Gravidity modifies the associations of age and spousal age difference with couple's fecundability: a large cohort study from China.

STUDY QUESTION: Do couple's age ranges for optimal fecundability, and the associations with fecundability of couple's age combinations and age differences differ with gravidity? SUMMARY ANSWER: The couple's age range of optimal fecundability and age combinations differed with gravidity, and gravidity might modify the associations of age and spousal age difference with couple's fecundability. WHAT IS KNOWN ALREADY: Age is one of the strongest determinants of fecundability, but the existing studies have certain limitations in study population, couple's extreme age combinations and age differences, and have not explored whether the association between age and fecundability differs with gravidity. STUDY DESIGN, SIZE, DURATION: Retrospective cohort study. 5 407 499 general reproductive-aged couples (not diagnosed with infertility) participated in the National Free Pre-conception Check-up Projects during 2015-2017. They were followed up for pregnancy outcomes through telephone interviews every 3 months until they became pregnant or were followed up for 1 year. PARTICIPANTS/MATERIALS, SETTING, METHODS: The main outcome was time to pregnancy, and the fecundability odds ratios and 95% CIs were estimated using the Cox models for discrete survival time. The associations of age and spousal age difference with fecundability were evaluated by restricted cubic splines. MAIN RESULTS AND THE ROLE OF CHANCE: In this large cohort of general reproductive-aged population, the age of optimal fecundability of multigravida couples was older than that of nulligravida couples, but their subsequent fecundability declined more sharply with age. The decline in female fecundability was more pronounced with age, with fecundability dropping by ∼30% in both nulligravida and multigravida couples whose female partners aged ≥35 years. In the nulligravida group, the fecundability of couples who were both ≤24 years with the same age was the highest, which decreased steadily with the increase of spousal age difference, and younger male partners did not seem to contribute to improving couple's fecundability. In the multigravida group, couples with female partners aged 25-34 years and a spousal age difference of -5 to 5 years showed higher fecundability, and the effect of spousal age difference on couple's fecundability became suddenly apparent when female partners aged around 40 years. Young male partners were unable to change the decisive effect of female partner's age over 40 years on couple's reduced fecundability, regardless of gravidity. LIMITATIONS, REASONS FOR CAUTION: Lacking the time for couples to attempt pregnancy before enrollment, and some couples might suspend pregnancy plans during follow-up because of certain emergencies, which would misestimate the fecundability. Due to the lack of information on sperm quality and sexual frequency of couples, we could not adjust for these factors. Moreover, due to population characteristics, the extrapolation of our results required caution. WIDER IMPLICATIONS OF THE FINDINGS: The couple's age range of optimal fecundability, age combinations, and spousal age difference on fecundability varied with gravidity. Female age-related decline in fecundability was more dominant in couple's fecundability. Targeted fertility guidance should be provided to couples with different age combinations and gravidities. STUDY FUNDING/COMPETING INTEREST(S): This research received funding from the Project of National Research Institute for Family Planning (Grant No. 2018NRIFPJ03), the National Key Research and Development Program of China (Grant No. 2016YFC1000307), and the National Human Genetic Resources Sharing Service Platform (Grant No. 2005DKA21300), People's Republic of China. The funders had no role in study design, analysis, decision to publish, or preparation of the manuscript. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Evaluating the Impact of Maternal Exposure to Ozone on Twin Fetal Growth in China.

Unlike singletons, twins require attention not only to the birth weight of the fetuses but also to discordance (i.e., the differences between weights) because twin growth discordance is a significant factor contributing to perinatal mortality and morbidity in twin pregnancies. However, the impact of maternal air pollution exposure on twin growth discordance has rarely been investigated. We examined the association of long-term ozone exposure during preconception and pregnancy with the birth weight of twins and twin growth discordance among 35,795 twins from the National Free Preconception Health Examination Project between January 2010 and December 2019. Linear mixed-effect models and random-effect logistic regression models were used to examine the associations of ozone exposure with the birth weight-related outcomes (i.e., birth weight of twins and within-pair birth weight difference) and risk of twin growth discordance, respectively, after adjustment for demographic characteristics and lifestyle. We found that an interquartile range (IQR) increase (15 µg/m3) in ozone exposure during the entire pregnancy was associated with a reduction (-28.96g, 95% confidence interval [CI]: -46.37, -11.56) in the total birth weight of twins, and ozone had a more pronounced impact on the birth weight of the smaller fetuses (-18.28 g, 95% CI: -27.22, -9.34) compared to the larger fetuses (-9.88 g, 95% CI: -18.84, -0.92) in twin pregnancies. An IQR increase in ozone exposure during the entire pregnancy was associated with a significant increase (8.41 g, 95% CI: 4.13, 12.69) in the within-pair birth weight difference; the odds ratio (OR) of twin growth discordance related to ozone exposure increased by 9% (OR = 1.09, 95% CI: 1.01, 1.18). However, no consistently significant associations were observed for ozone exposure during prepregnancy. Male-male twin pairs and those who were born prematurely appeared to be more susceptible to ozone exposure than their counterparts. Long-term ozone exposure during pregnancy was associated with twin growth discordance, and our findings provide reference data for future studies.

