Four-band terahertz metamaterial absorber based on Dirac semimetal for a refractive index sensing application.

We design a four-band narrow-band near-perfect absorber based on bulk Dirac semimetal (BDS) metamaterial in the terahertz region. The absorber has a top-to-bottom three-layer structure of a BDS layer, an insulating dielectric slab, and a gold layer. The BDS is flexible and tunable, allowing the Fermi energy level to be adjusted by changing the applied bias voltage, thus changing the absorption characteristics of the absorber. We use the time-domain finite-difference method to simulate the absorption characteristics of the absorber, which could achieve four discrete near-perfect absorption peaks at 0.98 THz, 1.70 THz, 2.02 THz, and 2.36 THz. The absorber is polarization sensitive, and the conversion between four-band absorption and three-band absorption is achieved by changing the incident polarization angle. We also change the structure of the absorber to study the absorption characteristics and break the structural symmetry to achieve a larger number of absorption peaks. Besides, the sensing performance of four-band narrow-band absorption is analyzed, and the maximum sensitivity of the absorber is 112.78 GHz/RIU. The device should have vast application prospects for bio-detection and high-sensitivity biosensing detection.

Extreme temperature exposure increases the risk of preterm birth in women with abnormal pre-pregnancy body mass index: a cohort study in a southern province of China.

Background: Prior literature has found that extreme temperature exposure is associated with preterm birth (PTB). However, current evidence provides heterogeneous conclusions, and data on extreme cold and across different pre-pregnancy body mass index (BMI) statuses are limited. Methods: We conducted a population-based retrospective cohort of 251,257 women between 2014 and 2017 in Guangdong, China, to evaluate whether the association between extreme temperature exposure and PTB varied in pre-pregnancy BMI status. Participants were divided into three categories based on pre-pregnancy BMI: underweight (BMI < 18.5 kg/m2), normal weight (18.5-23.9 kg/m2), overweight or obesity (≥ 24.0 kg/m2). We fitted Cox proportional hazards models to assess the association between daily mean temperature and PTB at each trimester for each BMI category separately. The hazard ratios (HRs) at the 5th and 95th percentiles of temperature (defined as low and high temperatures respectively) were provided using the median temperature at each trimester as a reference. Results: 58,220 (23.2%) were underweight, and 27,865 (11.1%) were overweight or obese. Of the 251,257 women, 18,612 (7.41%) had PTB delivery. Both low-and high-temperature exposure increased the risk of PTB in the third trimester, while cold exposure mostly mitigated the risk for the first and second trimesters. The association with low temperature was the strongest in the third trimester, especially for underweight women (HR: 1.825; 95%CI: 1.529 ~ 2.179), while the association with high temperature was the strongest also in the third trimester, especially for obese or overweight women (HR:1.825; 95%CI:1.502 ~ 2.218). Furthermore, the attributable fractions of PTB risk in the third trimester were estimated as 5.59% (95% CI: 3.58, 7.98%) for cold exposure among underweight women and 3.31% (95% CI: 2.01, 4.88%) for hot exposure among overweight or obese women. Conclusion: Exposure to either low temperature in the third trimester or high temperature during pregnancy was associated with a higher risk of PTB. Moreover, pre-pregnancy BMI status might affect the susceptibility of pregnant women. Such findings would be useful to develop targeted measures for vulnerable populations.

Epidemiology of hepatitis B virus infection among preconception couples in South China: a cross-sectional study.

