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Objective: The FASTER trial compared first and second trimester screening methods for aneuploidy. We examined relationships between maternal serum markers and common congenital anomalies in the pediatric outcome data set of 36 837 subjects.Methods: We used nested case-control studies, with cases defined by the most common anomalies in our follow-up database, and up to four controls matched by enrollment site, maternal age and race, enrollment gestational age, and infant gender. Serum markers were dichotomized to > or = 2 or < 0.5 multiples of the median (MoM). Odds ratios (ORs) and 95% confidence intervals (CI) were estimated.Results: Statistically significant (p < 0.05) associations were found between inhibin A > or = 2 MoM with fetal multicystic dysplastic kidney (MCDK) (OR = 27.5, 95% CI: 2.8-267.7) and two-vessel cord (OR = 4.22, 95% CI:1.6-10.9); hCG of > or = 2 MoM with MCDK (OR = 19.56, 95% CI: 1.9-196.2) and hydrocele (OR = 2.48, 95% CI: 1.3-4.6); and PAPP-A > or = 2.0 MoM with hydrocele (OR = 1.88, 95% CI:1.1-3.3).Conclusion: In this large prospective study, significant associations were found between several maternal serum markers and congenital anomalies. This suggests potential additional benefits to screening programs that are primarily designed to detect aneuploidy. [ABSTRACT FROM AUTHOR]

The purpose of this study was to assess the validity and reliability of the FitMate metabolic system (Cosmed, Rome, Italy) in measuring oxygen consumption and estimating resting metabolic rate (RMR). The FitMate is a new, small (20 x 24 cm) metabolic analyzer designed for measurement of oxygen consumption and energy expenditure during rest and exercise. Subjects included 60 healthy adults (N = 30 males, N = 30 females) ranging in age from 19 to 65 years (mean +/- SD age, 36.9 +/- 13.4 years) and body mass index (BMI) from 19.2 to 44.8 kg/m2 (27.7 +/- 6.2 kg/m2). Subjects were given two 10 min RMR tests in one test session during which RMR was measured simultaneously with the Douglas bag and FitMate systems. No significant differences were found between Douglas bag and FitMate systems for oxygen consumption (242 +/- 49 and 240 +/- 49 ml/min, respectively, P = 0.066, r = 0.97, mean +/- SD absolute difference 2.83 +/- 11.68 ml/min) or RMR (1,662 +/- 340 and 1,668 +/- 344 kcal/day, P = 0.579, r = 0.97, mean +/- SD absolute difference 5.81 +/- 80.70 kcal/day). These data indicate that the FitMate is a reliable and valid system for measuring oxygen consumption and RMR in adults. [ABSTRACT FROM AUTHOR]

Serial cultures of endotracheal tube aspirates were carried out in 94 neonates who were intubated and had been ventilated for longer than one week. A similar change in bacterial colonisation with duration of ventilation was seen in infants who subsequently developed sepsis and those who did not. In both groups, 177 aspirates (more than 90%) obtained during the first week of ventilation were sterile. Thereafter, colonisation with mixed Gram positive flora emerged followed by growth of Gram negative bacilli. For the infants who developed sepsis, the correlation between pathogens isolated from blood during the episodes of sepsis and those from previous endotracheal tube isolates was poor; in only five of the 26 cases of sepsis (19%) was the same single strain of organism isolated from culture of the blood and of the endotracheal tube aspirate. Other markers of infection such as endotracheal tube aspirate white blood cell counts and changes in bacterial flora were not useful in predicting systemic infection. Routine surveillance cultures of endotracheal tube aspirates in ventilated infants are not helpful in predicting the pathogens that are isolated from the blood during episodes of sepsis. [ABSTRACT FROM AUTHOR]

