Comprehensive Analysis of Human Cytomegalovirus- and HIV-Mediated Plasma Membrane Remodeling in Macrophages.

The plasma membrane (PM) must be overcome by viruses during entry and release. Furthermore, the PM represents the cellular communication compartment and the immune system interface. Hence, viruses have evolved sophisticated strategies to remodel the PM, for instance to avoid immune sensing and clearance of infected cells. We performed a comprehensive analysis of cell surface dysregulation by two human-pathogenic viruses, human cytomegalovirus (HCMV) and human immunodeficiency virus type 1 (HIV-1), in primary macrophages, which are classical antigen-presenting cells and orchestrators of the immune system. Scanning ion conductance microscopy revealed a loss of roughness and an overall smooth phenotype of HCMV-infected macrophages, in contrast to HIV-1 infection. This phenotype was also evident on the molecular level. When we screened for cell surface receptors modulated by HCMV, 42 of 332 receptors tested were up- or downregulated, whereas HIV-1 affected only 7 receptors. In particular CD164, CD84, and CD180 were targeted by HCMV. Mechanistically, HCMV induced transcriptional silencing of these receptors in an interferon (IFN)-independent manner, and expression was reduced not only by lab-adapted HCMV but also by clinical HCMV isolates. Altogether, our plasma membrane profiling of human macrophages provides clues to understand how viruses evade the immune system and identified novel cell surface receptors targeted by HCMV. IMPORTANCE The PM is a key component that viruses have to cope with. It is a barrier for infection and egress and is critically involved in antiviral immune signaling. We hence asked the question how two immunomodulatory viruses, HIV-1 and HCMV, dysregulate this compartment in infected macrophages, relevant in vivo targets of both viruses. We employed a contact-free microscopic technique to image the PM of infected cells and performed a phenotypic flow cytometry-based screen to identify receptor modulations on a molecular level. Our results show that HIV-1 and HCMV differentially manipulate the PM of macrophages. While HIV-1-mediated changes are relatively subtle, HCMV induces major alterations of the PM. We identify novel immune receptors manipulated by HCMV and define mechanisms of how HCMV interferes with receptor expression. Altogether, our study reveals differential strategies of how two human-pathogenic viruses manipulate infected cells and identifies potential novel pathways of HCMV immune evasion.

Accuracy of immediate antepartum ultrasound estimated fetal weight and its impact on mode of delivery and outcome - a cohort analysis.

BACKGROUND: The aim of the study was to investigate the accuracy of ultrasound-derived estimated fetal weight (EFW) and to determine its impact on management and outcome of delivery. METHODS: In this single-center cohort analysis, women with a singleton term pregnancy in the beginning stages of labor were included. Women with immediately antepartum EFW (N = 492) were compared to women without ultrasound (N = 515). RESULTS: EFW was correct (deviation from birth weight ≤ 10%) in 72.2% (355/492) of patients with fetal biometry; 19.7% (97/492) were underestimated, and 8.1% (40/492) were overestimated. Newborns with a lower birth weight were more frequently overestimated, and newborns with higher birth weight were more frequently underestimated. The mean difference between EFW and real birth weight was - 114.5 g (standard deviation ±313 g, 95% confidence interval 87.1-142.0). The rate of non-reassuring fetal heart tracing (9.8% vs. 1.9%, P < 0.001) and of caesarean delivery (9.1% vs. 5.0%, P = 0.013) was higher in women with EFW. Overestimation was associated with an increased risk for delivery by caesarean section (odds ratio 2.80; 95% confidence interval 1.2-6.5, P = 0.017). After adjustment, EFW remained associated with increased non-reassuring fetal heart tracing (odds ratio 4.73; 95% confidence interval 2.3-9.6) and caesarean delivery (odds ratio 1.86; 95% confidence interval 1.1-3.1). The incidence of perineal tears of grade 3/4, shoulder dystocia, postnatal depression and neonatal acidosis did not differ between groups. CONCLUSIONS: Antepartum ultrasound-derived EFW does not improve maternal and fetal outcome and is therefore not recommended.

The Treatment of Illnesses Arising in Pregnancy.

