Long-term exposure to PM2.5 and mortality in a national cohort in South Korea: effect modification by community deprivation, medical infrastructure, and greenness.

BACKGROUND: Long-term exposure to PM2.5 has been linked to increased mortality risk. However, limited studies have examined the potential modifying effect of community-level characteristics on this association, particularly in Asian contexts. This study aimed to estimate the effects of long-term exposure to PM2.5 on mortality in South Korea and to examine whether community-level deprivation, medical infrastructure, and greenness modify these associations. METHODS: We conducted a nationwide cohort study using the National Health Insurance Service-National Sample Cohort. A total of 394,701 participants aged 30 years or older in 2006 were followed until 2019. Based on modelled PM2.5 concentrations, 1 to 3-year and 5-year moving averages of PM2.5 concentrations were assigned to each participant at the district level. Time-varying Cox proportional-hazards models were used to estimate the association between PM2.5 and non-accidental, circulatory, and respiratory mortality. We further conducted stratified analysis by community-level deprivation index, medical index, and normalized difference vegetation index to represent greenness. RESULTS: PM2.5 exposure, based on 5-year moving averages, was positively associated with non-accidental (Hazard ratio, HR: 1.10, 95% Confidence Interval, CI: 1.01, 1.20, per 10 µg/m3 increase) and circulatory mortality (HR: 1.22, 95% CI: 1.01, 1.47). The 1-year moving average of PM2.5 was associated with respiratory mortality (HR: 1.33, 95% CI: 1.05, 1.67). We observed higher associations between PM2.5 and mortality in communities with higher deprivation and limited medical infrastructure. Communities with higher greenness showed lower risk for circulatory mortality but higher risk for respiratory mortality in association with PM2.5. CONCLUSIONS: Our study found mortality effects of long-term PM2.5 exposure and underlined the role of community-level factors in modifying these association. These findings highlight the importance of considering socio-environmental contexts in the design of air quality policies to reduce health disparities and enhance overall public health outcomes.

RNA Interference With Zilebesiran for Mild to Moderate Hypertension: The KARDIA-1 Randomized Clinical Trial.

Importance: Angiotensinogen is the most upstream precursor of the renin-angiotensin-aldosterone system, a key pathway in blood pressure (BP) regulation. Zilebesiran, an investigational RNA interference therapeutic, targets hepatic angiotensinogen synthesis. Objective: To evaluate antihypertensive efficacy and safety of different zilebesiran dosing regimens. Design, Setting, and Participants: This phase 2, randomized, double-blind, dose-ranging study of zilebesiran vs placebo was performed at 78 sites across 4 countries. Screening initiation occurred in July 2021 and the last patient visit of the 6-month study occurred in June 2023. Adults with mild to moderate hypertension, defined as daytime mean ambulatory systolic BP (SBP) of 135 to 160 mm Hg following antihypertensive washout, were randomized. Interventions: Randomization to 1 of 4 subcutaneous zilebesiran regimens (150, 300, or 600 mg once every 6 months or 300 mg once every 3 months) or placebo (once every 3 months) for 6 months. Main Outcomes and Measures: The primary end point was between-group difference in least-squares mean (LSM) change from baseline to month 3 in 24-hour mean ambulatory SBP. Results: Of 394 randomized patients, 377 (302 receiving zilebesiran and 75 receiving placebo) comprised the full analysis set (93 Black patients [24.7%]; 167 [44.3%] women; mean [SD] age, 57 [11] years). At 3 months, 24-hour mean ambulatory SBP changes from baseline were -7.3 mm Hg (95% CI, -10.3 to -4.4) with zilebesiran, 150 mg, once every 6 months; -10.0 mm Hg (95% CI, -12.0 to -7.9) with zilebesiran, 300 mg, once every 3 months or every 6 months; -8.9 mm Hg (95% CI, -11.9 to -6.0) with zilebesiran, 600 mg, once every 6 months; and 6.8 mm Hg (95% CI, 3.6-9.9) with placebo. LSM differences vs placebo in change from baseline to month 3 were -14.1 mm Hg (95% CI, -19.2 to -9.0; P < .001) with zilebesiran, 150 mg, once every 6 months; -16.7 mm Hg (95% CI, -21.2 to -12.3; P < .001) with zilebesiran, 300 mg, once every 3 months or every 6 months; and -15.7 mm Hg (95% CI, -20.8 to -10.6; P < .001) with zilebesiran, 600 mg, once every 6 months. Over 6 months, 60.9% of patients receiving zilebesiran had adverse events vs 50.7% patients receiving placebo and 3.6% had serious adverse events vs 6.7% receiving placebo. Nonserious drug-related adverse events occurred in 16.9% of zilebesiran-treated patients (principally injection site reactions and mild hyperkalemia) and 8.0% of placebo-treated patients. Conclusions and Relevance: In adults with mild to moderate hypertension, treatment with zilebesiran across a range of doses at 3-month or 6-month intervals significantly reduced 24-hour mean ambulatory SBP at month 3. Trial Registration: ClinicalTrials.gov Identifier: NCT04936035.

