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Non-invasive prenatal testing (NIPT) for the detection of foetal aneuploidy through analysis of cell-free DNA (cfDNA) in maternal blood is offered routinely by many healthcare providers across the developed world. This testing has recently been recommended for evaluative implementation in the UK National Health Service (NHS) foetal anomaly screening pathway as a contingent screen following an increased risk of trisomy 21, 18 or 13. In preparation for delivering a national service, we have implemented cfDNA-based NIPT in our Regional Genetics Laboratory. Here, we describe our validation and verification processes and initial experiences of the technology prior to rollout of a national screening service.
Data are presented from more than 1000 patients (215 retrospective and 840 prospective) from ‘high- and low-risk pregnancies’ with outcome data following birth or confirmatory invasive prenatal sampling. NIPT was by the Illumina Verifi® test.
Our data confirm a high-fidelity service with a failure rate of ~0.24% and a high sensitivity and specificity for the detection of foetal trisomy 13, 18 and 21. Secondly, the data show that a significant proportion of patients continue their pregnancies without prenatal invasive testing or intervention after receiving a high-risk cfDNA-based result. A total of 46.5% of patients referred to date were referred for reasons other than high screen risk. Ten percent (76/840 clinical service referrals) of patients were referred with ultrasonographic finding of a foetal structural anomaly, and data analysis indicates high- and low-risk scan indications for NIPT.
NIPT can be successfully implemented into NHS regional genetics laboratories to provide high-quality services. NHS provision of NIPT in patients with high-risk screen results will allow for a reduction of invasive testing and partially improve equality of access to cfDNA-based NIPT in the pregnant population. Patients at low risk for a classic trisomy or with other clinical indications are likely to continue to access cfDNA-based NIPT as a private test.
To define optimal thromboprophylaxis strategy after stent implantation in superior or total cavopulmonary connections.
Stent thrombosis is a rare complication of intravascular stenting, with a perceived higher risk in single-ventricle patients.
All patients who underwent stent implantation within superior or total cavopulmonary connections (caval vein, innominate vein, Fontan, or branch pulmonary arteries) were included. Cohort was divided into aspirin therapy alone versus advanced anticoagulation, including warfarin, enoxaparin, heparin, or clopidogrel. Primary endpoint was in-stent or downstream thrombus, and secondary endpoints included bleeding complications.
A total of 58 patients with single-ventricle circulation underwent 72 stent implantations. Of them 14 stents (19%) were implanted post-superior cavopulmonary connection and 58 (81%) post-total cavopulmonary connection. Indications for stenting included vessel/conduit stenosis (67%), external compression (18%), and thrombotic occlusion (15%). Advanced anticoagulation was prescribed for 32 (44%) patients and aspirin for 40 (56%) patients. Median follow up was 1.1 (25th–75th percentile, 0.5–2.6) years. Echocardiograms were available in 71 patients (99%), and advanced imaging in 44 patients (61%). Thrombosis was present in two patients on advanced anticoagulation (6.3%) and none noted in patients on aspirin (p = 0.187). Both patients with in-stent thrombus underwent initial stenting due to occlusive left pulmonary artery thrombus acutely post-superior cavopulmonary connection. There were seven (22%) significant bleeding complications for advanced anticoagulation and none for aspirin (p < 0.001).
Antithrombotic strategy does not appear to affect rates of in-stent thrombus in single-ventricle circulations. Aspirin alone may be sufficient for most patients undergoing stent implantation, while pre-existing thrombus may warrant advanced anticoagulation.
Transcatheter right ventricle decompression in neonates with pulmonary atresia and intact ventricular septum is technically challenging, with risk of cardiac perforation and death. Further, despite successful right ventricle decompression, re-intervention on the pulmonary valve is common. The association between technical factors during right ventricle decompression and the risks of complications and re-intervention are not well described.
