PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome: A case report and review of the literature.

PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome is a rare autoinflammatory disorder often arising in pediatric patients. We present a case of an 18-year-old female with a past medical history of growth failure, immunoglobulin A nephropathy, and inflammatory arthritis who presented to a pediatric dermatology clinic with findings of acne, psoriasiform dermatitis, and hidradenitis suppurativa, whose clinical, genetic, and laboratory findings were most consistent with PAMI syndrome. We conducted a literature review to better characterize this rare condition in the context of dermatologic findings. Recognition of the distinctive skin findings seen in PAMI syndrome can help distinguish it from other inflammatory disorders, enabling expedited diagnosis and treatment.

PBI-05204, a supercritical CO2 extract of Nerium oleander, suppresses glioblastoma stem cells by inhibiting GRP78 and inducing programmed necroptotic cell death.

Successful treatment of glioblastoma multiforme (GBM), an aggressive form of primary brain neoplasm, mandates the need to develop new therapeutic strategies. In this study, we investigated the potential of PBI-05204 in targeting GBM stem cells (GSCs) and the underlying mechanisms. Treatment with PBI-05204 significantly reduced both the number and size of tumor spheres derived from patient-derived GSCs (GBM9, GSC28 and TS543), and suppressed the tumorigenesis of GBM9 xenografts. Moreover, PBI-05204 treatment led to a significant decrease in the expression of CD44 and NANOG, crucial markers of progenitor stem cells, in GBM9 and GSC28 GSCs. This treatment also down-regulated GRP78 expression in both GSC types. Knocking down GRP78 expression through GRP78 siRNA transfection in GBM9 and GSC28 GSCs also resulted in reduced spheroid size and CD44 expression. Combining PBI-05204 with GRP78 siRNA further decreased spheroid numbers compared to GRP78 siRNA treatment alone. PBI-05204 treatment led to increased expression of pRIP1K and pRIP3K, along with enhanced binding of RIPK1/RIPK3 in GBM9 and GSC28 cells, resembling the effects observed in GRP78-silenced GSCs, suggesting that PBI-05204 induced necroptosis in these cells. Furthermore, oleandrin, a principle active cardiac glycoside component of PBI-05204, showed the ability to inhibit the self-renewal capacity in GSCs. These findings highlight the potential of PBI-05204 as a promising candidate for the development of novel therapies that target GBM stem cells.

Subcellular location of L1 retrotransposon-encoded ORF1p, reverse transcription products, and DNA sensors in lupus granulocytes.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p. RESULTS: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis. CONCLUSIONS: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease.

A prospective cohort study exploring the joint influence of sunlight exposure and tanning bed use on basal cell carcinoma, squamous cell carcinoma, and melanoma risk.

Exposure to solar ultraviolet (UV) radiation and use of UV-emitting tanning devices are known risk factors for skin cancer. Few studies have explored the interaction between these risk factors, namely how the risk of skin cancer increases among those who both have been exposed to high levels of natural sunlight and regularly use tanning beds. Nurses' Health Study II followed 116,430 women, aged 25-42, from 1991 to 2011. Cumulative average UV exposure was based on participants' residences at follow-up periods. History of severe sunburn during ages 15-20 was used as a proxy for early-life sunlight exposure. Tanning bed use in early life data was collected. Participants reported melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) diagnoses. We built multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of skin cancer associated with joint effects of sunlight exposure and tanning bed use. Participants with high sunlight exposure and tanning bed use during high school/college had an increased risk of BCC (HR = 1.53, 95% CI 1.37-1.71, Pinteraction=0.01; vs. low sun exposure and no tanning bed use). Participants with a history of severe sunburns and tanning bed use during high school/college were at increased risk of BCC (HR = 1.62, 95% CI 1.47-1.79, Pinteraction=0.02; vs. no sunburns and no tanning bed use). No significant interactions were found between sunlight exposure and tanning bed use on SCC and melanoma risk. We found significant interactions between sunlight exposure and tanning bed use on the risk of BCC.

A Prospective Cohort Study Exploring the Joint Influence of Sunlight Exposure and Tanning Bed Use on Basal Cell Carcinoma, Squamous Cell Carcinoma, and Melanoma Risk.