OBJECTIVES: Hepatitis B virus (HBV) infection is a global public health threat, and couples of reproductive age comprise a key population in aiming to reduce both the vertical and horizontal transmission of HBV. We aimed to update knowledge on the seroepidemiology status of HBV in Guangdong, China among a large number of couples planning conception, and to identify high-risk subgroups. DESIGN: A cross-sectional study was performed in Guangdong, China from 2014 to 2017. SETTING: The data were collected from 641 642 couples (1 283 284 individuals) participating in the National Free Preconception Health Examination Project in Guangdong, China from 1 January 2014 to 31 December 2017. For each participant, sociodemographic data were obtained and a serum sample was tested for HBV infection status. RESULTS: 161 204 individuals (12.56%) were positive for hepatitis B surface antigen (HBsAg+), and 47 318 (3.69%) were positive for both HBsAg and hepatitis B e antigen (HBsAg+ and HBeAg+). There was a higher prevalence of HBsAg+ (12.77% vs 9.42%, p<0.05) and HBsAg+ and HBeAg+ (3.77% vs 2.45%, p<0.05) among the participants with a Guangdong household registration than a non-Guangdong household registration. Similarly, the prevalence of HBsAg (13.26% vs 11.72%, p<0.05) and HBsAg+ and HBeAg+ (4.31% vs 2.94%, p<0.05) was higher among participants not living in the Pearl River Delta than those living in the Pearl River Delta. At the couple level, 12 446 couples (1.94%) were both positive; in 51 849 (8.08%), only the wife was positive; in 84 463 (13.16%), only the husband was positive. Moreover, HBsAg+ prevalence was lowest in couples where both individuals were vaccinated (18.63%) and highest in couples where neither the wife or husband was vaccinated (24.46%). CONCLUSION: There was a relatively high HBsAg+ prevalence in married couples in this high-epidemic region and urgent prevention strategies are required, such as ensuring access to health services for those not living in the Pearl River Delta, and expanding vaccine programmes to high-risk adults.

Inhibitory Effects of Extracellular Vesicles from iPS-Cell-Derived Mesenchymal Stem Cells on the Onset of Sialadenitis in Sjögren's Syndrome Are Mediated by Immunomodulatory Splenocytes and Improved by Inhibiting miR-125b.

Extracellular vesicles (EVs) from allogeneic-tissue-derived mesenchymal stem cells (MSCs) are promising to improve Sjögren's syndrome (SS) treatment, but their application is hindered by high variations in and limited expandability of tissue MSCs. We derived standardized and scalable MSCs from iPS cells (iMSCs) and reported that EVs from young but not aging iMSCs (iEVs) inhibited sialadenitis onset in SS mouse models. Here, we aim to determine cellular mechanisms and optimization approaches of SS-inhibitory effects of iEVs. In NOD.B10.H2b mice at the pre-disease stage of SS, we examined the biodistribution and recipient cells of iEVs with imaging, flow cytometry, and qRT-PCR. Intravenously infused iEVs accumulated in the spleen but not salivary glands or cervical lymph nodes and were mainly taken up by macrophages. In the spleen, young but not aging iEVs increased M2 macrophages, decreased Th17 cells, and changed expression of related immunomodulatory molecules. Loading miR-125b inhibitors into aging iEVs significantly improved their effects on repressing sialadenitis onset and regulating immunomodulatory splenocytes. These data indicated that young but not aging iEVs suppress SS onset by regulating immunomodulatory splenocytes, and inhibiting miR-125b in aging iEVs restores such effects, which is promising to maximize production of effective iEVs from highly expanded iMSCs for future clinical application.

Sphingosine-1-Phosphate Alleviates Irradiation Induced Salivary Gland Hypofunction through Preserving Endothelial Cells and Resident Macrophages.

Radiotherapy for head-and-neck cancers frequently causes long-term hypofunction of salivary glands that severely compromises quality of life and is difficult to treat. Here, we studied effects and mechanisms of Sphingosine-1-phosphate (S1P), a versatile signaling sphingolipid, in preventing irreversible dry mouth caused by radiotherapy. Mouse submandibular glands (SMGs) were irradiated with or without intra-SMG S1P pretreatment. The saliva flow rate was measured following pilocarpine stimulation. The expression of genes related to S1P signaling and radiation damage was examined by flow cytometry, immunohistochemistry, quantitative RT-PCR, Western blotting, and/or single-cell RNA-sequencing. S1P pretreatment ameliorated irradiation-induced salivary dysfunction in mice through a decrease in irradiation-induced oxidative stress and consequent apoptosis and cellular senescence, which is related to the enhancement of Nrf2-regulated anti-oxidative response. In mouse SMGs, endothelial cells and resident macrophages are the major cells capable of producing S1P and expressing the pro-regenerative S1P receptor S1pr1. Both mouse SMGs and human endothelial cells are protected from irradiation damage by S1P pretreatment, likely through the S1pr1/Akt/eNOS axis. Moreover, intra-SMG-injected S1P did not affect the growth and radiosensitivity of head-and-neck cancer in a mouse model. These data indicate that S1P signaling pathway is a promising target for alleviating irradiation-induced salivary gland hypofunction.

