Association between obesity and cancer risk in adults with HIV in Korea.

INTRODUCTION: This study aimed to investigate the association between obesity and cancer risk as well as site-specific cancer risks in adults with HIV using a nationwide health screening database in Korea. METHODS: Of the 16,671 adults with a new diagnosis of HIV from 2004 to 2020, 456 incident cancer cases and 1814 individually matched controls by sex, year of birth, year of HIV diagnosis, and follow-up duration (1 : 4 ratio) were included in this nested case-control study. The association between obesity (BMI ≥25 kg/m 2 ) and cancer risks was estimated and presented as odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Of the 456 cancer incident cases, there were 146 AIDS-defining cancer cases and 310 non-AIDS-defining cancer cases. Compared with nonobese adults with HIV, obese adults with HIV were at higher risk of non-AIDS-defining cancer (OR = 1.478, 95% CI = 1.118-1.955). Otherwise, the overall risk of AIDS-defining cancer (OR = 0.816, 95% CI = 0.520-1.279) and each type of AIDS-defining cancer (Kaposi sarcoma and non-Hodgkin's lymphoma) were not high in obese adults with HIV. Of the specific types of non-AIDS-defining cancers, obesity was associated with an increased risk of colorectal cancer (OR = 3.090, 95% CI = 1.110-8.604) and liver, bile duct, and pancreatic cancers (OR = 2.532, 95% CI = 1.141-5.617). CONCLUSION: Obesity, which is one of the important health concerns in HIV management, was associated with an increased risk of non-AIDS-defining cancer but not AIDS-defining cancer.

Economic Burden of Cancer for the First Five Years after Cancer Diagnosis in Patients with Human Immunodeficiency Virus in Korea.

This study aimed to estimate the medical cost of cancer in the first five years of diagnosis and in the final six months before death in people who developed cancer after human immunodeficiency virus (HIV) infection in Korea. The study utilized the Korea National Health Insurance Service-National Health Information Database (NHIS-NHID). Among 16,671 patients diagnosed with HIV infection from 2004 to 2020 in Korea, we identified 757 patients newly diagnosed with cancer after HIV diagnosis. The medical costs for 60 months after diagnosis and the last six months before death were calculated from 2006 to 2020. The mean annual medical cost due to cancer in HIV-infected people with cancer was higher for acquired immunodeficiency syndrome (AIDS)-defining cancers (48,242 USD) than for non-AIDS-defining cancers (24,338 USD), particularly non-Hodgkin's lymphoma (53,007 USD), for the first year of cancer diagnosis. Approximately 25% of the cost for the first year was disbursed during the first month of cancer diagnosis. From the second year, the mean annual medical cost due to cancer was significantly reduced. The total medical cost was higher for non-AIDS-defining cancers, reflecting their higher incidence rates despite lower mean medical costs. The mean monthly total medical cost per HIV-infected person who died after cancer diagnosis increased closer to the time of death. The estimated burden of medical costs in patients with HIV in the present study may be an important index for defining healthcare policies in HIV patients in whom the cancer-related burden is expected to increase.

Molecular mechanisms of the virulence and efficacy of a highly virulent Vibrio anguillarum strain and its formalin-inactivated vaccine in rainbow trout.

In this study, we have isolated four strains of Vibrio anguillarum, revealing that they share the same serotype of O1, biochemical characteristics and virulence factor genes. However, there were differences in haemolytic activity among the bacterial strains; a strain with lower pathogenicity showed γ-haemolytic activity, whereas other virulent strains showed α-haemolytic activity on blood agar and higher empA gene expression in RTG-2 cell line. The most virulent strain was V. anguillarum RTBHR from diseased masu salmon (Oncorhynchus masou), which resulted in mortality of 100% and 93.3% when injected intraperitoneally at concentrations of 9 × 105 and 6.3 × 105 colony-forming units/fish in rainbow trout (Oncorhynchus mykiss) and Coho salmon (Oncorhynchus kisutch), respectively. A formalin-inactivated vaccine of V. anguillarum RTBHR induced a protective and specific immunity in rainbow trout as the vaccinated fish exhibited low cumulative mortality in a challenge test and a high specific antibody response in enzyme-linked immunosorbent assay at 8 weeks post-vaccination. The produced antibody was bound to bacterial proteins of 30-37 kDa in size. This adaptive immune response was detected as early as day 1, with quantitative polymerase chain reaction analysis revealing the upregulated expression of genes encoding for TCRα, T-bet, mIgM and sIgM in rainbow trout. This suggested that the vaccine induced T (probably a more dominant Th1 response) and B cell responses. In conclusion, the vaccine successfully protected fish from V. anguillarum infection by eliciting cellular and humoral immune responses.

