Emerging chemotherapy-based treatments in anaplastic thyroid cancer: an updated analysis of prospective studies.

Background: For patients with anaplastic thyroid cancer (ATC) without mutational driver genes, chemotherapy is suggested to be the first-line treatment option. However, the benefits of chemotherapy in treating ATC are limited. In this analysis, we collected the prospective data reported since 2010 to analyze the emerging chemotherapy-based treatments in ATC comprehensively. Methods: For this updated analysis, we searched PubMed (MEDLINE), Web of Science, Embase, and Cochrane CENTRAL databases from 1 January 2010 to 7 February 2024 for prospective clinical studies that contained chemotherapy-based treatments. This analysis was done to pool overall survival (OS), progression-free survival (PFS), objective response rates (ORRs), disease control rates (DCRs), and grade 3 or worse treatment-related adverse events (TRAEs). Results: Six prospective clinical trials with 232 patients were included. Chemotherapy was commonly combined with targeted therapy or radiotherapy. The pooled median OS was 6.0 months (95% CI 4.1-9.7), and the median PFS was 3.2 months (95% CI 1.9-6.0) in patients with ATC who received chemotherapy-based strategies. The integrated ORR and DCR were 21% (95% CI 15%-27%) and 64% (95% CI 55%-72%), respectively. Regarding the grade 3 or worse TRAE, the pooled incidence was 68% (95% CI 47%-86%). Conclusion: Although the emerging chemotherapy-based treatments showed antitumor activity in patients with ATC, these strategies failed to prolong the survival time substantially. More practical, safe, and novel therapeutic regimens for patients with ATC warrant further investigations.

Tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: an effective analysis based on real-world retrospective studies.

Background: Tyrosine kinase inhibitors (TKIs) contribute to the treatment of patients with anaplastic thyroid cancer (ATC). Although prospective clinical studies of TKIs exhibit limited efficacy, whether ATC patients benefit from TKI treatment in real-world clinical practice may enlighten future explorations. Therefore, we conducted this effective analysis based on real-world retrospective studies to illustrate the efficacy of TKI treatment in ATC patients. Methods: We systematically searched the online databases on September 03, 2023. Survival curves were collected and reconstructed to summarize the pooled curves. Responses were analyzed by using the "meta" package. The primary endpoints were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: 12 studies involving 227 patients were enrolled in the study. Therapeutic strategies included: anlotinib, lenvatinib, dabrafenib plus trametinib, vemurafenib, pembrolizumab plus dabrafenib and trametinib, pembrolizumab plus lenvatinib, pembrolizumab plus trametinib, and sorafenib. The pooled median OS and PFS were 6.37 months (95% CI 4.19-10.33) and 5.50 months (95% CI 2.17-12.03). The integrated ORR and DCR were 32% (95% CI 23%-41%) and 40% (95% CI 12%-74%). Conclusion: In real-world clinical practice, ATC patients could benefit from TKI therapy. In future studies, more basic experiments and clinical explorations are needed to enhance the effects of TKIs in the treatment of patients with ATC.

Artificial light at night, MRI-based measures of brain iron deposition and incidence of multiple mental disorders.

BACKGROUND: Epidemiologic evidence on whether iron accumulation in brain modified the association between artificial light at night (ALAN) and incident mental disorders is lacking. The authors aims to investigate modification of brain iron deposition on the associations of ALAN with multiple mental disorders in the middle-aged and older adults. METHODS: This prospective study used data from the UK Biobank. ALAN was drawn from satellite datasets. Susceptibility-weighted magnetic resonance imaging was used to ascertain iron content of each brain region. T2* signal loss was used as indices of iron deposition. The main outcomes are impacts of ALAN exposure on onset of wide spectrum of physician-diagnosed mental disorders, which was estimated by time-varying Cox proportional hazard model. The authors further conducted stratified analyses by levels of iron brain deposition to examine the potential modifying effects. RESULTS: Among 298,283 participants followed for a median of 10.91 years, higher ALAN exposure was associated with increased risk of mental disorders. An IQR (11.37 nW/cm2/sr) increase in annual levels of ALAN was associated with an HR of 1.050 (95 % CI: 1.034,1.066) for any mental disorder, 1.076 (95 % CI: 1.053,1.099) for substance use disorder, and 1.036 (95 % CI: 1.004,1.069) for depression disorder in fully adjusted models. The exposure-response curves showed steeper trends at lower ALAN levels and a plateau at higher exposures. The associations were stronger in participants with high iron deposition in left hippocampus, left accumbens and left pallidum. CONCLUSIONS: ALAN was associated with multiple mental disorders in the middle-aged and older adults, and the findings indicated stricter standards of ALAN is needed and targeted preventive measures are warranted, especially with high brain iron deposition.

