bluuebunny/crossref_metadata_2025 huggingface dataset:
006 Effect of apolipoprotein e ε4 allele on medial temporal lobe atrophy in ischaemic stroke patients
Authors: Khlif Mohamed Salah , Werden Emilio , Egorova Natalia , Khan Wasim , Brodtmann Amy
Published: May 2018

Introduction

Apolipoprotein E (APOE) ε4 allele is a known risk factor for the development of cognitive impairment. APOE ε4 carriers have been reported as having lower hippocampal volume in Alzheimer’s disease, mild cognitive impairment, and in healthy cohorts,1 but this is not well investigated in stroke. Here, we compared the regional volume in the medial temporal lobe in ischaemic stroke survivors, with and without the ε4 allele, three (time point 1, t1) and twelve (t2) months after stroke.

Methods

21 APOE ε4 carriers and 21 non-carriers, matched for lesion size and location and for neurological impairment as measured by NIHSS, were sampled from the CANVAS study, a longitudinal imaging study in stroke survivors.2 A mixed-effect linear model was used to analyse the effect of the ε4 allele on hippocampal, entorhinal, and para-hippocampal volumes, adjusting for age, sex, years of education, and total intracranial volume. Volumes were estimated using the longitudinal stream in FreeSurfer 5.3.

Results

The left hippocampal (pt1=0.038, pt2=0.040) and entorhinal (pt1=0.044, pt2=0.038) volumes were significantly lower in the ε4-carrier group at each time point. The right entorhinal (pt1=pt2=0.002) and para-hippocampal (pt1=0.018, pt2=0.020) volumes were also significantly lower in the ε4-carrier group, but there was no difference in the right hippocampal volume (pt1=pt2=0.055) between the two groups. The group-time interaction was significant for the left para-hippocampal cortex (p=0.019): ε4 non-carriers showed a significant volume increase (p=0.018) between t1 and t2.

Conclusion

These findings suggest that stroke survivors who carry the APOE-ε4 allele will experience greater atrophy in the medial temporal lobe in the twelve months following their stroke.

References

1. Manning EN, et al. e4 Is Associated with Disproportionate Progressive Hippocampal Atrophy in AD. PLoS ONE2014;9(5):e97608.

2. Brodtmann A, et al. Charting cognitive and volumetric trajectories after stroke: Protocol for the Cognition And Neocortical Volume After Stroke (CANVAS) study. Int J Stroke2014;9(6):824–828.
061 Ocrelizumab reduces disability progression independent of relapse activity in patients with relapsing multiple sclerosis (RMS) (ENCORE)
Authors: Kappos Ludwig , Wolinsky Jerry S , Giovannoni Gavin , Arnold Douglas L , Lublin Fred , Wang Qing , Model Fabian , Wei Wei , Garren Hideki , Manfrini Marianna , Belachew Shibeshih , Hauser Stephen
Published: May 2018

Introduction

Ocrelizumab-(OCR) showed superior efficacy vs interferon beta-1a-(IFNβ1a) in OPERA I/II trials in RMS. Confirmed disability progression-(CDP) based on composite of Expanded Disability Status Scale-(EDSS), timed 25-foot walk-(T25FW) and 9-hole peg test-(9HPT) may better characterise aspects of disability progression than EDSS alone and has improved sensitivity for assessing progression in secondary progressive MS-(SPMS).

Methods

RMS patients, including relapsing SPMS patients, in OPERA I/II-(NCT01247324/NCT01412333) received IV-OCR 600 mg (q24w) or SC-IFNβ1a 44 µg (tiw) over 96 weeks. CCDP was defined as disability progression measured by EDSS (increase ≥1.0 or 0.5 if baseline >5.5) or ≥20% T25FW increase or ≥20% 9 HPT increase, confirmed after ≥12/≥24 weeks. Definition-1 of CCDP-IRA=reference EDSS/T25FW/9HPT was re-baselined at first available assessment ≥30 days, after each relapse and no relapse should occur between baseline and initial disability progression [IDP], and within 30 days post-IDP and 30 days prior to IDP confirmation. Definition-2=period of no relapse for 30 days post-IDP confirmation. Subgroup analysis included patients at potentially higher SPMS risk based on baseline-EDSS ≥4.0 and pyramidal Kurtzke Functional Systems Score ≥2.

Results

In the pooled intention-to-treat (ITT) cohort (n=1,656), risk reduction (RR; OCR vs IFNβ1a) for 12-/24 week CCDP was 34% (30.7% vs 21.5%; p<0.001) and 31% (22.6% vs 16.1%; p=0.002). The 12-/24 week CCDP-IRA RRs for Definition-1 were 24% (25.4% vs 19.6%; p=0.010) and 22% (19.2% vs 14.9%; p=0.046); and for Definition-2, 25% (25.4% vs 19.5%; p=0.008) and 23% (19.2% vs 14.8%; p=0.039). In the subgroup at higher SPMS risk, 12-/24 week RRs for CCDP-IRA (Definition-2) were 40% (31.2% vs 19.1%; p=0.022) and 36% (26.9% vs 16.6%; p=0.064). All CCDP-IRA components in the ITT and subgroups followed similar trends.

Conclusion

Results show that considerable disability progression in RMS occurs independently of protocol-defined relapses. Ocrelizumab significantly reduced progression vs IFNβ1a in the OPERA ITT population of RMS patients and more so in the subgroup at higher SPMS risk.
064 Expert consensus on standards for multiple sclerosis care: results from a modified delphi process
Authors: Butzkueven Helmut , Hobart Jeremy , Bowen Amy , Eberhard Lucy , Pepper George , Giovannoni Gavin
Published: May 2018

Introduction

The importance of prompt intervention in multiple sclerosis (MS) was described in the widely endorsed report, Brain health: time matters in multiple sclerosis.1 The present study aimed to define standards for the timing of key steps in the care pathway.

