TRAF1 from a Structural Perspective.

Tumor necrosis factor receptor-associated factor (TRAF) proteins play pivotal roles in a multitude of cellular signaling pathways, encompassing immune response, cell fate determination, development, and thrombosis. Their involvement in these processes hinges largely on their ability to interact directly with diverse receptors via the TRAF domain. Given the limited binding interface, understanding how specific TRAF domains engage with various receptors and how structurally similar binding interfaces of TRAF family members adapt their distinct binding partners has been the subject of extensive structural investigations over several decades. This review presents an in-depth exploration of the current insights into the structural and molecular diversity exhibited by the TRAF domain and TRAF-binding motifs across a range of receptors, with a specific focus on TRAF1.

Skin Deep: The Potential of Microbiome Cosmetics.

The interplay between the skin microbiome and its host is a complex facet of dermatological health and has become a critical focus in the development of microbiome cosmetics. The skin microbiome, comprising various microorganisms, is essential from birth, develops over the lifespan, and performs vital roles in protecting our body against pathogens, training the immune system, and facilitating the breakdown of organic matter. Dysbiosis, an imbalance of these microorganisms, has been implicated in a number of skin conditions such as acne, atopic dermatitis, and skin cancer. Recent scientific findings have spurred cosmetic companies to develop products that preserve and enhance the skin's microbial diversity balance. These products may incorporate elements like prebiotics, probiotics, and postbiotics, which are beneficial for the skin microbiome. Beyond topical products, there's increasing interest in ingestible beauty supplements (i.e. oral probiotics), highlighting the connection between the gut and skin. This review examines the influence of the microbiome on skin health and the emerging trends of microbiome skincare products.

All-Cause and Cause-Specific Mortality among Patients with Vitiligo: A Nationwide Population-Based Study in Korea.

Vitiligo is a common autoimmune skin disorder; however, there is limited information about risks of mortality among patients with vitiligo. Therefore, we aimed to investigate the mortality in patients with vitiligo. A population-based cohort study was conducted using the data linkage of the National Health Insurance Service database and the National Death Registry. Patients with incident vitiligo were matched with sociodemographic factors-matched controls without vitiligo in a 1:5 ratio. All-cause and cause-specific mortalities were compared between patients with vitiligo and controls. In total, 107,424 patients with incident vitiligo and 537,120 matched controls were included. The mortality rates were 34.8 and 45.3 per 10,000 person-years in patients and controls, respectively. Patients with vitiligo showed a significantly lower risk of mortality (adjusted hazard ratio = 0.75, 95% confidence interval = 0.72-0.78). The cause-specific mortality from infectious diseases, oncologic diseases, hematologic diseases, endocrine diseases, neurologic diseases, cardiovascular diseases, respiratory diseases, and renal/urogenital disease was significantly lower in patients with vitiligo. Patients with vitiligo were associated with a lower risk of mortality, suggesting that vitiligo-associated autoimmunity might contribute to reduced morbidity and mortality.

Risk of Subsequent Vitiligo in Transplant Recipients With Comorbid Graft-vs-Host Disease.

Importance: Vitiligo is a multifactorial, depigmenting skin disorder characterized by selective loss of melanocytes. Large-scale studies are lacking to determine the risk of vitiligo in transplant recipients with graft-vs-host disease (GVHD). Objective: To investigate the incidence rates and risk of vitiligo in patients who had received solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) overall and by HSCT graft type and concomitant GVHD. Design, Setting, and Participants: This population-based cohort study included data from the National Health Insurance Service database of Korea for patients aged 20 years or older who had received a transplant (SOT or HSCT) between January 2010 and December 2017, with follow-up until December 2019. A cohort of age- and sex-matched (1:5) control individuals who did not receive a transplant was included for comparison. Data were analyzed from July 2021 to December 2021. Exposure: Transplant (SOT or HSCT) and GVHD. Main Outcomes and Measures: The main outcome was risk of vitiligo, assessed using multivariable Cox proportional hazards regression analyses adjusting for potential confounding factors. Results: The study included 23 829 patients who had undergone SOT or HSCT (62.78% male; mean [SD] age, 49.58 [11.59] years) and 119 145 age- and sex-matched controls. Patients who had undergone transplant had a significantly higher risk of vitiligo compared with controls (adjusted hazard ratio [AHR], 1.73; 95% CI, 1.35-2.22). Risk of vitiligo was also slightly higher in kidney transplant recipients and liver transplant recipients compared with the controls but was highest in HSCT recipients (AHR, 12.69; 95% CI, 5.11-31.50). Patients who had received allogeneic grafts (AHR, 14.43; 95% CI, 5.61-37.15), those who had received autologous grafts (AHR, 5.71; 95% CI, 1.20-3.18), those with comorbid GVHD (AHR, 24.09; 95% CI, 9.16-63.35), and those without GVHD (AHR, 8.21; 95% CI, 3.08-21.87) had a higher risk of vitiligo compared with controls. Conclusion and Relevance: In this study, risk of vitiligo was significantly higher in transplant recipients, especially in HSCT recipients and those with allogeneic grafts or comorbid GVHD. These findings provide new insights into the association between the risk of vitiligo and transplant and GVHD. Clinicians should be aware of these risks, implementing a multidisciplinary approach for monitoring.