Exposure to solar ultraviolet (UV) radiation and use of UV-emitting tanning devices are known risk factors for skin cancer. Few studies have explored the interaction between these risk factors, namely how the risk of skin cancer increases among those who both have been exposed to high levels of natural sunlight and regularly use tanning beds. Nurses' Health Study II followed 116,430 women, aged 25-42, from 1991 to 2011. Cumulative average UV exposure was based on participants' residences at follow-up periods. History of severe sunburn during ages 15-20 was used as a proxy for early-life sunlight exposure. Tanning bed use in early life data was collected. Participants reported melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC) diagnoses. We built multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of skin cancer associated with joint effects of sunlight exposure and tanning bed use. Participants with high sunlight exposure and tanning bed use during high school/college had an increased risk of BCC (HR=1.53, CI 1.37-1.71, P interaction =0.01; vs. low UV exposure and no tanning bed use). Participants with a history of severe sunburns and tanning bed use during high school/college were at increased risk of BCC (HR=1.62, CI 1.47-1.79, P interaction =0.02; vs. no sunburns and no tanning bed use). No significant interactions were found between sunlight exposure and tanning bed use on SCC and melanoma risk. We found significant interactions between sunlight exposure and tanning bed use on the risk of BCC.

Applications and Best Practices for Geospatial Analysis Research in Dermatology.

Dermatologic diseases often exhibit distinct geographic patterns, underscoring the significant role of regional environmental, genetic, and sociocultural factors in driving their prevalence and manifestations. Geographic information and geospatial analysis enable researchers to investigate the spatial distribution of adverse health outcomes and their relationship with socioeconomic and environmental risk factors that are inherently geographic. Health geographers and spatial epidemiologists have developed numerous geospatial analytical tools to collect, process, visualize, and analyze geographic data. These tools help provide vital spatial context to the comprehension of the underlying dynamics behind health outcomes. By identifying areas with high rates of dermatologic disease and areas with barriers to access to quality dermatologic care, findings from studies utilizing geospatial analysis can inform the design and targeting of policy and intervention to help improve dermatologic healthcare outcomes and promote health equity. This article emphasizes the significance of geospatial data and analysis in dermatology research. We explore the common processes in data acquisition, harmonization, and geospatial analytics while conducting spatially and dermatologically relevant research. The article also highlights the practical application of geospatial analysis through instances drawn from the dermatology literature.

Evaluation of the Protective Effect of Compound Kushen Injection Against Radiation- induced Pneumonitis in Mice.

Background Radiation-induced lung injury (RILI) via inflammation is a common adverse effect of thoracic radiation that negatively impacts patient quality of life and survival. Compound kushen injection (CKI), a botanical drug treatment, was examined for its ability to reduce RILI, and inflammatory responses and improve survival in mice exposed total lung irradiation (TLI). CKI's specific mechanisms of action were also evaluated. Methods C3H mice underwent TLI and were treated with CKI (2, 4, or 8 mL/kg) intraperitoneally once a day for 8 weeks. The effects of CKI on survival were estimated by Kaplan-Meier survival analysis and compared by log-rank test. RILI damage was evaluated by histopathology and micro-computed tomography (CT). Inflammatory cytokines and cyclooxygenase metabolites were examined by IHC staining, western blot, and ELISA. Results Pre-irradiation treatment with 4 or 8 mL/kg CKI starting 2 weeks before TLI or concurrent treatment with 8 mL/kg CKI were associated with a significantly longer survival compared with TLI vehicle-treated group ( P < 0.05). Micro-CT images evaluations showed that concurrent treatment with 8 mL/kg CKI was associated with significantly lower incidence of RILI ( P < 0.05). Histological evaluations revealed that concurrent TLI treatment of CKI (4 and 8 mL/kg) significantly reduced lung inflammation (p < 0.05). Mechanistic investigation showed that at 72 hours after radiation, TLI plus vehicle mice had significantly elevated serum IL6, IL17A, and TGF-ß levels compared with non-irradiated, age-matched normal mice; in contrast, levels of these cytokines in mice that received TLI plus CKI treatment were lower than those in the TLI plus vehicle-treated mice ( P < 0.05) and similar to the nonirradiated mice. IHC staining showed that the CKI treatment led to a reduction of TGF-ß positive cells in the lung tissues of TLI mice (P < 0.01). The concurrent CKI with TLI treatment group had a significant reduction in COX-2 activity and COX-2 metabolites compared with the TLI vehicle-treated group ( P < 0.05). Conclusions These data suggest that CKI treatment was associated with reduced radiation-induced inflammation in lung tissues, reduced RILI, and improved survival. Further investigation of CKI in human clinical trials as a potential radioprotector against RILI to improve patients' quality of life and survival is warranted.