Methods

An international group of 29 MS neurologists was recruited from regions with high MS prevalence to participate in a modified Delphi process. Across five rounds, they defined ‘core’, ‘achievable’ and ‘aspirational’ time frames (to reflect a minimum, good and high standard of MS care, respectively). A 31-member Reviewing Group of MS nurses, experts with MS and allied healthcare professionals reviewed the results and provided feedback to four Chairs.

Results

Consensus was reached (≥75% agreement; n=21) on core, achievable and aspirational time frames for events spanning the MS care pathway. Here, we will present 21 achievable standards related to referral, diagnosis, treatment decisions, monitoring and managing new symptoms. For example, the Panel agreed that most MS teams should be aiming to1 complete a diagnostic workup for MS within 4 weeks of a patient being referred to a neurologist,2 assess patient eligibility for a suitable disease-modifying therapy within 3 weeks of diagnosis,3 perform follow-up clinical evaluations every 6 months, and4 offer an annual MRI scan.

Conclusion

These standards will inform tools for clinics and people with MS and act as a potential future benchmark for established and developing MS clinics across the globe aiming to deliver the highest quality care.

Reference

. Giovannoni G, et al. Mult Scler Relat Disord2016;9(Suppl 1):S5–S48.
072 Clinical audit of stroke admissions associated with atrial fibrillation and anticoagulation rates
Authors: Khan Zainab , Gopinath Sumana , Levy Stanley
Published: May 2018

Introduction

Atrial fibrillation (AF) increases the risk of potentially fatal or disabling ischaemic stroke, and a systematic review found <70% of eligible patients with AF are using oral anticoagulants (OACs).1

Methods

Medical records of patients admitted with stroke/TIA associated with known or new diagnosis of AF from 1 st July 2016 to 30th June 2017 were reviewed. This data was to be compared to a similar audit conducted in 2009. Data collected included age, sex, history of AF, adequacy of anticoagulation (before and after admission) and vascular risk factors.

Results

49 patients (29 males, average age 76 years) were included in the study. Incidence of AF was found to be 27.9% in stroke and 8.4% among TIA admissions. Known AF occurred in 34 (82.9%) of the stroke admissions and 8 (100%) of the TIA admissions. Therefore, AF was diagnosed post-stroke in 17.1% of participants. Prior to stroke and TIA 61.9% of patients were receiving anticoagulants. Treatment prior to stroke or TIA consisted of 11 (26.2%) on DOACs, 15 (35.7%) on warfarin, 5 (11.9%) on anti-platelets, and 11 (26.2%) with no anti-thrombotics. Sub-therapeutic INRs (<2.0) upon admission were found in 60% of participants using warfarin. Among the 11 untreated patients, 1 patient was non-compliant, 1 had recent SAH, but no explanation was found for the remaining 9 participants. Anticoagulation rates improved on discharge with 40 (81.6%) patients prescribed either DOACs or warfarin.

Conclusion

Anticoagulation rates have improved since 2009 (61.9% vs 41%) in stroke/TIA admissions associated with AF. However, use of anticoagulants in this population remains inadequate. Furthermore, 60% of patients on warfarin had sub-therapeutic INRs upon admission. There is still a need for improved screening for AF, with only a slight decrease in rates of new diagnosis of AF compared to the 2009 audit (from 22% to 17.1%).

Reference

. Ogilvie IM, Newton N, Welner SA, Cowell W, Lip G. Underuse of Oral Anticoagulants in Atrial Fibrillation: A Systematic Review. The American Journal of Medicine2009;124(7):11. https://doi.org/10.1016/j.amjmed.2009.11.025
008 Revascularisation surgery for non-moyamoya symptomatic intracranial stenosis and occlusion
Authors: Stoodley Marcus , Rogers Jeffrey , Gunawardena Manuri , Morgan Michael
Published: May 2018

Introduction

Previous trials rejected a role of extracranial-to-intracranial bypass surgery for managing symptomatic atheromatous disease. However, haemodynamic insufficiency may still be a rationale for surgery, provided it can be performed with low morbidity and that patency is robust.

Methods

Consecutive patients undergoing bypass surgery for non-moyamoya symptomatic intracranial arterial stenosis and occlusion were retrospectively identified. The clinical course and surgical outcomes of the cohort were evaluated at six-weeks, six-months, and annually thereafter.

Results

Between 1992 and 2017, 112 patients underwent 127 bypasses. The angiographic abnormality was arterial occlusion in 80% and stenosis in 20%. Procedures were to prevent future stroke (76%) and stroke reversal (24%), with revascularisation using an arterial pedicle graft in 80% and venous interposition graft (VIG) in 20%. A poor outcome (bypass occlusion, new stroke, new neurological deficit, or worsening neurologic deficit) occurred in 8.9% of patients. The risk of poor outcome was significantly lower with arterial pedicle grafts (Odds ratio=0.15), bypass for prophylaxis against future stroke (Odds ratio=0.11), or anterior circulation bypass (Odds ratio=0.17). Over the first eight years following surgery there were no poor outcomes in the 66 cases exhibiting all three of these characteristics.

