bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental Transmission of the Chronic Wasting Disease Agent to Swine after Oral or Intracranial Inoculation
Authors: Moore S. Jo , West Greenlee M. Heather , Kondru Naveen , Manne Sireesha , Smith Jodi D. , Kunkle Robert A. , Kanthasamy Anumantha , Greenlee Justin J. 
Published: July 2017

ABSTRACT

Chronic wasting disease (CWD) is a naturally occurring, fatal neurodegenerative disease of cervids. The potential for swine to serve as hosts for the agent of CWD is unknown. The purpose of this study was to investigate the susceptibility of swine to the CWD agent following experimental oral or intracranial inoculation. Crossbred piglets were assigned to three groups, intracranially inoculated (
n
= 20), orally inoculated (
n
= 19), and noninoculated (
n
= 9). At approximately the age at which commercial pigs reach market weight, half of the pigs in each group were culled (“market weight” groups). The remaining pigs (“aged” groups) were allowed to incubate for up to 73 months postinoculation (mpi). Tissues collected at necropsy were examined for disease-associated prion protein (PrP
Sc
) by Western blotting (WB), antigen capture enzyme immunoassay (EIA), immunohistochemistry (IHC), and
in vitro
real-time quaking-induced conversion (RT-QuIC). Brain samples from selected pigs were also bioassayed in mice expressing porcine prion protein. Four intracranially inoculated aged pigs and one orally inoculated aged pig were positive by EIA, IHC, and/or WB. By RT-QuIC, PrP
Sc
was detected in lymphoid and/or brain tissue from one or more pigs in each inoculated group. The bioassay was positive in four out of five pigs assayed. This study demonstrates that pigs can support low-level amplification of CWD prions, although the species barrier to CWD infection is relatively high. However, detection of infectivity in orally inoculated pigs with a mouse bioassay raises the possibility that naturally exposed pigs could act as a reservoir of CWD infectivity.

IMPORTANCE
We challenged domestic swine with the chronic wasting disease agent by inoculation directly into the brain (intracranially) or by oral gavage (orally). Disease-associated prion protein (PrP
Sc
) was detected in brain and lymphoid tissues from intracranially and orally inoculated pigs as early as 8 months of age (6 months postinoculation). Only one pig developed clinical neurologic signs suggestive of prion disease. The amount of PrP
Sc
in the brains and lymphoid tissues of positive pigs was small, especially in orally inoculated pigs. Regardless, positive results obtained with orally inoculated pigs suggest that it may be possible for swine to serve as a reservoir for prion disease under natural conditions.
Structural and Functional Basis for an EBNA1 Hexameric Ring in Epstein-Barr Virus Episome Maintenance
Authors: Deakyne Julianna S. , Malecka Kimberly A. , Messick Troy E. , Lieberman Paul M. 
Published: July 2017

ABSTRACT

Epstein-Barr virus (EBV) establishes a stable latent infection that can persist for the life of the host. EBNA1 is required for the replication, maintenance, and segregation of the latent episome, but the structural features of EBNA1 that confer each of these functions are not completely understood. Here, we have solved the X-ray crystal structure of an EBNA1 DNA-binding domain (DBD) and discovered a novel hexameric ring oligomeric form. The oligomeric interface pivoted around residue T585 as a joint that links and stabilizes higher-order EBNA1 complexes. Substitution mutations around the interface destabilized higher-order complex formation and altered the cooperative DNA-binding properties of EBNA1. Mutations had both positive and negative effects on EBNA1-dependent DNA replication and episome maintenance with OriP. We found that one naturally occurring polymorphism in the oligomer interface (T585P) had greater cooperative DNA binding
in vitro
, minor defects in DNA replication, and pronounced defects in episome maintenance. The T585P mutant was compromised for binding to OriP
in vivo
as well as for assembling the origin recognition complex subunit 2 (ORC2) and trimethylated histone 3 lysine 4 (H3K4me3) at OriP. The T585P mutant was also compromised for forming stable subnuclear foci in living cells. These findings reveal a novel oligomeric structure of EBNA1 with an interface subject to naturally occurring polymorphisms that modulate EBNA1 functional properties. We propose that EBNA1 dimers can assemble into higher-order oligomeric structures important for diverse functions of EBNA1.

