Mental health burden of patients with activity-limiting skin conditions: a national analysis.

Cutaneous diseases are the fourth leading cause of nonfatal disease burden globally. In this study, we aimed to investigate the psychological symptom burden in patients with chronic activity-limiting cutaneous diseases. Our findings suggest that this patient population experience a wide range of interference with their daily lives and exhibit higher psychological burdens and lower quality of life. This study also identified that patients with activity-limiting skin conditions do not seem to seek more professional help or take more medications, which may suggest a potential gap in adequate mental health support and resources.

Characterization of intravascular papillary endothelial hyperplasia: a multicentre cohort.

Intravascular papillary endothelial hyperplasia (IPEH) is an uncommon benign malformation of the skin and subcutaneous tissue. In this retrospective multicentre study, we aimed to investigate the clinical and pathological features of 261 patients with IPEH. IPEH is classified into three categories; in our study, the proportions were pure (50%), mixed (46%) and extravascular (4%). IPEH frequently stained positive for immunohistochemical markers such as CD31, CD34, smooth muscle actin and erythroblast transformation-specific-related gene. Clinicians' initial impression of the lesion often included ambiguous terms such as 'soft tissue mass'. There is an opportunity for increased awareness of this lesion and its consideration within a differential diagnosis.

WHIM Syndrome Caused by Waldenström's Macroglobulinemia-Associated Mutation CXCR4 (L329fs).

WHIM syndrome is an autosomal dominant immunodeficiency disease caused by mutations affecting the carboxy-terminus of CXCR4. To characterize novel genetic causes of the syndrome, we recruited a pediatric patient with possible WHIM syndrome, performed CXCR4 gene sequencing and compared his clinical phenotype and CXCR4 tail amino acid sequences with other patients with WHIM syndrome carrying CXCR4 (R334X) mutations. We identified and biochemically characterized a heterozygous 5 base pair deletion (nucleotides 986-990) located in the portion of the open reading frame (ORF) of CXCR4 that encodes the carboxy-terminal domain of the receptor. This CXCR4 (L329fs) mutation causes a frame-shift at codon 329 resulting in replacement of the final 24 predicted amino acids of the receptor with 12 missense amino acids. Like previously reported WHIM mutations, this frame-shift mutation CXCR4 (L329fs) decreased receptor downregulation in response to the CXCR4 agonist CXCL12 in patient PBMCs as well as in transfected K562 and HEK 293 cells, but increased calcium flux responses in K562 cells to CXCL12 stimulation. Thus, CXCR4 (L329fs) appears to be a de novo autosomal dominant frame-shift gain-of-function mutation that like other carboxy-terminus mutations causes WHIM syndrome. The same CXCR4 (L329fs) frame-shift variant has been reported to occur in tumor cells from a patient with Waldenström's Macroglobulemia (WM), but is caused by a distinct genetic mechanism: insertion of a single nucleotide in the L329 codon, providing additional evidence that the carboxy-terminus of CXCR4 is a genetic hotspot for mutation.

Clinicopathologic features of ecthyma gangrenosum: a single integrated health system cohort.

Ecthyma gangrenosum is an uncommon cutaneous eruption that can initially present with painless macules, which rapidly evolve into necrotic ulcers. This study sought to characterize clinicopathologic features of ecthyma gangrenosum from a single integrated health system. Our cohort consisted of 82 individuals diagnosed with ecthyma gangrenosum. Lesions were most commonly found in the lower extremities (55%) and the truncal region (20%). A wide variety of fungal and bacterial etiologies were found among our cohort. The majority of patients with EG were immunocompromised (79%) and 38% of patients also experienced sepsis. The mortality rate seen in our cohort was approximately 34%. No statistical differences in mortality outcome due to EG related complications were seen between pathogen etiology, and distribution or location of lesions. Patients who were septic or immunocompromised died more frequently than non-septic or immunocompetent patients, suggesting poorer prognosis.

A systematic review of patient-reported outcome measures for advanced skin cancer patients.