Same environment, stratified impacts? Air pollution, extreme temperatures, and birth weight in South China.

This paper investigates whether associations between birth weights and prenatal ambient environmental conditions-pollution and extreme temperatures-differ by 1) maternal education; 2) children's innate health; and 3) interactions between these two. We link birth records from Guangzhou, China, during a period of high pollution, to ambient air pollution (PM10 and a composite measure) and extreme temperature data. We first use mean regressions to test whether, overall, maternal education is an "effect modifier" in the relationships between ambient air pollution, extreme temperature, and birth weight. We then use conditional quantile regressions to test for effect heterogeneity according to the unobserved innate vulnerability of babies after conditioning on other confounders. Results show that 1) the negative association between ambient exposures and birth weight is twice as large at lower conditional quantiles of birth weights as at the median; 2) the protection associated with college-educated mothers with respect to pollution and extreme heat is heterogeneous and potentially substantial: between 0.02 and 0.34 standard deviations of birth weights, depending on the conditional quantiles; 3) this protection is amplified under more extreme ambient conditions and for infants with greater unobserved innate vulnerabilities.

Effects of varicocele and microsurgical varicocelectomy on the metabolites in semen.

The influence of varicocele and microsurgical varicocelectomy on semen quality remains unclear. Few studies have investigated the relationship between semen metabolism and the abnormalities in reproductive function caused by varicocele, however, there is no study on the changes of semen metabolism after microsurgical varicocelectomy. Here, we used the non-targeted and targeted metabolic analysis to investigate the different metabolites in seminal plasma within normal, varicocele, and varicocelectomy groups. We clearly showed that varicocele significantly affects semen metabolism, and microsurgical varicocelectomy can reverse this metabolic abnormality. Moreover, we characterized the landscape of three dipeptides in the seminal plasma of patients with varicocele that have not been identified previously in human tissues or biofluids. Interestingly, the levels of these three dipeptides decreased after microsurgical varicocelectomy coincident with an improvement in semen quality. Western blotting confirmed the downregulation of DPEP3 (dipeptidase 3) in the varicocele group and the upregulation of DPEP3 in the varicocelectomy group. Furthermore, we found that eight metabolites may be helpful to distinguish varicocele patients from normal subjects. Our results may be applied to earlier diagnosis or to predict the outcome of microsurgery for varicocele.

The Asian Games, air pollution and birth outcomes in South China: An instrumental variable approach.

We estimate the effects of air-pollution exposure on low birthweight, birthweight, and prematurity risk in South China, for all expectant mothers and by maternal age group and child sex. We do so by exploiting exogenous improvement in air quality during the 2010 Guangzhou Asian Games, when strict regulations were mandated to assure better air quality. We use daily air-pollution levels collected from monitoring stations in Guangzhou, the Asian Games host city, and Shenzhen, a nearby control city, between 2009 and 2011. We first show that air quality during the Asian Games significantly improved in Guangzhou, relative to Shenzhen. Next, using birth-certificate data for both cities for 2009-2011 and using expected pregnancy overlap with the Asian Games as an instrumental variable, we study the effects of three pollutants (PM10, SO2, and NO2) on birth outcomes. Four main conclusions emerge: 1) air pollutants significantly reduce average birthweight and increase preterm risk; 2) for birthweight, late pregnancy is most sensitive to PM10 exposure, but there is not consistent evidence of a sensitive period for other pollutants and outcomes; 3) for birthweight, babies of mothers who are at least 35 years old show more vulnerability to all three air pollutants; and 4) male babies show more vulnerability than female babies to PM10 and SO2, but birthweights of female babies are more sensitive than those of male babies to NO2.

Derivation and Characterization of Mesenchymal Stem Cells from iPS Cells.

Mesenchymal stem/stromal cells (MSCs) show excellent therapeutic potentials in many preclinical studies and clinical trials. However, the clinical application of conventional tissue-derived MSCs faces challenges of limited scalability and high donor variations. To address these challenges, we established a protocol for deriving and characterizing MSCs from human induced pluripotent stem cells (iPSCs) with a theoretically limitless expandability. The iPSC-MSCs show biological properties comparable to or better than early passage bone marrow MSCs and can be scaled up to huge amounts with uniform properties.