Association between Obesity Indexes and Thyroid Cancer Risk in Korean Women: Nested Case-Control Study.

Objective: This study aimed to identify the association between various obesity indexes, including waist circumference (WC), waist−hip ratio (WHR), waist−height ratio (WHTR), and BMI, and their combinations with body mass index (BMI) and thyroid cancer risk. Methods: Of the 65,639 participants who completed a follow-up survey of the Health Examinee Study (HEXA), a prospective cohort of the Korean Genome and Epidemiology Study, 412 female incident thyroid cancer cases, and 1648 birth year- and enrollment year-matched female controls were included. Multiple conditional logistic regression was used to estimate the association between obesity indexes and thyroid cancer risk. Results: The risk of developing thyroid cancer was increased by 1.37-fold (95% confidence interval (CI) = 1.03−1.81) higher in the obese BMI group (≥25.0 Kg/m2) compared to that in the normal BMI group (<23.0 Kg/m2). Obesity in terms of WC (≥85.0 cm) and WHTR (≥0.5) was associated with an increased risk of thyroid cancer (OR 1.55, 95% CI = 1.16−2.07; OR 1.37, 95% CI = 1.07−1.75, respectively). However, increased WHR levels did not show any significant association. Women with both obese levels of BMI (≥25.0 Kg/m2) and other obesity indexes (WC ≥ 85.0 cm, WHR ≥ 0.85, or WHTR ≥ 0.5) showed an increased risk of thyroid cancer with OR of 1.63 (95% CI = 1.14−2.31), 1.49 (95% CI = 1.05−2.12), and 1.42 (95% CI = 1.04−1.94), compared to those with normal levels of BMI and each obesity index. Conclusion: These results provide evidence of the contribution of both total and central adiposity across the lifespan of thyroid cancer incidence. Risk factor modifications must be considered to explain the current thyroid cancer epidemic.

Clinical Characteristics of Macrolide-Refractory Mycoplasma pneumoniae Pneumonia in Korean Children: A Multicenter Retrospective Study.

Mycoplasma pneumoniae is a major causative pathogen of community-acquired pneumonia in children, and the treatment of choice is macrolides. There is an increasing trend in reports of refractory clinical responses despite macrolide treatment due to the emergence of macrolide-resistant M. pneumoniae. Early discrimination of macrolide-refractory M. pneumoniae pneumonia (MrMP) from macrolide-sensitive M. pneumoniae pneumonia (MSMP) is vital; however, testing for macrolide susceptibility at the time of admission is not feasible. This study aimed to identify the characteristics of MrMP in Korean children, in comparison with those of MSMP. In this multicenter study, board-certified pediatric pulmonologists at 22 tertiary hospitals reviewed the medical records from 2010 to 2015 of 5294 children who were hospitalized with M. pneumoniae pneumonia and administered macrolides as the initial treatment. One-way analysis of variance and the Kruskal-Wallis test were used to compare differences between groups. Of 5294 patients (mean age, 5.6 years) included in this analysis, 240 (4.5%), 925 (17.5%), and 4129 (78.0%) had MrMP, macrolide-less effective M. pneumoniae pneumonia, and MSMP, respectively. Compared with the MSMP group, the MrMP group had a longer fever duration, overall (13.0 days) and after macrolide use (8.0 days). A higher proportion of MrMP patients had respiratory distress, pleural effusion, and lobar pneumonia. The mean aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and C-reactive protein levels were the highest in the MrMP group, along with higher incidences of extrapulmonary manifestations and atelectasis (during and post infection). Pre-existing conditions were present in 17.4% (n = 725/4159) of patients, with asthma being the most common (n = 334/4811, 6.9%). This study verified that MrMP patients show more severe initial radiographic findings and clinical courses than MSMP patients. MrMP should be promptly managed by agents other than macrolides.