Sexual size dimorphism is thought to contribute to the greater mortality and morbidity of men compared with women. However, the timing of onset of sexual size dimorphism remains uncertain. The authors determined whether human fetuses exhibit sexual size dimorphism in the first trimester of pregnancy. Using a prospective cohort study, conducted in 1999-2002 in the United States, they identified 27,655 women who conceived spontaneously and 1,008 whose conception was assisted by in vitro fertilization or intrauterine insemination and for whom a first-trimester measurement of fetal crown-rump length was available. First-trimester size was expressed as the difference between the observed and expected size of the fetus, expressed as equivalence to days of gestational age. The authors evaluated the association between fetal sex, first-trimester size, and birth weight. Eight to 12 weeks after conception, males were larger than females (mean difference: assisted conception = 0.4 days, 95% confidence interval (CI): 0.1, 0.7, p = 0.008; spontaneous conception = 0.3 days, 95% CI: 0.2, 0.4, p < 0.00001). The size discrepancy remained significant at birth (mean birth weight difference: assisted conception = 90 g, 95% CI: 22, 159, p = 0.009; spontaneous conception = 120 g, 95% CI: 107, 132, p < 0.00001). These data demonstrate that human fetuses exhibit sexual size dimorphism in the first trimester of pregnancy. [ABSTRACT FROM AUTHOR]

Four new pentadentate N5-donor ligands, [ N -(1-methyl-2-imidazolyl)methyl- N -(2-pyridyl)-methyl- N -(bis-2-pyridylmethyl)-amine] ( L 1 ), [ N -bis(1-methyl-2-imidazolyl)methyl- N -(bis-2-pyridylmethyl)amine] ( L 2 ), ( N -(isoquinolin-3-ylmethyl)-1,1-di(pyridin-2-yl)- N -(pyridin-2-ylmethyl)methanamine ( L 3 ), and N , N -bis(isoquinolin-3-ylmethyl)-1,1-di(pyridin-2-yl)methanamine ( L 4 ), have been synthesized based on the N4Py ligand framework, where one or two pyridyl arms of the N4Py parent are replaced by ( N -methyl)imidazolyl or N -(isoquinolin-3-ylmethyl) moieties. Using these four pentadentate ligands, the mononuclear complexes [Fe II (CH 3 CN)( L 1 )] 2+ ( 1a ), [Fe II (CH 3 CN)( L 2 )] 2+ ( 2a ), [Fe II (CH 3 CN)( L 3 )] 2+ ( 3a ), and [Fe II (CH 3 CN)( L 4 )] 2+ ( 4a ) have been synthesized and characterized. The half-wave potentials ( E 1/2 ) of the complexes become more positive in the order: 2a < 1a < 4a ≤ 3a ≤ [Fe(N4Py)(CH 3 CN)] 2+ . The order of redox potentials correlates well with the Fe-N amine distances observed by crystallography, which are 2a > 1a ≥ 4a > 3a ≥ [Fe(N4Py)(CH 3 CN)] 2+ . The corresponding ferryl complexes [Fe IV (O)( L 1 )] 2+ ( 1b ), [Fe IV (O)( L 2 )] 2+ ( 2b ), [Fe IV (O)( L 3 )] 2+ ( 3b ), and [Fe IV (O)( L 4 )] 2+ ( 4b ) were prepared by the reaction of the ferrous complexes with isopropyl 2-iodoxybenzoate (IBX ester) in acetonitrile. The greenish complexes 3b and 4b were also isolated in the solid state by the reaction of the ferrous complexes in CH 3 CN with ceric ammonium nitrate in water. Mössbauer spectroscopy and magnetic measurements (using superconducting quantum interference device) show that the four complexes 1b, 2b, 3b , and 4b are low-spin ( S = 1) Fe IV ═O complexes. UV/vis spectra of the four Fe IV ═O complexes in acetonitrile show typical long-wavelength absorptions of around 700 nm, which are expected for Fe IV ═O complexes with N4Py-type ligands. The wavelengths of these absorptions decrease in the following order: 721 nm ( 2b ) > 706 nm ( 1b ) > 696 nm ( 4b ) > 695 nm ( 3b ) = 695 nm ([Fe IV (O) (N4Py)] 2+ ), indicating that the replacement of the pyridyl arms with ( N -methyl) imidazolyl moieties makes L 1 and L 2 exert weaker ligand fields than the parent N4Py ligand, while the ligand field strengths of L 3 and L 4 are similar to the N4Py parent despite the replacement of the pyridyl arms with N -(isoquinolin-3-ylmethyl) moieties. Consequently, complexes 1b and 2b tend to be less stable than the parent [Fe IV (O)(N4Py)] 2+ complex: the half-life sequence at room temperature is 1.67 h ( 2b ) < 16 h ( 1b ) < 45 h ( 4b ) < 63 h ( 3b ) ≈ 60 h ([Fe IV (O)(N4Py)] 2+ ). Compared to the parent complex, 1b and 2b exhibit enhanced reactivity in both the oxidation of thioanisole in the oxygen atom transfer (OAT) reaction and the oxygenation of C-H bonds of aromatic and aliphatic substrates, presumed to occur via an oxygen rebound process. Furthermore, the second-order rate constants for hydrogen atom transfer (HAT) reactions affected by the ferryl complexes can be directly related to the C-H bond dissociation energies of a range of substrates that have been studied. Using either IBX ester or H 2 O 2 as an oxidant, all four new Fe II complexes display good performance in catalytic reactions involving both HAT and OAT reactions.

