Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.

The sodium-chloride cotransporter (NCC) is critical for kidney physiology1. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron2,3, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome4. As a key player in salt handling, the NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years5-7. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.

SpliceAPP: an interactive web server to predict splicing errors arising from human mutations.

BACKGROUND: Splicing variants are a major class of pathogenic mutations, with their severity equivalent to nonsense mutations. However, redundant and degenerate splicing signals hinder functional assessments of sequence variations within introns, particularly at branch sites. We have established a massively parallel splicing assay to assess the impact on splicing of 11,191 disease-relevant variants. Based on the experimental results, we then applied regression-based methods to identify factors determining splicing decisions and their respective weights. RESULTS: Our statistical modeling is highly sensitive, accurately annotating the splicing defects of near-exon intronic variants, outperforming state-of-the-art predictive tools. We have incorporated the algorithm and branchpoint information into a web-based tool, SpliceAPP, to provide an interactive application. This user-friendly website allows users to upload any genetic variants with genome coordinates (e.g., chr15 74,687,208 A G), and the tool will output predictions for splicing error scores and evaluate the impact on nearby splice sites. Additionally, users can query branch site information within the region of interest. CONCLUSIONS: In summary, SpliceAPP represents a pioneering approach to screening pathogenic intronic variants, contributing to the development of precision medicine. It also facilitates the annotation of splicing motifs. SpliceAPP is freely accessible using the link https://bc.imb.sinica.edu.tw/SpliceAPP . Source code can be downloaded at https://github.com/hsinnan75/SpliceAPP .

Engineered extracellular vesicles carrying let-7a-5p for alleviating inflammation in acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a life-threatening respiratory condition characterized by severe inflammation and lung tissue damage, frequently causing rapid respiratory failure and long-term complications. The microRNA let-7a-5p is involved in the progression of lung injury, inflammation, and fibrosis by regulating immune cell activation and cytokine production. This study aims to use an innovative cellular electroporation platform to generate extracellular vesicles (EVs) carring let-7a-5p (EV-let-7a-5p) derived from transfected Wharton's jelly-mesenchymal stem cells (WJ-MSCs) as a potential gene therapy for ALI. METHODS: A cellular nanoporation (CNP) method was used to induce the production and release of EV-let-7a-5p from WJ-MSCs transfected with the relevant plasmid DNA. EV-let-7a-5p in the conditioned medium were isolated using a tangential flow filtration (TFF) system. EV characterization followed the minimal consensus guidelines outlined by the International Society for Extracellular Vesicles. We conducted a thorough set of therapeutic assessments, including the antifibrotic effects using a transforming growth factor beta (TGF-ß)-induced cell model, the modulation effects on macrophage polarization, and the influence of EV-let-7a-5p in a rat model of hyperoxia-induced ALI. RESULTS: The CNP platform significantly increased EV secretion from transfected WJ-MSCs, and the encapsulated let-7a-5p in engineered EVs was markedly higher than that in untreated WJ-MSCs. These EV-let-7a-5p did not influence cell proliferation and effectively mitigated the TGF-ß-induced fibrotic phenotype by downregulating SMAD2/3 phosphorylation in LL29 cells. Furthermore, EV-let-7a-5p regulated M2-like macrophage activation in an inflammatory microenvironment and significantly induced interleukin (IL)-10 secretion, demonstrating their modulatory effect on inflammation. Administering EVs from untreated WJ-MSCs slightly improved lung function and increased let-7a-5p expression in plasma in the hyperoxia-induced ALI rat model. In comparison, EV-let-7a-5p significantly reduced macrophage infiltration and collagen deposition while increasing IL-10 expression, causing a substantial improvement in lung function. CONCLUSION: This study reveals that the use of the CNP platform to stimulate and transfect WJ-MSCs could generate an abundance of let-7a-5p-enriched EVs, which underscores the therapeutic potential in countering inflammatory responses, fibrotic activation, and hyperoxia-induced lung injury. These results provide potential avenues for developing innovative therapeutic approaches for more effective interventions in ALI.