IMPORTANCE
Epstein-Barr virus is a human gammaherpesvirus that is causally associated with various cancers. Carcinogenic properties are linked to the ability of the virus to persist in the latent form for the lifetime of the host. EBNA1 is a sequence-specific DNA-binding protein that is consistently expressed in EBV tumors and is the only viral protein required to maintain the viral episome during latency. The structural and biochemical mechanisms by which EBNA1 allows the long-term persistence of the EBV genome are currently unclear. Here, we have solved the crystal structure of an EBNA1 hexameric ring and characterized key residues in the interface required for higher-order complex formation and long-term plasmid maintenance.
McKenzie Method of Mechanical Diagnosis and Therapy was slightly more effective than placebo for pain, but not for disability, in patients with chronic non-specific low back pain: a randomised placebo controlled trial with short and longer term follow-up
Authors: Garcia Alessandra Narciso , Costa Lucíola da Cunha Menezes , Hancock Mark J , Souza Fabrício Soares de , Gomes Geórgia Vieira Freschi de Oliveira , Almeida Matheus Oliveira de , Costa Leonardo Oliveira Pena 
Published: July 2017

BackgroundThe McKenzie Method of Mechanical Diagnosis and Therapy (MDT) is one of the exercise approaches recommended by low back pain (LBP) guidelines. We investigated the efficacy of MDT compared with placebo in patients with chronic LBP.MethodsThis was a prospectively registered, two-arm randomised placebo controlled trial, with a blinded assessor. A total of 148 patients seeking care for chronic LBP were randomly allocated to either MDT (n=74) or placebo (n=74). Patients from both groups received 10 treatment sessions over 5 weeks. Patients from both groups also received an educational booklet. Clinical outcomes were obtained at the end of treatment (5 weeks) and 3, 6 and 12 months after randomisation. Primary outcomes were pain intensity and disability at the end of treatment (5 weeks). We also conducted a subgroup analysis to identify potential treatment effect modifiers that could predict a better response to MDT treatment.ResultsThe MDT group had greater improvements in pain intensity at the end of treatment (mean difference (MD) −1.00, 95% CI −2.09 to −0.01) but not for disability (MD −0.84, 95% CI −2.62 to 0.93). We did not detect between-group differences for any secondary outcomes, nor were any treatment effect modifiers identified. Patients did not report any adverse events.ConclusionWe found a small and likely not clinically relevant difference in pain intensity favouring the MDT method immediately at the end of 5 weeks of treatment but not for disability. No other difference was found for any of the primary or secondary outcomes at any follow-up times.Trial registration numberClinicalTrials.gov (NCT02123394)
Maternal alcohol use disorder and child school attendance outcomes for non-Indigenous and Indigenous children in Western Australia: a population cohort record linkage study
Authors: Hafekost Katherine , Lawrence David , O’Leary Colleen , Bower Carol , Semmens James , Zubrick Stephen R 
Published: July 2017

ObjectivesExamine the relationship between maternal alcohol use disorder and child school attendance outcomes for non-Indigenous and Indigenous children in Western Australia.DesignPopulation cohort study.SettingRoutinely collected linked administrative health, education and child protection data.ParticipantsThose in-scope for the study were women with a birth recorded on the Western Australian Midwives Notification System (1989–2007). Women who had an alcohol-related diagnosis (International Classification of Diseases Revisions 9/10) recorded on the Hospital Morbidity, Mental Health Inpatients and Outpatients, and Drug and Alcohol Office data sets formed the exposed group. The comparison cohort was frequency-matched to the exposed cohort based on maternal age within Indigenous status and child’s year of birth.Primary outcome measureChild’s school attendance was obtained from the Department of Education (2008–2012). Poor attendance was defined as <80% attendance for non-Indigenous children and <60% attendance for Indigenous children.Results11 430 exposed children and 26 850 unexposed children had a linked attendance record. Maternal alcohol use disorder was significantly associated with increased odds of poor attendance (non-Indigenous: OR=1.61, 95% CI 1.50 to 1.74; Indigenous: OR=1.66, 95% CI 1.54 to 1.79). With adjustment for maternal and child factors, there was no significant difference between the timing of alcohol diagnosis relative to pregnancy and attendance outcomes. The population attributable fraction was higher in the Indigenous cohort than the non-Indigenous cohort (6.0% vs 1.3%).ConclusionsMaternal alcohol use disorder was associated with a significantly increased odds of poor school attendance for non-Indigenous and Indigenous children. There was no significant difference between the timing of diagnoses and odds of poor school attendance. This suggests that the effect of maternal alcohol use disorder may not be driven by the neurodevelopmental effects of alcohol exposure in utero, but may be mediated through family or social factors for which we were unable to adjust.
The effect of blinding on estimates of mortality in randomised clinical trials of intensive care interventions: protocol for a systematic review and meta-analysis
Authors: Anthon Carl Thomas , Granholm Anders , Perner Anders , Laake Jon Henrik , Møller Morten Hylander 
Published: July 2017

