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Background: SMA is a neurodegenerative disease caused by biallelic deletion/mutation of the survival motor neuron (SMN1) gene. In the phase 1 trial (NCT02122952), SMN GRT onasemnogene abeparvovec (AVXS-101) improved outcomes of 15 symptomatic SMA1 patients (3 at a lower dose [cohort 1] and 12 at the proposed therapeutic dose [cohort 2]). This report describes long-term follow-up study design and data from the phase 1 study. Methods: Patients in the phase 1 study could rollover into a long-term follow-up study (NCT03421977). The primary objective is to collect long-term safety data (serious adverse events, hospitalizations, and adverse events of special interest). Annual follow-up will occur for 15 years. Additionally, patient record transfers from local clinician(s) will be requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include physical examination to assess developmental milestones. Results: As of September 27, 2018, the oldest patients are 59.2 (cohort 1) and 52.1 (cohort 2) months old and free of permanent ventilation. Preliminary data, including survival and developmental milestones, will be presented. Conclusions: Patients treated with a one-time dose of AVXS-101 continue to gain strength, develop, and achieve new milestones, demonstrating a long-term, durable response.
Introduction: Depending on the time and day of initial Emergency Department (ED) presentation, some patients may require a return to the ED the following day for ultrasound examination. Return visits for ultrasound may be time and resource intensive for both patients and the ED. Qualitative experience suggests that a percentage of return ultrasounds could be performed at a non-ED facility. Our objective was to undertake a retrospective audit of return for ultrasound usage, patterns and outcomes at 2 academic EDs. Methods: A retrospective review of all adult patients returning to the ED for ultrasound at both LHSC ED sites in 2016 was undertaken. Each chart was independently reviewed by two emergency medicine consultants. Charts were assessed for day and time of initial presentation and return, type of ultrasound ordered, and length of ED stay on initial presentation and return visit. Opinion based questions were considered by reviewers, including urgency of diagnosis clarification required, if symptoms were still present on return, and if any medical or surgical treatment or follow up was arranged based on ultrasound results. Agreement between reviewers was assessed. Results: After eliminating charts for which the return visit was not for a scheduled ultrasound examination, 328 patient charts were reviewed. 63% of patients were female and median [IQR] age was 40 years [27-56]. Abdomen/pelvis represented 50% of the ultrasounds; renal 24%; venous Doppler 15.9%. Symptoms were still present and documented in 79% of cases. 22% of cases required a medical intervention and 9% an immediate surgical intervention. 11% of patients were admitted to hospital on their return visit. Outpatient follow-up based on US results was initiated in 29% of cases. Median [IQR] combined LOS was 479.5 minutes [358.5-621.75]. Agreement between reviewers for opinion based questions was poor (63%-96%). Conclusion: Ideally, formal ultrasound should be available on a 24 hour basis for ED patients in order to avoid return visits. A percentage of return for ultrasound examinations do not result in any significant change in treatment. Emergency departments should consider the development of pathways to avoid return visits for follow up ultrasound when possible. The low incidence of surgical treatment in those returning for US suggests that this population could be served in a non-hospital setting. Further research is required to support this conclusion.
This paper considers the timing and mechanisms of deforestation in the Western Isles of Scotland, focusing in particular on the landscape around the Calanais stone circles, one of the best preserved late Neolithic/early Bronze Age monumental landscapes in north-west Europe. We present new archaeological and palaeoenvironmental evidence from a soil and peat sequence at the site of Aird Calanais, which spans the main period of use of the Calanais circles. We then draw on a new synthesis of archaeobotanical and palynological evidence from across the Western Isles and a review of comparable data from the wider North Atlantic zone, before assessing the role of early farming communities in clearing the wooded landscapes of the region. Pollen and radiocarbon dating at the site of Aird Calanais reveal that a layer of birch branches, dating to the late Neolithic (2912–2881 cal bc), was contemporaneous with a decline in woodland at the site, as well as with the major phase of Neolithic activity at the Calanais stone circle complex. However, our synthesis of the pollen and plant macrofossil evidence from across the Western Isles suggests that the picture across these islands was altogether more complex: woodlands declined both before, as well as during, the Neolithic and deciduous woodlands remained sufficiently abundant for Neolithic fuel procurement. Finally, we consider the implications of the results for understanding the interactions between first farmers and woodlands in the wider North Atlantic region.