Contrived Materials and a Data Set for the Evaluation of Liquid Biopsy Tests: A Blood Profiling Atlas in Cancer (BLOODPAC) Community Study.

The Blood Profiling Atlas in Cancer (BLOODPAC) Consortium is a collaborative effort involving stakeholders from the public, industry, academia, and regulatory agencies focused on developing shared best practices on liquid biopsy. This report describes the results from the JFDI (Just Freaking Do It) study, a BLOODPAC initiative to develop standards on the use of contrived materials mimicking cell-free circulating tumor DNA, to comparatively evaluate clinical laboratory testing procedures. Nine independent laboratories tested the concordance, sensitivity, and specificity of commercially available contrived materials with known variant-allele frequencies (VAFs) ranging from 0.1% to 5.0%. Each participating laboratory utilized its own proprietary evaluation procedures. The results demonstrated high levels of concordance and sensitivity at VAFs of >0.1%, but reduced concordance and sensitivity at a VAF of 0.1%; these findings were similar to those from previous studies, suggesting that commercially available contrived materials can support the evaluation of testing procedures across multiple technologies. Such materials may enable more objective comparisons of results on materials formulated in-house at each center in multicenter trials. A unique goal of the collaborative effort was to develop a data resource, the BLOODPAC Data Commons, now available to the liquid-biopsy community for further study. This resource can be used to support independent evaluations of results, data extension through data integration and new studies, and retrospective evaluation of data collection.

Long-Term Apparent Temperature, Extreme Temperature Exposure, and Depressive Symptoms: A Longitudinal Study in China.

Temperature is increasingly understood to impact mental health. However, evidence of the long-term effect of temperature exposure on the risk of depressive symptoms is still scarce. Based on the China Health and Retirement Longitudinal Study (CHARLS), this study estimated associations between long-term apparent temperature, extreme temperature, and depressive symptoms in middle-aged and older adults. Results showed that a 1 °C increase or decrease from optimum apparent temperature (12.72 °C) was associated with a 2.7% (95% CI: 1.3%, 4.1%) and 2.3% (95% CI: 1.1%, 3.5%) increased risk of depressive symptoms, respectively. This study also found that each percent increase in annual change in ice days, cool nights, cool days, cold spell durations, and tropical nights was associated with higher risk of depressive symptoms, with HRs (95%CI) of 1.289 (1.114-1.491), 2.064 (1.507-2.825), 1.315 (1.061-1.631), 1.645 (1.306-2.072), and 1.344 (1.127-1.602), respectively. The results also indicated that people living in northern China have attenuated risk of low apparent temperature. Older people were also observed at higher risk relating to more cool nights. Middle-aged people, rural residents, and people with lower household income might have higher related risk of depressive symptoms due to increased tropical nights. Given the dual effect of climate change and global aging, these findings have great significance for policy making and adaptive strategies for long-term temperature and extreme temperature exposure.

Air pollution, greenness and risk of overweight among middle-aged and older adults: A cohort study in China.

