Confined placental mosaicism: Distribution of chromosomally abnormal cells over the term placenta.

OBJECTIVE: Non-invasive prenatal testing (NIPT) investigates placental DNA and may detect confined placental mosaicism (CPM). The aim of this study was to confirm CPM in the term placenta in cases with abnormal NIPT but normal follow-up cytogenetic studies of fetus and mother. Additionally we examined the distribution of abnormal cells over the placenta. METHODS: Four chorionic villus (CV) biopsies from four placental quadrants were requested in cases where CPM was assumed. Both cell lineages of the CV, cytotrophoblast (CTB) and mesenchymal core (MC), were analyzed separately with SNP array. RESULTS: The chromosome aberration was confirmed in 67 % of the placentas. Three quarters of the CTB and MC biopsies from these mosaic placentas were uniformly normal (57 %) or abnormal (20 %), and a minority showed mosaicism. Among 16 cases of CPM where first trimester CV were examined as well, 11 had chromosomally normal results during pregnancy. DISCUSSION: Cytogenetic investigations of term placental biopsies suspected to be affected with CPM did not reveal the chromosome aberration in one third of the placentas. This is caused by the patchy pattern in which chromosomally abnormal cells are distributed over the placenta with the majority of the biopsies being uniformly normal. Further CPM research, including its clinical impact, requires the analysis of more than four biopsies to get insight into the extent of the affected part. Moreover, a subset of CPM type 1 and 3 seems to be only detectable with NIPT and not with first trimester CVS.

Impact of gene expression profiling on diagnosis and survival after metastasis in patients with uveal melanoma.

Surveillance frequency for metastasis is guided by gene expression profiling (GEP). This study evaluated the effect of GEP on time to diagnosis of metastasis, subsequent treatment and survival. A retrospective study was conducted of 110 uveal melanoma patients with GEP (DecisionDx-UM, Castle Biosciences, Friendswood, Texas, USA) and 110 American Joint Committee on Cancer-matched controls. Surveillance testing and treatment for metastasis were compared between the two groups and by GEP class. Rates of metastasis, overall survival and melanoma-related mortality were calculated using Kaplan-Meier estimates. Baseline characteristics and follow-up time were balanced in the two groups. Patients' GEP classification was 1A in 41%, 1B in 25.5% and 2 in 33.6%. Metastasis was diagnosed in 26.4% ( n  = 29) in the GEP group and 23.6% ( n  = 26) in the no GEP group ( P  = 0.75). Median time to metastasis was 30.5 and 22.3 months in the GEP and no GEP groups, respectively ( P  = 0.44). Median months to metastasis were 34.7, 75.8 and 26.1 in class 1A, 1B and 2 patients, respectively ( P  = 0.28). Disease-specific 5-year survival rates were 89.4% [95% confidence interval (CI): 81.0-94.2%] and 84.1% (95% CI: 74.9-90.1%) in the GEP and no GEP groups respectively ( P  = 0.49). Median time to death from metastasis was 10.1 months in the GEP group and 8.5 months in the no GEP group ( P  = 0.40). There were no significant differences in time to metastasis diagnosis and survival outcomes in patients with and without GEP. To realize the full benefit of GEP, more sensitive techniques for detection of metastasis and adjuvant therapies are required.

First trimester anomaly scan using virtual reality (VR FETUS study): study protocol for a randomized clinical trial.

