bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of oncology drug approval between Health Canada and the US Food and Drug Administration
Authors: Ezeife Doreen A. , Truong Tony H. , Heng Daniel Y. C. , Bourque Sylvie , Welch Stephen A. , Tang Patricia A.
Published: January 2015

BACKGROUND

The drug approval timeline is a lengthy process that often varies between countries. The objective of this study was to delineate the Canadian drug approval timeline for oncology drugs and to compare the time to drug approval between Health Canada (HC) and the US Food and Drug Administration (FDA).

METHODS

In total, 54 antineoplastic drugs that were approved by the FDA between 1989 and 2012 were reviewed. For each drug, the following milestones were determined: the dates of submission and approval for both the FDA and HC and the dates of availability on provincial drug formularies in Canadian provinces and territories. The time intervals between the aforementioned milestones were calculated.

RESULTS

Of 54 FDA‐approved drugs, 49 drugs were approved by HC at the time of the current study. The median time from submission to approval was 9 months (interquartile range [IQR], 6‐14.5 months) for the FDA and 12 months (IQR, 10‐21.1 months) for HC (P < .0006). The time from HC approval to the placement of a drug on a provincial drug formulary was a median of 16.7 months (IQR, 5.9‐27.2 months), and there was no interprovincial variability among the 5 Canadian provinces that were analyzed (P = .5).

CONCLUSIONS

The time from HC submission to HC approval takes 3 months longer than the same time interval for the FDA. To the authors' knowledge, this is the first documentation of the time required to bring an oncology drug from HC submission to placement on a provincial drug formulary. Cancer 2015;121:1688–1693. © 2015 American Cancer Society.
Reducing indeterminate thyroid FNAs
Authors: Renshaw Andrew A. , Gould Edwin W.
Published: January 2015

BACKGROUND

The Bethesda System recommends limiting the percentage of cases diagnosed as indeterminate in thyroid fine‐needle aspirations (TFNAs). However, studies are lacking that document how to decrease the rate of indeterminate TFNAs and its effects.

METHODS

The authors modified the Bethesda criteria to reduce the rate of indeterminate TFNAs (“atypical cells of undetermined significance” and “suspicious for a follicular/Hurthle cell neoplasm”) by reassigning cases that may have been categorized as indeterminate to “suspicious for papillary carcinoma” or “favor benign” for an 18‐month period and correlated this with histologic follow‐up.

RESULTS

The indeterminate rate decreased from 14.4% (Bethesda) to 8.2% (modified Bethesda;P < .001). There was no significant difference in the risk of malignancy for the 2 groups (23.6% vs 17.3%, respectively; chi‐squareP = .39). There were 6 false‐positive diagnoses in the Bethesda group compared with none in the modified Bethesda group (P = .06). In the Bethesda group, but not in the modified Bethesda group, the indeterminate rate was correlated with the overall rate of malignant and suspicious for papillary carcinoma diagnoses.

CONCLUSIONS

Modifying the Bethesda criteria can decrease indeterminate TFNAs diagnoses without a significant decrease in the risk of malignancy. The modified Bethesda criteria, but not the Bethesda criteria, are independent of the malignancy rate.Cancer (Cancer Cytopathol)2015;123:237–243.©2015 American Cancer Society.
Robust state estimation for Markov jump genetic regulatory networks based on passivity theory
Authors: Lu Li , He Bing , Man Chuntao , Wang Shun
Published: January 2015

