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.

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.

The Hidden Costs of Psoriasis: A Population-Based Study Evaluating How Psoriasis Severity Impacts Work Absenteeism.

BACKGROUND: Psoriasis patients experience physical and emotional burdens, which may lead to work-related productivity loss. This loss carries professional and financial repercussions. It is unknown whether the extent of psoriasis affects work absenteeism. OBJECTIVE: This study aims to compare work absenteeism between employed adults with mild versus moderate-to-severe psoriasis. METHODS: A national, cross-sectional study using the 2009 to 2019 Medical Expenditure Panel Survey evaluated 5,209,956 (weighted) adults aged ≥ 22 years. Work absenteeism was compared between adults with mild (4,521,687 weighted) and moderate-to-severe psoriasis (688,269 weighted). RESULTS: Work absenteeism, as measured by the average number of episodes per year that someone was absent from work for at least a half day, was significantly higher in patients with moderate-to-severe psoriasis than in patients with mild disease (4.4 episodes vs 2.8 episodes, P=0.002). Multivariable logistic regression models showed moderate-to-severe patients were 2.68 times more likely (95% CI:1.72-4.21; P<0.001) to take a half-day or more off from work than those with mild disease after adjusting for age, sex, race, ethnicity, poverty, cognitive limitations, insurance, education, and comorbidities. CONCLUSION: Disease severity directly impacts work absenteeism in psoriasis patients. Early diagnosis and treatment with appropriate therapies are needed to reduce disease severity and limit economic loss and professional ramifications associated with psoriasis. J Drugs Dermatol. 2024;23(8):640-644.  doi:10.36849/JDD.7550.

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.

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.

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.

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.

COVID-19 and pneumothorax: a multicentre retrospective case series.

INTRODUCTION: Pneumothorax and pneumomediastinum have both been noted to complicate cases of coronavirus disease 2019 (COVID-19) requiring hospital admission. We report the largest case series yet described of patients with both these pathologies (including nonventilated patients). METHODS: Cases were collected retrospectively from UK hospitals with inclusion criteria limited to a diagnosis of COVID-19 and the presence of either pneumothorax or pneumomediastinum. Patients included in the study presented between March and June 2020. Details obtained from the medical record included demographics, radiology, laboratory investigations, clinical management and survival. RESULTS: 71 patients from 16 centres were included in the study, of whom 60 had pneumothoraces (six with pneumomediastinum in addition) and 11 had pneumomediastinum alone. Two of these patients had two distinct episodes of pneumothorax, occurring bilaterally in sequential fashion, bringing the total number of pneumothoraces included to 62. Clinical scenarios included patients who had presented to hospital with pneumothorax, patients who had developed pneumothorax or pneumomediastinum during their inpatient admission with COVID-19 and patients who developed their complication while intubated and ventilated, either with or without concurrent extracorporeal membrane oxygenation. Survival at 28 days was not significantly different following pneumothorax (63.1±6.5%) or isolated pneumomediastinum (53.0±18.7%; p=0.854). The incidence of pneumothorax was higher in males. 28-day survival was not different between the sexes (males 62.5±7.7% versus females 68.4±10.7%; p=0.619). Patients aged ≥70 years had a significantly lower 28-day survival than younger individuals (≥70 years 41.7±13.5% survival versus <70 years 70.9±6.8% survival; p=0.018 log-rank). CONCLUSION: These cases suggest that pneumothorax is a complication of COVID-19. Pneumothorax does not seem to be an independent marker of poor prognosis and we encourage continuation of active treatment where clinically possible.

Aminocaproic Acid and Tranexamic Acid Fail to Reverse Dabigatran-Induced Coagulopathy.