Autoimmune and Autoinflammatory Connective Tissue Disorders Following COVID-19.

Importance: Multiple cases of autoimmune and autoinflammatory diseases after COVID-19 have been reported. However, their incidences and risks have rarely been quantified. Objective: To investigate the incidences and risks of autoimmune and autoinflammatory connective tissue disorders after COVID-19. Design, Setting, and Participants: This was a retrospective population-based study conducted between October 8, 2020, and December 31, 2021, that used nationwide data from the Korea Disease Control and Prevention Agency COVID-19 National Health Insurance Service cohort and included individuals who received a diagnosis of COVID-19 via polymerase chain reaction testing and a control group with no evidence of COVID-19 identified from National Health Insurance Service of Korea cohort. Data analysis was conducted from September 2022 to August 2023. Exposures: Receipt of diagnosis of COVID-19. Main Outcomes and Measures: The primary outcomes were the incidence and risk of autoimmune and autoinflammatory connective tissue disorders following COVID-19. A total of 32 covariates, including demographics, socioeconomic statuses, lifestyle factors, and comorbidity profiles, were balanced through inverse probability weighting. The incidences and risks of autoimmune and autoinflammatory connective tissue disorders were compared between the groups using multivariable Cox proportional hazard analyses. Results: A total of 354 527 individuals with COVID-19 (mean [SD] age, 52.24 [15.55] years; 179 041 women [50.50%]) and 6 134 940 controls (mean [SD] age, 52.05 [15.63] years; 3 074 573 women [50.12%]) were included. The risks of alopecia areata (adjusted hazard ratio [aHR], 1.12; 95% CI, 1.05-1.19), alopecia totalis (aHR, 1.74; 95% CI, 1.39-2.17), antineutrophil cytoplasmic antibody-associated vasculitis (aHR, 2.76; 95% CI, 1.64-4.65), Crohn disease (aHR, 1.68; 95% CI, 1.31-2.15), and sarcoidosis (aHR, 1.59; 95% CI, 1.00-2.52) were higher in the COVID-19 group. The risks of alopecia totalis, psoriasis, vitiligo, vasculitis, Crohn disease, ulcerative colitis, rheumatoid arthritis, adult-onset Still disease, Sjögren syndrome, ankylosing spondylitis, and sarcoidosis were associated with the severity of COVID-19. Conclusions and Relevance: In this retrospective cohort study, COVID-19 was associated with a substantial risk for autoimmune and autoinflammatory connective tissue disorders, indicating that long-term management of patients with COVID-19 should include evaluation for such disorders.

Implementation of Systematic Bioanalysis of Antibody-Drug Conjugates for Preclinical Pharmacokinetic Study of Ado-Trastuzumab Emtansine (T-DM1) in Rats.

Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies covalently bound to cytotoxic drugs by a linker. They are designed to selectively bind target antigens and present a promising cancer treatment without the debilitating side effects of conventional chemotherapies. Ado-trastuzumab emtansine (T-DM1) is an ADC that received US FDA approval for the treatment of HER2-positive breast cancer. The purpose of this study was to optimize methods for the quantification of T-DM1 in rats. We optimized four analytical methods: (1) an enzyme-linked immunosorbent assay (ELISA) to quantify the total trastuzumab levels in all drug-to-antibody ratios (DARs), including DAR 0; (2) an ELISA to quantify the conjugated trastuzumab levels in all DARs except DAR 0; (3) an LC-MS/MS analysis to quantify the levels of released DM1; and (4) a bridging ELISA to quantify the level of anti-drug antibodies (ADAs) of T-DM1. We analyzed serum and plasma samples from rats injected intravenously with T-DM1 (20 mg/kg, single dose) using these optimized methods. Based on these applied analytical methods, we evaluated the quantification, pharmacokinetics, and immunogenicity of T-DM1. This study establishes the systematic bioanalysis of ADCs with validated assays, including drug stability in matrix and ADA assay, for future investigation on the efficacy and safety of ADC development.

