Bearing Fault Diagnosis via Stepwise Sparse Regularization with an Adaptive Sparse Dictionary.

Vibration monitoring is one of the most effective approaches for bearing fault diagnosis. Within this category of techniques, sparsity constraint-based regularization has received considerable attention for its capability to accurately extract repetitive transients from noisy vibration signals. The optimal solution of a sparse regularization problem is determined by the regularization term and the data fitting term in the cost function according to their weights, so a tradeoff between sparsity and data fidelity has to be made inevitably, which restricts conventional regularization methods from maintaining strong sparsity-promoting capability and high fitting accuracy at the same time. To address the limitation, a stepwise sparse regularization (SSR) method with an adaptive sparse dictionary is proposed. In this method, the bearing fault diagnosis is modeled as a multi-parameter optimization problem, including time indexes of the sparse dictionary and sparse coefficients. Firstly, sparsity-enhanced optimization is conducted by amplifying the regularization parameter, making the time indexes and the number of atoms adaptively converge to the moments when impulses occur and the number of impulses, respectively. Then, fidelity-enhanced optimization is carried out by removing the regularization term, thereby obtaining the high-precision reconstruction amplitudes. Simulations and experiments verify that the reconstruction accuracy of the SSR method outperforms other sparse regularization methods under most noise conditions, and thus the proposed method can provide more accurate results for bearing fault diagnosis.

A recurrent positional encoding circular attention mechanism network for biomedical image segmentation.

Deep-learning-based medical image segmentation techniques can assist doctors in disease diagnosis and rapid treatment. However, existing medical image segmentation models do not fully consider the dependence between feature segments in the feature extraction process, and the correlated features can be further extracted. Therefore, a recurrent positional encoding circular attention mechanism network (RPECAMNet) is proposed based on relative positional encoding for medical image segmentation. Multiple residual modules are used to extract the primary features of the medical images, which are thereafter converted into one-dimensional data for relative positional encoding. The recursive former is used to further extract features from medical images, and decoding is performed using deconvolution. An adaptive loss function is designed to train the model and achieve accurate medical-image segmentation. Finally, the proposed model is used to conduct comparative experiments on the synapse and self-constructed kidney datasets to verify the accuracy of the proposed model for medical image segmentation.

Nitrogen removal performance of bioretention cells under polyethylene (PE) microplastic stress.

The use of bioretention cells as a stormwater control measure allows stormwater runoff to be collected and filtered, effectively removing microplastics and other pollutants from stormwater. This study investigated the effect of polyethylene microplastics (PE-MPs) retention on the bioretention cell, in terms of denitrification performance and microbial community structure. Four PE-MP exposures were compared at different concentrations of 0, 250, 500 and 1000 mg/L under alternating dry and wet period conditions. Results showed that the removal efficiency reduced by 14.99%, 28.37% and 18.59% with PE-MP concentrations of 250, 500 and 1000 mg/L. The NO3--N removal efficiency increased by 36.19%, 20.19% and 35.39%. After 8 days of dry conditions, the NO3--N removal efficiencies of the bioretention cells were reduced by 36.66%, 46.86% and 31.11% compared to those after 2 days of dry conditions. Microbial sequencing results indicated that the accumulation of PE-MPs changed the microbial community structure within the bioretention cell filler material, promoting the growth of bacteria such as Actinobacteria, Bacteroidetes and Firmicutes. Furthermore, PE-MPs reduced the relative abundance of nitrifying bacteria (e.g. Nitrospira) within the bioretention cell and promoted denitrifying bacteria (e.g. Dechloromonas and Hydrogenophaga), along with numerous other genera such as Azotobacter and Nocardia.

Performance evaluation of a low-cost loess-based filler for bioretention cells.

