Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model.

Microglia help limit the progression of Alzheimer's disease (AD) by constraining amyloid-ß (Aß) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aß and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aß plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aß load, mitigated some Aß-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.

Evaluating causal influence of maternal educational attainment on offspring birthweight via observational study and Mendelian randomization analyses.

Background: Although extensive discussions on the influence of maternal educational attainment on offspring birthweight, the conclusion remains controversial, and it is challenging to comprehensively assess the causal association between them. Methods: To estimate effect of maternal educational attainment on the birthweight of first child, we first conducted an individual-level analysis with UK Biobank participants of white ancestry (n = 208,162). We then implemented Mendelian randomization (MR) methods including inverse variance weighted (IVW) MR and multivariable MR to assess the causal relation between maternal education and maternal-specific birthweight. Finally, using the UK Biobank parent-offspring trio data (n = 618), we performed a polygenic score based MR to simultaneously adjust for confounding effects of fetal-specific birthweight and paternal educational attainment. We also conducted simulations for power evaluation and sensitivity analyses for horizontal pleiotropy of instruments. Results: We observed that birthweight of first child was positively influenced by maternal education, with 7 years of maternal education as the reference, adjusted effect = 44.8 (95%CIs 38.0-51.6, P = 6.15 × 10-38), 54.9 (95%CIs 47.6-62.2, P = 4.21 × 10-128), and 89.4 (95%CIs 82.1-96.7, P = 4.28 × 10-34) for 10, 15 and 20 years of maternal educational attainment, respectively. A causal relation between maternal education and offspring birthweight was revealed by IVW MR (estimated effect = 0.074 for one standard deviation increase in maternal education years, 95%CIs 0.054-0.093, P = 2.56 × 10-13) and by complementary MR methods. This connection was not substantially affected by paternal education or horizontal pleiotropy. Further, we found a positive but insignificant causal association (adjusted effect = 24.0, 95%CIs -150.1-198.1, P = 0.787) between maternal education and offspring birthweight after simultaneously controlling for fetal genome and paternal education; this null causality was largely due to limited power of small sample sizes of parent-offspring trios. Conclusion: This study offers supportive evidence for a causal association between maternal education and offspring birthweight, highlighting the significance of enhancing maternal education to prevent low birthweight.

APOE3ch alters microglial response and suppresses Aß-induced tau seeding and spread.

A recent case report described an individual who was a homozygous carrier of the APOE3 Christchurch (APOE3ch) mutation and resistant to autosomal dominant Alzheimer's Disease (AD) caused by a PSEN1-E280A mutation. Whether APOE3ch contributed to the protective effect remains unclear. We generated a humanized APOE3ch knock-in mouse and crossed it to an amyloid-ß (Aß) plaque-depositing model. We injected AD-tau brain extract to investigate tau seeding and spreading in the presence or absence of amyloid. Similar to the case report, APOE3ch expression resulted in peripheral dyslipidemia and a marked reduction in plaque-associated tau pathology. Additionally, we observed decreased amyloid response and enhanced microglial response around plaques. We also demonstrate increased myeloid cell phagocytosis and degradation of tau aggregates linked to weaker APOE3ch binding to heparin sulfate proteoglycans. APOE3ch influences the microglial response to Aß plaques, which suppresses Aß-induced tau seeding and spreading. The results reveal new possibilities to target Aß-induced tauopathy.

Identifying risk loci for obsessive-compulsive disorder and shared genetic component with schizophrenia: A large-scale multi-trait association analysis with summary statistics.