Long-term exposure to particulate matter and risk of Alzheimer's disease and vascular dementia in Korea: a national population-based Cohort Study.

BACKGROUND: The prevalence of age-related neurodegenerative diseases has risen in conjunction with an increase in life expectancy. Although there is emerging evidence that air pollution might accelerate or worsen dementia progression, studies on Asian regions remains limited. This study aimed to investigate the relationship between long-term exposure to PM10 and the risk of developing Alzheimer's disease and vascular dementia in the elderly population in South Korea. METHODS: The baseline population was 1.4 million people aged 65 years and above who participated in at least one national health checkup program from the National Health Insurance Service between 2008 and 2009. A nationwide retrospective cohort study was designed, and patients were followed from the date of cohort entry (January 1, 2008) to the date of dementia occurrence, death, moving residence, or the end of the study period (December 31, 2019), whichever came first. Long-term average PM10 exposure variable was constructed from national monitoring data considering time-dependent exposure. Extended Cox proportional hazard models with time-varying exposure were used to estimate hazard ratios (HR) for Alzheimer's disease and vascular dementia. RESULTS: A total of 1,436,361 participants were selected, of whom 167,988 were newly diagnosed with dementia (134,811 with Alzheimer's disease and 12,215 with vascular dementia). The results show that for every 10 µg/m3 increase in PM10, the HR was 0.99 (95% CI 0.98-1.00) for Alzheimer's disease and 1.05 (95% CI 1.02-1.08) for vascular dementia. Stratified analysis according to sex and age group showed that the risk of vascular dementia was higher in men and in those under 75 years of age. CONCLUSION: The results found that long-term PM10 exposure was significantly associated with the risk of developing vascular dementia but not with Alzheimer's disease. These findings suggest that the mechanism behind the PM10-dementia relationship could be linked to vascular damage.

Validity evaluation of indirect adjustment method for multiple unmeasured confounders: A simulation and empirical study.

BACKGROUND: An indirect adjustment method was developed to control for unmeasured confounders in a large administrative cohort study. A previous study that proposed the indirect adjustment method assessed the validity of the method by simulations but did not consider the direction of bias and scenarios with multiple missing confounders. In this study, we evaluated the direction and the magnitude of bias of the indirect adjustment method with multiple correlated unmeasured confounders using simulation and empirical datasets. METHODS: A simulation study was conducted to compare the bias of the indirect adjustment by varying the number of confounders, magnitude of correlation between confounders, and the number of adjustment variables. An empirical study was conducted by applying the indirect adjustment method to the association between PM10 and mortality using the Korea National Health and Nutrition Examination Survey linked Cause of Death data for 2007-2016. RESULTS: The simulations of the present study demonstrated that 1) when a confounder is positively associated with both exposure and outcome, indirect adjustment might bias the effect size downward; 2) the magnitude of bias might depend on the correlation between unmeasured confounders; and 3) indirect adjustment for multiple missing confounders at once could result in a higher bias than that for some of the missing confounders. Empirical analyses also showed consistent results, but the bias of indirectly adjusted effect estimates was sometimes larger than that of unadjusted effect estimates. CONCLUSIONS: The indirect adjustment method is a promising technique to reduce the bias from unmeasured confounding; however, it should be implemented carefully, particularly when there are multiple correlated unmeasured confounders of the same direction.