Esophagectomy in patients with esophageal squamous cell carcinoma and distant nodal metastasis.

The role of surgery in oligometastatic esophageal squamous cell carcinoma (ESCC) remains controversial. This study evaluated the oncological outcomes after esophagectomy in patients with ESCC with distant lymph node (LN) metastasis. Patients with ESCC and nodal metastasis treated with chemoradiotherapy or chemotherapy followed by esophagectomy between 2010 and 2020 were included. Overall survival (OS) and recurrence-free survival (RFS) were compared between patients with distant LN metastasis (dLN+) and exclusively regional LN metastasis (dLN-). The cohort comprised 69 dLN+ and 111 dLN- patients. Survival was significantly better in the dLN- group than in the dLN+ group (5-year OS, 51.9% vs. 25.5%, P < 0.001; RFS, 47.2% vs. 18.1%, P < 0.001). Stratified by the yp stage, 49 (44.1%) dLN- and 30 (43.5%) dLN+ patients achieved a pathological complete response (pCR). In the dLN- and dLN+ groups, the OS rates were significantly higher in the pCR group than in the non-pCR group (dLN-: 76.7% vs. 32.4%, P < 0.001; dLN+: 39.6% vs. 14.2%; P = 0.002). The dLN-/pCR group had the best OS, significantly outperforming the dLN-/non-pCR and dLN+/pCR groups. OS did not differ between the dLN-/non-pCR and dLN+/pCR groups. The dLN+/non-pCR group had the worst OS. The RFS analysis paralleled the OS findings. Patients with dLN+ disease had worse outcomes than their dLN- counterparts, irrespective of the pCR status. The survival rates were poor but comparable between the dLN+/pCR and dLN-/non-pCR groups. Adjuvant therapy may be required for dLN+ patients following systemic treatment and surgery, even after achieving pCR.

Assessment of sources and health risks of heavy metals in metropolitan household dust among preschool children: The LEAPP-HIT study.

The most common construction material used in Taiwan is concrete, potentially contaminated by geologic heavy metals (HMs). Younger children spend much time indoors, increasing HM exposure risks from household dust owing to their behaviors. We evaluated arsenic (As), cadmium (Cd), and lead (Pb) concentrations in fingernails among 280 preschoolers between 2017 and 2023. We also analyzed HM concentrations, including As, Cd, Pb, chromium (Cr), nickel (Ni), copper (Cu), zinc (Zn), iron (Fe), and manganese (Mn), in 90 household dust and 50 road dust samples from a residential area where children lived between 2019 and 2021 to deepen the understanding of sources and health risks of exposure to HMs from household dust. The average As, Cd, and Pb concentrations in fingernails were 0.12 ± 0.06, 0.05 ± 0.05, and 0.95 ± 0.77 µg/g, respectively. Soil parent materials, indoor construction activities, vehicle emissions, and mixed indoor combustion were the pollution sources of HMs in household dust. Higher Cr and Pb levels in household dust may pose non-carcinogenic risks to preschoolers. Addressing indoor construction and soil parent materials sources is vital for children's health. The finding of the present survey can be used for indoor environmental management to reduce the risks of HM exposure and avoid potential adverse health effects for younger children.

Impact of lifetime air pollution exposure patterns on the risk of chronic disease.