Due to limited samples, no genetic loci have been identified for obsessive-compulsive disorder (OCD) in genome-wide association studies. Additionally, although co-morbidities between OCD and schizophrenia (SCZ) were observed, their common genetic etiology was not completely known. Here, we conducted a comprehensive investigation regarding the genetic architecture of OCD and the common genetic foundation shared by OCD and SCZ using summary statistics data (2688 cases and 7037 controls for OCD; 53,386 cases and 77,258 controls for SCZ). We discovered significant genetic correlation between OCD and SCZ (r̂g=0.296, P = 2.82 × 10-11). We then performed two multi-trait association analyses to detect OCD-associated loci and colocalization analysis to detect causal variants. Parallel gene-level analyses were also implemented. We identified 323 OCD-relevant variants located within 12 loci, with four loci shared the same causal variants between OCD and SCZ. Further, the gene-level analyses discovered 8 OCD-associated genes. Finally, multiple functional analyses at both SNP and gene levels showed that these genetic association signals had significant enrichments in the regions of left ventricle and anterior cingulate cortex, and suggested an important role of pathways involving regulation of telomere maintenance, histone phosphorylation, and GnRH secretion. Overall, this study identified new genetic loci for OCD and provided substantial evidence supporting common genetic foundation underlying OCD and SCZ. The findings advanced our understanding of genetic architecture and pathophysiology of OCD as well as shedding light on shared genetic etiology of the two disorders.

Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.

Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids.

BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. METHODS: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE-/-) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE-/- cerebral organoids at Day 90. RESULTS: We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/ß-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. CONCLUSIONS: Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

Network structure of mobile phone addiction and anxiety symptoms among rural Chinese adolescents.

BACKGROUND: The incidence of mobile phone addiction among adolescents in rural areas of China is increasing year by year, and has already exceeded that of some cities. And phone addiction increases the risk of anxiety and poor sleep. Therefore, this study used network analysis to investigate the relationship between mobile phone addiction and anxiety symptoms, and the predictability to sleep quality. METHODS: From September 2021 to March 2022, a total of 1920 rural adolescents in Xuzhou, China were included. The survey included information on phone addiction, anxiety symptoms, and sleep quality. Network analysis was used to estimate the network structure of adolescents' mobile phone addiction and anxiety symptoms. LOWESS curve and linear regression were used to test the predictive ability of node-centrality on sleep quality. RESULTS: In the network of mobile phone addiction-anxiety symptoms, the most influential symptoms were Failure to cut down the time, Anxiety if not used for some time, and Alleviate loneliness. Irritability was the most prominent bridging symptom. Gender difference had no effect on network structure. Nodes in the network are not predictive of sleep quality. CONCLUSION: Failure to cut down the time is the most important symptom, suggesting that measures should be taken to reduce the amount of time spent on mobile phones. For example, increase outdoor exercise, increase the real company of friends and family, in order to reduce the occurrence of mobile phone addiction and anxiety.

Statistical tests for homogeneity of variance for clinical trials and recommendations.

In most clinical trials, the main interest is to test whether there are differences in the mean outcomes among the treatment groups. When the outcome is continuous, a common statistical test is a usual t-test for a two-group comparison. For more than 2 groups, an ANOVA setup is used and the test for equality for all groups is based on the F-distribution. A key assumption for these parametric tests is that data are normally, independently distributed and the response variances are equal. The robustness of these tests to the first two assumptions is quite well investigated, but the issues arising from heteroscedasticity are less studied. This paper reviews different methods for ascertaining homogeneity of variance across groups and investigates the consequences of heteroscedasticity on the tests. Simulations based on normal, heavy-tailed, and skewed normal data demonstrate that some of the less known methods, such as the Jackknife or Cochran's test, are quite effective in detecting differences in the variances.

Trem2 H157Y increases soluble TREM2 production and reduces amyloid pathology.