In recent years, dabigatran has emerged as a popular alternative to warfarin for treatment of atrial fibrillation. If rapid reversal is required, however, no reversal agent has clearly been established. The primary purpose of this manuscript was to evaluate the efficacy of tranexamic acid and aminocaproic acid as agents to reverse dabigatran-induced coagulopathy. Rats were randomly assigned to 6 groups. Each rat received either dabigatran or oral placebo, followed by saline, tranexamic acid, or aminocaproic acid. An activated clotting test was used to measure the coagulopathy. Neither tranexamic acid nor aminocaproic acid successfully reversed dabigatran-induced coagulopathy. In this rodent model of dabigatran-induced coagulopathy, neither tranexamic acid nor aminocaproic acid were able to reverse the coagulopathy.

Risk factors for apnea in pediatric patients transported by paramedics for out-of-hospital seizure.

STUDY OBJECTIVE: Apnea is a known complication of pediatric seizures, but patient factors that predispose children are unclear. We seek to quantify the risk of apnea attributable to midazolam and identify additional risk factors for apnea in children transported by paramedics for out-of-hospital seizure. METHODS: This is a 2-year retrospective study of pediatric patients transported by paramedics to 2 tertiary care centers. Patients were younger than 15 years and transported by paramedics to the pediatric emergency department (ED) for seizure. Patients with trauma and those with another pediatric ED diagnosis were excluded. Investigators abstracted charts for patient characteristics and predefined risk factors: developmental delay, treatment with antiepileptic medications, and seizure on pediatric ED arrival. Primary outcome was apnea defined as bag-mask ventilation or intubation for apnea by paramedics or by pediatric ED staff within 30 minutes of arrival. RESULTS: There were 1,584 patients who met inclusion criteria, with a median age of 2.3 years (Interquartile range 1.4 to 5.2 years). Paramedics treated 214 patients (13%) with midazolam. Seventy-one patients had apnea (4.5%): 44 patients were treated with midazolam and 27 patients were not treated with midazolam. After simultaneous evaluation of midazolam administration, age, fever, developmental delay, antiepileptic medication use, and seizure on pediatric ED arrival, 2 independent risk factors for apnea were identified: persistent seizure on arrival (odds ratio [OR]=15; 95% confidence interval [CI] 8 to 27) and administration of field midazolam (OR=4; 95% CI 2 to 7). CONCLUSION: We identified 2 risk factors for apnea in children transported for seizure: seizure on arrival to the pediatric ED and out-of-hospital administration of midazolam.

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.

Efficient human cytomegalovirus reactivation is maturation dependent in the Langerhans dendritic cell lineage and can be studied using a CD14+ experimental latency model.

Studies from a number of laboratories have shown that the myeloid lineage is prominent in human cytomegalovirus (HCMV) latency, reactivation, dissemination, and pathogenesis. Existing as a latent infection in CD34(+) progenitors and circulating CD14(+) monocytes, reactivation is observed upon differentiation to mature macrophage or dendritic cell (DC) phenotypes. Langerhans' cells (LCs) are a subset of periphery resident DCs that represent a DC population likely to encounter HCMV early during primary infection. Furthermore, we have previously shown that CD34(+) derived LCs are a site of HCMV reactivation ex vivo. Accordingly, we have utilized healthy-donor CD34(+) cells to study latency and reactivation of HCMV in LCs. However, the increasing difficulty acquiring healthy-donor CD34(+) cells--particularly from seropositive donors due to the screening regimens used--led us to investigate the use of CD14(+) monocytes to generate LCs. We show here that CD14(+) monocytes cultured with transforming growth factor ß generate Langerin-positive DCs (MoLCs). Consistent with observations using CD34(+) derived LCs, only mature MoLCs were permissive for HCMV infection. The lytic infection of mature MoLCs is productive and results in a marked inhibition in the capacity of these cells to promote T cell proliferation. Pertinently, differentiation of experimentally latent monocytes to the MoLC phenotype promotes reactivation in a maturation and interleukin-6 (IL-6)-dependent manner. Intriguingly, however, IL-6-mediated effects were restricted to mature LCs, in contrast to observations with classical CD14(+) derived DCs. Consequently, elucidation of the molecular basis behind the differential response of the two DC subsets should further our understanding of the fundamental mechanisms important for reactivation.

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.

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.

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.