bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques
Authors: Ayala Victor I. , Trivett Matthew T. , Barsov Eugene V. , Jain Sumiti , Piatak Michael , Trubey Charles M. , Alvord W. Gregory , Chertova Elena , Roser James D. , Smedley Jeremy , Komin Alexander , Keele Brandon F. , Ohlen Claes , Ott David E. 
Published: August 2016

ABSTRACTAIDS virus infections are rarely controlled by cell-mediated immunity, in part due to viral immune evasion and immunodeficiency resulting from CD4+T-cell infection. One likely aspect of this failure is that antiviral cellular immune responses are either absent or present at low levels during the initial establishment of infection. To test whether an extensive, timely, and effective response could reduce the establishment of infection from a high-dose inoculum, we adoptively transferred large numbers of T cells that were molecularly engineered with anti-simian immunodeficiency virus (anti-SIV) activity into rhesus macaques 3 days following an intrarectal SIV inoculation. To measurein vivoantiviral activity, we assessed the number of viruses transmitted using SIVmac239X, a molecularly tagged viral stock containing 10 genotypic variants, at a dose calculated to transmit 12 founder viruses. Single-genome sequencing of plasma virus revealed that the two animals receiving T cells expressing SIV-specific T-cell receptors (TCRs) had significantly fewer viral genotypes than the two control animals receiving non-SIV-specific T cells (means of 4.0 versus 7.5 transmitted viral genotypes;P= 0.044). Accounting for the likelihood of transmission of multiple viruses of a particular genotype, the calculated means of the total number of founder viruses transmitted were 4.5 and 14.5 in the experimental and control groups, respectively (P= 0.021). Thus, a large antiviral T-cell response timed with virus exposure can limit viral transmission. The presence of strong, preexisting T-cell responses, including those induced by vaccines, might help prevent the establishment of infection at the lower-exposure doses in humans that typically transmit only a single virus.IMPORTANCEThe establishment of AIDS virus infection in an individual is essentially a race between the spreading virus and host immune defenses. Cell-mediated immune responses induced by infection or vaccination are important contributors in limiting viral replication. However, in human immunodeficiency virus (HIV)/SIV infection, the virus usually wins the race, irreversibly crippling the immune system before an effective cellular immune response is developed and active. We found that providing an accelerated response by adoptively transferring large numbers of antiviral T cells shortly after a high-dose mucosal inoculation, while not preventing infection altogether, limited the number of individual viruses transmitted. Thus, the presence of strong, preexisting T-cell responses, including those induced by vaccines, might prevent infection in humans, where the virus exposure is considerably lower.
Heparan Sulfate Binding Promotes Accumulation of Intravitreally Delivered Adeno-associated Viral Vectors at the Retina for Enhanced Transduction but Weakly Influences Tropism
Authors: Woodard Kenton T. , Liang Katharine J. , Bennett William C. , Samulski R. Jude 
Published: August 2016

ABSTRACT

Many adeno-associated virus (AAV) serotypes efficiently transduce the retina when delivered to the subretinal space but show limited success when delivered to the vitreous due to the inner limiting membrane (ILM). Subretinal delivery of AAV serotype 2 (AAV2) and its heparan sulfate (HS)-binding-deficient capsid led to similar expression, indicating transduction of the outer retina occurred by HS-independent mechanisms. However, intravitreal delivery of HS-ablated recombinant AAV2 (rAAV2) led to a 300-fold decrease in transduction compared to AAV2. Fluorescence
in situ
hybridization of AAV transgenes was used to identify differences in retinal trafficking and revealed that HS binding was responsible for AAV2 accumulation at the ILM. This mechanism was tested on human
ex vivo
retinas and showed similar accumulation with HS-binding AAV2 capsid only. To evaluate if HS binding could be applied to other AAV serotypes to enhance their transduction, AAV1 and AAV8 were modified to bind HS with a single-amino-acid mutation and tested in mice. Both HS-binding mutants of AAV1 and AAV8 had higher intravitreal transduction than their non-HS-binding parent capsid due to increased retinal accumulation. To understand the influence that HS binding has on tropism, chimeric AAV2 capsids with dual-glycan usage were tested intravitreally in mice. Compared to HS binding alone, these chimeric capsids displayed enhanced transduction that was correlated with a change in tropism. Taken together, these data indicate that HS binding serves to sequester AAV capsids from the vitreous to the ILM but does not influence retinal tropism. The enhanced retinal transduction of HS-binding capsids provides a rational design strategy for engineering capsids for intravitreal delivery.