The sand and gravel fillers used in traditional bioretention cells are expensive and becoming increasingly scarce, and their performance is unstable. It is important to find a stable, reliable, and low-cost alternative filler for bioretention facilities. Using cement as a modified loess filler for bioretention cells is a low-cost and easily obtainable alternative. The loss rate and anti-scouring index of the cement-modified loess (CM) were analyzed under different curing times, cement addition amount, and compactness control conditions. This study found that the stability and strength of the cement-modified loess in water with a density of not less than 1.3 g/cm3, a curing time, of not less than 28 d and a cement addition amount not less than 10% meets the use requirements of the bioretention cell filler. X-ray diffraction and Fourier transform infrared spectroscopy of cement-modified materials with a 10% cement addition and a curing time of 28 days (CM28) and 56 days (CM56). Cement-modified materials with 2% straw and a curing time of 56 days (CS56) showed that the three kinds of modified loess all contain calcium carbonate and that the surface contains hydroxyl and amino functional groups that can effectively remove phosphorus. The specific surface areas of the CM56, CM28, and CS56 samples were 12.53 m2/g, 24.731 m2/g, and 26.252 m2/g, respectively, which are significantly higher than that of sand (0.791 m2/g). At the same time, the adsorption capacity of the ammonia nitrogen and the phosphate that was present in the three modified materials is better than that of sand. CM56, like sand, has rich microbial communities, which can entirely remove nitrate nitrogen in water under anaerobic conditions, indicating that CM56 can be used as an alternative filler for bioretention cells. The production of cement-modified loess is simple and cost-effective, and using modified loess as a filler can reduce the use of stone resources or other on-site materials. Current methods for improving the filler of bioretention cells are mainly based on sand. This experiment used loess to improve the filler. The performance of loess is better than sand, and can completely replace sand as the filler in bioretention cells.

Risk of Higher Blood Pressure in 3 to 6 Years Old Singleton Born From OHSS Patients Undergone With Fresh IVF/ICSI.

Background: A large registry-based study found the increasing disorders of cardiovascular and metabolism in IVF children but underlying mechanism is still unknown. Few studies have investigated any association between OHSS and cardiovascular or metabolic function in subsequent children. Objective: To evaluate the effect of ovarian hyperstimulation syndrome (OHSS) on blood pressure of singletons after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). Study Design: The singlet-center corhort study included 1780 singletons born with IVF/ICSI and 83 spontaneously conceived children from 2003 to 2014. Follow-up has lasted more than 10 years, and is still ongoing. This study analyzed data from follow-up surveys at 3 to 6 years of age. Participants Setting and Methods: We recruited 83 children (Group E) spontaneously conceived (SC) as control group and 1780 children born with IVF/ICSI including 126 children born to OHSS-fresh embryo transfer (ET) women (Group A), 1069 children born to non OHSS-ET women (Group B), 98 children conceived by women who developed into moderate or severe OHSS after oocyte retrieval and selected the frozen-thawed embryo transfer (FET) (Group C), 487 children conceived with non OHSS-FET (Group D). We evaluated cardiometabolic function, assessed BP in mmHg, heart rate, anthropometrics, and metabolic index including glucose, serum lipid (triglyceride, total cholesterol, low density lipoprotein, high density lipoprotein), thyroid function, of those children. The BP and heart rate were measured twice on the same day. We applied several multiple regression analyses to investigate the effect of OHSS in the early pregnancy. Main Findings: By the single factor analysis, the SBP and DBP in the SC group (SBP: 99.84 ± 8.9; DBP: 55.27 ± 8.8) were significantly lower than OHSS-ET group's, while the blood pressure was similar between the SC group and other three ART groups. Children had higher BP in the OHSS-ET group (SBP: 101.93 ± 8.17; DBP: 58.75 ± 8.48) than in the non OHSS-ET (SBP: 99.49 ± 8.91; DBP: 56.55 ± 8.02) or OHSS-FET group (SBP: 99.38 ± 8.17; DBP: 55.72 ± 7.94). After using multiple regression analysis to adjust current, early life, parental and ART characteristics, the differences in the SBP and DBP (B (95% confidence interval)) between OHSS-ET and non OHSS-ET remained significant (SBP: 3.193 (0.549 to 2.301); DBP: 3.440 (0.611 to 2.333)). And the BP showed no significant difference complementarily when compared non OHSS-FET group with non OHSS-ET group. In addition, the anthropometrics, fast glucose, serum lipid, and thyroid index did not differ among the ART groups. Principal Conclusions: OHSS might play an independent key role on offspring's BP even cardiovascular function. Electing frozen-thawed embryo transfer for high risk of OHSS population may reduce the risk of the high BP trend. Wider Implications of the Findings: It is a large sample study to investigate the effect of OHSS on offspring's health. These findings provide a clinic evidence of the impact of early environment (embryo even oocyte stage) on the offspring's cardiovascular health. Our study emphasis the importance of the accuracy of IVF clinic strategy and preventing the OHSS after fresh embryo transfer.