Automated Mass Screening for Comorbidities of Vitiligo Using the National Health Insurance Database.

Although the study design for identifying specific disease associations using a health insurance database has been well-established, few studies explore unknown comorbidities. We conducted a series of automated case-control studies for all International Classification of Disease, Tenth Revision, Clinical Modification diagnostic codes (A01-Z99) using the Korean National Health Insurance database from 2007 to 2017 to reveal undiscovered disease associations of vitiligo. A total of 90,297 patients with vitiligo and 90,297 age- and sex-matched controls without vitiligo were included, and disease associations for 1,265 relevant diagnostic codes were screened. A meta-analysis of the individual ORs for each International Classification of Disease, Tenth Revision code was performed to identify the possibility of selection bias. Finally, the association with vitiligo was significantly increased in 45 diseases and decreased in 6 diseases. We not only reaffirmed the positive correlation between vitiligo and other autoimmune diseases but also observed associations with obsessive-compulsive disorder and melanoma. In contrast, femur fracture showed a negative correlation. In this study, we attempted an automated mass screening and suggested a possible selection bias. In the era of large-scale databases, a systematic and comprehensive approach might be needed.

Analysis of Medication Errors Reported by Community Pharmacists in the Republic of Korea: A Cross-Sectional Study.

Background and objectives: We aimed to describe medication-related incidents or medication errors (MEs) reported by community pharmacists and analyze the prevalent medications involved. Materials and Methods: We extracted ME reports from databases comprising patient safety incidents reported to the Korean Pharmaceutical Association between January 2013 and June 2021. Medications were analyzed according to the second (therapeutic subgroup) and fifth (chemical substance) levels of the Anatomical Therapeutic Chemical classification. Results: A total of 9046 MEs were identified, most of which were near miss reports (88.3%). Among the errors that reached the patients (521 cases), harmful incidents accounted for 76.8%. Most MEs occurred during prescription (89.5%), while harmful MEs occurred mainly during dispensing (73.3%). In the prescription step, wrong drugs (44.8%), dosing errors (27.0%), and wrong durations (14.0%) were common. Anti-inflammatory and anti-rheumatic products (M01), drugs for acid-related disorders (A02), and antihistamines for systemic use (R06) were the most frequently reported medication classes involved. Harmful incidents were most common for dosing errors (31.0%) and wrong drugs (26.8%) and were common with warfarin, levothyroxine, and glimepiride. Conclusions: The MEs reported by community pharmacists were mainly prescribing errors, most of which were rectified before reaching patients. The prevalent medications involved in harmful errors include anti-diabetic, anti-thrombotic, and anti-inflammatory agents.

All-Cause and Cause-Specific Mortality Risks among Patients with Hidradenitis Suppurativa: A Korean Nationwide Population-Based Cohort Study.

Although previous studies have reported increased mortality in patients with hidradenitis suppurativa (HS), the cause-specific mortality and the clinical characteristics attributable to greater mortality remain unclear. The aim of this study was to investigate all-cause and cause-specific mortality risks associated with HS. A retrospective population-based cohort study using the data linkage of the Nationwide Health Insurance Service database and the National Death Registry of Korea was conducted. Patients were defined as individuals with ≥3 documented visits with HS from 2003 to 2019. Controls were matched at a 1:10 ratio with age, sex, insurance type, and income level. The study included 26,304 patients with HS and 263,040 controls. Patients with HS showed a higher risk of all-cause mortality (hazard ratio = 1.152, 95% confidence interval = 1.051-1.263) than controls. However, the difference was comparable after further adjustment for body mass index, smoking, drinking, and comorbidity (adjusted hazard ratio = 1.038, 95% confidence interval = 0.946-1.138). For cause-specific mortality, the mortality from suicide/psychiatric disease (adjusted hazard ratio = 1.449, 95% confidence interval = 1.098-2.911) and renal/urogenital disease (adjusted hazard ratio = 1.801, 95% confidence interval = 1.080-3.004) were independently higher among patients with HS even after adjustment for the confounding factors.

Association of All-Cause and Cause-Specific Mortality Risks With Pyoderma Gangrenosum.

