bluuebunny/crossref_metadata_2025 huggingface dataset:
A Study to Assess the Proarrhythmic Potential of Mirtazapine Using Concentration‐QTc (C‐QTc) Analysis
Authors: Gurkan Sevgi , Liu Fang , Chain Anne , Gutstein David E.
Published: July 2018

Most new chemical entities with systemic availability are required to be tested in a study specifically designed to exclude drug‐induced corrected QT interval (QTc) effects, the so‐called thorough QT/QTc study. Mirtazapine (Remeron™) is an antidepressant indicated for the treatment of episodes of major depression, which was originally approved in 1994 without a thorough QT study. To evaluate the proarrhythmic potential of mirtazapine, we performed a QT/QTc study with a novel design including implementation of an analysis of the relationship between drug concentration and the QTc interval as the primary assessment of proarrhythmic potential of mirtazapine. The least squares mean differences of the corrected QT interval between mirtazapine and placebo at the geometric mean maximum concentration of drug in blood plasma (90% confidence interval) were 2.39 milliseconds (0.70, 4.07) at the 45‐mg dose and 4.00 milliseconds (1.18, 6.83) at the 75‐mg dose level of mirtazapine. Modeling of the concentration/QTc relationship for moxifloxacin confirmed that the assay method was adequately sensitive. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45‐mg and 75‐mg doses of mirtazapine was not at a level generally considered to be clinically meaningful. This study further demonstrates that analysis of the relationship between drug concentration and the QTc interval may be a reasonable alternative to traditional TQT studies to assess risk of QT prolongation.
Platelets regulate leucocyte responses to Toll‐like receptor stimulation
Authors: Hally Kathryn E , La Flamme Anne C , Harding Scott A , Larsen Peter D
Published: July 2018

Objectives

Platelets are important regulators of vascular thrombosis and inflammation and are known to express Toll‐like receptors (TLRs). Through TLRs, platelets mediate a number of responses by interacting with leucocytes. Here, we report the extent to which platelets modulate in vitro peripheral blood mononuclear cells (PBMCs) and granulocyte responses to TLR4, TLR2/1 and TLR2/6 stimulation in healthy subjects.

Methods

Peripheral blood mononuclear cells and granulocytes from 10 healthy volunteers were cultured alone or cocultured with platelets. Cultures were left unstimulated or stimulated with 1 or 100 ng mL−1 of either LPS (TLR4 agonist), Pam3CSK4 (TLR2/1 agonist) or fibroblast‐stimulating lipopeptide (FSL)‐1 (TLR2/6 agonist). Neutrophil activation (CD66b expression), monocyte activation (HLA‐DR), granulocyte elastase production and PBMC cytokine and chemokine production were examined.

Results

Platelet coculture decreased neutrophil CD66b expression in response to LPS, Pam3CSK4 and FSL‐1, and modestly decreased monocyte HLA‐DR expression in response to low‐dose LPS. Platelets reduced granulocyte elastase secretion in response to low doses of all TLR agonists tested. In response to LPS, platelet coculture reduced IL‐6, tumor necrosis factor (TNF)‐α and MIP‐1β production, and increased IL‐10 production by PBMCs. In response to FSL‐1, platelets increased IL‐6, IL‐10 and MIP‐1β production, but reduced TNF‐α production. Platelet coculture did not alter PBMC cytokine/chemokine production in response to Pam3CSK4.

Conclusion

This study challenges the notion that platelets act solely in a pro‐inflammatory manner. Rather, platelets are complex immunomodulators that regulate leucocyte responses to TLR stimulation in a TLR agonist‐specific manner. Platelets may modulate leucocyte responses to dampen inflammation, and this platelet effect may play an important role in reducing inflammation‐mediated host damage.
Association between maternal body mass index in early pregnancy and anorexia nervosa in daughters
Authors: Razaz Neda , Cnattingius Sven
Published: July 2018

Background

The etiology of anorexia nervosa is poorly understood. Although genetic factors play a major role, maternal factors, and obstetric complications are possible environmental causes. We investigated the association between maternal overweight and obesity in early pregnancy and risk of anorexia nervosa in daughters.

Methods

A retrospective cohort study including all live singleton females born in Sweden from 1992 through 2002. Anorexia nervosa diagnosis was identified by using the nation‐wide Swedish Patient and Cause of Death Registers. Multivariable Cox hazards regression was used to estimate adjusted hazard ratios (aHRs) and 95% CIs, adjusting for confounders. Stratified Cox regressions were applied to data on siblings to adjust for unmeasured familial confounding.

Results

Among 486,688 live singleton females, 2,414 (0.50%) were diagnosed with anorexia nervosa through 2012. The aHR of anorexia nervosa decreased linearly by maternal BMI (p‐value for trend < .001). When compared with daughters of normal weight mothers (body mass index [BMI] 18.5–24.9), aHRs (95%CI) of anorexia nervosa were 0.74 (0.65–0.84) in daughters of overweight mothers (BMI 25–29.9) and 0.61 (0.47–0.78) in daughters of mothers with obesity Grade I (BMI 30–34.9). In sibling control analysis, no associations were observed between maternal BMI and aHRs of anorexia nervosa in offspring.