BACKGROUND: The treatment of pregnant women who have illnesses unrelated to pregnancy can cause uncertainty among physicians. METHODS: We searched the PubMed database and specialty guidelines from Germany and abroad (the guidelines of the German Society for Gynecology and Obstetrics, the American Congress of Obstetri cians and Gynecologists, and the Royal College of Obstetricians and Gynaecologists) over the period 2007-2016 for information on standards for the diagnosis and treatment of five illnesses that can arise in pregnancy: bronchial asthma, migraine, hypothyroidism, hyperthyroidism, and varicose veins. RESULTS: Any diagnostic tests that are carried out in pregnant women should be simple and goal-directed. The choice of drugs that can be used is limited. For many drugs, no embryotoxic or teratogenic effect is suspected, but the level of evidence is low. CONCLUSION: When illnesses unrelated to pregnancy arise in pregnant women, attention must be paid to potential diver gences from the typical disease course and to pos sible drug side effects on the fetus in order to prevent serious complications for both mother and child.

Can the Rate of C-sections Performed in a Level I Perinatal Center Be Reduced? - An Analysis of the University Gynecology Clinic Rostock, 2008 - 2014.

INTRODUCTION: In Germany the rate of deliveries by cesarean section is continually increasing. Many different reasons have been put forward to explain this trend. The aim of this study was to examine how the C-section rate developed at the University Gynecology Clinic Rostock, one of the biggest maternity hospitals and level I perinatal centers in Germany, based on various maternal and neonatal parameters. The aim was also to identify potential risk factors for C-sections. MATERIAL AND METHOD: Various obstetric parameters were obtained from the birth cohort (2008 to 2014; n = 20 091) of the University Gynecology Clinic Rostock. The data was used to calculate parameter-specific C-section rates. Potential risk factors for C-section were identified by regression analysis. RESULTS: The C-section rate dropped from 26.24% to 23.57%. The rate of repeat C-sections also declined. The mean age of the pregnant women increased. Nevertheless, the frequency of cesarean sections in pregnant women aged more than 35 years declined. Rates of being overweight or obese preconception increased. C-section rates increased as BMI values preconception increased. There was a perceptible trend towards attempting the vaginal delivery of children in breech presentation and of twins. The frequency of depressed neonates after vaginal delivery and after C-section decreased. Rates for mild and advanced acidosis increased after both C-sections and vaginal deliveries. Previous C-section, older maternal age, overweight and obesity prior to conception, breech presentation and multiple pregnancies all increased the risk of cesarean sections. CONCLUSION: This study showed that reducing the rates of C-sections without a deterioration in neonatal outcomes can be achieved even in a large maternity hospital that cares for many high-risk pregnancies.

Acute-phase proteins in prediction of preeclampsia in patients with abnormal midtrimester uterine Doppler velocimetry.

AIMS: Manifestation of preeclampsia is characterized by an inflammatory response and altered expression of acute-phase proteins. In this study, we examined the predictive value of serum amyloid A, progranulin, transthyretin, C-reactive protein and interleukin-6. Soluble endoglin was used as control. METHODS: Maternal serum levels of the putative biomarkers were measured in 49 women with a midtrimester bilateral abnormal uterine artery Doppler velocimetry. RESULTS: Preeclampsia developed in 26.5 %. 75.0 % had an early-onset disease (<34 + 0 weeks). Delivery <34 + 0 weeks was indicated in 16.3 %. 12.2 % of patients developed a normotensive intrauterine growth restriction. All of the putative biomarkers were not predictive for preeclampsia. But serum levels of progranulin and also of soluble endoglin were increased in cases with development of a severe normotensive intrauterine growth restriction. Only soluble endoglin was predictive for the development of preeclampsia with an area under curve in the receiver operating curve analysis of 0.761 (P = 0.006). Using a cut-off level of ≥9.14 ng/mL, sensitivity, specificity, positive predictive value and negative predictive value were 53.9, 88.9, 63.6 and 84.2 %, respectively. CONCLUSIONS: Inflammation is a late event during development of preeclampsia, and acute-phase proteins are not predictive for the disease in a high-risk population without clinical symptoms during the second trimester. Progranulin is a putative new biomarker for an early detection of intrauterine growth restriction in women without concomitant hypertensive disorders. Soluble endoglin improved predictive values for preeclampsia in patients with abnormal uterine Doppler.