Background: In 2016, the American College of Obstetricians and Gynecologists recommended antenatal corticosteroids in the late preterm period for women at risk for preterm delivery. Limited real-world evidence exists on neonatal outcomes, particularly for twin gestations, following the guideline change. The study objective is to determine the association of antenatal corticosteroids in late preterm singleton and twin pregnancies with respiratory complications and hypoglycemia in a real-world clinical setting., Methods: This is a retrospective cohort study comprising late preterm deliveries (4,341 mother-child pairs) within the Mount Sinai Health System, 2012-2018. The exposure of interest is antenatal corticosteroid administration of betamethasone during pregnancy between 34 0/7 and 36 6/7 weeks. Our primary outcomes are neonatal respiratory complications and hypoglycemia. Multivariable logistic regression was used to estimate the association between antenatal corticosteroid exposure and these two outcomes. We stratified the study population by singleton gestations and twins to minimize the potential confounding from different obstetric management between the two groups., Results: Among a total of 4,341 mother-child pairs (3,309 singleton and 1,032 twin mother-child pairs), 745 mothers received betamethasone, of which 40.94% (305/745) received the full course. Relative to no treatment, a full course of betamethasone was associated with reduced odds of respiratory complications (OR = 0.53, 95% CI:[0.31-0.85], p < 0.01) and increased odds of hypoglycemia (OR = 1.86, 95%CI:[1.34-2.56], p < 0.01) in singletons; however, the association with respiratory complications was not significant in twins (OR = 0.42, 95% CI:[0.11-1.23], p = 0.16), but was associated with increased odds of hypoglycemia (OR = 2.18, 95% CI:[1.12-4.10], p = 0.02). A partial course of betamethasone (relative to no treatment) was not significantly associated with any of the outcomes, other than respiratory complications in twins (OR = 0.34, 95% CI:[0.12-0.82], p = 0.02)., Conclusions: Exposure to antenatal corticosteroids in singletons and twins is associated with increased odds of hypoglycemia. Among singletons, exposure to the full dosage (i.e. two doses) was associated with decreased odds of respiratory complications but this was only the case for partial dose among twins. Twin gestations were not studied by the Antenatal Late Preterm Steroids trial. Therefore, our study findings will contribute to the paucity of evidence on the benefit of antenatal corticosteroids in this group. Health systems should systematically monitor guideline implementations to improve patient outcomes., (© 2022. The Author(s).)

Preeclampsia is a heterogeneous and complex disease associated with rising morbidity and mortality in pregnant women and newborns in the US. Early recognition of patients at risk is a pressing clinical need to reduce the risk of adverse outcomes. We assessed whether information routinely collected in electronic medical records (EMR) could enhance the prediction of preeclampsia risk beyond what is achieved in standard of care assessments. We developed a digital phenotyping algorithm to curate 108,557 pregnancies from EMRs across the Mount Sinai Health System, accurately reconstructing pregnancy journeys and normalizing these journeys across different hospital EMR systems. We then applied machine learning approaches to a training dataset (N = 60,879) to construct predictive models of preeclampsia across three major pregnancy time periods (ante-, intra-, and postpartum). The resulting models predicted preeclampsia with high accuracy across the different pregnancy periods, with areas under the receiver operating characteristic curves (AUC) of 0.92, 0.82, and 0.89 at 37 gestational weeks, intrapartum and postpartum, respectively. We observed comparable performance in two independent patient cohorts. While our machine learning approach identified known risk factors of preeclampsia (such as blood pressure, weight, and maternal age), it also identified other potential risk factors, such as complete blood count related characteristics for the antepartum period. Our model not only has utility for earlier identification of patients at risk for preeclampsia, but given the prediction accuracy exceeds what is currently achieved in clinical practice, our model provides a path for promoting personalized precision therapeutic strategies for patients at risk., (© 2022. The Author(s).)