Conclusion

Prophylactic arterial pedicle bypass surgery for anterior circulation ischemia is associated with high graft patency and low stroke and surgical complication rates. Higher risks are associated with acute procedures, typically for posterior circulation pathology and requiring VIGs. A carefully selected subset of individuals with haemodynamic insufficiency and ischaemic symptoms are likely to benefit from cerebral revascularisation surgery.
086 The rapid efficacy of natalizumab vs fingolimod in patients with active relapsing-remitting multiple sclerosis (RRMS): results from reveal, a randomised, head-to-head study
Authors: Butzkueven Helmut , Jeffery Douglas , Arnold Douglas L , Filippi Massimo , Geurts Jeroen JG , Dong Qunming , Campbell Nolan , Licata Stephanie , Ho Pei-Ran
Published: May 2018

Introduction

REVEAL was designed as a 1 year, multicentre, randomised, rater- and sponsor-blinded, prospective study comparing natalizumab and fingolimod in patients with active RRMS. Although the study closed early (for non-safety/non-efficacy reasons), data permitted comparison of effects occurring shortly after treatment initiation. This analysis compares onset of efficacy with natalizumab and fingolimod in REVEAL.

Methods

Patients were randomised to open-label intravenous natalizumab 300 mg every 4 weeks (n=54) or oral fingolimod 0.5 mg once daily (n=54). Magnetic resonance imaging was scheduled every 4 weeks for the first 24 weeks and at weeks 36 and 52. Analyses included Kaplan-Meier and Cox regression, negative binomial regression (annualised relapse rate [ARR] and number of T1 gadolinium-enhancing [Gd+] lesions) and a negative binomial generalised estimating equation (cumulative Gd +lesions over time).

Results

As expected for a randomised study, patient characteristics and follow-up time (median 39 weeks) were generally similar between groups. Natalizumab patients were less likely than fingolimod patients to develop new Gd +lesions (for ≥1 lesion, cumulative probability 40.68% vs 57.99%; hazard ratio [HR]=1.678 [95% CI: 0.865 to 3.255]; p=0.1258; for ≥2 lesions, cumulative probability 11.54% vs 48.48%; HR=4.053 [95% CI: 1.474 to 11.144]; p=0.007). Natalizumab patients consistently had 63%–72% fewer Gd +lesions than fingolimod patients, with between-group differences apparent within 4 weeks and reaching significance by 12 weeks (p=0.030). ARR was 83% lower with natalizumab than with fingolimod (0.05 vs 0.29; p=0.023), and cumulative probability of relapse was 1.85% with natalizumab vs 22.28% with fingolimod (HR=12.184 [95% CI: 1.552 to 95.634]; p=0.017). Adverse events were consistent with known safety profiles.

Conclusion

These results suggest that natalizumab reduces disease activity more rapidly and to a greater extent than fingolimod in patients with active RRMS. Given the early study closure, available data did not permit primary endpoint evaluation, and interpretation of these results requires caution.

Study Support

Biogen.
009 The ambulance clinical triage-for acute stroke treatment (ACT-FAST) algorithmic pre-hospital triage tool for endovascular thrombectomy: ongoing paramedic validation
Authors: Zhao Henry , Pesavento Lauren , Rodrigues Edrich , Salvaris Patrick , Smith Karen , Bernard Stephen , Stephenson Michael , Parsons Mark , Yassi Nawaf , Davis Stephen M , Campbell Bruce CV
Published: May 2018

Introduction

The ambulance clinical triage-for acute stroke treatment (ACT-FAST) algorithm is a severity based 3-step paramedic triage tool for pre-hospital recognition of large vessel occlusion (LVO), designed to improve specificity and paramedic assessment reliability compared to existing triage scales. ACT-FAST sequentially assesses 1. Unilateral arm fall to stretcher <10 s; 2a. Severe language disturbance (right arm weak), or 2b. Severe gaze deviation/hemi-neglect assessed by shoulder tap (left arm weak); 3. Clinical eligibility questions. We present the results of the ongoing Ambulance Victoria paramedic validation study.

Methods

Ambulance Victoria paramedics assessed ACT-FAST in all suspected stroke patients pre-hospital in metropolitan Melbourne, Australia, and in the Royal Melbourne Hospital Emergency Department since July 2017. Algorithm results were validated against a comparator of ICA/M1 occlusion on CT-angiography with NIHSS ≥6 (Class 1 indications for endovascular thrombectomy).

Results

Data were available from n=119 assessments (ED n=68, pre-hospital n=51). Patient diagnoses were LVO n=20 (15.6%), non-LVO infarcts n=45 (38.5%), ICH n=10 (8.3%) and no stroke on imaging n=44 (37.6%). ACT-FAST showed 85% sensitivity, 88.9% specificity, 60.7% (72% excluding ICH) positive predictive value and 96.7% negative predictive value for LVO. Of 10 false-positives, 4 received thrombectomy for non-Class 1 indications (basilar/M2 occlusions/cervical dissection), 3 were ICH, and 1 was tumour. Three false-negatives were LVO with milder syndromes.