The controversy that has existed for many years over the nature of the continuum X-ray emission components in X-ray binaries is reviewed, in which workers have been polarized between the Eastern model with a small central Comptonizing region around the compact object and alternative models. We present measurements of the radial extent of the Comptonizing ADC in low mass X-ray binaries which rule out the Eastern model and show that, the ADC is extended (the Birmingham model). Dip ingress timing shows conclusively that the ADC radial extent varies from 7% of the accretion disc radius in faint sources, to 65% in bright sources. Remarkably, the size depends strongly on the source luminosity suggesting that the ADC is formed by irradiation of the disc by the neutron star and the hot inner disc. These results have fundamental implications for the correct description of Comptonization in X-ray binaries, and the spectral form is derived for the Comptonized emission of an extended ADC led by soft, seed photons from the underlying disc which differs substantially from that of the Eastern model. Measured ADC electron températures provide values of the Compton radius in broad agreement with measured values of the radial extent of the ADC. Finally, we show that the results are inconsistent with the non-thermal emission being produced in a jet, and so provide evidence against the recent suggestion that all LMXB have jets.
We present our models of the effect of binaries on high-resolution spectroscopic surveys. We want to determine how many binary stars will be observed, whether unresolved binaries will contaminate measurements of chemical abundances, and how we can use spectroscopic surveys to better constrain the population of binary stars in the Galaxy. Using a rapid binary-evolution algorithm that enables modelling of the most complex binary systems we generate a series of large binary populations in the Galactic disc and evaluate the results. As a first application we use our model to study the binary fraction in APOGEE giants. We find tentative evidence for a change in binary fraction with metallicity.
To evaluate the agreement between the current National Healthcare Safety Network (NHSN) definition for ventriculitis and others found in the literature among patients with an external ventricular drain (EVD)
Retrospective cohort study from January 2009 to December 2014
Neurology and neurosurgery intensive care unit of a large tertiary-care center
Patients with an EVD were included. Patients with an infection prior to EVD placement or a permanent ventricular shunt were excluded.
We reviewed the charts of patients with positive cerebrospinal fluid (CSF) cultures and/or abnormal CSF results while they had an EVD in place and applied various ventriculitis definitions.
We identified 48 patients with a total of 52 cases of ventriculitis (41 CSF culture-positive cases and 11 cases based on abnormal CSF test results) using the NHSN definition. The most common organisms causing ventriculitis were gram-positive commensals (79.2%); however, 45% showed growth of only 1 colony on 1 piece of media. Approximately 60% of the ventriculitis cases by the NHSN definition met the Honda criteria, approximately 56% met the Gozal criteria, and 23% met Citerio’s definition. Cases defined using Honda versus Gozal definitions had a moderate agreement (κ=0.528; P<.05) whereas comparisons of Honda versus Citerio definitions (κ=0.338; P<.05) and Citerio versus Gozal definitions (κ=0.384; P<.05) had only fair agreements.
The agreement between published ventriculostomy-associated infection (VAI) definitions in this cohort was moderate to fair. A VAI surveillance definition that better defines contaminants is needed for more homogenous application of surveillance definitions between institutions and better comparison of rates.
Cortisol is the primary output of the hypothalamic–pituitary–adrenal (HPA) axis and is central to the biological stress response, with wide-ranging effects on psychiatric health. Despite well-studied biological pathways of glucocorticoid function, little attention has been paid to the role of genetic variation. Conventional salivary, urinary and serum measures are strongly influenced by diurnal variation and transient reactivity. Recently developed technology can be used to measure cortisol accumulation over several months in hair, thus indexing chronic HPA function.
In a socio-economically diverse sample of 1070 twins/multiples (ages 7.80–19.47 years) from the Texas Twin Project, we estimated effects of sex, age and socio-economic status (SES) on hair concentrations of cortisol and its inactive metabolite, cortisone, along with their interactions with genetic and environmental factors. This is the first genetic study of hair neuroendocrine concentrations and the largest twin study of neuroendocrine concentrations in any tissue type.
Glucocorticoid concentrations increased with age for females, but not males. Genetic factors accounted for approximately half of the variation in cortisol and cortisone. Shared environmental effects dissipated over adolescence. Higher SES was related to shallower increases in cortisol with age. SES was unrelated to cortisone, and did not significantly moderate genetic effects on either cortisol or cortisone.