Long-term exposure to air pollution can lead to cardiovascular disease, metabolic syndrome, and chronic respiratory disease. However, from a lifetime perspective, the critical period of air pollution exposure in terms of health risk is unknown. This study aimed to evaluate the impact of air pollution exposure at different life stages. The study participants were recruited from community centers in Northern Taiwan between October 2018 and April 2021. Their annual averages for fine particulate matter (PM2.5) exposure were derived from a national visibility database. Lifetime PM2.5 exposures were determined using residential address information and were separated into three stages (<20, 20-40, and >40 years). We employed exponentially weighted moving averages, applying different weights to the aforementioned life stages to simulate various weighting distribution patterns. Regression models were implemented to examine associations between weighting distributions and disease risk. We applied a random forest model to compare the relative importance of the three exposure life stages. We also compared model performance by evaluating the accuracy and F1 scores (the harmonic mean of precision and recall) of late-stage (>40 years) and lifetime exposure models. Models with 89% weighting on late-stage exposure showed significant associations between PM2.5 exposure and metabolic syndrome, hypertension, diabetes, and cardiovascular disease, but not gout or osteoarthritis. Lifetime exposure models showed higher precision, accuracy, and F1 scores for metabolic syndrome, hypertension, diabetes, and cardiovascular disease, whereas late-stage models showed lower performance metrics for these outcomes. We conclude that exposure to high-level PM2.5 after 40 years of age may increase the risk of metabolic syndrome, hypertension, diabetes, and cardiovascular disease. However, models considering lifetime exposure showed higher precision, accuracy, and F1 scores and lower equal error rates than models incorporating only late-stage exposures. Future studies regarding long-term air pollution modelling are required considering lifelong exposure pattern. .1.

Establishing Functional Retina in a Dish: Progress and Promises of Induced Pluripotent Stem Cell-Based Retinal Neuron Differentiation.

The human eye plays a critical role in vision perception, but various retinal degenerative diseases such as retinitis pigmentosa (RP), glaucoma, and age-related macular degeneration (AMD) can lead to vision loss or blindness. Although progress has been made in understanding retinal development and in clinical research, current treatments remain inadequate for curing or reversing these degenerative conditions. Animal models have limited relevance to humans, and obtaining human eye tissue samples is challenging due to ethical and legal considerations. Consequently, researchers have turned to stem cell-based approaches, specifically induced pluripotent stem cells (iPSCs), to generate distinct retinal cell populations and develop cell replacement therapies. iPSCs offer a novel platform for studying the key stages of human retinogenesis and disease-specific mechanisms. Stem cell technology has facilitated the production of diverse retinal cell types, including retinal ganglion cells (RGCs) and photoreceptors, and the development of retinal organoids has emerged as a valuable in vitro tool for investigating retinal neuron differentiation and modeling retinal diseases. This review focuses on the protocols, culture conditions, and techniques employed in differentiating retinal neurons from iPSCs. Furthermore, it emphasizes the significance of molecular and functional validation of the differentiated cells.

Blood Biomarkers as Prognostic Indicators for Neurological Injury in COVID-19 Patients: A Systematic Review and Meta-Analysis.

Coronavirus disease 2019 (COVID-19) has been linked to various neurological complications. This meta-analysis assessed the relationship between glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) levels in the blood and neurological injury in COVID-19 patients. A comprehensive search of various databases was conducted until 18 August 2023, to find studies reporting GFAP and NfL blood levels in COVID-19 patients with neurological complications. GFAP and NfL levels were estimated between COVID-19 patients and healthy controls, and meta-analyses were performed using RevMan 5.4 software for analysis. In the 21 collected studies, it was found that COVID-19 patients had significantly higher levels of pooled GFAP (SMD = 0.52; 95% CI: 0.31, 0.73; p ≤ 0.001) and NfL (SMD = 0.60; 95% CI: 0.37, 0.82; p ≤ 0.001) when compared to the healthy controls. The pooled GFAP (SMD = 0.86; 95% CI: 0.26, 1.45; p ≤ 0.01) and NfL (SMD = 0.87; 95% CI: 0.48, 1.26; p ≤ 0.001) were significantly higher in non-survivors. These findings indicate a significant association between COVID-19 severity and elevated levels of GFAP and NfL, suggesting that GFAP and NfL could serve as potential diagnostic and prognostic markers for the early detection and monitoring of COVID-19-related neurological injuries.