Large overlap in neutrophil transcriptome between lupus and COVID-19 with limited lupus-specific gene expression.

OBJECTIVES: To illuminate the poorly understood aetiology of SLE by comparing the gene expression profile of SLE neutrophils with that of neutrophils from patients infected by SARS-CoV-2, a disease (COVID-19) with well-defined antigens and a similar type I interferon response. METHODS: RNA sequencing of neutrophils from patients with SLE (n=15) and healthy controls (n=12) was analysed for differential gene expression and modulated pathways. The same analyses were performed on a similar neutrophil dataset from patients with SARS-CoV-2 infection (n=30) and healthy controls (n=8). Next, we carried out comparative analyses to identify common and unique transcriptional changes between the two disease contexts, emphasising genes regulated in opposite directions. RESULTS: We identified 372 differentially expressed genes in SLE neutrophils compared with healthy donor neutrophils (≥2 fold, p<0.05), 181 of which were concordant with transcriptional changes in SARS-CoV-2-infected individuals compared with their respective healthy controls. In contrast, 118 genes demonstrated statistically significant alterations exclusive to SLE, including 28 genes that were differentially expressed in opposite directions in the two diseases. CONCLUSIONS: The substantial overlap between neutrophil responses in SLE and COVID-19 suggests that the unknown cause of SLE is functionally similar to a viral infection and drives a similar immune activation and type I interferon response. Conversely, the genes regulated in the opposite direction represent responses unique to SLE. These include tyrosylprotein sulfotransferase-1 and nucleic acid deaminases of the APOBEC family, which can catalyse cytosine-to-uridine editing of both RNA and DNA, and other RNA-modifying enzymes.

Best Practices for Research in Virtual and Augmented Reality in Dermatology.

Virtual reality (VR) and augmented reality (AR) technologies have advanced rapidly in recent years. These cutting-edge technologies provide dermatology researchers, educators, proceduralists, and patients with opportunities in new scientific horizons. VR is a technology that facilitates immersive human experiences by allowing users to connect with various simulated environments through natural head and hand movements, whereas AR supplements a user's perception of their real environment with virtual elements. Despite technological advancements, there is limited literature on the methodological steps for conducting rigorous VR and AR research in dermatology. Effective storyboarding, user-driven design, and interdisciplinary teamwork play a central role in ensuring that VR/AR applications meet the specific needs of dermatology clinical and research teams. We present a step-by-step approach for their design, team composition, and evaluation in dermatology research, medical education, procedures, and habit formation strategies. We also discuss current VR and AR dermatology applications and the importance of ethical and safety considerations in deploying this new technology.

Specialties with Few Underrepresented Applicants Lack Diversity Information on Residency Websites.

INTRODUCTION: With the advent of virtual interviews and the increasing accessibility of internet resources, students increasingly rely on program websites for residency application decisions. In this cross-sectional study, we evaluated the presence of diversity or inclusion information in the least diverse US specialties' residency program websites, including dermatology, orthopedic surgery, otolaryngology, plastic surgery, and urology residency programs. METHODS: Two authors independently reviewed each Accreditation Council for Graduate Medical Education-accredited non-military US residency program website and ranked the websites' diversity and inclusion information using six pre-determined criteria based on previous studies in the literature. RESULTS: This study reveals that more than half of residency programs of each specialty met zero of the diversity and inclusion information criteria. CONCLUSIONS: Residency program websites in the least diverse specialties are lacking important information for prospective applicants that may help signal programs' commitment to inclusivity and attract a diverse candidate pool.

Understanding melanoma in situ: Lentigo maligna surgical treatment terminology and guideline adherence, a targeted review.