Association of Fine Particulate Matter and Its Components with Macrosomia: A Nationwide Birth Cohort Study of 336 Chinese Cities.

To examine the associations between macrosomia risk and exposure to fine particulate matter (PM2.5) and its chemical components during pregnancy, we collected birth records between 2010 and 2015 in mainland China from the National Free Preconception Health Examination Project and used satellite-based models to estimate concentrations of PM2.5 mass and five main components, namely, black carbon (BC), organic carbon (OC), nitrate (NO3-), sulfate (SO42-), and ammonium (NH4+). Associations between macrosomia risk and prenatal exposure to PM2.5 were examined by logistic regression analysis, and the sensitive subgroups were explored by stratified analyses. Of the 3,248,263 singleton newborns from 336 cities, 165,119 (5.1%) had macrosomia. Each interquartile range increase in concentration of PM2.5 during the entire pregnancy was associated with increased risk of macrosomia (odds ratio (OR) = 1.18; 95% confidence interval (CI), 1.17-1.20). Among specific components, the largest effect estimates were found on NO3- (OR = 1.36; 95% CI, 1.35-1.38) followed by OC (OR = 1.23; 95% CI, 1.22-1.24), NH4+ (OR = 1.22; 95% CI, 1.21-1.23), and BC (OR = 1.21; 95% CI, 1.20-1.22). We also that found boys, women with a normal or lower prepregnancy body mass index, and women with irregular or no folic acid supplementation experienced higher risk of macrosomia associated with PM2.5 exposure.

Effects of Intestinal Microorganisms on Influenza-Infected Mice with Antibiotic-Induced Intestinal Dysbiosis, through the TLR7 Signaling Pathway.

BACKGROUND: Stability of intestinal flora is not only important for maintaining stable immune functions; it is also a key immune channel communicating the interaction between lung and intestine. In this study, probiotics and fecal microbiota transplantation (FMT) were used to regulate influenza-infected mice with antibiotic-induced intestinal dysbiosis and the effects of intestinal microorganisms on these mice were subsequently observed and evaluated. METHODS: Mice are housed in a normal environment with intranasal infection with influenza virus (FM1). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to determine messenger RNA expression and lung viral replication of toll-like receptor 7 (TLR7), myeloid differentiation primary reaction 88 (MyD88) and nuclear factor κB (ss) p65 in the TLR7 signaling pathway. Western blotting is used to measure the expression levels of TLR7, MyD88, and NF-κB p65 proteins. Flow cytometry was used to detect the proportion of Th17/T regulated cells. RESULTS: Results showed that compared with the simple virus group, both diversity and species of intestinal flora in influenza-infected mice with antibiotic-induced intestinal dysbiosis were lower, in vivo viral replication was significantly increased, lung and intestinal tissues were seriously damaged, degree of inflammation increased, expression of the TLR7 signaling pathway increased, and the Th1/Th2:Th17/Treg ratio decreased. Probiotics and FMT effectively regulated intestinal flora, improved pathological lung changes and inflammation caused by influenza infection, and adjusted the TLR7 signaling pathway and the Th1/Th2:Th17/Treg ratio. This effect was not obvious in TLR7-⁣/- mice.In summary, by affecting the TLR7 signaling pathway, intestinal microorganisms reduced the inflammatory response in the lungs of influenza-infected mice with imbalances in antibiotic flora. CONCLUSIONS: By affecting the TLR7 signaling pathway, intestinal microorganisms reduced the inflammatory response in the lungs of influenza-infected mice with imbalances in antibiotic flora. In summary, damage to lung tissue and intestinal mucosa in influenza-infected mice with antibiotic-induced intestinal dysbiosis is more serious compared to simple virus-infected mice. Improving intestinal flora using probiotics or FMT can alleviate intestinal inflammation and improve pulmonary inflammation through the TLR7 signaling pathway.

