Investigation of statistical methods used in prognostic prediction models for obstetric care: A 10 year-span cross-sectional study.

INTRODUCTION: Obstetric care is a highly active area in the development and application of prognostic prediction models. The development and validation of these models often require the utilization of advanced statistical techniques. However, failure to adhere to rigorous methodological standards could greatly undermine the reliability and trustworthiness of the resultant models. Consequently, the aim of our study was to examine the current statistical practices employed in obstetric care and offer recommendations to enhance the utilization of statistical methods in the development of prognostic prediction models. MATERIAL AND METHODS: We conducted a cross-sectional survey using a sample of studies developing or validating prognostic prediction models for obstetric care published in a 10-year span (2011-2020). A structured questionnaire was developed to investigate the statistical issues in five domains, including model derivation (predictor selection and algorithm development), model validation (internal and external), model performance, model presentation, and risk threshold setting. On the ground of survey results and existing guidelines, a list of recommendations for statistical methods in prognostic models was developed. RESULTS: A total of 112 eligible studies were included, with 107 reporting model development and five exclusively reporting external validation. During model development, 58.9% of the studies did not include any form of validation. Of these, 46.4% used stepwise regression in a crude manner for predictor selection, while two-thirds made decisions on retaining or dropping candidate predictors solely based on p-values. Additionally, 26.2% transformed continuous predictors into categorical variables, and 80.4% did not consider nonlinear relationships between predictors and outcomes. Surprisingly, 94.4% of the studies did not examine the correlation between predictors. Moreover, 47.1% of the studies did not compare population characteristics between the development and external validation datasets, and only one-fifth evaluated both discrimination and calibration. Furthermore, 53.6% of the studies did not clearly present the model, and less than half established a risk threshold to define risk categories. In light of these findings, 10 recommendations were formulated to promote the appropriate use of statistical methods. CONCLUSIONS: The use of statistical methods is not yet optimal. Ten recommendations were offered to assist the statistical methods of prognostic prediction models in obstetric care.

A nomogram for predicting breast cancer specific survival in elderly patients with breast cancer: a SEER population-based analysis.

BACKGROUND: The number of elderly patients diagnosed with breast cancer is increasing worldwide. However, treatment decisions for these patients are highly variable. Although researchers have identified the effects of surgery, radiotherapy, endocrine therapy, and chemotherapy in elderly patients with breast cancer, clinicians still struggle to make appropriate decisions for these patients. METHODS: We identified 75,525 female breast cancer patients aged ≥ 70 years in the Surveillance, Epidemiology, and End Results (SEER) database treated between January 1, 2010, and December 31, 2016. The patients were further divided into training and testing cohorts. The cumulative occurrence of breast cancer-specific deaths (BCSDs) and other cause-specific deaths (OCSD) was calculated using the cumulative incidence function. In the univariate analysis, risk factors were screened using the Fine-Gray model. In the multivariate analysis for competing risks, the sub-distribution hazard ratio with a 95% confidence interval for each independent predictor associated with BCSD was calculated for the construction of nomograms. Based on the above analyses, a competing risk nomogram was constructed to predict the probability of BCSD in the 1st, 3rd, and 5th years after treatment. During validation, the concordance index (C-index) was selected to quantify the predictive ability of the competing risk model. RESULTS: A total of 33,118 patients were included in this study, with 24,838 in the training group and 8,280 in the testing group. Age, race, marital status, cancer grade, tumor stage, node stage, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor--2 status, and treatment including surgery, radiation, and chemotherapy were used to establish a nomogram. The C-index of 0.852 (0.842-0.862) in the training cohort and 0.876 (0.868-0.892) in the testing cohort indicated satisfactory discriminative ability of the nomogram. Calibration plots showed favorable consistency between the nomogram predictions and actual observations in both the training and validation cohorts. CONCLUSIONS: Our study identified independent predictors of BCSD in elderly patients with breast cancer. A prognostic nomogram was developed and validated to aid clinical decision-making.