From Cells to Organs: The Present and Future of Regenerative Medicine.

Regenerative medicine promises a bright future where damaged body parts can be restored, rejuvenated, and replaced. The application of regenerative medicine is interdisciplinary and covers nearly all fields of medical sciences and molecular engineering. This review provides a road map on how regenerative medicine is applied on the levels of cell, tissue, and organ and summarizes the advantages and limitation of human pluripotent stem cells in disease modeling and regenerative application.

The age-standardized incidence, mortality, and case fatality rates of COVID-19 in 79 countries: a cross-sectional comparison and their correlations with associated factors.

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, crude incidence and mortality rates have been widely reported; however, age-standardized rates are more suitable for comparisons. In this study, we estimated and compared the age-standardized incidence, mortality, and case fatality rates (CFRs) among countries and investigated the relationship between these rates and factors associated with healthcare resources: gross domestic product per capita, number of hospital beds per population, and number of doctors per population. METHODS: The incidence, mortality, and CFRs of 79 countries were age-standardized using the World Health Organization standard population. The rates for persons 60 years or older were also calculated. The relationships among the rates were analysed using trend lines and coefficients of determination (R2). Pearson correlation coefficients between the rates and the healthcare resource-related factors were calculated. RESULTS: The countries with the highest age-standardized incidence, mortality, and CFRs were Czechia (14,253 cases/100,000), Mexico (182 deaths/100,000), and Mexico (6.7%), respectively. The R2 between the incidence and mortality rates was 0.852 for all ages and 0.945 for those 60 years or older. The healthcare resources-related factors were associated positively with incidence rates and negatively with CFRs, with weaker correlations among the elderly. CONCLUSIONS: Compared to age-standardized rates, crude rates showed greater variation among countries. Medical resources may be important in preventing COVID-19-related deaths; however, considering the small variation in fatality among the elderly, preventive measures such as vaccination are more important, especially for the elderly population, to minimize the mortality rates.

Prenatal and postnatal exposures to four metals mixture and IQ in 6-year-old children: A prospective cohort study in South Korea.

BACKGROUND: Humans are exposed to a mixture of metals during their lifetime; however, evidence of neurotoxicity of such mixtures in critical time windows is still insufficient. We aimed to elucidate the associations of four metals mixture across multiple time points with children's intelligence quotient (IQ) in a prospective cohort study. METHODS: Prenatal exposure and exposure at age 4 and 6 years to four types of blood metals, namely lead, mercury, cadmium, and manganese were quantified in 502 pregnant women and their children who participated in the Environment and Development Cohort study. Children' s IQ scores were assessed using the Wechsler Intelligence Scale at age 6. Bayesian kernel machine regression (BKMR), quantile g-computation models, and elastic net (ENET) models were used to assess the associations of their blood metals mixture with IQ scores. RESULTS: Multivariate linear regression models indicated that postnatal blood manganese exposure at the age of 4 years was significantly negatively associated with children's IQ [ß =  - 5.99, 95% confidence interval (CI): -11.37 to - 0.61]. In the multi-chemical BKMR and quantile g-computation model, statistically significant inverse associations were found between the mixture of prenatal and postnatal metals and children's IQ score (Difference in children' IQ per quartile increase: -2.83; 95% CI: -5.28, -0.38). Interestingly, we found that manganese levels at both age of 4 and 6 years were contributing factors to children's IQ in the mixture models, namely, BKMR, quantile g-computation, and ENET models. CONCLUSIONS: Multi-pollutant mixtures of prenatal and postnatal exposures to four metals affected child IQ at 6 years of age. We found a relationship between manganese exposure at both age 4, and 6 years and children's IQ. Additional studies are warranted to confirm these associations and to control the exposure to different metals during pregnancy and preschool childhood.

Particulate air pollution and survival after stroke in older adults: A retrospective cohort study in Korea.

