Measuring disease burden of dominant variants of COVID-19 in Taiwan.

Objectives: The disability-adjusted life years (DALYs) of COVID-19 have been applied as a time-based measurement to estimate years of life lost due to premature mortality or healthy life lost in different countries. Limited information was found for DALYs among different variants of concern (VOC). Methods: Disease severities based on categories of asymptomatic, mild, moderate, severe, and critical cases were explored among different VOC by analyzing the proportions in confirmed cases. DALY or years of healthy life lost due to disability (YLD)-based annual burdens of COVID-19 on different ages, genders as well as trend analysis were also evaluated for VOC in Taiwan. Results: Different trends were observed in years of life lost due to premature mortality (YLLs) or YLD for various age or gender categories. Disease severity at critical stage had the highest percentage for overall YLDs encompassed from 2020 to 2022. Also, critical-grade cases were found to be predominantly caused by Wild-type, Alpha, and Omicron variants in 2020, 2021, and 2022, respectively. Conclusion: Precautionary measures are also suggested for policy makers to take in specific seasons, age or gender groups based on YLL and YLD analyses.

The association between plasma angiopoietin-like protein 4, glucose and lipid metabolism during pregnancy, placental function, and risk of delivering large-for-gestational-age neonates.

BACKGROUND: Large-for-gestational-age (LGA) neonates have increased risk of adverse pregnancy outcomes and adult metabolic diseases. We aimed to investigate the relationship between plasma angiopoietin-like protein 4 (ANGPTL4), a protein involved in lipid and glucose metabolism during pregnancy, placental function, growth factors, and the risk of LGA. METHODS: We conducted a prospective cohort study and recruited women with singleton pregnancies at the National Taiwan University Hospital between 2013 and 2018. First trimester maternal plasma ANGPTL4 concentrations were measured. RESULTS: Among 353 pregnant women recruited, the LGA group had higher first trimester plasma ANGPTL4 concentrations than the appropriate-for-gestational-age group. Plasma ANGPTL4 was associated with hemoglobin A1c, post-load plasma glucose, plasma triglyceride, plasma free fatty acid concentrations, plasma growth hormone variant (GH-V), and birth weight, but was not associated with cord blood growth factors. After adjusting for age, body mass index, hemoglobin A1c, and plasma triglyceride concentrations, plasma ANGPTL4 concentrations were significantly associated with LGA risk, and its predictive performance, as measured by the area under the receiver operating characteristic curve, outperformed traditional risk factors for LGA. CONCLUSIONS: Plasma ANGPTL4 is associated with glucose and lipid metabolism during pregnancy, plasma GH-V, and birth weight, and is an early biomarker for predicting the risk of LGA.

Advanced maternal age-related clustering of metabolic abnormalities is associated with risks of adverse pregnancy outcomes.

AIMS: Advanced maternal age (AMA) is correlated with higher risk of adverse pregnancy outcomes while the pathophysiology remains unclear. Our study aimed to investigate whether AMA is linked to the clustering of metabolic abnormalities, which in turn is associated with an increased risk of adverse pregnancy outcomes. METHOD: A total of 857 pregnant woman were recruited in a prospective cohort at National Taiwan University Hospital, from November 2013 to April 2018. Metabolic abnormalities during pregnancy were defined as following: fasting plasma glucose ≥92 mg/dl, body mass index (BMI) ≥24 kg/m2, plasma high-density lipoprotein cholesterol <50 mg/dl, hyper-triglyceridemia (≥140 mg/dl in the first trimester or ≥220 mg/dl in the second trimester), and blood pressure ≥130/85 mmHg. RESULT: Incidence of large for gestational age (LGA), primary caesarean section (CS), and the presence of any adverse pregnancy outcome increased with age. The advanced-age group tended to have more metabolic abnormalities in both the first and the second trimesters. There was a significant association between the number of metabolic abnormalities in the first and the second trimesters and the incidence of LGA, gestational hypertension or preeclampsia, primary CS, preterm birth, and the presence of any adverse pregnancy outcome, adjusted for maternal age. CONCLUSION: AMA is associated with clustering of metabolic abnormalities during pregnancy, and clustering of metabolic abnormalities is correlated with increased risk of adverse pregnancy outcomes.