This is a multicentre retrospective study among the participating centres of the Congenital Catheterization Research Collaborative. Between 2005 and 2015, all neonates with pulmonary atresia and intact ventricular septum and attempted transcatheter right ventricle decompression were included. Technical factors evaluated included the use and characteristics of radiofrequency energy, maximal balloon-to-pulmonary valve annulus ratio, infundibular diameter, and right ventricle systolic pressure pre- and post-valvuloplasty (BPV). The primary end point was cardiac perforation or death; the secondary end point was re-intervention.
A total of 99 neonates underwent transcatheter right ventricle decompression at a median of 3 days (IQR 2–5) of age, including 63 patients by radiofrequency and 32 by wire perforation of the pulmonary valve. There were 32 complications including 10 (10.5%) cardiac perforations, of which two resulted in death. Cardiac perforation was associated with the use of radiofrequency (p=0.047), longer radiofrequency duration (3.5 versus 2.0 seconds, p=0.02), and higher maximal radiofrequency energy (7.5 versus 5.0 J, p<0.01) but not with patient weight (p=0.09), pulmonary valve diameter (p=0.23), or infundibular diameter (p=0.57). Re-intervention was performed in 36 patients and was associated with higher post-intervention right ventricle pressure (median 60 versus 50 mmHg, p=0.041) and residual valve gradient (median 15 versus 10 mmHg, p=0.046), but not with balloon-to-pulmonary valve annulus ratio, atmospheric pressure used during BPV, or the presence of a residual balloon waist during BPV. Re-intervention was not associated with any right ventricle anatomic characteristics, including pulmonary valve diameter.
Technical factors surrounding transcatheter right ventricle decompression in pulmonary atresia and intact ventricular septum influence the risk of procedural complications but not the risk of future re-intervention. Cardiac perforation is associated with the use of radiofrequency energy, as well as radiofrequency application characteristics. Re-intervention after right ventricle decompression for pulmonary atresia and intact ventricular septum is common and relates to haemodynamic measures surrounding initial BPV.
To evaluate differences in interstage growth of pulmonary arteries between use of polytetrafluoroethylene and femoral vein homograft as Sano shunt during stage-I Norwood palliation.
A retrospective review of all patients who survived to the second stage following Norwood–Sano operation at two institutions was performed. Either polytetrafluoroethylene or the valved segment of femoral vein homograft was used for construction of the Sano shunt. The size of pulmonary arteries was compared at pre-Glenn catheterisation.
A total of 48 neonates with the diagnosis of hypoplastic left heart syndrome or its variants comprised the study population. Femoral vein homograft of 5–6 mm diameter was used in 14 and polytetrafluoroethylene graft of 5 mm was used in 34 patients. The two groups were comparable in terms of preoperative demographics and age at time of pre-Glenn catheterisation (3.9±0.7 versus 3.4±0.8 months, p=0.06). Patients who received femoral vein homograft demonstrated a significantly higher pre-Glenn Nakata index [264 (130–460) versus 165 (108–234) mm2/m2, p=0.004]. The individual branch pulmonary arteries were significantly larger in the femoral vein group (right, 7.8±3.6 versus 5.0±1.2, p=0.014; left, 7.2±2.1 versus 5.6±1.9, p=0.02). There were no differences in cardiac index, Qp:Qs, ventricular end-diastolic pressure or systemic oxygen saturations.
Utilisation of a valved segment of femoral vein homograft as right ventricle to pulmonary artery conduit during Norwood–Sano operation confers better interstage growth of the pulmonary arteries. Further studies are needed to evaluate the impact of femoral vein homograft on single ventricle function.
After the Portuguese discovered the Cape Verde Islands in AD 1456 they divided its main island, Santiago, into two governing captaincies. The founding settlement in the south-west, Cidade Velha, soon became the Islands’ capital and a thriving trade centre; in contrast, that in the east, Alcatrazes, only lasted as an official seat from 1484–1516 and is held to have ‘failed’ (see Richter 2015).