BACKGROUND: Exposure to air pollution may increase the risk of obesity, but living in greener space may reduce this risk. Epidemiological evidence, however, is inconsistent. METHODS: Using data from the China Health and Retirement Longitudinal Study (2011-2015), we conducted a nationwide cohort study of 7424 adults. We measured overweight/obesity according to body mass index. We used annual average ground-level air pollutants, including ozone (O3), nitrogen dioxide (NO2), and particulate matter with aerodynamic diameters ≤2.5 µm (PM2.5), to demonstrate air pollution levels. We used the Normalized difference vegetation index (NDVI) to measure greenness exposure. We used time-varying Cox proportional hazard regression models to analyze the connections among air pollution, greenness, and the development of overweight/obesity in middle-aged and older adults in China. We also conducted mediation analyses to examine the mediating effects of air pollution. RESULTS: We found that lower risk of overweight/obesity was associated with more greenness exposure and lower levels of air pollution. We identified that an interquartile increment in NDVI was correlated with a lower hazard ratio (HR) of becoming overweight or obese (HR = 0.806, 95% confidence interval [CI]: 0.754-0.862). Although a 10 µg/m3 increase in PM2.5 and NO2 was correlated with higher risks (HR = 1.049, 95% CI = 1.022-1.075, HR = 1.376, 95% CI = 1.264-1.499). Effects of PM2.5 on being overweight or obese were stronger in men than in women. According to the mediation analysis, PM2.5 and NO2 mediated 8.85% and 19.22% of the association between greenness and being overweight or obese. CONCLUSIONS: An increased risk of being overweight or obese in middle-aged and older adults in China was associated with long-term exposure to higher levels of PM2.5 and NO2. This risk was reduced through NDVI exposure, and the associations were partially mediated by air pollutants. To verify these findings, fine-scale studies are needed.

The establishment of Air Quality Health Index in China: A comparative analysis of methodological approaches.

BACKGROUND: The Air Quality Index (AQI) has been criticized because it does not adequately account for the health effect of multi-pollutants. Although the developed Air Quality Health Index (AQHI) is a more effective communication tool, little is known about the best method to construct AQHI on long time and large spatial scales. OBJECTIVES: To further evaluate the validity of existing approaches to the establishment of AQHI on both long time and larger spatial scales. METHODS: By introducing 3 approaches addressing multi-pollutant exposures: cumulative risk index (CRI), supervised principal component analysis (SPCA), and Bayesian multi-pollutants weighted model (BMP), we constructed CRI-AQHI, SPCA-AQHI, BMP-AQHI and standard-AQHI on cardiovascular mortality in China from 2015 to 2019 at both the national and geographic regional levels. We further assessed the performance of the four methods in estimating the joint effect of multi-pollutants by simulations under various scenarios of pollution effect. RESULTS: The results of national China showed that the BMP-AQHI improved the goodness of fit of the standard-AQHI by 108.24%, followed by CRI-AQHI (5.02%), and all AQHIs performed better than AQI, consistent with 6 geographic regional results. In addition, the simulation result showed that the BMP method provided stable and relatively accurate estimations of the short-term combined effect of exposure to multi-pollutants. CONCLUSIONS: AQHI based on BMP could communicate the air pollution risk to the public more effectively than the current AQHI and AQI.

Long-Term Temperature Variability and Risk of Dyslipidemia Among Middle-Aged and Elderly Adults: A Prospective Cohort Study - China, 2011-2018.

What is already known about this topic?: Long-term temperature variability (TV) has been examined to be associated with cardiovascular disease (CVD). TV-related dyslipidemia helps us understand the mechanism of how climate change affects CVD. What is added by this report?: Based on the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2018, this study estimated the long-term effect of TV on dyslipidemia in middle-aged and elderly adults. What are the implications for public health practice?: This study suggested that long-term TV may increase the risk of dyslipidemia. With the threat of climate change, these findings have great significance for making policies and adaptive strategies to reduce relevant risk of CVD.

Associations between greenness and blood pressure and hypertension in Chinese middle-aged and elderly population: A longitudinal study.