[Clinical observation of acupuncture at Huiyin (CV 1) for chronic severe functional constipation].

OBJECTIVE: To compare the effect of acupuncture at Huiyin (CV 1) and oral administration of western medication in treatment of chronic severe functional constipation (CSFC). METHODS: A total of 64 patients with CSFC were randomly divided into an acupuncture group (32 cases, 5 cases dropped off) and a western medication group (32 cases, 4 cases dropped off). Both groups were given routine basic treatment. The acupuncture group was treated by directly puncture of 20-30 mm at Huiyin (CV 1), once a day for the first 4 weeks, 5 times a week, once every other day for the next 4 weeks, 3 times a week, totally for 8 weeks. The western medication group was treated with 2 mg prucalopride succinate tablets orally before breakfast every day for 8 weeks. The average number of weekly spontaneous bowel movement (SBM) of the two groups were observed before treatment and 1-8 weeks into treatment. The constipation symptom score before and after treatment, and in follow-up of 1 month after treatment, as well as quality of life [patient assessment of constipation quality of life questionnaire (PAC-QOL) score and the proportion of patients of PAC-QOL score difference before and after treatment≥1] before and after treatment were compared in the two groups. The clinical effects of the two groups were evaluated after treatment and in follow-up. RESULTS: Compared before treatment, the average number of weekly SBM in the two groups was increased 1-8 weeks into treatment (P<0.05). The average number of weekly SBM in the acupuncture group was less than that in the western medication group 1 week into treatment (P<0.05), and the average number of weekly SBM in the observation group was more than that in the western medication group 4-8 weeks into treatment (P<0.05). The scores of constipation symptom after treatment and in follow-up and scores of PAC-QOL after-treatment in the two groups were lower than those before treatment (P<0.05), and those in the acupuncture group were lower than the western medication group (P<0.05). The proportion of patients of PAC-QOL score difference before and after treatment≥1 in the acupuncture group was higher than that in the west medication group (P<0.05). The total effective rates after treatment and in follow-up in the acupuncture group were 81.5% (22/27) and 78.3% (18/23), respectively, which were better than 42.9% (12/28) and 43.5% (10/23) in the western medication group (P<0.05). CONCLUSION: Acupuncture at Huiyin (CV 1) can effectively increase the number of spontaneous defecation in patients with CSFC, reduce constipation symptoms, improve the quality of life, and the effect after treatment and in follow-up is better than oral western medication.

Spatiotemporal Patterns of Adverse Pregnancy Outcomes in Rural Areas of Henan, China.

The spatial patterns of adverse pregnancy outcomes (APOs) are complex, vary by place, and remain not entirely clear. This study investigated spatiotemporal patterns of APOs in rural areas of Henan, China. We used data from 1,315,327 singleton pregnancies during 2013-2016 in rural areas of Henan, China, from the National Free Pre-pregnancy Checkup Program (NFPCP). A spatiotemporal analysis of APOs was conducted based on the time of conception and current address. Results of seasonality decomposed showed a slight decline in the incidence rate of APOs (12.93% to 11.27% in the compound trend) among the participants from 2013 to 2016 and also variation in annual periodicity (peaking in autumn at 12.66% and hitting bottom in spring at 11.16%). Spatial clusters of APOs were concentrated in an intersection band of northwestern to southeastern Henan Province (with a relative risk ratio ranging from 3.66 to 1.20), the northwestern and northern portion for temporal variation (having a trend in the cluster ranged from -6.25% to 83.93). This study provides an overall picture of APOs that presented downward trends over time, seasonal fluctuation, and clustered patterns across space and over time in Henan Province-the most populated province in China. The findings of this study warrant future studies to investigate underlying influential factors of spatial variation of APOs.

Whole-exome sequencing reveals novel variants associated with abnormal uterine bleeding caused by copper intrauterine device.