Impact of maternal hepatitis B carrier status on congenital abnormalities: a systematic review and meta-analysis.

OBJECTIVES: This study aims to explore whether maternal hepatitis B carrier status is associated with an increased risk of congenital abnormalities. DESIGN: A systematic review and meta-analysis of observational studies. DATA SOURCES: PubMed, Embase (Ovid), Scopus, the China National Knowledge Infrastructure (CNKI) and the Wanfang databases. STUDY SELECTION: Five databases were searched systematically from inception to 7 September 2021. Cohort and case-control studies that investigated the association between maternal hepatitis B virus (HBV) infection and congenital abnormalities were included. This study was conducted according to MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently collected data, as well as assessed risk of bias by using Newcastle-Ottawa Scale. We pooled crude relative risk (cRR) and adjusted OR (aOR) by DerSimonian-Laird random-effects model. Heterogeneity was explored by I 2 statistics, Cochran's Q test. Several subgroup analyses and sensitivity analyses were performed. RESULTS: In total, 14 studies involving 16 205 pregnant women exposed to HBV were included. The pooled cRR of 1.15 (95% CI: 0.92 to 1.45; 14 studies included) showed a marginal but not significant association between maternal HBV-carrier status and congenital abnormalities. However, the pooled aOR of 1.40 (95% CI: 1.01 to 1.93; 8 studies included) indicated that pregnant women with HBV infection might be associated with a higher risk of congenital abnormalities. Subgroup analyses of adjusted data showed a higher pooling cRR or aOR on high prevalence HBV infection populations, as well as studies from Asia and Oceania. CONCLUSIONS: Maternal hepatitis B carrier status might be at potential risk for congenital abnormalities. The existing evidence was not sufficient to draw a firm conclusion. Additional studies may be warranted to confirm the association. PROSPERO REGISTRATION NUMBER: CRD42020205459.

The reporting of prognostic prediction models for obstetric care was poor: a cross-sectional survey of 10-year publications.

BACKGROUND: To investigate the reporting of prognostic prediction model studies in obstetric care through a cross-sectional survey design. METHODS: PubMed was searched to identify prognostic prediction model studies in obstetric care published from January 2011 to December 2020. The quality of reporting was assessed by the TRIPOD checklist. The overall adherence by study and the adherence by item were calculated separately, and linear regression analysis was conducted to explore the association between overall adherence and prespecified study characteristics. RESULTS: A total of 121 studies were included, while no study completely adhered to the TRIPOD. The results showed that the overall adherence was poor (median 46.4%), and no significant improvement was observed after the release of the TRIPOD (43.9 to 46.7%). Studies including both model development and external validation had higher reporting quality versus those including model development only (68.1% vs. 44.8%). Among the 37 items required by the TRIPOD, 10 items were reported adequately with an adherence rate over of 80%, and the remaining 27 items had an adherence rate ranging from 2.5 to 79.3%. In addition, 11 items had a report rate lower than 25.0% and even covered key methodological aspects, including blinding assessment of predictors (2.5%), methods for model-building procedures (4.5%) and predictor handling (13.5%), how to use the model (13.5%), and presentation of model performance (14.4%). CONCLUSIONS: In a 10-year span, prognostic prediction studies in obstetric care continued to be poorly reported and did not improve even after the release of the TRIPOD checklist. Substantial efforts are warranted to improve the reporting of obstetric prognostic prediction models, particularly those that adhere to the TRIPOD checklist are highly desirable.

Diagnostic value of core needle biopsy for determining HER2 status in breast cancer, especially in the HER2-low population.