Conclusions

The rate of anorexia nervosa decreased with maternal overweight and obesity in a dose–response manner. However, the sibling control analysis suggests that these findings are not consistent with causals effects of maternal BMI on anorexia nervosa in offspring.
Software implementation of UI interface for realizing communication robot in community‐centric system
Authors: Yamashita Yoshihiro , Nishitani Takao , Tamura Eichi , Shimokawara Eri , Yamaguchi Toru
Published: July 2018

In this paper, we describe the implementation and evaluation of a noncontact type of propagation system, which is an essential element of the communication function of people and robots, which is indispensable for the reality of our proposed community‐centric systems. We implemented this algorithm on JavaVM, which is the most portable, realized real‐time performance and got the possibility of deploying the algorithm on robot system. In addition, in preparation for future expansion, we got the guideline of the improvement to the communication UI by bottleneck analysis.
Theoretical studies on energy degradation estimation and minimization in laminar convective flow towards the microscale
Authors: Rastogi Pallavi , Mahulikar Shripad P.
Published: July 2018

The energy degraded into heat (qdeg) in laminar microconvective flow is of fundamental interest for minimizing the irreversibilities. The change in qdeg for N—number of microtubes each of diameter (DN) is studied relative to the reference tube (N = 1) of 1 mm diameter, towards the microscale. The total mass flow rate and total heat flow rate to be removed are kept fixed through all N tubes. Results show that for given l, there exists an optimum DN ( = DN,opt) and a corresponding optimum N at which, the change in sum‐total qdeg is minimum. As l decreases, DN,opt shifts towards the microscale. General criterion for DN,opt is analytically obtained in terms of Peclet number, Brinkman number, and dimensionless microtube length. The reported study and findings are of significance for the optimum design of microchannel heat sinks.
Triple diffusive flow of nanofluid with buoyancy forces and nonlinear thermal radiation over a horizontal plate
Authors: Archana M. , Reddy M. G. , Gireesha B. J. , Prasannakumara B. C. , Shehzad S. A.
Published: July 2018

The present attempt is made to elaborate the features of triple diffusive convective flow of an incompressible nanoliquid induced by horizontal surface under buoyancy forces. The effect of nonlinear thermal radiation is taken into account. Heat flux model of radiation is formulated through Rosseland's approximation. The radiation phenomenon plays a key role in modern solar energy equipment's. The nondimensional variables are introduced to convert the dimensional mathematical expressions into dimensionless single independent variable. Numerical scheme is developed to obtain the solution of mathematical model. The importance of controlling constraints on flow quantities are characterized through plots. The quantities of engineering importance are computed and elaborated graphically. It is noticed that the presence of salts and nanoparticles enhance the thermal performance of base liquid. The liquid temperature and its relevant thickness of thermal layer improved significantly with an increment in the values of radiative parameter. The larger values of parameters of Brownian motion and thermophoretic correspond to higher temperature profiles.
Postsynthetic Covalent Modification in Covalent Organic Frameworks
Authors: Yusran Yusran , Fang Qianrong , Qiu Shilun
Published: July 2018

The modification of covalent organic frameworks (COFs) based on postsynthetic covalent linkages is discussed in this review. In this strategy, the COF is preparedas scaffold and then assembled with functional groups with preservation of structural skeleton. Recent studies indicate that a number of COFs, such as COF‐5 and 3D‐OH‐COOF, are controllable to postsynthetic modification. Furthermore, covalentmodifications including triazole, ester, amide, sulfide, o‐carbamate, ether, and oxime are suitable for postsynthetic functionalization. The rapid development of postsynthetic modification demonstrates that this approach will provide a general platform to create COFs as robust functional porous materials for wide applications.
Pharmacometabolomics Reveals Irinotecan Mechanism of Action in Cancer Patients
Authors: Bao Xun , Wu Jianmei , Kim Seongho , LoRusso Patricia , Li Jing
Published: July 2018

The purpose of this study was to identify early circulating metabolite changes implicated in the mechanism of action of irinotecan, a DNA topoisomerase I inhibitor, in cancer patients. A liquid chromatography–tandem mass spectrometry–based targeted metabolomic platform capable of measuring 254 endogenous metabolites was applied to profile circulating metabolites in plasma samples collected pre‐ and post‐irinotecan treatment from 13 cancer patients. To gain further mechanistic insights, metabolic profiling was also performed for the culture medium of human primary hepatocytes (HepatoCells) and 2 cancer cell lines on exposure to SN‐38 (an active metabolite of irinotecan). Intracellular reactive oxygen species (ROS) was detected by dihydroethidium assay. Irinotecan induced a global metabolic change in patient plasma, as represented by elevations of circulating purine/pyrimidine nucleobases, acylcarnitines, and specific amino acid metabolites. The plasma metabolic signature was well replicated in HepatoCells medium on SN‐38 exposure, whereas in cancer cell medium SN‐38 induced accumulation of pyrimidine/purine nucleosides and nucleobases while having no impact on acylcarnitines and amino acid metabolites. SN‐38 induced ROS in HepatoCells, but not in cancer cells. Distinct metabolite signatures of SN‐38 exposure in HepatoCells medium and cancer cell medium revealed different mechanisms of drug action on hepatocytes and cancer cells. Elevations in circulating purine/pyrimidine nucleobases may stem from nucleotide degradation following irinotecan‐induced DNA double‐strand breaks. Accumulations of circulating acylcarnitines and specific amino acid metabolites may reflect, at least in part, irinotecan‐induced mitochondrial dysfunction and oxidative stress in the liver. The plasma metabolic signature of irinotecan exposure provides early insights into irinotecan mechanism of action in patients.
Polymorphisms in TRAIL predict long‐term survival and extrahepatic recurrence following initial hepatectomy for hepatocellular carcinoma
Authors: Imaoka Yuki , Ohira Masahiro , Yano Takuya , Nakano Ryosuke , Tanimine Naoki , Shimizu Seiichi , Kuroda Shintaro , Tahara Hiroyuki , Kobayashi Tsuyoshi , Ohdan Hideki
Published: July 2018