L1cam alternative shorter transcripts encoding the extracellular domains were overexpressed in the intestine of L1cam knockdown mice.

Hirschsprung disease (HSCR) is a congenital disorder of functional bowel obstruction due to the absence of enteric ganglia in distal bowel. Different L1cam variants were reportedly associated with L1cam syndrome and HSCR, whose phenotypes lacked predictable relevance to their genotypes. Using next-generation sequencing (NGS), we found an L1CAM de novo frameshift mutation in a female with mild hydrocephalus and skip-type HSCR. A nearly identical L1cam variant was introduced into FVB/NJ mice via the CRISPR-EZ method. A silent mutation was created via ssODN to gain an artificial Ncol restriction enzyme site for easier genotyping. Six L1cam protein-coding alternative transcripts were quantitatively measured. Immunofluorescence staining with polyclonal and monoclonal L1cam antibodies was used to characterize L1cam isoform proteins in enteric ganglia. Fifteen mice, seven males and eight females, generated via CRISPR-EZ, were confirmed to carry the L1cam frameshift variant, resulting in a premature stop codon. There was no prominent hydrocephalus nor HSCR-like presentation in these mice, but male infertility was noticed after observation for three generations in a total of 176 mice. Full-length L1cam transcripts were detected at a very low level in the intestinal tissues and almost none in the brain of these mice. Alternative shorter transcripts encoding the extracellular domains were overexpressed in the intestine of L1cam knockdown mice. Immunofluorescence confirmed no fulllength L1cam protein in enteric ganglia. These shorter L1cam isoform proteins might play a role in protecting L1cam knockdown mice from HSCR.

Disease burden due to COVID-19 in Taiwan: Disability-adjusted life years (DALYs) with implication of Monte Carlo simulations.

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) has affected a large number of countries. Informing the public and decision makers of the COVID-19's economic burdens is essential for understanding the real pandemic impact. METHODS: COVID-19 premature mortality and disability impact in Taiwan was analyzed using the Taiwan National Infectious Disease Statistics System (TNIDSS) by estimating the sex/age-specific years of life lost through death (YLLs), the number of years lived with disability (YLDs), and the disability-adjusted life years (DALYs) from January 2020 to November 2021. RESULTS: Taiwan recorded 1004.13 DALYs (95% CI: 1002.75-1005.61) per 100,000 population for COVID-19, with YLLs accounting for 99.5% (95% CI: 99.3%99.6%) of all DALYs, with males suffering more from the disease than females. For population aged ≥ 70 years, the disease burdens of YLDs and YLLs were 0.1% and 99.9%, respectively. Furthermore, we found that duration of disease in critical state contributed 63.9% of the variance in DALY estimations. CONCLUSIONS: The nationwide estimation of DALYs in Taiwan provides insights into the demographic distributions and key epidemiological parameter for DALYs. The essentiality of enforcing protective precautions when needed is also implicated. The higher YLLs percentage in DALYs also revealed the fact of high confirmed death rates in Taiwan. To reduce infection risks and disease, it is crucial to maintain moderate social distancing, border control, hygiene measures, and increase vaccine coverage levels.

Dengue Meteorological Determinants during Epidemic and Non-Epidemic Periods in Taiwan.