PM2.5 exposure increases the risk of preterm birth in pre-pregnancy impaired fasting glucose women: A cohort study in a Southern province of China.

Previous studies have indicated maternal exposure to particles with aerodynamic diameter <2.5 µm (PM2.5) is associated with preterm birth (PTB). However, no study has investigated this effect in pre-pregnancy impaired fasting glucose (IFG) women. This study aimed to differentiate the effects of maternal PM2.5 exposure on PTB between pre-pregnancy IFG and normoglycemia women, and to further identify the susceptible window. This cohort study was conducted between January 2014 and December 2017 in 21 Chinese cities. All the recruited women received pre-pregnancy fasting serum glucose (FSG) tests and were followed up for their delivery outcomes. The PM2.5 exposures were estimated by the daily air pollution concentrations of the nearby monitors. Women with FSG below 7.0 mmol/L were included in the analysis. We employed the Cox proportional hazards models to examine whether PM2.5 exposure was associated with PTB. 237957 women were included and 7055 (3.0%) of them were pre-pregnancy IFG. During the entire pregnancy, we found 24.1% (HR = 1.241; 95% CI: 1.069, 1.439), 61.8% (HR = 1.618; 95% CI: 1.311, 1.997) and 18.6% (HR = 1.186; 95% CI: 1.004, 1.402) of increases in risk for all PTB, early PTB (20-33 gestational weeks) and late PTB (34-36 gestational weeks) among the pre-pregnancy IFG women, and 15.9% (HR = 1.159; 95% CI: 1.127, 1.192), 33.9% (HR = 1.339; 95% CI: 1.255, 1.430) and 13.2% (HR = 1.132; 95% CI: 1.098, 1.168) of increases in risk for all PTB, early PTB and late PTB among the normoglycemia women, with each 10 µg/m3 increment of PM2.5 exposure, respectively. Furthermore, PM2.5 exposure had the strongest effect on all PTB during trimester 1 (0-12 gestational weeks) among the pre-pregnancy IFG women, compared with the less strong effect during trimester 1 among the normoglycemia women. In conclusion, pre-pregnancy IFG increases the risk of PTB attributed to PM2.5, especially during trimester 1. Moreover, the effects of PM2.5 are greater on early PTB than late PTB for both pre-pregnancy IFG and normoglycemia women.

A scalable system for generation of mesenchymal stem cells derived from induced pluripotent cells employing bioreactors and degradable microcarriers.

Human mesenchymal stem cells (hMSCs) are effective in treating disorders resulting from an inflammatory or heightened immune response. The hMSCs derived from induced pluripotent stem cells (ihMSCs) share the characteristics of tissue derived hMSCs but lack challenges associated with limited tissue sources and donor variation. To meet the expected future demand for ihMSCs, there is a need to develop scalable methods for their production at clinical yields while retaining immunomodulatory efficacy. Herein, we describe a platform for the scalable expansion and rapid harvest of ihMSCs with robust immunomodulatory activity using degradable gelatin methacryloyl (GelMA) microcarriers. GelMA microcarriers were rapidly and reproducibly fabricated using a custom microfluidic step emulsification device at relatively low cost. Using vertical wheel bioreactors, 8.8 to 16.3-fold expansion of ihMSCs was achieved over 8 days. Complete recovery by 5-minute digestion of the microcarriers with standard cell dissociation reagents resulted in >95% viability. The ihMSCs matched or exceeded immunomodulatory potential in vitro when compared with ihMSCs expanded on monolayers. This is the first description of a robust, scalable, and cost-effective method for generation of immunomodulatory ihMSCs, representing a significant contribution to their translational potential.

Identification of Molecules Responsible for Therapeutic Effects of Extracellular Vesicles Produced from iPSC-Derived MSCs on Sjo¨gren's Syndrome.

