Influence of Anatomic Locations of T1b Melanomas and Patient Age on Outcomes.

BACKGROUND: There are no guidelines on when to more strongly recommend sentinel lymph node biopsy (SLNB) for T1b melanomas. OBJECTIVE: To examine whether anatomic locations of T1b melanomas and patient age influence metastases. METHODS: We conducted a retrospective study using data from two hospitals in Los Angeles County from January 2010 through January 2020. RESULTS: Out of 620 patients with primary melanomas, 566 melanomas were staged based on the American Joint Committee on Cancer 8th edition melanoma staging. Forty-one were T1b, of which 13 were located on the face/ear/scalp and 28 were located elsewhere. T1b melanomas located on the face/ear/scalp had an increased risk of lymph node or distant metastasis compared with other anatomic sites (31% vs 3.6%, P=0.028). For all melanomas, the risk of lymph node or distant metastasis decreased with age of 64 years or greater (P<0.001 and P=0.034). For T1b melanomas, the risk of distant metastasis increased with increasing age (P=0.047). LIMITATIONS: Data were from a single county.  Conclusion: T1b melanomas of the face/ear/scalp demonstrated a higher risk of lymph node or distant metastasis and may help guide the recommendation of SLNB, imaging, and surveillance. Younger patients may be more strongly considered for SLNB and older patients with T1b melanomas may warrant imaging.  J Drugs Dermatol. 2024;23(5):306-310. doi:10.36849/JDD.7667.

Comorbidity Burden in Psoriasis Patients with Skin of Color.

Background: Psoriasis is a chronic disease with increased risk of numerous comorbidities. Known differences exist regarding treatment outcomes for psoriasis patients with skin of color (SOC). However, factors contributing to these differences are relatively unknown. Objectives: This study aims to compare the comorbidity burden in SOC psoriasis patients vs. White patients, as measured by the Charlson Comorbidity Index (CCI) score. Methods: We utilized the National Ambulatory Medical Care Survey (NAMCS) to identify visits for adult psoriasis patients occurring in the years 2002-2016 and 2018. The CCI was used to objectively measure comorbidity burden. Patients were identified by race, and SOC was defined as any reported race besides White Only. A multiple linear regression was run to compare the CCI among adult psoriasis patients based on race and ethnicity, controlling for age, sex, insurance status, and geographic region. Results: A total of 39,176,928 weighted visits were analyzed. Compared to White patients, patients with SOC did not have statistically significant differences in comorbidity burden, as measured by CCI score (p=0.073 for Black/African American Only vs. White Only, p=0.073 for American Indian/Alaska Native Only vs. White Only, p=0.435 for Asian Only vs. White Only, p=0.403 for Native Hawaiian/Pacific Islander Only vs. White Only, p=0.195 for Other vs. White Only). Conclusion: Patients with SOC were not found to have differences in comorbidity burden compared to White patients. These results highlight that social factors such as socioeconomic status and access to healthcare may contribute more directly to psoriasis treatment outcomes than patient race.

Multi-omics and imaging mass cytometry characterization of human kidneys to identify pathways and phenotypes associated with impaired kidney function.

Despite the recent advances in our understanding of the role of lipids, metabolites, and related enzymes in mediating kidney injury, there is limited integrated multi-omics data identifying potential metabolic pathways driving impaired kidney function. The limited availability of kidney biopsies from living donors with acute kidney injury has remained a major constraint. Here, we validated the use of deceased transplant donor kidneys as a good model to study acute kidney injury in humans and characterized these kidneys using imaging and multi-omics approaches. We noted consistent changes in kidney injury and inflammatory markers in donors with reduced kidney function. Neighborhood and correlation analyses of imaging mass cytometry data showed that subsets of kidney cells (proximal tubular cells and fibroblasts) are associated with the expression profile of kidney immune cells, potentially linking these cells to kidney inflammation. Integrated transcriptomic and metabolomic analysis of human kidneys showed that kidney arachidonic acid metabolism and seven other metabolic pathways were upregulated following diminished kidney function. To validate the arachidonic acid pathway in impaired kidney function we demonstrated increased levels of cytosolic phospholipase A2 protein and related lipid mediators (prostaglandin E2) in the injured kidneys. Further, inhibition of cytosolic phospholipase A2 reduced injury and inflammation in human kidney proximal tubular epithelial cells in vitro. Thus, our study identified cell types and metabolic pathways that may be critical for controlling inflammation associated with impaired kidney function in humans.

Complementary and Alternative Medicine for Hidradenitis Suppurativa Discussed on TikTok: A Cross-Sectional Analysis.