BACKGROUND: In recent years it has become clear that fetal anomalies can already be detected at the end of the first trimester of pregnancy by two-dimensional (2D) ultrasound. This is why increasingly in developed countries the first trimester anomaly scan is being offered as part of standard care. We have developed a Virtual Reality (VR) approach to improve the diagnostic abilities of 2D ultrasound. Three-dimensional (3D) ultrasound datasets are used in VR assessment, enabling real depth perception and unique interaction. The aim of this study is to investigate whether first trimester 3D VR ultrasound is of additional value in terms of diagnostic accuracy for the detection of fetal anomalies. Health-related quality of life, cost-effectiveness and also the perspective of both patient and ultrasonographer on the 3D VR modality will be studied. METHODS: Women in the first trimester of a high risk pregnancy for a fetus with a congenital anomaly are eligible for inclusion. This is a randomized controlled trial with two intervention arms. The control group receives 'care as usual': a second trimester 2D advanced ultrasound examination. The intervention group will undergo an additional first trimester 2D and 3D VR ultrasound examination. Following each examination participants will fill in validated questionnaires evaluating their quality of life and healthcare related expenses. Participants' and ultrasonographers' perspectives on the 3D VR ultrasound will be surveyed. The primary outcome will be the detection of fetal anomalies. The additional first trimester 3D VR ultrasound examination will be compared to 'care as usual'. Neonatal or histopathological examinations are considered the gold standard for the detection of congenital anomalies. To reach statistical significance and 80% power with a detection rate of 65% for second trimester ultrasound examination and 70% for the combined detection of first trimester 3D VR and second trimester ultrasound examination, a sample size of 2800 participants is needed. DISCUSSION: First trimester 3D VR detection of fetal anomalies may improve patients' quality of life through reassurance or earlier identification of malformations. Results of this study will provide policymakers and healthcare professionals with the highest level of evidence for cost-effectiveness of first trimester ultrasound using a 3D VR approach. TRIAL REGISTRATION: Dutch Trial Registration number NTR6309 , date of registration 26 January 2017.

Recurrence after hospitalization for acute coronary syndrome among HIV-infected and HIV-uninfected individuals.

OBJECTIVES: We evaluated the association of HIV infection and immunodeficiency with acute coronary syndrome (ACS) recurrence, and with all-cause mortality as a secondary outcome, after hospitalization for ACS among HIV-infected and HIV-uninfected individuals. METHODS: We conducted a retrospective cohort study within Kaiser Permanente Northern California of HIV-infected and HIV-uninfected adults discharged after ACS hospitalization [types: ST-elevation myocardial infarction (STEMI), non-STEMI, or unstable angina] during 1996-2010. We compared the outcomes of ACS recurrence and all-cause mortality within 3 years, both overall by HIV status and stratified by recent CD4 count, with HIV-uninfected individuals as the reference group. Hazard ratios (HRs) were obtained from Cox regression models with adjustment for age, sex, race/ethnicity, year, ACS type, smoking, and cardiovascular risk factors. RESULTS: Among 226 HIV-infected and 86 321 HIV-uninfected individuals with ACS, HIV-infected individuals had a similar risk of ACS recurrence compared with HIV-uninfected individuals [HR 1.08; 95% confidence interval (CI) 0.76-1.54]. HIV infection was independently associated with all-cause mortality after ACS hospitalization overall (HR 2.52; 95% CI 1.81-3.52). In CD4-stratified models, post-ACS mortality was higher for HIV-infected individuals with CD4 counts of 201-499 cells/µL (HR 2.64; 95% CI 1.66-4.20) and < 200 cells/µL (HR 5.41; 95% CI 3.14-9.34), but not those with CD4 counts ≥ 500 cells/µL (HR 0.67; 95% CI 0.22-2.08), compared with HIV-uninfected individuals (P trend < 0.001). CONCLUSIONS: HIV infection and immunodeficiency were not associated with recurrence of ACS after hospitalization. All-cause mortality was higher among HIV-infected compared with HIV-uninfected individuals, but there was no excess mortality risk among HIV-infected individuals with high CD4 counts.

[Etiological structure of influenza and other ARVI in St. Petersburg during epidemic seasons 2012-2016.]

The etiological structure of influenza and other acute respiratory viral infections including their rate of incidence in St. Petersburg and Leningrad region during 4 epidemic seasons has been studied. Seasonality of some respiratory viruses was shown and peaks of circulation of RSV, adenovirus, parainfluenza viruses, rhinovirus, bocavirus, metapneumovirus and coronavirus were marked. The interference of influenza A viruses and RSV, RSV and rhinoviruses was highlighted. A high incidence of adenovirus infection in organized communities and RSV infection in children was revealed.