The identification of the key factors influencing dengue occurrence is critical for a successful response to the outbreak. It was interesting to consider possible differences in meteorological factors affecting dengue incidence during epidemic and non-epidemic periods. In this study, the overall correlation between weekly dengue incidence rates and meteorological variables were conducted in southern Taiwan (Tainan and Kaohsiung cities) from 2007 to 2017. The lagged-time Poisson regression analysis based on generalized estimating equation (GEE) was also performed. This study found that the best-fitting Poisson models with the smallest QICu values to characterize the relationships between dengue fever cases and meteorological factors in Tainan (QICu = −8.49 × 10−3) and Kaohsiung (−3116.30) for epidemic periods, respectively. During dengue epidemics, the maximum temperature with 2-month lag (ß = 0.8400, p < 0.001) and minimum temperature with 5-month lag (0.3832, p < 0.001). During non-epidemic periods, the minimum temperature with 3-month lag (0.1737, p < 0.001) and mean temperature with 2-month lag (2.6743, p < 0.001) had a positive effect on dengue incidence in Tainan and Kaohsiung, respectively.

Image and Speech Recognition Technology in the Development of an Elderly Care Robot: Practical Issues Review and Improvement Strategies.

As the world's population is aging and there is a shortage of sufficient caring manpower, the development of intelligent care robots is a feasible solution. At present, plenty of care robots have been developed, but humanized care robots that can suitably respond to the individual behaviors of elderly people, such as pose, expression, gaze, and speech are generally lacking. To achieve the interaction, the main objectives of this study are: (1) conducting a literature review and analyzing the status quo on the following four core tasks of image and speech recognition technology: human pose recognition, human facial expression recognition, eye gazing recognition, and Chinese speech recognition; (2) proposing improvement strategies for these tasks based on the results of the literature review. The results of the study on these improvement strategies will provide the basis for using human facial expression robots in elderly care.

Demographic Control Measure Implications of Tuberculosis Infection for Migrant Workers across Taiwan Regions.

A sharp increase in migrant workers has raised concerns for TB epidemics, yet optimal TB control strategies remain unclear in Taiwan regions. This study assessed intervention efforts on reducing tuberculosis (TB) infection among migrant workers. We performed large-scale data analyses and used them to develop a control-based migrant worker-associated susceptible-latently infected-infectious-recovered (SLTR) model. We used the SLTR model to assess potential intervention strategies such as social distancing, early screening, and directly observed treatment, short-course (DOTS) for TB transmission among migrant workers and locals in three major hotspot cities from 2018 to 2023. We showed that social distancing was the best single strategy, while the best dual measure was social distancing coupled with early screening. However, the effectiveness of the triple strategy was marginally (1-3%) better than that of the dual measure. Our study provides a mechanistic framework to facilitate understanding of TB transmission dynamics between locals and migrant workers and to recommend better prevention strategies in anticipation of achieving WHO's milestones by the next decade. Our work has implications for migrant worker-associated TB infection prevention on a global scale and provides a knowledge base for exploring how outcomes can be best implemented by alternative control measure approaches.

Gestational hypertriglyceridemia and adverse pregnancy outcomes: A search for cutoffs using generalized additive models.

OBJECTIVE: To explore cutoffs of gestational hypertriglyceridemia based on the risk of adverse pregnancy outcomes. METHODS: Pregnant women who visited National Taiwan University Hospital for prenatal care were included. Fasting plasma TG in the first and second trimesters were measured. Adverse pregnancy outcomes, including gestational diabetes and large for gestational age, were recorded and used in simple and multiple generalized additive models (GAM) to identify cutoffs for gestational hypertriglyceridemia. RESULTS: We recruited 807 pregnant woman-newborn pairs. Using GAM analyses, we identified plasma TG at 95 or 140 mg/dL (1.07 or 1.58 mmol/L) in the first trimester, and 173 or 220 mg/dl (1.95 or 2.48 mmol/L) in the second trimester as potential cutoffs. Gestational hypertriglyceridemia defined by the higher cutoffs in both trimesters were associated with adverse pregnancy outcomes and had a more reasonable prevalence and better specificity than the lower cutoffs (First trimester plasma TG ≥ 140 mg/dL, adjusted OR 2.56, 95% CI 1.17-5.69, p = 0.019, prevalence 19%, specificity 83%; Second trimester plasma TG ≥ 220 mg/dL, adjusted OR 1.70, 95% CI 1.00-2.87, p = 0.049, prevalence 19%, specificity 81%). CONCLUSIONS: Fasting plasma TG ≥ 140 mg/dL in the first trimester and ≥ 220 mg/dL in the second trimester can be used as cutoffs of gestational hypertriglyceridemia.