BACKGROUND: Hidradenitis suppurativa (HS) is a painful, chronic inflammatory skin disease that negatively affects patient quality of life, and conventional treatments are variably effective. As a result, patients often turn to complementary and alternative medicine (CAM) for pain relief. Social media enables HS patients to share treatment recommendations. TikTok is a popular social media platform, but little is known about the HS treatments discussed in TikTok videos.  Objective: To evaluate the content and quality of information on TikTok regarding CAM HS therapies.  Methods: A cross-sectional analysis was conducted by performing a search in TikTok using the terms #hidradenitissuppurativa, #hswarrior, #naturalremedy, #complementarymedicine, #alternativemedicine, and #HStreatment. Two independent reviewers evaluated video quality using the DISCERN and AVA instruments. Linear regressions compared the engagement, DISCERN, and AVA scores among different uploader types. RESULTS: In total, 91 TikTok videos were analyzed. Videos were uploaded by non-physicians (82.4), dermatologists (6.6%), and private companies (11.0%). The average DISCERN and AVA scores were 36.2 and 1.6, respectively (poor quality). Common CAM therapies were natural salves, turmeric, Epsom salts, elimination diets, and zinc supplements. Physician-uploaded videos were of significantly higher quality than videos by other uploader types, with an average DISCERN and AVA score of 44.3 (P<0.009) and 2.6 (P<0.001), respectively (fair quality). CONCLUSION: TikTok videos were poor quality (low DISCERN and AVA scores); physician-uploaded videos were fair quality. Dermatologists can improve video quality by adequately discussing the supporting evidence, mechanisms of action, and remaining questions for HS treatments.  J Drugs Dermatol. 2024;23(3):e93-96. doi:10.36849/JDD.7738e.

Janus-kinase inhibitors in dermatology: A review of their use in psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease.

Recent studies on molecular pathways have elucidated novel therapeutic approaches in inflammatory and autoimmune skin disorders. Specifically, the dysregulation of the Janus kinase signal transducer and activator of transcription (JAK-STAT) cascade plays a central role in the pathogenesis of many skin conditions. JAK inhibitors, with their ability to selectively target immune responses, are potential treatment options. Using the National Library of Medicine, we provide a comprehensive review of the use of United States Food and Drug Administration (FDA)-approved and emerging JAK or tyrosine kinase 2 (TYK2) inhibitors in a wide range of dermatologic conditions, including psoriasis, vitiligo, systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. In patients with psoriasis, oral deucravacitinib (TYK2 inhibitor) has been approved as a once-daily therapy with demonstrated superiority and efficacy over apremilast and placebo and tolerable safety profiles. In patients with vitiligo, topical ruxolitinib (JAK1 inhibitor) is approved as a twice-daily treatment for repigmentation. The efficacy of several other JAK inhibitors has also been demonstrated in several clinical trials and case studies for systemic lupus erythematosus, hidradenitis suppurativa, dermatomyositis, lichen planus, lichen planopilaris, sarcoidosis and graft-versus-host disease. Further investigations with long-term clinical trials are necessary to confirm their utility in treatment and safety for these diseases.

Spatially resolved multiomics of human cardiac niches.

The function of a cell is defined by its intrinsic characteristics and its niche: the tissue microenvironment in which it dwells. Here we combine single-cell and spatial transcriptomics data to discover cellular niches within eight regions of the human heart. We map cells to microanatomical locations and integrate knowledge-based and unsupervised structural annotations. We also profile the cells of the human cardiac conduction system1. The results revealed their distinctive repertoire of ion channels, G-protein-coupled receptors (GPCRs) and regulatory networks, and implicated FOXP2 in the pacemaker phenotype. We show that the sinoatrial node is compartmentalized, with a core of pacemaker cells, fibroblasts and glial cells supporting glutamatergic signalling. Using a custom CellPhoneDB.org module, we identify trans-synaptic pacemaker cell interactions with glia. We introduce a druggable target prediction tool, drug2cell, which leverages single-cell profiles and drug-target interactions to provide mechanistic insights into the chronotropic effects of drugs, including GLP-1 analogues. In the epicardium, we show enrichment of both IgG+ and IgA+ plasma cells forming immune niches that may contribute to infection defence. Overall, we provide new clarity to cardiac electro-anatomy and immunology, and our suite of computational approaches can be applied to other tissues and organs.

Shared decision-making and satisfaction with care in patients with psoriasis: A population-based study in the United States.

BACKGROUND: Shared decision-making (SDM) is a critical component of the patient-physician relationship. Although SDM has been reported to improve patient knowledge in other fields, it is still relatively unknown in dermatology. OBJECTIVE: To determine the association between SDM and satisfaction with care among patients with psoriasis. METHODS: Cross-sectional study using data from the 2014 to 2017 and 2019 Medical Expenditure Panel Survey. RESULTS: A weighted total of 3,715,027 patients with psoriasis were identified. The average SDM score was 3.6 (of 4), and the average satisfaction with care score was 8.6 (of 10). Approximately 42% of the cohort reported having a high SDM (score, ≥3.9). Patients who had high SDM had, on average, 85% higher satisfaction with care (P < .001) after adjusting for covariates. LIMITATIONS: The results of our study should be interpreted within the context of the Medical Expenditure Panel Survey database. The ability to measure SDM was limited by the 7 items from Medical Expenditure Panel Survey, which may not fully capture active participation in shared decision-making. CONCLUSION: A majority of patients with psoriasis are not participating in highly SDM. It is important to construct a framework for carrying out SDM efficiently to enhance physician-patient communication and improve patient outcomes.