Choosing between Higher and Lower Resolution Microarrays: do Pregnant Women Have Sufficient Knowledge to Make Informed Choices Consistent with their Attitude?

Developments in prenatal testing allow the detection of more findings. SNP arrays in prenatal diagnosis (PND) can be analyzed at 0.5 Mb resolution detecting more clinically relevant anomalies, or at 5 Mb resolution. We investigated whether women had sufficient knowledge to make informed choices regarding the scope of their prenatal test that were consistent with their attitude. Pregnant women could choose between testing at 5 or at 0.5 Mb array. Consenting women (N = 69) received pre-test genetic counseling by phone and filled out the Measure of Informed Choice questionnaire designed for this study. Choices based on sufficient knowledge and consistent with attitude were considered informed. Sixty-two percent of the women made an adequately informed choice, based on sufficient knowledge and attitude-consistent with their choice of microarray resolution. Women who made an informed choice, opted for 0.5 Mb array resolution more often. There were no differences between women making adequately informed or less informed choices regarding level of experienced anxiety or doubts. Over time on T0 and T1, anxiety and doubts significantly decreased. While previous studies demonstrated that knowledge is an important component in informed decision-making, this study underlines that a consistent attitude might be equally important for decision-making. We advocate more focus on attitude-consistency and deliberation as compared to only a strong focus on knowledge.

Ibuprofen does not reverse ventilatory acclimatization to chronic hypoxia.

Ventilatory acclimatization to hypoxia involves an increase in the acute hypoxic ventilatory response that is blocked by non-steroidal anti-inflammatory drugs administered during sustained hypoxia. We tested the hypothesis that inflammatory signals are necessary to sustain ventilatory acclimatization to hypoxia once it is established. Adult, rats were acclimatized to normoxia or chronic hypoxia (CH, [Formula: see text] =70Torr) for 11-12days and treated with ibuprofen or saline for the last 2days of hypoxia. Ventilation, metabolic rate, and arterial blood gas responses to O2 and CO2 were not affected by ibuprofen after acclimatization had been established. Immunohistochemistry and image analysis showed acute (1h) hypoxia activated microglia in a medullary respiratory center (nucleus tractus solitarius, NTS) and this was blocked by ibuprofen administered from the beginning of hypoxic exposure. Microglia returned to the control state after 7days of CH and were not affected by ibuprofen administered for 2 more days of CH. In contrast, NTS astrocytes were activated by CH but not acute hypoxia and activation was not reversed by administering ibuprofen for the last 2days of CH. Hence, ibuprofen cannot reverse ventilatory acclimatization or astrocyte activation after they have been established by sustained hypoxia. The results are consistent with a model for microglia activation or other ibuprofen-sensitive processes being necessary for the induction but not maintenance of ventilatory acclimatization to hypoxia.

Frequency of submicroscopic chromosomal aberrations in pregnancies without increased risk for structural chromosomal aberrations: systematic review and meta-analysis.

OBJECTIVE: To establish, based on a systematic literature review, the frequency of pathogenic submicroscopic chromosomal aberrations in fetuses that are not at increased risk for unbalanced structural chromosomal aberrations, with the aim of determining whether high-resolution testing for submicroscopic aberrations is beneficial in a general pregnant population. METHODS: EMBASE, PubMed, Web of Science and CENTRAL databases were searched systematically on 3 June 2016 for all relevant articles on the prevalence of pathogenic submicroscopic copy number variants (CNVs) in fetuses referred for prenatal invasive testing because of advanced maternal age (AMA) or parental anxiety (ANX). Relevant full-text articles were analyzed and the prevalence of submicroscopic CNVs was calculated based on the extracted data. Meta-analysis was conducted in a pooled cohort of 10 614 fetuses based on the 10 largest studies (n > 300) of a total of 19 that were relevant. RESULTS: Pooled estimate analysis indicated that 0.84% (95% CI, 0.55-1.30%) of fetuses that had invasive testing because of AMA/ANX carried a pathogenic clinically significant submicroscopic aberration. The onset/penetrance of submicroscopic findings was studied in 10 314 fetuses reported in eight papers that presented aberrant cases with all necessary details to allow assessment of the findings. The pooled estimates resulting from meta-analysis of the data indicated that an early-onset syndromic disorder was detected in 0.37% (95% CI, 0.27-0.52%) of cases, a susceptibility CNV was found in 0.30% (95% CI, 0.14-0.67%) and late-onset diseases were reported in 0.11% (95% CI, 0.05%-0.21%). The prevalence of early-onset syndromic disorders caused by a submicroscopic aberration was calculated to be 1:270. When the risk for submicroscopic aberrations is added to the individual risk for microscopic chromosomal aberrations, all pregnant women have a risk of higher than 1 in 180 for a relevant chromosomal aberration, and pregnant women under 36 years of age have a higher risk for submicroscopic pathogenic aberrations than for Down syndrome. CONCLUSION: This systematic review shows that a significant proportion of fetuses in a general pregnant population carry a submicroscopic pathogenic CNV. Based on these figures, all women should be informed on their individual risk for all pathogenic chromosomal aberrations and not only for common trisomies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Advanced genomic testing may aid in counseling of isolated agenesis of the corpus callosum on prenatal ultrasound.