BACKGROUND: Malignant melanoma in-situ, lentigo maligna (MMIS-LM) can be successfully treated with several different surgical techniques; however, the literature is inconsistent in defining them. OBJECTIVE: To comprehensively define and describe the national guideline recommended surgical techniques used to treat MMIS-LM to help clarify and standardize this terminology to ensure compliance with the guidelines. METHODS: A targeted literature review was performed from 1990 to 2022 focusing on articles that discussed the national guideline recommended surgical techniques of wide local excision, Mohs micrographic surgery (MMS), modified Mohs surgery, and staged excision/Slow-Mohs for MMIS-LM, as well as the related methods of tissue processing. National Comprehensive Cancer Network and American Academy of Dermatology guidelines were reviewed to identify how the techniques need to be employed to be compliant with guideline recommendations. RESULTS: We describe the various surgical and tissue processing techniques and discuss advantages and disadvantages of each. LIMITATIONS: This paper was styled as a narrative review defining and clarifying terminology and technique and does not investigate these topics more broadly. CONCLUSION: Understanding the methodology and terminology for these surgical procedures and tissue processing methods is critical so that both general dermatologists and surgeons can employ these techniques effectively for optimal patient care.

Alopecia areata in underrepresented groups: preliminary analysis of the all of us research program.

Alopecia areata (AA) is an autoimmune condition characterized by patchy, nonscarring hair loss. Few studies of AA have adequately included participants from underrepresented groups when evaluating the burden of AA in the United States. We conducted a cross-sectional study of personal/demographic factors and AA using the ongoing All of Us (AoU) Research Program. AoU enrolls adults over 18 years either as direct volunteers or through participating Health Care Provider Organizations by prioritizing recruiting underrepresented groups. We linked data from surveys and electronic health records (EHRs) to estimate the prevalence of AA by race/ethnicity, physical disability, sexual orientation/gender identity (LGBTQIA +), income, and education. The latest AoU release (version 5) includes 329,038 participants. Average age was 51.8 years (standard deviation, SD 16.7), and 60.2% of participants were female. Of these, 251,597 (76.5%) had EHR data and 752 were diagnosed with AA (prevalence, 0.30%; 95% CI 0.28-0.32). We used multivariate logistic regression adjusted for age and other factors to estimate the odds ratio (OR) and 95% confidence intervals (CIs) for prevalence of AA. Compared to Whites, Blacks and Hispanics had higher odds of AA (OR, 1.72; 95% CI 1.39-2.11 and OR, 2.13; 95% CI 1.74-2.59, respectively). Lower odds of AA were observed in participants with less than a high school degree (OR, 0.80; 95% CI 0.59-1.08), household income ≤ $35,000 (OR, 0.67; 95% CI 0.54-0.83), and no health insurance (OR 0.35; 95% CI 0.20-0.56). In this diverse population of US adults, participants with skin of color had higher prevalence of AA. Lower prevalence of AA among individuals with lower education and income levels and those lacking health insurance may reflect limited access to dermatologic care and potentially higher levels of undiagnosed AA in these groups.

The Value of Partnerships in Multi-Component Skin Cancer Prevention Interventions.

Melanoma causes most skin cancer-related deaths, yet melanoma mortality rates can be decreased by life-long reduction of ultraviolet radiation exposure and early detection. The disease is readily detectable through skin examinations by trained medical providers; however, the U.S. Preventive Services Task Force cites insufficient evidence to recommend "visual skin examination by a clinician to screen for skin cancer" in asymptomatic adults in the United States. As a coastal state with much outdoor occupational and recreational exposure to ultraviolet light, Rhode Island has developed a coordinated statewide partnership of stakeholders who provide valuable resources and expertise that maximize the reach and efficacy of targeted skin cancer prevention and screening programs. These programs include public skin cancer screening events, shade planning efforts, distribution of sunscreen at state parks and beaches, and educational programming.

Evaluation of a Fourth-Year Student Pharmacist Research Process at a Community Teaching Health System.