Probabilistic Risk Analysis to Assess Dietary Exposure to Aluminum in the Taiwanese Population.

Aluminum (Al) exposure at human dietary levels raises health concerns, yet little is known about the Al exposure from the Taiwanese diet. The amount of aluminum (Al)-containing food consumption in the Taiwanese total diet is increasing, which contributes to the total diet consumption., which raises the health concerns. In this study, we aim to assess estimated weekly intake (EWI) and the percentage of provisional tolerable weekly intake (%PTWI) of the dietary exposure to Al in different age-sex groups. We also applied probabilistic risk analyses to quantify the parameters' uncertainty by focusing on the distribution function for the Al concentration in food, consumption rate, and body weight in specific age groups. Results indicated that the EWIs declined with increasing age after 6-years old (7-12 > 13-15 > 16-18 > 19-64 > 65+). Results indicated that the EWIs gradually declined after 6-year of age. The EWIs of Al-rich food in cake + waffle, kelp, snacks, and bread contributed 20%, 17%, 17%, and 11%, respectively, to the total EWIs, corresponding with the much higher consumption rates for these four foods. The 75th percentile of EWIs for the children aged 34-6 years had a %PTWI valued at over 100%, indicating a potential risk of Al intake via dietary exposure. Our findings show that there is a concern about the consumption of Al-rich foods for children in Taiwan.

Protective equipment and health education program could benefit students from dust pollution.

In recent years, children living in the downstream of the Choshui River in Taiwan have been exposed to violent dust episodes. For the sake of the health of these children, we aimed to investigate the effectiveness of protective equipment (sand-proof plastic cover and air purifier) installed outside/inside the classrooms on students' pulmonary function and evaluate the health education program for preventing the adverse consequences of exposure to river-dust episodes. Public elementary school students in Yunlin County, which was severely affected by river-dust, were selected as the participants. Study 1 consisted of three-wave follow-up data (801 person-times) in high-/low-dust exposure regions to examine pulmonary function. Study 2 used 147 and 73 students in the high-/low-dust exposure regions, respectively, to establish our health education intervention. Paired t tests, repeated measures ANOVA, and generalized estimating equation were used to analyze the short- and long-term effects. The results showed that the students' pulmonary function in schools that installed protective equipment was improved. The health education (such as the usage of correct masks and our designed PM2.5 full-cover sand-proof clothing) improved the students' cognition and behaviors related to river-dust episodes and yielded both short- and long-term effects. Therefore, we suggest more schools with high-dust exposure to adopt protective equipment and health education program. Our designed PM2.5 full-cover sand-proof clothing can prevent from not only haze but also droplet transmission by infectious diseases such as COVID-19.

Google analytics of a pilot study to characterize the visitor website statistics and implicate for enrollment strategies in Medical University.

BACKGROUND: Taiwan's colleges and universities are struggling to maintain their student enrollment rates owing to the declining fertility rate. Focusing on students in higher education programs, this study aims to analyze online behavioral patterns for university departmental websites and accordingly, suggests response strategies to increase the rate of enrollment. METHODS: We use Google Analytics to examine the websites of two departments in a medical university between February 1 and July 30, 2018. We study website patterns during the study periods for three college admission routes: STARS program, personal applications, and admission through examination and placement. RESULTS: Most website visitors during the three visiting date ranges for the two departments are 18-24 years. The visitor groups are mainly freshmen at the university and their parents. The homepage and Subject Credits, Course Planning, Teacher Lineup, and Certificate of Subjects were the most visited webpages. The overall number of daily page views varied by academic event. CONCLUSIONS: University departments should enhance the presentation of featured courses on their webpage or distinguish course characteristics from those of competing departments in the curriculum to ensure clear market segmentation. In addition, departments should consider examining online data to identify suitable high schools that can be visited to attract potential students and to improve students' willingness to choose their university.