Background

Liver natural killer (NK) cells are the first cells to respond to infections and malignancies, such as intraoperative tumor spill. Liver NK cells express tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL), a marker for hepatocellular carcinoma (HCC). However, the influence of TRAIL single‐nucleotide polymorphisms (SNPs) on hepatectomy patients with HCC remains unclear.

Methods

Here, we investigated TRAIL SNPs (rs1131568, rs1131579, and rs1131580) located at positions 1525, 1588, and 1595 of exon 5 of the TNFSF10 gene. A total of 104 HCC patients who underwent initial hepatectomy were analyzed. Kaplan–Meier survival analysis and Cox proportional hazard regression were conducted to evaluate the associations between TRAIL genotypes and clinical HCC outcomes.

Results

Patients harboring the homozygous AA genotype of TRAIL SNPs rs1131568 and rs1131579 and the TT genotype of the TRAIL SNP rs1131580 had lower overall survival and higher rates of extrahepatic recurrence (EHR) than patients harboring the wild type or heterozygous genotypes. Moreover, univariate and multivariate Cox regression analysis revealed that the homozygous genotypes of the target TRAIL SNPs were independent predictive factors for EHR after initial hepatectomy for HCC.

Conclusion

Our findings revealed that the homozygous genotypes of TRAIL SNPs are independent predictors of EHR in initial hepatectomy patients with HCC.
Frontline Science: RIP2 promotes house dust mite–induced allergic airway inflammation
Authors: Miller Madelyn H , Shehat Michael G , Alcedo Karel P , Spinel Lina P , Soulakova Julia , Tigno-Aranjuez Justine T
Published: July 2018

House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called “Atopic March.” It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors. NOD2 is a member of the NOD-like receptor family, which has been reported to be involved in the establishment of type 2 immunity and in blocking respiratory tolerance. NOD2 mediates its effects through its downstream effector kinase, receptor interacting protein (RIP2). It has not been shown if RIP2 is involved in the innate response to HDM and in the resulting generation of type 2 immunity. Furthermore, the role of RIP2 in modulating allergic airway inflammation has been controversial. In this study, we show that RIP2 is activated in airway epithelial cells in response to HDM and is important for the production of CCL2. Using a murine HDM asthma model, we demonstrate that lung pathology, local airway inflammation, inflammatory cytokines, HDM-specific IgG1 antibody production, and HDM-specific Th2 responses are all reduced in RIP2 knockout mice compared to WT animals. These data illustrate that RIP2 can be activated by a relevant allergic stimulus and that such activation can contribute to allergic airway inflammation. These findings also suggest that RIP2 inhibitors might have some efficacy in down-regulating the inflammatory response in type 2 dominated diseases.
Detection of Intestinal Pneumatosis Location by Following Hyperechoic Foci in the Portal Vein Along Its Branches With Real‐time Ultrasound
Authors: Hosokawa Takahiro , Takahashi Hiroaki , Tanami Yutaka , Sato Yumiko , Hosokawa Mayumi , Oguma Eiji
Published: July 2018

Portal venous gas is occasionally encountered in children with intestinal pneumatosis, identified on real‐time ultrasound imaging as hyperechoic foci with quick movement. The origin of the portal venous gas can be identified by following the hyperechoic foci along the branches of the portal vein, providing an estimate of the location of intestinal pneumatosis. This approach may be useful for predicting the patient's prognosis. Our report describes 2 cases of portal venous gas while estimating the area of intestinal pneumatosis, which were evaluated with real‐time ultrasound.
Tidal shifts in the vertical distribution of bivalve larvae: Vertical advection vs. active behavior
Authors: Weinstock Jane B. , Morello Scott L. , Conlon LeAnn M. , Xue Huijie , Yund Philip O.
Published: July 2018

Some previous studies, though not all, have reported that vertical distributions of bivalve larvae shift upward in the water column on flood tides and downward on ebb tides. When observed, such shifts have been interpreted as reflecting the vertical migration of larvae (i.e., an active behavioral process). This interpretation assumes that tidally driven vertical advection is insignificant compared to larval swimming speeds, but that assumption may not be valid in all regions. We demonstrated that the vertical distribution of mussel (Mytilus edulis) larvae shifted upward on flood tides on all surveyed dates at sites in the eastern Gulf of Maine. We then used a high‐resolution coastal circulation model to predict the vertical distribution of passive particles at one site on four sample dates. The modeled distribution shifts explained 99% of the variance in the larval vertical distribution. Finally, we conducted a multipart meta‐analysis of published papers on tidal shifts to assess whether variation in the results among studies could be explained by tidal vertical advection via two proxies—tidal range and shelf slope. For well‐replicated studies that could be analyzed with a paired t‐test, tidal range explained 78% of the variance in the test statistic. A multiple regression approach applied to distributional shifts from a broader set of studies indicated significant effects of tidal range and interactions between tidal range, slope, and slope heterogeneity. Our results demonstrate the importance of considering passive processes when evaluating how the vertical distribution of weakly swimming meroplankton varies between tidal phases.
Effect of the pH of the electrolyte on the formation and on the corrosion properties of ceria based coating on carbon steel
Authors: Bourenane Nadjette , Hamlaoui Youcef , Remazeilles Celine , Pedraza Fernando
Published: July 2018