Although many studies have evaluated the effects of ambient particulate matter with diameters of less than 2.5 µm (PM2.5) on stroke mortality in the general population, little is known about the mortality effects of PM2.5 in post-stroke populations. Therefore, a retrospective cohort was constructed using information from the health insurance database to evaluate whether exposure to PM2.5 is associated with increased mortality in aged stroke survivors residing in seven Korean metropolitan cities. A total of 45,513 older adults (≥65 years) who visited emergency rooms due to stroke and who were discharged alive between 2008 and 2016 were followed up. By using district-level modeled PM2.5 concentrations and a time-varying Cox proportional hazard model, associations between 1-month and 2-month moving average PM2.5 exposures and mortality in stroke survivors were evaluated. The annual average concentration of PM2.5 was 27.9 µg/m3 in the seven metropolitan cities, and 14,880 subjects died during the follow-up period. A 10 µg/m3 increase in the 1-month and 2-month moving average PM2.5 exposures was associated with mortality hazard ratios of 1.07 (95% confidence interval: 1.05, 1.09) and 1.06 (95% confidence interval: 1.03, 1.08), respectively. The effects of PM2.5 were similar across types of stroke (ischemic and hemorrhagic), age groups (65-74, 75-84, and ≥85), and income groups (low and high) but were greater in women than in men. This study highlights the adverse health effects of ambient PM2.5 in post-stroke populations. Active avoidance behaviors against PM2.5 are recommended for aged stroke survivors.

Association between weekly fruit and vegetable consumption and depressive symptoms: results from the Korean Elderly Environmental Panel study.

OBJECTIVES: Although previous studies have investigated the correlation between fruit and vegetable consumption and depression, the results remain inconclusive. The present study aimed to investigate the association between weekly fruit and vegetable consumption and depressive symptoms in elderly Koreans. METHODS: A multiple covariate linear regression analysis was performed using the data of 1,226 elderly individuals ≥ 60 years of age who participated in the Korean Elderly Environmental Panel II study from 2012 to 2014. Depressive symptoms were evaluated using the Korean version of the Short form Geriatric Depression Scale (SGDS-K). Generalized linear mixed-effects models were constructed to analyze the repeated measurements of 305 people who participated in the survey every year. RESULTS: After adjusting for confounders, SGDS-K scores were negatively associated with the frequency of weekly fruit consumption as follows (ß [95% confidence interval; CI]: -0.17 [-0.28 to -0.05], -0.17 [-0.27 to -0.07], -0.42 [-0.54 to 0.29], and -0.33 [-0.44 to -0.21]) for less than 1 time/wk, 1-3 times/wk, 4-6 times/wk, and daily, respectively, compared to no consumption. The SGDS-K scores were also negatively associated with the frequency of vegetable consumption (ß [95% CI]: -0.86 [-1.18 to -0.55], -0.18 [-0.35 to -0.01], -0.36 [-0.53 to -0.18], and -0.15 [-0.29 to 0.00]) in the above order, respectively. CONCLUSIONS: Fruit consumption was inversely associated with depression levels in a dose-dependent manner. Although there was no dose-response relationship between vegetable consumption and the level of depression, it was negatively associated with SGDS-K scores.

Types of COVID-19 clusters and their relationship with social distancing in the Seoul metropolitan area, South Korea.

BACKGROUND: The complete contact tracing of coronavirus disease-19 (COVID-19) cases in South Korea allows a unique opportunity to investigate cluster characteristics. This study aimed to investigate all reported COVID-19 clusters in the Seoul metropolitan area from January 23 to September 24, 2020. METHODS: Publicly available COVID-19 data was collected from the Seoul Metropolitan City and Gyeonggi Province. Community clusters with ≥5 cases were characterized by size and duration, categorized using K-means clustering, and the correlation between the types of clusters and the level of social distancing investigated. RESULTS: A total of 134 clusters comprised of 4033 cases were identified. The clusters were categorized into small (type I and II), medium (type III), and large (type IV) clusters. A comparable number of daily reported cases in different time periods were composed of different types of clusters. Increased social distancing was related to a shift from large to small-sized clusters. CONCLUSIONS: Classification of clusters may provide opportunities to understand the pattern of COVID-19 outbreaks better and implement more effective suppression strategies. Social distancing administered by the government may effectively suppress large clusters but may not effectively control small and sporadic clusters.

Associations Between Thyroid Hormone Levels and Urinary Concentrations of Bisphenol A, F, and S in 6-Year-old Children in Korea.