Importance: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis. Few studies have evaluated the mortality outcomes of patients with PG. Objective: To investigate all-cause and cause-specific mortality in patients with PG. Design, Setting, and Participants: This retrospective population-based cohort study used data from the National Health Insurance Service database of Korea and the National Death Registry of Korea from patients with incident PG (≥3 documented visits with an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code of L88) during January 2003 to December 2019. For comparison, a 1:20 cohort of age-, sex-, insurance type-, and income level-matched controls without any documented visit with an ICD-10 code of L88 during the entire observation was included. Exposures: Pyoderma gangrenosum. Main Outcomes and Measures: The participants were observed from the index date to their death, emigration, or the end of the observation period to investigate all-cause and cause-specific mortality during the 17-year study period. Results: In total, 3386 patients with PG (1450 women [42.8%]; mean [SD] age, 57.8 [16.4] years) and 67 720 controls (29 000 women [42.8%]; mean [SD] age, 57.8 [16.3] years) were analyzed. All-cause mortality risk was greater in patients with PG than in controls (adjusted hazard ratio [aHR], 2.122; 95% CI, 1.971-2.285) after adjustment for smoking, drinking, body mass index, and comorbidities. Patients experienced greater mortality of infectious disease (aHR, 3.855; 95% CI, 2.640-5.628), neoplasm (aHR, 1.618; 95% CI, 1.363-1.920), hematologic disease (aHR, 12.298; 95% CI, 3.904-38.734), endocrine disease (aHR, 6.322; 95% CI, 5.026-7.953), neurologic disease (aHR, 2.039; 95% CI, 1.337-3.109), cardiovascular disease (aHR, 1.979; 95% CI, 1.645-2.382), respiratory disease (aHR, 1.757; 95% CI, 1.365-2.263), gastrointestinal disease (aHR, 2.278; 95% CI, 1.522-3.408), connective tissue disease (aHR, 8.685; 95% CI, 4.963-15.199), and kidney/urogenital disease (aHR, 3.617; 95% CI, 2.488-5.259) than controls. Compared with idiopathic PG (aHR, 2.062; 95% CI, 1.897-2.241), PG that was associated with solid organ cancer (aHR, 2.313; 95% CI, 1.956-2.737) and hematologic cancer (aHR, 8.330; 95% CI, 5.473-12.679) showed greater mortality, whereas PG that was associated with inflammatory bowel diseases showed a slightly better prognosis (aHR, 1.742; 95% CI, 0.964-3.148). Conclusions and Relevance: The results of this cohort study suggest that patients with PG had a higher all-cause and cause-specific mortality risk than the general population.

Treatment of Actinic Keratosis: The Best Choice through an Observational Study.

Actinic keratosis (AK) is a precancerous lesion that can progress to invasive squamous cell carcinoma if untreated. However, no gold standard treatment has been established. We aimed to investigate the management of AK by comparing the effectiveness and treatment duration of treatment modalities, including cryotherapy, imiquimod (IMQ), and photodynamic therapy (PDT). We reviewed the medical records of 316 patients diagnosed with AK at Seoul St. Mary's Hospital from February 2015 to May 2020, and a total of 195 patients were included. The clearance rate was the highest in PDT, followed by cryotherapy and IMQ (82.4%, 71.2%, and 68.0%, respectively). The recurrence rate was the lowest in cryotherapy, followed by PDT and IMQ (3.5%, 6.7%, and 10.5%, respectively, p < 0.05). The average treatment duration was shortest with PDT, followed by IMQ and cryotherapy (5.5 weeks, 6.8 weeks, and 9.1 weeks, respectively, p < 0.05). The number of hospital visits was lowest for PDT, followed by cryotherapy and IMQ (1.8, 2.8, and 3.6, respectively, p < 0.05). PDT showed the highest clearance rate, a moderate recurrence rate, the shortest treatment duration, and the least number of visits, suggesting that PDT could be the first choice for treatment of AK. Considering the advantages as a topical agent, IMQ could also be a treatment option.

Ultrasmall polymer-coated cerium oxide nanoparticles as a traumatic brain injury therapy.