Embryo morphologic quality in relation to the metabolic and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection: a matched cohort study.

BACKGROUND: Embryos with higher morphologic quality grading may have a greater potential to achieve clinical pregnancy that leads to a live birth regardless of the type of cleavage-stage embryos or blastocysts. Few studies have investigated the impacts of embryo grading on the long-term health of the offspring. OBJECTIVE: This pilot study aimed to examine the associations between embryo morphologic quality and the physical, metabolic, and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection at preschool age. STUDY DESIGN: This matched cohort study included singletons born to infertile couples who underwent fresh cleavage-stage embryo transfer cycles with good- or poor-quality embryos from 2014 to 2016 at the reproductive center of the Women's Hospital, School of Medicine, Zhejiang University. A total of 144 children, aged 4 to 6 years, participated in the follow-up assessment from 2020 to 2021, and the response rate of poor-quality embryo offspring was 39%. Singletons in the good-quality embryo group were matched with singletons in the poor-quality embryo group at a 2:1 ratio according to the fertilization method and the children's age (±1 year). We measured the offspring's height, weight, body mass index, blood pressure, thyroid hormone levels, and metabolic indicators. Neurodevelopmental assessments were performed using the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition, and the Adaptive Behavior Assessment System, Second Edition. We also collected data from the medical records. A linear regression model was used to analyze the association between embryo morphologic quality and offspring health outcomes. RESULTS: A total of 48 singletons conceived with poor-quality embryo transfer and 96 matched singletons conceived with good-quality embryo transfer were included in the final analysis. Age, sex, height, weight, body mass index, blood pressure, thyroid function, and metabolic indicators were comparable between the 2 groups. After adjustment for potential risk factors by linear regression model 1 and model 2, poor-quality embryo offspring exhibited a tendency toward higher free thyroxine levels than offspring of good-quality embryo transfers (beta, 0.22; 95% confidence interval, 0.09-0.90; beta, 0.22; 95% confidence interval, 0.09-0.91, respectively), but this difference was not clinically significant. Regarding neurodevelopmental assessments, there was no difference in the full-scale intelligence quotient based on the Wechsler Preschool and Primary Scale of Intelligence (109.96±12.42 vs 109.60±14.46; P=.88) or the general adaptive index based on the Adaptive Behavior Assessment System (108.26±11.70 vs 108.08±13.44; P=.94) between the 2 groups. The subindices of the 2 tests were also comparable. These findings remained after linear regression analysis. CONCLUSION: At 4 to 6 years of age, singletons born from poor-quality embryo transfers have comparable metabolic and cognitive development as those born from good-quality embryo transfers using fresh cleavage-stage embryos. The results of this pilot study indicate that poor-quality embryos that can survive implantation and end in live birth are likely to have a developmental potential comparable to that of good-quality embryos.

Bayesian sample-size determination methods considering both worthwhileness and unpromisingness for exploratory two-arm randomized clinical trials with binary endpoints.