Alternative adjustment for seasonality and long-term time-trend in time-series analysis for long-term environmental exposures and disease counts.

BACKGROUND: Time-series analysis with case-only data is a prominent method for the effect of environmental determinants on disease events in environmental epidemiology. In this analysis, adjustment for seasonality and long-term time-trend is crucial to obtain valid findings. When applying this analysis for long-term exposure (e.g., months, years) of which effects are usually studied via survival analysis with individual-level longitudinal data, unlike its application for short-term exposure (e.g., days, weeks), a standard adjustment method for seasonality and long-term time-trend can extremely inflate standard error of coefficient estimates of the effects. Given that individual-level longitudinal data are difficult to construct and often available to limited populations, if this inflation of standard error can be solved, rich case-only data over regions and countries would be very useful to test a variety of research hypotheses considering unique local contexts. METHODS: We discuss adjustment methods for seasonality and time-trend used in time-series analysis in environmental epidemiology and explain why standard errors can be inflated. We suggest alternative methods to solve this problem. We conduct simulation analyses based on real data for Seoul, South Korea, 2002-2013, and time-series analysis using real data for seven major South Korean cities, 2006-2013 to identify whether the association between long-term exposure and health outcomes can be estimated via time-series analysis with alternative adjustment methods. RESULTS: Simulation analyses and real-data analysis confirmed that frequently used adjustment methods such as a spline function of a variable representing time extremely inflate standard errors of estimates for associations between long-term exposure and health outcomes. Instead, alternative methods such as a combination of functions of variables representing time can make sufficient adjustment with efficiency. CONCLUSIONS: Our findings suggest that time-series analysis with case-only data can be applied for estimating long-term exposure effects. Rich case-only data such as death certificates and hospitalization records combined with repeated measurements of environmental determinants across countries would have high potentials for investigating the effects of long-term exposure on health outcomes allowing for unique contexts of local populations.

Multi-dimensional community characteristics in linking particulate matter pollution and cause-specific mortality: 72 communities of South Korea.

Concentration-response function for exposure to ambient particulate matter (PM) and mortality (i.e., relative risk, RR) may be inequal across communities by socioeconomic conditions. Investigation on specific mechanisms of this inequality regarding susceptibility to PM, beyond non-specific "socioeconomic conditions", would provide policy-relevant implications for tackling this inequality. However, such investigation via epidemiological studies is challenged by residual confounding by correlated mechanisms and different loss of life expectancy by PM exposures between communities. Here, we aimed to assess community characteristics including different aspects of socioeconomic deprivation, medical resources, health behaviors, air quality, and greenness in their relation to inequal RR for PM10 and cause-specific mortality in 72 municipalities in South Korea, 2006-2013, considering these challenges. We found that a 10 µg/m3 increase in PM10 on average across 46 days was associated with a 1.05% (95% CI: 0.24, 1.88) increase in all-cause mortality (ALL), 1.32% (95% CI: -0.29, 2.95) increase in cardiovascular mortality (CVD), and 6.47% (95% CI: 3.06, 10.00) increase in respiratory mortality (RES). The association between PM10 and mortality was higher in communities with higher ratio of SO2 to PM10 (ALL and RES), higher material deprivation (ALL, CVD, and RES), lower medical resources (CVD), higher prevalence of drinking (ALL and CVD), and lower prevalence of smoking (CVD and RES). Lag-structures showed smaller loss of life expectancy by PM exposures in communities with higher prevalence of smoking. Our findings suggest that PM-related health inequalities are shaped by a variety of mechanisms relating to susceptibility to PM exposures and different loss of life expectancy. Health policies controlling community characteristics may contribute to minimizing PM10-related health inequalities in those perspectives.

Effects of long-term exposure to air pollution on all-cause mortality and cause-specific mortality in seven major cities of South Korea: Korean national health and nutritional examination surveys with mortality follow-up.