Pyruvate Kinase Differentially Alters Metabolic Signatures during Head and Neck Carcinogenesis.

During glycolysis, the muscle isoform of pyruvate kinase PKM2 produces ATP in exchange for dephosphorylation of phosphoenolpyruvate (PEP) into pyruvate. PKM2 has been considered as a tumor-promoting factor in most cancers, whereas the regulatory role of PKM2 during head and neck carcinogenesis remained to be delineated. PKM2 mRNA and protein expression was examined in head and neck tumorous specimens. The role of PKM2 in controlling cellular malignancy was determined in shRNA-mediated PKM2-deficient head and neck squamous cell carcinoma (HNSC) cells. In agreement with the results in other cancers, PKM2 expression is enriched in both mouse and human HNSC tissues. Nevertheless, PKM2 mRNA expression reversely correlated with tumor stage, and greater recurrence-free survival rates are evident in the PKM2high HNSC population, arguing that PKM2 may be tumor-suppressive. Multifaceted analyses showed a greater in vivo xenografic tumor growth and an enhanced cisplatin resistance in response to PKM2 loss, whereas PKM2 silencing led to reduced cell motility. At the molecular level, metabolic shifts towards mitochondrial metabolism and activation of oncogenic Protein kinase B (PKB/Akt) and extracellular signal-regulated kinase (ERK) signals were detected in PKM2-silencing HNSC cells. In sum, our findings demonstrated that PKM2 differentially modulated head and neck tumorigenicity via metabolic reprogramming.

Oral and inhalation bioaccessibility of mercury in contaminated soils and potential health risk to the kidneys and neurodevelopment of children in Taiwan.

Health risk assessments of exposure to mercury (Hg) from soils via ingestion and inhalation are indispensable for Taiwanese people living in the vicinity of Hg-contaminated sites. In this study, anthropogenic soils were collected from various polluted sources in Taiwan. In vitro oral and inhalation bioaccessible fractions of Hg were analyzed to avoid from overestimating the exposure risk. Discrepancies in oral and inhalation bioaccessible levels of Hg in soils were found using different in vitro assays with different pH levels and chemical compositions. The freshly contaminated soil (soil S7) polluted by chlor-alkali production activity sampled before the site was remediated had the highest total Hg concentration of 1346 mg/kg, with the highest oral bioaccessibility of 26.2% as analyzed by SW-846 Method 1340 and inhalation bioaccessibility of 30.5% as analyzed by modified Gamble's solution. The lesser extent of aging of Hg in soil S7 increased the Hg availability for humans, which was also found based on results of a sequential extraction procedure. Results of the hazard quotient showed that soil ingestion was the main pathway causing non-carcinogenic risks for children and adults. Children were also exposed to higher risks than were adults due to higher frequencies of hand-to-mouth behaviors and lower body weights. Furthermore, hazard index results adjusted for oral and inhalation bioaccessible Hg were lower than those obtained based on the total Hg content; however, an unacceptable value of the non-carcinogenic risk (> 1) for children living near soil S7 was still observed. This study suggests that children living near sites polluted for a short period of time may suffer potential renal effects regardless of the bioaccessibility. Our findings provide suggestions for decision makers on setting new strategies for managing risks of Hg-contaminated soils in Taiwan.

[Improving the Pap Smear Screening Rate for Cervical Cancer in a Health Management Center: A Quality Improvement Program].

BACKGROUND & PROBLEMS: Early detection tests are highly effective in helping adult women prevent the onset of cervical cancer. However, the cervical Pap smear screening rate in a health management center was only 54.3% in 2020. PURPOSE: This project was developed to improve the Pap smear screening rate for cervical cancer in a health management center. RESOLUTION: The strategies developed included revising the health examination lists, developing an online appointment booking system, designing a patient decision aid, creating a standardized simulation moulage for education, and rechecking patient's National Health Insurance cards. RESULTS: After implementation of these strategies, the Pap smear screening rate for cervical cancer rose from 54.3% to 81.2%. The screening rate at the health management center in 2022 reached 96.6%. CONCLUSIONS: Shared decision-making can elucidate the comprehensive options available to clients and support them in considering their options and achieving informed choices regarding Pap smear preferences.

