Malignant melanoma arising in a burn scar.

Secondary malignancies are rare but devastating complications of longstanding burn scars. Squamous cell carcinoma is the most common, followed by basal cell carcinoma and melanomas. There are fewer than 50 total reported cases of malignant melanomas arising in burn scars. We report a case of malignant melanoma arising within a longstanding burn scar confirmed by histology, FISH, and PRAME staining to further characterize melanomas arising in burn scars and to illustrate the diagnostic challenges they present.

Integrated plasma metabolomic and cytokine analysis reveals a distinct immunometabolic signature in atopic dermatitis.

Importance: Disease models for atopic dermatitis (AD) have primarily focused on understanding underlying environmental, immunologic, and genetic etiologies. However, the role of metabolic mechanisms in AD remains understudied. Objective: To investigate the circulating blood metabolomic and cytokine profile of AD as compared to healthy control patients. Design: This study collected plasma from 20 atopic dermatitis with moderate-to-severe itch (score of ≥5 on the itch Numeric Rating Scale and IGA score ≥3) and 24 healthy control patients. Mass-spectrometry based metabolite data were compared between AD and healthy controls. Unsupervised and supervised machine learning algorithms and univariate analysis analyzed metabolic concentrations. Metabolite enrichment and pathway analyses were performed on metabolites with significant fold change between AD and healthy control patients. To investigate the correlation between metabolites levels and cytokines, Spearman's rank correlation coefficients were calculated between metabolites and cytokines. Setting: Patients were recruited from the Johns Hopkins Itch Center and dermatology outpatient clinics in the Johns Hopkins Outpatient Center. Participants: The study included 20 atopic dermatitis patients and 24 healthy control patients. Main outcomes and measures: Fold changes of metabolites in AD vs healthy control plasma. Results: In patients with AD, amino acids isoleucine, tyrosine, threonine, tryptophan, valine, methionine, and phenylalanine, the amino acid derivatives creatinine, indole-3-acrylic acid, acetyl-L-carnitine, L-carnitine, 2-hydroxycinnamic acid, N-acetylaspartic acid, and the fatty amide oleamide had greater than 2-fold decrease (all P-values<0.0001) compared to healthy controls. Enriched metabolites were involved in branched-chain amino acid (valine, leucine, and isoleucine) degradation, catecholamine biosynthesis, thyroid hormone synthesis, threonine metabolism, and branched and long-chain fatty acid metabolism. Dysregulated metabolites in AD were positively correlated cytokines TARC and MCP-4 and negatively correlated with IL-1a and CCL20. Conclusions and relevance: Our study characterized novel dysregulated circulating plasma metabolites and metabolic pathways that may be involved in the pathogenesis of AD. These metabolic pathways serve as potential future biomarkers and therapeutic targets in the treatment of AD.

Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/µL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

Symptoms of Cognitive Impairment Among Children With Atopic Dermatitis.

Importance: Previous studies suggest that atopic dermatitis (AD) is associated with cognitive impairment in children, but these studies have relied primarily on neurodevelopmental diagnoses (rather than symptoms) as proxy measures of cognitive function. It remains unknown if certain subpopulations of children with AD are at greater risk of cognitive impairment. Objective: To examine the association of AD with symptoms of cognitive impairment (difficulty in learning or memory) among US children and whether this association varies according to the presence or absence of neurodevelopmental comorbidities (attention-deficit/hyperactivity disorder [ADHD], developmental delay, or learning disability). Design, Setting, and Participants: This cross-sectional study used 2021 data from the US National Health Interview Survey collected on children aged 17 years or younger without intellectual disability or autism. The presence of AD was based on a parent or adult caregiver's report indicating either a current diagnosis of AD or a previous medical confirmation of AD by a health care professional. Main Outcomes and Measures: Difficulty with learning or memory as reported by the child's caregiver. Results: Among the weighted total of 69 732 807 participants, 9 223 013 (13.2%) had AD. Compared with children without AD, children with AD were more likely to experience difficulties with learning (10.8% [95% CI, 7.8%-15.8%] vs 5.9% [95% CI, 5.1%-6.9%]; P < .001) and difficulties with memory (11.1% [95% CI, 8.0%-15.9%] vs 5.8% [95% CI, 4.9%-6.9%]; P < .001). In multivariable logistic regression models adjusted for sociodemographic factors, asthma, food allergies, and seasonal allergies or hay fever, AD was associated with increased odds of difficulties in learning (adjusted odds ratio [AOR], 1.77; 95% CI, 1.28-2.45) and memory (AOR, 1.69; 95% CI, 1.19-2.41). In analyses stratified by neurodevelopmental comorbidities, AD was associated with 2- to 3-fold greater odds of memory difficulties among children with any neurodevelopmental disorder (AOR, 2.26; 95% CI, 1.43-3.57), including ADHD (AOR, 2.90; 95% CI, 1.60-5.24) or learning disabilities (AOR, 2.04; 95% CI, 1.04-4.00). However, AD was not associated with learning or memory difficulties among children without neurodevelopmental conditions. Conclusions and Relevance: Results of this cross-sectional study suggest that pediatric AD was generally associated with greater odds of reported difficulties in learning and memory. However, this association was primarily limited to children with neurodevelopmental comorbidities, such as ADHD or learning disabilities. These findings may improve the risk stratification of children with AD for cognitive impairments and suggest that evaluation for cognitive difficulties should be prioritized among children with AD and neurodevelopmental disorders.