IntroductionEvidence exists that unblinded randomised clinical trials (RCTs) overestimate intervention effects compared with blinded RCTs. It has been suggested that this is less pronounced for objective (ie, not subject to interpretation) outcome measures, including mortality. This may not apply in the intensive care unit (ICU), as most deaths are preceded by decisions to withhold or withdraw treatments. Lack of blinding of physicians in RCTs of ICU interventions may potentially influence the decision towards a higher threshold for discontinuing treatment in patients who receive the investigational treatment and/or a lower threshold for discontinuing treatment in patients who receive the comparator (control). This may have important implications for patients, caregivers, researchers and society. Accordingly, we aim to assess whether lack of blinding affects mortality effect estimates in RCTs of ICU interventions.Methods and analysisWe will conduct a systematic review with meta-analyses and assess the effect of blinding versus no blinding on mortality effect estimates in RCTs of interventions used in adult ICU patients.We will systematically search the Cochrane Library for systematic reviews reporting mortality effect estimates of any intervention used in adult ICU patients which includes at least one RCT with ‘low risk of bias’ in the bias domains ‘blinding of participants and personnel’ and/or ‘blinding of outcome assessment’ and one RCT with ‘unclear’ or ‘high risk of bias’ in the same bias domain(s). For each intervention, we will compare summary mortality effect estimates in blinded versus unblinded trials.Ethics and disseminationThis research does not require ethical approval as we will use summary data from trials already approved by relevant ethical institutions. We will report the results in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement and submit the final paper to an international peer-reviewed journal.Trial registration numberPROSPERO, registration number: CRD42017056212.
A directly comparative two-gate case–control diagnostic accuracy study of the pure tone screen and HearCheck screener tests for identifying hearing impairment in school children
Authors: Ukoumunne Obioha C , Hyde Chris , Ozolins Mara , Zhelev Zhivko , Errington Sam , Taylor Rod S , Benton Claire , Moody Joanne , Cocking Laura , Watson Julian , Fortnum Heather 
Published: July 2017

ObjectivesThis study directly compared the accuracy of two audiometry-based tests for screening school children for hearing impairment: the currently used test, pure tone screen and a device newly applied to children, HearCheck Screener.DesignTwo-gate case–control diagnostic test accuracy study.Setting and participantsHearing impaired children (‘intended cases’) aged 4–6 years were recruited between February 2013 and August 2014 from collaborating audiology services. Children with no previously identified impairment (‘intended controls’) were recruited from Foundation and Year 1 of schools between February 2013 and June 2014 in central England. The reference standard was pure tone audiometry. Tests were administered at Nottingham Hearing Biomedical Research Unit or, for some intended cases only, in the participant’s home.Main outcome measuresSensitivity and specificity of the pure tone screen and HearCheck tests based on pure tone audiometry result as reference standard.Results315 children (630 ears) were recruited; 75 from audiology services and 240 from schools. Full test and reference standard data were obtained for 600 ears; 155 ears were classified as truly impaired and 445 as truly hearing based on the pure tone audiometry assessment. Sensitivity was estimated to be 94.2% (95% CI 89.0% to 97.0%) for pure tone screen and 89.0% (95% CI 82.9% to 93.1%) for HearCheck (difference=5.2% favouring pure tone screen; 95% CI 0.2% to 10.1%; p=0.02). Estimates for specificity were 82.2% (95% CI 77.7% to 86.0%) for pure tone screen and 86.5% (95% CI 82.5% to 89.8%) for HearCheck (difference=4.3% favouring HearCheck; 95% CI0.4% to 8.2%; p=0.02).ConclusionPure tone screen was better than HearCheck with respect to sensitivity but inferior with respect to specificity. As avoiding missed cases is arguably of greater importance for school entry screening, pure tone screen is probably preferable in this context.Study registration numberCurrent controlled trials:ISRCTN61668996.
Modern to Glacial age subglacial meltwater drainage at Law Dome, coastal East Antarctica from topography, sediments and jökulhlaup observations
Authors: Goodwin Ian D. , Roberts Jason L. , Etheridge David M. , Hellstrom John , Moy Andrew D. , Ribo Marta , Smith Andrew M. 
Published: July 2017

