It has been proposed that mitochondrial DNA variations can affect mitochondrial function, increasing the risk of drug-induced liver injury. This study aims to explore the association between mitochondrial DNA (mtDNA) variants and anti-tuberculosis drug-induced liver injury (ATT_DILI) in Korean tuberculosis patients. Whole mitochondrial genomes from 185 patients (61 with ATT_DILI and 124 without liver injury) were sequenced. Comparative analyses examined mtDNA variants, variant counts, and haplogroups between the two groups, adjusted with Bonferroni correction. The m.16189 T > C variant, associated with reduced mtDNA copy number, was more frequent in ATT_DILI cases (39.3

Background: Extracellular vesicles (EVs) are secreted by all bacteria, including those that cause sepsis, and are distributed throughout the bloodstream before getting excreted in the urine. The study aimed to analyze bacterialderived extracellular vesicles in the urine of patients with sepsis and compare them with those in healthy controls. Methods: The study included a total of 25 patients, comprising 9 cases with positive bacterial cultures in clinically significant specimens and 11 healthy controls. Urine samples, either midstream or collected via Foley catheter, were obtained before the initiation of antibiotic treatment. Extracellular vesicles were isolated from these samples using centrifugation. Metagenomic analysis was conducted on the isolated EV samples, focusing on bacterial 16S rDNA to identify the bacterial genera present. Results: In all febrile patients with culture-positive cases, genetic material from multiple bacterial genera was detected through metagenomic analysis, although the specific bacteria identified in clinical cultures were not found in most cases. The bacterial distributions observed in the normal control group were markedly different from those in the febrile patients. Conclusions: The findings suggest that bacterial components are likely entering the bloodstream from multiple sites within the body in the form of extracellular vesicles, both in septic and normal states. The distinct bacterial distributions observed in the urine of sepsis patients compared to healthy individuals require further investigation to understand the underlying mechanisms.

Anti-tuberculosis (AT) medications, including isoniazid (INH), can cause drug-induced liver injury (DILI), but the underlying mechanism remains unclear. In this study, we aimed to identify genetic factors that may increase the susceptibility of individuals to AT-DILI and to examine genetic interactions that may lead to isoniazid (INH)-induced hepatotoxicity. We performed a targeted sequencing analysis of 380 pharmacogenes in a discovery cohort of 112 patients (35 AT-DILI patients and 77 controls) receiving AT treatment for active tuberculosis. Pharmacogenome-wide association analysis was also conducted using 1048 population controls (Korea1K). NAT2 and ATP7B genotypes were analyzed in a replication cohort of 165 patients (37 AT-DILI patients and 128 controls) to validate the effects of both risk genotypes. NAT2 ultraslow acetylators (UAs) were found to have a greater risk of AT-DILI than other genotypes (odds ratio [OR] 5.6 [95% confidence interval; 2.5-13.2], P = 7.2 × 10-6). The presence of ATP7B gene 832R/R homozygosity (rs1061472) was found to co-occur with NAT2 UA in AT-DILI patients (P = 0.017) and to amplify the risk in NAT2 UA (OR 32.5 [4.5-1423], P = 7.5 × 10-6). In vitro experiments using human liver-derived cell lines (HepG2 and SNU387 cells) revealed toxic synergism between INH and Cu, which were strongly augmented in cells with defective NAT2 and ATP7B activity, leading to increased mitochondrial reactive oxygen species generation, mitochondrial dysfunction, DNA damage, and apoptosis. These findings link the co-occurrence of ATP7B and NAT2 genotypes to the risk of INH-induced hepatotoxicity, providing novel mechanistic insight into individual AT-DILI susceptibility. Yoon et al. showed that individuals who carry NAT2 UAs and ATP7B 832R/R genotypes are at increased risk of developing isoniazid hepatotoxicity, primarily due to the increased synergistic toxicity between isoniazid and copper, which exacerbates mitochondrial dysfunction-related apoptosis.