Collagen type IV (Col IV) is a basement membrane protein associated with early blood vessel morphogenesis and is essential for blood vessel stability. Defects in vascular Col IV deposition are the basis of heritable disorders, such as small vessel disease, marked by cerebral hemorrhage and drastically shorten lifespan. To date, little is known about how endothelial cells regulate the intracellular transport and selective secretion of Col IV in response to angiogenic cues, leaving a void in our understanding of this critical process. Our aim was to identify trafficking pathways that regulate Col IV deposition during angiogenic blood vessel development. We have identified the GTPase Rab10 as a major regulator of Col IV vesicular trafficking during vascular development using both in vitro imaging and biochemistry as well as in vivo models. Knockdown of Rab10 reduced de novo Col IV secretion in vivo and in vitro. Mechanistically, we determined that Rab10 is an indirect mediator of Col IV secretion, partnering with atypical Rab25 to deliver the enzyme lysyl hydroxylase 3 (LH3) to Col IV-containing vesicles staged for secretion. Loss of Rab10 or Rab25 results in depletion of LH3 from Col IV-containing vesicles and rapid lysosomal degradation of Col IV. Furthermore, we demonstrate that Rab10 is Notch responsive, indicating a novel connection between permissive Notch-based vessel maturation programs and vesicle trafficking. Our results illustrate both a new trafficking-based component in the regulated secretion of Col IV and how this vesicle trafficking program interfaces with Notch signaling to fine-tune basement membrane secretion during blood vessel development., (© 2021. The Author(s).)

Here we present the synthesis of a unique diferrous [2Fe-2S] 0 complex with only three-coordinate iron ions via reduction of a four-coordinate diferric [2Fe-2S] 2+ complex with concomitant ligand loss. The obtained compounds were thoroughly examined for their properties ( e.g. by 57 Fe Mössbauer spectroscopy and magnetic susceptibility measurements). Facile cleavage of the [2Fe-2S] rhombus, commonly seen as rather stable, by CS 2 is also shown.

Objective: To evaluate the efficacy of topical mupirocin in reducing Staphylococcus aureus colonization in infants in the neonatal intensive care unit (NICU)., Study Design: A prospective double-blind randomized controlled trial of mupirocin vs placebo in S aureus-colonized infants was conducted in a tertiary care NICU between October 2016 and December 2019. Weekly universal active surveillance with polymerase chain reaction screening identified colonized infants. Colonized infants received a 5-day course of mupirocin (mupirocin group) or petroleum jelly (control group). Repeat courses were given for additional positive screens., Results: A total of 216 infants were enrolled; 205 were included in data analyses. Primary decolonization was more successful for mupirocin-treated infants (86 of 104 [83%]) than for controls (20 of 101; 20%) (P < .001). Although recurrent S aureus colonization occurred frequently (59 of 81 [73%] mupirocin-treated and 26 of 33 [79%] controls), subsequent decolonization remained more successful for mupirocin-treated infants than for controls (38 of 49 [78%] vs 2 of 21 [10%]; P < .001). Subgroup analyses of infants of ≤30 weeks' gestational age yielded similar results; decolonization occurred more often in mupirocin-treated infants compared with control infants (63 of 76 [83%] vs 13 of 74 [18%]; P < .001). Bacterial sterile site infections tended to be less frequent in mupirocin-treated infants compared with controls (2 of 104 [2%] vs 8 of 101 [8%]; P = .057). No invasive S aureus infections occurred in mupirocin-treated infants, but 50% of infections in controls were from S aureus, and 1 resulted in death., Conclusions: Universal active surveillance and targeted treatment with topical mupirocin is a successful decolonization strategy for NICU infants and may prevent S aureus infection. However, S aureus colonization frequently recurs, necessitating repeat treatment., Trial Registration: Clinicaltrials.gov: NCT02967432., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions., Competing Interests: Competing interest statement: N.U.F.D. is a cofounder of NOUS Imaging.