BACKGROUND: Greenness is an emerging modifiable environmental factor of high blood pressure and hypertension. However, current evidence is inconsistent, and high-quality studies are urgently needed, especially in developing country with high disease burden of hypertension. METHODS: A longitudinal study was designed and 9,649 participants (aged ≥45 years) with 22,854 number of visits among three waves between 2011 and 2015 were included based on the China Health and Retirement Longitudinal Study. Long term greenness exposure was assessed by annual normalized difference vegetation index (NDVI). Linear and generalized linear mixed effect models were used to estimate the associations between greenness and blood exposure level and hypertension risk, respectively. RESULTS: The median NDVI level was 0.51, with a range from 0.09 to 0.74. An interquartile range (0.15) increase in NDVI was related to 1.05 mmHg reduction (95% CI: -1.65, -0.45) of systolic blood pressure, 0.72 mmHg reduction (95% CI: -1.06, -0.37) of diastolic blood pressure, and 12% (95% CI: 1%, 22%) lower odds of hypertension risk. The association of greenness and blood pressure was significantly stronger in the younger (<60 years) than in the older (≥60 years), and partially mediated by body mass index. CONCLUSIONS: These findings highlight the protective effect of greenness on blood pressure and hypertension in Chines middle-aged and elderly population, especially in the younger (<60 years), and suggest policy makers to take greenness level into special consideration in the process of urbanization.

Discovery of a wild, genetically pure Chinese giant salamander creates new conservation opportunities.

Effective conservation of threatened biota relies on accurate assessments and scientific guidance. As an unfortunate example, Chinese giant salamanders ( Andrias, CGS) remain critically endangered in nature. Misguided conservation efforts, e.g., commercial propagation and releasing of millions of likely non-indigenous or interspecific hybrids, have further compromised conservation initiatives. Limited information on wild populations of CGS poses a significant conservation challenge. Following 18-month long field monitoring, we now report the discovery of a wild population of CGS in a closed nature reserve in Jiangxi Province, China. Genomic assessments reveal its genetic distinctiveness and do not detect genetic admixture with other species. Based on morphological and molecular evidences, we describe this CGS as a new species Andrias jiangxiensis sp. nov. This is the only known species of CGS today with a genetically pure, reproducing, in situ population. This discovery emphasizes the important role that closed nature reserves play in protecting species, and the necessity of integrating long-term field monitoring and genetic assessments. It sets a new pathway for discovering and conserving endangered species, especially for those biotas that are similarly being extirpated by anthropogenic translocations and overexploitation.

Long-term exposure to ozone and diabetes incidence: A longitudinal cohort study in China.

BACKGROUND: Ozone (O3) has become a prominent air pollutant problem as other pollutants concentrations have decreased obviously since China published Air Pollution Action Plan Pollution Prevention Action Plan in 2013. Few studies examined the association between O3 and diabetes especially in developing countries. This study was designed to investigate the above topic in China. METHODS: We conducted a prospective cohort study based on a nationwide survey of 13,548 adults from China Health and Retirement Longitudinal Study. City-level exposure to ozone for each participant was matched through ChinaHighO3 dataset. Time-varying cox proportional hazard regression model was applied to determine the association. Stratification analyses were conducted to explore potential effect modification. RESULTS: The annual mean concentration of O3 was 86.6 µg/m3. A 10 µg/m3 increase in 1-year average O3 concentration was associated with 5.7% (95% CI: 1.004-1.114) relative increment in hazards ratio of diabetes incidence in the fully adjusted model. Results stayed stable when controlling for physical activity, PM2.5 and mean temperature. CONCLUSIONS: Our findings provided initial support for a positive and robust association between long-term exposure to O3 and diabetes incidence in a developing country. More scientific and social attention should be attached to the ozone-induced risks of diabetes occurrence.

Effect of freezing treatment of soybean on soymilk nutritional components, protein digestibility, and functional components.

Soymilk is a popular beverage in many countries owing to its nutrition and health effects. To increase household consumption of soymilk, instant soybeans were developed by freezing and subsequent drying pretreatment, which overcome the time-consuming need of soaking during soymilk preparation for home making. However, compared with the traditional soymilk making, the nutritional quality and functional properties of this soymilk made from the soybean by direct grinding in water without soaking are not clear yet. Soymilk made from untreated soybeans, soaked soybeans, and soaking, freezing, and air-drying soybeans (FADTS) were compared on their properties including nutritional components, in vitro protein digestibility, and functional components. It was found that FADTS was the best at extracting lipid and Ca, good at extracting of protein, carbohydrate, oligosaccharides, Fe, phytic acids, and tannins, and in producing soymilks with highest in vitro protein digestibility. The soluble protein and protein digestibility of FADTS (4 day) increased significantly from 44.4% and 78.5% of control to 56.2% and 85.0%, respectively. Soymilk from 4 days FADTS contained similar protein content and higher Fe content (4.40 mg/kg) compared to soaked sample (3.82 mg/kg). The results revealed that FADTS performed better at producing soymilk than untreated and soaked soybeans.