A randomized exploratory clinical trial comparing an experimental treatment with a control treatment on a binary endpoint is often conducted to make a go or no-go decision. Such an exploratory trial needs to have an adequate sample size such that it will provide convincing evidence that the experimental treatment is either worthwhile or unpromising relative to the control treatment. In this paper, we propose three new sample-size determination methods for an exploratory trial, which utilize the posterior probabilities calculated from predefined efficacy and inefficacy criteria leading to a declaration of the worthwhileness or unpromisingness of the experimental treatment. Simulation studies, including numerical investigation, showed that all three methods could declare the experimental treatment as worthwhile or unpromising with a high probability when the true response probability of the experimental treatment group is higher or lower, respectively, than that of the control treatment group.

Impact of maternal prepregnancy body mass index on cognitive and metabolic profiles of singletons born after in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the effect of elevated maternal prepregnancy body mass index (BMI) on intelligence and growth of singletons after in vitro fertilization (IVF) with or without intracytoplasmic sperm injection (ICSI). DESIGN: Cohort study. SETTING: University hospital. PATIENT(S): Singletons born to infertile couples who underwent an autologous IVF/ICSI cycle from 2002 to 2012 and were followed up with at the age of 3-6 years from 2009 to 2017. INTERVENTIONS(S): We compared the health of offspring born to overweight/obese women and normal weight women through assisted reproductive technology (ART). MAIN OUTCOME MEASURE(S): Age- and sex-specific BMI z-scores, verbal intelligence quotient (VIQ), performance intelligence quotient (PIQ), and full intelligence quotient (FIQ). RESULT(S): After adjusting for confounders, obese women were more likely than normal-BMI women to have obese children (20.0% vs. 5.1%), and overweight women had increased risks of having overweight children (13.6% vs. 8.2%) or obese children (10.1% vs. 5.1%) compared with normal-BMI women. Maternal prepregnancy BMI had a weakly negative effect on estimated IQ of children, but after adjusting for parental educational level, the IQ scores of offspring were similar between groups. However, after adjusting for confounders, offspring of obese women showed increased prevalence of intellectual disability (IQ <80) in VIQ (16.9% vs. 8.5%) and FIQ (10.8% vs. 3.9%) compared with normal-BMI women. CONCLUSION(S): Maternal prepregnancy obesity is associated with increased risks for obesity and overweight at early ages in offspring conceived through IVF/ICSI and may also affect the risk of intellectual disability of offspring. Overall, we suggest that weight management is essential for women before entering an IVF/ICSI cycle for ensuring long-term child health.

Motor development delay in offspring is associated with prenatal telbivudine exposure.

Telbivudine is an orally nucleoside analog with potent and specific antihepatitis B virus (HBV) activity, and it has been reported to block mother-to-infant transmission. However, few studies have focused on the safety of prenatal exposure for offspring development.This is a prospective noninterventional study. Participants were enrolled during delivery through the Women's Hospital of Zhejiang University School of Medicine between January 2012 and September 2013. Neonate's umbilical cord arterial blood (UCAB) was collected after delivery. Hepatitis B virus DNA copy, HBV serology, alanine aminotransferase (ALT), creatine kinase (CK), creatinine (CRE), and blood urea nitrogen (BUN) were measured. The development of the offspring was evaluated by the Chinese Revision of Bayley Scales of Child Development (BSCD-CR) at 12 to 24 months old.Around 30 and 31 chronic hepatitis B mothers were recruited in untreated group (non-LdT group) and telbivudine-treatment group (LdT group), respectively, and 2 children (one in non-LdT group and 1 in LdT group) were lost in follow-up. Sixty-one normal women and their children were recruited as a normal control (control group). Compared with non-LdT group, telbivudine treatment effectively blocks HBV transmission from mother to infant. However, CK in UCAB was significantly increased in the LdT group. Moreover, children with prenatal telbivudine exposure showed lower level of serum creatinine than non-LdT group, reduction of psychomotor developmental index and increased risk of motor development delay.Prenatal telbivudine exposure is correlated with motor development delay in offspring.