BACKGROUND: The rare p.H157Y variant of TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) was found to increase Alzheimer's disease (AD) risk. This mutation is located at the cleavage site of TREM2 extracellular domain. Ectopic expression of TREM2-H157Y in HEK293 cells resulted in increased TREM2 shedding. However, the physiological outcomes of the TREM2 H157Y mutation remain unknown in the absence and presence of AD related pathologies. METHODS: We generated a novel Trem2 H157Y knock-in mouse model through CRISPR/Cas9 technology and investigated the effects of Trem2 H157Y on TREM2 proteolytic processing, synaptic function, and AD-related amyloid pathologies by conducting biochemical assays, targeted mass spectrometry analysis of TREM2, hippocampal electrophysiology, immunofluorescent staining, in vivo micro-dialysis, and cortical bulk RNA sequencing. RESULTS: Consistent with previous in vitro findings, Trem2 H157Y increases TREM2 shedding with elevated soluble TREM2 levels in the brain and serum. Moreover, Trem2 H157Y enhances synaptic plasticity without affecting microglial density and morphology, or TREM2 signaling. In the presence of amyloid pathology, Trem2 H157Y accelerates amyloid-ß (Aß) clearance and reduces amyloid burden, dystrophic neurites, and gliosis in two independent founder lines. Targeted mass spectrometry analysis of TREM2 revealed higher ratios of soluble to full-length TREM2-H157Y compared to wild-type TREM2, indicating that the H157Y mutation promotes TREM2 shedding in the presence of Aß. TREM2 signaling was further found reduced in Trem2 H157Y homozygous mice. Transcriptomic profiling revealed that Trem2 H157Y downregulates neuroinflammation-related genes and an immune module correlated with the amyloid pathology. CONCLUSION: Taken together, our findings suggest beneficial effects of the Trem2 H157Y mutation in synaptic function and in mitigating amyloid pathology. Considering the genetic association of TREM2 p.H157Y with AD risk, we speculate TREM2 H157Y in humans might increase AD risk through an amyloid-independent pathway, such as its effects on tauopathy and neurodegeneration which merit further investigation.

Genetic correlation and gene-based pleiotropy analysis for four major neurodegenerative diseases with summary statistics.

Recent genome-wide association studies suggested shared genetic components between neurodegenerative diseases. However, pleiotropic association patterns among them remain poorly understood. We here analyzed 4 major neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and found suggestively positive genetic correlation. We next implemented a gene-centric pleiotropy analysis with a powerful method called PLACO and detected 280 pleiotropic associations (226 unique genes) with these diseases. Functional analyses demonstrated that these genes were enriched in the pancreas, liver, heart, blood, brain, and muscle tissues; and that 42 pleiotropic genes exhibited drug-gene interactions with 341 drugs. Using Mendelian randomization, we discovered that AD and PD can increase the risk of developing ALS, and that AD and ALS can also increase the risk of developing FTD, respectively. Overall, this study provides in-depth insights into shared genetic components and causal relationship among the 4 major neurodegenerative diseases, indicating genetic overlap and causality commonly drive their co-occurrence. It also has important implications on the etiology understanding, drug development and therapeutic targets for neurodegenerative diseases.

Network connectivity between anxiety, depressive symptoms and psychological capital in Chinese university students during the COVID-19 campus closure.

BACKGROUND: In the context of the outbreak of COVID-19 within mainland China, to understand the mental health status of university students during campus closure, this study analyzes the relationship between anxiety, depressive symptoms, and psychological capital and to reveals their central symptoms. METHODS: A total of 12,945 university students were included in this study from April 10 to 19, 2022. Anxiety and depressive symptoms were measured by the seven-item Generalized Anxiety Disorder Scale (GAD-7) and two-item Patient Health Questionnaires (PHQ-2). Psychological capital was measured using the Psychological Capital Questionnaire (PCQ-24). The centrality and bridge centrality indexes were used to identify central and bridge symptoms, respectively. Network Comparison Test (NCT) was also administered to check whether network traits differed by gender and place of residence. RESULTS: The most influential node in this study was Trouble relaxing (GAD4), followed by Uncontrollable worry (GAD2) and Excessive worry (GAD3). The main bridging symptoms were Depressed mood (PHQ2), Psychological capital. There are no differences in the network structure of students by place of residence, while there are more significant differences in the network structure of students by gender. CONCLUSION: Central and bridging symptoms may be the core symptoms that trigger or maintain the development of anxiety and depression among university students during the COVID-19 campus closure. Timely and reasonable interventions targeting these symptoms may help reduce depression and anxiety in this population. In addition, improving university students' psychological capital may likewise contribute to the development of their good mental health.

Elevating microglia TREM2 reduces amyloid seeding and suppresses disease-associated microglia.

