Single-cell sequencing delineates T-cell clonality and pathogenesis of the parapsoriasis disease group.

BACKGROUND: Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is often underdiagnosed in early stages because of similarities with benign dermatoses such as atopic dermatitis (AD). Furthermore, the delineation from what is called "parapsoriasis en plaque", a disease that can appear either in a small- or large-plaque form, is still controversial. OBJECTIVE: We sought to characterize the parapsoriasis disease spectrum. METHODS: We performed single-cell RNA sequencing of skin biopsies from patients within the parapsoriasis-to-early-stage MF spectrum, stratified for small and large plaques, and compared them to AD, psoriasis, and healthy control skin. RESULTS: Six of 8 large-plaque lesions harbored either an expanded alpha/beta or gamma/delta T-cell clone with downregulation of CD7 expression, consistent with a diagnosis of early-stage MF. In contrast, 6 of 7 small-plaque lesions were polyclonal in nature, thereby lacking a lymphomatous phenotype, and also revealed a less inflammatory microenvironment than early-stage MF or AD. Of note, polyclonal small- and large-plaque lesions characteristically harbored a population of NPY+ innate lymphoid cells and displayed a stromal signature of complement upregulation and antimicrobial hyperresponsiveness in fibroblasts and sweat gland cells, respectively. These conditions were clearly distinct from AD or psoriasis, which uniquely harbored CD3+CRTH2+ IL-13 expressing "TH2A" cells, or strong type 17 inflammation, respectively. CONCLUSION: These data position polyclonal small- and large-plaque parapsoriasis lesions as a separate disease entity that characteristically harbors a so far undescribed innate lymphoid cell population. We thus propose a new term, "polyclonal parapsoriasis en plaque", for this kind of lesion because they can be clearly differentiated from early- and advanced-stage MF, psoriasis, and AD on several cellular and molecular levels.

Single-cell RNA sequencing comparison of CD4+, CD8+ and TCR-γδ+ cutaneous T-cell lymphomas reveals subset-specific molecular phenotypes.

BACKGROUND: Malignant clones of primary cutaneous T-cell lymphomas (CTCL) can show a CD4, CD8 or TCR-γδ phenotype, but their individual impact on tumor biology and skin lesion formation remains ill-defined. OBJECTIVES: To perform a comprehensive molecular characterization of CD4+ vs. CD8+ and TCR-γ/δ+ CTCL lesions. METHODS: We performed scRNA-seq of 18 CTCL skin biopsies to compare classic CD4+ advanced-stage mycosis fungoides (MF) with TCR-γ/δ+MF and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma (Berti's lymphoma). RESULTS: Malignant clones of TCR-γ/δ+MF and Berti's lymphoma showed similar clustering patterns distinct from CD4+MF, along with increased expression of cytotoxic markers such as NKG7, CTSW, GZMA, and GZMM. Only advanced-stage CD4+MF clones expressed central memory T-cell markers (SELL, CCR7, LEF1), alongside B1/B2 blood involvement, whereas TCR-γ/δ+MF and Berti's lymphoma harbored a more tissue-resident phenotype (CD69, CXCR4, NR4A1) without detectable cells in the blood. CD4+MF and TCR-γ/δ+MF skin lesions harbored strong type 2 immune activation across myeloid cells, while Berti's lymphoma was more skewed towards type 1 immune responses. Both CD4+MF and TCR-γ/δ+MF lesions showed upregulation of keratinocyte hyperactivation markers such as S100As and KRT16 genes. This increase was entirely absent in Berti's lymphoma, possibly reflecting an aberrant keratinocyte response to invading tumor cells, that could contribute to the formation of the typical ulcero-necrotic lesions within this entity. CONCLUSIONS: Our scRNAseq profiling study reveals specific molecular patterns associated with distinct CTCL subtypes.

Exogenous Insulin Therapy Is Associated with the Risk of Advanced Colorectal Adenoma in Patients with Diabetes Mellitus.