Stonehenge is a site that continues to yield surprises. Excavation in 2009 added a new and unexpected feature: a smaller, dismantled stone circle on the banks of the River Avon, connected to Stonehenge itself by the Avenue. This new structure has been labelled ‘Bluestonehenge’ from the evidence that it once held a circle of bluestones that were later removed to Stonehenge. Investigation of the Avenue closer to Stonehenge revealed deep periglacial fissures within it. Their alignment on Stonehenge's solstitial axis (midwinter sunset–midsummer sunrise) raises questions about the early origins of this ritual landscape.
We describe a versatile infrared camera/spectrograph, IRIS, designed and constructed at the Anglo-Australian Observatory for use on the Anglo-Australian Telescope. A variety of optical configurations can be selected under remote control to provide several direct image scales and a few low-resolution spectroscopic formats. Two cross-dispersed transmission echelles are of novel design, as is the use of a modified Bowen-Burch system to provide a fast f/ratio in the widest-field option. The drive electronics includes a choice of readout schemes for versatility, and continuous display when the array is not taking data, to facilitate field acquisition and focusing.
The linearity of the detector has been studied in detail. Although outwardly good, slight nonlinearities prevent removal of fixed-pattern noise from the data without application of a cubic linearising function.
Specific control and data-reduction software has been written. We describe also a scanning mode developed for spectroscopic imaging.
Our knowledge of the universe comes from recording the photon and particle fluxes incident on the Earth from space. We thus require sensitive measurement across the entire energy spectrum, using large telescopes with efficient instrumentation located on superb sites. Technological advances and engineering constraints are nearing the point where we are recording as many photons arriving at a site as is possible. Major advances in the future will come from improving the quality of the site. The ultimate site is, of course, beyond the Earth’s atmosphere, such as on the Moon, but economic limitations prevent our exploiting this avenue to the degree that the scientific community desires. Here we describe an alternative, which offers many of the advantages of space for a fraction of the cost: the Antarctic Plateau.
Due to the wide bandgap and other key materials properties of 4H-SiC, SiC MOSFETs
offer performance advantages over competing Si-based power devices. For example,
SiC can more easily be used to fabricate MOSFETs with very high voltage ratings,
and with lower switching losses. Silicon carbide power MOSFET development has
progressed rapidly since the market release of Cree’s 1200V 4H-SiC
power MOSFET in 2011. This is due to continued advancements in SiC substrate
quality, epitaxial growth capabilities, and device processing. For example,
high-quality epitaxial growth of thick, low-doped SiC has enabled the
fabrication of SiC MOSFETs capable of blocking extremely high voltages (up to
15kV); while dopant control for thin highly-doped epitaxial layers has helped
enable low on-resistance 900V SiC MOSFET production. Device design and
processing improvements have resulted in lower MOSFET specific on-resistance for
each successive device generation. SiC MOSFETs have been shown to have a long
device lifetime, based on the results of accelerated lifetime testing, such as
high-temperature reverse-bias (HTRB) stress and time-dependent dielectric
The correspondences between the names in the Scylding genealogy at the beginning of Beowulf and three names in the upper reaches of the genealogy of Æthelwulf in the Anglo-Saxon Chronicle, Beaw, Sceldwa and Sceaf, frequently appear in arguments for a late dating of Beowulf. But these arguments overlook many aspects of Æthelwulf's genealogy that disrupt their case for a late dating. As H. Munro Chadwick pointed out over a century ago, the forms Sceldwa and Beaw found in the Chronicle for Scyld and Beow are not West Saxon spellings, and the -wa suffix of Sceldwa and Tætwa suggests that these forms may be archaic. Thus spelling alone indicates that these names were probably copied from an older, non-West Saxon text. Furthermore, the very presence of these names in the royal pedigree is puzzling. On one level the presence of Scyld is easy to explain: Scyld and the Scyldings were famous in heroic legend, and his inclusion in Æthelwulf's pedigree provides reflected glory for the West Saxon dynasty and implies genealogical, political and cultural connections between the West Saxons and the Danes that could be useful for Alfred and his heirs to foster. But on another level his inclusion is rather surprising: according to genealogical conventions, the presence of Scyld implies that the West Saxon royal family is a cadet branch of the Scylding dynasty, and is thus potentially subordinate to Scandinavian rulers in England claiming direct descent from Scyld.