Estimating Short- and Long-Term Associations Between Air Quality Index and COVID-19 Transmission: Evidence From 257 Chinese Cities.

Objectives: To evaluate the long- and short-term effects of air pollution on COVID-19 transmission simultaneously, especially in high air pollution level countries. Methods: Quasi-Poisson regression was applied to estimate the association between exposure to air pollution and daily new confirmed cases of COVID-19, with mutual adjustment for long- and short-term air quality index (AQI). The independent effects were also estimated and compared. We further assessed the modification effect of within-city migration (WM) index to the associations. Results: We found a significant 1.61% (95%CI: 0.51%, 2.72%) and 0.35% (95%CI: 0.24%, 0.46%) increase in daily confirmed cases per 1 unit increase in long- and short-term AQI. Higher estimates were observed for long-term impact. The stratifying result showed that the association was significant when the within-city migration index was low. A 1.25% (95%CI: 0.0.04%, 2.47%) and 0.41% (95%CI: 0.30%, 0.52%) increase for long- and short-term effect respectively in low within-city migration index was observed. Conclusions: There existed positive associations between long- and short-term AQI and COVID-19 transmission, and within-city migration index modified the association. Our findings will be of strategic significance for long-run COVID-19 control.

The Improvement of Air Quality and Associated Mortality during the COVID-19 Lockdown in One Megacity of China: An Empirical Strategy.

Although the lockdown policy implemented during the COVID-19 pandemic indeed improved the air quality and reduced the related health risks, the real effects of the lockdown and its resulting health risks remain unclear considering the effects of unobserved confounders and the longstanding efforts of the government regarding air pollution. We compared air pollution between the lockdown period and the period before the lockdown using a difference-in-differences (DID) model and estimated the mortality burden caused by the number of deaths related to air pollution changes. The NO2 and CO concentrations during the lockdown period (17 days) declined by 8.94 µg/m3 (relative change: 16.94%; 95% CI: 3.71, 14.16) and 0.20 mg/m3 (relative change: 16.95%; 95% CI: 0.04, 0.35) on an average day, respectively, and O3 increased by 8.41 µg/m3 (relative change: 32.80%; 95% CI: 4.39, 12.43); no meaningful impacts of the lockdown policy on the PM2.5, PM10, SO2, or the AQI values were observed. Based on the three clearly changed air pollutants, the lockdown policy prevented 8.22 (95% CI: 3.97, 12.49) all-cause deaths. Our findings suggest that the overall excess deaths caused by air pollution during the lockdown period declined. It is beneficial for human health when strict control measures, such as upgrading industry structure and promoting green transportation, are taken to reduce emissions, especially in cities with serious air pollution in China, such as Shijiazhuang.

The Mortality Effect of Apparent Temperature: A Multi-City Study in Asia.

(1) Background: The health effect of temperature has become a rising public health topic. The objective of this study is to assess the association between apparent temperature and non-accidental deaths, and the mortality burden attributed to cold and heat temperature; (2) Methods: The daily data on temperature and deaths were collected from 10 cities in Thailand, Korea and China. We fitted a time-series regression with a distributed lag nonlinear model (DLNM) to derive the health risk of temperature for each city and then pooled them to get the overall cumulative risk by multivariate meta-analysis. Additionally, we calculated the attributable fraction of deaths for heat and cold, which was defined as temperatures above and below minimum-mortality temperature (MMT); (3) Results: There are regional heterogeneities in the minimum mortality percentiles (MMP) and attributable fractions for different countries. The MMP varied from about the 5-10th percentile in Thailand to 63-93rd percentile in China and Korea. The attributable fractions of the total deaths due to short-term exposure to temperature in Asia is 7.62%, of which the cold effect (6.44%) is much higher than the heat effect (1.18%); (4) Conclusions: Our study suggested that apparent temperature was associated with an increase in non-accidental mortality. Most of the temperature-related mortality burden was attributable to cold, except for Thailand.