Aim: This study aimed to explore the genetic risk factors and validate variants of abnormal uterine bleeding after copper intrauterine device insertion. Methods: Whole-exome sequencing was performed and several variants were validated by Sequenom MassARRAY. Results: Eight variants showed potential clinical damage according to American College of Medical Genetics and Genomics criteria. By combined analysis of screening and validation, NFASC RS2802808 C>G p.Ile971Met (Pallele = 0.009 and Pgenotype = 0.027) and PIGR RS2275531 C>T p.Gly365Ser (Pallele = 0.009 and Pgenotype = 0.013) variants were identified as significantly associated with abnormal uterine bleeding with a false discovery rate <0.05. NFASC and PIGR may play a role in abnormal uterine bleeding by regulating coagulation fibrinolysis and endometrial epithelium inflammation functions. Conclusion: These findings provide a genetic basis for clinical individualization and precision of intrauterine device implantation.

Abnormal uterine bleeding (AUB) after Cu intrauterine device (Cu-IUD) insertion is the most common side effect of Cu-IUD use. AUB is a multifactorial process that relates to endometrial-related genetic factors, ovulatory function-related genetic factors, coagulation, the fibrinolytic system, contraction of the uterine arteries and endometritis inflammatory factor. This is the first study to explore the underlying genetic mechanisms of AUB related to the use of Cu-IUDs by whole-exome sequencing in the Chinese Han population. The authors found that variants of NFASC and PIGR genes were significantly associated with AUB in women using Cu-IUDs. NFASC and PIGR may be involved in coagulation fibrinolysis and endometrial epithelium inflammation functions, indicating its potential functions in AUB. This study could provide a genetic basis for studies on the individualization and precision of IUD use in the future.

Forsythiaside A improves Influenza A virus infection through TLR7 signaling pathway in the lungs of mice.

BACKGROUND: Influenza A virus infection due to drug resistance and side effects of the conventional antiviral drugs yet remains a serious public health threat for humans and animals. Forsythiaside A is an effective ingredient isolated from the Chinese herbal medicine forsythia. It has various pharmacological effects and has a good therapeutic effect against a variety of infectious diseases. This study aimed to further explore the immunological mechanism of Forsythiaside A in the treatment of influenza virus-infected mice and its effect on the Toll-like receptor 7 (TLR7) signaling pathway in the lungs of these mice. METHODS: C57/BL6J mice and TLR7-/- mice were infected with the FM1 strains (H1N1 and A/FM/1/4) of the Influenza A virus. Each group of experimental mice were divided into the mock, virus, oseltamivir, and Forsythiaside A groups. Weight change, lung index change, and the mRNA and protein expression levels of key factors in the TLR7 signaling pathway were detected. Flow cytometry was used to detect the changes in the Th1/Th2 and Th17/Treg ratios. RESULTS: After infection with the Influenza A virus, the weight loss of C57/BL6J mice treated with forsythoside A and oseltamivir decreased, and the pathological tissue sections showed that the inflammatory damage was reduced. The expression levels of the key factors, TLR7, myeloid differentiation factor 88(Myd88), and nuclear factor-kappa B (NF-κB) in the TLR7 signaling pathway were significantly reduced. Flow cytometry showed that Th1/Th2 and Th17/Treg ratios decreased after Forsythiaside A treatment. In the TLR7-/- mice, there was no significant change after Forsythiaside A treatment in the virus group. CONCLUSIONS: Forsythiaside A affects the TLR7 signaling pathway in mouse lung immune cells and reduces the inflammatory response caused by the Influenza A virus FM1 strain in mouse lungs.

The type of previous abortion modifies the association between air pollution and the risk of preterm birth.

BACKGROUND: Air pollution and previous abortion have been reported to be related to preterm birth (PTB). But rare study examined the effect of air pollution on PTB risk among mothers with previous abortion. OBJECTIVE: To estimate the effect of air pollution on PTB and the potential effect modification of previous abortion on such an association in rural part of Henan province (China). METHOD: Based on National Free Preconception Health Examination Project (NFPHEP), information from the medical records of 57,337 mothers with previous abortion were obtained. An inverse distance-weighted model was used to estimate exposure levels of air pollutants. The effect of air pollution on the risk of PTB was estimated with a multiple logistic regression model. Stratified and interaction analyses were undertaken to explore the potential effect modification of previous abortion on this association. RESULTS: The risk of PTB was positively associated with exposure to levels of nitrogen dioxide (NO2; OR: 1.03; 95%CI: 1.02-1.04)], and sulfur dioxide (SO2; 1.04; 1.02-1.07), and negatively associated with ozone (O3) exposure (0.97; 0.97-0.98) during the entire pregnancy. Besides, we observed a positive effect of carbon monoxide (CO) exposure during the third trimester of pregnancy on PTB (1.14; 1.01-1.29). The type of previous abortion could modify the effect of air pollution on the PTB risk (P-interaction < 0.05). Compared with mothers with previous induced abortion, mothers with previous spontaneous abortion carried a higher risk of PTB induced by NO2, CO, and O3. CONCLUSIONS: The risk of PTB was positively associated with levels of NO2, SO2 and CO, and negatively associated with the O3 level. The types of previous abortion could modify the effect of air pollution on PTB. Mothers who had an abortion previously, especially spontaneous abortion, should avoid exposure to air pollution to improve their pregnancy outcome.