Shared decision-making and satisfaction with care: a population-based study in patients with acne with skin of colour in the USA.

Little is known about differences in shared decision-making and patient satisfaction with acne care among different ethnicities and races. We conducted a cross-sectional study to determine differences between patients with acne who are White and those with skin of colour (SOC), i.e. (i) engagement in shared decision-making, and (ii) patient satisfaction with care, using the 2009-2017 and 2019 Medical Panel Expenditure Survey. Patients with acne with SOC were nearly two times more likely to engage in high shared decision-making compared with White patients [adjusted odds ratio 1.80, 95% confidence interval (CI) 1.30-2.51, P < 0.001]. Patients with SOC with acne reported lower satisfaction with care compared with White patients (ß = -0.38, 95% CI -0.69 to -0.06, P = 0.02). Patients with SOC who had acne reported higher levels of shared decision-making than White patients. However, compared with the White patients, patients with SOC report lower satisfaction with their care. There may be other factors contributing to lower satisfaction with care in patients with SOC who have acne.

Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.

Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.

Disparities in nonmelanoma skin cancer in Hispanic/Latino patients based on Mohs micrographic surgery defect size: A multicenter retrospective study.

BACKGROUND: There is limited literature regarding potential disparities in nonmelanoma skin cancer for patients with skin of color. OBJECTIVE: Use the sizes of Mohs micrographic surgery defects to examine disparities in nonmelanoma skin cancer among Hispanic/Latino patients with a secondary aim to examine the effect of insurance type. METHODS: We conducted a multicenter retrospective study using data from 3 major institutions in Los Angeles County. A total of 3486 Mohs micrographic surgeries of basal cell, squamous cell, and basosquamous cell carcinomas were analyzed. RESULTS: Mohs micrographic surgery defect sizes were 17% larger among Hispanic/Latino patients compared with non-Hispanic White patients. More notably, when comparing defect sizes of squamous cell carcinomas to those of basal cell carcinomas, defects were 80% larger among Hispanic/Latino patients compared to non-Hispanic White patients who had 25% larger defect sizes. Compared to patients with Medicare, patients with health maintenance organization and Medicaid/health maintenance organization had 22% and 52% larger defect sizes, respectively, whereas patients with preferred provider organization, had 10% smaller defect sizes. LIMITATIONS: The data included were from a single county population. CONCLUSION: Disparities regarding nonmelanoma skin cancer exist between patients with skin of color and White patients. Patients and the medical community need to be cognizant that skin cancer can develop in patients regardless of their race and ethnicity.

Mechanism of succinate efflux upon reperfusion of the ischaemic heart.

AIMS: Succinate accumulates several-fold in the ischaemic heart and is then rapidly oxidized upon reperfusion, contributing to reactive oxygen species production by mitochondria. In addition, a significant amount of the accumulated succinate is released from the heart into the circulation at reperfusion, potentially activating the G-protein-coupled succinate receptor (SUCNR1). However, the factors that determine the proportion of succinate oxidation or release, and the mechanism of this release, are not known. METHODS AND RESULTS: To address these questions, we assessed the fate of accumulated succinate upon reperfusion of anoxic cardiomyocytes, and of the ischaemic heart both ex vivo and in vivo. The release of accumulated succinate was selective and was enhanced by acidification of the intracellular milieu. Furthermore, pharmacological inhibition, or haploinsufficiency of the monocarboxylate transporter 1 (MCT1) significantly decreased succinate efflux from the reperfused heart. CONCLUSION: Succinate release upon reperfusion of the ischaemic heart is mediated by MCT1 and is facilitated by the acidification of the myocardium during ischaemia. These findings will allow the signalling interaction between succinate released from reperfused ischaemic myocardium and SUCNR1 to be explored.

Targeting succinate dehydrogenase with malonate ester prodrugs decreases renal ischemia reperfusion injury.

Renal ischemia reperfusion (IR) injury leads to significant patient morbidity and mortality, and its amelioration is an urgent unmet clinical need. Succinate accumulates during ischemia and its oxidation by the mitochondrial enzyme succinate dehydrogenase (SDH) drives the ROS production that underlies IR injury. Consequently, compounds that inhibit SDH may have therapeutic potential against renal IR injury. Among these, the competitive SDH inhibitor malonate, administered as a cell-permeable malonate ester prodrug, has shown promise in models of cardiac IR injury, but the efficacy of malonate ester prodrugs against renal IR injury have not been investigated. Here we show that succinate accumulates during ischemia in mouse, pig and human models of renal IR injury, and that its rapid oxidation by SDH upon reperfusion drives IR injury. We then show that the malonate ester prodrug, dimethyl malonate (DMM), can ameliorate renal IR injury when administered at reperfusion but not prior to ischemia in the mouse. Finally, we show that another malonate ester prodrug, diacetoxymethyl malonate (MAM), is more potent than DMM because of its faster esterase hydrolysis. Our data show that the mitochondrial mechanisms of renal IR injury are conserved in the mouse, pig and human and that inhibition of SDH by 'tuned' malonate ester prodrugs, such as MAM, is a promising therapeutic strategy in the treatment of clinical renal IR injury.