The construction of the air quality health index (AQHI) and a validity comparison based on three different methods.

The most common currently used air quality risk communication tool, the Air Quality Index (AQI), has been criticized. As a result, Canada proposed the Air Quality Health Index (AQHI) to communicate the health risks of multiple pollutants. However, the AQHI is calculated by directly summing the excess risks from single-pollutant models, which may overestimate the effects of the pollutants. To solve this problem, we introduced two methods for estimating the joint effects of multiple pollutants: the cumulative risk index (CRI) and supervised principal component analysis (SPCA). Based on three methods, i.e., the standard, CRI and SPCA methods, we constructed three types of AQHIs and compared their validity to select the best communication tool. Our results showed that compared with the AQI, all three AQHIs had a linear relationship with mortality. In addition, the CRI-AQHI had the best goodness of fit and captured the overall health risk of pollution mixtures most robustly among various cause-specific mortalities when identifying health risks. Our study indicated that the CRI-AQHI may have the potential to be a better alternative to the standard AQHI in communicating air pollution-related health risks to the public.

The association between ozone and years of life lost from stroke, 2013-2017: A retrospective regression analysis in 48 major Chinese cities.

The adverse impact of ozone on public health has attracted worldwide attention. However, few studies have addressed the contribution of ozone to disease burden caused by cardiovascular diseases. This study aimed to examine the association between short-term ozone exposure and years of life lost (YLL) from stroke in 48 Chinese cities. City-specific relative change of YLL was estimated by a generalized additive model, then pooled using random-effects meta-analysis. The potential effect modification of individual, climatic, and city-level characteristics was also evaluated. A 10 µg/m3 increase in three-day moving average of ozone concentration was associated with 0.54% (95% CI: 0.41%, 0.66%), 0.25% (95% CI: 0.10%, 0.40%), and 0.70% (95% CI: 0.48%, 0.92%) relative increment in YLL from stroke, haemorrhagic stroke, and ischaemic stroke, respectively. The association magnitudes were larger in elderly people, females, or higher quartile groups of temperature (all p < 0.01). The potential avoidable life lost due to YLL from stroke was 5.5 days per deceased person if ozone concentration could reduce to the standard recommended by the World Health Organization (100 µg/m3). Our findings provided robust evidence on the impact of short-term ozone exposure on YLL from stroke and called for more stringent regulation of ozone.

The burden of sulfur dioxide pollution on years of life lost from chronic obstructive pulmonary disease: A nationwide analysis in China.

BACKGROUND: Sulfur dioxide (SO2) is one of the major gaseous pollutants in China and other developing countries. Few multicity studies have been done to examine the short-term effect of SO2 on cause-specific years of life lost (YLL). This study was designed to investigate the burden of chronic obstructive pulmonary disease (COPD) associated with SO2 exposure. METHODS: A 5-year time-series study was conducted in 48 Chinese cities from 2013 to 2017. Generalized additive models were first used to estimate the city-specific relationship. Then, random-effects meta-analyses were applied to pool the estimates. Furthermore, the roles of potential modifiers and the related economic loss estimated by the method of value per statistical life year were also evaluated. RESULTS: The annual mean concentration of SO2 was 27.1 µg/m3. A 10 µg/m3 increase in 4-day moving average (lag03) of SO2 concentration was associated with 0.83% (95% CI: 0.13%, 1.53%) relative increment in YLL from COPD, and relevant percent change of mortality was 0.78% (95% CI: 0.16%, 1.41%). Moreover, a significantly higher effect was observed in the warm season, particularly in the south region. SO2 exposure was estimated to account for 1.89% of the total economic loss due to YLL from COPD. CONCLUSIONS: Our findings showed a positive association between short-term exposure to SO2 and YLL from COPD and highlighted the importance of continuous control of SO2 pollution to reduce corresponding attributable disease burden.