Influence of margin design and restorative material on the stress distribution of endocrowns: a 3D finite element analysis.

BACKGROUND: This study aimed to evaluate the stress distributions in endocrown restorations as applied to endodontically treated teeth (ETT), according to the factors of "margin design" (four levels) and "restorative material" (six levels). METHODS: Four 3D-finite elements models were constructed for endocrown restored molars considering different margin designs. Model A was prepared with a flat butt joint margin and received an endocrown with a 2.0-mm occlusal thickness. Model B was prepared with a 20° bevel margin and received an endocrown with a 2.0-mm occlusal thickness. Model C was prepared with an axial reduction and 1-mm shoulder margin and received an endocrown with a 2.0-mm occlusal thickness. Model D was prepared with an anatomic margin and received an endocrown with a 2.0-mm occlusal thickness. The following endocrown materials were used: In-Ceram Zirconia (Zr), Vita Suprinity (VS), IPS Empress (IE), Grandio blocs (GR), VisCalor bulk (VS), and CopraPeek Light (CP). The Load application (600 N) was performed at the food bolus and tooth surface during the closing phase of the chewing cycle. The results for the endocrown and tooth remnants were determined according to the von Mises stress. The failure risk of the cement layer was also calculated based on the normal stress criterion. RESULTS: Model D (with an anatomic margin) showed the greatest stress concentrations, especially in the irregular and sharp angles of the restoration and tooth remnants. The stress concentrated on the dentin was significantly lower in Model B with a 20° bevel margin (20.86 MPa), i.e., 1.3 times lower than the other three margin designs (27.80 MPa). Restorative materials with higher elastic moduli present higher stress concentrations inside the endocrown and transmit less stress to the cement layer, resulting in lower bonding failure risks. In contrast, materials with an elastic modulus similar to that of dentin presented with a more homogeneous stress distribution on the whole structure. CONCLUSIONS: An endocrown with a 20° bevel margin design could be a favorable preparation option for ETT. Composite resins (GR and VC) exhibit a more even stress distribution, and seem to be more promising materials for endocrown molars.

Interactive Effects of Maternal Vitamin D Status and Socio-Economic Status on the Risk of Spontaneous Abortion: Evidence from Henan Province, China.

BACKGROUND: Maternal vitamin D deficiency might generate adverse reproductive outcomes, and socio-economic inequalities in micronutrient-related diseases have often been found. This study aimed to explore the interactive effects of maternal vitamin D status and socio-economic status (SES) on risk of spontaneous abortion. METHODS: A population-based case-control study was conducted including 293 women with spontaneous abortion and 498 control women in December 2009 and January, 2010 in Henan Province, China. Information on pregnancy outcomes, maternal demographic, lifestyle and exposure factors and blood samples were collected at the same time. Vitamin D deficiency was defined as 25(OH)D < 20 ng/mL. SES index was constructed with principal component analysis by aggregating women's and their husbands' education level and occupation, and household income and expenditure. Interactive effects were assessed on a multiplicative scale with ratio of the odds ratio (ROR). RESULTS: Compared to those with high SES and vitamin D sufficiency, women with vitamin D deficiency and low SES index had an increased risk of spontaneous abortion (aOR: 1.99; 95% CI: 1.23-3.23). The ROR was 2.06 (95% CI: 1.04-4.10), indicating a significant positive multiplicative interaction. CONCLUSIONS: Maternal low SES may strengthen the effect of vitamin D deficiency exposure on spontaneous abortion risk in this Chinese population.

Optimal cuspal coverage of ceramic restorations using CAD/CAM: Biomechanical characteristic analysis by 3D finite element analysis and in vitro investigation.

