Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

OBJECTIVE: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield. DESIGN: Retrospective analysis of data from two prospective cohort studies. SETTING: Fetal medicine centres in the UK and USA. POPULATION: Fetuses with increased NT ≥3.5 mm at 11-14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213). METHODS: We grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. MAIN OUTCOME MEASURES: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. RESULTS: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis.

Effect of niacin on triglyceride-rich lipoprotein apolipoprotein B-48 kinetics in statin-treated patients with type 2 diabetes.

AIM: To investigate the effects of extended-release (ER) niacin on apolipoprotein B-48 (apoB-48) kinetics in statin-treated patients with type 2 diabetes (T2DM). METHODS: A total of 12 men with T2DM were randomized to rosuvastatin or rosuvastatin plus ER niacin for 12 weeks and then crossed to the alternate therapy. Postprandial metabolic studies were performed at the end of each treatment period. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. ApoB-48 kinetics were determined using stable isotope tracer kinetics with fractional catabolic rates (FCRs) and secretion rates derived using a non-steady-state compartmental model. Area-under-the-curve (AUC) and incremental AUC (iAUC) for plasma triglyceride and apoB-48 were also calculated over the 10-h period after ingestion of the fat meal. RESULTS: In statin-treated patients with T2DM, apoB-48 concentration was lower with ER niacin (8.24 ± 1.98 vs 5.48 ± 1.14 mg/l, p = 0.03) compared with statin alone. Postprandial triglyceride and apoB-48 AUC were also significantly lower on ER niacin treatment (-15 and -26%, respectively; p < 0.05), without any change to triglyceride and apoB-48 iAUC. ApoB-48 secretion rate in the basal state (3.21 ± 0.34 vs 2.50 ± 0.31 mg/kg/day; p = 0.04) and number of apoB-48-containing particles secreted in response to the fat load (1.35 ± 0.19 vs 0.84 ± 0.12 mg/kg; p = 0.02) were lower on ER niacin. ApoB-48 FCR was not altered with ER niacin (8.78 ± 1.04 vs 9.17 ± 1.26 pools/day; p = 0.79). CONCLUSIONS: ER niacin reduces apoB-48 concentration by lowering fasting and postprandial apoB-48 secretion rate. This effect may be beneficial for lowering atherogenic postprandial lipoproteins and may provide cardiovascular disease risk benefit in patients with T2DM.

A direct D-bar reconstruction algorithm for recovering a complex conductivity in 2-D.

A direct reconstruction algorithm for complex conductivities in W2,∞ (Ω), where Ω is a bounded, simply connected Lipschitz domain in ℝ2, is presented. The framework is based on the uniqueness proof by Francini [Inverse Problems 20 2000], but equations relating the Dirichlet-to-Neumann to the scattering transform and the exponentially growing solutions are not present in that work, and are derived here. The algorithm constitutes the first D-bar method for the reconstruction of conductivities and permittivities in two dimensions. Reconstructions of numerically simulated chest phantoms with discontinuities at the organ boundaries are included.

Fast absolute 3D CGO-based electrical impedance tomography on experimental tank data.

Objective.To present the first 3D CGO-based absolute EIT reconstructions from experimental tank data.Approach.CGO-based methods for absolute EIT imaging are compared to traditional TV regularized non-linear least squares reconstruction methods. Additional robustness testing is performed by considering incorrect modeling of domain shape.Main Results.The CGO-based methods are fast, and show strong robustness to incorrect domain modeling comparable to classic difference EIT imaging and fewer boundary artefacts than the TV regularized non-linear least squares reference reconstructions.Significance.This work is the first to demonstrate fully 3D CGO-based absolute EIT reconstruction on experimental data and also compares to TV-regularized absolute reconstruction. The speed (1-5 s) and quality of the reconstructions is encouraging for future work in absolute EIT.

3D ELECTRICAL IMPEDANCE TOMOGRAPHY RECONSTRUCTIONS FROM SIMULATED ELECTRODE DATA USING DIRECT INVERSION texp AND CALDERÓN METHODS.