Airborne microorganisms are associated with human health and awareness of the important influence of nano-sized extracellular vesicles (EVs) on health has risen. Thus, we analyzed the micro-sized microbes (m-MBs) and nano-sized microbial EVs (n-MEVs) of outdoor and indoor air through a field study in Seoul, Korea. We conducted 16S rDNA-based metagenomic analysis of m-MBs and n-MEVs in outdoor airborne dust (OAD), indoor airborne dust (IAD), and indoor dust from carpets (IDC). The dominant taxa in OAD were altered depending upon the outside environment, such as sunny, haze, and rainy. Also, dominant taxa in IAD and IDC were changed depending on the outside environment. In addition, there were differences of microbiome composition and diversity between the m-MB and n-MEV in OAD, IAD, and IDC. m-MB in OAD were more correlated with that of IDC, whereas n-MEVs in OAD were more related to those in IAD. Thus, indoor bioaerosols can be affected by different source according to bioaerosol size. Additionally, risk of bioaerosols can be different according to dominant taxa, and therefore we suggested that further study for risk of dominant taxa according to environments is necessary. We suggested that nano-sized microbial EVs should be included as parameters to manage air quality.

Over several decades, the disease pattern of intractable disease has changed from acute infection to chronic disease accompanied by immune and metabolic dysfunction. In addition, scientific evidence has shown that humans are holobionts; of the DNA in humans, 1% is derived from the human genome, and 99% is derived from microbial genomes (the microbiome). Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles and key messengers in cell-to-cell communication. Many publications indicate that microbial EVs are both positively and negatively involved in the pathogenesis of various intractable diseases, including inflammatory diseases, metabolic disorders, and cancers. Microbial EVs in feces, blood, and urine show significant differences in their profiles between patients with a particular disease and healthy subjects, demonstrating the potential of microbial EVs as biomarkers for disease diagnosis, especially for assessing disease risk. Furthermore, microbial EV therapy offers a variety of advantages over live biotherapeutics and human cell EV (or exosome) therapy for the treatment of intractable diseases. In summary, microbial EVs are a new tool in medicine, and microbial EV technology might provide us with innovative diagnostic and therapeutic solutions in precision medicine.

Background: Children in the affected area were exposed to large amounts of volatile organic compounds (VOCs) from the Hebei Spirit oil spill accident. Objectives: We investigated the lung function loss from the exposure to VOCs in a longitudinal panel of 224 children 1, 3, and 5 years after the VOC exposure event. Methods: Atmospheric estimated concentration of total VOCs (TVOCs), benzene, toluene, ethylbenzene, and xylene for 4 days immediately after the accident were calculated for each village (n = 83) using a modeling technique. Forced expiratory volume in 1 s (FEV1) as an indicator of airway status was measured 1, 3, and 5 years after the exposure in 224 children 4~9 years of age at the exposure to the oil spill. Multiple linear regression and linear mixed models were used to evaluate the associations, with adjustment for smoking and second-hand smoke at home. Results: Among the TVOCs (geometric mean: 1319.5 mg/m3·4 d), xylene (9.4), toluene (8.5), ethylbenzene (5.2), and benzene (2.0) were dominant in the order of air concentration level. In 224 children, percent predicted FEV1 (ppFEV1), adjusted for smoking and second-hand smoke at home, was 100.7% after 1 year, 96.2% after 3 years, and 94.6% after 5 years, and the loss over the period was significant (p < 0.0001). After 1 and 3 years, TVOCs, xylene, toluene, and ethylbenzene were significantly associated with ppFEV1. After 5 years, the associations were not significant. Throughout the 5 years’ repeated measurements in the panel, TVOCs, xylene, toluene, and ethylbenzene were significantly associated with ppFEV1. Conclusions: Exposure to VOCs from the oil spill resulted in lung function loss among children, which remained significant up to 5 years after the exposure.