The effects of the modification of the pH in 0.1 M cerium nitrate solutions in the elaboration and corrosion resistance of ceria based coatings on carbon steel are investigated. Increasing the concentration of acetic acid impedes an efficient electrodeposition. At low concentrations, acetic acid seems to prevent the precipitation of Ce(OH)3 and the formation of even films of cerium oxides is favored. The increase of pH through the addition of NaOH to the cerium nitrate solutions with 0.008 M of acetic acid is shown to provide superior corrosion resistance for exposures in air and immersed in 0.5 M NaCl for 30 days.
Optimization of the atmospheric corrosivity mapping of Guangdong Province
Authors: Huang Juncong , Meng Xiaobo , Zheng Zhijun , Gao Yan
Published: July 2018

Atmospheric corrosivity maps can effectively assess atmospheric corrosion risks and provide guidance for anticorrosion measures. Since the atmospheric corrosion rate of materials is affected by many natural and environmental factors, a dose‐response function may establish a quantitative relationship between the influencing factors and the atmospheric corrosion rate. In order to map the atmospheric corrosivity of Guangdong Province, corrosion rate data of 48 exposed sites and the atmospheric and environmental data of 102 monitoring stations were collected first. Then a dose‐response function suitable for Guangdong Province was established through function design and then improved through accuracy assessment. Finally, the maps were drawn by different numbers of data and an optimal integrated one was obtained.
An iterative two‐step heuristic for the parallel drone scheduling traveling salesman problem
Authors: Mbiadou Saleu Raïssa G. , Deroussi Laurent , Feillet Dominique , Grangeon Nathalie , Quilliot Alain
Published: July 2018

A recent evolution in urban logistics involves the usage of drones. In this article, we address a heuristic solution of the parallel drone scheduling traveling salesman problem, recently introduced by Murray and Chu. In this problem, deliveries are split between a vehicle and drones. The vehicle performs a classical delivery tour, while the drones are constrained to perform back and forth trips. The objective is to minimize completion time. We propose an iterative two‐step heuristic, composed of: a coding step that transforms a solution into a customer sequence, and a decoding step that decomposes the customer sequence into a tour for the vehicle and trips for the drones. Decoding is expressed as a bicriteria shortest path problem and is carried out by dynamic programming. Experiments conducted on benchmark instances confirm the efficiency of the approach and give some insights on this drone delivery system.
Excellent outcome of acute lymphoblastic leukaemia with TCF3‐PBX1 rearrangement in Hong Kong
Authors: Lin Anna , Cheng Frankie W.T. , Chiang Alan K.S. , Luk Chung‐wing , Li Rever C.H. , Ling Alvin S.C. , Cheuk Daniel K.L. , Chang Kai‐on , Ku Dennis , Lee Vincent , Ha Shau‐Yin , Li Chi‐Kong
Published: July 2018

Objective

The aim of this study was to review clinical outcomes and prognosis of paediatric patients with acute lymphoblastic leukaemia (ALL) with TCF3‐PBX1 rearrangement.

Patients

All children in Hong Kong diagnosed with ALL with TCF3‐PBX1 rearrangement over the past two decades were included.

Methods

Six hundred and twenty‐four newly diagnosed patients with ALL from four consecutive studies were enrolled from 1997 to 2016. Patients carrying TCF3‐PBX1 rearrangement and patients at intermediate risk without the gene expression were compared for clinical characteristics, overall survival and event‐free survival (EFS).

Results

The TCF3‐PBX1 rearrangement was detected in 30 of 624 patients (4.8%). Results were consistent across the consecutive clinical trials employed in the past two decades. Compared with 239 intermediate risk patients without TCF3‐PBX1 rearrangement, the 5‐year overall survival and EFS for patients with TCF3‐PBX1 rearrangement was superior, with both at 100% (P = 0.12 and P = 0.029).

Conclusion

This population‐based study over the past 20 years demonstrated that patients with TCF3‐PBX1 rearrangement had favourable EFS compared with other intermediate risk patients treated with a similar chemotherapy backbone.
Token economy to improve adherence to activities of daily living
Authors: Hickey Victoria , Flesch Laura , Lane Adam , Pai Ahna L.H. , Huber John , Badia Priscila , Davies Stella M. , Dandoy Christopher E.
Published: July 2018

Background

Participation in key activities of daily living (ADL), including daily bathing, physical activity, and oral hygiene, can decrease the risk of bloodstream infections, oral complications, and deconditioning in pediatric patients undergoing hematopoietic stem cell transplant (HSCT). However, many patients fail to perform ADL during their inpatient stay. To improve inpatient adherence to ADL, we tested a token economy to engage patients, families, and the clinical team in improving adherence to these important health behaviors during this critical time.

Methods

We used a controlled before‐after study design to test our hypothesis. All patients were prescribed three ADL. We used an “all or none” measurement for each component of the ADL 1‐2‐3 initiative to measure adherence. HSCT patients with poor ADL adherence (<20%) were eligible to receive the intervention, which consisted of rewarding patients through an ADL via a token economy.

