Utilizing systems genetics to enhance understanding into molecular targets of skin cancer.

Despite progress made with immune checkpoint inhibitors and targeted therapies, skin cancer remains a significant public health concern in the United States. The intricacies of the disease, encompassing genetics, immune responses, and external factors, call for a comprehensive approach. Techniques in systems genetics, including transcriptional correlation analysis, functional pathway enrichment analysis, and protein-protein interaction network analysis, prove valuable in deciphering intricate molecular mechanisms and identifying potential diagnostic and therapeutic targets for skin cancer. Recent studies demonstrate the efficacy of these techniques in uncovering molecular processes and pinpointing diagnostic markers for various skin cancer types, highlighting the potential of systems genetics in advancing innovative therapies. While certain limitations exist, such as generalizability and contextualization of external factors, the ongoing progress in AI technologies provides hope in overcoming these challenges. By providing protocols and a practical example involving Braf, we aim to inspire early-career experimental dermatologists to adopt these tools and seamlessly integrate these techniques into their skin cancer research, positioning them at the forefront of innovative approaches in combating this devastating disease.

Oral Cannabidiol for Seborrheic Dermatitis in Patients With Parkinson Disease: Randomized Clinical Trial.

BACKGROUND: Seborrheic dermatitis (SD) affects 18.6%-59% of persons with Parkinson disease (PD), and recent studies provide evidence that oral cannabidiol (CBD) therapy could reduce sebum production in addition to improving motor and psychiatric symptoms in PD. Therefore, oral CBD could be useful for improving symptoms of both commonly co-occurring conditions. OBJECTIVE: This study investigates whether oral CBD therapy is associated with a decrease in SD severity in PD. METHODS: Facial photographs were collected as a component of a randomized (1:1 CBD vs placebo), parallel, double-blind, placebo-controlled trial assessing the efficacy of a short-term 2.5 mg per kg per day oral sesame solution CBD-rich cannabis extract (formulated to 100 mg/mL CBD and 3.3 mg/mL THC) for reducing motor symptoms in PD. Participants took 1.25 mg per kg per day each morning for 4 ±1 days and then twice daily for 10 ±4 days. Reviewers analyzed the photographs independently and provided a severity ranking based on the Seborrheic Dermatitis Area and Severity Index (SEDASI) scale. Baseline demographic and disease characteristics, as well as posttreatment SEDASI averages and the presence of SD, were analyzed with 2-tailed t tests and Pearson χ2 tests. SEDASI was analyzed with longitudinal regression, and SD was analyzed with generalized estimating equations. RESULTS: A total of 27 participants received a placebo and 26 received CBD for 16 days. SD severity was low in both groups at baseline, and there was no treatment effect. The risk ratio for patients receiving CBD, post versus pre, was 0.69 (95% CI 0.41-1.18; P=.15), compared to 1.20 (95% CI 0.88-1.65; P=.26) for the patients receiving the placebo. The within-group pre-post change was not statistically significant for either group, but they differed from each other (P=.07) because there was an estimated improvement for the CBD group and an estimated worsening for the placebo group. CONCLUSIONS: This study does not provide solid evidence that oral CBD therapy reduces the presence of SD among patients with PD. While this study was sufficiently powered to detect the primary outcome (efficacy of CBD on PD motor symptoms), it was underpowered for the secondary outcomes of detecting changes in the presence and severity of SD. Multiple mechanisms exist through which CBD can exert beneficial effects on SD pathogenesis. Larger studies, including participants with increased disease severity and longer treatment periods, may better elucidate treatment effects and are needed to determine CBD's true efficacy for affecting SD severity. TRIAL REGISTRATION: ClinicalTrials.gov NCT03582137; https://clinicaltrials.gov/ct2/show/NCT03582137.

Integrative Approaches to Sleep Management in Skin Disease: Systematic Review.