PURPOSE: The status of human epidermal growth factor receptor 2 (HER2) is important for treatment decision-making of breast cancer and was commonly determined by core needle biopsy (CNB). The concordance of CNB with surgical excision biopsy (SEB) has been verified, but remain unclear according to the newly developed classification of HER2 status. Our study aimed to re-evaluate the diagnostic value of CNB for determining HER2 status in breast cancer, especially in the HER2-low population. METHODS: Eligible breast cancer patients in West China Hospital between January 1, 2007 and December 31, 2021 were enrolled consecutively and data were extracted from the Hospital Information System. The agreement of HER2 status between CNB and SEB was calculated by concordance rate and κ statistics, as well as the sensitivity, specificity, positive, and negative predictive values (PPV & NPV). Logistic models were used to explore potential factors associated with the discordance between both tests. RESULTS: Of 1829 eligible patients, 1097 (60.0%) and 1358 (74.2%) were consistent between CNB and SEB by pathological and clinical classifications, respectively, with κ value being 0.46 (0.43-0.49) and 0.57 (0.53-0.60). The sensitivity (50.9%-52.7%) and PPV (50.5%-55.2%) of CNB were especially low among IHC 1+ and 2+/ISH - subgroups by pathological classifications; however, it showed the highest sensitivity (77.5%) and the lowest specificity (73.9%) in HER2-low population by clinical classifications. Advanced N stages might be a stable indicator for the discordance between both tests. CONCLUSION: The diagnostic value of CNB was limited for determining HER2 status in breast cancer, especially in HER2-low population.

Effect of adjuvant chemotherapy on the survival outcomes of elderly breast cancer: A retrospective cohort study based on SEER database.

BACKGROUND: Currently, the proportion of standard chemotherapy for elderly patients is much lower than that for young patients, with little evidence from clinical trials supporting the use of chemotherapy for elderly patients. The effectiveness of chemotherapy for the elderly suffering from breast cancer remains to be further verified. METHODS: A total of 75,525 female breast cancer patients aged 70 years or older were hereby identified, all from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010 to December 31, 2016. Kaplan-Meier analysis and multivariable Cox proportional model were performed to evaluate the effectiveness of chemotherapy on overall survival (OS) and breast cancer-specific survival (BCSS). Propensity score matching (PSM) (PSM ratio: 1:1, caliper: 0.2 standard deviation of propensity score) was applied to construct balanced cohorts with or without chemotherapy based on demographic and pathophysiological characteristics. RESULTS: A total of 33,177 eligible patients were included, with 5273 (15.89%) receiving chemotherapy. Through PSM, 8360 patients were successfully matched, and balances between groups were almost reached. In the matched data set, multivariable Cox analysis reveals that chemotherapy was associated with a 36% and 21% risk reduction on OS (HR = 0.64, 95% CI 0.58 to 0.71) and BCSS (HR = 0.79, 95% CI 0.69 to 0.91), respectively. Furthermore, subgroups with more adjacent lymph nodes involved by tumor, or nonluminal A, were inclined to benefit more from chemotherapy. Moreover, chemotherapy did not increase the chances of dying from heart disease. CONCLUSIONS: The present study provided evidence that chemotherapy may improve the prognosis of elderly breast cancer, especially for those subpopulations that benefit more from chemotherapy treatment.

Dose-response association between maternal pre-pregnancy bodyweight and gestational diabetes mellitus following ART treatment: a population-based cohort study.

BACKGROUND: The impact of maternal pre-pregnancy bodyweight on gestational diabetes mellitus (GDM) following assisted reproductive technology (ART) treatment has been insufficiently investigated. The aim of this study was to investigate the association between maternal pre-pregnancy bodyweight and GDM following ART. METHODS: From January 2014 to March 2019, this population-based retrospective cohort study included pregnancies achieved by ART treatment in a pregnancy registration database in China. Multivariate regression analysis and restricted cubic splines were used to explore the association between bodyweight and GDM. RESULTS: A total of 6,598 pregnancies were included. The incidence of GDM was 26.0% (1715/6598). A total of 868 (13.2%) pregnant women were underweight, 665 (10.8%) were overweight, and 145 (2.20%) were obesity. We found a linear dose-response relation between maternal body mass index and GDM by restricted cubic splines, where one unit body mass index increase was associated with the 15% elevated risk of GDM (adjusted odds ratio [OR] 1.15, 95% CI 1.08-1.22). Compared to the normal weight group, maternal underweight was associated with lower risk of GDM (adjusted OR 0.68, 95% CI 0.57-0.82), while increased risk was found for overweight (adjusted OR 1.54 95% CI 1.29-1.84) and obesity (adjusted OR 1.74, 95% CI 1.23-2.47). CONCLUSIONS: Our study found a linear dose-effect relationship between pre-pregnancy bodyweight and GDM following ART treatment. The findings in this study support the clinical recommendation of advising women with overweight or obesity to lose weight prior to ART treatment.