BACKGROUND/AIMS: Exogenous insulin therapy increases systemic exposure to insulin which may promote the development of colorectal neoplasia. We sought to evaluate the association between exogenous insulin therapy and the incidence of advanced adenoma in type 2 diabetes mellitus. METHODS: A retrospective cohort study was conducted from January 1, 2007, to January 1, 2018, in a regional health system serving the United States Philadelphia metropolitan area, Central New Jersey, and South Central Pennsylvania. Study patients consisted of a random sample of patients with type 2 diabetes mellitus aged 40-80 years who had undergone two rounds of colonoscopy examinations. The exposure was cumulative duration of insulin therapy (i.e., no use, 1-365 days and > 365 days). The outcome was time to incident advanced adenoma. RESULTS: Of the 975 eligible patients, 184 patients accumulated > 365 days of insulin therapy before the follow-up colonoscopy. The mean (standard deviation) duration between the two rounds of colonoscopy examination was 5.1 (2.9) years among the insulin users and 5.3 (3.9) years among non-users. Compared to no insulin exposure, receiving > 365 days of insulin therapy was associated with an increased incidence of advanced adenoma (adjusted hazard ratio [aHR] 4.84, 95% confidence interval [CI] 2.82-8.30), right-sided advanced adenoma (aHR 5.48, 95% CI 2.90-10.35), and 3 or more adenomas (aHR 2.61, 95% CI 1.46-4.69) at the follow-up colonoscopy examination. CONCLUSION: Insulin therapy is associated with an increased risk of advanced adenoma and may serve as a novel risk-stratification factor to enhance the efficiency of existing colorectal cancer screening and surveillance programs.

A rare case of herpes simplex virus encephalitis from viral reactivation following surgically treated traumatic brain injury.

OBJECTIVE: Herpes simplex virus encephalitis (HSVE) is associated with significant morbidity and mortality. Here, we present the occurrence of HSVE in a 36-year-old immunocompetent patient following craniotomy for a traumatic acute subdural hematoma (ASDH). METHODS: Imaging after four days of progressive headache following a fall with head-strike demonstrated a 1 cm thick left holohemispheric ASDH with significant cerebral compression, edema, and 8 mm of left-to-right midline shift, and an emergent craniotomy and ASDH evacuation were performed, with additional treatment needed for reaccumulation. Postoperatively, the patient developed a worsening leukocytosis, became febrile, and was hypotensive requiring vasopressor support. RESULTS: Despite empiric antibiotics, the patient remained persistently febrile with significant leukocytosis. Repeat head CT showed a new left insular hypodensity and a subsequent viral encephalitis panel was positive for HSV-1. The patient was then started on intravenous acyclovir, with progressive neurological exam improvement. Of note, the patient was noted to have a positive serum HSV-1 IgG antibody titer, indicative of prior infection. CONCLUSIONS: Given the known systemic immunosuppression in brain injury and the high prevalence of HSV seropositivity, clinicians should consider the possibility of HSVE from HSV reactivation in TBI patients with persistent fever, leukocytosis, and/or neurological deficits without an obvious etiology.

Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis.

BACKGROUND: Chronic nodular prurigo (CNPG) is an inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuroimmunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type 2 cytokines such as IL-4, IL-13, and IL-31. OBJECTIVES: This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD). METHODS: We profiled skin lesions from patients with CNPG in comparison with AD and healthy control individuals using single-cell RNA sequencing combined with T-cell receptor sequencing. RESULTS: We found type 2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+IL9R+IL13+ cytotoxic T-cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14-IL24+ secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin B in fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings. CONCLUSIONS: These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD but is rather characterized by upregulated stromal remodeling mechanisms that might have a direct impact on itch fibers.

Online Health Information for Acne Keloidalis Nuchae has a Difficult Level of Readability.

BACKGROUND: Acne keloidalis nuchae (AKN) is an inflammatory disorder primarily seen in individuals of color, characterized by acneiform and keloidal lesions on the occipital scalp/nuchal region. More than 50% of patients with keloids are known to search their condition on the internet. We sought to determine the level of readability of patient education materials (PEM) available to patients. The term 'acne keloidalis nuchae' was searched and screened for the top 100 search results on the Google® search engine. For evaluation, 6 readability metrics (Flesch-Kincaid grade level, Gunning Fog index, Coleman-Liau index, SMOG index, automated readability, and Linsear Write Formula) were collected by entering text from each reference site into an automatic readability calculator for computation. Median readability scores of AKN PEMs ranged from 10.3th to 13.5th grade levels. Overall, readability median above the 8th-grade level were consistently seen across all 6 readability measures, with some median scores reaching university undergraduate levels. More readable educational tools are needed for acne keloidalis nuchae online. J Drugs Dermatol. 2023;21(2):195-196. doi:10.36849/JDD.7110.