Evidence from cohort studies on the effects of long-term exposure to air pollution on mortality is limited in South Korea, which has high concentration of particles compared to North America, Western Europe, and Japan, and low exposure compared to China. To reduce knowledge gaps between other countries and South Korea, we investigated the association between all-cause, cardiovascular, and respiratory mortality and long-term exposure to PM10 and, as a surrogate for fine particles from local emission sources, SO2 and NO2. Participants comprised 18,220 subjects (97,114.4 person-years) residing in 73 districts of seven major cities of South Korea who were assigned to measurements of fixed-site monitoring stations and followed up. We applied Cox proportional hazard models with time-varying exposure up to three years average of air pollutants. We adjusted for individual and district-level covariates measured at baseline such as age, sex, socioeconomic positions, and health behaviors. We found that hazard ratios of PM10 and SO2 for all-cause mortality leveled off over approximately 5 ppb of SO2 and 35-50 µg/m3 of PM10. Interquartile range increases of PM10 (5.05 µg/m3), SO2 (2.09 ppb), and NO2 (11.41 ppb) were associated with 14.4% (95% CI: -0.4, 31.4), 18.1% (-4.5, 46.0), and 18.9% (-8.7, 54.7) increases in cardiovascular mortality, respectively. We did not find positive associations for respiratory mortality. The increase in cardiovascular mortality varied by sex (for PM10, in females, 27.4% (5.8, 53.5) increase), smoking (in non-smokers, 35.9% (12.7, 64.0) increase), drinking (in drinkers, 24.5% (2.1, 51.8) increase), marital status (in those not married, 23.1% (1.1, 49.9)), employment status (for SO2, in those employed, 79.4% (16.1, 177.3) increase), body mass index (in those ≥23, 47.6% (10.4, 97.3) increase), and community deprivation (for PM10, in less deprived communities, 21.0% (1.3, 44.4) increase). In summary, long-term exposure to air pollution is associated with mortality risk in South Korea. Our results suggest that the health effect of long-term exposure to air pollution may not be equal by sex, health behaviors and socioeconomic positions.

Rejection of workers' compensation claims may increase depressive symptoms among firefighters with occupational injury: a nationwide study in South Korea.

OBJECTIVES: This study sought to examine whether the experience of occupational injuries was associated with depressive symptoms and whether the rejection of workers' compensation claims was associated with depressive symptoms among Korean firefighters. METHODS: We conducted a nationwide survey of 6793 Korean firefighters in 2015. Based on the experience of occupational injuries and workers' compensation claims over the past year, respondents were classified into four groups: "Not injured", "Injured, not applied", "Injured, applied, but rejected" and "Injured, applied, and accepted." Depressive symptoms over the preceding week were assessed using the 11-item version of the Centers for Epidemiologic Studies Depression Scale. RESULTS: Compared to firefighters who did not get injured, injured firefighters had a higher prevalence of depressive symptoms (PR 2.01, 95% CI 1.83, 2.22) after controlling for confounders including job assignment. Also, when we restricted the analysis to injured firefighters, a higher prevalence of depressive symptoms was observed among "Injured, applied, but rejected" (PR 1.70, 95% CI 1.11, 2.59) group, compared to "Injured, applied, and accepted" group. CONCLUSIONS: This finding suggests that rejection of workers' compensation claims, as well as the experience of occupational injuries, may increase the risk of depressive symptoms among Korean firefighters.

Bacterial Disease Complex Including Bleached Spot, Soft Rot, and Blight on Onion Seedlings Caused by Complex Infections.