Experiences of quitting smoking in prisons: A qualitative study of people in custody.

INTRODUCTION: Smoking prevalence among people in custody (PIC) is extremely high, and prison-based smoking cessation interventions are needed. The study explored the quitting experiences of PIC who participated in the 'Quit to Win' contest (QTW). METHODS: This qualitative study, conducted from 2019 to 2021 in two Hong Kong prisons, included semi-structured individual interviews with 26 PIC (13 men and 13 women) who were participants in QTW and two correctional staff who coordinated QTW. A semi-structured interview guide with open-ended questions was developed to examine multilevel factors that promote or impede smoking cessation in prisons. Maximum variation sampling was used to ensure a diverse range of social, demographic, and smoking profiles. Data were managed and analyzed using thematic analysis. RESULTS: Two themes were identified from the data: 1) quitting in prison: barriers and facilitators; and 2) QTW in prison: a trigger for behavior change. Barriers (i.e. stress, boredom, isolation, lack of self-autonomy, nicotine dependence and lack of cessation medication, barriers to moving to a different wing) and facilitators (i.e. concerns about health, money savings, and the smoke-free wing) that impeded or supported smoking cessation during incarceration were identified. QTW provided health education, quitting incentives, and social support that helped PIC overcome the barriers of quitting by serving as a trigger for behavior change. Notably, social visits with family were identified as key drivers of PIC's quitting success, whereas their suspension during the COVID-19 pandemic disincentivized their abstinence. CONCLUSIONS: This study introduced the QTW contest to prisons and provided qualitative evidence on the multilevel factors promoting or impeding smoking cessation in prison. QTW helped PIC overcome the barriers of quitting by serving as a trigger for behavior change. Future prison-based interventions should leverage social support, enhance stress-coping skills, facilitate access to pharmacotherapy, and collaborate with correctional services agencies.

Characterizing Interest in and Uptake of Preexposure Prophylaxis for HIV Prevention Among Men in a US State Correctional System.

BACKGROUND: People experiencing incarceration are disproportionately impacted by HIV and are potential candidates for HIV preexposure prophylaxis (PrEP). We explored factors associated with PrEP interest and PrEP uptake and described barriers to PrEP uptake among incarcerated men in a state correctional system. METHODS: From September 2019 to July 2022, incarcerated men at the Rhode Island Department of Corrections were screened for PrEP eligibility and referred to a PrEP initiation study. We used bivariate analyses and multivariable logistic regression models to explore factors associated with PrEP interest and uptake in the screening sample. RESULTS: Of the men screened and determined to be eligible for PrEP, approximately half (50%) were interested in taking PrEP. Individuals identifying as men who have sex with men (adjusted odds ratio, 4.46; 95% confidence interval, 1.86-11.4) and having multiple female sex partners (adjusted odds ratio, 2.98; 95% confidence interval, 1.47-6.27) were more likely to express interest in PrEP (interested/not interested) than those not reporting these behavioral factors. Preexposure prophylaxis uptake (yes/no) was 38%. Lack of PrEP interest, low self-perceived risk of HIV acquisition, and unpredictable lengths of incarceration were the most frequently encountered barriers to PrEP uptake. CONCLUSIONS: Men reporting sexual transmission behaviors were more interested in PrEP and had higher uptake than other men. Preexposure prophylaxis interest and HIV risk factors were both moderately high, which suggests that men experiencing incarceration should be screened for and offered PrEP as part of standard clinical care. Study findings have important implications for research and practice to adapt PrEP care to correctional systems.

Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis.

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.

Prurigo Nodularis: New insights into pathogenesis and novel therapeutics.

Prurigo nodularis (PN) is an inflammatory skin condition characterized by intensely pruritic nodules on the skin. PN patients suffer from an intractable itch-scratch cycle leading to impaired sleep, psychosocial distress, and a significant disruption in quality of life. The pathogenesis of PN is associated with immune and neural dysregulation, mediated by inflammatory cytokines (such as IL-4, -13, -17, -22, and -31) and neuropeptides (such as substance P and calcitonin gene-related peptide). There is a role for type 2 inflammation in PN in addition to Th17 and Th22-mediated inflammation. The neuroimmune feedback loop in PN involves neuropeptides released from nerve fibers that cause vasodilation and further recruitment of inflammatory cells. Inflammatory cells, particularly mast cells and eosinophils, degranulate and release neurotoxins, as well as nerve growth factor, which may contribute to the neuronal hyperplasia seen in the dermis of PN patients and neural sensitization. Recent studies have also indicated underlying genetic susceptibility to PN in addition to environmental factors, the existence of various disease endotypes centered around degrees of Type 2 inflammation or underlying myelopathy or spinal disc disease, and significant race and ethnicity-based differences with African-Americans having densely fibrotic skin lesions. Dupilumab became the first FDA approved therapeutic for PN, and there are several other agents currently in development. The anti-IL-31RA inhibitor nemolizumab is in late stage development with positive phase 3 data reported. In addition, the oral JAK1 inhibitors, abrocitinib and povorcitinib, are in phase 2 trials while a topical JAK1/2 inhibitor, ruxolitinib, is in phase 3 studies.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Transcriptomic and proteomic analysis of tumor suppressive effects of GZ17-6.02 against mycosis fungoides.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL). Despite having a wide variety of therapeutic agents available for the treatment of MF, patients often suffer from a significant decrease in quality of life and rarely achieve long-term remission or complete cure, highlighting a need to develop novel therapeutic agents for this disease. The present study was undertaken to evaluate the efficacy of a novel anti-tumor agent, GZ17-6.02, which is composed of curcumin, harmine, and isovanillin, against MF in vitro and in murine models. Treatment of HH and MyLa cells with GZ17-6.02 inhibited the growth of both cell lines with IC50 ± standard errors for growth inhibition of 14.37 ± 1.19 µg/mL and 14.56 ± 1.35 µg/mL, respectively, and increased the percentage of cells in late apoptosis (p = .0304 for HH; p = .0301 for MyLa). Transcriptomic and proteomic analyses revealed that GZ17-6.02 suppressed several pathways, including tumor necrosis factor (TNF)-ɑ signaling via nuclear factor (NF)-kB, mammalian target of rapamycin complex (mTORC)1, and Pi3K/Akt/mTOR signaling. In a subcutaneous tumor model, GZ17-6.02 decreased tumor volume (p = .002) and weight (p = .009) compared to control conditions. Proteomic analysis of tumor samples showed that GZ17-6.02 suppressed the expression of several proteins that may promote CTCL growth, including mitogen-activated protein kinase (MAPK)1, MAPK3, Growth factor receptor bound protein (GRB)2, and Mediator of RAP80 interactions and targeting subunit of 40 kDa (MERIT)40.

Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Atopic dermatitis, cognitive function and psychiatric comorbidities across early childhood and adolescence in a population-based UK birth cohort.