Abstract
Rare jökulhlaup events, also known as subglacial lake outburst flood events, have been observed at the Law Dome ice margin and provide an insight into the physical characteristics of subglacial meltwater and drainage. The subglacial topography based on data from the BEDMAP2 and ICECAP projects, together with subsurface transects of the ice margin obtained using ground-penetrating radar, reveal several lakes and lake-like depressions and the drainage pathways of two jökulhlaup events. Oxygen isotope typing of the meltwater during the most recent (2014) jökulhlaup event, combined with ice margin stratigraphy, enable the identification of ice tunnel melt pathways that exploit the 30–90° dipping basal ice layering. The presence of subglacial meltwater beneath Law Dome during the Holocene to Glacial periods is confirmed by the dendritic drainage pattern in the subglacial morphology and extensive layers of basal regelation ice and subglacial carbonate precipitate deposits found within the Løken Moraines sediments. These subglacial carbonates, including ooid layers, formed from the mixing of glacial meltwater and seawater at 72 ka BP. The combined evidence indicates that the ocean discharge of subglacial meltwater may be variable and/or is periodically blocked by basal freezing events near the ice sheet terminus.
Reproducibility of airway luminal size in asthma measured by HRCT
Authors: Brown Robert H. , Henderson Robert J. , Sugar Elizabeth A. , Holbrook Janet T. , Wise Robert A. 
Published: July 2017

Brown RH, Henderson RJ, Sugar EA, Holbrook JT, Wise RA, on behalf of the American Lung Association Airways Clinical Research Centers. Reproducibility of airway luminal size in asthma measured by HRCT. J Appl Physiol 123: 876–883, 2017. First published July 13, 2017; doi:10.1152/japplphysiol.00307.2017.—High-resolution CT (HRCT) is a well-established imaging technology used to measure lung and airway morphology in vivo. However, there is a surprising lack of studies examining HRCT reproducibility. The CPAP Trial was a multicenter, randomized, three-parallel-arm, sham-controlled 12-wk clinical trial to assess the use of a nocturnal continuous positive airway pressure (CPAP) device on airway reactivity to methacholine. The lack of a treatment effect of CPAP on clinical or HRCT measures provided an opportunity for the current analysis. We assessed the reproducibility of HRCT imaging over 12 wk. Intraclass correlation coefficients (ICCs) were calculated for individual airway segments, individual lung lobes, both lungs, and air trapping. The ICC [95% confidence interval (CI)] for airway luminal size at total lung capacity ranged from 0.95 (0.91, 0.97) to 0.47 (0.27, 0.69). The ICC (95% CI) for airway luminal size at functional residual capacity ranged from 0.91 (0.85, 0.95) to 0.32 (0.11, 0.65). The ICC measurements for airway distensibility index and wall thickness were lower, ranging from poor (0.08) to moderate (0.63) agreement. The ICC for air trapping at functional residual capacity was 0.89 (0.81, 0.94) and varied only modestly by lobe from 0.76 (0.61, 0.87) to 0.95 (0.92, 0.97). In stable well-controlled asthmatic subjects, it is possible to reproducibly image unstimulated airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability. NEW & NOTEWORTHY There is a surprising lack of studies examining the reproducibility of high-resolution CT in asthma. The current study examined reproducibility of airway measurements. In stable well-controlled asthmatic subjects, it is possible to reproducibly image airway luminal areas over time, by region, and by size at total lung capacity throughout the lungs. Therefore, any changes in luminal size on repeat CT imaging are more likely due to changes in disease state and less likely due to normal variability.
Fast voltage-sensitive dye imaging of excitatory and inhibitory synaptic transmission in the rat granular retrosplenial cortex
Authors: Nixima Ken'ichi , Okanoya Kazuo , Ichinohe Noritaka , Kurotani Tohru 
Published: July 2017