Treatment Patterns and Outcomes in Patients with Esophageal Cancer: An Analysis of a Multidisciplinary Tumor Board Database.

BACKGROUND: Multidisciplinary management strategies are standard in esophageal cancer. Based on a multidisciplinary tumor board (MTB) database in a high-volume center, we aimed to evaluate real-world treatment patterns and patient outcomes in patients with esophageal cancer. In addition, we determined the impact of MTB discussions on patient prognosis. METHODS: Patients diagnosed with esophageal cancer between 2010 and 2019 were retrospectively reviewed. The pattern of treatment modalities and overall survival (OS) of patients with limited, locally advanced, and advanced/metastatic disease were reported. RESULTS: Data from 1132 patients, including 247 patients with limited esophageal cancer, 606 patients with locally advanced esophageal cancer, and 279 patients with advanced/metastatic esophageal cancer were included. Upfront surgery was the most common (56.3%) treatment modality for patients with limited esophageal cancer, while treatment for locally advanced esophageal cancer included upfront surgery (19.1%), neoadjuvant chemoradiotherapy (44.9%), and definitive chemoradiotherapy (36.0%); however, 27.9% of patients undergoing neoadjuvant chemoradiotherapy did not receive planned esophagectomy. Definitive chemoradiotherapy was mainly used for patients with locally advanced and advanced/metastatic disease, but had an incompletion rate of 22.0% and 33.7%, respectively. Regarding survival, the 5-year OS rates were 56.4%, 26.3%, and 5.1% in patients with limited, locally advanced, and advanced/metastatic disease, respectively. Additionally, patients whose clinical management was discussed in the MTB had a significantly better 5-year OS rate than the other patients (27.3% vs. 20.5%, p < 0.001). CONCLUSIONS: We report the real-world data of treatment patterns and patient outcomes in patients with esophageal cancer with respect to multidisciplinary management, and demonstrate the positive impact of MTB discussions on patient prognosis.

Associations of maternal food safety-related risk perceptions and protective behaviors with daily mercury intake and internal doses of Taiwanese women and their preschool children.

Mercury (Hg) is a well-known toxicant that can affect children's neurodevelopment. This study attempted to evaluate the internal dose of Hg in hair and fingernails and external Hg exposure from dietary consumption in 283 pairs of mothers and their children aged under 6 years in Taiwan. Mean Hg levels in hair and fingernail samples were 1.07 ± 0.67 and 0.42 ± 0.34 µg/g for mothers, and 1.11 ± 1.22 and 0.36 ± 0.26 µg/g for children, respectively. Our results showed that 42% of mothers and 41% of children had hair Hg levels exceeding the US Environmental Protection Agency recommended value of 1 µg/g. Hg exposure in children was greater than that of their mothers. Estimated daily intake (EDI) levels of Hg among preschool children were 3.3-times higher than those of their mothers. A sensitivity analysis indicated that fish consumption was the main potential factor of Hg exposure among both mothers and their children. External Hg exposure using estimated daily dietary ingestion by mothers was a surrogate for internal hair Hg concentrations. However, poor correlations were found between EDI Hg levels and hair Hg levels among children aged 4-6 years. Exposure sources from food and other media, such as soil and dust, need to be considered to arrive at more-valid risk assessments for younger children's exposure to Hg. Children of mothers who did not have food safety-related risk perceptions or protective behaviors had significantly higher hair Hg concentrations compared to children whose mothers had risk perceptions and protective behaviors. Hg exposure of women of childbearing age and preschool children in Taiwan is still an area of great concern. Providing food safety information and risk-benefits of fish consumption for mothers may avoid harm to the developing nervous systems of their children.