The first numerical implementation of a t exp method in 3D using simulated electrode data is presented. Results are compared to Calderón's method as well as more common TV and smoothness regularization-based methods. The t exp method for EIT is based on tailor-made non-linear Fourier transforms involving the measured current and voltage data. Low-pass filtering in the non-linear Fourier domain is used to stabilize the reconstruction process. In 2D, t exp methods have shown great promise for providing robust real-time absolute and time-difference conductivity reconstructions but have yet to be used on practical electrode data in 3D, until now. Results are presented for simulated data for conductivity and permittivity with disjoint non-radially symmetric targets on spherical domains and noisy voltage data. The 3D t exp and Calderón methods are demonstrated to provide comparable quality to their 2D counterparts, and hold promise for real-time reconstructions due to their fast, non-optimized, computational cost.

Fenofibrate concomitantly decreases serum proprotein convertase subtilisin/kexin type 9 and very-low-density lipoprotein particle concentrations in statin-treated type 2 diabetic patients.

AIM: Diabetic dyslipidaemia, characterized by hypertriglyceridaemia as a result of elevated serum very-low-density lipoprotein (VLDL) concentrations, contributes to the increased risk of cardiovascular disease (CVD) in type 2 diabetes (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) may play a role in regulating VLDL metabolism. We investigated the effect of fenofibrate on serum PCSK9 and VLDL particle concentrations in T2DM patients already receiving statin therapy. METHODS: In a double-blind randomized crossover study, 15 statin-treated T2DM patients (63 +/- 8 years, body mass index (BMI) 29 +/- 3 kg/m(2)) were treated with fenofibrate (145 mg/day) or matching placebo for 12 weeks. Serum PCSK9 concentrations were measured by immunoassay. VLDL particle concentration and size were determined by nuclear magnetic resonance spectroscopy. RESULTS: Fenofibrate decreased serum triglycerides (-23%), VLDL-triglycerides (-51%), total cholesterol (-11%), LDL-cholesterol (-16%), apolipoprotein B-100 (-16%), apolipoprotein C-III (-20%) and PCSK9 (-13%) concentrations compared with placebo (p < 0.05). Fenofibrate also decreased serum concentrations of large (-45%), medium (-66%) and small VLDL (-67%) particles (p < 0.05), without altering VLDL particle size. Serum PCSK9 reduction correlated with decreases in total (r = 0.526, p = 0.044) and small (r = 0.629, p = 0.021) VLDL particle concentrations. CONCLUSIONS: Fenofibrate concomitantly decreased serum PCSK9 and VLDL particle concentrations in statin-treated T2DM patients. These findings support a mechanistic link between PCSK9 and VLDL metabolism, possibly through an effect of PSK9 on VLDL receptor degradation.

Search for L5 Earth Trojans with DECam.

Most of the major planets in the Solar System support populations of co-orbiting bodies, known as Trojans, at their L4 and L5 Lagrange points. In contrast, Earth has only one known co-orbiting companion. This paper presents the results from a search for Earth Trojans using the DECam instrument on the Blanco Telescope at CTIO. This search found no additional Trojans in spite of greater coverage compared to previous surveys of the L5 point. Therefore, the main result of this work is to place the most stringent constraints to date on the population of Earth Trojans. These constraints depend on assumptions regarding the underlying population properties, especially the slope of the magnitude distribution (which in turn depends on the size and albedo distributions of the objects). For standard assumptions, we calculate upper limits to a 90% confidence limit on the L5 population of N ET < 1 for magnitude H < 15.5, N ET =60-85 for H < 19.7, and N ET = 97 for H=20.4. This latter magnitude limit corresponds to Trojans ∼300 m in size for albedo 0.15. At H=19.7, these upper limits are consistent with previous L4 Earth Trojan constraints and significantly improve L5 constraints.

Comparing D-bar and common regularization-based methods for electrical impedance tomography.