Many patient-reported outcome measures (PROMs) have been used to study quality of life (QOL) in the skin cancer population. Advanced melanoma and non-melanoma skin cancer (NMSC) may be associated with increased morbidity, mortality, and treatment side effects; however, it is unclear which PROM is valid and appropriate to use in these populations for both clinical and research purposes. We aimed to identify the PROMs that have been used to measure QOL in advanced skin cancer patients and determine which of these PROMs have been validated to assess QOL outcomes in this population. A PubMed and EMBASE search was conducted from its inception to March 2021 according to PRISMA guidelines with a comprehensive list of search terms under three main topics: (1) PROM; (2) advanced skin cancer; and (3) staging and interventions. We included articles utilizing a PROM measuring QOL and having a patient population with advanced skin cancer defined as melanoma stage > T1a or non-melanoma AJCC stage T3 or greater. Advanced skin cancer patients were also defined as those with metastasis or requiring adjuvant therapy (systemic chemotherapy, radiation, and immunotherapy). Studies were excluded according to the following criteria: mix of low-risk and advanced skin cancer patients in the study population without stratification into low-risk and advanced groups, stage T1a melanoma or mix of stages without stratification, low-risk NMSC, no PROM (i.e., study specific questionnaires), non-English publication, review article or protocol paper, conference abstract, or populations including non-skin cancers. A total of 1,998 articles were identified. 82 met our inclusion criteria resulting in 22 PROMs: five generic health-related (QWB-SA, AQoL-8D, EQ-5D, SF-36, and PRISM), six general cancer (EORTC QLQ-C30, EORTC QLQ-C36, LASA, IOC, Rotterdam Symptom Checklist, and FACT-G), nine disease-focused or specialized (EORTC QLQ-H&N35, EORTC QLQ-MEL38, EORTC QLQ-BR23, Facial Disability Index, FACT-H&N, FACT-BRM, FACT-B, FACT-M, and scqolit), and two general dermatology (Skindex-16 and DLQI) PROMs. All PROMs have been generally validated except for EORTC QLQ-MEL38. Only two PROMs have been validated in the advanced melanoma population: FACT-M and EORTC QLQ-C36. No PROMS have been validated in the advanced NMSC population. The PROMs that were validated in the advanced melanoma population do not include QOL issues unique to advanced skin tumors such as odor, bleeding, itching, wound care burden, and public embarrassment. Breast cancer and head and neck cancer instruments were adapted but not validated for use in the advanced skin cancer population due to the lack of an adequate instrument for this population. This study highlights the need for PROM instrument validation or creation specifically geared toward the advanced skin cancer population. Future studies should aim to develop and validate a PROM to assess QOL in this population.

Global herpes zoster incidence, burden of disease, and vaccine availability: a narrative review.

Herpes zoster (HZ) is a neurocutaneous disease that causes significant morbidity worldwide. The disease is caused by the reactivation of the varicella-zoster virus (VZV), which leads to the development of a painful, vesicular rash and can cause complications such as post-herpetic neuralgia and vision loss. Globally, the incidence of HZ is increasing, and it incurs billions in cost annually to the healthcare system and to society through loss of productivity. With the advent of effective vaccines such as the live attenuated vaccine, Zostavax®, in 2006, and more recently the adjuvant recombinant subunit vaccine, Shingrix®, in 2017, HZ has become a preventable disease. However, access to the vaccines remains mostly limited to countries with developed economies, such as the United States and Canada. Even among countries with developed economies that license the vaccine, few have implemented HZ vaccination into their national immunization schedules due to cost-effectiveness considerations. In this review, we discuss the currently available HZ vaccines, landscape of HZ vaccine guidelines, and economic burden of disease in countries with developed and developing economies, as well as barriers and considerations in HZ vaccine access on a global scale.

International medical graduate dermatologists in rural and medically underserved areas: a national cross-sectional analysis.

International medical graduates (IMGs) comprise a quarter of the United States (US) physician workforce but are a diminishing minority among dermatologists. Studies on IMGs in other specialties have demonstrated their importance in addressing provider shortage in rural and medically underserved areas (MUAs), but this trend has not been systematically explored within dermatology. This study aims to assess the state-by-state distribution of IMG dermatologists in the US as compared to US medical graduates (USMGs) with focus on provider density in rural settings and MUAs. A national cross-sectional study was performed on actively practicing dermatologists who submitted Medicare claims within 1 year of July 2020; rural and MUA-serving status were determined based on federally designated rural-urban Continuum Codes and Census Bureau data. Nationally, the density of dermatologists has increased from 3.4 per 100,000 persons in 2016 to 3.66 per 100,000 persons in 2020. However, 70% of US states continue to have fewer than 4 dermatologists per 100,000 persons, the estimated minimum necessary to adequately care for a population. Among 12,009 dermatologists, only 576 (4.8%) are IMGs, with disparate distribution across the US: Kansas has the greatest percentage of IMGs with the latter comprising 8.3% of its state dermatology workforce, whereas 8 states have no IMGs. Notably, a significantly greater percentage of IMG dermatologists (43.9%) work in areas designated as MUAs compared to USMGs (37.4%) (P < 0.01). In contrast, a lower percentage of IMG dermatologists (2.8%) work in rural settings compared to USMGs (4.8%) (P = 0.03). Interestingly, no significant difference was observed when rural dermatologists were further stratified by MUA-serving status. These findings corroborate the importance of IMGs in providing greater access to dermatological care in areas with healthcare provider shortage. Further studies on the underlying causes of the decline of IMGs within dermatology are needed.