TREM2 is exclusively expressed by microglia in the brain and is strongly linked to the risk for Alzheimer's disease (AD). As microglial responses modulated by TREM2 are central to AD pathogenesis, enhancing TREM2 signaling has been explored as an AD therapeutic strategy. However, the effective therapeutic window targeting TREM2 is unclear. Here, by using microglia-specific inducible mouse models overexpressing human wild-type TREM2 (TREM2-WT) or R47H risk variant (TREM2-R47H), we show that TREM2-WT expression reduces amyloid deposition and neuritic dystrophy only during the early amyloid seeding stage, whereas TREM2-R47H exacerbates amyloid burden during the middle amyloid rapid growth stage. Single-cell RNA sequencing reveals suppressed disease-associated microglia (DAM) signature and reduced DAM population upon TREM2-WT expression in the early stage, whereas upregulated antigen presentation pathway is detected with TREM2-R47H expression in the middle stage. Together, our findings highlight the dynamic effects of TREM2 in modulating AD pathogenesis and emphasize the beneficial effect of enhancing TREM2 function in the early stage of AD development.

Prediction of small-for-gestational-age neonates at 33-39 weeks' gestation in China: logistic regression modeling of the contributions of second- and third-trimester ultrasound data and maternal factors.

OBJECTIVES: A screening model for prediction of small-for-gestational-age (SGA) neonates (SGAp) was established by logistic regression using ultrasound data and maternal factors (MF). We aimed to evaluate the ability of SGAp as well as abdominal circumference (AC) and estimated fetal weight (EFW) measurements to predict SGA neonates at 33-39 weeks' gestation. METHODS: This retrospective study evaluated 5298 singleton pregnancies that had involved three ultrasound examinations at 21+0-27+6, 28+0-32+6, and 33+0-39+6 weeks. All ultrasound data were transformed to MoM values (multiple of the median). Multivariate logistic regression was used to analyze the correlation between SGA status and various variables (ultrasound data and MF) during pregnancy to build the SGAp model. EFW was calculated according to the Hadlock formula at 33-39 weeks of gestation. The predictive performance of SGAp, AC MoM value at 33+0-39+6 weeks (AC-M), EFW MoM value (EFW-M), EFW-M plus MF, AC value at 33+0-39+6 weeks (AC), AC growth velocity, EFW, and EFW plus MF was evaluated using ROC curves. The detection rate (DR) of SGA neonate with SGAp, AC-M, EFW-M, and EFW-M plus MF at false positive rate (FPR) of 5% and 10%, and the FPR at DR of 85%, 90%, and 95% were observed. RESULTS: The AUCs of SGAp, AC-M, EFW-M, EFW-M plus MF, AC, AC growth velocity, EFW, and EFW plus MF for SGA neonates screening were 0.933 (95%CI: 0.916-0.950), 0.906 (95%CI: 0.887-0.925), 0.920 (95%CI: 0.903-0.936), 0.925 (95%CI: 0.909-0.941), 0.818 (95%CI: 0.791-0.845), 0.786 (95%CI: 0.752-0.821), 0.810 (95%CI: 0.782-0.838), and 0.834 (95%CI: 0.807-0.860), respectively. The screening efficiency of SGAp, AC-M, EFW-M, and EFW-M plus MF are significantly higher than AC, AC growth velocity, EFW, and EFW plus MF. The DR of SGAp, AC-M, EFW-M, and EFW-M plus MF for SGA neonates were 80.4%, 69.6%, 73.8% and 74.3% at 10% FPR. The AUCs of SGAp, AC-M, EFW-M, and EFW-M plus MF 0.950 (95%CI: 0.932-0.967), 0.929 (95%CI: 0.909-0.948), 0.938 (95%CI: 0.921-0.956) and 0.941 (95%CI: 0.924-0.957), respectively for screening SGA neonates delivered within 2 weeks after the assessment. The DR for these births increased to 85.8%, 75.8%, 80.0%, and 82.5%, respectively. CONCLUSION: The rational use of ultrasound data can significantly improve the prediction of SGA statuses.

Extracellular Protons Mediate Presynaptic Homeostatic Potentiation at the Mouse Neuromuscular Junction.