Although mounting evidence suggests that the microbiome has a tremendous influence on intractable disease, the relationship between circulating microbial extracellular vesicles (EVs) and respiratory disease remains unexplored. Here, we developed predictive diagnostic models for COPD, asthma, and lung cancer by applying machine learning to microbial EV metagenomes isolated from patient serum and coded by their accumulated taxonomic hierarchy. All models demonstrated high predictive strength with mean AUC values ranging from 0.93 to 0.99 with various important features at the genus and phylum levels. Application of the clinical models in mice showed that various foods reduced high-fat diet-associated asthma and lung cancer risk, while COPD was minimally affected. In conclusion, this study offers a novel methodology for respiratory disease prediction and highlights the utility of serum microbial EVs as data-rich features for noninvasive diagnosis.

https://e-aair.org Special attention has been focused on in the role of microbiome in human health and disease over the past decade, with significant advances in culture-independent technologies for investigating microbial communities mainly through analyzing the gut microbiota. The dysbiosis of the gut microbiota is associated with several diseases ranging from localized gastrointestinal to neurological, hepatic, and respiratory disorders.1 Changes in the production of short-chain fatty acids and other metabolites due to an imbalance in the composition of these intestinal microbes have been suggested to be a possible pathogenic mechanism2; however, they can not explain diverse functions of microbes in the host.

BACKGROUND: Because severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) rarely occur, clinical data based on large-scale studies are still lacking. OBJECTIVE: To provide information on culprit drugs and clinical characteristics, including morbidity and mortality of SCARs based on a nationwide registry. METHODS: SCAR cases that occurred from 2010 to 2015 were recruited to the Korean SCAR registry from 34 tertiary referral hospitals. Demographics, causative drugs, causality, and clinical outcomes were collected by reviewing the medical record. RESULTS: A total of 745 SCAR cases (384 SJS/TEN cases and 361 DRESS cases) due to 149 drugs were registered. The main causative drugs were allopurinol (14.0%), carbamazepine (9.5%), vancomycin (4.7%), and antituberculous agents (6.3%). A strong preference for SJS/TEN was observed in carbonic anhydrase inhibitors (100%), nonsteroidal anti-inflammatory drugs (84%), and acetaminophen (83%), whereas dapsone (100%), antituberculous agents (81%), and glycopeptide antibacterials (78%) were more likely to cause DRESS. The mortality rate was 6.6% (SJS/TEN 8.9% and DRESS 4.2%). The median time to death was 19 days and 29 days in SJS/TEN and DRESS respectively, and 89.8% of deaths occurred within 60 days after the onset of the skin symptoms. CONCLUSION: Allopurinol, carbamazepine, vancomycin, and antituberculous agents were the leading causes of SCARs in Korea. Some drugs preferentially caused a specific phenotype. The mortality rate of SCARs was 6.6%, and most of the deaths occurred within 2 months. (C) 2020 American Academy of Allergy, Asthma & Immunology

Background The Coronavirus Disease 2019 (COVID-19) has been placing severe strain on global healthcare systems and medical education programs, leading to growing demands for medical students to assume the role of preliminary healthcare providers. Objectives To assess the perception and attitudes of medical students about clinical clerkship training during the COVID-19 pandemic. Design A cross-sectional survey with web-based 3-fields/14-items questionnaire was conducted, from April 7 to 14, 2020, to evaluate their self-assessed perception and attitudes on clerkship training of hospital practice under the COVID-19 outbreak and spread among 161 (78 on pre-clerkship course, 83 on clinical clerkship course) medical students at Dankook University College of Medicine, Cheonan, Republic of Korea. Results Of the 151 medical students who completed the survey, 81 students (53.7%) considered themselves familiar with COVID-19. Although the students were concerned about the spread of the virus during clinical clerkship training, 118 (78.1%) students preferred the clerkship training in a hospital practice. The students in the clinical clerkship program preferred this over those in the pre-clerkship program (85.7% vs. 70.2%, P = 0.03), primarily because a clinical clerkship could not be replaced by an online class during the COVID-19 pandemic. In addition, their responses indicated, in order of significance, fear of not completing the clerkship course on time, willingness to participate as a preliminary healthcare provider in pandemic, the potential waste of tuition, and belief that a hospital is rather safe. The change in the academic calendar had not a positive impact on the lifestyles of many students. Conclusions In circumstances such as the COVID-19 pandemic, educational strategies to clinical clerkship training for medical students should be developed to provide them with the opportunity to be actively involved in hospital practice under strict safety guidance focused on preventing virus infection and transmission.