AIM: The present in vitro study aimed to evaluate the stress distribution patterns, resistance to fracture, and failure modes of endodontically treated molars restored with different cuspal coverage options. MATERIALS AND METHODS: Three-dimensional models of mandibular first molars with six kinds of typical cuspal coverage were generated: T1: mesiobuccal cuspal coverage; T2: coverage of all buccal cusps; T3: mesiolingual cuspal coverage; T4: coverage of all lingual cusps; T5: mesiobuccal and mesiolingual cuspal coverage; T6: coverage of all cusps. All restorations were fabricated with zirconia-reinforced lithium silicate ceramic. The stress and its distributions under axial and oblique loading were analyzed by finite element analysis (FEA). Sixty human mandibular molar samples were randomly allocated into six groups (n = 10) to simulate the application of six types of restorations with different cuspal coverage, as in the FEA analysis, and were then subjected to a compressive test. All fractured specimens were subjected to fractography. Data were analyzed by one-way analysis of variance (ANOVA), the Tukey post hoc test, and the Fisher exact test (α = 0.05). RESULTS: The T2 and T6 groups presented superior stress distribution patterns under both axial and oblique loading compared with the other models. The fracture loads in the T2 (1627 ± 358 N) and T6 (1639 ± 355 N) groups were significantly higher than those in the other groups (P < 0.05). The T2 and T6 groups exhibited more restorable failure modes. Fractography showed more cracks below the cementoenamel junction in the T3, T4, and T5 groups. CONCLUSIONS: Onlay restorations with whole functional cuspal coverage provided comparable effects to coverage of all cusps in endodontically treated molars, and both methods exhibited a more even stress distribution and fracture resistance and better mechanical performance in high occlusal areas than other types of cuspal coverage. (Int J Comput Dent 2022;25(3):267-276; doi: 10.3290/j.ijcd.b2599709).

Preconception alcohol consumption and risk of miscarriage in over 4.5 million Chinese women aged 20-49 years.

OBJECTIVE: To assess the impact of preconception alcohol consumption on risk of miscarriage incidence, and further evaluate the association between maternal periconception drinking abstinence and miscarriage. METHODS: We performed a population-based, retrospective cohort study in China between 1 January 2013 and 31 December 2016. Alcohol intake and potential confounding factors were reported in standard questionnaires. Participants who became pregnant were recontacted for pregnancy outcome information within 1 year. A total 4 531 680 women with available data on preconception alcohol intake and miscarriage were included in the final analyses. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The prevalence of miscarriage was 2.70% among 4 531 680 women. Compared with non-drinkers, the adjusted OR of miscarriage was 1.06 (95% CI 1.02 to 1.10) and 1.59 (95% CI 1.15 to 2.20) in maternal occasional drinkers and regular drinkers, respectively. Compared with couples in which neither the male nor the female consumed alcohol, the adjusted OR for miscarriage among women was 1.09 (95% CI 1.07 to 1.10), 1.13 (95% CI 1.06 to 1.21) and 1.12 (95% CI 1.07 to 1.17) in the couples in which only the female drank alcohol, only the male drank alcohol, and both drank alcohol, respectively. The adjusted OR was 0.58 (95% CI 0.51 to 0.65) in women with alcohol abstinence compared with alcohol drinkers. CONCLUSIONS: Preconception alcohol consumption was associated with higher odds of miscarriage, and an increasing risk was found with paternal and maternal alcohol drinking. Periconception alcohol abstinence was inversely associated with miscarriage.

Prenatal exposure to air pollution and the risk of preterm birth in rural population of Henan Province.

Due to the poor living and healthcare conditions, preterm birth (PTB) in rural population is a pressing health issue. However, PTB studies in rural population are rare. To explore the effects of air pollutants on PTB in rural population, we collected 697,316 medical records during 2014-2016 based on the National Free Preconception Health Examination Project. Logistic regression models were used to estimate the association between air pollutants and PTB and the modifying effects of demographic characteristics. Relative contribution and principal component analysis-generalized linear model (PCA-GLM) analysis were used to explore the most significant air pollutant and gestational period. Our results demonstrated that PTB risk is positively associated with exposure to air pollutants including PM10, PM2.5, SO2, NO2, and CO, while negatively associated with O3 exposure (P < 0.05). In addition, we found that NO2 was the largest contributor to the risk of PTB caused by air pollutants (26.5%). The third trimester of pregnancy was the most sensitive exposure window. PCA-GLM analysis showed that the first component (a combination of PM, SO2, NO2, and CO) increased the risk of PTB. Moreover, we found that rural women who are younger, had higher educated, multi-parity, or smoke appeared to be more sensitive to the association between air pollutants exposure and PTB (P-interaction<0.05). Our findings suggested that increased air pollutants except O3 were associated with elevated PTB risk, especially among vulnerable mothers. Therefore, the effects of air pollutants exposure on PTB should be mitigated by restricting emission sources of NO2 and SO2 in rural population, especially during the third trimester.