BACKGROUND: Dermatological conditions, especially when severe, can lead to sleep disturbances that affect a patient's quality of life. However, limited research exists on the efficacy of treatments for improving sleep parameters in skin conditions. OBJECTIVE: The objective was to perform a systematic review of the literature on dermatological conditions and the treatments available for improving sleep parameters. METHODS: A literature review was performed using the PubMed, Ovid MEDLINE, Embase, Cochrane, and ClinicalTrials.gov databases from 1945 to 2021. After filtering based on our exclusion criteria, studies were graded using the SORT (Strength of Recommendation Taxonomy) algorithm, and only those receiving a grade of "2" or better were included. RESULTS: In total, 25 treatment studies (n=11,025) assessing sleep parameters related to dermatological conditions were found. Dupilumab appeared to be the best-supported and most effective treatment for improving sleep in atopic dermatitis (AD) but had frequent adverse effects. Topical treatments for AD were mostly ineffective, but procedural treatments showed some promise. Treatments for other conditions appeared efficacious. CONCLUSIONS: The evaluation of sleep parameter changes in dermatological treatments is predominantly restricted to AD. Systemic interventions such as dupilumab and procedural interventions were the most efficacious. Sleep changes in other dermatoses were limited by a paucity of available studies. The inclusion of a sleep assessment component to a broader range of dermatological treatment studies is warranted.

Clinical Efficacy of Nutritional Supplements in Atopic Dermatitis: Systematic Review.

BACKGROUND: Atopic dermatitis (AD), also known as eczema, is a chronic inflammatory skin condition that presents with symptoms of intense pruritus, dryness, and erythema. Dissatisfaction with first-line therapies for AD, the desire to avoid steroids, and the extreme cost of effective biologics have created a demand for alternative treatment options such as oral vitamins and nutritional supplements. OBJECTIVE: The purpose of this review was to assess the effectiveness of oral nutritional supplements, pre- and probiotics, and vitamin deficiencies and supplements on AD symptomology and clinical course. METHODS: We searched Scopus, PubMed, and MEDLINE (Ovid interface) for English-language articles published between 1993 and 2023. The final search was conducted on June 22, 2023. The search terms comprised the following: "(Atopic Dermatitis or Atopic Eczema) AND (supplement OR vitamin OR mineral OR micronutrients OR Fish Oil OR Omega Fatty Acid OR Probiotics OR Prebiotics OR apple cider vinegar OR collagen OR herbal OR fiber)." RESULTS: A total of 18 studies-3 (17%) evaluating vitamins, 4 (22%) evaluating herbal medicine compounds, 2 (11%) evaluating single-ingredient nutritional supplements, and 9 (50%) evaluating pre- and probiotics-involving 881 patients were included in this review. CONCLUSIONS: Overall, there is weak evidence to support any one nutritional supplement intervention for the alleviation of AD symptoms. Multiple trials (4/18, 22%) showed promise for supplements such as Zemaphyte, kefir, and freeze-dried whey with Cuscuta campestris Yuncker extract. The most evidence was found on the effectiveness of probiotics on the clinical course of AD. Lactiplantibacillus plantarum, Ligilactobacillus salivarius, and Lactobacillus acidophilus specifically showed evidence of efficacy and safety across multiple studies (6/18, 33%). However, larger, more extensive randomized controlled trials are needed to determine the true effectiveness of these supplements on the broader population. TRIAL REGISTRATION: PROSPERO CRD42023470596; https://tinyurl.com/4a9477u7.

Prescribing Patterns of Oral Antibiotics and Isotretinoin for Acne in a Colorado Hospital System: Retrospective Cohort Study.