Prediction of preeclampsia and induced delivery at <34 weeks gestation by sFLT-1 and PlGF in patients with abnormal midtrimester uterine Doppler velocimetry: a prospective cohort analysis.

BACKGROUND: Women with bilateral abnormal uterine artery Doppler velocimetry (UtADV) are at increased risk for an adverse pregnancy outcome. This study aimed to determine if additional assessment of midtrimester angiogenic factors improves the predictive accuracy of Doppler results for various outcome parameters. METHODS: Women with a bilateral abnormal UtADV, which was defined as a postsystolic incision and/or an increased pulsatility index greater than the 95th centile, and a singleton pregnancy were prospectively recruited between 19 + 0 and 26 + 6 weeks of gestation. Maternal serum levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT-1) were measured with a fully automated immunoassay and their ratio was calculated. RESULTS: Angiogenic factors could predict the development of preeclampsia (PE), as well as induced delivery at <34 weeks of gestation, but failed to predict the development of normotensive intrauterine growth restriction. Twelve (24.0%) of the 50 recruited women developed PE. Nine of these patients had early-onset disease (<34 + 0 weeks). Six (12.0%) patients were delivered at <34 + 0 weeks. The most useful test results in the prediction of PE and induced delivery at <34 + 0 weeks were observed using the sFLT-1/PlGF >95th centile ratio with a sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of 66.7%, 89.5%, 66.7%, and 89.5% for PE, and 85.7%, 86.1%, 50.1%, and 97.4% for induced delivery, respectively. Positive and negative likelihood ratios were 6.33 (95% CI 2.31-17.38) and 0.37 (95% CI 0.17-0.84) for PE, and 6.14 (95% CI 2.76-13.69) and 0.17 (0.03-1.02) for induced delivery, respectively. Corresponding odds ratios were 17.0 (95% CI 3.5-83.0) and 37.0 (95% CI 3.8-363.9), respectively. CONCLUSIONS: Measurement of angiogenic factors improves the specificity of an abnormal UtADV for prediction of PE. Compared with prediction of PE an abnormal sFLT-1/PlGF ratio revealed higher sensitivity for prediction of induced delivery at <34 + 0 weeks. The NPV of 97% will help to reassure most patients with an abnormal UtADV and a normal sFLT-1/PlGF ratio.

Hantavirus infections by Puumala or Dobrava-Belgrade virus in pregnant women.

BACKGROUND: Hantavirus infection in humans usually occurs via inhalation of infectious aerosolized excreta of rodents. Horizontal human-to-human transmission was reported only for the highly virulent Andes virus. The likelihood of vertical transmission and the clinical outcome of hantavirus infections in pregnancy is still unpredictable. OBJECTIVES: Very few data were published about the impact of hantaviruses in pregnancy. Here we present four cases of pregnant women infected by European hantaviruses. The risk of vertical virus transmission was investigated. STUDY DESIGN: Four pregnant women with clinical signs of acute hantavirus disease were investigated for hantavirus IgM and IgG after onset of clinical symptoms. Furthermore, the newborns were tested for presence of viral RNA and antibodies in cord blood and, if any parameter was found positive, 8-12 months after delivery. RESULTS: Four women suffered from a hantavirus infection, two of them due to infection by Puumala virus and two by Dobrava-Belgrade virus. Three women delivered healthy babies by vaginal route and one woman by Caesarean section (week 28). In no case hantavirus RNA was detected in cord blood after delivery or in the 8-12 month old babies. Hantavirus IgG was detectable in the cord blood of 3 babies (but not in the preterm child); these antibodies disappeared after 8-12 months indicating a passive transfer of immunoglobulins. No child had any clinical sign of hantavirus infection. CONCLUSIONS: In this study, the absence of vertical hantavirus transmission was demonstrated for pregnant women with onset of hantavirus disease between gestation weeks 14 and 28.