Recent research indicated that extracellular vesicles (EVs) derived from mesenchymal stem/stromal cells (MSCs) are a promising alternative to MSCs for immunomodulatory therapy. However, the contents of MSC-EVs would change as their parent MSCs change, hence the therapeutic efficacy of MSC-derived EVs (MSC-EVs) would largely depend on donors, tissue sources and culture conditions of MSCs. To overcome limitations of tissue-derived MSCs, we previously used MSCs derived from human induced pluripotent stem cells (iMSCs) to produce EVs and demonstrated their therapeutic potential in a mouse model of secondary Sjo¨gren's Syndrome. Here, we further found that EVs from early-passage iMSCs had better immunomodulatory potency than EVs from late-passage iMSCs in TLR4-stimulated splenocytes and in a mouse model of primary Sjögren's syndrome. Comparative molecular profiling using proteomics and microRNA sequencing revealed distinctive molecular profiles of iMSC-EVs with or without immunomodulation capacity. Amongst them, manipulation of TGF-ß1, miR-21 and miR-125b levels in iMSC-EVs significantly affected their immunosuppressive effects. These findings would help improve our understanding of the molecular mechanism underlying iMSC-EV-mediated immunomodulation and further provide strategies to improve regulatory function of EVs for the treatment of immune-mediated diseases.

Beyond the mean: Quantile regression to differentiate the distributional effects of ambient PM2.5 constituents on sperm quality among men.

Ambient PM2.5 (particulate matter ≤ 2.5 µm in aerodynamic diameter) constituents have been related to mean changes in semen quality, but focusing on the mean response may not well capture distributional and heterogeneous effects of PM2.5 constituents on semen quality. In this study, 2314 semen samples of 622 men between Jan 1, 2019 and Dec 31, 2019 from Guangdong Human Sperm Bank were subjected to semen quality analysis. Daily average concentrations of PM2.5 constituents including 4 water-soluble ions and 15 metals/metalloid were measured for 7 days per month at 3 fixed atmospheric pollutant monitoring stations. We used quantile regression for longitudinal data to examine whether the associations between PM2.5 constituents and quality indicators of semen varied across quantiles of outcome distribution. Heterogeneous associations were found between PM2.5 constituents and sperm quality across different quantiles. An interquartile range (14.0 µg/m3) increase in PM2.5 mass was negatively associated with lower tails of sperm concentration and upper tails of sperm count distribution. PM2.5 vanadium exposure was significantly related to the 90th percentile of sperm count distribution, but not to the lower quantiles. In addition, those subjects with relatively high sperm motility were more susceptible to sulfate, chromium, and manganese constituents in PM2.5. Our results indicate that PM2.5 and certain constituents were associated with sperm quality, especially sperm motility, and the associations are more pronounced in men with relatively high or low sperm motility.

CXCL10 potentiates immune checkpoint blockade therapy in homologous recombination-deficient tumors.

Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability, and has been proven to be a biomarker for target therapy. However, until now, no research has explored the changes in the transcriptomics landscape of HRD tumors. Methods: The HRD score was established from SNP array data of breast cancer patients from the cancer genome atlas (TCGA) database. The transcriptome data of patients with different HRD scores were analyzed to identify biomarkers associated with HRD. The candidate biomarkers were validated in the gene expression omnibus (GEO) database and immunotherapy cohorts. Results: Based on data from the gene expression profile and clinical characteristics from 1310 breast cancer patients, including TCGA database and GEO database, we found that downstream targets of the cGAS-STING pathway, such as CXCL10, were upregulated in HRD tumors and could be used as a predictor of survival outcome in triple-negative breast cancer (TNBC) patients. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that the expression of CXCL10 was positively correlated with neoantigen load and infiltrating immune cells. Finally, in vivo experimental data and clinical trial data confirmed that the expression of CXCL10 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Conclusions: Together, our study not only revealed that CXCL10 is associated with HRD but also introduced a potential new perspective for identifying prognostic biomarkers of immunotherapy.

Identification of biomarkers complementary to homologous recombination deficiency for improving the clinical outcome of ovarian serous cystadenocarcinoma.