IMPORTANCE
Adeno-associated virus (AAV) has become the vector of choice for viral gene transfer and has shown great promise in clinical trials. The need for development of an easy, less invasive injection route for ocular gene therapy is met by intravitreal delivery, but delivery of AAV by this route results in poor transduction outcomes. The inner limiting membrane (ILM) creates a barrier separating the vitreous and the retina. Binding of AAV to heparan sulfate proteoglycan (HSPG) at the ILM may allow the virus to traverse this barrier for better retinal transduction. We show that HSPG binding is correlated with greater accumulation and penetration of AAV in the retina. We demonstrated that this accumulation is conserved across mouse and human retinas and that the addition of HSPG binding to other AAV capsids can increase the number of vectors accumulating at the ILM without dictating tropism.
High-risk glycated hemoglobin trajectories established by mid-20s: findings from a birth cohort study
Authors: Shearer Dara M , Thomson W Murray , Broadbent Jonathan M , McLean Rachael , Poulton Richie , Mann Jim 
Published: August 2016

ObjectiveTo describe the natural history of glycemia (as measured by glycated hemoglobin (HbA1c)) over 12 years using group-based trajectory modeling (GBTM), and to examine baseline predictors of trajectory.Research design and methodsHbA1c data collected at ages 26, 32 and 38 in the long-running, prospective Dunedin Multidisciplinary Health and Development Study were used to assign study members (n=893) to trajectories applying GBTM. A generalization of the model allowed the statistical linking of baseline demographic, smoking and anthropometric characteristics to group membership probability.ResultsMean HbA1c increased with age, as did prevalence of prediabetes, diabetes and dysglycemia. The greatest increase occurred between ages 26 and 32. Glycemic health status at age 26 predicted glycemic health status at age 38. 3 HbA1c trajectory groups were identified: ‘low’ (n=98, 11.0%); ‘medium’ (n=482, 54.0%); and ‘high’ (n=313, 35.0%) with mean HbA1c of 29.6, 34.1, and 38.7 mmol/mol, respectively, at age 38. High waist circumference (≥880 mm for women and ≥1020 mm for men), high waist-height ratio (≥0.50), and being a smoker at age 26 predicted membership of the least favorable trajectory over the next 12 years. High body mass index (≥30) at age 26 did not predict of trajectory.ConclusionsTrajectories of HbA1c are established relatively early in adulthood. HbA1c levels, waist circumference, waist-height ratio, and smoking status at age 26 are valid clinical predictors for future dysglycemic risk. The identification of HbA1c trajectories and their predictors introduces the possibility of an individualized approach to prevention at an earlier stage than is currently done.
Demographic and socioeconomic inequalities in the risk of emergency hospital admission for violence: cross-sectional analysis of a national database in Wales
Authors: Long Sara Jayne , Fone David , Gartner Andrea , Bellis Mark A 
Published: August 2016

ObjectivesTo investigate the risk of emergency hospital admissions for violence (EHAV) associated with demographic and socioeconomic factors in Wales between 2007/2008 and 2013/2014, and to describe the site of injury causing admission.DesignDatabase analysis of 7 years’ hospital admissions using the Patient Episode Database for Wales (PEDW).Setting and participantsWales, UK, successive annual populations ∼2.8 million aged 0–74 years.Primary outcomeThe first emergency admission for violence in each year of the study, defined by the International Classification of Diseases V.10 (ICD-10) codes for assaults (X85-X99, Y00-Y09) in any coding position.ResultsA total of 11 033 admissions for assault. The majority of admissions resulted from head injuries. The overall crude admission rate declined over the study period, from 69.9 per 100 000 to 43.2 per 100 000, with the largest decrease in the most deprived quintile of deprivation. A generalised linear count model with a negative binomial log link, adjusted for year, age group, gender, deprivation quintile and settlement type, showed the relative risk was highest in age group 18–19 years (RR=6.75, 95% CI 5.88 to 7.75) compared with the reference category aged 10–14 years. The risk decreased with age after 25 years. Risk of admission was substantially higher in males (RR=4.55, 95% CI 4.31 to 4.81), for residents of the most deprived areas of Wales (RR=3.60, 95% CI 3.32 to 3.90) compared with the least deprived, and higher in cities (RR=1.37, 95% CI 1.27 to 1.49) and towns (RR=1.32, 95% CI 1.21 to 1.45) compared with villages.ConclusionsDespite identifying a narrowing in the gap between prevalence of violence in richer and poorer communities, violence remains strongly associated with young men living in areas of socioeconomic deprivation. There is potential for a greater reduction, given that violence is mostly preventable. Recommendations for reducing inequalities in the risk of admission for violence are discussed.
OPAL: a randomised, placebo-controlled trial of opioid analgesia for the reduction of pain severity in people with acute spinal pain. Trial protocol
Authors: Lin Chung-Wei Christine , McLachlan Andrew J , Latimer Jane , Day Ric O , Billot Laurent , Koes Bart W , Maher Chris G 
Published: August 2016