Results

Twenty‐one patients participated in the study. ADL adherence for the 14 days prior to intervention in study subjects (n = 294 inpatient days) averaged 0.51 ADL per day (95% CI 0.45–0.57). In the 14 days postinitiation of the token economy intervention (n = 294 inpatient days), the average adherence was 2.5 ADL per day (95% CI 2.4–2.5; P = <0.001).

Discussion

Positive reinforcement through a token economy system is associated with improved adherence to ADL in hospitalized pediatric patients who demonstrated poor ADL adherence at baseline. We believe this intervention can positively impact adherence to targeted health behaviors with the ability to correlate with improved health outcomes.
Gain of function conferred by selenocysteine: catalytic enhancement of one‐electron transfer reactions by thioredoxin reductase
Authors: Barber Drew R. , Hondal Robert J.
Published: July 2018

Selenocysteine (Sec) is the 21st amino acid in the genetic code and it is present in a small number of proteins where it replaces the much more commonly used amino acid cysteine (Cys). It is both more complicated and bioenergetically costly to insert Sec into a protein in comparison to Cys, and this cost is most likely compensated by a gain of function to the enzyme/protein in which it is incorporated. Here we investigate one such gain of function, the enhancement of one‐electron transfer catalysis. We compared the ability of Sec‐containing mouse mitochondrial thioredoxin reductase (mTrxR2) to catalyze the reduction of bovine cytochrome c, ascorbyl radical, and dehydroascorbate in comparison to Cys‐containing thioredoxin reductases from D. melanogaster (DmTrxR) and P. falciparum (PfTrxR). The Sec‐containing mTrxR2 was able to reduce all three substrates, while the Cys‐containing enzymes had little or no activity. In addition, we constructed Cys➔Sec mutants of DmTrxR and PfTrxR and found that this substitution resulted in a gain of function, as these mutant enzymes were now able to catalyze the reduction of these substrates. We also found that in the case of PfTrxR, reduction of cytochrome c was enhanced five‐fold in a truncated PfTrxR in which the C‐terminal redox center was removed. This shows that some of the ability of thioredoxin reductase to reduce this substrate comes from the flavin coenzyme. We also discuss a possible mechanism by which Sec‐containing thioredoxin reductase reduces dehydroascorbate to ascorbate by two sequential, one‐electron reductions, in part catalyzed by Sec.
Cysteine residues contribute to the dimerization and enzymatic activity of human nuclear dUTP nucleotidohydrolase (nDut)
Authors: Rotoli Shawna M. , Jones Julia L. , Caradonna Salvatore J.
Published: July 2018

dUTPase is an enzyme found in all organisms that have thymine as a constituent of DNA. Through evolution, humans have two major isoforms of dUTPase: a mitochondrial (mDut) and a nuclear (nDut) isoform. The nuclear isoform of dUTPase is a 164‐amino‐acids‐long protein containing three cysteine residues. nDut's starting methionine is post‐translationally cleaved, leaving four unique amino acids on its amino‐terminus including one cysteine residue (C3). These are not present in the mitochondrial isoform (mDut). Using mass spectrometry analyses of recombinant dUTPase constructs, we have discovered an intermolecular disulfide bridge between cysteine‐3 of each nDut monomer. We have found that these two residues stabilize a dimer configuration that is unique to the nDut isoform. We have also uncovered an intramolecular disulfide linkage between cysteine residues C78 and C134, stabilizing the monomeric state of the protein. Of note, both disulfide linkages are essential for nDut's enzymatic activity and dimeric formation can be augmented by the addition of the oxidizing agent, hydrogen peroxide to cells. Analyses of endogenous cellular dUTPase proteins confirm these differences between the two isoforms. We observed that mDut appears to be a mixture of monomer, dimer, and trimer conformations, as well as higher‐order subunit interactions. In contrast, nDut appeared to exist only in monomeric and dimeric forms. Cysteine‐based redox “switches” have recently emerged as a distinct class of post‐translational modification. In light of this and our results, we propose that nDut possesses a redox switch whereby cysteine interactions regulate nDut's dUTP‐hydrolyzing activity.
Points to consider for analyzing efficacy outcomes in long‐term extension clinical trials
Authors: Ratitch Bohdana , Lipkovich Ilya , Erickson Janelle Shannon , Zhang Lu , Mallinckrodt Craig H.
Published: July 2018

This article focuses on 2 objectives in the analysis of efficacy in long‐term extension studies of chronic diseases: (1) defining and discussing estimands of interest in such studies and (2) evaluating the performance of several multiple imputation methods that may be useful in estimating some of these estimands. Specifically, 4 estimands are defined and their clinical utility and inferential ramifications discussed. The performance of several multiple imputation methods and approaches were evaluated using simulated data. Results suggested that when interest is in a binary outcome derived from an underlying continuous measurement, it is preferable to impute the underlying continuous value that is subsequently dichotomized rather than to directly impute the binary outcome. Results also demonstrated that multivariate Gaussian models with Markov chain Monte Carlo imputation and sequential regression have minimal bias and the anticipated confidence interval coverage, even in settings with ordinal data where departures from normality are a concern. These approaches are further illustrated using a long‐term extension study in psoriasis.
Analysis of the initiation of an extreme North Pacific jet retraction using piecewise tendency diagnosis
Authors: Breeden Melissa , Martin Jonathan E.
Published: July 2018