Purpose Recently, there has been a rise in the interest to understand the composition of indoor dust due to its association with lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and lung cancer. Furthermore, it has been found that bacterial extracellular vesicles (EVs) within indoor dust particles can induce pulmonary inflammation, suggesting that these might play a role in lung disease. Methods We performed microbiome analysis of indoor dust EVs isolated from mattresses in apartments and hospitals. We developed diagnostic models based on the bacterial EVs antibodies detected in serum samples via enzyme-linked immunosorbent assay (ELISA) in this analysis. Results Proteobacteria was the most abundant bacterial EV taxa observed at the phylum level while Pseudomonas, Enterobacteriaceae (f) and Acinetobacter were the most prominent organisms at the genus level, followed by Staphylococcus. Based on the microbiome analysis, serum anti-bacterial EV immunoglobulin G (IgG), IgG1 and IgG4 were analyzed using ELISA with EV antibodies that targeted Staphylococcus aureus, Acinetobacter baumannii, Enterobacter cloacae and Pseudomonas aeruginosa. The levels of anti-bacterial EV antibodies were found to be significantly higher in patients with asthma, COPD and lung cancer compared to the healthy control group. We then developed a diagnostic model through logistic regression of antibodies that showed significant differences between groups with smoking history as a covariate. Four different variable selection methods were compared to construct an optimal diagnostic model with area under the curves ranging from 0.72 to 0.81. Conclusions The results of this study suggest that ELISA-based analysis of anti-bacterial EV antibodies titers can be used as a diagnostic tool for lung disease. The present findings provide insights into the pathogenesis of lung disease as well as a foundation for developing a novel diagnostic methodology that synergizes microbial EV metagenomics and immune assays.

The human microbiome has been recently associated with human health and disease. Brain tumors (BTs) are a particularly difficult condition to directly link to the microbiome, as microorganisms cannot generally cross the blood–brain barrier (BBB). However, some nanosized extracellular vesicles (EVs) released from microorganisms can cross the BBB and enter the brain. Therefore, we conducted metagenomic analysis of microbial EVs in both serum (152 BT patients and 198 healthy controls (HC)) and brain tissue (5 BT patients and 5 HC) samples based on the V3–V4 regions of 16S rDNA. We then developed diagnostic models through logistic regression and machine learning algorithms using serum EV metagenomic data to assess the ability of various dietary supplements to reduce BT risk in vivo. Models incorporating the stepwise method and the linear discriminant analysis effect size (LEfSe) method yielded 12 and 29 significant genera as potential biomarkers, respectively. Models using the selected biomarkers yielded areas under the curves (AUCs) >0.93, and the model using machine learning resulted in an AUC of 0.99. In addition, Dialister and [Eubacterium] rectale were significantly lower in both blood and tissue samples of BT patients than in those of HCs. In vivo tests showed that BT risk was decreased through the addition of sorghum, brown rice oil, and garlic but conversely increased by the addition of bellflower and pear. In conclusion, serum EV metagenomics shows promise as a rich data source for highly accurate detection of BT risk, and several foods have potential for mitigating BT risk.