BACKGROUND: Atopic dermatitis (AD) may affect cognitive function, but studies are limited and inconsistent. The effect of AD severity on cognition remains underexplored and few previous studies have examined clinically validated or repeated measures of cognition throughout childhood. OBJECTIVES: To evaluate the relationship of AD activity and severity with validated measures of general cognition in a longitudinal birth cohort. METHODS: We conducted cross-sectional analyses using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK cohort of 14 975 individuals followed prospectively since their birth in 1991-92. AD was assessed 11 times between the age of 6 and 166 months. Mothers were asked if their child had an 'itchy, dry skin rash in the joints and creases', and AD status was time-updated accordingly as 'never', 'maybe', 'inactive', 'active/mild' or 'active/moderate-severe'. General cognition [i.e. intelligence quotient (IQ)] was measured at 18, 49, 103 and 186 months of age using the Griffiths Mental Development Scales (GMDS), Wechsler Preschool and Primary Scale of Intelligence (WPPSI), Wechsler Intelligence Scale for Children (WISC) and Wechsler Abbreviated Scale of Intelligence (WASI), respectively. Multivariable linear regression was used to compare IQ with respect to nearest time-updated AD status. Secondary analyses were stratified by the presence or absence of psychiatric or learning disorders. An exploratory longitudinal analysis of IQ across all four outcome assessments was conducted using generalized estimating equations. RESULTS: No significant associations between AD status and full-scale IQ scores on the GMDS, WPPSI, WISC and WASI were observed after adjustment for sociodemographic factors, atopic comorbidities and sleep characteristics. However, at 8 years of age, WISC Performance IQ was slightly, although statistically significantly, lower among children with active/moderate-severe AD [ß coefficient -2.16, 95% confidence interval (CI) -4.12 to -0.19] and Verbal IQ was slightly, but statistically significantly, higher among those with inactive AD (ß coefficient 1.31, 95% CI 0.28-2.34) compared with those without AD. Analyses stratified by psychiatric or learning disorders, and exploratory longitudinal analyses of cognition revealed similar findings. CONCLUSIONS: We did not find any clinically meaningful associations between AD activity and severity and general cognitive function during early childhood and adolescence. Future studies should incorporate objective measures of AD severity and investigate outcomes beyond IQ.

Progressive Skull Osteolysis in the Setting of Endotine Implantation: A Case Report.

OBJECTIVES: To report a case of a 71-year-old woman who presented 8 years following 2 endoscopic brow lift procedures for evaluation of bony irregularities of her frontoparietal skull. To highlight a novel complication of Endotine fixation following an endoscopic brow lift procedure. METHODS: A chart review, bicoronal cranioplasty and a review of literature. RESULTS: The patient was satisfied with her post-surgical outcome and no complications were observed at the 1-month follow-up visit. A review of the literature revealed no previous reports of focal skull osteolysis relating to Endotine implants. CONCLUSION: We believe that our patient's focal calvarial osteolysis is a direct complication of Endotine fixation. Future research into the long-term effects of endoscopic brow lift procedures using Endotine implants is necessary to help ensure patient safety and guide future practices.

The effect of an exopolysaccharide probiotic molecule from Bacillus subtilis on breast cancer cells.

Introduction: Many well-known risk factors for breast cancer are associated with dysbiosis (an aberrant microbiome). However, how bacterial products modulate cancer are poorly understood. In this study, we investigated the effect of an exopolysaccharide (EPS) produced by the commensal bacterium Bacillus subtilis on breast cancer phenotypes. Although B. subtilis is commonly included in probiotic preparations and its EPS protects against inflammatory diseases, it was virtually unknown whether B. subtilis-derived EPS affects cancer. Methods: This work investigated effects of EPS on phenotypes of breast cancer cells as a cancer model. The phenotypes included proliferation, mammosphere formation, cell migration, and tumor growth in two immune compromised mouse models. RNA sequencing was performed on RNA from four breast cancer cells treated with PBS or EPS. IKKß or STAT1 signaling was assessed using pharmacologic or RNAi-mediated knock down approaches. Results: Short-term treatment with EPS inhibited proliferation of certain breast cancer cells (T47D, MDA-MB-468, HCC1428, MDA-MB-453) while having little effect on others (MCF-7, MDA-MB-231, BT549, ZR-75-30). EPS induced G1/G0 cell cycle arrest of T47D cells while increasing apoptosis of MDA-MB-468 cells. EPS also enhanced aggressive phenotypes in T47D cells including cell migration and cancer stem cell survival. Long-term treatment with EPS (months) led to resistance in vitro and promoted tumor growth in immunocompromised mice. RNA-sequence analysis showed that EPS increased expression of pro-inflammatory pathways including STAT1 and NF-κB. IKKß and/or STAT1 signaling was necessary for EPS to modulate phenotypes of EPS sensitive breast cancer cells. Discussion: These results demonstrate a multifaceted role for an EPS molecule secreted by the probiotic bacterium B. subtilis on breast cancer cell phenotypes. These results warrant future studies in immune competent mice and different cancer models to fully understand potential benefits and/or side effects of long-term use of probiotics.