An unusually prolonged retraction of the tropopause‐level jet transformed the circulation in the North Pacific for weeks in mid‐February and March 2006 and preceded the development of a long‐lived negative Pacific–North American pattern. The initiation of this jet retraction, associated with a series of anticyclonic/LC1 wave‐breaking events at high latitude, is investigated through the lens of quasi‐geostrophic (QG) piecewise tendency analysis. Two key anticyclonic anomalies divert and retract the jet through serial LC1 wave‐breaking events, mostly confined to the 315–330 K isentropic layer and occurring in regions of strong deformation. The rapid development of the first anomaly coinciding with the beginning of retraction is diagnosed in a QG framework, in order to quantify contributions to QG height tendencies from various processes. The resultant analysis reveals that growth was induced by a deep potential vorticity intrusion that perturbed the jet, while the remainder of the ridge's life cycle was largely governed by upper‐level deformation in the jet exit region. Deformation facilitated both growth and decay, as the phasing between the ridge and deformation changed. Baroclinic development also contributed to growth but, unlike prior published analyses of anticyclones in the North Pacific, was not the dominant term.
On the estimation of the strength of supramolecular complexes of fullerenes
Authors: Denis Pablo A.
Published: July 2018

The accurate estimation of the free energy changes in solution for supramolecular complexes is one of the most important challenges for quantum chemistry in this century. In general, there is a good correlation between the association constants determined experimentally and the gas phase binding energies calculated using the most popular density functional methods. However, when the receptors adopt very different structures in the gas and condensed phase, this approach does not work, leading to unreliable predictions. We discuss this problem in detail using three popular fullerene receptors: Aida's dimeric porphyrins, buckycatchers I, and II. We found that it is possible to obtain a reliable order of affinities using gas phase binding energies when a special attention is put on analyzing the structure adopted by the receptor in the gas and condensed phases.
Prediction of the force demands of tall buildings through the enhanced pushover procedures
Authors: Amini Mohamad Amin , Poursha Mehdi
Published: July 2018

This paper attempts to comprehensively evaluate the accuracy of the enhanced pushover procedures in estimating the force demands of tall building structures. In this process, the efficiency of different pushover methods in taking the higher modes effect into account for the computation of the force demands is assessed. The enhanced pushover methods including the modal pushover analysis, force‐based adaptive pushover, displacement‐based adaptive pushover, consecutive modal pushover (CMP), single‐run multimode pushover (SMP), nonadaptive displacement‐based pushover, and adaptive force‐based multimode pushover procedures, as well as the conventional pushover analysis, are applied to the three special steel moment‐resisting frames to compute the internal force demands of structural members. The seismic force demands resulting from the enhanced pushover procedures are compared with those from the nonlinear response history analysis (NL‐RHA) as a benchmark solution. Furthermore, in order to evaluate approximately the degree to which the higher modes may affect deformation and force demands of tall buildings, the ratio of structural demands computed by the NL‐RHA to those obtained by the conventional pushover analysis is determined. The results demonstrate that the CMP and SMP procedures can accurately estimate the force demands of tall buildings. It is shown that the effects of higher modes on the story drifts and column shear forces and bending moments are larger than those on the other force demands.
String theory of supertubes
Authors: Martinec Emil J. , Massai Stefano
Published: July 2018

Abstract

String theory on AdS
3 backgrounds arises as an IR limit of Little String Theory on NS5-branes. A wide variety of holographic RG flows from the fivebrane theory in the UV to (orbifolds of) AdS
3 in the IR is amenable to exact treatment in worldsheet string theory as a class of null-gauged WZW models. The condensate of stringy winding operators which resolves the near-source structure of fivebranes on the Coulomb branch plays a crucial role in AdS
3, revealing stringy structure invisible to the supergravity approximation. The D-brane sector contains precursors of the long strings which dominate black hole entropy in the dual spacetime CFT.
The spectrum of 2+1 dimensional Yang-Mills theory on a twisted spatial torus
Authors: Pérez Margarita García , González-Arroyo Antonio , Koren Mateusz , Okawa Masanori
Published: July 2018

Abstract

We compute and analyse the low-lying spectrum of 2+1 dimensional SU(N) Yang-Mills theory on a spatial torus of sizel×lwith twisted boundary conditions. This paper extends our previous work [1]. In that paper we studied the sector with non-vanishing electric flux and concluded that the energies only depend on the parameters through two combinations:x=λN l/(4π) (withλthe ’t Hooft coupling) and the twist angle$$ \tilde{\theta} $$θ˜defined in terms of the magnetic flux piercing the two-dimensional box. Here we made a more complete study and we are able to condense our results, obtained by non-perturbative lattice methods, into a simple expression which has important implications for the absence of tachyonic instabilities, volume independence and non-commutative field theory. Then we extend our study to the sector of vanishing electric flux. We conclude that the onset of the would-be large-volume glueball states occurs at an approximately fixed value ofx, much before the stringy torelon states have become very massive.
Correction to: Medical and financial burden of acute intermittent porphyria
Authors: Neeleman Rochus A. , Wagenmakers Margreet A. E. M. , Koole‐Lesuis Rita H. , Mijnhout G. Sophie , Wilson J. H. Paul , Friesema Edith C. H. , Langendonk Janneke G.
Published: July 2018