IntroductionLow back pain and neck pain are extremely prevalent and are responsible for an enormous burden of disease globally. Strong analgesics, such as opioid analgesics, are recommended by clinical guidelines for people with acute low back pain or neck pain who are slow to recover and require more pain relief. Opioid analgesics are widely and increasingly used, but there are no strong efficacy data supporting the use of opioid analgesics for acute low back pain or neck pain. Concerns regarding opioid use are further heightened by the risks of adverse events, some of which can be serious (eg, dependency, misuse and overdose).Methods and analysisOPAL is a randomised, placebo-controlled, triple-blinded trial that will investigate the judicious use of an opioid analgesic in 346 participants with acute low back pain and/or neck pain who are slow to recover. Participants will be recruited from general practice and randomised to receive the opioid analgesic (controlled release oxycodone plus naloxone up to 20 mg per day) or placebo in addition to guideline-based care (eg, reassurance and advice of staying active) for up to 6 weeks. Participants will be followed-up for 3 months for effectiveness outcomes. The primary outcome will be pain severity. Secondary outcomes will include physical functioning and time to recovery. Medication-related adverse events will be assessed and a cost-effectiveness analysis will be conducted. We will additionally assess long-term use and risk of misuse of opioid analgesics for up to 12 months.Ethics and disseminationEthical approval has been obtained. Trial results will be disseminated by publications and conference presentations, and via the media.Trial registration numberACTRN12615000775516: Pre-results.
Rescue mechanical thrombectomy using a retrievable stent for thromboembolic occlusion occurring during coil embolization of ruptured intracranial aneurysms
Authors: Ahn Jun Hyong , Jun Hyo Sub , Song Joon Ho , Cho Byung Moon , Lee Ho Kook , Kim Byong-Cheol , Hyun Dong-Keun , Chang In Bok 
Published: August 2016

ObjectiveTo examine the safety and efficacy of mechanical thrombectomy using a retrievable stent for thromboembolic occlusion occurring during coil embolization of ruptured intracranial aneurysms.MethodsBetween June 2011 and June 2015, 631 consecutive patients with ruptured intracranial aneurysms underwent coil embolization at 6 hospitals. Among 53 patients who had thromboembolic complications, 15 patients harboring 15 aneurysms underwent rescue mechanical thrombectomy with a retrievable stent for the treatment of thromboembolic occlusion during the coiling of ruptured aneurysms. The patients' clinical and radiologic outcomes were retrospectively reviewed.ResultsOf the 15 aneurysms, coiling alone was used for 13 (86.7%), and stent-assisted coiling was performed for 2 (13.3%). Thromboembolic occlusion most frequently occurred distal to the aneurysm (n=10, 66.7%), followed by proximal to the aneurysm (n=3, 20%), and at the coil−parent vessel interface (n=2, 13.3%). All patients underwent mechanical thrombectomy with a retrievable stent, including 5 patients who were initially treated with an IA tirofiban infusion. Complete recanalization (Thrombolysis in Cerebral Infarction (TICI) 3) was obtained in 13 (86.7%) and partial recanalization (TICI 2b) in 2 (13.3%). Two patients who had received IA tirofiban before mechanical thrombectomy had hemorrhagic complications. At 6 months after discharge, 9 patients had a modified Rankin Scale (mRS) score of 1, 3 patients were mRS 2, 1 patient was mRS 3, 1 patient was mRS 4, and 1 patient was mRS 6.ConclusionsRescue mechanical thrombectomy using a retrievable stent can be a useful treatment for thromboembolic occlusion occurring during coil embolization of ruptured intracranial aneurysms.
Endovascular treatment of complex intracranial aneurysms using Acandis Acclino stents
Authors: Brassel Friedhelm , Grieb Dominik , Meila Dan , Schlunz-Hendann Martin , Greling Björn , Melber Katharina 
Published: August 2016