Phase 1/2 study assessing the safety and efficacy of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation-positive advanced cutaneous melanoma.

The combination of dabrafenib and trametinib demonstrated encouraging antitumor activity and tolerability, at initial analysis, in Japanese patients with BRAF V600 mutant advanced melanoma warranting further investigation. This study evaluated the safety and tolerability, pharmacokinetics (PK) and preliminary efficacy of dabrafenib 150 mg b.i.d. plus trametinib 2 mg q.d. in Japanese patients with BRAF V600E/K mutant solid tumors (phase 1) and melanoma (phase 2). Phase 1 was primarily intended to assess safety and tolerability as assessed by adverse events (AE), and the primary end-point in phase 2 was to assess confirmed overall response rate (ORR). The secondary end-points in phase 1 included PK, confirmed/unconfirmed ORR and duration of response (DOR). The secondary end-points in phase 2 were PK, unconfirmed ORR, DOR, safety and tolerability. A total of 12 cutaneous melanoma patients were enrolled in the study (six in phase 1 and six in phase 2) and received the combination therapy of dabrafenib and trametinib. Common AE (≥50.0%) included pyrexia (75%), increased aspartate aminotransferase (67%), peripheral edema (50%) and nasopharyngitis (50%). The investigator-assessed ORR was reported in five patients (83%) in phase 1 and was also reported in five patients (83%; 95% confidence interval, 35.9-99.6; P < 0.0001) in phase 2. Plasma concentrations of both dabrafenib and trametinib seemed to a reach steady state by week 3. Overall, efficacy and PK properties for the dabrafenib plus trametinib combination in Japanese patients were comparable with those seen in global studies.

Safety, tolerability, and pharmacokinetic profile of dabrafenib in Japanese patients with BRAF V600 mutation-positive solid tumors: a phase 1 study.

Background Dabrafenib is a BRAF inhibitor that has demonstrated clinical activity with a good tolerability profile in patients with BRAF V600E mutated metastatic melanoma. This study evaluated the safety and tolerability, pharmacokinetics and preliminary efficacy of dabrafenib in Japanese patients. Methods This phase I, open-label, dose escalation study was conducted in 12 Japanese patients with BRAF V600 mutation positive solid tumours. Primary endpoint was safety, assessed by monitoring and recording of all adverse events (AEs), serious AEs, drug-related AEs; secondary endpoints were pharmacokinetic profiles and efficacy measured by tumour response. This study is registered with ClinicalTrials.gov, number NCT01582997. Results Of the 12 patients enrolled, 3 each received 75 mg and 100 mg dabrafenib while 6 received 150 mg dabrafenib twice daily orally. Melanoma and thyroid cancer were the primary tumours reported in 11 (92%) and 1 (8%) patients respectively. Most AEs were grade 1 or 2 and considered related to study treatment. Most common AEs reported in the 12 patients were alopecia in 7 (58%); pyrexia, arthralgia and leukopenia in 6 (50%) each, hyperkeratosis and nausea in 4 (33%) each. Partial response as best overall response was reported in 7 of 12 (58%) patients and in 6 (55%) with malignant melanoma. No dose-limiting toxicity (DLTs) were reported during the DLT evaluation periods. Conclusions Dabrafenib was well tolerated and rapidly absorbed administered as single- or multiple dose. Comparable safety and pharmacokinetic profiles were observed compared with non-Japanese patients. Dabrafenib has promising clinical activity in Japanese patients with BRAF mutated malignant melanoma.

Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine.