The impact of biparental hepatitis B virus infection on pregnancy outcomes in patients undergoing assisted reproductive technology treatment: a systematic review and meta-analysis.

PURPOSE: To evaluate the association between biparental hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] seropositivity) and pregnancy outcomes in patients undergoing assisted reproductive technology (ART) treatment, including clinical pregnancy rate (CPR) and live birth rate (LBR). METHODS: We searched various literature databases from the earliest date available until May 20, 2021, including PubMed, Embase, Medline, Web of Science, Scopus, CNKI, and Wangfang. Four patterns of biparental HBV infection for pregnancy outcomes following ART were synthesized separately by using random-effects model. We also performed subgroup analyses (matched or unmatched) and two forms of sensitivity analysis. RESULTS: A total of 25 retrospective cohort studies, involving more than 19,269 couples, were included. Maternal and paternal HBV co-infection (crude relative risk [cRR]: 0.58, 95% confidence interval: 0.28-1.23), either maternal or paternal infection (cRR: 1.05, 0.88-1.24), maternal HBV infection alone (cRR: 0.96, 0.79-1.16), or paternal HBV infection alone (cRR: 1.02, 0.91-1.13) were not associated with significant reductions in CPR at per woman level. These patterns of infection were also not significantly associated with decreased LBR at per woman level. However, paternal HBV infection alone reduced CPR (adjusted odds ratio: 0.54, 0.33-0.86) and LBR (cRR: 0.52, 0.28-0.99) at per cycle level. Subgroup analyses and sensitivity analyses were mostly consistent with the primary results. CONCLUSIONS: Paternal HBV infection alone probably decrease CPR after ART at per cycle level. However, maternal HBV infection was not associated with reductions in CPR and LBR in women undergoing ART at per woman level.

Macrophage-Secreted S100A4 Supports Breast Cancer Metastasis by Remodeling the Extracellular Matrix in the Premetastatic Niche.

Metastasis is the major cause of cancer-related mortalities. A tumor-supportive microenvironment, also known as the premetastatic niche at secondary tumor sites, plays a crucial role in metastasis. Remodeling of the extracellular matrix (ECM) is essential for premetastatic niche formation, especially for circulating tumor cell colonization. However, the underlying molecular mechanism that contributes to this effect remains unclear. Here, we developed a lung metastasis model with 4T1 breast cancer cells and found that the metastasis critically depended on the early recruitment of macrophages to the lung. Disruption of macrophage recruitment reduced fibroblast activation and lung metastasis. Furthermore, we identified the secreted protein S100A4, which is produced by M2 macrophages and participates in fibroblast activation and ECM protein deposition via the ERK signaling pathway. Collectively, these results indicate that recruiting S100A4-expressing inflammatory macrophages plays a vital role in ECM remodeling in the premetastatic niche and may act as a potential therapeutic target for breast cancer lung metastasis.

Effects of Motherwort Injection Versus Intramuscular Oxytocin for Preventing Postpartum Hemorrhage Among Women Who Underwent Cesarean Section.