ObjectiveTo determine the safety and effectiveness of a new low-profile, laser-cut, closed-cell stent system in the treatment of complex intracranial aneurysms.MethodsA total number of 43 patients with complex intracranial aneurysms were treated using 60 Acandis Acclino stent systems (follow-up 2012–2016; mean 11 months). 36 patients presented with wide-necked intracranial aneurysms, dissecting aneurysms were seen in 7 patients. 39 patients received stent-assisted coiling. We analyzed demographic data and follow-up results.ResultsSixty stents were successfully deployed. In one paraophthalmic internal carotid artery aneurysm the stent could not be placed. Thirty-three wide necked aneurysms were treated by single or multiple stent-assisted coiling. Complete occlusion was achieved in 31 of those cases (94% Raymond−Roy occlusion classification, RROC 1). Two patients showed stable residual aneurysmal filling (RROC 3). In three wide-necked aneurysms, sole stenting was the preferred treatment. For dual stent-assisted procedures the kissing-Y stenting technique was successfully performed in 11 aneurysms. In all dissecting aneurysms constructive therapy with stenting and preservation of the affected parent artery was achieved. Additional subsequent coil embolization was intentionally planned and successfully performed in 6 of the 7 dissecting aneurysms. The overall directly procedure-related complication rate was 7%, including one death.ConclusionsEndovascular treatment of complex intracranial aneurysms using Acclino stents is a feasible and safe procedure with low complication rates. Even severe cases can be treated among others using the kissing-Y stenting technique, with good mid-term results.
Radiographic anatomy of juvenile bovine limbs
Authors: Hoey S. E. , Biedrzycki A. H. , Livesey M. J. , Drees R. 
Published: August 2016

Juvenile bovine patients who present with clinical signs of lameness are commonly evaluated using radiographic techniques both within a hospital setting and in a farm environment. The radiographic development of the juvenile bovine skeleton is currently poorly documented. In this study, the limbs of four heifer calves were sequentially radiographed to assess development of the juvenile bovine appendicular skeleton in the first 12 months of life. Images were acquired at three weeks, three months, six months, nine months and one year of age. The normal radiographic anatomy of the fore limbs and hindlimbs and the changes over the first 12 months are described. The majority of physes remain open throughout this period, with the exception of the proximal physes of the proximal and middle phalanges, the proximal radial physis, and the proximal humeral physis which close radiographically between 9 months and 12 months of age, and fusion of the fourth and central tarsal bones occurs between 9 months and 12 months of age. The results of this study may aid in differentiating normal and abnormal anatomy in the juvenile bovine limb.
Usefulness of Health Registers for detection of bleeding events in outcome studies
Authors: Skeppholm Mika , Friberg Leif 
Published: August 2016

SummaryAdministrative and claims databases are attractive for safety studies of anticoagulant and antithrombotic drugs. However, the validity of such data is often uncertain. It was our aim to assess the usefulness of the Swedish administrative health databases for detection of major bleeding events. All individuals with atrial fibrillation in Stockholm County from 2006 to 2013 (n=78,022) were identified from the Swedish Patient register. A search for bleeding diagnoses was done in the Patient register and in the Cause of Death register. The medical records of a random sample of 761 patients were studied and classified in a blinded and pre-specified way. The highest sensitivity (99.5%) and specificity (94.0%) were obtained by counting fatal bleeding events with the bleeding diagnosis recorded as first or second cause of death, and all hospitalisations without regard to the position of the diagnosis. Codes for transfusions were unreliable and did not increase accuracy. The registries identified 99.4% of intracranial bleeding events and 82.6% of gastrointestinal bleeding events correctly. All patients classified as „no bleedings” were indeed without bleeding. Overall the sensitivity was 85.5% and the specificity 95.9% for major bleeding events. In conclusion, Swedish nationwide health registries are well suited for conducting outcome studies involving identification of bleeding events. The use of a diagnostic code for bleeding, irrespective of its position as primary or secondary diagnosis, provided the best sensitivity and specificity for detection of bleeding events, as long as it was limited to contacts resulting in hospital admission.
Glycoproteomics Reveals Decorin Peptides With Anti-Myostatin Activity in Human Atrial Fibrillation
Authors: Barallobre-Barreiro Javier , Gupta Shashi K. , Zoccarato Anna , Kitazume-Taneike Rika , Fava Marika , Yin Xiaoke , Werner Tessa , Hirt Marc N. , Zampetaki Anna , Viviano Alessandro , Chong Mei , Bern Marshall , Kourliouros Antonios , Domenech Nieves , Willeit Peter , Shah Ajay M. , Jahangiri Marjan , Schaefer Liliana , Fischer Jens W. , Iozzo Renato V. , Viner Rosa , Thum Thomas , Heineke Joerg , Kichler Antoine , Otsu Kinya , Mayr Manuel 
Published: August 2016