OBJECTIVE: To compare D-bar difference reconstruction with regularized linear reconstruction in electrical impedance tomography. APPROACH: A standard regularized linear approach using a Laplacian penalty and the GREIT method for comparison to the D-bar difference images. Simulated data was generated using a circular phantom with small objects, as well as a 'Pac-Man' shaped conductivity target. An L-curve method was used for parameter selection in both D-bar and the regularized methods. MAIN RESULTS: We found that the D-bar method had a more position independent point spread function, was less sensitive to errors in electrode position and behaved differently with respect to additive noise than the regularized methods. SIGNIFICANCE: The results allow a novel pathway between traditional and D-bar algorithm comparison.

Beltrami-net: domain-independent deep D-bar learning for absolute imaging with electrical impedance tomography (a-EIT).

OBJECTIVE: To develop, and demonstrate the feasibility of, a novel image reconstruction method for absolute electrical impedance tomography (a-EIT) that pairs deep learning techniques with real-time robust D-bar methods and examine the influence of prior information on the reconstruction. APPROACH: A D-bar method is paired with a trained convolutional neural network (CNN) as a post-processing step. Training data is simulated for the network using no knowledge of the boundary shape by using an associated nonphysical Beltrami equation rather than simulating the traditional current and voltage data specific to a given domain. This allows the training data to be boundary shape independent. The method is tested on experimental data from two EIT systems (ACT4 and KIT4) with separate training sets of varying prior information. MAIN RESULTS: Post-processing the D-bar images with a CNN produces significant improvements in image quality measured by structural SIMilarity indices (SSIMs) as well as relative [Formula: see text] and [Formula: see text] image errors. SIGNIFICANCE: This work demonstrates that more general networks can be trained without being specific about boundary shape, a key challenge in EIT image reconstruction. The work is promising for future studies involving databases of anatomical atlases.

Robust computation in 2D absolute EIT (a-EIT) using D-bar methods with the 'exp' approximation.

OBJECTIVE: Absolute images have important applications in medical electrical impedance tomography (EIT) imaging, but the traditional minimization and statistical based computations are very sensitive to modeling errors and noise. In this paper, it is demonstrated that D-bar reconstruction methods for absolute EIT are robust to such errors. APPROACH: The effects of errors in domain shape and electrode placement on absolute images computed with 2D D-bar reconstruction algorithms are studied on experimental data. MAIN RESULTS: It is demonstrated with tank data from several EIT systems that these methods are quite robust to such modeling errors, and furthermore the artefacts arising from such modeling errors are similar to those occurring in classic time-difference EIT imaging. SIGNIFICANCE: This study is promising for clinical applications where absolute EIT images are desirable but previously thought impossible.

EIT Imaging of admittivities with a D-bar method and spatial prior: experimental results for absolute and difference imaging.

Electrical impedance tomography (EIT) is an emerging imaging modality that uses harmless electrical measurements taken on electrodes at a body's surface to recover information about the internal electrical conductivity and or permittivity. The image reconstruction task of EIT is a highly nonlinear inverse problem that is sensitive to noise and modeling errors making the image reconstruction task challenging. D-bar methods solve the nonlinear problem directly, bypassing the need for detailed and time-intensive forward models, to provide absolute (static) as well as time-difference EIT images. Coupling the D-bar methodology with the inclusion of high confidence a priori data results in a noise-robust regularized image reconstruction method. In this work, the a priori D-bar method for complex admittivities is demonstrated effective on experimental tank data for absolute imaging for the first time. Additionally, the method is adjusted for, and tested on, time-difference imaging scenarios. The ability of the method to be used for conductivity, permittivity, absolute as well as time-difference imaging provides the user with great flexibility without a high computational cost.

Cardiac findings in an individual with neurofibromatosis 1 and sudden death.