Genetic factors account for sizable proportions of glucocorticoid variation across the entire age range examined, whereas shared environmental influences are modest, and only apparent at earlier ages. Chronic glucocorticoid output appears to be more consistently related to biological sex, age and genotype than to experiential factors that cluster within nuclear families.
This article presents new values for the Scottish marine radiocarbon reservoir effect (MRE) during the Mesolithic at 4540–4240 BC (6490–6190 BP) and the Medieval period at AD 1460–1630 (490–320 BP). The results give a ΔR of –126±39 14C yr for the Mesolithic and of –130±36 14C yr for the Medieval. We recalculate previously published MRE values for the earlier Holocene in this region, at 6480–6290 BC (8430–8180 BP). Here, MRE values are slightly elevated, with a ΔR of 64±41 14C yr, possibly relating to the 8.2ka BP cold event. New values for the Mesolithic and Medieval indicate lower MRE values, broadly consistent with an existing data set of 37 mid- to late Holocene assessments for Scottish waters, indicating stable ocean conditions. We compare the intercept and probability density function (PDF) methods for assessing ΔR. The ΔR values are indistinguishable, but confidence intervals are slightly larger with the PDF method. We therefore apply this more conservative method to calculate ΔR. The MRE values presented fill important gaps in understanding Scottish marine 14C dynamics, providing confidence when calibrating material from critical periods in Scotland’s prehistory, particularly the Mesolithic, when the use of marine resources by coastal populations was high.
Timber procurement and the use of woodlands are key issues in understanding the open landscapes of the Norse and Medieval periods in the North Atlantic islands. This paper outlines evidence for the timing and mechanisms of woodland use and deforestation in an area of southern Iceland, which is tracked through the mapping and analysis of charcoal production pits. Precise dating of the use of these charcoal production pits within a Bayesian framework is demonstrated through the combination of tephrochronology, sediment accumulation rates, and multiple radiocarbon dates on the archaeological charcoal. Two phases of charcoal production and woodland exploitation have been demonstrated, the first within the first 2 centuries of settlement (cal AD 870–1050) and the second phase over 100 yr later (cal AD 1185–1295). The implications for using charcoal as a medium for 14C dating in Iceland and the wider North Atlantic are then explored. Archaeobotanical analysis of the charcoal sampled from the pits has indicated that birch roundwood was the dominant wood used, that the roundwood was stripped from larger shrubs/trees in late spring/early summer, and that certain sizes and ages of roundwood were harvested. Finally, the timing of the charcoal production is placed into the wider debate on deforestation across Iceland during the Norse and early Medieval periods.
Lake Mývatn is an interior highland lake in northern Iceland that forms a unique ecosystem of international scientific importance and is surrounded by a landscape rich in archaeological and paleoenvironmental sites. A significant freshwater reservoir effect (FRE) has been identified in carbon from the lake at some Viking (about AD 870–1000) archaeological sites in the wider region (Mývatnssveit). Previous accelerator mass spectrometry (AMS) measurements indicated this FRE was about 1500–1900 14C yr. Here, we present the results of a study using stable isotope and 14C measurements to quantify the Mývatn FRE for both the Viking and modern periods. This work has identified a temporally variable FRE that is greatly in excess of previous assessments. New, paired samples of contemporaneous bone from terrestrial herbivores and omnivores (including humans) from Viking sites demonstrate at least some omnivore diets incorporated sufficient freshwater resources to result in a herbivore-omnivore age offset of up to 400 14C yr. Modern samples of benthic detritus, aquatic plants, zooplankton, invertebrates, and freshwater fish indicate an FRE in excess of 5000 14C yr in some species. Likely geothermal mechanisms for this large FRE are discussed, along with implications for both chronological reconstruction and integrated investigation of stable and radioactive isotopes.
This paper examines 2 potential sources of the radiocarbon offset between human and terrestrial mammal (horse) bones recovered from Norse (∼AD 870–1000) pagan graves in Mývatnssveit, north Iceland. These are the marine and freshwater 14C reservoir effects that may be incorporated into human bones from dietary sources. The size of the marine 14C reservoir effect (MRE) during the Norse period was investigated by measurement of multiple paired samples (terrestrial mammal and marine mollusk shell) at 2 archaeological sites in Mývatnssveit and 1 site on the north Icelandic coast. These produced 3 new δR values for the north coast of Iceland, indicating a δR of 106 ± 10 14C yr at AD 868–985, and of 144 ± 28 14C yr at AD 1280–1400. These values are statistically comparable and give an overall weighted mean δR of 111 ± 10 14C yr.