BACKGROUND: Guidelines established by the American Academy of Dermatology recommend oral antibiotics as first-line therapy for mild, moderate, and severe acne. However, it is recommended to minimize the duration of oral antibiotic use, and there is increasing support for other systemic agents for acne. OBJECTIVE: We sought to characterize the use of oral antibiotics and isotretinoin for the treatment of acne in the pediatric and young adult population aged 10 through 20 years and the adult population aged 21 to 45 years from 2011 to 2019. METHODS: We conducted a retrospective, observational cohort study using electronic data from the enterprise data warehouse of the University of Colorado Anschutz Medical Campus and its affiliates, with data in the format of the Observational Health Data Sciences and Informatics (OHDSI) Observational Medical Outcomes Partnership (OMOP) common data model. Categorical values (sex, race, and ethnicity) were compared using chi-square tests, and continuous variables (age) were compared using 2-tailed t tests. RESULTS: Our cohort of 15,704 patients was composed of mostly White (12,776/15,704, 81.4%), non-Hispanic or Latino (13,307/15,704, 84.7%), and female (11,093/15,704, 70.6%) patients. Among the 4605 male patients in the eligible cohort, 1810 (39%) received an oral antibiotic treatment, in comparison to 3109 (28%) of the 11,093 eligible women (P<.001). Among the 4605 men who were eligible for treatment with isotretinoin in this population, 988 (21.5%) received a course of isotretinoin, compared to only 10.4% (1159/11,093) eligible women (P<.001). Male patients were 1.67 times more likely to have received an antibiotic prescription (odds ratio [OR] 1.67, 95% CI 1.55-1.79) and over twice as likely to have received an isotretinoin prescription (OR 2.34, 95% CI 2.13-2.57) than female patients. CONCLUSIONS: Minocycline was the most frequently prescribed antibiotic for the treatment of acne in this study cohort. From 2015 to 2019, there was no significant change in the number of antibiotic prescriptions over time. Men were significantly more likely to receive both oral antibiotics and isotretinoin than female patients. Multiple factors could be contributing to this discrepancy, including the burden of iPLEDGE, additional systemic treatment options for female patients, and the difference in acne severity across sexes. We could not determine the difference in severity of acne between male and female patients in our cohort, and further research is needed to ascertain the variation across sexes.

The Importance of Gender-Neutral Terminology in Risk Evaluation and Mitigation Strategy Programs: A Call to Action.

The use of risk evaluation and mitigation strategy (REMS) programs is frequently required for prescriptions with potentially teratogenic effects, especially in the field of dermatology. Among these REMS programs, the most well-known example is isotretinoin, an oral retinoid that uses the iPLEDGE system. iPLEDGE has strict regulations and a lengthy approval process, and until recently, patients were grouped into 3 categories: male, female, or female of reproductive potential. This strict grouping has posed problems in the medical community, especially for gender-diverse individuals where their perceived gender conflates with their assigned grouping causing patient-specific distress. The distinction between gender-a multifactorial perception of identity-and biological sex is addressed under new iPLEDGE guidelines. Dermatologists now register patients under one of 2 categories: patients who can become pregnant and those who cannot become pregnant. This change simultaneously improves the accessibility to isotretinoin among gender-diverse individuals, while limiting prescription barriers. Despite initial success being limited due to lengthy system conversions, a registration process based on reproductive potential ultimately enhances iPLEDGE's goal to prevent potential birth defects. We propose that other REMS programs follow the standard set by the iPLEDGE system, including those for the medications thalidomide, acitretin, and mycophenolate mofetil, all of which currently have a similar taxonomy to that of the old iPLEDGE system. Implementing the standardization of gender-neutral terminology can maximize enrollment and minimize distress. Current and ongoing refinement of iPLEDGE and other REMS is needed to build protocols solely around the prevention of birth defects without regard to sex or gender.

Distinguishing Gender Identity From Biological Sex in Dermatologic Health Care: Methods, Harms, and Paths Forward.

Accurate assessment of gender identity and biological sex in dermatology research is crucial since their conflation or poor demarcation undermines patient respect and study accuracy. Clearer guidance is needed for health care researchers, particularly in light of the notable disparities in skin disease rates, skincare practices, literature representation, and the persistent underrepresentation of transgender and nonbinary patients.

Prescribing Patterns of Dupilumab for Atopic Dermatitis in Adults: Retrospective, Observational Cohort Study.