Vascular lesions in neurofibromatosis 1 (NF1) are infrequently recognised as manifestations of the disease, yet they can produce serious complications. Most individuals with NF1 vasculopathy are asymptomatic, which may contribute to underestimation of its frequency. A recent study indicates that vascular changes in individuals with NF1 contribute to mortality at younger ages. We report the sudden death of a young man with NF1. On autopsy examination there was evidence of an intramyocardial vasculopathy characteristic of the vascular pathology previously described in NF1. Other cardiac findings included non-specific cardiomyopathic changes, myocardial fibrosis, and a "floppy" mitral valve.

Fear information and social phobic beliefs in children: a prospective paradigm and preliminary results.

This paper presents a first attempt to develop a prospective paradigm to test Rachman's (Behav. Res. Ther. 15 (1977) 375) theory of fear acquisition for social fears. Following the prospective paradigm for animal fears developed by Field et al. (Behav. Res. Ther. 39 (2001) 1259) an attempt is made to adapt this paradigm to look at the effect of fear information in the development of social fears. A large group of normal children (N=135) who were at an age (10-13 years) at which social concerns are most pertinent were tested using this paradigm. They were given positive, negative or neutral information about three social situations: public speaking, eating in public, and meeting a new group of children. Children's fear beliefs were measured before and after the information was given and the information was given by a teacher, a same age peer or no information was given (a control). The results indicate that although information can change social fear beliefs it is dependent upon the type of social activity and who provides the information. The implications of these initial results for our understanding of both the role of fear information in the development of social fear beliefs, and the limitations of this current paradigm are discussed.

Selenium in the Blackfoot, Salt, and Bear river watersheds.

Nine stream sites in the Blackfoot River, Salt River, and Bear River watersheds in southeast Idaho, USA were sampled in May 2001 for water, surficial sediment, aquatic plants, aquatic invertebrates, and fish. Selenium was measured in these aquatic ecosystem components, and a hazard assessment was performed on the data. Water quality characteristics such as pH, hardness, and specific conductance were relatively uniform among the nine sites. Of the aquatic components assessed, water was the least contaminated with selenium because measured concentrations were below the national water quality criterion of 5 microg/L at eight of the nine sites. In contrast, selenium was elevated in sediment, aquatic plants, aquatic invertebrates, and fish from several sites, suggesting deposition in sediments and food web cycling through plants and invertebrates. Selenium was elevated to concentrations of concern in fish at eight sites (> 4 microg/g in whole body). A hazard assessment of selenium in the aquatic environment suggested a moderate hazard at upper Angus Creek (UAC) and Smoky Creek (SC), and high hazard at Little Blackfoot River (LiB), Blackfoot River gaging station (BGS), State Land Creek (SLC), upper (UGC) and lower Georgetown Creek (LGC), Deer Creek (DC), and Crow Creek (CC). The results of this study indicate that selenium concentrations from the phosphate mining area of southeast Idaho were sufficiently eleated in several ecosystem components to cause adverse effects to aquatic resources in southeastern Idaho.

Commotio cordis--a report of three cases.

Commotio cordis is a recognised cause of sudden death in which an apparently minor blow to the chest causes ventricular fibrillation and cardiac arrest. It is best known for causing death during games of youth baseball in the United States, but individual cases have been recorded as a result of a wide range of activities, principally sporting. The underlying biochemical and mechano-electric causes have been well documented. However, there are few reported cases where commotio cordis is implicated as the cause of death in homicide cases. We present three cases from the north-east of England where an assault caused death by this mechanism.

Hazard assessment of inorganics to three endangered fish in the Green River, Utah.