Risks of consuming cadmium-contaminated shellfish under seawater acidification scenario: Estimates of PBPK and benchmark dose.

We aim to assess the risks of renal dysfunction and osteoporosis that is attributed to the seawater acidification caused cadmium (Cd) level increase in human consumed shellfish. A physiology-based pharmacokinetic model was used to estimate Cd concentrations in urine and blood among shellfish-only consumers and among the general population. We used the benchmark dose (BMD) method to determine the threshold limits of Cd in urine for renal dysfunction and in blood for osteoporosis for assessing the human health risk. Our results revealed that seawater acidification could increase the Cd accumulation in shellfish by 10-13% compared to the situations under current pH levels. Under the lower seawater pH level, the daily intake of Cd could increase by 21%-67% among shellfish-only consumers, and by 13%-17% among the general population. Our findings indicated that seawater acidification would lead to a marginal increase in Cd intake among humans in shellfish-only consumers. The results of BMDs of urinary Cd showed that the threshold limits for renal dysfunction at 5% were 3.00 µg g-1 in males and 12.35 µg g-1 in females. For osteoporosis, the estimated BMDs of blood Cd were 7.95 µg L-1 in males and 1.23 µg L-1 in females. These results of the risk of Cd intake showed that the consumption of Cd-contaminated shellfish in the general population is largely unaffected by changes in seawater pH levels. Notably, the potential impact of seawater acidification on renal dysfunction for males in shellfish-only consumers face a 14% increase of risk.

Assessing dietary exposure risk to neonicotinoid residues among preschool children in regions of Taiwan.

Neonicotinoids (NEOs) are a class of pesticides widely used worldwide. This study analyzed post-cooking residues of NEO pesticides and assessed their potential health risks for preschool children (0-6 years old) by conducting a total diet study (TDS). It involved food sampling, preparation, analysis of pesticide residues, estimation of food consumption data, and assessment of food safety risks. Food sampling was conducted between March and June 2015. A total of 128 food samples were obtained from 4 parts of Taiwan. After the food had been prepared, the 128 samples were aggregated into 32 composite food items and the NEO residues analyzed. Acetamiprid had the highest detection rate of the NEO residues (59.4%), and the concentrations ranged from not detected to 80.5 µg/kg. The estimated daily intake (EDI) of NEO residues among preschool children was found to be lower than the adjusted acceptable daily intake (ADI) even for highly exposed groups. The results showed that NEO pesticides were primarily detected in preserved fruits, cherry tomato, rape, bell fruit, and baby bok choy. The main health risk posed by detected NEO residues at high consumption rates for preschool children was attributed to acetamiprid (34.20 %ADI) and imidacloprid (23.69 %ADI), respectively. Therefore, this research implicates that the present level of NEO residues in the diets for preschool children in Taiwan does not exceed 100 %ADI.

Association Between Ambient Air Pollution and Elevated Risk of Tuberculosis Development.