In 2018, a bacterial disease complex composed of bleached spots and soft rot-blight on onion seedlings was observed in nursery beds in Changnyeong, a major onion-producing county in South Korea. Four bacteria isolated from the diseased lesions were identified: Pseudomonas viridiflava, Acidovorax avenae subsp. avenae, Pantoea ananatis, and Xanthomonas axonopodis, respectively. We referred to the four strains as a "bacterial disease complex" because they were isolated from the same sample with multiple symptoms. We examined the synergistic activity among the four strains to understand their relationships and roles. We monitored in vivo bacterial population density and disease progression after artificially inoculating the bacteria on onion seedlings at a temperature of 22 or 28°C. The disease pattern progressed sooner at 28 than at 22°C (by an average of 4 to 6 days). The rate of disease progression induced by inoculation of P. ananatis alone was consistent with that induced by coinoculation of P. ananatis with the other strains, regardless of the temperature (22 or 28°C). The in vivo growth of P. ananatis on onion seedlings was not different after inoculation alone versus together with the other strains. The rate of disease progression induced by P. viridiflava was similar when inoculated alone and when inoculated with other tree strains at 28°C, but disease progression induced by inoculation alone was slower at 22°C. The in vivo growth of P. viridiflava or X. axonopodis on onion seedlings decreased rapidly or gradually, respectively, when inoculated with the other strains. Coinfection with the other three strains had repression effects on the growth of P. viridiflava, a slight effect on X. axonopodis, and no effect on P. or A. avenae subsp. avenae in vivo. These results indicate that the strains coexist or interact antagonistically, rather than synergistically, depending on the conditions. These results were consistent with the results of the in vitro growth inhibition assay, in which P. viridiflava growth was inhibited by X. axonopodis or P. ananatis. These results also confirmed that X. axonopodis is present on bleached spots and P. viridiflava on soft rot-blight lesions, and that P. viridiflava and P. ananatis cause soft rot-blight but do not coexist. A. avenae subsp. avenae is a minor causative pathogen of bleached spots on onion seedlings, but it is not significantly affected by temperature and has no antagonistic or synergistic interactions with X. axonopodis.

Sleep duration and mortality in Korean adults: a population-based prospective cohort study.

BACKGROUND: Increasing evidence suggests that sleep duration is associated with risks of various diseases including type 2 diabetes, cardiovascular disease (CVD), and certain types of cancer. However, the relationship with mortality is not clear, particularly in non-European populations. In this study, we investigated the association between sleep duration and mortality in a population-based prospective cohort of Korean adults. METHODS: This analysis included 34,264 participants (14,704 men and 19,560 women) of the Korea National Health and Nutrition Examination Survey (KNHANES) 2007-2013 who agreed to mortality follow-up through December 31, 2016. Sleep duration was self-reported at baseline and was categorized into four groups: ≤4, 5-6, 7-8, and ≥ 9 h/day. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the associations with mortality (all-cause as well as CVD- and cancer-specific), adjusting for potential confounders. RESULTS: During up to 9.5 years of follow-up, we identified a total of 1028 deaths. We observed the lowest mortality at 5-6 h/day sleep. Compared with 7-8 h/day of sleep, short (≤4 h/day) and long (≥9 h/day) sleep were associated with a 1.05-fold (95% CI = 0.79-1.39) and 1.47-fold (95% CI = 1.15-1.87) higher all-cause mortality, respectively. After additional adjustment for self-rated health, the positive association with short sleep disappeared (HR = 0.99, 95% CI = 0.75-1.32) and the association with long sleep was slightly attenuated (HR = 1.38, 95% CI = 1.08-1.76). Long sleep was also nonsignificantly positively associated with both cancer-mortality (HR = 1.30, 95% CI = 0.86-1.98) and CVD-mortality (HR = 1.27, 95% CI = 0.73-2.21). There was no statistically significant evidence for nonlinearity in the relationships between sleep duration and mortality (all-cause as well as CVD- and cancer-specific). Effect modification by age, sex, education, and occupation were not statistically significant. CONCLUSIONS: Our findings suggest that long sleep duration is associated with an increased all-cause mortality in Korean adults.

On inferences about lag effects using lag models in air pollution time-series studies.

The choice of lag length is a matter of uncertainty in air pollution time-series studies. Lag models and model selections are widely used for inferences about lag effects, but there is lack of discussion on the integration of the two. We aimed to provide theoretical discussion on the performance of lag models, and the impact of model selections on inferences about lag effects. Bias and model selections based upon information criteria, statistical significance, effect size, and model averaging were discussed in the context of lag analysis. A simulation with eight of PM2.5-mortality relation scenarios was also conducted in order to explore the performances of lag models and to compare the model selections. The application of lag models with an insufficient lag interval taken into account (i.e. insufficient lag models) provides biased estimates. We provided features of the model selections and showed their pitfalls in lag analysis of air pollution time-series studies. We also discussed limitations of meta-analysis which fails to consider the application of different lag models in individual studies. To foster exploration on air pollution-lag-response relations with relevant tools, we encourage researchers to compare different lag models in terms of effect estimates and variance estimates, and to report their favored models and competing models together based upon scientific knowledge supporting lag-response relations.

