soluble CD14 Levels in the Jackson Heart Study: Associations With Cardiovascular Disease Risk and Genetic Variants.

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Analysis of Factors Contributing to Perioperative Mohs Micrographic Surgery Anxiety: Patient Survey Study at an Academic Center.

BACKGROUND: 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. OBJECTIVE: Investigate factors influencing perioperative MMS patient anxiety, especially those with debated impact or unclear data. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Sexual orientation and gender identity (SOGI) data in dermatologic studies and opportunities for inclusion.

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.

Interferon and Toll-Like Receptor 7 Response in COVID-19: Implications of Topical Imiquimod for Prophylaxis and Treatment.

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.

Infantile myofibromatosis: multiple firm nodules in a premature newborn.

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.

An Analysis of Skin of Color Dermatology Related Content on Instagram.

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.