Due to a typesetting error the wrong figure 2 was used.
Teaching clinical skills in the theatre of medicine
Authors: Gormley Gerard J. , Murphy Paul
Published: July 2018

None
Public issues or issue publics? The distribution of genuine political attitudes
Authors: DUFRESNE YANNICK , OUELLET CATHERINE
Published: July 2018

There is an inherent conflict between the political marketing model of humans and pioneering theories in electoral behavior research. While political marketing logic implies an issue-based and highly volatile voting behavior, voting theories conventionally assume that positional issues have little effect on how individuals vote, and so parties have little incentive to develop issue-based electoral strategies. However, few people would challenge the role that marketing now plays in the modern campaign process. How can we reconcile these theories? This paper revisits the role and impact of positional issues on voting behavior by testing whether specific issues affect different subgroups of voters as contended by the ‘issue-public’ theory. The results show that previous models underestimate issue voting. Once measurement accuracy is improved and the salience-based heterogeneity of issue effects is taken into consideration, positional issues have non-negligible effects on individual vote choice. Furthermore, salience-based heterogeneity is shown to explain better the variation in issue voting than heterogeneity based on political sophistication.
05 Long-term health-related quality of life in adult survivors of pediatric intracranial germ cell tumour
Authors: Lo Andrea , Laperriere Normand , Hodgson David , Goddard Karen
Published: July 2018

PURPOSE: To investigate health-related quality of life (HRQOL ) in survivors of intracranial germ cell tumors (IGCT). METHODS: Survivors of IGCT were invited to complete the 36-Item Short Form Survey Instrument (SF-36). The SF-36 is scored from 0-100, with a higher number representing a more favorable HRQOL. RESULTS: The study cohort consisted of 12 survivors of IGCT, 6 males and 6 females. Median age was 13 years at diagnosis, and 26 years at time of study. Median follow-up was 11 years. Five patients had germinomas, and 7 had non-germinomatous germ cell tumors. All 12 patients received radiation therapy (RT), 10 to the craniospinal axis, 1 to the whole ventricles and 1 to the tumor bed alone. Nine patients received chemotherapy. Mean SF-36 scores were 67.9 (standard deviation [SD] 33.2) for physical functioning, 58.3 (SD 37.4) for role limitations due to physical health, 77.8 (SD 32.8) for role limitations due to emotional problems, 43.1 (SD 18.4) for vitality, 74.3 (SD 15.3) for mental health; 62.5 (SD 32.0) for social functioning, 74.2 (SD 33.4) for pain, and 57.1 (SD 24.0) for general health; mean scores were >1 SD lower than that of Canadian normative data for vitality, social functioning and general health. Physical component score was 43.6 (SD 13.9) and mental component score was 47.6 (SD 11.2), normalized to a US population with mean of 50 and SD of 10. CONCLUSIONS: Long-term HRQOL for survivors of IGCT is lower than that of the overall population, particularly in vitality, social functioning and general health.
11 Study of Polynucleotide Kinase/Phosphatase (PNKP) Mutations Found in a Patient with Microcephaly, Seizures, and Developmental Delay (MCSZ) and Glioblastoma
Authors: Jiang Bingcheng , Ene Chibawanye I. , Cole Bonnie , Ojemann Jeff , Leary Sarah , Fanta Mesfin , Subedi Sudip , Weinfeld Michael
Published: July 2018

The enzyme polynucleotide kinase/phosphatase (PNKP) plays a key role in DNA repair by resolving the chemistry at DNA strand breaks. Mutations in PNKP (chromosome 19q13.4) are known to cause MCSZ, a serious neurodevelopmental disorder, but to date there has been no link to cancer initiation or progression. However, a child with MCSZ recently presented at Seattle Children's Hospital with a 3-cm glioblastoma. The child was shown to have two germline mutations in PNKP. To study the effects of the PNKP mutations found in this patient, we generated mutant PNKP cDNAs carrying either the individual mutations or the double mutation using site directed mutagenesis. These cDNAs were incorporated into bacterial and mammalian expression vectors. The bacterially expressed mutant proteins as well as the wild type have been purified and are undergoing testing for PNKP DNA kinase and phosphatase activity. The PNKP cDNAs, fused to GFP, were expressed in Hela and HCT116 human cancer cell lines. High-content analysis and micro-irradiation techniques are being used to determine PNKP localization within the cells and recruitment to damaged DNA. Our preliminary results indicate that the mutations alter the ratio of nuclear to cytoplasmic PNKP compared to the wild-type protein.
24 Radiation induced meningioma in adult survivors of childhood leukemia or primary brain tumor treated with cranial radiotherapy: Incidence and screening recommendations
Authors: Dosani Maryam , Tran Jordan , Conway Jessica L , Goddard Karen
Published: July 2018