OBJECTIVE: Isolated agenesis of the corpus callosum on fetal ultrasound has a varied prognosis. Microarray and exome sequencing (ES) might aid in prenatal counseling. METHOD: This study includes 25 fetuses with apparently isolated complete corpus callosum (cACC) on ultrasound. All cases were offered single nucleotide polymorphism array. Complementary ES was offered postnatally in selected cases. Clinical physical and neurodevelopmental follow-up was collected. RESULTS: Eighteen cases opted for single nucleotide polymorphism array testing, which detected a causal anomaly in 2/18 (11.1%; 95% CI 2.0%-31%). Among ongoing pregnancies without a causal anomaly on microarray, 30% (95% CI 8.5%-60%) showed intellectual disability. Postnatal magnetic resonance imaging and physical examination often (64%; 95% CI 38%-85%, and 64%; 95% CI 38%-85%, respectively) revealed additional physical anomalies in cases without a causal anomaly on microarray. Two cases appeared truly isolated after birth. Postnatal sequencing in 4 of 16 cases without a causal anomaly on microarray but with intellectual disability and/or additional postnatal physical anomalies revealed 2 single-gene disorders. Therefore, the estimated diagnostic yield of ES in chromosomally normal cACC fetuses is between 2/4 (50%; 95% CI 11%-89%) and 2/16 (13.3%; 95% CI 2.4%-36%). CONCLUSION: In accordance with current guidelines, we conclude that microarray should be offered in case of isolated cACC on ultrasound. ES is likely to be informative for prenatal counseling and should be offered if microarray is normal.

Prenatal and postnatal findings in small-for-gestational-age fetuses without structural ultrasound anomalies at 18-24 weeks.