Acute toxicity tests were conducted with three life stages of Colorado squawfish (Ptychocheilus lucius), razorback sucker (Xyrauchen texanus), and bonytail (Gila elegans) in a reconstituted water quality simulating the middle part of the Green River of Utah. Tests were conducted with boron, lithium, selenate, selenite, uranium, vanadium, and zinc. The overall rank order of toxicity to all species and life stages combined from most to least toxic was vanadium = zinc > selenite > lithium = uranium > selenate > boron. There was no difference between the three species in their sensitivity to the seven inorganics based on a rank-order evaluation at the species level. Colorado squawfish were 2-5 times more sensitive to selenate and selenite at the swimup life stage than older stages, whereas razorback suckers displayed equal sensitivity among life stages. Bonytail exhibited equal sensitivity to selenite, but were five times more sensitive to selenate at the swimup life stage than the older stages. Comparison of 96-hr LC50 values with a limited number of environmental water concentrations in Ashley Creek, Utah, which receives irrigation drainwater, revealed moderate hazard ratios for boron, selenate, selenite, and zinc, low hazard ratios for uranium and vanadium, but unknown ratios for lithium. These inorganic contaminants in drainwaters may adversely affect endangered fish in the Green River.

Insights into the pathogenesis of neurofibromatosis 1 vasculopathy.

Intrinsic lesions of arterial walls are an important manifestation of neurofibromatosis 1 (NF1). Neurofibromin is expressed in blood vessel endothelial and smooth muscle cells, and NF1 vasculopathy may result from an alteration of neurofibromin function in these cells. Elucidation of the role of neurofibromin in the maintenance and repair of blood vessels may lead to novel approaches to the treatment of NF1 vasculopathy and vascular disease in general.

Hazard evaluation of inorganics, singly and in mixtures, to flannelmouth sucker Catostomus latipinnis in the San Juan River, New Mexico.

Larval flannelmouth sucker (Catostomus latipinnis) were exposed to arsenate, boron, copper, molybdenum, selenate, selenite, uranium, vanadium, and zinc singly, and to five mixtures of five to nine inorganics. The exposures were conducted in reconstituted water representative of the San Juan River near Shiprock, New Mexico. The mixtures simulated environmental ratios reported for sites along the San Juan River (San Juan River backwater, Fruitland marsh, Hogback East Drain, Mancos River, and McElmo Creek). The rank order of the individual inorganics, from most to least toxic, was: copper > zinc > vanadium > selenite > selenate > arsenate > uranium > boron > molybdenum. All five mixtures exhibited additive toxicity to flannelmouth sucker. In a limited number of tests, 44-day-old and 13-day-old larvae exhibited no difference in sensitivity to three mixtures. Copper was the major toxic component in four mixtures (San Juan backwater, Hogback East Drain, Mancos River, and McElmo Creek), whereas zinc was the major toxic component in the Fruitland marsh mixture, which did not contain copper. The Hogback East Drain was the most toxic mixture tested. Comparison of 96-h LC50 values with reported environmental water concentrations from the San Juan River revealed low hazard ratios for arsenic, boron, molybdenum, selenate, selenite, uranium, and vanadium, moderate hazard ratios for zinc and the Fruitland marsh mixture, and high hazard ratios for copper at three sites and four environmental mixtures representing a San Juan backwater, Hogback East Drain, Mancos River, and McElmo Creek. The high hazard ratios suggest that inorganic contaminants could adversely affect larval flannelmouth sucker in the San Juan River at four sites receiving elevated inorganics.

Selenium in eggs and milt of razorback Sucker (Xyrauchen texanus) in the middle Green River, Utah.

Eggs from three female and milt from five male endangered razorback suckers (Xyrauchen texanus) were collected from the Razorback Bar (about 20 km upstream of Ashley Creek) in the Green River of northeastern Utah. Eggs, but not milt, had concentrations of selenium that were above the range of selenium concentrations in control fish from laboratory studies or reference fish from field studies. The concentrations, however, were below those reported in selenium-exposed fish that had reproductive problems in laboratory studies or field investigations. Tests with three streamside spawned pairs of razorback suckers, which were sampled for eggs and milt in this study, resulted in no hatching of fertilized eggs. Concentrations of selenium in eggs and milt were significantly correlated with selenium concentrations in muscle plugs taken from the same fish, but egg and milt concentrations were not significantly different from muscle plugs. Selenium concentrations in eggs of razorback suckers in the Green River may be sufficiently elevated to cause reproductive problems that are contributing to the decline of this species in the upper Colorado River Basin.