BACKGROUND: Broad-scale evidence has shown the significant association between ambient air pollutants and the development of tuberculosis (TB). However, the impact of air quality on the risk of TB in Taiwan is still poorly understood. OBJECTIVE: To develop a probabilistic integrated population-level risk assessment approach for evaluating the contribution of ambient air pollution exposure to the risk of TB development among different regions of Taiwan. MATERIALS AND METHODS: A Bayesian-based probabilistic risk assessment model was implemented to link exposure concentrations of various air pollutants quantified in a probabilistic manner with the population-based exposure-response models developed by using an epidemiological investigation. RESULTS: The increment of the risk of TB occurred in a region with a higher level of air pollution, indicating a strong relationship between ambient air pollution exposures and TB incidences. Carbon monoxide (CO) exposure showed the highest population attributable fraction (PAF), followed by nitrogen oxides (NOX) and nitrogen dioxide (NO2) exposures. In a region with higher ambient air pollution, it is most likely (80% risk probability) that the contributions of CO exposure to development of TB were 1.6-12.2% (range of median PAFs), whereas NOX and NO2 exposures contributed 1.2-9.8% to developing TB. CONCLUSION: Our findings provide strong empirical support for the hypothesis and observations from the literature that poor air quality is highly likely to link aetiologically to the risk of TB. Therefore, substantial reductions in CO, NOX, and NO2 exposures are predicted to have health benefits to susceptible and latently infected individuals that provide complementary mitigation efforts in reducing the burden of TB. Considering that people continue to be exposed to both TB bacilli and ambient air pollutants, our approach can be applied for different countries/regions to identify which air pollutants contribute to a higher risk of TB in order to develop potential mitigation programs.

Distinctive genetic variation of long-segment Hirschsprung's disease in Taiwan.

BACKGROUND: Hirschsprung's disease (HSCR) is a congenital disorder with the absence of myenteric and submucosal ganglion cells within distal gut. Due to multigenic inheritance and interactions, we employed next-generation sequencing (NGS) to investigate genetic backgrounds of long-segment HSCR (L-HSCR) in Taiwan. METHODS: Genomic DNA extracted from peripheral blood of L-HSCR patients was subjected to capture-based NGS, based on a 31-gene panel. The variants with allele frequency <0.05 and predicted by computational methods as deleterious were further validated by Sanger sequencing in patients and their family as well to tell de novo from inherited variants. RESULTS: Between 2015/04 and 2018/05, this study enrolled 23 L-HSCR patients, including 15 (65.2%) sporadic cases and 8 (34.8%) familial patients in 4 different families. Six sporadic and seven familial cases showed possible harmful variants across eight different genes, accounting for an overall detection rate of 56.5%. These variants mainly resided in SEMA3C, followed by RET, NRG1, and NTRK1. Three sporadic and 2 familial cases exhibited strong pathogenic variants as a deletional frameshift or stop codon in RET, L1CAM or NRG1. In a HSCR family, the father passed on a pathogenic RET frameshift to two daughters; however, only one developed HSCR. CONCLUSION: Using NGS, we disclosed deleterious mutations such as a frameshift or stop codon in either familial or sporadic patients. Our cases with isolated L-HSCR or even total colonic aganglionosis appeared to exhibit complex patterns of inheritance and incomplete penetrance even in families with the same genetic variants, reflecting the possible effects of environmental factors and genetic modifiers.

Assessing the seasonality of occupancy number-associated CO2 level in a Taiwan hospital.

This study enabled the assessment of indoor CO2 levels and evaluated the relationship between occupancy numbers with CO2 levels in a Taiwan hospital. The measurements were conducted over four seasons for five working days (Monday to Friday), with sampling conducted simultaneously from 09:00 am to 5:00 pm and across six locations (for spatial variability): hall (H), registration and cashier (RC), waiting area (WA), occupational therapy room (OT), physical therapy room (PT), and outdoors (O). Based on the analysis, three of the five indoor sampling sites showed significant differences in seasonal CO2 concentrations (p < 0.0001). Based on our result, the physical therapy room had the highest level of CO2 concentration that exceeded the IAQ standard in Taiwan Environmental Protection Agency (EPA) in all seasons, in that the number of occupants contributing to nearly 40% of the variation in CO2 measured. Our results also showed that the indoor/outdoor (I/O) ratios of CO2 concentration for all locations and seasons exceeded 1 in ~ 100% of those locations. The median I/O ratio at sites WA and OT was 2.37 and 2.08 during four seasons, respectively. The highest median I/O ratio was found at site PT, with a calculated range of 2.69 in spring to 3.90 in fall. The highest correlation of occupancy number and CO2 concentration also occurred in PT which correlation coefficients were estimated at 0.47, 0.65, 0.63, and 0.40 in spring, summer, fall, and winter. The findings of the present study can be used to understand occupancy number and its effect on CO2 levels in a hospital environment, as well as the effect of time of day (Monday to Friday) on the number of patients admitted.