Rodent granular retrosplenial cortex (GRS) has dense connections between the anterior thalamic nuclei (ATN) and hippocampal formation. GRS superficial pyramidal neurons exhibit distinctive late spiking (LS) firing property and form patchy clusters with prominent apical dendritic bundles. The aim of this study was to investigate spatiotemporal dynamics of signal transduction in the GRS induced by ATN afferent stimulation by using fast voltage-sensitive dye imaging in rat brain slices. In coronal slices, layer 1a stimulation, which presumably activated thalamic fibers, evoked propagation of excitatory synaptic signals from layers 2–4 to layers 5–6 in a direction perpendicular to the layer axis, followed by transverse signal propagation within each layer. In the presence of ionotropic glutamate receptor antagonists, inhibitory responses were observed in superficial layers, induced by direct activation of inhibitory interneurons in layer 1. In horizontal slices, excitatory signals in deep layers propagated transversely mainly from posterior to anterior via superficial layers. Cortical inhibitory responses upon layer 1a stimulation in horizontal slices were weaker than those in the coronal slices. Observed differences between coronal and horizontal planes suggest anisotropy of the intracortical circuitry. In conclusion, ATN inputs are processed differently in coronal and horizontal planes of the GRS and then conveyed to other cortical areas. In both planes, GRS superficial layers play an important role in signal propagation, which suggests that superficial neuronal cascade is crucial in the integration of multiple information sources. NEW & NOTEWORTHY Superficial neurons in the rat granular retrosplenial cortex (GRS) show distinctive late-spiking (LS) firing property. However, little is known about spatiotemporal dynamics of signal transduction in the GRS. We demonstrated LS neuron network relaying thalamic inputs to deep layers and anisotropic distribution of inhibition between coronal and horizontal planes. Since deep layers of the GRS receive inputs from the subiculum, GRS circuits may work as an integrator of multiple sources such as sensory and memory information.
Blood Pressure and Arterial Load After Transcatheter Aortic Valve Replacement for Aortic Stenosis
Authors: Lindman Brian R. , Otto Catherine M. , Douglas Pamela S. , Hahn Rebecca T. , Elmariah Sammy , Weissman Neil J. , Stewart William J. , Ayele Girma M. , Zhang Feifan , Zajarias Alan , Maniar Hersh S. , Jilaihawi Hasan , Blackstone Eugene , Chinnakondepalli Khaja M. , Tuzcu E. Murat , Leon Martin B. , Pibarot Philippe 
Published: July 2017

Background—
After aortic valve replacement, left ventricular afterload is often characterized by the residual valve obstruction. Our objective was to determine whether higher systemic arterial afterload—as reflected in blood pressure, pulsatile and resistive load—is associated with adverse clinical outcomes after transcatheter aortic valve replacement (TAVR).

Methods and Results—

Total, pulsatile, and resistive arterial load were measured in 2141 patients with severe aortic stenosis treated with TAVR in the PARTNER I trial (Placement of Aortic Transcatheter Valve) who had systolic blood pressure (SBP) and an echocardiogram obtained 30 days after TAVR. The primary end point was 30-day to 1-year all-cause mortality. Lower SBP at 30 days after TAVR was associated with higher mortality (20.0% for SBP 100–129 mm Hg versus 12.0% for SBP 130–170 mm Hg;
P
<0.001). This association remained significant after adjustment, was consistent across subgroups, and confirmed in sensitivity analyses. In adjusted models that included SBP, higher total and pulsatile arterial load were associated with increased mortality (
P
<0.001 for all), but resistive load was not. Patients with low 30-day SBP and high pulsatile load had a 3-fold higher mortality than those with high 30-day SBP and low pulsatile load (26.1% versus 8.1%; hazard ratio, 3.62; 95% confidence interval, 2.36–5.55).

Conclusions—
Even after relief of valve obstruction in patients with aortic stenosis, there is an independent association between post-TAVR blood pressure, systemic arterial load, and mortality. Blood pressure goals in patients with a history of aortic stenosis may need to be redefined. Increased pulsatile arterial load, rather than blood pressure, may be a target for adjunctive medical therapy to improve outcomes after TAVR.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00530894