In this article, the robust state estimation problem for Markov jump genetic regulatory networks (GRNs) based on passivity theory is investigated. Moreover, the effect of time‐varying delays is taken into account. The focus is on designing a linear state estimator to estimate the concentrations of the mRNAs and the proteins of the GRNs, such that the dynamics of the state estimation error can be stochastically stable while achieving the prescribed passivity performance. By applying the Lyapunov–Krasovskii functional method, delay‐dependent criteria are established to ensure the existence of the mode‐dependent estimator in the form of linear matrix inequalities. Based on the obtained results, the parameters of the desired estimator gains can be further calculated. Finally, a numerical example is given to illustrate the effectiveness of our proposed methods. © 2015 Wiley Periodicals, Inc. Complexity 21: 214–223, 2016
Using topology information for quality‐aware Peer‐to‐Peer multilayer video streaming
Authors: Sluijs Niels , Wauters Tim , Develder Chris , De Turck Filip , Demeester Piet , Dhoedt Bart
Published: January 2015

Due to increasing bandwidth capacities, the Internet has become a viable transport medium for a (live) video. Often, delivery of video streams relies on the client–server paradigm and therefore exhibits limited scalability. The Peer‐to‐Peer (P2P) network model is an attractive and scalable candidate to stream video content to end users. However, these P2P frameworks typically operate in a network agnostic mode. Introducing network topology information into these P2P frameworks offers opportunities to enhance the performance.

In this paper, we introduce a model to include network information when streaming a (multilayered) video in P2P frameworks. An important metric for video stream providers is the content quality perceived by end users. The optimization studied here aims at maximizing the number of users receiving a high quality video.

The paper addresses the optimization problem seen from the stream provider's viewpoint, having access to network topology information. An exact optimization approach is presented for benchmarking purposes and a heuristic approach to cope with realistic network sizes. In addition, we present an approach to decide the deployment location of peering functionality. The results show that our strategy significantly decreases the fraction of destinations receiving only the base layer, and by introducing extra peering functionality, network capacities are used more efficiently. Copyright © 2015 John Wiley & Sons, Ltd.
Implement retention strategies to help students on autism spectrum
Authors: Gomez Cynthia
Published: January 2015

Do you know the retention rate among students with autism‐spectrum disorder at your institution, or how their retention rate compares with that of other students served by your disability services unit? That's valuable information that could help you determine whether you're providing students with ASD adequate support or whether you need to implement new strategies to help those students succeed.
Help your unit remain calm, focused during high‐stress times
Authors: Gomez Cynthia
Published: January 2015

The field of disability services requires the ability to remain calm and focused amid chaos, which can seem like the norm on any college campus — at least during key times of the year, such as the start of the fall semester and finals week. But that chaos is just business as usual. So too, are wearing multiple hats and doing more with fewer resources. However, what happens when unexpected crises come your unit's way, such as a student on the autism spectrum whose behavior has landed him in trouble with campus police?
Understand autism meltdowns and share strategies to minimize, manage occurrences
Authors: Bedrossian Louise
Published: January 2015

The percentage of students with autism spectrum disorders in higher education is increasing. But they often struggle with greater levels of stress and anxiety than others, making them susceptible to meltdowns. Since disability services providers are usually the primary resource for averting or responding to meltdowns by students on the spectrum, they should be knowledgeable of the underlying issues triggering such behaviors and familiar with strategies to help students forestall such occurrences.
Tackle IT accessibility through cross‐functional team
Authors: Gomez Cynthia
Published: January 2015

From institutional websites to learning management systems to consumer electronics used to enhance learning, technology is a necessary fact of daily life for college students today. Unfortunately, not all such technology is accessible to those with disabilities. And when the students your unit serves encounter technological access barriers, they may run to you for help, requiring you to drop everything to figure out how to provide them with equal access. Perhaps worse, they may feel as if your institution simply doesn't care about their needs.
The rise of Astyanax cavefish
Authors: Gross Joshua B. , Meyer Bradley , Perkins Molly
Published: January 2015