Porous electrodes are widely used in the industry because of their high surface area to volume ratio. However, the stochastic morphology of most commercially available porous electrodes results in poor electrical connections in the solid phase and inefficient mass transport through the pore phase. This can be especially detrimental for gas-evolving processes such as water electrolysis for hydrogen and oxygen generation. Bicontinuous interfacially jammed emulsion gels (bijels) offer templates from which to create porous electrodes with robust solid-state interconnectivity and a uniform pore structure that facilitate improved electron and mass transport. In this study, gas release rates and electrochemical experiments are utilized to study the effects of powder- and bijel-derived microstructures on hydrogen generation by water electrolysis. The bijel-derived electrodes are shown to expel product gas faster and require up to 25% less overpotential to drive water electrolysis over the range of current densities tested (-5 to -40 mA/cm 2 ) than their powder-derived analogs. Our findings suggest that the uniform and bicontinuous domains of bijel-derived porous electrodes can mitigate the limited current distribution and deleterious bubble effect found in stochastic electrodes, in turn improving the overall performance of electrolytic processes requiring transport of gaseous species.

Five-year absolute breast cancer risk prediction models are required to comply with national guidelines regarding risk reduction regimens. Models including the Gail model are under-utilized in the general population for various reasons, including difficulty in accurately completing some clinical fields. The purpose of this study was to determine if a streamlined risk model could be designed without substantial loss in performance. Only the clinical risk factors that were easily answered by women will be retained and combined with an objective validated polygenic risk score (PRS) to ultimately improve overall compliance with professional recommendations. We first undertook a review of a series of 2,339 Caucasian, African American and Hispanic women from the USA who underwent clinical testing. We first used deidentified test request forms to identify the clinical risk factors that were best answered by women in a clinical setting and then compared the 5-year risks for the full model and the streamlined model in this clinical series. We used OPERA analysis on previously published case-control data from 11,924 Gail model samples to determine clinical risk factors to include in a streamlined model: first degree family history and age that could then be combined with the PRS. Next, to ensure that the addition of PRS to the streamlined model was indeed beneficial, we compared risk stratification using the Streamlined model with and without PRS for the existing case-control datasets comprising 1,313 cases and 10,611 controls of African-American (n = 7421), Caucasian (n = 1155) and Hispanic (n = 3348) women, using the area under the curve to determine model performance. The improvement in risk discrimination from adding the PRS risk score to the Streamlined model was 52%, 46% and 62% for African-American, Caucasian and Hispanic women, respectively, based on changes in log OPERA. There was no statistically significant difference in mean risk scores between the Gail model plus risk PRS compared to the Streamlined model plus PRS. This study demonstrates that validated PRS can be used to streamline a clinical test for primary care practice without diminishing test performance. Importantly, by eliminating risk factors that women find hard to recall or that require obtaining medical records, this model may facilitate increased clinical adoption of 5-year risk breast cancer risk prediction test in keeping with national standards and guidelines for breast cancer risk reduction., Competing Interests: RA and ES are current employees of Genetic Technologies Ltd. JL and SG were previous employees of Genetic technologies Ltd. This study was fully funded by Genetics Technologies Ltd. The risk model analysed in the present study is, or has been, commercially available under the tradename BREVAGenplus®. The product is covered by provisional patent application AU2018213400. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Caring for older patients with neurocognitive disorders can be challenging, especially when family members disagree regarding optimal care. This article explores the role and utilization of mediators in the healthcare setting.