Objectives: Subject to ethical constraints, real-world data are an important resource for evaluating treatment effects of medication use during pregnancy and the postpartum period. This study investigated whether motherwort injection, a traditional Chinese medicine preparation, was more effective than intramuscular (IM) oxytocin for preventing postpartum hemorrhage (PPH) in a real-world setting when intravenous (IV) oxytocin is administered. Methods: We conducted an active-controlled, propensity-score matched cohort study using an established pregnancy registry database. Women who underwent cesarean section and received IV oxytocin at the third stage of labor were included. We used an active-comparator design to minimize indication bias, in which we compared IM motherwort injection in the uterus versus IM oxytocin, both on top of IV oxytocin use. We applied 1:1 propensity-score matching (PSM) to balance patient baseline characteristics and used a logistic regression model to estimate treatment effect (i.e., risk difference (RD) and odds ratio (OR)) by using the counterfactual framework. The outcomes of interest were blood loss over 500 ml within 2 h after delivery (PPH, primary) and blood loss over 1,000 ml (severe PPH, secondary). We conducted four sensitivity analyses to examine the robustness of the results. Results: A total of 22,519 pregnant women underwent cesarean sections, among which 4,081 (18.12%) PPH and 480 (2.13%) severe PPH occurred. Among included women, 586 (2.60%) were administrated with IM motherwort injection, and 21,933 (97.40%) used IM oxytocin. After PSM, patient baseline characteristics were well balanced. Compared with IM oxytocin, the use of IM motherwort injection was associated with significantly lower risk of PPH (RD -25.26%, 95% CI -30.04% to -20.47%, p < 0.001; OR 0.25, 95% CI 0.18 to 0.32, p < 0.001) and severe PPH (RD -3.58%, 95% CI -5.87% to -1.30%, p < 0.001; OR 0.39, 95% CI 0.20 to 0.71, p < 0.002). Sensitivity analyses showed that the results were similar. Conclusion: With the use of data from a real-world setting, the findings consistently showed that among women undergoing cesarean section who had received IV oxytocin, the additional use of IM motherwort injection could achieve a lower risk of PPH as compared to the additional use of IM oxytocin. Our study suggested a paradigm for investigating the treatment effect of Chinese herbal medicine in the real-world practice setting.

A methodological framework for tackling confounding by indication when assessing the treatment effects of Chinese herbal injections in the real world.

AIM: In the context of integrative medicine, whether Chinese herbal injections are effective in routine practice has become a question of broad interest. However, confounding by indication (i.e., indication bias) is a prevalent and highly challenging methodological issue when using routinely collected health care data to assess the real-world effectiveness of Chinese herbal injections. METHODS AND RESULTS: We proposed a methodological approach to tackling confounding by indication in assessing the real-world effectiveness of Chinese herbal injections, incorporating empirical experiences, a literature review and interactive discussions, and a panel of external experts to finally achieve a consensus. This approach consisted of three cohesive steps, including a full understanding of treatment patterns, construction of fair comparisons by identifying appropriate combination treatments and comparators, and using statistical methods to further control for confounding. In the investigation of treatment patterns, we proposed five domains to identify treatment patterns with Chinese herbal injections, and we offered five patterns of combination treatments to characterize how Chinese herbal injections are used in conjunction with other treatments. In constructing fair comparisons, we suggested the use of both nonuse and active comparators; given the diverse combination treatments, we developed six scenarios that may form fair comparisons. In the statistical analysis, we discussed five statistical models for controlling confounding by indication, including their pros and cons. We also included a practical example to illustrate the usefulness of the methodological approach. CONCLUSION: The proposed approach may serve as an effective tool to guide researchers to reliably assess the effectiveness of Chinese herbal injections in the context of integrative medicine.

The application of radiomics in predicting gene mutations in cancer.

With the development of genome sequencing, the role of molecular targeted therapy in cancer is becoming increasingly important. However, genetic testing remains expensive, invasive, and time-consuming, and thus unavailable for all patients. Radiogenomics aims to correlate imaging characteristics with gene expression patterns, gene mutations, and other genome-related characteristics. Due to the noninvasive nature of medical imaging, the field of radiogenomics is rapidly developing and may serve as a substitute tool for genetic testing. In this article, we briefly summarise the current role of radiogenomics in predicting gene mutations in brain, lung, colorectal, breast, and kidney tumours. KEY POINTS: • The role of molecular targeted therapy in individual cancer-precision therapy is becoming increasingly important with the development of genetic testing. • Radiogenomics may provide accurate imaging biomarkers as a substitute for genetic testing. • While the field of radiogenomics holds great promise, there are still a number of limitations that need to be overcome.

