Prenatal identification of trisomy 18 (Edwards syndrome)

PhDThis thesis is a critical literature review of trisomy 18 (Edwards syndrome), focused on maternal serum and ultrasound markers between 10 and 20 weeks’ gestation. Based on comprehensive meta-analyses, existing findings are clarified, new knowledge has emerged, and novel statistical modeling demonstrates clinically useful algorithms to guide screening policies. Trisomy 18 is, after Down syndrome, the autosomal aneuploidy with the highest birth prevalence, about 2.4/10,000. Only 1 in 5 live born survives to two weeks, with 1 in 20 surviving one year. Strategies for identifying trisomy 18 in early pregnancy rely on reinterpretation of markers measured as part of Down syndrome screening. Diagnosis requires collecting fetal or placental material obtained from an invasive procedure (amniocentesis or a chorionic villus sampling) and subsequent karyotyping or specific aneuploidy testing such as fluorescent in situ hybridization. The second trimester Triple Test (serum markers alpha-fetoprotein, unconjugated estriol and human chorionic gonadotropin [hCG]) has an 81% detection rate at a 0.4% false positive rate. Adding pregnancy-associated plasma protein-A (PAPP-A) is effective; the detection rate improves to 88% while false positives are reduced to 0.1%. In the first trimester Combined Test, the serum markers (free β hCG and PAPP) in combination with unbiased estimates of ultrasound marker nuchal translucency (NT) thickness, yields detection and false positive rates of 86% and 0.2%, respectively. For these tests, hCG and free β hCG measurements are essentially interchangeable. Combining existing markers from both trimesters into a Full Integrated Test (NT, PAPP-A, and the Triple Test), also yields high performance (91% detection rate at 0.2% false positive rate). Ultrasound markers, apart from NT, are not suitable for routine practice, but some could be used in specialist centers. In the future, testing of circulating cell free nucleic acids in maternal plasma may allow for a reduction in the use of invasive procedures

The Single-Photon Router

We have embedded an artificial atom, a superconducting "transmon" qubit, in an open transmission line and investigated the strong scattering of incident microwave photons ($\sim6$ GHz). When an input coherent state, with an average photon number $N\ll1$ is on resonance with the artificial atom, we observe extinction of up to 90% in the forward propagating field. We use two-tone spectroscopy to study scattering from excited states and we observe electromagnetically induced transparency (EIT). We then use EIT to make a single-photon router, where we can control to what output port an incoming signal is delivered. The maximum on-off ratio is around 90% with a rise and fall time on the order of nanoseconds, consistent with theoretical expectations. The router can easily be extended to have multiple output ports and it can be viewed as a rudimentary quantum node, an important step towards building quantum information networks.Comment: 5 pages, 3 figure

Subclinical inflammation associated with prolonged TIMP-1 upregulation and arterial stiffness after gestational diabetes mellitus : a hospital-based cohort study

Background: Gestational diabetes mellitus (GDM) has significant implications for the future health of the mother. Some clinical studies have suggested subclinical inflammation and vascular dysfunction after GDM. We aimed to study whether concentrations of high-sensitivity C-reactive protein (hsCRP), tissue inhibitor of metalloproteinase-1 (TIMP-1), matrix metalloproteinase-8 (MMP-8) and -9, as well as values of arterial stiffness differ between women with and without a history of GDM a few years after delivery. We also investigated possible effects of obesity on the results. Methods: We studied two cohorts-120 women with a history of GDM and 120 controls-on average 3.7 years after delivery. Serum concentrations of hsCRP were determined by immunonephelometric and immunoturbidimetric methods, MMP-8 by immunofluorometric assay, and MMP-9 and TIMP-1 by enzyme-linked immunosorbent assays. Pulse wave velocity (PWV) was determined using the foot-to-foot velocity method from carotid and femoral waveforms by using a SphygmoCor device. Arterial compliance was measured non-invasively by an HDI/PulseWave T CR-2000 arterial tonometer. All 240 women were also included in subgroup analyses to study the effect of obesity on the results. Multiple linear regression analyses were performed with adjustment for confounding factors. Results: PWV after pregnancy complicated by GDM was significantly higher than after normal pregnancy, 6.44 +/- 0.83 (SD) vs. 6.17 +/- 0.74 m/s (p = 0.009). Previous GDM was also one of the significant determinants of PWV in multiple linear regression analyses. On the other hand, compliance indices of both large (p = 0.092) and small (p = 0.681) arteries did not differ between the study cohorts. Serum TIMP-1 levels were significantly increased after previous GDM (p = 0.020). However, no differences were found in the serum levels of MMP-8, MMP-9 or hsCRP. In subgroup analyses, there were significantly higher concentrations of hsCRP (p = 0.015) and higher PWV (p <0.001) among obese women compared with non-obese ones. Conclusions: PWV values were significantly higher after GDM compared with normoglycemic pregnancies and were associated with prolonged TIMP-1 upregulation. Cardiovascular risk factors were more common in participants with high BMI than in those with previous GDM.Peer reviewe

Reduced Power in Fronto-Parietal Theta EEG Linked to Impaired Attention-Sampling in Adult ADHD