Associations of MCM8 rs3761873 and rs16991617 variants with abnormal uterine bleeding induced by copper intrauterine device.

AIM: Intrauterine device (IUD) is a commonly used contraceptive method worldwide. Abnormal uterine bleeding (AUB) is one of the most common side effects of Cu-IUDs. Since AUB varies among Cu-IUD users, changes in the bleeding-related genetic factors may contribute to AUB. This study aimed to determine the genetic risk factors of AUB after Cu-IUD insertion. METHODS: We conducted a case-control study on women who experienced AUB after Cu-IUD insertion (case:control = 62:59). Six candidate variants were genotyped using the Sequenom MassARRAY. Genotype and allele frequencies were analyzed using SHEsisPlus. We performed Pearson's Chi-squared test to analyze categorical data, and ESEfinder to predict the impact on splicing regulation. RESULTS: MCM8 coding sequence variants: rs3761873-A>C was in Exon 7 and rs16991617 A>G was in Exon 12 of all 19 exons, both of which were significantly different between cases and controls (pallele  = 0.039 and pgenotype  = 0.092). rs6022 and rs6029 in F5 gene and rs3761873 and rs16991617 in the MCM8 gene showed strong linkage disequilibrium (R2 > 0.8). ESEfinder indicated that the variants of MCM8 may affect the splicing regulation. CONCLUSIONS: MCM8 rs376187 and rs16991617 were associated with AUB in Cu-IUDs users. MCM8 may play a role in AUB by regulating functions of reproductive organs and primary ovarian insufficiency. Our findings may improve the understanding of the genetic basis of AUB caused by Cu-IUDs.

Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model.

The rapid spread of antibiotic resistance among Enterococcus has prompted considerable interest in determining the dosage regimen of linezolid combined with fosfomycin. A checkerboard assay was employed to evaluate whether linezolid combined with fosfomycin had a synergistic effect on Enterococcus isolates from the hospital, including three drug-resistant strains (MIC of linezolid [MICLZD], ≥8 mg/L; MIC of fosfomycin [MICFOF], ≥256 mg/L). The in vitro static time-kill assay, dynamic pharmacokinetic (PK)/pharmacodynamic (PD) model, and semimechanistic PK/PD model were used to explore and predict effective combined dosage regimens. The checkerboard assay and in vitro static time-kill assay demonstrated that linezolid combined with fosfomycin has a synergistic effect on drug-resistant and sensitive Enterococcus. In the in vitro PK/PD model, the dosage regimen of linezolid (8 mg/L or 12 mg/L, steady-state concentration) combined with fosfomycin (6 g or 8 g) via a 0.5-h infusion every 8 h effectively suppressed bacterial growth at 24 h with a 3 log10 CFU/mL decrease compared with the initial inocula against two resistant and one sensitive Enterococcus isolates. The semimechanistic PK/PD model predicted that linezolid (more than 16 mg/L) combined with fosfomycin (6 g or 10 g) via a 0.5-h infusion every 8 h was required to achieve a 4 log10 CFU/mL decrease at 24 h against Enterococcus isolates (MICLZD ≥ 8 mg/L and MICFOF ≥ 256 mg/L). According to the prediction of the semimechanical PK/PD model, the effect of the combination was driven by linezolid, with fosfomycin enhancing the effect. Our study is the first to explore the synergistic effects of these two drugs from a qualitative and quantitative perspective and provides a simulation tool for future studies. IMPORTANCE In this study, we found that linezolid combined with fosfomycin could kill Enterococcus in vitro and that the administered dose was significantly lower after the combination treatment, which could reduce adverse effects and the development of drug resistance. The potential mechanism of the two-drug combination against Enterococcus was revealed from a quantitative perspective, which is an important step toward dose optimization in simulated humans. We hope that our research will help build a better relationship between clinicians and patients as we work together to address the challenges of antibiotic resistance in the 21st century.

Pharmacodynamics of Linezolid Plus Fosfomycin Against Vancomycin-Resistant Enterococcus faecium in a Hollow Fiber Infection Model.