OBJECTIVES: Bisphenol A (BPA) is used in the electrical, mechanical, medical, and food industries. Previous studies have suggested that BPA is an endocrine disruptor. Regulation of BPA has led to increased use of bisphenol F (BPF) and bisphenol S (BPS). However, few studies have investigated the associations of BPF and BPS with thyroid dysfunction in children. Our study investigated the associations of prenatal BPA and early childhood BPA, BPF, and BPS exposure with thyroid function in 6-year-old children. METHODS: Prenatal BPA concentrations were measured during the second trimester of pregnancy in an established prospective birth cohort. We measured urinary BPA, BPF, and BPS concentrations and thyroid hormone levels (thyroid-stimulating hormone, total T3, and free T4) in 6-year-old children (n=574). We examined the associations between urinary bisphenol concentrations and percentage change of thyroid hormone concentrations using multivariate linear regression. We also compared thyroid hormone levels by dividing the cohort according to BPA, BPF, and BPS concentrations. RESULTS: The associations between prenatal BPA and total T3 levels were statistically significant in all models, except for girls when using a crude model. The associations between urinary BPA and BPS concentrations and levels of all thyroid hormones were not statistically significant. However, we observed that lower free T4 levels (-1.94%; 95% confidence interval, -3.82 to -0.03) were associated with higher urinary BPF concentrations in girls only. CONCLUSIONS: Our findings identified significant associations between prenatal BPA exposure and total T3 levels in all children and between BPF exposure and free T4 levels in girls only.

Convergence of human pluripotent stem cell, organoid, and genome editing technologies.

The last decade has seen many exciting technological breakthroughs that greatly expanded the toolboxes for biological and biomedical research, yet few have had more impact than induced pluripotent stem cells and modern-day genome editing. These technologies are providing unprecedented opportunities to improve physiological relevance of experimental models, further our understanding of developmental processes, and develop novel therapies. One of the research areas that benefit greatly from these technological advances is the three-dimensional human organoid culture systems that resemble human tissues morphologically and physiologically. Here we summarize the development of human pluripotent stem cells and their differentiation through organoid formation. We further discuss how genetic modifications, genome editing in particular, were applied to answer basic biological and biomedical questions using organoid cultures of both somatic and pluripotent stem cell origins. Finally, we discuss the potential challenges of applying human pluripotent stem cell and organoid technologies for safety and efficiency evaluation of emerging genome editing tools.

Associations between surrounding residential greenness and intelligence quotient in 6-year-old children.

BACKGROUND: Residential greenness has been reported to be positively associated with health benefits for children, including improved cognitive function. We investigated the association between the intelligence quotient (IQ) of 6-year-old children in Seoul, South Korea and surrounding greenness currently and during the mothers' pregnancy. We also analyzed whether these effects differed by the type of greenness, such as natural or built greenness. METHODS: This study considered 189 mother-child dyads from the Environment and Development of Children Cohort study, who lived in Seoul during the prenatal period and when the child was 6 years old. We defined surrounding greenness using Landsat image data from Korean Arirang satellite images with buffers within 100 m - 2000 m of the radius of each participant's residential address. We separately analyzed two types of greenness, namely natural and built greenness. The children's IQ (total, verbal, and performance IQ) was measured using the Korean Educational Developmental Institute's Wechsler Intelligence Scale for Children. RESULTS: Prenatal exposure to built greenness in 500 m and 1000 m buffers was associated with children's total IQ in a full model [difference in IQ (95% CI): 3.46(0.68, 6.24) and 3.42 (0.53, 6.31) per interquartile increase in proportion of greenness]. However, postnatal exposure to built greenness in all buffers was associated in children's total IQ. We found a stronger association between children's total IQ and built greenness rather than natural greenness. CONCLUSIONS: We found that 6-year-old children tended to score higher on total IQ if they lived in greener neighborhoods. The results provide further evidence of the health benefits of greenness and provide support for urban planning and public health to build healthy urban cities for children and pregnant women.

Long-term exposure to moderate fine particulate matter concentrations and cause-specific mortality in an ageing society.