The freshwater reservoir effect was similarly quantified using freshwater fish bones from a site in Mývatnssveit. These show an offset of between 1285 and 1830 14C yr, where the fish are depleted in 14C relative to the terrestrial mammals. This is attributed to the input of geothermally derived CO2 into the groundwater and subsequently into Lake Mývatn. We conclude the following: i) some of the Norse inhabitants of Mývatnssveit incorporated non-terrestrial resources into their diet that may be identified from the stable isotope composition of their bone collagen; ii) the MRE off the north Icelandic coast during the Norse period fits a spatial gradient of wider North Atlantic MRE values with increasing values to the northwest; and iii) it is important to consider the effect that geothermal activity could have on the 14C activity of samples influenced by groundwater at Icelandic archaeological sites.
Cygnus X-1 was in the Soft State between May and September 1996 for the first time in more than 20 years creating an opportunity to study the thermal component, its spectral evolution, time variability and its relation to the hard component during intensity variations. We will show how the luminosity of the thermal component changes in relation to its temperature and attempt to determine whether the emitting area varied during the variations.
XBT 0748-676 is a dipping LMXB source, with dips in X-ray intensity occurring at the orbital period of ~ 3.8 hrs. It is a member of the sub-group of dipping sources also including XB 1916-053 and XB 1254-690 in which the spectral evolution in dipping has previously been modelled by the “absorbed plus unabsorbed” approach, in which the dip spectra are modelled by two terms, each having the same form as used for non-dip emission, one of which is strongly absorbed but one which is not absorbed, which has a normalisation decreasing strongly in dipping. This energy-independent decrease has sometimes been taken to imply electron scattering in the absorber.
We revisit the problem of why stars become red giants. We modify the physics of a standard stellar evolution code in order to determine what does and what does not contribute to a star becoming a red giant. In particular, we have run tests to try to separate the effects of changes in the mean molecular weight and in the energy generation. The implications for why stars become red giants are discussed. We find that while a change in the mean molecular weight is necessary (but not sufficient) for a 1-M⊙ star to become a red giant, this is not the case in a star of 5 M⊙. It therefore seems that there may be more than one way to make a giant.
We present montage, a post-processing nucleosynthesis code that combines a traditional network for isotopes lighter than calcium with a rapid algorithm for calculating the s-process nucleosynthesis of the heavier isotopes. The separation of those parts of the network where only neutron-capture and beta-decay reactions are significant provides a substantial advantage in computational efficiency. We present the yields for a complete set of s-process isotopes for a 3-M⊙, Z = 0.02 stellar model, as a demonstration of the utility of the approach. Future work will include a large grid of models suitable for use in calculations of Galactic chemical evolution.
Symptoms of obsessive–compulsive disorder (OCD) have been described in
neuropsychiatric syndromes associated with streptococcal infections. It
is proposed that antibodies raised against streptococcal proteins
cross-react with neuronal proteins (antigens) in the brain, particularly
in the basal ganglia, which is a brain region implicated in OCD
To test the hypothesis that post-streptococcal autoimmunity, directed
against neuronal antigens, may contribute to the pathogenesis of OCD in
Ninety-six participants with OCD were tested for the presence of
anti-streptolysin-O titres (ASOT) and the presence of anti-basal ganglia
antibodies (ABGA) in a cross-sectional study. The ABGA were tested for
with western blots using three recombinant antigens; aldolase C, enolase
and pyruvate kinase. The findings were compared with those in a control
group of individuals with depression (n = 33) and
schizophrenia (n = 17).
Positivity for ABGA was observed in 19/96 (19.8%) participants with OCD
compared with 2/50 (4%) of controls (Fisher's exact test
P = 0.012). The majority of positive OCD sera (13/19)
had antibodies against the enolase antigen. No clinical variables were
associated with ABGA positivity. Positivity for ASOT was not associated
with ABGA positivity nor found at an increased incidence in participants
with OCD compared with controls.
These findings support the hypothesis that central nervous system
autoimmunity may have an aetiological role in some adults with OCD.
Further study is required to examine whether the antibodies concerned are
pathogenic and whether exposure to streptococcal infection in vulnerable
individuals is a risk factor for the development of OCD.