Gemcitabine-based therapy remains the mainstay of treatment for patients with biliary tract cancers (BTCs) with no second-line treatment(s) established yet. Aberrant activation of the MAPK pathway in patients with BTC indicates its importance in BTC. Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this phase IIa open-label, single-arm study, we investigated the efficacy and safety of trametinib in Japanese patients with advanced BTC refractory to gemcitabine-based therapy. All patients received oral trametinib 2 mg once daily until progressive disease (PD), death, or unacceptable toxicity. The primary objective was to determine the 12-week non-PD rate. Secondary assessments included safety, progression-free survival (PFS), overall survival, and overall response rate. Targeted exome sequencing was used to identify biomarkers for sensitivity or resistance to trametinib monotherapy. Twenty patients (median age, 61.5 years) with carcinoma of gall bladder (40%), intrahepatic (25%) or extrahepatic (30%) bile duct, and ampulla of Vater (5%) were enrolled. The non-PD rate at week 12 was 10% (95% confidence interval, 1.2-31.7); it did not reach the threshold rate of 25%. Median PFS was 10.6 weeks (95% confidence interval, 4.6-12.1) and 1-year overall survival was 20.0%. Stable disease and PD were observed in 13 (65%) and seven (35%) patients, respectively. No new safety signals were reported. Although the primary end-point was not met, prolonged PFS was observed in one patient having six somatic variants including synonymous NF1 exon 12 splice variant and a loss-of-function variant in ARID1A. Efforts to understand responsive mutations and sensitivity to targeted therapies are warranted. This trial was registered with ClinicalTrials.gov: NCT01943864.

Reduced Intellectual Ability in Offspring of Ovarian Hyperstimulation Syndrome: A Cohort Study.

BACKGROUND: Ovarian hyperstimulation syndrome (OHSS), a complication of ovarian stimulation, has various adverse effects on both pregnant women and their offspring. However, whether OHSS will affect intellectual ability in offspring is still unknown. METHODS: We recruited 86 Chinese children born to OHSS women and 172 children conceived with non-OHSS In Vitro Fertilization (IVF) in this cohort study. Their intellectual ability was assessed according to the Revised Chinese Version of the Wechsler Intelligence Scale for Children (C-WISC). Verbal Intelligence Quotient (VIQ), Performance Intelligence Quotient (PIQ), and Full Intelligence Quotient (FIQ) were calculated. The investigation was registered in Chinese Clinical Trial Registry (ChiCTR-SOC-16009555). FINDINGS: OHSS offspring scored less on C-WISC (mean (standard deviation [SD]): (VIQ=92.7 (14.7), PIQ=108.9 (13.1), FIQ=100.6 (13.4)) compared with non-OHSS IVF offspring (VIQ=100.1 (13.2), PIQ=113.7 (10.8), FIQ=107.4 (11.5)). The prevalence of low IQ (<80) children was 4.7 times higher in OHSS offspring compared with non-OHSS offspring. Maternal estradiol level on hCG administration day was negatively associated with FIQ in offspring. INTERPRETATION: OHSS offspring displayed reduced intellectual ability. Prenatal estradiol exposure might be involved in underlying mechanism.

Ofatumumab combined with chlorambucil for previously untreated chronic lymphocytic leukemia: a phase I/II, open-label study in Japan.

Elderly/comorbid patients with chronic lymphocytic leukemia (CLL) require low-toxicity treatments. Internationally, the standard treatment for such patients is chlorambucil and an anti-CD20 therapy; however, chlorambucil is not approved in Japan. The aim of the present study was to evaluate the safety, efficacy and pharmacokinetics of ofatumumab in combination with chlorambucil in Japanese patients with previously untreated CLL who were inappropriate for fludarabine-based therapy. Ten patients were enrolled and treated in this study, all of whom received at least one dose of the study drugs. The tolerability of the treatment was confirmed initially with three patients. The overall response rate was 50%, as determined by the Independent Review Committee (IRC) with computerized tomography. All patients were alive at follow-up, and only one patient had progressive disease. The most common treatment-related adverse events (AEs) were thrombocytopenia (n = 10), neutropenia (n = 9) and rash (n = 6). One grade 3 serious AE related to the study drug occurred (hypoxia). The results indicate that ofatumumab combined with chlorambucil is an effective treatment for Japanese CLL patients, with a manageable safety profile.