Ambient sulfur dioxide and years of life lost from stroke in China: a time-series analysis in 48 cities.

BACKGROUND AND OBJECTIVES: Sulfur dioxide (SO2) is a ubiquitous air pollutant and its concentration in China remains at a higher level in the world. However, evidence regarding short-term effect of SO2 on years of life lost (YLL) from stroke is scarce. We aim to estimate the short-term association between SO2 pollution and YLL for stroke and the related excess life years and economic loss. METHODS: A national time-series study was conducted in 48 Chinese cities from 2013 to 2017. Generalized additive model coupled with random-effects model were used to explore the effects of SO2 on YLL from stroke. Stratified analyses were performed by demographical and geographical factors, and the effect modification of city-level factors was estimated. In addition, the related economic loss was calculated using the method of the value per statistical life year (VSLY). RESULTS: Averaged daily mean SO2 concentration was 27.1 µg/m3 in 48 Chinese cities from 2013 to 2017. Per 10 µg/m3 increase in the concentration of SO2 (lag03) was associated with an increment of 0.70% (95% confidence interval: 0.27%,1.13%), 0.51% (-0.01%,1.04%), 0.71% (0.14%,1.28%) increase in YLL from total stroke, hemorrhagic and ischemic stroke, respectively. The effect of short-term ambient SO2 exposure on YLL from stroke was more pronounced in the less-educated population and those living in the south. The corresponding excess economic loss during the study period due to SO2-related YLL from stroke accounted for 0.08% (0.03%, 0.13%) of the GDP in China. CONCLUSIONS: Our results provide evidence from China that short-term exposure to SO2 is positively associated with YLL from stroke and its major subtypes in certain subgroups of population. This study calls for greater awareness of the adverse health effect due to SO2 in China and other developing countries, as well as local-specific implementation of air pollution mitigation measures.

Establishment of a type II insulin-like growth factor receptor gene site-integrated SKBR3 cell line using CRISPR/Cas9.

Human epidermal growth factor receptor 2 (HER-2)+ breast cancer has a high recurrence rate and a poor prognosis, with drug resistance contributing to disease progression. The present study aimed to establish a SKBR3 cell line with type II insulin-like growth factor receptor (IGR-IIR) gene site integration using the CRISPR/Cas9 system, and to provide a cell model for exploring the mechanism responsible for the effect of IGF-IIR on trastuzumab resistance in HER-2+ breast cancer cells. In the present study, six single guide (sg)RNA pairs according to the adeno-associated virus integration site 1 (AAVS1) gene sequence were designed and synthesized, and the Universal CRISPR Activity assay CRISPR/Cas9 rapid construction and activity detection kit was used to connect the annealed oligo with the pCS vector. The sgRNA with the highest efficiency was selected to construct a Cas9/sgRNA expression vector using AsiSI + Bstz17I restriction enzymes to cut IGF-IIR. The fragment was ligated into an human AAVS1-KI vector to construct the IGF-IIR targeting vector. The Cas9/sgRNA and IGF-IIR targeting vectors were electroporated into SKBR3 cells, screened using puromycin and identified via PCR, and the mixed cloned cells generated via IGF-IIR gene targeted integration were obtained. The semi-solid and limited dilution methods were used for monoclonal cell preparation, and the results revealed that a Cas9/sgRNA vector that targeted the AAVS1 was successfully constructed. sgRNA activity detection demonstrated that sgRNA2 had the highest efficiency, while enzyme digestion and sequencing confirmed that the IGF-IIR target vector was successfully constructed. The optimum conditions for electrotransfection were 1,200 V, 20 ms and 2 pulses, and the optimal screening concentration of puromycin was 0.5 µg/ml. Using these conditions, the IGF-IIR targeting vector and pCS-sgRNA2 plasmid were successfully transfected into SKBR3 cells, and PCR identification and sequencing verified the correct genotype of mixed clone fragments. The monoclonal cells proliferate slowly and gradually underwent apoptosis. Overall, the present study successfully obtained a mixed clone cell line with site-specific integration of the IGF-IIR gene at the AAVS1.