OBJECTIVE: To assess phenotypic and genotypic characteristics of small-for-gestational-age (SGA) fetuses without structural anomalies at 18-24 weeks' gestation. METHODS: This retrospective study included structurally normal singleton fetuses with an abdominal circumference ≤ 5th percentile on detailed ultrasound examination between 18 and 24 weeks' gestation. Cases were stratified according to the absence or presence of other abnormal ultrasound findings, such as abnormal amniotic fluid or soft markers. All patients were offered invasive prenatal testing with rapid aneuploidy detection by qualitative fluorescence polymerase chain reaction (QF-PCR) and, if normal, consecutive single nucleotide polymorphism (SNP) array was also offered. Detailed postnatal follow-up (≥ 5 months) was performed. In cases in which a syndromic phenotype became apparent within 5 months after birth and SNP array had not been performed prenatally, it was performed postnatally. RESULTS: A total of 211 pregnancies were eligible for inclusion. Of the 158 cases with isolated SGA on ultrasound, 36 opted for invasive prenatal testing. One case of trisomy 21 and one case of a submicroscopic abnormality (a susceptibility locus for neurodevelopmental disease) were detected. Postnatal follow-up showed a postnatal apparent syndromic phenotype in 10 cases. In one case this was due to trisomy 21 and the other nine (5.8%; 95% CI, 2.8-10.0%) cases had normal SNP array results. In 32/53 cases with SGA and associated ultrasound abnormalities, parents opted for invasive testing. One case of trisomy 21 and one of triploidy were found. In 11 cases a syndromic phenotype became apparent after birth. One was due to trisomy 21 and in one case a submicroscopic anomaly (a susceptibility locus) was found. The remaining syndromic cases (17.3%; 95% CI, 8.7-29.0%) had normal SNP array results. CONCLUSION: Testing for chromosomal anomalies should be offered in cases of SGA between 18 and 24 weeks' gestation. Whole chromosome anomalies occur in 1.3% (95% CI, 0.2-3.9%) of isolated SGA and 5.8% (95% CI, 1.5-14.0%) of associated SGA. In 0.6% (95% CI, 0.1-2.8%) and 1.9% (95% CI, 0.2-8.2%), respectively, SNP array detected a susceptibility locus for neurodevelopmental disease that would not be detected by karyotyping, QF-PCR or non-invasive prenatal testing. Therefore, and because the genetic causes of SGA are diverse, we suggest SNP array testing in cases of SGA. Thorough postnatal examination and follow-up of infants that presented with reduced fetal growth is important because chromosomally normal syndromic phenotypes occur frequently in SGA fetuses. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

[Clinical and laboratory presentation of the influenza A (H1N1pdm 2009) in children and adults during the period of 2009-2013 in St. Petersburg].

Comparative analysis of the clinical laboratory data from 419 children and 468 adults hospitalized during the pandemic of A (H1N1pdm 2009) and pre- and post-pandemic periods (2010-2013) showed that the clinical presentation of the pandemic influenza in patients of all ages is generally typical for influenza, and its character is determined by the degree of involvement of lungs in the process. Besides, the incidence of pneumonia in adults is statistically significantly higher than in children. During all compared periods hyperthermia (≥ 39 degrees C), hemorrhagic and dyspeptic syndrome were observed. Some differences in the main clinical manifestations of pneumonia in recovered patients and patients who died of the severe pandemic influenza were observed. The regularities of the cytokine reactions depending on the intensity of intoxication and occurrence of complications were determined in patients of all ages. Medical efficacy of inclusion of antiviral chemotherapeutic agents into complex influenza treatment was proved.

A prospective investigation of cell dose in single-unit umbilical cord blood transplantation for adults with high-risk hematologic malignancies.

Umbilical cord blood (UCB) as an allogeneic transplant source is generally limited to units with pre-cryopreservation total nucleated cell (TNC) doses ⩾2.5 × 10(7) NC/kg. We prospectively investigated single UCB transplantation, with cord units as low as 1 × 10(7) NC/kg, all processed with post-thaw albumin-dextran dilution. We transplanted 104 adult patients with 84% having relapsed/refractory disease. The median TNC dose was 2.1 × 10(7) NC/kg (range: 1.0-4.4 × 10(7)) and median CD34+ cell dose was 1.0 × 10(5)/kg (range: 0.0-3.7 × 10(5)/kg). Post-manipulation cell recovery and viability were 96% and 99%, respectively. Median times to neutrophil and platelet engraftment were 16 and 43 days, respectively. Univariate factors predicting neutrophil engraftment included TNC (P=0.03) and CD34+ cell dose (P=0.01). CD34+ dose predicted platelet engraftment (P<0.001). In multivariate analysis, CD34+ dose remained significant for neutrophil and platelet engraftment (P<0.0001 and P<0.0001, respectively). The 100-day and 1-year overall survival were 70% and 46%, respectively (95% confidence interval: 36%-56% at 1 year). The subset transplanted with 1-1.5 × 10(7) NC/kg had similar 100-day and 1-year survivals of 73% and 45%, respectively. Single-unit UCB transplantation using small units, processed as described, leads to favorable engraftment and acceptable outcomes in poor prognosis patients. CD34+ cell dose (⩾1.5 × 10(5)/kg) helps predict faster engraftment and can aid in graft selection.