Ovarian cancer patients with homologous recombination deficiency (HRD) tumors would benefit from PARP inhibitor (PARPi) therapy. However, patients with HRD tumors account for less than 50% of the whole cohort, so new biomarkers still need to be developed. Based on the data from the SNP array and somatic mutation profiles in the ovarian cancer genome, we found that high frequency of actionable mutations existed in patients with non-HRD tumors. Through transcriptome analysis, we identified that a downstream target of the cGAS-STING pathway, CXCL11, was upregulated in HRD tumors and could be used as a predictor of survival outcome. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL11 expression signature was closely correlated with cytotoxic cells, neoantigen load and immune checkpoint blockade (ICB). Clinical trial data confirmed that the expression of CXCL11 could be used as a biomarker for anti-PD-1/PD-L1 therapy. Finally, in vivo and in vitro experiments showed that cancer cells with PARPi treatment increased the expression of CXCL11. Collectively, our study not only provides biomarkers of ovarian cancer complementary to the HRD score but also introduces a potential new perspective for identifying prognostic biomarkers of immunotherapy.

Associations of pre-pregnancy impaired fasting glucose and body mass index among pregnant women without pre-existing diabetes with offspring being large for gestational age and preterm birth: a cohort study in China.

INTRODUCTION: Associations of pre-pregnancy impaired fasting glucose (IFG) and body mass index (BMI) with large for gestational age (LGA) and preterm birth (PTB) have been poorly understood. We aimed to investigate the associations of maternal BMI, separately and together with pre-pregnancy IFG, with LGA and PTB in Chinese population. We also aimed to quantify these associations by maternal age. RESEARCH DESIGN AND METHODS: This was a retrospective cohort study of women from the National Free Preconception Health Examination Project with singleton birth from 121 counties/districts in 21 cities of Guangdong Province, China, from January 1, 2013 to December 31, 2017. Women were included if they did not have pre-existing chronic diseases (diabetes, hypertension, etc). Participants were divided into eight groups according to their BMI (underweight (BMI <18.5 kg/m2), normal weight (18.5-23.9 kg/m2), overweight (24.0-27.9 kg/m2), and obesity (≥28.0 kg/m2)) and pre-pregnancy fasting glucose status (normoglycemia (fasting glucose concentration <6.1 mmol/L) and IFG (6.1-7.0 mmol/L)). Adjusted incidence risk ratios (aIRRs) and 95% CIs of LGA, severe LGA, PTB and early PTB were estimated. RESULTS: We included 634 030 women. The incidences of LGA, severe LGA, PTB and early PTB for the study population were 7.1%, 2.5%, 5.1% and 1.1%, respectively. Compared with normal weight mothers with normoglycemia, overweight and obese mothers irrespective of IFG had a higher risk of LGA (eg, obesity with IFG aIRR 1.85 (1.60-2.14)) and severe LGA (eg, obesity with IFG 2.19 (1.73-2.79)). The associations of BMI and pre-pregnancy fasting glucose status with LGA were similar found among women of all age groups. Underweight with normoglycemia had 6.0% higher risk of PTB (1.06 (1.03-1.09)) and 8.0% higher risk of early PTB (1.08 (1.02-1.17)), underweight with IFG had 14.0% higher risk of PTB (1.14 (1.02-1.27)), and obese mothers with IFG had 45.0% higher risk of PTB (1.45 (1.18-1.78)). The associations of BMI and pre-pregnancy fasting glucose status with PTB differed by maternal age. CONCLUSION: Overweight and obesity regardless of IFG were associated with an increased risk of LGA, and these associations were similarly observed among mothers of all age groups. Underweight regardless of IFG, and obesity with IFG were associated with an increased risk of PTB, but the associations differed by maternal age. Findings from this study may have implications for risk assessment and counselling before pregnancy.

Temperature variation and preterm birth among live singleton deliveries in Shenzhen, China: A time-to-event analysis.