Prevalence of Prediabetes Risk in Offspring Born to Mothers with Hyperandrogenism.

BACKGROUND: Excessive androgen exposure during pregnancy has been suggested to induce diabetic phenotypes in offspring in animal models. The aim of this study was to investigate whether pregestational maternal hyperandrogenism in human influenced the glucose metabolism in offspring via epigenetic memory from mother's oocyte to child's somatic cells. METHODS: Of 1782 reproductive-aged women detected pregestational serum androgen, 1406 were pregnant between 2005 and 2010. Of 1198 women who delivered, 1116 eligible mothers (147 with hyperandrogenism and 969 normal) were recruited. 1216 children (156 children born to mothers with hyperandrogenism and 1060 born to normal mother) were followed up their glycometabolism in mean age of 5years. Imprinting genes of oocyte from mothers and lymphocytes from children were examined. A pregestational hyperandrogenism rat model was also established. FINDINGS: Children born to women with hyperandrogenism showed increased serum fasting glucose and insulin levels, and were more prone to prediabetes (adjusted RR: 3.98 (95%CI 1.16-13.58)). Oocytes from women with hyperandrogenism showed increased insulin-like growth factor 2 (IGF2) expression. Lymphocytes from their children also showed increased IGF2 expression and decreased IGF2 methylation. Treatment of human oocytes with dihydrotestosterone upregulated IGF2 and downregulated DNMT3a levels. In rat, pregestational hyperandrogenism induced diabetic phenotypes and impaired insulin secretion in offspring. In consistent with the findings in human, hyperandrogenism also increased Igf2 expression and decreased DNMT3a in rat oocytes. Importantly, the same altered methylation signatures of Igf2 were identified in the offspring pancreatic islets. INTERPRETATION: Pregestational hyperandrogenism may predispose offspring to glucose metabolism disorder via epigenetic oocyte inheritance. Clinical trial registry no.: ChiCTR-OCC-14004537; www.chictr.org.

Test Statistics and Confidence Intervals to Establish Noninferiority between Treatments with Ordinal Categorical Data.

The problem for establishing noninferiority is discussed between a new treatment and a standard (control) treatment with ordinal categorical data. A measure of treatment effect is used and a method of specifying noninferiority margin for the measure is provided. Two Z-type test statistics are proposed where the estimation of variance is constructed under the shifted null hypothesis using U-statistics. Furthermore, the confidence interval and the sample size formula are given based on the proposed test statistics. The proposed procedure is applied to a dataset from a clinical trial. A simulation study is conducted to compare the performance of the proposed test statistics with that of the existing ones, and the results show that the proposed test statistics are better in terms of the deviation from nominal level and the power.

Altered thyroid hormone profile in offspring after exposure to high estradiol environment during the first trimester of pregnancy: a cross-sectional study.