Controlling Pharmaceutical Costs in a Student-Run Free Clinic in a Resource-Limited Patient Setting.

Our institution's student-run free clinic has been able to offer medication at no out-of-pocket cost to all patients since it opened in 2004. We have employed two strategies to manage prescription drug costs while simultaneously increasing medication coverage: (1) using Patient Drug Assistance Programs (PDAPs) and (2) developing an institutional-level partnership with pharmaceutical charities for medication subsidization. In this study, we aimed to analyze the financial impact of these measures on the clinic.A query of clinic data over the past 5 years identified 299 active PDAPs, corresponding to 299 fully-subsidized prescriptions. In 2017, there were 35 active PDAPs, increasing to 52 (2018), 62 (2019), and 82 (2020) before a decline to 68 PDAPs in 2021. The company affiliated with the most PDAPs varied annually: GlaxoSmithKline (2017), Lilly (2018, 2019, 2020), and both GlaxoSmithKline and Lilly (2021). The most frequent medications were sitagliptin (2017), insulin (2018, 2019), albuterol (2017, 2018), and dulaglutide (2020, 2021).In addition, data extracted from the private company subsidization program was analyzed for the year 2021. Program membership was $10,000 for institution-wide medication subsidization for all uninsured patients in the hospital system. In total, the clinic was able to acquire 220 medications with a 96% subsidy, corresponding to a direct clinic cost of $2,101.28. Comparatively, the market value of these medications was $52,401.51.Utilization of free drug acquisition programs and partnerships with pharmaceutical charities allowed for an increase in cost-savings and medications provided. Although the process for applying for medication assistance programs is complex, these programs serve as powerful tools for providing medications that may otherwise be unavailable due to cost. Other clinics and healthcare settings with uninsured patients should consider these programs as a means to ease medication cost burden.

Disparities in the Use of Teledermatology During the COVID-19 Pandemic Lockdown in a Pediatric Dermatology Practice.

Background: The COVID-19 pandemic required a rapid expansion of teledermatology services. Objective: Analyze demographic shifts in a pediatric dermatology practice session with children of color. Methods: A retrospective chart review of pediatric dermatology patients seen in the 4 practice weeks preceding the New York COVID-19 lockdown and comparable teledermatology visits during the COVID-19 pandemic lockdown. Demographic differences (e.g., race, age, gender, and household income) were analyzed. Results: A greater proportion of patients seen were White during lockdown (59.7%), compared with pre-lockdown (43.6%), with a reduction in Asian patients seen in lockdown (6.0%) compared with pre-lockdown (24.5%). A lower proportion of no-show patients (4.3%, 3/70 scheduled) were noted in lockdown compared with pre-lockdown (16%, 18/112). Preferred provider organizations (PPO) and higher-income zip codes were more common for children seen during lockdown. Limitations: The sample addresses a limited New York pediatric dermatology practice during a short time period. Conclusions: White patients and patients with PPO were more likely to access telehealth, supporting disparity in teledermatology services. These results demonstrate reduced health care access for lower-income and Asian children during the COVID-19 pandemic lockdown.

Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement.

BACKGROUND: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics. OBJECTIVE: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity. METHODS: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set. RESULTS: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05). LIMITATIONS: This study was limited by a small sample size and predominantly female FFA patients. CONCLUSION: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition.

An Analysis of Skin of Color Publications in the Journal of Drugs in Dermatology from 2018 to 2020.

As the United States population becomes increasingly diverse, it is exceedingly important for dermatologists to be knowledgeable about treating patients with skin of color (SOC). The published literature is an especially valuable resource for treating SOC.

Self-reported Secondhand Marijuana Smoke (SHMS) Exposure in Two New York City (NYC) Subsidized Housing Settings, 2018: NYC Housing Authority and Lower-Income Private Sector Buildings.