Frequent occurrence of respiratory symptoms in children is associated with exposure to air pollution, land use types, and parental mental health in the Greater Taipei area.

Although studies have investigated the individual effects of air pollution, land use types, and parental mental health on children's respiratory health, few studies have examined the effects of these risk factors simultaneously in children aged <2 years. We investigated the effects of exposure to air pollution, land use types surrounding residences, and parental mental health on the frequent occurrence of respiratory symptoms in children aged <2 years in the Greater Taipei area. Participants were recruited from an ongoing Taiwanese birth cohort study. We analyzed the data of the participants who had been recruited from January 2011 to April 2014 and had responded to the follow-up questionnaires at 6, 12, and 24 months. Self-administered questionnaires were used to collect participants' sociodemographic background and health, such as respiratory symptoms, and parental mental health. Pre- and postnatal pollution levels were estimated using the spatial interpolation technique (ordinary kriging) at children's residential addresses. Land use types surrounding participants' homes were evaluated by performing buffer analysis. Multiple logistic regression analyses were conducted to examine the effects of risk factors on the frequent occurrence of child respiratory symptoms in children aged 6, 12, and 24 months. We included 228, 360, and 441 children aged 6, 12, and 24 months, respectively. Our results indicated that postnatal exposure to PM2.5 and O3 was positively associated with children's respiratory symptoms. Traffic-related land-use types, sports facilities, and commercial land surrounding homes exerted adverse effects on children's respiratory symptoms, whereas the presence of schools in the neighborhood was beneficial. Parental mental health was also associated with children's respiratory symptoms. Postnatal exposure to air pollution and land use types surrounding residences were associated with respiratory health in children aged <2 years. The residential environment is a critical factor affecting children's respiratory health of children aged <2 years.

Predictors of adherence, contamination and dropout in home-based walking by lung and oesophageal cancer patients from two randomised control trials: An exploratory study.

OBJECTIVES: In this study, we examined predictors of exercise adherence, contamination and dropout in lung and oesophageal cancer patients who participated in two randomised controlled trials. METHODS: We used data on 188 lung and oesophageal cancer patients from two previous studies (intervention: moderate-intensity walking for 12 weeks). Baseline measurements included demographic variables, disease characteristics, Hospital Anxiety and Depression Scale and Bouchard 3-day physical activity (PA) record. We used multiple linear and logistic regressions to analyse predictors of exercise adherence in the walking group, contamination in the control group and dropout in both groups. RESULTS: Pre-intervention exercise habits and baseline depression scores predicted adherence, with an explanatory power of 16.7% (p < 0.0001). Pre-intervention exercise habits (odds ratio [OR] 19.65, 95% confidence interval [CI] 2.76-139.97), baseline moderate PA (min/day) (OR 1.03, 95% CI 1.01-1.05) and baseline vigorous PA (min/day) (OR 1.09, 95% CI 1.01-1.18) predicted contamination. Baseline mild PA (10 min/day) (OR 0.94, 95% CI 0.89-0.99) predicted dropout. CONCLUSIONS: Pre-intervention exercise habits and baseline depression levels predicted exercise adherence in the walking group. In the control group, pre-intervention exercise habits and baseline moderate and vigorous PA predicted contamination. Baseline mild PA predicted dropout rates in both groups.