Assessing health burden risk and control effect on dengue fever infection in the southern region of Taiwan.

BACKGROUND: The high prevalence of dengue in Taiwan and the consecutive large dengue outbreaks in the period 2014-2015 suggest that current control interventions are suboptimal. Understanding the effect of control effort is crucial to inform future control strategies. OBJECTIVES: We developed a framework to measure season-based health burden risk from 2001 to 2014. We reconstructed various intervention coverage to assess the attributable effect of dengue infection control efforts. MATERIALS AND METHODS: A dengue-mosquito-human transmission dynamic was used to quantify the vector-host interactions and to estimate the disease epidemics. We used disability-adjusted life years (DALYs) to assess health burden risk. A temperature-basic reproduction number (R0)-DALYs relationship was constructed to examine the potential impacts of temperature on health burden. Finally, a health burden risk model linked a control measure model to evaluate the effect of dengue control interventions. RESULTS: We showed that R0 and DALYs peaked at 25°C with estimates of 2.37 and 1387, respectively. Results indicated that most dengue cases occurred in fall with estimated DALYs of 323 (267-379, 95% CI) at 50% risk probability. We found that repellent spray had by far the largest control effect with an effectiveness of ~71% in all seasons. Pesticide spray and container clean-up have both made important contributions to reducing prevalence/incidence. Repellent, pesticide spray, container clean-up together with Wolbachia infection suppress dengue outbreak by ~90%. CONCLUSION: Our presented modeling framework provides a useful tool to measure dengue health burden risk and to quantify the effect of dengue control on dengue infection prevalence and disease incidence in the southern region of Taiwan.

Children are particularly vulnerable to environmental tobacco smoke exposure: Evidence from biomarkers of tobacco-specific nitrosamines, and oxidative stress.

BACKGROUND: Worldwide, smoking is a major public health problem, with exposure to environmental tobacco smoke (ETS) affecting both smokers, and passive smokers, including children. Despite ETS also describing secondhand, and thirdhand smoke (SHS, and THS respectively), the health effects of exposure to passive smoking via these sources are not fully understood, particularly in children. Although cotinine, the primary proximate metabolite of nicotine, has been widely used as a biomarker of ETS exposure, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), the metabolite of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), provides a uniquely important contribution, both as a biomarker of exposure, and as a specific risk indicator for pulmonary carcinogenesis. METHODS: We used LC-MS/MS to study NNK metabolites, cotinine, and 8-oxo-7,8-dihydro-2'-deoxyguanosine (a biomarker of oxidative stress), in the urine of 110 non-smoking adults (age range: 23-62) and 101 children (age range: 9-11), exposed to ETS. RESULTS: In our study of passive smoking adults, and children exposed to ETS, we showed that although the children had a similar urinary level of cotinine compared to the adults, the children had approximately two times higher levels of urinary total NNAL (P = 0.002), and free NNAL (P = 0.01), than adults. The children also had three times lower ability to detoxify NNK than adults (P < 0.001). Furthermore, the children showed 1.5 times higher ratio of total NNAL/cotinine than adults (P = 0.01), implying that THS is another important source of ETS in this population. Furthermore, ETS exposure in children appeared to lead to an increase in levels of oxidative stress. CONCLUSIONS: Taken together, our results demonstrate that, in children, THS may play an important role in the ETS exposure, and that children are at particular risk of ETS-induced health effects.