No medication has been approved for secondary injuries after traumatic brain injury (TBI). While free radicals are considered a major mediator of secondary injury, conventional antioxidants only have modest clinical efficacy. Here, we synthesized CX201 consisting of core cerium oxide nanoparticles coated with 6-aminocaproic acid and polyvinylpyrrolidone in aqueous phase. CX201 with 3.49 ± 1.11 nm of core and 6.49 ± 0.56 nm of hydrodynamic diameter showed multi-enzymatic antioxidant function. Owing to its excellent physiological stability and cell viability, CX201 had a neuroprotective effect in vitro. In a TBI animal model, an investigator-blinded randomized experiment showed a single intravenously injected CX201 significantly improved functional recovery compared to the control. CX201 reduced lipid peroxidation and inflammatory cell recruitment at the damaged brain. These suggest ultrasmall CX201 can efficiently reduce secondary brain injuries after TBI. Given the absence of current therapies, CX201 may be proposed as a novel therapeutic strategy for TBI.

Leukaemia Cutis: Clinical Features and Outcomes of 56 Patients.

Leukaemia is a malignant neoplasm of the haematopoietic system. Cutaneous manifestations of leukaemia are called leukaemia cutis, and are regarded as a sign of poorer prognosis and shorter survival time. A single-institution retrospective review was performed of medical records of patients diagnosed with leukaemia cutis in the dermatology department of Seoul St Mary's Hospital between January 2012 and April 2021. Fifty-six cases with cutaneous leukaemic involvement and underlying haematological malignancy were included (40 acute myelogenous leukaemia, 8 acute lymphoblastic leukaemia, 3 chronic myeloid leukaemia, 2 chronic lymphocytic leukaemia, and 3 myelodysplastic syndrome). Male-female ratio 1.9:1, mean age at diagnosis 45.8 years. Plaques (28%) and papules (27%) were the most common skin lesions, followed by patches (18%) and nodules (16%). Mean time from diagnosis of leukaemia to development of leukaemia cutis was 12.3 months. Forty-six patients (84%) died during the 7-year follow-up; mean time from diagnosis of leukaemia cutis to death was 5.4 months. The results suggest that leukaemia cutis is associated with poor outcomes in patients with leukaemia. Comprehensive skin examination of these patients may help diagnose leukaemia cutis early, enabling prompt treatment.

Smoking and Periodontitis Can Play a Synergistic Role in the Development of Psoriasis: A Nationwide Cohort Study.

BACKGROUND: Periodontitis is a chronic inflammatory disorder involving the periodontium. The precise nature of the association between periodontitis and psoriasis has not been determined. OBJECTIVE: This nationwide population-based study investigated the relationship between periodontitis and the risk of psoriasis. METHODS: A health screening database, which is a sub-dataset of the Korean National Health Insurance System database, was used in this study. Subjects with (n = 1,063,004) and without (n = 8,655,587) periodontitis who underwent health examinations from January to December 2009 were followed for 9 years. RESULTS: In multivariable analysis, compared to the non-periodontitis group, periodontitis patients had a significantly higher risk of developing psoriasis (hazard ratio 1.116, 95% confidence interval 1.101-1.13). Non-smokers with periodontitis had an 11% increase in risk of psoriasis and smokers with periodontitis had a 26.5% increase in risk of psoriasis compared to non-smokers without periodontitis. CONCLUSION: Our study highlights periodontitis as a potential independent risk factor for psoriasis, increasing awareness of the synergistic role of smoking and periodontitis in the pathogenesis of psoriasis.

Epigallocatechin-3-gallate Can Prevent Type 2 Human Papillomavirus E7 from Suppressing Interferon-Stimulated Genes.

Human papillomavirus (HPV) in high-risk groups is known to suppress the type I interferon (IFN) signaling pathway leading to the transcription of interferon-stimulated genes (ISGs), which have many antiviral functions. However, the effects of HPV on the action of various ISGs in low-risk groups are not fully understood. We aimed to investigate whether antiviral ISGs are expressed in transfected keratinocytes with type 2 HPV (HPV-2) E7. The mRNA and protein expressions of ISGs and type I IFN signaling pathway components were evaluated by quantitative real-time polymerase chain reaction, western blot, immunofluorescence, and/or immunohistochemistry. Compared with normal skin, mRNA expression of all ISGs in HPV-2 positive cutaneous warts was significantly decreased (p < 0.05). In comparison with empty vector transfection, E7 transfection significantly down-regulated the mRNA and protein expressions of ISGs and type I IFN signaling pathway components, which were significantly up-regulated by E7 siRNA transfection (p < 0.05). Interestingly, epigallocatechin-3-gallate (EGCG) pretreatment up-regulated the mRNA and protein expressions of ISGs and type I IFN signaling pathway components, which were significantly down-regulated by E7 transfection (p < 0.05). Our results demonstrate that EGCG is a potential candidate for cutaneous wart prevention.