Comparison of health risks by heat wave definition: Applicability of wet-bulb globe temperature for heat wave criteria.

Despite the active applications of thermal comfort indices for heat wave definitions, there is lack of evaluation for the impact of extended days of high temperature on health outcomes using many of the indices. This study compared the impact of heat waves on health outcomes among different heat wave definitions based on thermal comfort and air temperature. We compared heat waves in South Korea (cities and provinces) for the warm season for 2011-2014, using air temperature, heat index (HI), and web-bulb globe temperature (WBGT). Heat waves were defined as days with daily maximum values of each index at a specified threshold (literature-based, the 90th and 95th percentiles) or above. Distributed lag non-linear models and meta-analysis were used to estimate risk of mortality and hospitalization for all-causes, cardiovascular causes, respiratory causes and heat disorders during heat wave days compared to non-heat wave days. WBGT identified 1.15 times longer maximum heat wave duration for the study periods than air temperature when the thresholds were based on 90th and 95th percentiles. Over the study period, for heat waves defined by WBGT and HI, the Southwestern region showed the highest total number of heat wave days, whereas for air temperature the longest heat wave days were identified in the southeastern region. The highest and most significant impact of heat waves were found by WBGT for hospitalization from heat disorders (Relative risk = 2.959, 95% CI: 1.566-5.594). In sensitivity analyses using different structure of lags and temperature metrics (e.g., daily mean and minimum), the impacts of heat waves on most health outcomes substantially increased by using WBGT for heat wave definitions. As a result, WBGT and its thresholds can be used to relate heat waves and heat-related diseases to improve the prevention effectiveness of heat wave warnings and give informative health guidelines according to the range of WBGT thresholds.

Impacts of high temperature on adverse birth outcomes in Seoul, Korea: Disparities by individual- and community-level characteristics.

BACKGROUND: Few studies have examined temperature's effect on adverse birth outcomes and relevant effect modifiers. OBJECTIVES: We investigated associations between heat and adverse birth outcomes and how individual and community characteristics affect these associations for Seoul, Korea, 2004-2012. METHODS: We applied logistic regression to estimate associations between heat index during pregnancy, 4 weeks before delivery, and 1 week before delivery and risk of preterm birth and term low birth weight. We investigated effect modification by individual (infant's sex, mother's age, and mother's educational level) and community characteristics (socioeconomic status (SES) and percentage of green areas near residence at the gu level, which is similar to borough in Western countries). We also evaluated associations by combinations of individual- and community-level SES. RESULTS: Heat exposure during whole pregnancy was significantly associated with risk of preterm birth. An interquartile (IQR) increase (5.5 °C) in heat index during whole pregnancy was associated with an odds ratio (OR) of 1.033 (95% CI 1.005, 1.061) with NO2 adjustment, and 1.028 (95% CI 0.998, 1.059) with PM10 adjustment, for preterm birth. We also found significant associations with heat exposure during 4 weeks before delivery and 1 week before delivery on preterm birth. We did not observe significant associations with term low birth weight. Higher risk of heat on preterm birth was associated with some individual characteristics such as infants with younger or older mothers and lower community-level SES. For combinations of individual- and community-level SES, the highest and most significant estimated effect was found for infants with low educated mothers living in low SES communities, with suggestions of effects of both individual-and community-level SES. CONCLUSIONS: Our findings have implications for evaluating impacts of high temperatures on birth outcomes, estimating health impacts of climate change, and identifying which subpopulations and factors are most relevant for disparities in this association.

Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans.

It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the Tmax changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h → 0.75 h). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CLint,BCRP,intestine of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction).

Bortezomib pharmacokinetics in tumor response and peripheral neuropathy in multiple myeloma patients receiving bortezomib-containing therapy.