BACKGROUND: The increasing number of babies conceived by in vitro fertilization and embryo transfer (IVF-ET) shifts concern from pregnancy outcomes to long-time health of offspring. Maternal high estradiol (E2) is a major characteristic of IVF-ET and lasts throughout the first trimester of pregnancy. The fetal thyroid develops during this period and may thus be affected by exposure to the supra-physiological E2. The aim of this study is to investigate whether the high E2 maternal environment in the first trimester increases the risk of thyroid dysfunction in children born following IVF-ET. METHODS: A cross-sectional survey design was used to carry out face-to-face interviews with consecutive children attending the hospital. A total of 949 singletons born after fresh embryo transfer (ET) (n=357), frozen ET (n=212), and natural conception (NC) (n=380), aged 3 to 10 years old, were included. All children were thoroughly examined. Meanwhile, another 183 newborns, including 55 fresh ET, 48 frozen ET, and 80 NC were studied. Levels of serum T3, FT3, T4, FT4, and TSH and levels of maternal E2 at different stages of the first trimester were examined. RESULTS: The mean serum E2 levels of women undergoing fresh ET during the first trimester of pregnancy were significantly higher than those of the women undergoing frozen ET or following NC. The thyroid hormone profile, especially the levels of T4, FT4, and TSH, were significantly increased in 3- to 10-year-old children conceived by fresh ET compared to NC. The same tendency was confirmed in newborns. However, levels of T4 and TSH in the frozen ET group were nearer to that of the NC group. Furthermore, levels of T4 and FT4 in fresh ET were positively correlated with maternal serum levels of E2 during early pregnancy. CONCLUSIONS: The maternal high E2 environment in the first trimester is correlated with increased risk of thyroid dysfunction. Frozen ET could reduce risks of thyroid damage in children conceived by IVF. Further studies are needed to confirm these findings and to better determine the underlying molecular mechanisms and clinical significance. TRIAL REGISTRATION: ChicCTR-OCC-14004682 (22-05-2014).

Cardiovascular dysfunction in offspring of ovarian-hyperstimulated women and effects of estradiol and progesterone: a retrospective cohort study and proteomics analysis.

CONTEXT: The cardiovascular dysfunction in children born with assisted reproductive technologies has been of great concern. However, the association of ovarian hyperstimulation syndrome (OHSS), a complication of assisted reproductive technologies, with worse cardiovascular functions and underlying mechanism remains unknown. OBJECTIVES: The objective of the study was to assess the cardiovascular functions of children born to mothers with OHSS and investigate the underlying regulator(s). DESIGN AND SETTING: This was a retrospective cohort recruited in a university hospital. PARTICIPANTS AND METHODS: We assessed the cardiovascular functions by Doppler echography in 42 children born to OHSS women, 34 children of mothers with non-OHSS in vitro fertilization, and 48 spontaneously conceived (SC) children (mean age ∼ 4.5 y). Groups were matched for gestational age at delivery and birth weight. An isobaric tag for relative and absolute quantitation-labeled proteomics analysis was performed with another set of umbilical arteries from OHSS and SC pregnancies (n = 3 for both groups). RESULTS: Children of OHSS mothers showed a significantly decreased mitral ratio of early to late mitral peak velocities, reduced systolic and diastolic diameters of common carotid arteries, and impaired flow-mediated dilation compared with non-OHSS in vitro fertilization and SC children. Intima-media thickness and arterial stiffness indices were similar in the three groups. In the proteomics study, 1640 proteins were identified from OHSS and SC umbilical arteries, and 40 differentially expressed proteins were selected for further analysis. Estradiol and progesterone were identified as activated upstream regulators. CONCLUSIONS: Children born to ovarian-hyperstimulated women displayed cardiovascular dysfunctions. The underlying mechanisms may involve the effects of supraphysiological estradiol and progesterone levels.

Combined linkage and association mapping reveals CYCD5;1 as a quantitative trait gene for endoreduplication in Arabidopsis.

Endoreduplication is the process where a cell replicates its genome without mitosis and cytokinesis, often followed by cell differentiation. This alternative cell cycle results in various levels of endoploidy, reaching 4× or higher one haploid set of chromosomes. Endoreduplication is found in animals and is widespread in plants, where it plays a major role in cellular differentiation and plant development. Here, we show that variation in endoreduplication between Arabidopsis thaliana accessions Columbia-0 and Kashmir is controlled by two major quantitative trait loci, ENDO-1 and ENDO-2. A local candidate gene association analysis in a set of 87 accessions, combined with expression analysis, identified CYCD5;1 as the most likely candidate gene underlying ENDO-2, operating as a rate-determining factor of endoreduplication. In accordance, both the overexpression and silencing of CYCD5;1 were effective in changing DNA ploidy levels, confirming CYCD5;1 to be a previously undescribed quantitative trait gene underlying endoreduplication in Arabidopsis.