Attention-deficit/hyperactivity disorder (ADHD) in adults is understudied, especially regarding neural mechanisms such as oscillatory control of attention sampling. We report an electroencephalography (EEG) study of such cortical mechanisms, in ADHD-diagnosed adults during administration of Test of Variables of Attention (TOVA), a gold-standard continuous performance test for ADHD that measures the ability to sustain attention and inhibit impulsivity. We recorded 53 adults (28 female, 25 male, aged 18-60), and 18 matched healthy controls, using 128-channel EEG. We analyzed sensor-space features established as neural correlates of attention: timing-sensitivity and phase-synchrony of response activations, and event-related (de)synchronization (ERS/D) of alpha and theta frequency band activity; in frontal and parietal scalp regions. TOVA test performance significantly distinguished ADHD adults from neurotypical controls, in commission errors, response time variability (RTV) and d' (response sensitivity). The ADHD group showed significantly weaker target-locked and responselocked amplitudes, that were strongly right-lateralized at the N2 wave, and weaker phase synchrony (longer reset poststimulus). They also manifested significantly less parietal prestimulus 8-Hz theta ERS, less frontal and parietal poststimulus 4-Hz theta ERS, and more frontal and parietal prestimulus alpha ERS during correct trials. These differences may reflect excessive modulation of endogenous activity by strong entrainment to stimulus (alpha), combined with deficient modulation by neural entrainment to task (theta), which in TOVA involves monitoring stimulus spatial location (not predicted occurrence onset which is regular and task-irrelevant). Building on the hypotheses of theta coding for relational structure and rhythmic attention sampling, our results suggest that ADHD adults have impaired attention sampling in relational categorization tasks.Peer reviewe

dc SQUID Phase Qubit

This thesis examines the behavior of dc SQUID phase qubits in terms of their proposed use in a quantum computer. In a phase qubit, the two lowest energy states (n=0 and n=1) of a current-biased Josephson junction form the qubit states, with the gauge invariant phase difference across the junction being relatively well defined. In a dc SQUID phase qubit, the Josephson junction is isolated from the environment using an inductive isolation network and Josephson junction, which are connected across the phase qubit junction to form a dc SQUID. Five dc SQUID phase qubits were examined at temperatures down to 25 mK. Three of the devices had qubit junctions that were Nb/AlOx/Nb junctions with critical currents of roughly 30 microamps. The other two had Al/AlOx/Al junctions with critical currents of roughly 1.3 microamps. The device that had the best performance was an Al/AlOx/Al device with a relaxation time of 30 ns and a coherence time of 24 ns. The devices were characterized using microwave spectroscopy, Rabi oscillations, relaxation and Ramsey fringe measurements. I was also able to see coupling between two Nb/AlOx/Nb dc SQUID phase qubits and perform Rabi oscillations with them. The Nb/AlOx/Nb devices had a relaxation time and coherence time that were half that of the Al/AlOx/Al device. One of the goals of this work was to understand the nature of parasitic quantum systems (TLSs) that interact with the qubit. Coupling between a TLS and a qubit causes an avoided level crossing in the transition spectrum of the qubit. In the Al/AlOx/Al devices unintentional avoided level crossings were visible with sizes up to 240 MHz, although most visible splittings were of order ~20 MHz. The measured spectra were compared to a model of the avoided level crossing based on the TLSs coupling to the junction, through either the critical current or the voltage across the junction

Giant Cross Kerr Effect for Propagating Microwaves Induced by an Artificial Atom

We have investigated the cross Kerr phase shift of propagating microwave fields strongly coupled to an artificial atom. The artificial atom is a superconducting transmon qubit in an open transmission line. We demonstrate average phase shifts of 11 degrees per photon between two coherent microwave fields both at the single-photon level. At high control power, we observe phase shifts up to 30 degrees. Our results provide an important step towards quantum gates with propagating photons in the microwave regime.Comment: 5 pages, 4 figure

Screening for trisomies by cell-free DNA testing of maternal blood: consequences of a failed result

Objectives: First, to report the distribution of fetal fraction and the rate of failed result in trisomies 21, 18 and 13 , by comparison with pregnancies unaffected by these trisomies, secondly, examine the possible effects of maternal and fetal characteristics on the fetal fraction and thirdly, consider the options for the further management of pregnancies with failed cfDNA result. Methods: This was a cohort study of 10,698 singleton pregnancies undergoing screening for fetal trisomies 21, 18 and 13 by cfDNA testing at 10 14 weeks’ gestation There were 160 cases of trisomy 21, 50 of trisomy 18, 16 of trisomy 13 and 10,472 unaffected by these trisomies. Multivariate regression analysis was used to determine significant predictors of fetal fraction and failed result amongst maternal and fetal characteristics. Results: Fetal fraction decreased with increasing body m ass index and maternal age, was lower in women of South Asian racial origin than in Caucasians and in assisted than natural conceptions, and increased with fetal crown rump length, serum PAPP A and free hCG. The median fetal fraction was 11.0% (IQR 8.3-14.4%) in the unaffected group, 10.7% (IQR 7.8-14.3%) in trisomy 21, 8.6% (IQR 5.0-10.2%) in trisomy 18 and 7.0% (IQR 6.0-9.4%) in trisomy 13. There was a failed result from cfDNA testing after first sampling in 2.9% of the unaffected group, 1.9% of trisomy 21, 8.0% of trisomy 18 and 6.3% of trisomy 13. In the cases of failed result, 7% of women had invasive testing, mainly because of high risk from the combined test and/or presence of sonographic features suggestive of trisomies 18 and 13. All cases of trisomies were detected prenatally. Conclusions: In cases of failed cfDNA test the rate of trisomies 18 and 13, but not trisomy 21, are higher than in those with a successful test. In the management of such cases, the decision in favor of invasive testing sh ould depend on the risk of prior screening and the results of detailed ultrasound examination