Cervical pessary for preventing preterm birth in singletons and twin pregnancies: an update systematic review and meta-analysis.

OBJECTIVES: To evaluate the effectiveness of cervical pessary in preventing preterm birth (PTB) and improving perinatal outcomes among singleton and twin pregnancies. METHODS: Electronic databases were systematically searched from their inception until 14 March 2019. Randomized clinical trials comparing the effectiveness of cervical pessary placement with expectant management were included. The primary outcome was the incidence of PTB <34 weeks. RESULTS: Thirteen studies were included, involving eight studies about singleton and six studies about twin pregnancies. For singleton pregnancies with short cervical length, cervical pessary, comparing with expectant treatment, seemed have no effectiveness in preventing PTB <34 weeks (relative risk, 95% confidence interval, 0.73, 0.42-1.28), <37 weeks (0.69, 0.43-1.09), and <28 weeks (0.79, 0.42-1.48); while for twin pregnancies with short cervical length, cervical pessary also did not reduce the risk of PTB <34 weeks (0.81, 0.49-1.35), <37 weeks (0.93, 0.83-1.05), and <28 weeks (0.72, 0.38-1.38). However, cervical pessary seemed have the effectiveness of reducing the risk of spontaneous PTB <28 weeks (0.50, 0.25-0.99) and low birth weight (<1500 g) (0.68, 0.50-0.94) among twin pregnancies with short cervical length. In addition, cervical pessary increased the rate of vaginal discharge and did not improve perinatal outcomes among both singleton and twin pregnancies. CONCLUSIONS: Comparing with the expectant treatment, the effectiveness of cervical pessary for reducing the risk of PTB remains uncertain. Additional trials are warranted to further evaluate the effectiveness of cervical pessary.

Toward a better understanding about real-world evidence.

BACKGROUND: There has been an interest in real-world evidence (RWE) in recent years. RWE is usually generated from data derived from routine healthcare, such as electronic healthcare records and disease registries. While RWE has many advantages, it is often open to various biases, which may distort results. Appropriate understanding and interpretation are critical to the best use of RWE in healthcare decisions. METHODS: On the basis of a literature review and empirical research experience, we summarised the concept and methodological framework of RWE, and discussed in detail methodological issues specific to routinely collected healthcare data and observational studies using such data. RESULTS: RWE is derived from a spectrum of data generated from the real-world setting, using two broad study designs including observational studies and pragmatic clinical trials. Real-world data may usually be collected through routine practice or sometimes actively collected with a research purpose. Observational studies using routinely collected data (RCD) are the most common type of RWE, although they are prone to biases. When planning and implementing RWE studies, coherent working steps are warranted, including definition of a clear and answerable research question, development of a research team, selection of a fit-for-purpose data source, choice of state-of-the-art study design, establishing a database with transparent data processing, performing multiple statistical analysis to control bias, and reporting results in accordance with established guidelines. CONCLUSIONS: RWE has been mounting over the years. The appropriate interpretation and use of such evidence often warrant adequate understanding about methodology. Researchers and policymakers should be aware of the methodological pitfalls when generating and interpreting RWE.

Texture Analysis of Computed Tomography Images in the Lung of Patients With Breast Cancer.

OBJECTIVE: The aim of this study was to investigate whether the texture features of lung computed tomography images were altered by primary breast cancer without pulmonary metastasis. METHODS: Texture analysis was performed on the regions of interest of lung computed tomography images from 36 patients with breast cancer and 36 healthy controls. Texture parameters between subjects with different clinical stages and hormone receptor (HR) statuses in patients with breast cancer were analyzed. RESULTS: Three texture parameters (mean, SD, and variance) were significantly different between patients with breast cancer and healthy controls and between preoperative and postoperative stages in patients with breast cancer. All 3 parameters showed an increasing trend under the tumor-bearing state. These parameters were significantly higher in the stage III + IV group than in the stage I + II group. The variance parameter was significantly higher in the HR-negative group than in the HR-positive group. CONCLUSIONS: Texture analysis may serve as a novel additional tool for discovering conventionally invisible changes in the lung tissue of patients with breast cancer.