Since the date of the Beowulf manuscript is widely agreed upon, the very question which prompts this volume (and the conference it derives from, and even the 1980 conference with its 1981 proceedings volume) must assume that the date of the poem may not be the same as the date of the manuscript. It is certain that there must have been a moment of first inscription for the poem, and that the time and place of that moment remains a central point of interest for students of the poem. In this essay, I will bring new evidence to bear on this venerable question, and my argument shall be that Beowulf is metrically conservative according to a variety of independent metrical criteria. Further, I will suggest that that conservatism is so varied and consistent as to strongly indicate that the original version of Beowulf must be placed among the very earliest of the longer narrative Old English poems that survive, probably in the eighth century.
Of course, it remains true, I believe, that the moment of inscription is only one of the moments of interest which might engage modern scholars of the poem. As I argued in Authors, Audiences, and Old English Verse, our focus on authorship (and on moments of authorship) may sometimes cause us to lose sight of what can be gained by also considering audience, and I proposed there two later audiences for Beowulf, one located at Alfred's Wessex court in the late ninth century, and another, sometime around the turn of the eleventh century, perhaps in Canterbury, represented most clearly by the author of Maldon.
As the introduction to this collection makes clear, the various forms of linguistic and metrical evidence bearing on the dating of Beowulf point to a date of composition fairly early in the Anglo-Saxon period. In his article for The Dating of Beowulf in 1980, Thomas Cable proposed a rough guide to the metrical dating of poems using the incidence of type C, D, and E verses, which decline in frequency over the Anglo-Saxon period. Cable's criterion places Beowulf toward the beginning of a relative chronology. Since then, much additional metrical and linguistic evidence has been gathered that places Beowulf in the early to mid-eighth century. R.D. Fulk's A History of Old English Meter is the most substantial work of this kind, for it examines the presence of archaic metrical features through-out the corpus of Old English poetry and finds that Beowulf is by far the most archaic poem. Since that work, other scholars have written articles on individual metrical or linguistic features of the poetic corpus, which have corroborated the conclusions that Fulk so carefully reached.
Some scholars, however, remain dubious about the reliability of this type of evidence. At this point, the force of linguistic scholarship is too formidable to be undermined by the doubts raised by E.G. Stanley, who urged that the poem should not be dated by means of sundry linguistic oddities that could well be scribal error or just a few bad lines.
From the publication of the poem's editio princeps in 1815 to the emergence of the present collection two centuries later, few topics in Anglo-Saxon studies have generated as much speculation and scholarship as the dating of Beowulf. Marshaling disparate forms of evidence and argumentation, scholars have assigned dates to Beowulf that range from the seventh to the eleventh century. Various individuals have been unpersuasively identified as the author of Beowulf and dozens of kings, clerics, and contexts have been associated with the poem's genesis. Scholarship on the dating of Beowulf is markedly uneven in quality: alongside sober and thoughtful argumentation, there has been a great deal of improbable hypothesizing about the author of the poem or the milieu in which it was composed. Awareness of the qualitative differences in the scholarly literature is tacitly registered in the relative frequency with which publications are cited, but these differences have rarely received explicit discussion. This introduction to the dating of Beowulf controversy examines the changing standards of evidence, methodology, and argumentation that have attended this topic, particularly in the past thirty years. The dating of Beowulf has not been a static or monolithic subject, but has undergone considerable change in the disputes it connotes and the practices it encompasses. In the following account, emphasis will be given to the reasons for prevailing opinions rather than to the multiplicity of opinions as such.