Transdermal approaches to vaccinations in the COVID-19 pandemic era.

The COVID-19 pandemic has necessitated rapid vaccine development for the control of the disease. Most vaccinations, including those currently approved for COVID-19 are administered intramuscularly and subcutaneously using hypodermic needles. However, there are several disadvantages including pain and fear of needlesticks, the need for two doses, the need for trained health care professionals for vaccine administration, and barriers to global distribution given the need for cold supply chain. Recently, transdermal techniques have been under investigation for vaccines including COVID-19. Microneedle array technology utilizes multiple microscopic projections from a plate which delivers a vaccine in the form of a patch placed on the skin, allowing for painless antigen delivery with improved immune response. In this review, we discuss challenges of existing vaccines and review the literature on the science behind transdermal vaccines including microneedles, current evidence of application in infectious diseases including COVID-19, and considerations for implementation and global access.

Charge-Mediated Pyrin Oligomerization Nucleates Antiviral IFI16 Sensing of Herpesvirus DNA.

The formation of multimerized protein assemblies has emerged as a core component of immune signal amplification, yet the biochemical basis of this phenomenon remains unclear for many mammalian proteins within host defense pathways. The interferon-inducible protein 16 (IFI16) is a viral DNA sensor that oligomerizes upon binding to nuclear viral DNA and induces downstream antiviral responses. Here, we identify the pyrin domain (PYD) residues that mediate IFI16 oligomerization in a charge-dependent manner. Based on structure modeling, these residues are predicted to be surface exposed within distinct α-helices. By generating oligomerization-deficient mutants, we demonstrate that IFI16 homotypic clustering is necessary for its assembly onto parental viral genomes at the nuclear periphery upon herpes simplex virus 1 (HSV-1) infection. Preventing oligomerization severely hampered the capacity of IFI16 to induce antiviral cytokine expression, suppress viral protein levels, and restrict viral progeny production. Restoring oligomerization via residue-specific charge mimics partially rescued IFI16 antiviral roles. We show that pyrin domains from PYHIN proteins are functionally interchangeable, facilitating cooperative assembly with the IFI16 HINs, highlighting an inherent role for pyrin domains in antiviral response. Using immunoaffinity purification and targeted mass spectrometry, we establish that oligomerization promotes IFI16 interactions with proteins involved in transcriptional regulation, including PAF1C, UBTF, and ND10 bodies. We further discover PAF1C as an HSV-1 restriction factor. Altogether, our study uncovers intrinsic properties that govern IFI16 oligomerization, which serves as a signal amplification platform to activate innate immune responses and to recruit transcriptional regulatory proteins that suppress HSV-1 replication.IMPORTANCE The ability of mammalian cells to detect the genomes of nuclear-replicating viruses via cellular DNA sensors is fundamental to innate immunity. Recently, mounting evidence is supporting the universal role of polymerization in these host defense factors as a signal amplification strategy. Yet, what has remained unclear are the intrinsic properties that govern their immune signal transmission. Here, we uncover the biochemical basis for oligomerization of the nuclear DNA sensor, IFI16. Upon infection with herpes simplex virus 1 (HSV-1) in human fibroblasts, we characterize the contribution of IFI16 oligomerization to downstream protein interactions and antiviral functions, including cytokine induction and suppression of HSV-1 replication. Until now, the global characterization of oligomerization-dependent protein interactions for an immune receptor has never been explored. Our integrative quantitative proteomics, molecular CRISPR/Cas9-based assays, mutational analyses, and confocal microscopy shed light on the dynamics of immune signaling cascades activated against pathogens.