The optimal therapy for severe infections caused by vancomycin-resistant Enterococcus faecium (VREfm) remains unclear, but the combination of linezolid and fosfomycin may be a good choice. The 24-h static-concentration time-kill study (SCTK) was used to preliminarily explore the pharmacodynamics of linezolid combined with fosfomycin against three clinical isolates. Subsequently, a hollow-fibre infection model (HFIM) was used for the first time to further investigate the pharmacodynamic activity of the co-administration regimen against selected isolates over 72 h. To further quantify the relationship between fosfomycin resistance and bacterial virulence in VREfm, the Galleria mellonella infection model and virulence genes expression experiments were also performed. The results of SCTK showed that the combination of linezolid and fosfomycin had additive effect on all strains. In the HFIM, the dosage regimen of linezolid (12 mg/L, steady-state concentration) combined with fosfomycin (8 g administered intravenously every 8 h as a 1 h infusion) not only produced a sustained bactericidal effect of 3∼4 log10 CFU/mL over 72 h, but also completely eradicated the resistant subpopulations. The expression of virulence genes was down-regulated to at least 0.222-fold in fosfomycin-resistant strains compared with baseline isolate, while survival rates of G. mellonella was increased (G. mellonella survival ≥45% at 72 h). For severe infections caused by VREfm, neither linezolid nor fosfomycin monotherapy regimens inhibited amplification of the resistant subpopulations, and the development of fosfomycin resistance was at the expense of the virulence of VREfm. The combination of linezolid with fosfomycin produced a sustained bactericidal effect and completely eradicated the resistant subpopulations. Linezolid plus Fosfomycin is a promising combination for therapy of severe infections caused by VREfm.

Incidence of Macrosomia in Rural Areas - Henan Province, China, 2013-2017.

INTRODUCTION: Macrosomia has short-term and long-term adverse health effects and is thus an important public health concern. Recent decades have witnessed increasing incidence of macrosomia in many countries. METHODS: The present study used a large population-based birth cohort study to depict incidence of macrosomia among live births in rural areas of Henan Province of China from 2013 to 2017. RESULTS: Among the 1,262,916 births, 82,353 were cases of macrosomia. The overall incidence of all types of macrosomia, of macrosomia with birth weight <4,500 g, and of macrosomia with birth weight ≥4,500 g were 6.52%, 5.30%, and 1.22%, respectively. From 2013 to 2017, the incidence of macrosomia decreased by 31.3% from 7.96% in 2013 to 5.47% in 2017 ( [Formula: see text]=946.96, [Formula: see text]<0.001). Male infants and infants ≥42 gestational weeks had significantly higher incidence of macrosomia than that of female infants and infants <42 gestational weeks (P<0.001). CONCLUSION: Gestational weight control through nutrition management and physical activities during pregnancy are needed to reduce incidence of macrosomia.

Effect of Heat Softening versus Ultrasonic Removal of Root-End Gutta-Percha on the Quality of Root-End Preparation for Endodontic Microsurgery.

This study is aimed at comparing the efficacy of heat softening and ultrasonic removal of root-end gutta-percha during retrograde preparation for root apical microsurgery. Recently extracted single-rooted premolars (n = 40) were prepared with standardized endodontically treated and root-end resection and then randomly divided into four groups that received root-end cavity preparation using four different instruments: a diamond-coated ultrasonic tip (AS3D; SACTEON, Paris, France), AS3D with the modified plugger of cordless heat carrier (MSE; B&L Biotech, Bala Cynwyd, PA, USA), stainless steel ultrasonic tip (Jetip-2; B&L Biotech, Bala Cynwyd, PA, USA), or Jetip-2 with MSE. The time required for root-end preparation was recorded. The root apex samples were examined by scanning electron microscopy to assess root surface microcracks and marginal integrity. The remnants of gutta-percha on the cavity walls were evaluated using a stereomicroscope. Statistical analysis was performed using Student's t-test and Wilcoxon rank-sum test (P < 0.05). Usage of MSE with Jetip-2 significantly reduced preparation time from 99.8 ± 6.8 s to 32.4 ± 1.0 s (P = 0.009), the number of microcracks from 42 to 13 (P = 0.036), and the remnants of gutta-percha from 80% to 20% (P = 0.041). Similar results were observed for AS3D with MSE. The heat softening of MSE was effective in cleaning gutta-percha, thus greatly improving the efficiency of the root-end preparation, thereby producing a root-end cavity with fewer microcracks and better marginal integrity.