Purpose: Cranial radiotherapy (CRT) was commonly given for childhood leukemia and brain tumors. Survivors are at risk of late effects including radiation induced meningioma (RIM). Surveillance for RIM is not standardized . We aimed to determine the incidence, latency, and screening patterns for RIM. Materials and Methods: Retrospective chart review of all patients aged <18 years at the time of radiation (RT), treated with CRT for leukemia or a brain tumor in BC between 1981-2006. Patient, tumor, and treatment characteristics were collected. Actuarial statistics were calculated with Kaplan-Meier Curves. Patients were censored at the date of last normal cranial imaging, or development of a RIM. Results: 392 patients were identified. Median age (range) at CRT was 9.6 years. Median CRT dose was 28Gy. The original diagnosis was leukemia in 50%, glioma in 13%, medulloblastoma in 8%, ependymoma in 7%, neuroectodermal tumor in 7%, germ cell tumor in 5%, craniopharyngioma in 4%, and other pathologies in 6%. Median (range) of clinical follow-up (FU) was 13.2 (0-37.5) years. Median (range) of cranial imaging FU was 15.5 (0-21.2) years. There was no documented cranial imaging FU in 144 patients. Forty-eight patients developed a RIM. The median age (range) at RT for patients with RIM was 6.7 years. Only 8 of these cases presented with associated symptoms. The earliest RIM in our cohort occurred 10.2 years after CRT. On actuarial analysis, the median (95% CI) time to development of a meningioma was 29.8 (28.9-30.7) years. Incidence (95% CI) of meningioma at 10 years was 0%, 15 years was 5 (2-9)%, 20 years was 12 (6-18)%, 25 years was 33 (23-43)% and 30 years was 47 (37-68)%. Amongst patients with a RIM, the median dose of CRT was 45 Gy. The lowest dose of RT in a patient who developed RIM was 12 Gy. RT was delivered to the whole brain in 58% and partial brain in 42% of patients with a RIM. Conclusions: After CRT in pediatric patients, there is a significant risk of developing a RIM and a steady increase in this risk with ongoing follow-up. We recommend standardization of surveillance for these patients with screening beginning 10 years after completion of CRT.
28 A systematic review in quality of life of patients with meningiomas: Effort towards developing a disease-specific questionnaire
Authors: Mansouri A. , Shin Cheung V. Lam , Karmur B. , Shin Cheung J. Lam , Hachem L. , Taslimi S. , Nassiri F. , Suppiah S. , Drummond K. , Walbert T. , Goldbrunner R. , Santarius Y. , Jenkinson M. D. , Snyder J. , Lee I. , Devine K. , Schichor C. , Aldape K. D. , Zadeh G.
Published: July 2018

BACKGROUND: Meningiomas are the most common primary benign brain tumors in adults. Given the extended life expectancy of most meningiomas, consideration of quality of life (QOL) is important when selecting the optimal management strategy. There is currently a dearth of meningioma-specific QOL tools in the literature. OBJECTIVE: In this systematic review, we analyze the prevailing themes and propose toward building a meningioma-specific QOL assessment tool. METHODS: A systematic search was conducted, and only original studies based on adult patients were considered. QOL tools used in the various studies were analyzed for identification of prevailing themes in the qualitative analysis. The quality of the studies was also assessed. RESULTS: Sixteen articles met all inclusion criteria. Fifteen different QOL assessment tools assessed social and physical functioning, psychological, and emotional well-being. Patient perceptions and support networks had a major impact on QOL scores. Surgery negatively affected social functioning in younger patients, while radiation therapy had a variable impact. Any intervention appeared to have a greater negative impact on physical functioning compared to observation. CONCLUSION: Younger patients with meningiomas appear to be more vulnerable within social and physical functioning domains. All of these findings must be interpreted with great caution due to great clinical heterogeneity, limited generalizability, and risk of bias. For meningioma patients, the ideal QOL questionnaire would present outcomes that can be easily measured, presented, and compared across studies. Existing scales can be the foundation upon which a comprehensive, standard, and simple meningioma-specific survey can be prospectively developed and validated.
33 Is hypofractionation safer than single-fraction radio surgery? The effect of fractionation on radionecrosis
Authors: Donovan Elysia , Parpia Sameer , Greenspoon Jeffrey
Published: July 2018

Introduction: Radiation-induced brain necrosis (RN) is a relatively uncommon (5-20%) but potentially severe adverse effect of stereotactic radiosurgery (SRS) for brain metastasis(BM). We attempted to establish the effect of hypo-fractionation on RN rates by reviewing patients having simultaneous multi-fraction and single fraction treatment of BM at our centre. Methods: Patients receiving simultaneous 1 (20-24Gy) or 3 fraction (21-24Gy) SRS treatments were identified in our institution’s database. Serial post-SRS MRIs were reviewed to determine the lesion quotient (LQ), or maximum cross sectional area on T1 plus gadolinium divided by T2 FLAIR sequences. LQ less than 0.3 was considered RN. Result: Twenty-two patients were followed for a median 320 days. Sixteen patients developed radionecrosis in 21 of 62 lesions (33%), four of which were symptomatic (20%). Eleven of these lesions received 3 fractions and ten received one fraction. RN risk increased with increasing tumor volume (log odds ratio=1.12, p=0.04). There was no difference in incidence of RN in patients who received whole brain radiotherapy (WBRT) (p=0.11), hypo-fractionation (p=0.98) or had a higher maximum dose (p=0.71). Radiographic RN, however, did not clear in any patients who developed it. Eight patients developed a local recurrence (12%), six of which occurred in the single fraction group. Conclusion: Radionecrosis was significantly related to tumor volume but not fractionation, WBRT, or maximum dose. Overall, our results indicate patients receiving SRS for multiple brain metastasis have a higher rate of radionecrosis than the literature and poorer survival despite having equivalent local control.