Discussion

The ongoing ACT-FAST algorithm validation study shows high accuracy for clinical recognition of LVO. The streamlined algorithmic approach with just two examination items provides a more practical option for implementation in large emergency service networks. Accurate pre-hospital recognition of LVO will allow bypass to endovascular centres and early activation of neuro-intervention services to expedite endovascular thrombectomy.
Emergent management of the suspected pelvic fracture: challenges in the obese patient
Authors: Stewart Sarah K , Khan M
Published: May 2018

Pelvic fractures, although infrequent, are a significant cause of morbidity and mortality in the trauma population. Currently, the mainstay of emergent management of a suspected pelvic fracture is placement of a pelvic binder, and their use in the prehospital setting is recommended for any individual involved in high-energy trauma. Obesity in the trauma patient has been shown to be an independent risk factor of morbidity and mortality, and the incidence of pelvic and lower extremity fractures has consistently demonstrated to be higher in the obese patient compared with an individual with a normal body habitus. This article aims to highlight the challenges associated with pelvic fracture in the obese population.
Experimental platforms to study blast injury
Authors: Nguyen Thuy-Tien , Pearce A P , Carpanen D , Sory D , Grigoriadis G , Newell N , Clasper J , Bull A , Proud W G , Masouros S D
Published: May 2018

Injuries sustained due to attacks from explosive weapons are multiple in number, complex in nature, and not well characterised. Blast may cause damage to the human body by the direct effect of overpressure, penetration by highly energised fragments, and blunt trauma by violent displacements of the body. The ability to reproduce the injuries of such insults in a well-controlled fashion is essential in order to understand fully the unique mechanism by which they occur, and design better treatment and protection strategies to alleviate the resulting poor long-term outcomes. This paper reports a range of experimental platforms that have been developed for different blast injury models, their working mechanism, and main applications. These platforms include the shock tube, split-Hopkinson bars, the gas gun, drop towers and bespoke underbody blast simulators.
Republished: A novel combined approach using a Penumbra catheter and balloon catheter for cerebral venous sinus thrombosis
Authors: Matsuda Yoshikazu , Owai Yoshihiro , Kakishita Koji , Nakao Naoyuki
Published: May 2018

Cerebral venous sinus thrombosis is sometimes fatal. We describe a case of sinus thrombosis in a 43-year-old woman presenting with generalized seizure, delirium, and a 2 week history of headache and nausea. The patient underwent mechanical thrombectomy using a novel combined approach, in which a Shouryu HR balloon catheter (Kaneka) was anchored in the right transverse sinus (TS), sigmoid sinus (SS), and superior sagittal sinus (SSS), while a Penumbra 5 MAX ACE (Penumbra) catheter was moved back and forth between the right TS, SS, and SSS. Additionally, back and forth movement of the inflated balloon with aspiration—the so-called ‘dental floss technique’—was performed. Partial recanalization was eventually obtained. Follow-up angiography on postoperative day 7 showed a dramatic improvement in venous outflow. The patient was transferred to a rehabilitation hospital on postoperative day 42. We describe our combined approach using aspiration, and Penumbra and balloon catheters, to achieve mechanical thrombectomy for sinus thrombosis.
MOST-LIKELY-PATH IN ASIAN OPTION PRICING UNDER LOCAL VOLATILITY MODELS
Authors: ARGUIN LOUIS-PIERRE , LIU NIEN-LIN , WANG TAI-HO
Published: May 2018

This paper addresses the problem of approximating the price of options on discrete and continuous arithmetic averages of the underlying, i.e. discretely and continuously monitored Asian options, in local volatility models. A “path-integral”-type expression for option prices is obtained using a Brownian bridge representation for the transition density between consecutive sampling times and a Laplace asymptotic formula. In the limit where the sampling time window approaches zero, the option price is found to be approximated by a constrained variational problem on paths in time-price space. We refer to the optimizing path as the most-likely path (MLP). An approximation for the implied normal volatility follows accordingly. The small-time asymptotics and the existence of the MLP are also rigorously recovered using large deviation theory.
A Novel Method to Improve the Multiple-Scales Solution of the Forced Nonlinear Oscillators
Authors: Du Hai-En , Er Guo-Kang , Iu Vai Pan
Published: May 2018

We propose a novel procedure to improve the solutions obtained by perturbation methods for analyzing the solutions of strongly nonlinear systems in this paper. The proposed procedure is presented and then combined with the multiple-scales method for the optimum solutions of a class of forced oscillators with strong nonlinearity. The solutions obtained from conventional multiple-scales method and the proposed method are examined by the results from numerical continuation method. The results show that the proposed method is effective for the oscillators with nonlinear restoring force as well as nonlinear inertial force even if the nonlinearities are strong. Numerical results and comparison show that the proposed method can improve the solution a lot in comparison to the solution obtained by conventional multiple-scales method.
Distinct Mechanisms of Transcription Initiation by RNA Polymerases I and II
Authors: Engel Christoph , Neyer Simon , Cramer Patrick
Published: May 2018

RNA polymerases I and II (Pol I and Pol II) are the eukaryotic enzymes that catalyze DNA-dependent synthesis of ribosomal RNA and messenger RNA, respectively. Recent work shows that the transcribing forms of both enzymes are similar and the fundamental mechanisms of RNA chain elongation are conserved. However, the mechanisms of transcription initiation and its regulation differ between Pol I and Pol II. Recent structural studies of Pol I complexes with transcription initiation factors provided insights into how the polymerase recognizes its specific promoter DNA, how it may open DNA, and how initiation may be regulated. Comparison with the well-studied Pol II initiation system reveals a distinct architecture of the initiation complex and visualizes promoter- and gene-class-specific aspects of transcription initiation. On the basis of new structural studies, we derive a model of the Pol I transcription cycle and provide a molecular movie of Pol I transcription that can be used for teaching.
Temporal Activity Path Based Character Correction in Heterogeneous Social Networks via Multimedia Sources
Authors: Long Jun , Zhu Lei , Yang Zhan , Zhang Chengyuan , Yuan Xinpan
Published: May 2018