Clinicopathological Significance of Pathologic Complete Lymph Node Regression After Neoadjuvant Chemoradiotherapy in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Pathologic complete lymph node regression (LNR), where the lymph nodes show evidence of neoadjuvant treatment effect but have no viable residual tumor cells, is sometimes observed following neoadjuvant treatments and has been shown to be prognostic; conflicting results exist in the current literature. METHODS: Patients who received neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy for squamous carcinoma (ESCC) were retrospectively reviewed and classified according to their LNR score; 0: N(-) with no evidence of tumor involvement or regression; 1: N(-) with evidence of complete regression; 2: N(+) with < 50% viable tumor; and 3: N(+) with > 50% viable tumor. RESULTS: In total, 136 patients, comprising 73, 25, 16, and 22 patients with LNR scores of 0, 1, 2, or 3, respectively, were included. Pathologic complete LNR (LNR 1) was significantly associated with lower risks of lymphovascular invasion (0%, p < 0.001) and perineural invasion (4%, p = 0.038), and a higher rate of pathologic complete response in the primary tumor (76%, p < 0.001). The 5-year overall survival rates were 42.1%, 52.8%, and 8.0% in patients with an LNR score of 0, 1, and 2/3, respectively (p < 0.001). There was no significant difference between patients with LNR scores of 0 and 1 in overall survival (p = 0.454), disease-free survival (p = 0.501), and cumulative incidence of recurrences (hazard ratio 0.84, 95% confidence interval 0.432-1.623, p = 0.601). CONCLUSIONS: Pathologic complete LNR could be an indicator of nCRT sensitivity and can be regarded as a good prognostic factor in patients with ESCC. In the survival curve analysis that included patients with lymph node regression (LNR) scores of 0 (blue), 1 (red), and 2/3 (green), we found that patients with pathologic complete LNR (LNR 1), which suggests prior positive nodal involvement, had similar outcomes as those without evidence of prior tumor involvement in lymph node (LNR0).

Estimation of Soil and Dust Ingestion Rates from the Stochastic Human Exposure and Dose Simulation Soil and Dust Model for Children in Taiwan.

This study focuses on estimating the probabilistic soil and dust ingestion rates for children under 3 years old by the Stochastic Human Exposure and Dose Simulation Soil and Dust (SHEDS-S/D) model developed by the U.S. Environmental Protection Agency. The health risk of children's exposure to heavy metals through soil and dust ingestion and dermal absorption was then assessed in three exposure scenarios. In the exposure scenario of direct contact with soil, the average soil and dust ingestion rates for children aged 24 to 36 months were 90.7 and 29.8 mg day-1 in the sand and clay groups, respectively. Hand-to-mouth soil ingestion was identified as the main contributor to soil and dust ingestion rates, followed by hand-to-mouth dust ingestion and object-to-mouth dust ingestion. The soil-to-skin adherence factor was the most influential factor increasing the soil and dust ingestion rate based on a sensitivity analysis in the SHEDS-S/D model. Furthermore, the modeled soil and dust ingestion rates based on the SHEDS-S/D model were coincident with results calculated by the tracer element method. Our estimates highlight the soil ingestion rate as the key parameter increasing the risk for children, while a higher frequency of hand washing could potentially reduce the risk.

Effects of air pollution, land-use type, and maternal mental health on child development in the first two years of life in the Greater Taipei area.

INTRODUCTION: Few studies have investigated the associations of child development with air pollution, land-use type, and maternal mental health simultaneously. Therefore, we evaluated the effect of exposure to air pollutants during several critical periods of life, with adjustment for land-use type and maternal mental status, on child development at 6, 12, and 24 months of age in the Greater Taipei area. METHODS: Participants were selected from an ongoing Taiwanese birth cohort study. We analyzed the data of the participants who had been recruited from January 2011 to April 2014. Self-administered standardized questionnaires were used to collect information on sociodemographic factors, infant development and health, maternal mental status, etc. Air pollution levels in pre- and postnatal periods were estimated using a spatial interpolation technique (ordinary kriging) at children's residential addresses. Land-use types around participants' homes were evaluated using buffer analysis. We used multiple logistic regression analysis to examine the relationships between child development delay and environmental factors. RESULTS: In total, 228, 361, and 441 families completed child development forms at 6, 12, and 24 months of age, respectively. Our results indicated that prenatal exposure to particulate matter with aerodynamic diameter ≤10 µm and O3 and postnatal exposure to NO2 were negatively associated with child development. Traffic-related land-use types, gas stations, and power generation areas around participants' homes were also adversely correlated with child development. Moreover, poor maternal mental health was associated with child development delay. CONCLUSION: Prenatal exposure and postnatal exposure to air pollution were associated with development delay in children under 2 years of age, specifically those under 1 year of age, even after adjustment for land-use type and maternal mental status. Living environment is critical for the development of children under 2 years of age.