OBJECTIVE: Ambient temperature extremes due to heat exposure was an established risk factor for preterm birth (<37 gestational weeks). However, there is insufficient epidemiological evidence on the effects of temperature variation(TV), although TV is also associated with heat exposure and can influence human health risk. This study aimed to investigate the relationship between inter- and intraday TV and preterm birth (PTB). METHOD: A total of 1,388,994 live singleton births were collected from January 2003 to December 2012, from the Shenzhen Birth registry system. Daily temperature range (DTR) was defined as the difference between the highest and lowest recorded daily temperature. Intraday TV was defined as the maximum daily diurnal temperature range in a given week (Max-DTR). Inter-day TV was defined as the maximum increase or decrease in daily mean temperature between days t and t-1in a given week; either an increase (Temp-inc) or a decrease (Temp-dec). We used Cox proportional hazards models to estimate TV-related PTB risks during the first trimester, the second trimester, and in late pregnancy. RESULTS: The maximum values for DTR, Temp-inc, and Temp-dec were 17 °C, 8 °C and 11 °C, respectively. The greatest TV-related PTB risk occurred in the second trimester, with 5.8% (95%CI: 3.3%, 8.3%), 23.7% (95%CI: 19.6%, 27.9%), and 4.4% (95%CI: 1.8%, 7.1%) differences per 1 °C increase in Max-DTR, Temp-inc, and Temp-dec, respectively. Greater TV was associated with elevated PTB risk during the warm season. The association between TV and PTB was modified by seasons, maternal education and chronic conditions. CONCLUSIONS: Sharp TV is a likely risk factor for PTB. Policy makers and clinicians should recognize the potential role of TV in the etiology of PTB so that interventions can be designed to protect pregnant women and their fetuses against extreme temperatures.

Association of maternal pre-pregnancy low or increased body mass index with adverse pregnancy outcomes.

This study investigated the association between pre-pregnancy body mass index (BMI) and adverse pregnancy outcomes among women participated in the National Free Preconception Health Examination Project in Guangdong Province, China, and explored these associations according to maternal age. Pre-pregnancy BMI was classified into underweight (BMI < 18.5 kg/m2), healthy weight (18.5-23.9 kg/m2), overweight (24.0-27.9 kg/m2), and obesity (≥ 28.0 kg/m2) according to Chinese criteria. Outcomes were preterm birth (PTB, delivery before 37 weeks of gestation), large for gestational age (LGA, birthweight above the 90th percentile for gestational age by infants' sex), small for gestational age (SGA, birthweight below the 10th percentile for gestational age by infants' sex), primary caesarean delivery, shoulder dystocia or birth injury, and stillbirth. Adjusted incidence risk ratios (aIRR) were calculated for underweight, overweight and obesity, respectively. Compared with healthy weight, underweight was associated with increased risk of PTB (aIRR 1.06, 95%CI 1.04-1.09) and SGA (1.23, 1.22-1.26) but inversely associated with LGA (0.83, 0.82-0.85), primary caesarean delivery (0.88, 0.87-0.90) and stillbirth (0.73, 0.53-0.99). Overweight was associated with increased risk of LGA (1.17, 1.14-1.19), primary caesarean delivery (1.18, 1.16-1.20) and stillbirth (1.44, 1.03-2.06), but inversely associated with SGA (0.92, 0.90-0.95) and shoulder dystocia or birth injury (0.86, 0.79-0.93). Obesity was associated with increased risk of PTB (1.12, 1.05-1.20), LGA (1.32, 1.27-1.37), primary caesarean delivery (1.45, 1.40-1.50), but inversely associated with SGA (0.92, 0.87-0.97). The aIRRs for underweight, overweight and obesity in relation to these adverse pregnancy outcomes ranged from 0.65 to 1.52 according to maternal age. In Chinese population, maternal pre-pregnancy BMI was significantly associated with the risk of adverse pregnancy outcomes and the risk differs according to maternal age. Further investigation is warranted to determine whether and how counselling and interventions for women with low or increased BMI before pregnancy can reduce the risk of adverse pregnancy outcomes.

Extracellular vesicle mimics made from iPS cell-derived mesenchymal stem cells improve the treatment of metastatic prostate cancer.