Vast amount of multimedia data contains massive and multifarious social information which is used to construct large-scale social networks. In a complex social network, a character should be ideally denoted by one and only one vertex. However, it is pervasive that a character is denoted by two or more vertices with different names; thus it is usually considered as multiple, different characters. This problem causes incorrectness of results in network analysis and mining. The factual challenge is that character uniqueness is hard to correctly confirm due to lots of complicated factors, for example, name changing and anonymization, leading to character duplication. Early, limited research has shown that previous methods depended overly upon supplementary attribute information from databases. In this paper, we propose a novel method to merge the character vertices which refer to the same entity but are denoted with different names. With this method, we firstly build the relationship network among characters based on records of social activities participating, which are extracted from multimedia sources. Then we define temporal activity paths (TAPs) for each character over time. After that, we measure similarity of the TAPs for any two characters. If the similarity is high enough, the two vertices should be considered as the same character. Based on TAPs, we can determine whether to merge the two character vertices. Our experiments showed that this solution can accurately confirm character uniqueness in large-scale social network.
Identification of Hub Genes and Key Pathways Associated with Two Subtypes of Diffuse Large B-Cell Lymphoma Based on Gene Expression Profiling via Integrated Bioinformatics
Authors: Liu Zijian , Meng Jingshu , Li Xiaoqian , Zhu Fang , Liu Tao , Wu Gang , Zhang Liling
Published: May 2018

There is a significant difference in prognosis between the germinal center B-cell (GCB) and activated B-cell (ABC) subtypes of diffuse large B-cell lymphoma (DLBCL). However, the signaling pathways and driver genes involved in these disparate subtypes are ambiguous. This study integrated three cohort profile datasets, including 250 GCB samples and 250 ABC samples, to elucidate potential candidate hub genes and key pathways involved in these two subtypes. Differentially expressed genes (DEGs) were identified. After Gene Ontology functional enrichment analysis of the DEGs, protein-protein interaction (PPI) network and sub-PPI network analyses were conducted using the STRING database and Cytoscape software. Subsequently, the Oncomine database and the cBioportal online tool were employed to verify the alterations and differential expression of the 8 hub genes (MME, CD44, IRF4, STAT3, IL2RA, ETV6, CCND2, and CFLAR). Gene set enrichment analysis was also employed to identify the intersection of the key pathways (JAK-STAT, FOXO, and NF-κB pathways) validated in the above analyses. These hub genes and key pathways could improve our understanding of the process of tumorigenesis and the underlying molecular events and may be therapeutic targets for the precise treatment of these two subtypes with different prognoses.
Reissner Plates with Plastic Behavior: Probability of Failure
Authors: Pineda-León Ernesto , Rodríguez-Castellanos Alejandro , Tolentino Dante , Rosales-Juárez José Manuel , Felix-González Ivan , Supriyono
Published: May 2018

The current paper shows the application of the boundary element method for the analysis of plates under shear stress causing plasticity. In this case, the shear deformation of a plate is considered by means of Reissner’s theory. The probability of failure of a Reissner’s plate due to a proposed index plastic behaviorIPBis calculated taking into account the uncertainty in mechanical and geometrical properties. The problem is developed in three dimensions. The classic plasticity’s theory is applied and a formulation for initial stresses that lead to the boundary integral equations due to plasticity is also used. For the plasticity calculation, the von Misses criterion is used. To solve the nonlinear equations, an incremental method is employed. The results show a relatively small failure probability (PF) for the ranges of loads between0.6<W^<1.0. However, for values between1.0<W^<2.5, the probability of failure increases significantly. Consequently, forW^≥2.5, the plate failure is imminent. The results are compared to those that were found in the literature and the agreement is good.
Dynamic Pricing for Resource Consumption in Cloud Service
Authors: Cao Bin , Wang Kai , Xu Jinting , Hou Chenyu , Fan Jing , Que Hangning
Published: May 2018

This paper studies dynamic pricing for cloud service where different resources are consumed by different users. The traditional cloud resource pricing models can be divided into two categories: on‐demand service and reserved service. The former only takes the using time into account and is unfair for the users with long using time and little concurrency. The latter charges the same price to all the users and does not consider the resource consumption of users. Therefore, in this paper, we propose a flexible dynamic pricing model for cloud resources, which not only takes into account the occupying time and resource consumption of different users but also considers the maximal concurrency of resource consumption. As a result, on the one hand, this dynamic pricing model can help users save the cost of cloud resources. On the other hand, the profits of service providers are guaranteed. The key of the pricing model is how to efficiently calculate the maximal concurrency of resource consumption since the cost of providers is dynamically varied based on the maximal concurrency. To support this function in real time, we propose a data structure based on the classical B+ tree and the implementation for its corresponding basic operations like insertion, deletion, split, and query. Finally, the experiment results show that we can complete the dynamic pricing query on 10 million cloud resource usage records within 0.2 seconds on average.
Kinematics and Transmission Performance Analyses of a 2T2R Type 4-DOF Spatial Parallel Manipulator
Authors: An Haiyan , Li Bin , Wang Shoujun , Ge Weimin
Published: May 2018