Objective: To compare pulmonary and neurodevelopmental outcomes in extremely preterm infants with evolving bronchopulmonary dysplasia treated with either a 42-day course of dexamethasone or 9-day course(s) of dexamethasone., Study Design: This was a prospective, randomized study in 59 infants ≤27 weeks of gestation born between October 2006 and December 2010, who at day 10-21 of life had ventilatory support with mean airway pressure ≥8 cm H 2 O and FiO 2 ≥60%. Infants received dexamethasone 0.5 mg/k/day × 3 days followed by a slow taper (42-day group, n = 30) or dexamethasone 0.5 mg/k/day followed by a rapid taper (9-day group, n = 29). Infants in the 9-day group received additional 9-day courses if they again required entry support. The primary outcome was intact survival (normal neurologic examination, IQ >70, and functioning in school without supplemental educational support) at 7 years of age., Results: The 42-day and 9-day groups were similar for mean gestational age (25 weeks) and all baseline characteristics. Nineteen of 29 infants (66%) in the 9-day group received only 1 course of dexamethasone; therefore, the total steroid dose for the 42-day group (7.56 mg/kg) was significantly greater than that for the 9-day group (4.04 mg/kg), P < .001. Infants in the 42-day group had shorter duration of ventilation (25 vs 37 days), P < .005, received fewer transfusions (2 vs 3.5), P < .01, and reached full enteral feeds earlier (40 vs 46 days), P < .05. Intact survival at school age was significantly increased in the 42-day group (75%) compared with the 9-day group (34%), P < .005., Conclusion: A 42-day tapering course of dexamethasone in extremely preterm infants at high risk for bronchopulmonary dysplasia decreased hospital morbidities and increased rate of survival without handicap compared with a treatment protocol that attempted to minimize steroid exposure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Cell-free DNA (cfDNA) testing for fetal aneuploidy is one of the most important technical advances in prenatal care. Additional chromosome targets beyond common aneuploidies, including the 22q11.2 microdeletion, are now available because of this clinical testing technology. While there are numerous potential benefits, 22q11.2 microdeletion screening using cfDNA testing also presents significant limitations and pitfalls. Practitioners who are offering this test should provide comprehensive pretest and posttest prenatal counselling. The discussion should include the possibility of an absence of a result, as well as the risk of possible discordance between cfDNA screening results and the actual fetal genetic chromosomal constitution. The goal of this review is to provide an overview of the cfDNA testing technologies for 22q11.2 microdeletions screening, describe the current state of test validation and clinical experience, review "no results" and discordant findings based on differing technologies, and discuss management options., (© 2019 John Wiley & Sons, Ltd.)

Objective: We examined the effect of two strategies to prevent necrotizing enterocolitis (NEC) in extremely low birth weight (ELBW) infants-adherence to a standardized feeding protocol and use of a hospital-based milk bank to provide exclusive preterm human milk feedings., Study Design: We conducted a single-center observational study from 2010 to 2015. Infants received preterm human milk, initially trophic feeds from days 7 to 14 after birth, followed by advancement of 15 mL/kg/day to reach a goal of 180 mL/kg/day. Fortification was used selectively for weight gain < 15 g/kg/day. We determined the incidence of NEC, other morbidities, and growth., Results: The cohort included 398 ELBW infants who survived to day 14 without congenital anomalies. Mean gestational age was 26.2 ± 1.9 weeks. Maternal milk was used as the sole feeding in 62% of infants; preterm donor milk was used solely or as supplement in 29%. Full feeds were reached at a median of 27 (IQR 23, 33) days. Four infants (1%) developed NEC., Conclusion: Use of standardized feedings with a hospital-based milk bank is associated with an incidence of NEC lower than previously reported.

Objective: The unique biological behavior of sex chromosomes has implications for cell-free DNA (cfDNA) testing. Our purpose is to predict the (1) false positive/negative rates of cfDNA testing consequent to fetoplacental mosaicism for any sex chromosome aneuploidies (SCA) and (2) positive predictive value (PPV) and negative predictive values of a high-risk and low-risk cfDNA result for any SCA., Method: This is a retrospective analysis of 67 030 chorionic villus sampling karyotypes, including fetoplacental mosaicism cases., Results: Non-mosaic 45, X is associated with cystic hygroma/increased nuchal translucency and fetal anomalies. The false positive rate consequent to confined placental mosaicism is predicted to be 0.05%. The estimated false negative rate is in the range of 0% to 5.7% for all non-mosaic SCAs; it is 70% for mosaic 45, X with normal ultrasound. The predicted PPV on amniocytes is very high for most SCAs (94.4-99.4%). However, the stratified analysis shows that the PPV is much lower for 45, X without ultrasound anomalies compared with 45, X with abnormal scan (51% or 71%, vs 99%, respectively)., Conclusion: Mosaicism is a major issue for SCA cfDNA testing, and prenatal confirmation, preferentially with amniocentesis if there are no ultrasound anomalies, remains important in counseling. As PPV varies on the basis of the presence of an ultrasound anomaly, skilled evaluation is critical. © 2017 John Wiley & Sons, Ltd., (© 2017 John Wiley & Sons, Ltd.)