BACKGROUND: Extracellular vesicles (EVs) and their mimics from mesenchymal stem cells (MSCs) are promising drug carriers to improve cancer treatment, but their application is hindered by donor variations and expansion limitations of conventional tissue-derived MSCs. To circumvent these issues, we made EV-mimicking nanovesicles from standardized MSCs derived from human induced pluripotent stem cells (iPSCs) with a theoretically limitless expandability, and examined the targeting capacity of these nanovesicles to prostate cancer. METHODS: Nanovesicles are made from intact iPSC-MSCs through serial extrusion. The selective uptake of fluorescently labeled nanovesicles by prostate cancer cells vs. non-tumor cells was examined with flow cytometry. For in vivo tracing, nanovesicles were labeled with fluorescent dye DiR or renilla luciferase. In mice carrying subcutaneous or bone metastatic PC3 prostate cancer, the biodistribution of systemically infused nanovesicles was examined with in vivo and ex vivo imaging of DiR and luminescent signals. A chemotherapeutic drug, docetaxel, was loaded into nanovesicles during extrusion. The cytotoxicities of nanovesicle-encapsulated docetaxel on docetaxel-sensitive and -resistant prostate cancer cells and non-tumor cells were examined in comparison with free docetaxel. Therapeutic effects of nanovesicle-encapsulated docetaxel were examined in mice carrying subcutaneous or bone metastatic prostate cancer by monitoring tumor growth in comparison with free docetaxel. RESULTS: iPSC-MSC nanovesicles are more selectively taken up by prostate cancer cells vs. non-tumor cells in vitro compared with EVs, membrane-only EV-mimetic nanoghosts and liposomes, which is not affected by storage for up to 6 weeks. In mouse models of subcutaneous and bone metastatic PC3 prostate cancer, systemically infused nanovesicles accumulate in tumor regions with significantly higher selectivity than liposomes. The loading of docetaxel into nanovesicles was efficient and did not affect the selective uptake of nanovesicles by prostate cancer cells. The cytotoxicities of nanovesicle-encapsulated docetaxel are significantly stronger on docetaxel-resistant prostate cancer cells and weaker on non-tumor cells than free docetaxel. In mouse models of subcutaneous and bone metastatic prostate cancer, nanovesicle-encapsulated docetaxel significantly decreased the tumor growth and toxicity to white blood cells compared with free docetaxel. CONCLUSIONS: Our data indicate that EV-mimicking iPSC-MSC nanovesicles are promising to improve the treatment of metastatic prostate cancer.

Association of maternal ozone exposure with term low birth weight and susceptible window identification.

BACKGROUND: Ozone pollution keeps deteriorating in the context of climate change. Maternal ozone exposure may be associated with low birth weight (LBW), but the results are still inconsistent. The identification of the critical exposure windows, a specific period of particular susceptibility during pregnancy, remains unresolved. We aimed to evaluate whether ozone exposure was associated with term LBW and further identify the susceptible exposure windows. METHODS: A retrospective cohort study was conducted in Guangzhou, a megacity in the most populous and economically developed city clusters in China. We included 444,096 singleton live births between January 2015 and July 2017. From 11 fixed stations, we collected daily 1-h maximum and 8-h maximum moving average ozone level (O3-1 h and O3-8 h) and calculated exposures for each participant based on their district of residence during pregnancy. We used traditional Logistic regression to estimate the trimester-specific association between ozone exposure and term LBW, and further estimated monthly- and weekly association by distributed lag models (DLMs) with Logistic regression. Odds ratios (ORs) and 95% confidence intervals (CIs) of term LBW were calculated for an interquartile range (IQR) increase in ozone exposure. Stratified analyses and heterogeneity tests were conducted by maternal age and infant sex. RESULTS: The incidence of term LBW was 1.9%. During the study period, the mean O3-1 h and O3-8 h levels were 112.6 µg/m3 and 84.5 µg/m3, respectively. Increased O3-1 h (IQR: 90 µg/m3) and O3-8 h (73 µg/m3) exposure during the second trimester were associated with increased risk of term LBW. At a monthly level, the term LBW risk was associated with O3-1 h exposure during the 4th-6th month and O3-8 h exposure during the 6th month. By estimating the weekly-specific association, we observed that critical exposure windows were the 15th- 26th gestational weeks for O3-1 h, and the 20th-26th weeks for O3-8 h, respectively. Estimated ORs and 95% CIs ranged from 1.012 (1.000, 1.024) to 1.023 (1.007, 1.039). When examined by subgroups, the effects were present among women ≥ 35 years or < 25 years old and those with female babies. CONCLUSIONS: This study provides compelling evidence that exposure to O3 was associated with increased risk of term LBW, and gestational weeks 15th- 26th was found to be particularly susceptible. These findings provide a research basis for further mechanism examination, public health interventions, and targeted environmental policy-making.