A 2-RPU&2-SPS spatial parallel mechanism (SPM) is researched. Firstly, the number and property of degrees of freedom (DOF) of the SPM are analyzed by screw theory. There are two rotational and two translational movements (2R2T) of the mechanism that can be achieved. Secondly, the position analyses are researched. For the inverse position analysis, the explicit expression can be obtained from the independent motion parameters of the given mechanism, and the forward position problem is solved by calculating a set of nonlinear equation systems. Then we obtained the workspace of the mechanism based on the analytic formulae of the inverse displacement. Finally, by establishing the Jacobian matrix of the mechanism, the singularity of the mechanism is obtained, and the kinematics transmission performance of the mechanism is studied by using the index of the output efficiency of the limb output of the mechanism. This work will provide the theoretical basis for prototype development and application of the mechanism.
Relevance of Alternative Routes of Kynurenic Acid Production in the Brain
Authors: Ramos-Chávez L. A. , Lugo Huitrón R. , González Esquivel D. , Pineda B. , Ríos C. , Silva-Adaya D. , Sánchez-Chapul L. , Roldán-Roldán G. , Pérez de la Cruz V.
Published: May 2018

The catabolism of tryptophan has gained great importance in recent years due to the fact that the metabolites produced during this process, with neuroactive and redox properties, are involved in physiological and pathological events. One of these metabolites is kynurenic acid (KYNA), which is considered as a neuromodulator since it can interact with NMDA, nicotinic, and GPR35 receptors among others, modulating the release of neurotransmitters as glutamate, dopamine, and acetylcholine. Kynureninate production is attributed to kynurenine aminotransferases. However, in some physiological and pathological conditions, its high production cannot be explained just with kynurenine aminotransferases. This review focuses on the alternative mechanism whereby KYNA can be produced, either from D‐amino acids or by means of other enzymes as D‐amino acid oxidase or by the participation of free radicals. It is important to mention that an increase in KYNA levels in processes as brain development, aging, neurodegenerative diseases, and psychiatric disorders, which share common factors as oxidative stress, inflammation, immune response activation, and participation of gut microbiota that can also be related with the alternative routes of KYNA production, has been observed.
Treatment Patterns and Survival among Adult Patients with Advanced Soft Tissue Sarcoma: A Retrospective Medical Record Review in the United Kingdom, Spain, Germany, and France
Authors: Nagar Saurabh P. , Mytelka Daniel S. , Candrilli Sean D. , D’yachkova Yulia , Lorenzo Maria , Kasper Bernd , Lopez-Martin Jose Antonio , Kaye James A.
Published: May 2018

Objective. To describe real-world treatment patterns and outcomes for patients with advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy in the United Kingdom, Spain, Germany, and France. Methods. Physicians completed a web-based medical record abstraction for adult patients with advanced STS (other than Kaposi’s sarcoma or gastrointestinal stromal tumor) who received ≥1 line of systemic therapy. Clinical characteristics, treatments, tumor responses, and mortality data were recorded. Results. A total of 130 physicians provided data for 807 patients. Patients’ mean age at advanced STS diagnosis was 57.1 (±12.3) years; 59% were male. The most commonly identified histologic categories were leiomyosarcoma (28%), liposarcoma (13%), and rhabdomyosarcoma (11%). Overall, 57% of patients received only 1 line of therapy, 32% received 2 lines of therapy, and 11% received ≥3 lines of therapy. The most common first-line regimens were doxorubicin alone (41%), doxorubicin plus ifosfamide (19%), docetaxel plus gemcitabine (9%), paclitaxel alone (4%), and ifosfamide (4%). Median overall survival from start of treatment was estimated to be 17.6 months (95% confidence interval, 15.6–19.0 months). Conclusions. In real-world clinical practice, advanced STS is most commonly treated with older therapies in the United Kingdom, Spain, Germany, and France. New therapies that improve overall survival in advanced STS are needed.
Vibration Control of Wind Turbine Blade Based on Data Fitting and Pole Placement with Minimum‐Order Observer
Authors: Liu Tingrui , Chang Lin
Published: May 2018

Vibration control of wind turbine blade with minimum control cost is investigated. Realization of minimum control cost is based on pole placement with minimum‐order observer (PPMO). The blade analysis employs a novel compromise method between the 2D airfoil analysis method and the 3D coupled blade body analysis method based on data fitting. It not only ensures certain accuracy, but also greatly improves the speed of calculation. The Wilson method, developed on the basis of the blade momentum theory, is adopted to optimize the structural parameters of the blade, with all parameters fitted as general model Sin6 (Sum of Sine) fitting curves. Also the aerodynamic coefficients based on data obtained by Xfoil software are fitted. Pole placement technology based on minimum‐order observer is applied to control unstable vibrations of vertical bending and lateral bending with minimum control cost characterized by the energy consumption of the controller. The pole placement technology is a novel pole assignment technique based on self‐poles derived from constant stable eigenvalues, which can effectively avoid the mismatch problems caused by pole selection. The superiority of PPMO can be apparently demonstrated by comparison of linear quadratic regulator (LQR). Analytical proof of the control accuracy and feasibility analysis of the physical realization of the PPMO algorithm are also investigated by experimental platform of hardware‐in‐the‐loop simulation.
Two-Dimensional Modeling of Silicon Nanowires Radial Core-Shell Solar Cells
Authors: Zeng Qiang , Meng Na , Ma Yulong , Gu Han , Zhang Jing , Wei Qingzhu , Kuang Yawei , Yang Xifeng , Liu Yushen
Published: May 2018

Silicon nanowires radial core-shell solar cells have recently attracted significant attention as promising candidates for low cost photovoltaic application, benefit from its strong light trapping, and short radial carrier collection distances. In order to establish optics and electricity improvement, a two-dimensional model based on Shockley-Read-Hall recombination modes has been carried out for radial core-shell junction nanowires solar cell combined with guided resonance modes of light absorption. The impact of SiNWs diameter and absorption layer thickness on device electrical performance based on a fixed nanowires height and diameter-over-periodicity were investigated under illumination. The variation in quantum efficiency indicated that the performance is limited by the mismatch between light absorption and carriers’ collection length.
Multiple Liver Nodules Mimicking Metastatic Disease as Initial Presentation of Multiple Myeloma
Authors: Tiu Andrew C. , Potdar Rashmika , Arguello-Gerra Vivian , Morginstin Mark
Published: May 2018