Objective. To evaluate a process developed to support research by fourth-year student pharmacists enrolled in an advanced pharmacy practice experience at a health system affiliated with a school of pharmacy.Methods. In 2017, clinical, non-tenure track faculty transitioned from facilitating a fourth-year research elective to implementing a new student research process that matches students to research preceptors at the beginning of the academic year and provides training and resources to them throughout the year. This pre-post study evaluated student pharmacist research participation, dissemination, and placement into a residency or job position at the time of graduation, and then compared data for the three years before the new process was implemented to data for the three years after implementation.Results. Thirty-three fourth-year students assigned to the health system graduated from 2015 to 2017, and 31 graduated from 2018 to 2020. The percentage of students in each cohort who completed research projects increased significantly (48.5% vs 87.1%), the number of projects increased significantly (18 vs 35), the number of presentations increased significantly (29 vs 63), and the number of publications increased significantly (9 vs 20). The percentage of research students who pursued postgraduate training increased (68.8% vs 96.3%), as did their rate of placement into training programs (81.8% vs 92.3%). Of those students who did not participate in research, the percent who pursued training also increased (17.6% vs 75%), but the rate of placement remained the same (66.7%).Conclusion. Matching fourth-year student pharmacists to research preceptors at the beginning of the academic year and providing them with training and resources throughout the year was associated with increased research productivity.

Fraction B From Catfish Epidermal Secretions Kills Pancreatic Cancer Cells, Inhibits CD44 Expression and Stemness, and Alters Cancer Cell Metabolism.

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer related death in western countries. The successful treatment of PDAC remains limited. We investigated the effect of Fraction B, which is a fraction purified from catfish (Arius bilineatus, Val.) skin secretions containing proteins and lipids, on PDAC biology both in-vivo and in-vitro. We report here that Fraction B potently suppressed the proliferation of both human and mouse pancreatic cancer cells in vitro and significantly reduced the growth of their relevant xenograft (Panc02) and orthotopic tumors (human Panc-1 cells) (p < 0.05). The Reverse Phase Protein Array (RPPA) data obtained from the tumor tissues derived from orthotopic tumor bearing mice treated with Fraction B showed that Fraction B altered the cancer stem cells related pathways and regulated glucose and glutamine metabolism. The down-regulation of the cancer stem cell marker CD44 expression was further confirmed in Panc-1 cells. CBC and blood chemistry analyses showed no systemic toxicity in Fraction B treated Panc-1 tumor bearing mice compared to that of control group. Our data support that Fraction B is a potential candidate for PDAC treatment.

Trends in Operative Treatment of Pediatric and Adolescent Forearm Fractures Among American Board of Orthopaedic Surgery Part II Candidates.

BACKGROUND: Pediatric and adolescent forearm fractures are among the most common injuries treated by orthopaedic surgeons. Recent literature shows that there has been an increased interest in operative management for these injuries. The purpose of the current study was to examine the trends in case volume, patient age, surgeon fellowship training, and postoperative complications of surgically treated pediatric forearm fractures over >15-year period of American Board of Orthopaedic Surgery (ABOS) Part II Oral Examination candidates. METHODS: ABOS Part II candidates' Oral Examination Case List data from 2003 to 2019 was queried for all pediatric and adolescent (19 y of age and below) forearm fractures treated operatively. Patient demographics, fracture type, complications, and candidate fellowship type were identified for each case. Linear regression was used to delineate annual trends in patient age, complication rates, and case volume by fellowship type. Analysis of variance was performed to evaluate complication rates by fellowship type. Statistical significance for all comparative analyses was set at P-value <0.05. RESULTS: A total of 4178 pediatric and adolescent forearm fractures (mean age: 12.6 y; SD: 3.7 y) were treated surgically among ABOS Part II Oral Examination candidates during their 6-month collection periods from 2003 to 2019. The mean patient age decreased significantly (P<0.001) over the study timeframe, while complication rates increased (P<0.001). Pediatric fellowship-trained orthopaedic surgeons performed significantly more cases than general orthopaedic surgeons over recent years (P<0.001). No significant trends were identified between fellowship type and complication rates. The overall surgical complication rate was 17%. The complication rate of open fractures was 24%, which was significantly >15% complication rate of closed fractures (P<0.001). CONCLUSIONS: Fellowship-trained pediatric orthopaedic surgeons are performing an increasing number of pediatric and adolescent forearm fracture fixation when compared with other orthopaedic surgeons. The mean age of surgically managed pediatric forearm fracture patients has decreased from 2003 to 2019. There has been an increase in the rate of overall reported complications following pediatric forearm fracture surgery over recent years, without any significant association to any particular subspecialty. Future studies should evaluate the comparative effectiveness of surgical treatment of pediatric forearm fractures compared with closed management.