Additional value of prenatal genomic array testing in fetuses with isolated structural ultrasound abnormalities and a normal karyotype: a systematic review of the literature.

OBJECTIVE: To establish the prevalence of submicroscopic genetic copy number variants (CNVs) in fetuses with a structural ultrasound anomaly (restricted to one anatomical system) and a normal karyotype. The aim was to determine the diagnostic and prognostic value of genomic array testing in these pregnancies. METHODS: Embase and PubMed databases were systematically searched for all relevant articles on prevalence of pathogenic submicroscopic CNVs in fetuses with ultrasound anomalies. Reported cases were sorted into groups according to anatomical site of the detected ultrasound anomaly. The prevalence of causative submicroscopic CNVs was calculated for each group. RESULTS: Combined data of the reviewed studies (n = 18) indicated that fetuses with an ultrasound anomaly restricted to one anatomical system (n = 2220) had a 3.1-7.9% chance of carrying a causative submicroscopic CNV, depending on the anatomical system affected. This chance increased to 9.1% for fetuses with multiple ultrasound anomalies (n = 1139). CONCLUSION: This review indicates that 3.1-7.9% of fetuses with a structural ultrasound anomaly restricted to one anatomical system and a normal karyotype will show a submicroscopic CNV, which explains its phenotype and provides information for fetal prognosis. Therefore, we conclude that microarray has considerable diagnostic and prognostic value in these pregnancies.

Enzymatic coproduction of biodiesel and glycerol carbonate from soybean oil in solvent-free system.

The enzymatic coproduction of biodiesel and glycerol carbonate by transesterification of soybean oil and dimethyl carbonate (DMC) has been studied in a solvent-free system. The effects on biodiesel and glycerol carbonate conversion of reaction conditions including the kind of enzyme, the amount of enzyme, the molar ratio of DMC to soybean oil, the reaction temperature, and water addition were investigated. The optimal conditions for biodiesel and glycerol carbonate were 20% Novozym 435, 10:1 molar ratio of DMC to soybean oil, and 0.7% water addition. Under these conditions, the conversions of 96.4% biodiesel and 92.1% glycerol carbonate have been achieved after 48h.

Perinatal mortality and mode of delivery in monochorionic diamniotic twin pregnancies ≥ 32 weeks of gestation: a multicentre retrospective cohort study.

OBJECTIVE: To study perinatal mortality rates in a cohort of 465 monochorionic (MC) twins without twin-twin transfusion syndrome (TTS) born at 32 weeks of gestation or later since reported interauterine fetal death (IUFD) rates >32 weeks of gestations in the literature vary, leading to varying recommendations on the optimal timing of delivery, and to investigate the relation between perinatal mortality and mode of delivery. DESIGN: Multicentre retrospective cohort study. SETTING: Ten perinatal referral centres in the Netherlands. POPULATION: All MC twin pregnancies without TTTS delivered at ≥ 32 weeks of gestation between January 2000 and December 2005. METHODS: The medical records of all MC twin pregnancies without TTTS delivered at the ten perinatal referral centres in the Netherlands between January 2000 and December 2005 were reviewed. MAIN OUTCOME MEASURES: Perinatal mortality in relation to gestational age and mode of delivery at ≥ 32 weeks of gestation. RESULTS: After 32 weeks of gestation, five out of 930 fetuses died in utero and there were six neonatal deaths (6 per 1000 infants). In women who delivered ≥ 37 weeks, perinatal mortality was 7 per 1000 infants. Trial of labour was attempted in 376 women and was successful in 77%. There were three deaths in deliveries with a trial of labour (8 per 1000 deliveries), of which two were related to mode of delivery. Infants born by caesarean section without labour had an increased risk of neonatal morbidity and respiratory distress syndrome. CONCLUSIONS: In MC twin pregnancies the incidence of intrauterine fetal death is low ≥ 32 weeks of gestation. Therefore, planned preterm delivery before 36 weeks does not seem to be justified. The risk of intrapartum death is also low, at least in tertiary centres.