Numerous animals have invaded subterranean caverns and evolved remarkably similar features. These features include loss of vision and pigmentation, and gains in nonvisual sensation. This broad convergence echoes smaller‐scale convergence, in which members of the same species repeatedly evolve the same cave‐associated phenotypes. The blind Mexican tetra of the Sierra de El Abra region of northeastern Mexico has a complex origin, having recurrently colonized subterranean environments through numerous invasions of surface‐dwelling fish. These colonizations likely occurred ∼1–5 MYa. Despite evidence of historical and contemporary gene flow between cave and surface forms, the cave‐associated phenotype appears to remain quite stable in nature. This model system has provided insight to the mechanisms of phenotypic regression, the genetic basis for constructive trait evolution, and the origin of behavioral novelties. Here, we document the rise of this model system from its discovery by a Mexican surveyor in 1936, to a powerful system for cave biology and contemporary genetic research. The recently sequenced genome provides exciting opportunities for future research, and will help resolve several long‐standing biological problems. Developmental Dynamics 244:1031–1038, 2015. © 2015 Wiley Periodicals, Inc.
Generation and characterization of an endothelin‐2 iCre mouse
Authors: Cacioppo Joseph A. , Koo Yongbum , Lin Po‐Ching Patrick , Gal Arnon , Ko CheMyong
Published: January 2015

A novel transgenic mouse line that expresses codon‐improved Cre recombinase (iCre) under regulation of the Endothelin‐2 gene (edn2) promoter was developed for the conditional deletion of genes in Endothelin‐2 lineage cells and for the spatial and temporal localization of Endothelin‐2 expression. Endothelin‐2 (EDN2, ET‐2, previously VIC) is a transcriptionally regulated 21 amino acid peptide implicated in vascular homeostasis, and more recently in female reproduction, gastrointestinal function, immunology, and cancer pathogenesis that acts through membrane receptors and G‐protein signaling. A cassette (edn2‐iCre) was constructed that contained iCre, a polyadenylation sequence, and a neomycin selection marker in front of the endogenous start codon of the edn2 gene in a mouse genome BAC clone. The cassette was introduced into the C57BL/6 genome by pronuclear injection, and two lines of edn2‐iCre positive mice were produced. The edn2‐iCre mice were bred with ROSA26‐lacZ and Ai9 reporter mice to visualize areas of functional iCre expression. Strong expression was seen in the periovulatory ovary, stomach and small intestine, and colon. Uniquely, we report punctate expression in the corneal epithelium, the liver, the lung, the pituitary, the uterus, and the heart. In the embryo, expression is localized in developing hair follicles and the dermis. Therefore, edn2‐iCre mice will serve as a novel line for conditional gene deletion in these tissues. genesis 53:245–256, 2015. © 2015 Wiley Periodicals, Inc.
The relationship between risk of bias criteria, research outcomes, and study sponsorship in a cohort of preclinical thiazolidinedione animal studies: a meta‐analysis
Authors: Abdel‐Sattar M. , Krauth D. , Anglemyer A. , Bero L.
Published: January 2015

Introduction

There is little evidence regarding the influence of conflicts of interest on preclinical research. This study examines whether industry sponsorship is associated with increased risks of bias and/or effect sizes of outcomes in published preclinical thiazolidinedione (TZD) studies.

Methods

We identified preclinical TZD studies published between January 1, 1965, and November 14, 2012. Coders independently extracted information on study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source and investigator financial ties from the 112 studies meeting the inclusion criteria. The average standardized mean difference (SMD) across studies was calculated for plasma glucose (efficacy outcome) and weight gain (harm outcome). In subgroup analyses, TZD outcomes were assessed by sponsorship source and risk of bias criteria.

Results

Seven studies were funded by industry alone, 17 studies funded by both industry and non‐industry, 49 studies funded by non‐industry alone and 39 studies had no disclosures. None of the studies used sample size calculations, intention‐to‐treat analyses, blinding of investigators or concealment of allocation. Most studies reported favourable results (88 of 112) and conclusions (95 of 112) supporting TZD use. Efficacy estimates were significantly larger in six studies sponsored by industry alone (−3.41; 95% CI −5.21, −1.53; I2
= 93%) versus 42 studies sponsored by non‐industry sources (−0.97; 95% CI −1.37, −0.56; I2
= 81%; p‐value = 0.01). Harms estimates were significantly larger in four studies sponsored by industry alone (5.00; 95% CI 1.22, 8.77; I2
= 93%) versus 38 studies sponsored by non‐industry sources (0.30; 95% CI −0.08, 0.68; I2
= 79%; p‐value = 0.02). TZD efficacy and harms did not differ by disclosure of financial COIs or risks of bias.