Multiple myeloma is a malignant clonal proliferation of plasma cells in the bone marrow preceded by monoclonal gammopathy of undetermined significance. Initial presentation of multiple myeloma as extramedullary spread in soft tissues particularly in the liver is uncommon. We report a case of a 74-year-old African American female who presented with epigastric pain, hematemesis, elevated alkaline phosphatase, and gamma-glutamyl transferase. Initial impression was peptic ulcer disease; however, ultrasound and CT scan of the abdomen showed multiple liver nodules and perihepatic lymphadenopathy suggestive of metastatic disease. Biopsy of the liver nodules showed CD138 and kappa light chain-restricted positive cells consistent with extramedullary spread of multiple myeloma to the liver. The patient achieved partial response after 6 months of treatment with Velcade, cyclophosphamide, and dexamethasone (VCD). Due to severe neutropenia from cyclophosphamide, regimen was switched to Velcade, Revlimid, and dexamethasone (VRD) which resulted to very good partial response in 1 year which eventually persisted after 4 years. No controlled prospective studies have defined the standard treatment for multiple myeloma with extramedullary spread particularly to the liver. Treatment of multiple myeloma with extramedullary disease follows guidelines for multiple myeloma.
Tumorectomía Seguida de Radioterapia en el Tratamiento del Cáncer de mama Precoz
Authors: Baeza B. Ramon , Raventos E, Enrique
Published: May 2018

Sin resumen
Esofagitis por Reflujo y Significado Clínico de la Hernia Hiatal por Deslizamiento
Authors: Nervi O. Flavio
Published: May 2018

Sin resumen
Laboratorio de Parasitología.
Authors: Torres H. Marisa , Nuñez G. Rebecca , Canales R. Marilena
Published: May 2018

Sin resumen
La noción de competencia y su rol en las decisiones clínicas.
Authors: Lavados Montes Manuel , Chamorro Leighton Marcela , Cisternas Camus Daniel
Published: May 2018

Sin resumen
Etica e investigación clínica.
Authors: Valdivieso Dávila Andrés
Published: May 2018

Sin resumen
Intoxicaciones Agudas: Enfrentamiento clínico.
Authors: Paris Mancilla Enrique , Grandjean Cárdenas Tomás
Published: May 2018

Sin Resumen
Esófago de Barret
Authors: Rollan Rodriguez Antonio
Published: May 2018

Sin resumen
Retroalimentación (FeedBack): Técnica en la docencia clínica.
Authors: Moreno Bolton Rodrigo
Published: May 2018

Sin resumen
Tau Mutations Serve as a Novel Risk Factor for Cancer
Authors: Rossi Giacomina , Redaelli Veronica , Contiero Paolo , Fabiano Sabrina , Tagliabue Giovanna , Perego Paola , Benussi Luisa , Bruni Amalia C. , Filippini Graziella , Farinotti Mariangela , Giaccone Giorgio , Buiatiotis Simona , Manzoni Claudia , Ferrari Raffaele , Tagliavini Fabrizio
Published: May 2018

In addition to its well-recognized role in neurodegeneration, tau participates in maintenance of genome stability and chromosome integrity. In particular, peripheral cells from patients affected by frontotemporal lobar degeneration carrying a mutation in tau gene (genetic tauopathies), as well as cells from animal models, show chromosome numerical and structural aberrations, chromatin anomalies, and a propensity toward abnormal recombination. As genome instability is tightly linked to cancer development, we hypothesized that mutated tau may be a susceptibility factor for cancer. Here we conducted a retrospective cohort study comparing cancer incidence in families affected by genetic tauopathies to control families. In addition, we carried out a bioinformatics analysis to highlight pathways associated with the tau protein interactome. We report that the risk of developing cancer is significantly higher in families affected by genetic tauopathies, and a high proportion of tau protein interactors are involved in cellular processes particularly relevant to cancer. These findings disclose a novel role of tau as a risk factor for cancer, providing new insights in the various pathologic roles of mutated tau.

Significance: This study reveals a novel role for tau as a risk factor for cancer, providing new insights beyond its role in neurodegeneration. Cancer Res; 78(13); 3731–9. ©2018 AACR.
Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients
Authors: Sanai Nader , Li Jing , Boerner Julie , Stark Karri , Wu Jianmei , Kim Seongho , Derogatis Alanna , Mehta Shwetal , Dhruv Harshil D. , Heilbrun Lance K. , Berens Michael E. , LoRusso Patricia M.
Published: May 2018

Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood–brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma.

Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue.

Results: The AZD1775 plasma concentration–time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G2 arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study.

Conclusions: In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. Clin Cancer Res; 24(16); 3820–8. ©2018 AACR.