Association between maternal prepregnancy body mass index and pregnancy outcomes following assisted reproductive technology: A systematic review and dose-response meta-analysis.

This systematic review investigated dose-response relationship between maternal prepregnancy body mass index (BMI) and pregnancy outcomes following assisted reproductive technology, including clinical pregnancy rate (CPR), miscarriage rate (MR), and live birth rate (LBR). We searched four major databases and finally included 105 studies involving more than 271,632 pregnant women. We performed linear or nonlinear dose-response meta-analyses using random effects models. At per-woman level, pooling of unadjusted estimates shown an inverted J-shaped relationship between maternal BMI and CPR; pooling of adjusted estimates showed a linear association, suggesting statistical association between higher maternal BMI and lower CPR (adjusted OR [aOR] for 5-unit increase in BMI: 0.96, 95%CI: 0.94-0.98). At per-cycle level, linear dose-response relationship was found between maternal BMI and CPR (crude relative risk, RR, [cRR] for 5-unit increase in BMI 0.97, 0.96-0.98; aOR 0.96, 0.94-0.99). Linear dose-response relationship was established between maternal BMI and the outcomes of MR or LBR (higher BMI associated with higher MR [cRR 1.15, 1.08-1.22] and lower LBR [cRR 0.91, 0.88-0.94] at per-woman level). Sensitivity analyses showed no significant changes. In conclusion, there is dose-response relationship between maternal BMI and pregnancy outcomes following assisted reproductive technology. Higher BMI values may suggest suboptimal pregnancy outcomes.

Impact of maternal infection with hepatitis B virus on pregnancy complications and neonatal outcomes for women undergoing assisted reproductive technology treatment: A population-based study.

The aim of this study was to investigate the impact of maternal hepatitis B virus (HBV) status on pregnancy complications and neonatal outcomes for women undergoing assisted reproductive technology (ART). A total of 7,011 pregnancies achieved by ART were included from a population-based database involving 523,111 pregnancies. Exposures of hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) among pregnant women were routinely tested at the first antenatal visit for all pregnancies. We collected pregnancy complications (e.g., gestational diabetes mellitus [GDM], intrahepatic cholestasis of pregnancy [ICP]), neonatal outcomes and confounding variables from the same database. Univariate and multivariate analyses by adjusting confounders were conducted to evaluate the impact of maternal HBV infection. Prevalence of HBsAg seropositivity (HBsAg+) was 11.34% (95% CI 10.6-12.1) and that of HBsAg and HBeAg co-seropositivity (HBsAg+HBeAg+) was 2.55% (2.1-3.0) among included population. Compared with HBsAg-group, ICP risk in the HBsAg+group was higher (4.03% vs. 1.79%; adjusted odds ratio [aOR] 2.49, 1.65-3.77). Similarly, ICP prevalence in the HBsAg+HBeAg+ group was higher than that in the HBsAg-HBeAg- group (6.47% vs. 1.61%; aOR 4.78, 2.28-9.98). No associations were found between maternal HBV infection (i.e., HBsAg+, HBsAg+HBeAg+, or HBsAg+HBeAg-) and other adverse outcomes for women undergoing ART (i.e., GDM, pre-eclampsia, placental previa, premature separation of placenta, premature rupture of membranes, preterm birth and low birthweight) in this study. In conclusion, maternal HBV infection (HBsAg+or HBsAg+HBeAg+) probably increase ICP risk, but may not associate with other pregnancy complications or neonatal outcomes for pregnant women who underwent ART.

Computed tomography reveals microenvironment changes in premetastatic lung.