BACKGROUND: Long-term exposure to particulate matter <2.5 µm in size (PM2.5) is considered a risk factor for premature death. However, only a few studies have been conducted in areas with moderate PM2.5 concentrations. Moreover, an ageing society may be more susceptible to environmental exposure and future burden of mortality due to PM2.5. METHODS: This study estimates hazard ratios (HRs) for all-cause and cause-specific mortality from long-term exposure to moderate PM2.5 concentrations in the elderly populations of seven cities in South Korea. We also projected nationwide elderly mortality caused by long-term exposure to PM2.5, accounting for population ageing until 2045. Mortality in 1 720 230 elderly adults aged ≥65 years in 2008 was monitored across 2009-16 and linked to modelled PM2.5 concentrations. RESULTS: A total of 421 100 deaths occurred in 2009-16, and the mean of annual PM2.5 concentration ranged between 21.1 and 31.9 µg/m3 in most regions. The overall HR for a 10 µg/m3 increase in a 36-month PM2.5 moving average was 1.024 (95% confidence intervals: 1.009, 1.039). We estimated that 11 833 all-cause nationwide elderly deaths were attributable to PM2.5 exposure. Annual death tolls may increase to 17 948 by 2045. However, if PM2.5 is reduced to 5 µg/m3 by 2045, the tolls may show a lower increase to 3646. CONCLUSIONS: Long-term exposure to moderately high levels of PM2.5 was associated with increased mortality risk among the elderly. Thus, PM2.5 reduction in response to the projected ageing-associated mortality in South Korea is critical.

Short-Term Exposure to Fine Particulate Matter and Hospitalizations for Acute Lower Respiratory Infection in Korean Children: A Time-Series Study in Seven Metropolitan Cities.

Although several studies have evaluated the association between fine particulate matter (PM2.5) and acute lower respiratory infection (ALRI) in children, their results were inconsistent Therefore, we aimed to evaluate the association between short-term exposure to PM2.5 and ALRI hospitalizations in children (0-5 years) living in seven metropolitan cities of Korea. The ALRI hospitalization data of children living in seven metropolitan cities of Korea from 2008 to 2016 was acquired from a customized database constructed based on National Health Insurance data. The time-series data in a generalized additive model were used to evaluate the relationship between ALRI hospitalization and 7-day moving average PM2.5 exposure after adjusting for apparent temperature, day of the week, and time trends. We performed a meta-analysis using a two-stage design method. The estimates for each city were pooled to generate an average estimate of the associations. The average PM2.5 concentration in 7 metropolitan cities was 29.0 µg/m3 and a total of 713,588 ALRI hospitalizations were observed during the 9-year study period. A strong linear association was observed between PM2.5 and ALRI hospitalization. A 10 µg/m3 increase in the 7-day moving average of PM2.5 was associated with a 1.20% (95% CI: 0.71, 1.71) increase in ALRI hospitalization. While we found similar estimates in a stratified analysis by sex, we observed stronger estimates of the association in the warm season (1.71%, 95% CI: 0.94, 2.48) compared to the cold season (0.31%, 95% CI: -0.51, 1.13). In the two-pollutant models, the PM2.5 effect adjusted by SO2 was attenuated more than in the single pollutant model. Our results suggest a positive association between PM2.5 exposure and ALRI hospitalizations in Korean children, particularly in the warm season. The children need to refrain from going out on days when PM2.5 is high.

A comparison of hepato-cellular in vitro platforms to study CYP3A4 induction.

In vitro studies of drug toxicity and drug-drug interactions are crucial for drug development efforts. Currently, the utilization of primary human hepatocytes (PHHs) is the de facto standard for this purpose, due to their functional xenobiotic response and drug metabolizing CYP450 enzyme metabolism. However, PHHs are scarce, expensive, require laborious maintenance, and exhibit lot-to-lot heterogeneity. Alternative human in vitro platforms include hepatic cell lines, which are easy to access and maintain, and induced pluripotent stem cell (iPSC) derived hepatocytes. In this study, we provide a direct comparison of drug induced CYP3A4 and PXR expression levels of PHHs, hepatic cell lines Huh7 and HepG2, and iPSC derived hepatocyte like cells. Confluently cultured Huh7s exhibited an improved CYP3A4 expression and were inducible by up to 4.9-fold, and hepatocytes differentiated from human iPSCs displayed a 3.3-fold CYP3A4 induction. In addition, an increase in PXR expression levels was observed in both hepatic cell lines and iPSC derived hepatocytes upon rifampicin treatment, whereas a reproducible increase in PXR expression was not achieved in PHHs. Our results indicate that both hepatoma originated cell lines and iPSCs may provide alternative sources to primary hepatocytes, providing reliable and reproducible results for CYP3A4/PXR metabolism, upon in vitro maturation. This study may serve as a guide for the selection of suitable and feasible in vitro platforms for drug-drug interaction and toxicology studies.

