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.

Novel structure of secreted small molecular weight antigen Mtb12 from Mycobacterium tuberculosis.

Mtb12, a small protein secreted by Mycobacterium tuberculosis, is known to elicit immune responses in individuals infected with the pathogen. It serves as an antigen recognized by the host's immune system. Due to its immunogenic properties and pivotal role in tuberculosis (TB) pathogenesis, Mtb12 is considered a promising candidate for TB diagnosis and vaccine development. However, the structural and functional properties of Mtb12 are largely unexplored, representing a significant gap in our understanding of M. tuberculosis biology. In this study, we present the first structure of Mtb12, which features a unique tertiary configuration consisting of four beta strands and four alpha helices. Structural analysis reveals that Mtb12 has a surface adorned with a negatively charged pocket adjacent to a central cavity. The features of these structural elements and their potential effects on the function of Mtb12 warrant further exploration. These findings offer valuable insights for vaccine design and the development of diagnostic tools.

Novel structure of the anti-CRISPR protein AcrIE3 and its implication on the CRISPR-Cas inhibition.

As a response to viral infections, bacteria have evolved the CRISPR-Cas system as an adaptive immune mechanism, enabling them to target and eliminate viral genetic material introduced during infection. However, viruses have also evolved mechanisms to counteract this bacterial defense, including anti-CRISPR proteins, which can inactivate the CRISPR-Cas adaptive immune system, thus aiding the viruses in their survival and replication within bacterial hosts. In this study, we establish the high-resolution crystal structure of the Type IE anti-CRISPR protein, AcrIE3. Our structural examination showed that AcrIE3 adopts a helical bundle fold comprising four α-helices, with a notably extended loop at the N-terminus. Additionally, surface analysis of AcrIE3 revealed the presence of three acidic regions, which potentially play a crucial role in the inhibitory function of this protein. The structural information we have elucidated for AcrIE3 will provide crucial insights into fully understanding its inhibitory mechanism. Furthermore, this information is anticipated to be important for the application of the AcrIE family in genetic editing, paving the way for advancements in gene editing technologies.

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.

Autoimmune, Inflammatory, Atopic, Thyroid, and Psychiatric Outcomes of Offspring Born to Mothers With Alopecia Areata.

Importance: Alopecia areata (AA) is associated with diverse autoimmune and psychiatric disorders. However, an investigation on the long-term outcomes for offspring born to mothers diagnosed with AA is lacking. Objective: To investigate the risks for autoimmune, inflammatory, atopic, thyroid, and psychiatric outcomes of offspring born to mothers with AA. Design, Setting, and Participants: This retrospective population-based birth cohort study used the linked birth registration database with the Nationwide Health Insurance Service database of Korea. The participants included all newborns born to mothers with 3 or more visits with International Classification of Diseases, Tenth Revision code of L63 and 1:10 birth year, sex, insurance, income, and location of residence-matched control offspring born to mothers without AA during the years from 2003 to 2015. The analysis was conducted from July 2022 to January 2023. Exposure: Maternal AA. Main Outcomes and Measures: The occurrence of the following diseases was measured in newborns from birth to December 31, 2020: AA, alopecia totalis/universalis (AT/AU), vitiligo, psoriasis, inflammatory bowel disease, rheumatoid arthritis, atopic dermatitis, allergic rhinitis, asthma, hyperthyroidism, hypothyroidism, Graves disease, Hashimoto thyroiditis, attention-deficit hyperactivity disorder, mood disorder, and anxiety disorder. Multivariable Cox proportional hazard analyses were performed with the following covariates: birth year, age, insurance type, income level, location of residence, maternal age, mode of delivery, maternal history of atopic disorders, and autoimmune disorders. Results: In total, 67 364 offspring born to 46 352 mothers with AA and 673 640 controls born to 454 085 unaffected mothers were analyzed. The risk of AA (adjusted hazard ratio [aHR], 2.08; 95% CI, 1.88-2.30), AT/AU (aHR, 1.57; 95% CI, 1.18-2.08), vitiligo (aHR, 1.47; 95% CI, 1.32-1.63), atopic disorders (aHR, 1.07; 95% CI, 1.06-1.09), hypothyroidism (aHR, 1.14; 95% CI, 1.03-1.25), and psychiatric disorders (aHR, 1.15; 95% CI, 1.11-1.20) was significantly increased in offspring born to mothers with AA. Among them, 5088 born to mothers with AT/AU were at much greater risk for the development of AT/AU (aHR, 2.98; 95% CI, 1.48-6.00) and psychiatric disorders (aHR, 1.27; 95% CI, 1.12-1.44). Conclusions and Relevance: In this Korean retrospective population-based birth cohort study, maternal AA was associated with the development of autoimmune/inflammatory, atopic, thyroid, and psychiatric disorders in their offspring. Clinicians and parents need to be aware of the potential for these comorbidities to occur.