OBJECTIVES: Microenvironment changes had occurred in the metastatic organs before the arriving of the metastatic tumor cells. In this study, we evaluated the effectiveness of computed tomography (CT) images in quantifying the microenvironment changes in the premetastatic lung under both laboratory and clinical conditions. METHOD: Free-breathing Balb/c mice underwent micro-CT repeatedly after the implantation of 4T1 breast tumor. CT-derived indicators (aerated lung volume, lung tissue volume, total lung volume, mean lung density, and the ratio of aerated lung volume to the total lung volume) were quantified. Hematoxylin-eosin staining was used to display the microenvironment changes in premetastatic lung. Moreover, we examined healthy adult women, adult women with histopathologically confirmed primary breast cancer, and adult women with histopathologically confirmed primary breast cancer and lung metastases in our institution to test whether the indicators derived from lung CT images changed with the growth of breast cancer. RESULTS: In 4T1 tumor-bearing mice, lung density is increased before lung masses can be recognized on CT images and is correlated with the severity of inflammation in the lung microenvironment. In primary breast tumor-bearing patients, lung density is also increased before the clinical diagnosis of pulmonary metastasis and is correlated with disease score, which represents tumor progression. CONCLUSIONS: CT is a reliable and quantitative tool that yields dynamic information on metastatic processes. Microenvironmental changes had occurred in patients' lung tissue before the clinical diagnosis of pulmonary metastasis. Our research will provide new insight for clinical research on the premetastatic niche. KEY POINTS: • CT, which provides dynamic information on metastatic processes, is a reliable and quantitative tool to bridge laboratory and clinical studies of the premetastatic niche. • We confirmed that microenvironmental changes occurred in patients' lung tissue before clinicians could diagnose pulmonary metastasis. • Our results provide evidence for the study of the premetastatic niche by analyzing information obtained from CT images.

Creating rat hepatocyte organoid as an in vitro model for drug testing.

BACKGROUND: Liver organoids have recently been applied as models for liver disease and drug screening, especially when combined with liver-on-a-chip technologies. Compared to hepatocyte-like cells, primary hepatocytes have high functionality but cannot maintain their function when cultured in vitro. Mesenchymal stem cells (MSCs) enhance hepatocyte function and maintain hepatocyte metabolism when co-cultured with hepatocytes. MSCs can help induced pluripotent stem cells to generate an organoid structure via the MSC-based traction force triggered by extracellular matrix (ECM) proteins. In this study, primary hepatocytes were co-cultured with MSCs on a liver-derived ECM to generate liver organoids within a short duration. AIM: To create hepatocyte organoids by co-culturing primary hepatocytes with MSCs on a porcine liver extracellular matrix (PLECM) gel. METHODS: Perfusion and enzymatic hydrolysis were used to form the PLECM gel. Rat hepatocytes and human MSCs were mixed and plated on pre-solidified PLECM gel in a 48-well plate for 48 h to generate organoids. Generated organoids were evaluated through hematoxylin and eosin, periodic acid-Schiff, immuno-histological, and immunofluorescence staining, and quantitative PCR for alb, CYP450 gene markers, and urea cycle genes. Culture medium was collected to detect albumin (ALB) and urea production on days 2, 4, 6, 8, 14, and 20. RESULTS: The whole porcine liver was perfused and enzymatically hydrolyzed to form a PLECM gel. The structural components and basement membrane composition of the ECM, such as collagen type I, collagen type IV, fibronectin, and laminin, were demonstrated to be retained. Through interaction of human MSCs with the liver-derived ECM, primary hepatocytes and human MSCs assembled together into a 3D construction and generated primary hepatocyte organoids for 48 h. The mRNAs of the gene alb, the CYP450 gene markers cyp1a1, cyp1a2, and cyp3a2 as well as urea cycle genes arg-1, asl, ass-1, cps-1, nags were highly expressed in hepatocyte organoids. Long-term survival of the primary hepatocyte organoids, as well as stable functionality, was demonstrated via ALB and urea production in vitro. CONCLUSION: Our new method of creating primary hepatocyte organoids by co-culturing hepatocytes with MSCs on liver-derived ECM hydrogels could be used to develop models for liver disease and for drug screening.