Misalignment of a nascent strand and the use of an alternative template during DNA replication, a process termed "template-switching", can give rise to frequent mutations and genetic rearrangements. Mutational hotspots are frequently found associated with imperfect inverted repeats ("quasipalindromes" or "QPs") in many organisms, including bacteriophage, bacteria, yeast and mammals. Evidence suggests that QPs mutate by a replication template-switch whereby one copy of the inverted repeat templates synthesis of the other. To study quasipalindrome-associated mutagenesis ("QPM") more systematically, we have engineered mutational reporters in the lacZ gene of Escherichia coli, that revert to Lac + specifically by QPM. We and others have shown that QPM is more efficient during replication of the leading strand than it is on the lagging strand. We have previously shown that QPM is elevated and that the leading-strand bias is lost in mutants lacking the major 3' ssDNA exonucleases, ExoI and ExoVII. This suggests that one or both of these exonucleases more efficiently abort template-switches on the lagging strand. Here, we show that ExoI is primarily responsible for this bias and that its ability to be recruited by single-strand DNA binding protein plays a critical role in QPM avoidance and strand bias. In addition to these stand-alone exonucleases, loss of the 3' proofreading exonuclease activity of the replicative DNA polymerase III also greatly elevates QPM. This may be because template-switching is initiated by base misincorporation, leading to polymerase dissociation and subsequent nascent strand misalignment; alternatively or additionally, the proofreading exonuclease may scavenge displaced 3' DNA that would otherwise be free to misalign., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: No previous studies have reported the frequencies of individual chromosomal anomalies in normal-appearing fetuses stratified by maternal age (MA) and gestational age (GA). We therefore sought to (1) characterize the frequency of all fetal karyotype anomalies in sonographically normal appearing fetuses without pretest risk factors, and (2) assess MA and GA impact on the proportion of anomalies targeted by screening and consequent impact on residual risk following a negative result., Methods: Fetal karyotypes from samples without prior risk assessment or ultrasound anomalies were analyzed. We calculated, per single-year MA and in two GA intervals, the predicted frequency of each cytogenetic defect., Results: A total of 129 263 karyotypes were analyzed. The risk for significant, cytogenetically visible chromosomal anomalies, at 15 to 20 weeks GA, varies between 1/301 at MA of 18 years, and 1/9 at MA of 48 years. The proportion of clinically significant anomalies not addressed by current screening methods is 47% at MA of 18 years and 5% at MA of 48 years., Conclusions: By determining frequencies for individual karyotype anomalies stratified by MA and GA, in the setting of normal-appearing fetuses, a more personalized risk assessment, including the residual risk after a normal fetal aneuploidy screening result, can be provided. © 2016 John Wiley & Sons, Ltd., (© 2016 John Wiley & Sons, Ltd.)