At the vertebrate neuromuscular junction (NMJ), presynaptic homeostatic potentiation (PHP) refers to the upregulation of neurotransmitter release via an increase in quantal content (QC) when the postsynaptic nicotinic acetylcholine receptors (nAChRs) are partially blocked. The mechanism of PHP has not been completely worked out. In particular, the identity of the presumed retrograde signal is still a mystery. We investigated the role of acid-sensing ion channels (ASICs) and extracellular protons in mediating PHP at the mouse NMJ. We found that blocking AISCs using benzamil, psalmotoxin-1 (PcTx1), or mambalgin-3 (Mamb3) prevented PHP. Likewise, extracellular acidification from pH 7.4 to 7.2 triggered a significant, reversable increase in QC and this increase could be prevented by PcTx1. Interestingly, an acidic saline (pH 7.2) also precluded the subsequent induction of PHP. Using immunofluorescence we observed ASIC2a and ASIC1 subunits at the NMJ. Our results indicate that protons and ASIC channels are involved in activating PHP at the mouse NMJ. We speculate that the partial blockade of nAChRs leads to a modest decrease in the pH of the synaptic cleft (∼0.2 pH units) and this activates ASIC channels on the presynaptic nerve terminal.

Evaluation of Maternal Serum sHLA-G Levels for Trisomy 18 Fetuses Screening at Second Trimester.

Human leukocyte antigen-G (HLA-G) has been widely acknowledged to play critical roles in fetal-maternal maintenance. However, the significance of using maternal serum sHLA-G to detect prenatal chromosomal abnormality has not been investigated. In China, prenatal screening using maternal α-fetoprotein (AFP), unconjugated estriol (uE3), and free ß subunit human chorionic gonadotropin (ß-hCG) in the second trimester has been widely applied. In this study, we evaluated the use of sHLA-G as a screening marker, compared with traditional second trimester prenatal screening. Serum samples from 1,019 singleton women in their second trimester were assessed. Among them, 139 infants were confirmed with trisomy 21 (T21) by karyotyping, 83 were confirmed with trisomy 18 (T18), and the remaining 797 infants had no abnormalities. The sHLA-G levels in maternal sera were significantly lower in pregnant women with T18 fetuses (median: 47.8 U/ml, range: 9.8-234.2 U/ml) and significantly higher in those with T21 fetuses (median: 125.7 U/ml, range: 28.7-831.7 U/ml), compared with the normal controls (median: 106.3 U/ml, range: 50.5-1136.4 U/ml) (p < 0.001). The risk values of the screening of T21 or T18 fetuses were assessed using mean and standard deviation log10 analyte multiples of median (MoM) which showed that the predictive values of sHLA-G were the same as free ß-hCG, and superior to AFP and uE3 for T18 screening. Logistic regression analysis revealed that sHLA-G MoM was the highest risk factor associated with pregnant women carrying T18 fetuses [Exp(B): 171.26, 95% CI: 36.30-807.97, p < 0.001]. Receiver operating characteristic (ROC) analysis revealed that the area under ROC curve for sHLA-G MoM was 0.915 (95% CI, 0.871-0.959, p < 0.001), for AFP MoM was 0.796 (95% CI, 0.730-0.861, p < 0.001), for free ß-hCG MoM was 0.881 (95% CI, 0.829-0.934, p < 0.001), and for uE3 MoM was 0.876 (95% CI, 0.828-0.923, p < 0.001) in the T18 group. sHLA-G MoM demonstrated the best sensitivity and negative predictive value. For the first time, our findings reveal that sHLA-G is a better second trimester screening marker for the detection of T18 fetuses and the combined application of sHLA-G with AFP, free ß-hCG, and uE3 could improve clinical screening for T18 fetuses.

Comparison of Efficiencies of Non-invasive Prenatal Testing, Karyotyping, and Chromosomal Micro-Array for Diagnosing Fetal Chromosomal Anomalies in the Second and Third Trimesters.