The usefulness of pharmacokinetics of bortezomib for multiple myeloma (MM) with respect to the maximum response to bortezomib and bortezomib-induced peripheral neuropathy (BIPN) development was studied. Maximum response to subcutaneous bortezomib therapy and BIPN occurrence for the first 12 weeks of treatment in 35 MM patients treated by bortezomib-dexamethasone (VD) and bortezomib-melphalan-prednisone (VMP) were evaluated. On day 1 of cycle 1, seven whole-blood samples were collected for 3 h after dosing completion to obtain the maximum plasma concentration and area under the time-concentration curve during 3 h postdose (AUC0-3) in each patient. A total of 35 patients with complete data were analyzed and the overall response rate was 91.4%. Complete response (CR) was observed in 42.9% patients. The maximum plasma concentration (Cmax) was significant for the CR rate in two different models [full model: odds ratio (OR)=1.092; P=0.038, final model: OR=1.081; P=0.038]. In addition, Cmax was associated with a progression-free survival advantage. Overall, 48.6% of patients developed BIPN including peripheral sensory neuropathy and neuralgia. The VMP-treated patients had a higher risk compared with the VD-treated patients (OR=21.662; P=0.029). Cmax had a tendency to affect the occurrence of BIPN (≥grade 2) (OR=1.064; P=0.092). In real-world clinical practice using bortezomib for MM patients, Cmax among pharmacokinetic factors significantly affected the achievement of CR. The VMP-treated patients showed vulnerability to BIPN, suggesting the necessity for more careful monitoring.

Is ambient temperature associated with risk of infant mortality? A multi-city study in Korea.

BACKGROUND: Although numerous studies have shown increased risk of mortality from elevated temperatures for adults, limited studies have examined temperature's effect on mortality for infants. Our study investigated the city-specific and overall effects of ambient temperature on infant mortality in seven major cities in Korea, 2004-2007. METHODS: Birth cohort using a linked birth and death records included 777,570 births with 557 all-cause deaths. We estimated city-specific hazard ratios for each city using an extended Cox proportional hazards model with time-dependent covariates. Then we combined city-specific hazard ratios to generate overall hazard ratio across the seven cities using a Bayesian hierarchical model. Stratified analyses were conducted by cause of death (total and SIDS), exposure period (whole gestation, each trimester, lifetime, 1 month before death, and 2 weeks before death), sex, and maternal characteristics. RESULTS: Overall across the cities, we found significantly positive associations between ambient temperature during 1 month before death or 2 weeks before death and infant mortality from total or SIDS. The overall hazard ratio of infant mortality from total deaths and SIDS for a 1°C increase during 1 month before death was 1.52 (95% CI, 1.46-1.57) and 1.50 (95% CI, 1.35-1.66), respectively. We also found suggestive evidence that some factors such as mother's age may modify the association. CONCLUSIONS: Our findings have implications for establishment of policy to reduce the risk of infant mortality from high ambient temperature under climate change.

Does a lag-structure of temperature confound air pollution-lag-response relation? Simulation and application in 7 major cities, Korea (1998-2013).

BACKGROUND: Temperature must be controlled when estimating the associations of short-term exposure to air pollution and mortality. Given that multi-country studies have implied temperature has lagged effects, we aim to explore confounding by temperature-lag-response and investigate PM10-lag-mortality relation in 7 cities, Korea. METHODS: In a simulation study, we compared the performance of different methods to control for: the same day temperature, a lagged temperature and distributed lags of temperature. In a real data study, we explored PM10-lag-mortality relation in 7 cities using these different methods. RESULTS: We confirmed that a model with insufficient control of temperature offers a biased estimate of PM10 risk. The degree of bias was from -82% to 95% in simulation settings. A real data study shows estimates among different models by temperature adjustments and PM10 lag variables ranging from -0.3% to 0.4% increase in the risk of all-cause mortality, with a 10µg/m3 increase in PM10. Controlling for temperature as distributed lags for 21 days provided 0.25% (95% CI: 0.1, 0.4) increase in the risk of all-cause mortality. CONCLUSIONS: A lag structure of temperature can confound the air pollution-lag-response relation. Temperature-lag-response relation should be evaluated when estimating air pollution-lag-response relation. As a corollary, air pollution and temperature risk in mortality can be estimated using the same regression model.