Background:
Myocardial fibrosis is a feature of many cardiac diseases. We used proteomics to profile glycoproteins in the human cardiac extracellular matrix (ECM).

Methods:
Atrial specimens were analyzed by mass spectrometry after extraction of ECM proteins and enrichment for glycoproteins or glycopeptides.

Results:
ECM-related glycoproteins were identified in left and right atrial appendages from the same patients. Several known glycosylation sites were confirmed. In addition, putative and novel glycosylation sites were detected. On enrichment for glycoproteins, peptides of the small leucine-rich proteoglycan decorin were identified consistently in the flowthrough. Of all ECM proteins identified, decorin was found to be the most fragmented. Within its protein core, 18 different cleavage sites were identified. In contrast, less cleavage was observed for biglycan, the most closely related proteoglycan. Decorin processing differed between human ventricles and atria and was altered in disease. The C-terminus of decorin, important for the interaction with connective tissue growth factor, was detected predominantly in ventricles in comparison with atria. In contrast, atrial appendages from patients in persistent atrial fibrillation had greater levels of full-length decorin but also harbored a cleavage site that was not found in atrial appendages from patients in sinus rhythm. This cleavage site preceded the N-terminal domain of decorin that controls muscle growth by altering the binding capacity for myostatin. Myostatin expression was decreased in atrial appendages of patients with persistent atrial fibrillation and hearts of decorin null mice. A synthetic peptide corresponding to this decorin region dose-dependently inhibited the response to myostatin in cardiomyocytes and in perfused mouse hearts.

Conclusions:
This proteomics study is the first to analyze the human cardiac ECM. Novel processed forms of decorin protein core, uncovered in human atrial appendages, can regulate the local bioavailability of antihypertrophic and profibrotic growth factors.
The Impacts of Dry Dynamic Cores on Asymmetric Hurricane Intensification
Authors: Guimond Stephen R. , Reisner Jon M. , Marras Simone , Giraldo Francis X. 
Published: August 2016

Abstract
The fundamental pathways for tropical cyclone (TC) intensification are explored by considering axisymmetric and asymmetric impulsive thermal perturbations to balanced, TC-like vortices using the dynamic cores of three different nonlinear numerical models. Attempts at reproducing the results of previous work, which used the community WRF Model, revealed a discrepancy with the impacts of purely asymmetric thermal forcing. The current study finds that thermal asymmetries can have an important, largely positive role on the vortex intensification, whereas other studies find that asymmetric impacts are negligible.
Analysis of the spectral energetics of each numerical model indicates that the vortex response to asymmetric thermal perturbations is significantly damped in WRF relative to the other models. Spectral kinetic energy budgets show that this anomalous damping is primarily due to the increased removal of kinetic energy from the vertical divergence of the vertical pressure flux, which is related to the flux of inertia–gravity wave energy. The increased kinetic energy in the other two models is shown to originate around the scales of the heating and propagate upscale with time from nonlinear effects. For very large thermal amplitudes (50 K), the anomalous removal of kinetic energy due to inertia–gravity wave activity is much smaller, resulting in good agreement between models.
The results of this paper indicate that the numerical treatment of small-scale processes that project strongly onto inertia–gravity wave energy can lead to significant differences in asymmetric TC intensification. Sensitivity tests with different time integration schemes suggest that diffusion entering into the implicit solution procedure is partly responsible for the anomalous damping of energy.