In this study, we aimed to compare the efficiency of non-invasive prenatal testing (NIPT), karyotyping, and chromosomal micro-array (CMA) for the diagnosis of fetal chromosomal anomalies in the second and third trimesters. Pregnant women, who underwent amniocenteses for prenatal genetic diagnoses during their middle and late trimesters, were recruited at the Prenatal Diagnosis Center of Taizhou City. Maternal blood was separated for NIPT, and amniotic fluid cells were cultured for karyotyping and CMA. The diagnostic efficiency of NIPT for detecting fetal imbalanced anomalies was compared with karyotyping and CMA. A total of 69 fetal chromosomal imbalances were confirmed by CMA, 37 were diagnosed by NIPT and 35 were found by karyotyping. The sensitivities of NIPT and karyotyping for diagnosing aneuploidy were 96.3% and 100% respectively. Only one mosaic sexual chromosome monosomy was misdiagnosed by NIPT, whereas the sensitivity of NIPT and karyotyping was 70% and 30%, respectively, for detecting pathogenic deletions and duplications sized from 5-20 Mb. Taken together, our results suggest that the efficiency of NIPT was similar to the formula karyotyping for detecting chromosome imbalance in the second and third trimesters.

[Predictive factors of testicular sperm extraction in men with non-obstructive azoospermia].

Men with non-obstructive azoospermia (NOA) can achieve fertility by testicular sperm extraction (TESE) coupled with intracytoplasmic sperm injection (ICSI), the key to which is the successful retrieval of sperm from the testis. Although improved testicular sperm extraction techniques have increased the chances of sperm retrieval, to predict preoperatively the success of sperm retrieval from NOA patients remains challenging. A non-invasive diagnostic technique predicting the presence of sperm in the testis would be useful for avoiding possible surgical intervention. At present, some preoperative variables, such as serum FSH, inhibin B level, testis volume, genetic analysis, histopathology on diagnostic biopsy, Raman Spectroscopy, and molecular and protein markers, have provided new insights into the chances of successful sperm retrieval in NOA males. This review aims to evaluate the preoperative factors currently available for predicting the outcomes of sperm retrieval from NOA patients.

Is hepatitis B virus transmitted via the male germ line? A seroepidemiological study in fetuses.

OBJECTIVES: To detect father-to-fetus transmission of hepatitis B virus (HBV) in utero. METHODS: We conducted a study at the prenatal diagnosis center of Taizhou City. Fetuses with one or both parents carrying the hepatitis B surface antigen (HBsAg) were identified before genetic testing during the period 2008-2010. Intrauterine samples were obtained by amniocentesis or cordocentesis and tested for serological markers and by quantitative DNA assays. All neonates received combined hepatitis B immunoprophylaxis after delivery, and serological follow-up tests were performed at 1 year of age. RESULTS: Of the 407 couples enrolled in the study, HBV was carried by fathers only in 164, and none of their fetuses were found to be HBV DNA-positive in utero. All fetal serological markers were found to be of maternal but not paternal origin. The response rate to postnatal vaccination was 98.6%, and none of the children who failed immunoprophylaxis were the offspring of the HBV carrier fathers. CONCLUSIONS: The infection of fetuses with HBV from the spermatozoa of carrier fathers seems unlikely, especially in an area where pre-conception hepatitis B vaccination is routinely provided.

Comparison of warm and cold contrast media for hysterosalpingography: a prospective, randomized study.

OBJECTIVE: To compare the use of warm medium and cold medium for alleviating pain and side effects during hysterosalpingography (HSG). DESIGN: Prospective randomized study. SETTING: University hospital. PATIENT(S): Two hundred infertile women who needed HSG were recruited from January 2010 to June 2011. The exclusion criteria were acute low reproductive duct infection, known hypersensitivity to iodine, genital bleeding, or malignancy. INTERVENTION(S): Subjects were randomized to undergo HSG using a medium prewarmed to 37°C or a medium at room temperature. MAIN OUTCOME MEASURE(S): Incidence of vasovagal episodes and visual analog scale (VAS) pain scores during HSG. RESULT(S): Patients' VAS pain scores during HSG were significantly lower in the warm media group initially but showed no statistical difference at 30 minutes after injection. Medium temperature showed a linear association with VAS score. The total number of vasovagal episodes was higher in the cold medium group. CONCLUSION(S): Warm contrast medium alleviates the pain associated with HSG and decreases the incidence of vasovagal episodes during HSG. CLINICAL TRIALS REGISTRATION NUMBER: NCT01339338.