Assessment of temporal variation for the risk of particulate matters on asthma hospitalization.

Increased ambient concentration of particulate matters are considered as one of major causes for increased prevalence or exacerbation of asthma or asthma like symptoms. Recently, possible temporal variation in risks of PM on mortality has been suggested. We investigated short-term effect of both PM10 and PM2.5 on asthma hospitalization, and assessed temporal variation of PM risks in Seoul, Korea, 2003-2011. Generalized additive model was used to estimate PM risks on asthma hospitalization with consideration by long-term trend, influenza epidemic, day of week, meteorological factors. To assess temporal variation of PM risks, year-round PM risks were estimated. Stratified analysis by season and age-group were also conducted. Estimated RRs of PM on asthma hospitalization by an increase of 10㎍/㎥were 1.0084 (95% CI: 1.0041-1.0127) and 1.0156 (95% CI: 1.0055-1.0259) respectively with 7-days lag periods (lag06). PM2.5 had stronger effect than PM10 for all age group. Elderly group was most affected by PM. For the analysis of temporal variation of PM risks, we found increasing trend in total population and the elderly group. In the season-specific analysis, we also found increasing trend in winter for PM10, and in spring for PM2.5. PM10 and PM2.5 has adverse effect on asthma hospitalization with evidence suggesting temporal variation in PM risks. Further research will be needed to confirm the temporal variation of PM risk on asthma hospitalization, and to identify casual factors affecting this temporal variation. This study results could be evidentiary materials for establishing valid public health policies to reduce health burden or economic burden of asthma.

Retracted: Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans.

'Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans' by Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Gab-jin Park, Jongtae Lee, Taegon Hong, Sangil Jeon and Dong-Seok Yim The above article, published online on 06 February 2017 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief, K. Sandy Pang, and John Wiley & Sons, Ltd. The authors retracted the paper due to errors associated with use of log D vs. log P of telmisartan as inputs of the PBPK model. The authors concluded that there are too many changes in the article to be resolved by an Erratum, and had requested a retraction. Reference Bae, S. H., Park, W.-S., Han, S., Park, G., Lee, J., Hong, T., Jeon, S., and Yim, D.-S. (2016) Physiologically based pharmacokinetic predictions of intestinal BCRP-mediated effect of telmisartan on the pharmacokinetics of rosuvastatin in humans. Biopharm. Drug Dispos., doi: 10.1002/bdd.2060.

Characterization of particulate matter from diesel passenger cars tested on chassis dynamometers.

Emission characterization of particle number as well as particle mass from three diesel passenger cars equipped with diesel particulate filter (DPF), diesel oxidation catalyst (DOC) and exhaust gas recirculation (EGR) under the vehicle driving cycles and regulatory cycle. Total particle number emissions (PNEs) decreased gradually during speed-up of vehicle from 17.3 to 97.3km/hr. As the average vehicle speed increases, the size-segregated peak of particle number concentration shifts to smaller size ranges of particles. The correlation analysis with various particulate components such as particle number concentration (PNC), ultrafine particle number concentration (UFPNC) and particulate matter (PM) mass was conducted to compare gaseous compounds (CO, CO2, HC and NOx). The UFPNC and PM were not only emitted highly in Seoul during severe traffic jam conditions, but also have good correlation with hydrocarbons and NOx influencing high potential on secondary aerosol generation. The effect of the dilution temperature on total PNC under the New European Driving Cycle (NEDC), was slightly higher than the dilution ratio. In addition, the nuclei mode (DP: ≤13nm) was confirmed to be more sensitive to the dilution temperature rather than other particle size ranges. Comparison with particle composition between vehicle speed cycles and regulatory cycle showed that sulfate was slightly increased at regulatory cycle, while other components were relatively similar. During cold start test, semivolatile nucleation particles were increased due to effect of cold environment. Research on particle formation dependent on dilution conditions of diesel passenger cars under the NEDC is important to verify impact on vehicular traffic and secondary aerosol formation in Seoul.