Introduction: Recently, there has been rising interest in indoor dust due to its effects on negative health outcomes including asthma, COPD, and lung cancer. Furthermore, bacterial extracellular vesicles (EV) within dust can induce pulmonary inflammation. Methods: We performed microbiome analysis of indoor dust EVs isolated from mattresses in apartments and hospitals. Moreover, Serum IgG, IgG1, and IgG4 antibodies against dust EVs were measured in 88 healthy control, 239 asthmatics, 205 COPD patients, and 324 lung cancer patients. To identify variables associated independently with asthma, COPD and lung cancer, multiple logistic regression analysis was performed after ad­justment for age, gender, and cigarette smoking history. Results: Proteobacteria were the most abundant bacterial EV taxa at the phylum level while Pseudomonas, Enterobacteriaceae(f), and Acinetobacter were the most abundant at the genus level and Staphylococcus followed. Based on microbiome analysis, serum anti-bacterial EV IgG, IgG1, and IgG4 were analyzed through ELISA utilizing EV antibodies that targeted Staphylococcus aureus, Acinetobacter baumannii, Enterobacter cloacae, and Pseudomonas aeruginosa. As a result of comparative analysis of control, asthma, COPD, and lung cancer groups, anti-bacterial EV antibodies showed significant increases in asthma, COPD, and lung cancer patients. Conclusion: Present findings provide insights into the pathogenesis of asthma, COPD, and lung cancer, as well as a steppingstone for the development of a novel diagnostic methodology synergizing microbial EV metagenomics and immune assays.

Background: Raoultella planticola, considered to be an environmental organism, is a rare cause of human infections. Although in recent years the frequency of R. planticola infections reported in the literature has increased, few cases of pneumonia caused by R. planticola have been described. Here, we investigate the clinical characteristics, management, and clinical outcomes of pneumonia caused by R. planticola. Methods: Consecutive patients with pneumonia caused by R. planticola were included. The medical records of patients with R. planticola pneumonia treated at Dankook University Hospital from January 2011 to December 2017 were collected. Results: A total of 11 adult patients with R. planticola pneumonia were diagnosed and treated [10 males and 1 female; median age, 70 years (range: 51-79 years)]; 5 patients had underlying malignant conditions (45.5%). Antibacterial susceptibility testing showed that all isolates of R. planticola were susceptible to cephalosporins, carbapenems, fluoroquinolones, aminoglycosides, and beta-lactams/beta-lactamase inhibitors. Chest imaging revealed consolidation (8/11, 72.7%), ground-glass opacity (5/11, 45.5%), pleural effusion (5/11, 45.5%), and micronodules (3/11, 27.3%). Four patients (36.4%) required mechanical ventilation; three survived but one died of multiple organ dysfunction syndrome (principally pneumonia and septic shock). Conclusions: R. planticola pneumonia occurred mainly in patients with underlying risk factors such as malignant disease, cerebral infarction or hemorrhage, and chronic obstructive pulmonary disease. The organism was sensitive to most antibiotics, and the clinical outcomes were favorable after empirical antibiotic therapy.

PURPOSE:Associations between a wide variety of diseases and the microbiome have been extensively verified. Recently, there has been a rising interest in the role the microbiome plays in atopic dermatitis (AD). Furthermore, metagenomic analysis of microbe-derived extracellular vesicles (EVs) has revealed the importance and relevance of microbial EVs in human health.METHODS:We compared the diversity and proportion of microbial EVs in the sera of 24 AD patients and 49 healthy controls, and developed a diagnostic model. After separating microbial EVs from serum, we specifically targeted the V3-V4 hypervariable regions of the 16S rDNA gene for amplification and subsequent sequencing.RESULTS:Alpha and beta diversity between controls and AD patients both differed, but only the difference in beta diversity was significant. Proteobacteria, Firmicutes, and Bacteroidetes were the dominant phyla in healthy controls and AD patients, accounting for over 85% of the total serum bacterial EVs. Also, Proteobacteria, Firmicutes, Actinobacteria, Verrucomicrobia, and Cyanobacteria relative abundances were significantly different between the AD and control groups. At the genus level, the proportions of Escherichia-Shigella, Acinetobacter, Pseudomonas, and Enterococcus were drastically altered between the AD and control groups. AD diagnostic models developed using biomarkers selected on the basis of linear discriminant analysis effect size from the class to genus levels all yielded area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy of value 1.00.CONCLUSIONS:In summary, microbial EVs demonstrated the potential in their use as novel biomarkers for AD diagnosis. Therefore, future work should investigate larger case and control groups with cross-sectional or longitudinal clinical data to explore the utility and validity of serum microbiota EV-based AD diagnosis.