The Effect of Prenatal Cadmium Exposure on Attention-deficit/Hyperactivity Disorder in 6-Year-old Children in Korea.

OBJECTIVES: Prenatal cadmium (Cd) exposure may be associated with attention-deficit/hyperactivity disorder (ADHD) in children. Therefore, the objective of this study was to examine the relationship between Cd exposure during gestation and ADHD at 6 years of age. METHODS: As part of an ongoing cohort study (the Environment and Development of Children study), 479 mother-child pairs from Seoul, Korea were included for analysis between 2008 and 2011. The whole blood concentration of Cd was analyzed using atomic absorption spectrophotometry. The parents were surveyed about ADHD behaviors in their children at age 6. Multivariable linear regression models were used to investigate the relationship between prenatal exposure to Cd and ADHD at 6 years of age. RESULTS: Increased prenatal Cd concentrations were associated with increased scores for ADHD for girls, but not for boys, at age 6. A 2-fold increase in the prenatal Cd level was significantly associated with a 22.3% (95% confidence interval, 11.6 to 34.1) increase in ADHD in girls at 6 years of age, as indicated by the linear regression model. CONCLUSIONS: Our results identified significant associations between prenatal Cd exposure and ADHD scores in 6-year-old girls.

Annual and seasonal patterns in etiologies of pediatric community-acquired pneumonia due to respiratory viruses and Mycoplasma pneumoniae requiring hospitalization in South Korea.

BACKGROUND: Community-acquired pneumonia (CAP) is one of the leading worldwide causes of childhood morbidity and mortality. Its disease burden varies by age and etiology and is time dependent. We aimed to investigate the annual and seasonal patterns in etiologies of pediatric CAP requiring hospitalization. METHODS: We conducted a retrospective study in 30,994 children (aged 0-18 years) with CAP between 2010 and 2015 at 23 nationwide hospitals in South Korea. Mycoplasma pneumoniae (MP) pneumonia was clinically classified as macrolide-sensitive MP, macrolide-less effective MP (MLEP), and macrolide-refractory MP (MRMP) based on fever duration after initiation of macrolide treatment, regardless of the results of in vitro macrolide sensitivity tests. RESULTS: MP and respiratory syncytial virus (RSV) were the two most commonly identified pathogens of CAP. With the two epidemics of MP pneumonia (2011 and 2015), the rates of clinical MLEP and MRMP pneumonia showed increasing trends of 36.4% of the total MP pneumonia. In children < 2 years of age, RSV (34.0%) was the most common cause of CAP, followed by MP (9.4%); however, MP was the most common cause of CAP in children aged 2-18 years of age (45.3%). Systemic corticosteroid was most commonly administered for MP pneumonia. The rate of hospitalization in intensive care units was the highest for RSV pneumonia, and ventilator care was most commonly needed in cases of adenovirus pneumonia. CONCLUSIONS: The present study provides fundamental data to establish public health policies to decrease the disease burden due to CAP and improve pediatric health.

Targeting specificity of APOBEC-based cytosine base editor in human iPSCs determined by whole genome sequencing.

DNA base editors have enabled genome editing without generating DNA double strand breaks. The applications of this technology have been reported in a variety of animal and plant systems, however, their editing specificity in human stem cells has not been studied by unbiased genome-wide analysis. Here we investigate the fidelity of cytidine deaminase-mediated base editing in human induced pluripotent stem cells (iPSCs) by whole genome sequencing after sustained or transient base editor expression. While base-edited iPSC clones without significant off-target modifications are identified, this study also reveals the potential of APOBEC-based base editors in inducing unintended point mutations outside of likely in silico-predicted CRISPR-Cas9 off-targets. The majority of the off-target mutations are C:G->T:A transitions or C:G->G:C transversions enriched for the APOBEC mutagenesis signature. These results demonstrate that cytosine base editor-mediated editing may result in unintended genetic modifications with distinct patterns from that of the conventional CRISPR-Cas nucleases.