BACKGROUND: Atopic dermatitis (AD) is a common inflammatory disease caused by a type 2 T helper cell-mediated immune response to environmental antigens. Approximately 1 in 5 patients with AD presents with moderate to severe disease, and treatments approved by the Food and Drug Administration include emollients, topical glucocorticoids, and calcineurin inhibitors. Dupilumab, a fully human monoclonal antibody, improves AD via inhibition of interleukin-4 and interleukin-13. OBJECTIVE: Our aim was to characterize the prescribing patterns of dupilumab for AD in adults at a large university-affiliated health system. METHODS: A retrospective, observational cohort study was conducted using electronic data from the Observational Health Data Sciences and Informatics database, assessing data from the University of Colorado Medical Campus and its affiliates. The outcome measured was the prevalence of dupilumab prescribed for adults with AD (n=6421), between March 28, 2013, and March 28, 2021. We assessed whether the characteristics of patients who received dupilumab were different from those who did not. Each patient characteristic was assessed using a univariate logistic regression with the binary outcome of receiving or not receiving dupilumab. RESULTS: We found a population prevalence of 5.6% (6421/114,476) for AD. In our cohort, Black patients with AD were more than twice as likely to have received dupilumab compared to White patients (odds ratio 2.352, 95% CI 1.58-3.39). Patients with a diagnosis of atopic neurodermatitis were approximately twice as likely to have received dupilumab compared to those with other diagnostic variants of AD (odds ratio 1.87, 95% CI 1.01-3.22). CONCLUSIONS: Our results demonstrate that both patient racial characteristics and specific AD diagnoses were associated with variations in dupilumab prescription patterns.

Isotretinoin Use in Transmasculine Patients and Its Implication on Chest Masculinization Surgery: Scoping Review of the Literature.

BACKGROUND: Acne often worsens in transmasculine patients who are on prolonged testosterone therapy. Isotretinoin is an oral retinoid used in the treatment of severe or refractory cases of acne, but it has the potential to cause delayed wound healing. Transmasculine patients may potentially be prescribed treatment for acne with isotretinoin while also planning to undergo chest masculinization surgery. OBJECTIVE: This scoping review aims to determine whether isotretinoin has a negative impact on postoperative healing in transmasculine patients undergoing chest masculinization surgery. METHODS: A scoping review was performed using the PubMed and Ovid databases. A total of 16 publications were selected for inclusion. RESULTS: Acne tends to peak in transmasculine patients 6 months after initiation of testosterone treatment. Severe cases can be treated with isotretinoin; however, acne may recur once treatment is discontinued, given ongoing hormone therapy. There is little to no evidence in the medical literature regarding perioperative use of isotretinoin specifically among transmasculine patients undergoing chest masculinization surgery. In general, however, recent studies have found no evidence of increased hypertrophic scars or keloids in patients taking isotretinoin. CONCLUSIONS: Further studies are required to strengthen the current evidence that suggests that isotretinoin does not need to be discontinued before or after incisional or excisional surgeries, including chest masculinization surgery in transmasculine patients.

Exploring the interactions of antihistamine with retinoic acid receptor beta (RARB) by molecular dynamics simulations and genome-wide meta-analysis.

Kaposi sarcoma (KS) is one of the most common AIDS-related malignant neoplasms, which can leave lesions on the skin among HIV patients. These lesions can be treated with 9-cis-retinoic acid (9-cis-RA), an endogenous ligand of retinoic acid receptors that has been FDA-approved for treatment of KS. However, topical application of 9-cis-RA can induce several unpleasant side effects, like headache, hyperlipidemia, and nausea. Hence, alternative therapeutics with less side effects are desirable. There are case reports associating over-the-counter antihistamine usage with regression of KS. Antihistamines competitively bind to H1 receptor and block the action of histamine, best known for being released in response to allergens. Furthermore, there are already dozens of antihistamines that are FDA-approved with less side effects than 9-cis-RA. This led our team to conduct a series of in-silico assays to determine whether antihistamines can activate retinoic acid receptors. First, we utilized high-throughput virtual screening and molecular dynamics simulations to model high-affinity interactions between antihistamines and retinoic acid receptor beta (RARß). We then performed systems genetics analysis to identify a genetic association between H1 receptor itself and molecular pathways involved in KS. Together, these findings advocate for exploration of antihistamines against KS, starting with our two promising hit compounds, bepotastine and hydroxyzine, for experimental validation study in the future.

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.