Risk of autoimmune skin and connective tissue disorders after mRNA-based COVID-19 vaccination.

BACKGROUND: Data on the association between the development of autoimmune diseases and COVID-19 vaccination are limited. OBJECTIVE: To investigate the incidence and risk of autoimmune connective tissue disorders following mRNA-based COVID-19 vaccination. METHODS: This nationwide population-based study was conducted in South Korea. Individuals who received vaccination between September 8, 2020-December 31, 2021, were identified. Historical prepandemic controls were matched for age and sex in 1:1 ratio. The incidence rate and risk of disease outcomes were compared. RESULTS: A total of 3,838,120 vaccinated individuals and 3,834,804 controls without evidence of COVID-19 were included. The risk of alopecia areata, alopecia totalis, primary cicatricial alopecia, psoriasis, vitiligo, anti-neutrophil cytoplasmic antibody-associated vasculitis, sarcoidosis, Behcet disease, Crohn disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjogren syndrome, ankylosing spondylitis, dermato/polymyositis, and bullous pemphigoid was not significantly higher in vaccinated individuals than in controls. The risk was comparable according to age, sex, type of mRNA-based vaccine, and cross-vaccination status. LIMITATIONS: Possible selection bias and residual confounders. CONCLUSION: These findings suggest that most autoimmune connective tissue disorders are not associated with a significant increase in risk. However, caution is necessary when interpreting results for rare outcomes due to limited statistical power.

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.

Psychological Stress in Parents of Children with Atopic Dermatitis: A Cross-sectional Study from the Korea National Health and Nutrition Examination Survey.

Atopic dermatitis is a chronically relapsing inflammatory skin condition that has profound impacts on quality of life of patients and their family. The aim of this study is to investigate the psychological stress in parents of children with atopic dermatitis in Korea, using data from the Korean National Health and Nutrition Examination Survey (KNHANES). This cross-sectional study included parents of participants under 19 years of age (970 with atopic dermatitis and 5,733 without atopic dermatitis after excluding those who meet the exclusion criteria) from the 2009 to 2012 KNHANES. The psychological stress state was evaluated with the following four questionnaire items: self-perception of stress, depressed mood, suicidal ideation, and diagnosis of depression by a physician. After adjusting for age, gender, education level, occupation, and marital status, logistic regression analyses indicated that mothers of children with atopic dermatitis had a higher frequency of stress perception (adjusted odds ratio (aOR) 1.46 (95% confidence interval (95% CI) 1.22-1.74), p < 0.01) and suicidal ideation (aOR 1.40 (95% CI 1.1-1.79), p < 0.01) than those without atopic dermatitis. In contrast, fathers of children with atopic dermatitis did not show a significant difference in all items compared with those of children without atopic dermatitis. Understanding the psychological stress in parents of children with atopic dermatitis is important for clinicians, since evaluation, management and support for parents, especially mothers, of children with atopic dermatitis are required.

Atopic Disorders and Their Risks of Migraine: A Nationwide Population-Based Cohort Study.

PURPOSE: Migraine is a relatively common neurologic disorder. A possible link between atopic disorders and migraine has been suggested. This study investigated atopic disorders and their risks of migraine in the Korean population. METHODS: From the Korean National Health Insurance Service database, patients aged ≥ 20 years who underwent health screening between January and December of 2009 were enrolled. To evaluate the risk of migraine, Cox proportional hazards regression analyses were performed. RESULTS: In multivariable analysis, the atopic dermatitis group (adjusted hazard ratio [aHR], 1.28; 95% confidence interval [CI], 1.23-1.33), asthma group (aHR, 1.32; 95% CI, 1.30-1.34) and allergic rhinitis group (aHR, 1.45; 95% CI, 1.44-1.46) had significantly increased risks of migraine compared to their respective control groups (P < 0.001). The patients with 1 (aHR, 1.43; 95% CI, 1.42-1.44), 2 (aHR, 1.50; 95% CI, 1.47-1.53), and 3 (aHR, 1.64; 95% CI, 1.43-1.88) atopic disorders had significantly increased risks of migraine compared to the control group (P < 0.001). CONCLUSIONS: Our results demonstrate that patients with atopic disorders may have increased risk of migraine and that the larger the number of concomitant atopic disorders, the higher the risk of migraine.

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.