See related commentary by Vogelbaum, p. 3790
Ad5NULL-A20: A Tropism-Modified, αvβ6 Integrin-Selective Oncolytic Adenovirus for Epithelial Ovarian Cancer Therapies
Authors: Uusi-Kerttula Hanni , Davies James A. , Thompson Jill M. , Wongthida Phonphimon , Evgin Laura , Shim Kevin G. , Bradshaw Angela , Baker Alexander T. , Rizkallah Pierre J. , Jones Rachel , Hanna Louise , Hudson Emma , Vile Richard G. , Chester John D. , Parker Alan L.
Published: May 2018

Purpose: Virotherapies are maturing in the clinical setting. Adenoviruses (Ad) are excellent vectors for the manipulability and tolerance of transgenes. Poor tumor selectivity, off-target sequestration, and immune inactivation hamper clinical efficacy. We sought to completely redesign Ad5 into a refined, tumor-selective virotherapy targeted to αvβ6 integrin, which is expressed in a range of aggressively transformed epithelial cancers but nondetectable in healthy tissues.

Experimental Design: Ad5NULL-A20 harbors mutations in each major capsid protein to preclude uptake via all native pathways. Tumor-tropism via αvβ6 targeting was achieved by genetic insertion of A20 peptide (NAVPNLRGDLQVLAQKVART) within the fiber knob protein. The vector's selectivity in vitro and in vivo was assessed.

Results: The tropism-ablating triple mutation completely blocked all native cell entry pathways of Ad5NULL-A20 via coxsackie and adenovirus receptor (CAR), αvβ3/5 integrins, and coagulation factor 10 (FX). Ad5NULL-A20 efficiently and selectively transduced αvβ6+ cell lines and primary clinical ascites-derived EOC ex vivo, including in the presence of preexisting anti-Ad5 immunity. In vivo biodistribution of Ad5NULL-A20 following systemic delivery in non–tumor-bearing mice was significantly reduced in all off-target organs, including a remarkable 107-fold reduced genome accumulation in the liver compared with Ad5. Tumor uptake, transgene expression, and efficacy were confirmed in a peritoneal SKOV3 xenograft model of human EOC, where oncolytic Ad5NULL-A20–treated animals demonstrated significantly improved survival compared with those treated with oncolytic Ad5.

Conclusions: Oncolytic Ad5NULL-A20 virotherapies represent an excellent vector for local and systemic targeting of αvβ6-overexpressing cancers and exciting platforms for tumor-selective overexpression of therapeutic anticancer modalities, including immune checkpoint inhibitors. Clin Cancer Res; 24(17); 4215–24. ©2018 AACR.
Optical Coherence Tomography Angiography in Glaucoma: A Review
Authors: Van Melkebeke Lukas , Barbosa-Breda João , Huygens Marc , Stalmans Ingeborg
Published: May 2018

Background: Glaucoma is the leading cause of irreversible blindness worldwide. Several techniques exist for the diagnosis and follow-up of patients. Optical coherence tomography (OCT) angiography (OCTA) is a recently developed technique that provides a quantitative assessment of the microcirculation of the retina and choroid in a fast, noninvasive way. Despite it being a novel technique, several publications have already been done in the glaucoma field. However, a summary of findings is currently lacking. Aims: To perform a literature review to assess the role of OCTA in glaucoma diagnosis and follow-up. Methods: A database search was carried out using MEDLINE, Embase, and Web of Science, including all original works registered until July 23, 2017. Results: OCTA (1) has a high repeatability and reproducibility, (2) has good discriminatory power to differentiate normal eyes from glaucoma eyes, (3) is more strongly correlated with visual function than conventional OCT, (4) has good discriminatory power to differentiate early-glaucoma eyes from normal eyes (i.e., at least equal to that of OCT), (5) reaches a floor effect at a more advanced disease stage than OCT, and (6) is able to detect progression in glaucoma eyes. Conclusion: OCTA shows potential to become a part of everyday glaucoma management.
Effects of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers on All-Cause Mortality and Renal Outcomes in Patients with Diabetes and Albuminuria: a Systematic Review and Meta-Analysis
Authors: Wang Kanran , Hu Jinbo , Luo Ting , Wang Yue , Yang Shumin , Qing Hua , Cheng Qingfeng , Li Qifu
Published: May 2018

Background/Aims: Whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) could benefit patients with diabetes and albuminuria remains controversial. A systematic review and meta-analysis were conducted to answer this question by comparing ACE inhibitors or ARB with placebo among these patients. Methods: In this meta-analysis, electronic data sources (Medline, the Cochrane Collaboration, and EMBASE) were searched. Randomized controlled trials (RCTs) comparing ACE inhibitors or ARB with placebo in subjects with diabetes and albuminuria (defined as urinary albumin-to-creatinine ratio, UACR≥30mg/g Cr) were included. Outcomes parameters were all-cause mortality, end stage renal disease (ESRD), doubling of serum creatinine levels, and cardiovascular events (CV). Results: Twenty-six RCTs (including 20 for ACE inhibitors and 6 for ARB) were included, comprising 10378 participants with diabetes and albuminuria. Compared to placebo, treatment with ACE inhibitors or ARBs did not reduce all-cause mortality or CV. For renal outcomes, ARBs significantly reduced the risk of ESRD by 23% (odds ratio 0.77, 95%CI 0.65-0.92), while ACE inhibitors were not associated with a decreased risk of ESRD (0.69, 0.43-1.10). Both ACE inhibitors and ARBs reduced the risk of doubling of the serum creatinine level (0.60, 0.39-0.91 for ACE inhibitors; 0.75, 0.64-0.88 for ARBs), and subgroup analyses for patients with macroalbuminuria or microalbuminuria showed similar results. Conclusion: In patients with diabetes and albuminuria, ARBs reduced risks of ESRD and doubling of the serum creatinine level. ACE inhibitors and ARBs failed to reduce all-cause mortality and CV. Based on the renoprotective effects, ARBs may be preferred for diabetic patients with albuminuria.