Exposure to PM2.5 is associated with malignant pleural effusion in lung cancer patients.

Air pollution has been recognized to be a risk factor for lung cancer. The objective of this study was to investigate the effects of air pollution on heavy metal alterations in the pleural effusion of lung cancer patients. Pleural effusion was collected from patients with lung cancer and congestive heart failure (CHF). One-year average levels of particulate matter with an aerodynamic diameter of < 10 µm (PM10), PM2.5, NO2, and SO2 were linked to the exposure of these subjects. Traffic-related metals, included Al, Fe, Cu, Zn, and Pb, were determined in the pleural effusion. Logistic regression models were used to examine their associations. There were 63 lung cancer patients and 31 CHF patients enrolled in the current study. We found that PM10, PM2.5, and NO2 were negatively correlated with Al in the pleural effusion, whereas PM2.5 was positively correlated with Zn in the pleural effusion. Increases in 1 µg/m3 of PM2.5 and 1 ng/mL of Zn were associated with lung cancer (adjusted OR=2.394, 95% CI= 1.446-3.964 for PM2.5; adjusted OR=1.003, 95% CI=1.000-1.005 for Zn). Increases in PM2.5 and Zn in the pleural effusion increased the risk of malignant pleural effusion in lung cancer patients (adjusted OR=1.517; 95% CI=1.082-2.127 for PM2.5; adjusted OR=1.002, 95% CI=1.000-1.005 for Zn). Furthermore, we observed that adenocarcinomas increased in association with a 1-µg/m3 increase in PM2.5 (crude OR=1.683; 95% CI=1.006-2.817) in lung cancer patients. In conclusion, PM2.5 exposure and the possible resultant Zn in the pleural effusion associated with the development of malignant pleural effusion in lung cancer.

Experience of sorafenib treatment in differentiated thyroid cancer from Taiwan.

BACKGROUND: Sorafenib has been shown to prolong the progression free survival (PFS) of advanced radioiodine (RAI) refractory differentiated thyroid cancer (DTC) and has been approved by the FDA as the result of the phase III DECISION trial. Sorafenib has been reimbursed for the treatment of RAI refractory DTC in Taiwan since Jan 2017. High percentage of adverse events (AE) was noted in DECISION trial. We conducted a study to show the real-world experience of sorafenib in Taiwan. METHODS: We retrospectively collected the clinical data, including dose, AE, and PFS of sorafenib, of the DTC patients who received sorafenib treatment in National Cheng Kung University Hospital and China Medical University Hospital by chart review from 2012 to 2018. RESULTS: Thirty-six advanced DTC patients with progression were included in this study. The starting dose of sorafenib in most patients was 200 mg twice daily and the mean daily maintenance dose was 433 mg. Five patients had partial response (13.9%) and 28 patients had stable disease (77.8%). The median PFS was 17.3 months (95% confidence interval: 11.9-33.6 months). Daily maintenance dose ≥ 600 mg was associated with better PFS (median PFS, not reached). The most common toxicity of sorafenib was hand foot skin reaction (69%), followed by diarrhea (42%), and skin rash (33%). Most of the toxicities were grade I/II. CONCLUSION: Higher maintenance dose of sorafenib is associated with longer PFS while starting from half dose is feasible to minimize the incidence of high grade toxicities in the real-world use of sorafenib.