The percentage of adults in the United States reporting current marijuana use has more than doubled, from 4 to 9% between 2002 and 2018, suggesting that exposure to secondhand marijuana smoke (SHMS) has probably increased. Few studies have characterized the extent to which residents experience SHMS, particularly those living in multi-unit housing. It remains unknown how recently-implemented smoke-free housing policies (SFH) targeting cigarette smoke in public housing authorities (PHAs) will affect SHMS exposure. We sought to characterize prevalence of self-reported SHMS exposure among residents living in two different subsidized housing settings prior to SFH policy implementation in PHAs: New York City Housing Authority (NYCHA) buildings and private sector buildings where most residents receive Section 8 subsidy vouchers (herein 'Section 8' buildings). Residents were recruited from 21 purposefully-selected buildings: 10 NYCHA and 11 Section 8 buildings (> 15 floors). Survey responses were collected during April-July 2018 for NYCHA residents (n = 559) and August-November 2018 for Section 8 residents (n = 471). Of 4628 eligible residents, 1030 participated (response rates, 35% NYCHA, 32% Section 8). Overall, two-thirds of residents reported smelling marijuana smoke (67%) in their home over the past year, higher than reports of smelling cigarette smoke (60%). Smoking status and smelling SHS were both strong predictors of smelling SHMS (p < 0.05). Nearly two thirds of residents perceived smoking marijuana and smelling SHMS as harmful to health. Our findings suggest that, immediately prior to SFH rule implementation in PHAs, SHMS was pervasive in low-income multi-unit housing, suggesting SFH policies should expand to cover marijuana use.

Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells.

Dupilumab, an IL4R-blocking antibody, has shown clinical efficacy for atopic dermatitis (AD) treatment. In addition to conjunctivitis/blepharitis, the de novo appearance of head/neck dermatitis is now recognized as a distinct side effect, occurring in up to 10% of patients. Histopathological features distinct from AD suggest a drug effect, but exact underlying mechanisms remain unknown. We profiled punch biopsies from dupilumab-associated head and neck dermatitis (DAHND) by using single-cell RNA sequencing and compared data with untreated AD and healthy control skin. We show that dupilumab treatment was accompanied by normalization of IL-4/IL-13 downstream activity markers such as CCL13, CCL17, CCL18 and CCL26. By contrast, we found strong increases in type 22-associated markers (IL22, AHR) especially in oligoclonally expanded T cells, accompanied by enhanced keratinocyte activation and IL-22 receptor upregulation. Taken together, we demonstrate that dupilumab effectively dampens conventional type 2 inflammation in DAHND lesions, with concomitant hyperactivation of IL22-associated responses.

Vascular Mapping for Abdominal-Based Breast Reconstruction: A Comprehensive Review of Current and Upcoming Imaging Modalities.

Background: Preoperative vascular imaging is a very common element of surgical planning for abdominal-based breast reconstruction (ABBR). Surgeons must tailor which flap is best suited for each respective patient based on the patient's health and vascular anatomy. The goal of this review is to give surgeons practical tools for choosing which imaging technology best suits their patient's needs for successful breast reconstruction. Methods: A review of literature was undertaken on Google scholar to assess preoperative imaging modalities used for ABBR. Search terms included breast reconstruction, deep inferior epigastric perforator (DIEP) flap, and abdominal imaging. Articles were included based on relevance and significance to ABBR. Advantages and disadvantages of each imaging modality were then classified according to clinically relevant utility. Results: Overall, imaging technologies that produce 3-dimensional images were found to have greater resolution for identifying perforators and the pedicle network than 2- dimensional images. Conclusions: This paper addresses the strengths and weaknesses of the currently used imaging modalities described and also discusses new technologies that may be helpful in the future for planning of ABBR.

Incorporating Paid Caregivers Into Medical Education to Enhance Medical Student Exposure to This Essential Workforce.

The implications of the COVID-19 pandemic underscored the utility of home-based health care due in part to social distancing requirements, curtailment of elective hospital procedures, and patient apprehension of the health care setting. The pandemic particularly accentuated the integral role of paid caregivers (eg, home health aides, personal care attendants, and other home care workers) in caring for patients with chronic health conditions. Given the paradigm shift toward community- and value-based health care models, paid caregivers are likely to play an even greater role as care team members. Despite the increasingly prominent role paid caregivers are assuming in health care, especially for patients who are chronically ill, in our experience as medical students, we have very little exposure to these care team members, with most interactions occurring in brief, chance encounters. Specifically, we advocate for increased medical student exposure to paid caregivers to facilitate their recognition as valuable care team members. We propose to achieve this through (1) classroom-based module learning with live paid caregivers and (2) plain language communication training to enhance reciprocal engagement.