Background: More than a decade ago, researchers described a survey of Maternal Fetal Medicine fellows that showed that chorionic villus sampling training was limited for Maternal Fetal Medicine fellows in the United States. Prenatal screening and diagnosis have rapidly evolved since then and include the introduction of noninvasive aneuploidy screening that uses cell-free fetal DNA. Yet, chorionic villus sampling remains the only method available for first-trimester genetic diagnosis., Objective: This study evaluated the chorionic villus sampling training of Maternal Fetal Medicine fellows with respect to availability, competency standards, and education methods., Study Design: In November 2015, an electronic survey was sent to Maternal Fetal Medicine fellows and fellowship directors of accredited Maternal Fetal Medicine fellowship programs in the United States., Results: Fifty-eight percent of fellows (179/310) and 46% of program directors (35/76) responded. Ninety-five percent of Maternal Fetal Medicine fellows think that invasive diagnostic testing is essential to their training; 100% of fellows have amniocentesis training; and 65% have chorionic villus sampling training. The median number of chorionic villus sampling procedures that are expected during a fellowship in those who trained was 10. Eighty-eight percent of fellows and 89% of program directors state that chorionic villus sampling training could be better; 89% of fellows and 97% of directors would like access to simulated models. Barriers to training included lack of patients (71%) and lack of proficient attending supervisors (43%)., Conclusion: Since the last survey, >10 years ago, chorionic villus sampling training has declined further. A decrease in the number of procedures that are performed is the leading barrier to this training., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the performance of a single-nucleotide polymorphism (SNP)-based non-invasive prenatal test (NIPT) for the detection of fetal 22q11.2 deletion syndrome in clinical practice, assess clinical follow-up and review patient choices for women with high-risk results., Methods: In this study, 21 948 samples were submitted for screening for 22q11.2 deletion syndrome using a SNP-based NIPT and subsequently evaluated. Follow-up was conducted for all cases with a high-risk result., Results: Ninety-five cases were reported as high risk for fetal 22q11.2 deletion. Diagnostic testing results were available for 61 (64.2%) cases, which confirmed 11 (18.0%) true positives and identified 50 (82.0%) false positives, resulting in a positive predictive value (PPV) of 18.0%. Information regarding invasive testing was available for 84 (88.4%) high-risk cases: 57.1% (48/84) had invasive testing and 42.9% (36/84) did not. Ultrasound anomalies were present in 81.8% of true-positive and 18.0% of false-positive cases. Two additional cases were high risk for a maternal 22q11.2 deletion; one was confirmed by diagnostic testing and one had a positive family history. There were three pregnancy terminations related to screening results of 22q11.2 deletion, two of which were confirmed as true positive by invasive testing., Conclusions: Clinical experience with this SNP-based non-invasive screening test for 22q11.2 deletion syndrome indicates that these deletions have a frequency of approximately 1 in 1000 in the referral population with most identifiable through this test. Use of this screening method requires the availability of counseling and other management resources for high-risk pregnancies., (© 2015 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd. on behalf of the International Society of Ultrasound in Obstetrics and Gynecology.)

Objective: To validate an updated version (Version 2) of a single-nucleotide polymorphism (SNP)-based noninvasive prenatal test (NIPT) and to determine the likelihood of success when testing for fetal aneuploidies following a redraw., Methods: Version 2 was analytically validated using 587 plasma samples with known genotype (184 trisomy 21, 37 trisomy 18, 15 trisomy 13, 9 monosomy X, 4 triploidy and 338 euploid). Sensitivity, specificity and no-call rate were calculated, and a fetal-fraction adjustment was applied to enable projection of these values in a commercial distribution. Likelihood of success of a second blood draw was computed based on fetal fraction and maternal weight from the first draw., Results: Validation of this methodology yielded high sensitivities (≥99.4%) and specificities (100%) for all conditions tested with an observed no-call rate of 2.3%. The no-call threshold for sample calling was reduced to 2.8% fetal fraction. The redraw success rate was driven by higher initial fetal fractions and lower maternal weights, with the fetal fraction being the more significant variable., Conclusions: The enhanced version of this SNP-based NIPT method showed a reduced no-call rate and a reduced fetal-fraction threshold for sample calling in comparison to the earlier version, while maintaining high sensitivity and specificity., (© 2016 The Author(s) Published by S. Karger AG, Basel.)

Background: Efficacy of FRONTLINE TRITAK For Dogs (fipronil/(S)-methoprene/cyphenothrin, Merial, Inc., Duluth, GA) against Ixodes scapularis was evaluated in two separate, but concurrent laboratory studies., Methods: One day after topical treatment with placebo or active, dogs (n = 24) were infested with 50 unfed adult Ixodes scapularis ticks, with repeat infestations on Days 7, 14, 21 and 28. The number of live ticks was counted at 6 hours post-infestation in the first study (n = 12) and at 24 hours post-infestation in the second study (n = 12)., Results: Observed efficacies in study 1 were 93-99% at 6 hour assessments on Day 1 through Day 28 and in the second study, 98-100% at 24 hour assessments, occurring on Day 2 through Day 29., Conclusions: A single dose of FRONTLINE TRITAK For Dogs (fipronil/(S)-methoprene/cyphenothrin) (0.67 ml or 1.34 ml) prevented the establishment of a new infestation following treatment, as well as the repeated weekly re-infestations with Ixodes scapularis ticks, for 4 weeks.