Conclusions

Industry‐sponsored TZD animal studies have exaggerated efficacy and harms outcomes compared with studies funded by non‐industry sources. There was poor reporting of COIs.
TGF‐β converts Th1 cells into Th17 cells through stimulation of Runx1 expression
Authors: Liu Hou‐Pu , Cao Anthony T. , Feng Ting , Li Qingjie , Zhang Wenbo , Yao Suxia , Dann Sara M. , Elson Charles O. , Cong Yingzi
Published: January 2015

Differentiated CD4+ T cells preserve plasticity under various conditions. However, the stability of Th1 cells is unclear, as is whether Th1 cells can convert into Th17 cells and thereby contribute to the generation of IFN‐γ+IL‐17+CD4+ T cells, the number of which correlates with severity of colitis. We investigated whether IFN‐γ+Th1 cells can convert into Th17 cells under intestinal inflammation and the mechanisms involved. IFN‐γThy1.1+ Th1 cells were generated by culturing naïve CD4+ T cells from IFN‐γThy1.1 CBir1 TCR‐Tg reporter mice, whose TCR is specific for an immunodominant microbiota antigen, CBir1 flagellin, under Th1 polarizing conditions. IFN‐γThy1.1+ Th1 cells induced colitis in Rag−/− mice after adoptive transfer and converted into IL‐17+Th17, but not Foxp3+Treg cells in the inflamed intestines. TGF‐β and IL‐6, but not IL‐1β and IL‐23, regulated Th1 conversion into Th17 cells. TGF‐β induction of transcriptional factor Runx1 is crucial for the conversion, since silencing Runx1 by siRNA inhibited Th1 conversion into Th17 cells. Furthermore, TGF‐β enhanced histone H3K9 acetylation but inhibited H3K9 trimethylation of Runx1‐ and ROR‐γt‐binding sites on il‐17 or rorc gene in Th1 cells. We conclude that Th1 cells convert into Th17 cells under inflammatory conditions in intestines, which is possibly mediated by TGF‐β induction of Runx1.
Reactivity of Dinitrogen Bound to Mid‐ and Late‐Transition‐Metal Centers
Authors: Khoenkhoen Nitesh , de Bruin Bas , Reek Joost N. H. , Dzik Wojciech I.
Published: January 2015

This review presents a comprehensive overview of the reactions of N2 within the coordination sphere of transition metals of groups 6 to 9. Many of these metals mediate the reaction of N2 with protons under reductive conditions, which can lead to the (catalytic) formation of ammonia or hydrazine, and the mechanisms of these reactions somewhat resemble the mode of action of nitrogenase enzymes. Alternatively, coordinated N2 can react with carbon and silicon electrophiles and radicals to allow, for example, the catalytic formation of silylamines. Another approach in N2 activation involves the homolytic splitting of dinitrogen to form intermediate nitrides in analogy to the Haber–Bosch process. Thus formed nitrides can undergo follow‐up reactions with protons or carbon electrophiles. Molybdenum, tungsten, and iron reveal the richest chemistry of coordinated N2; however, chromium, manganese, rhenium, osmium, and cobalt systems provide alternative pathways in the making and breaking of bonds on the dinitrogen molecule.
Enzymatic synthesis and modification of surface‐active glycolipids
Authors: Pöhnlein Martin , Hausmann Rudolf , Lang Siegmund , Syldatk Christoph
Published: January 2015

Surfactants are an essential part of detergent or emulsifier formulations and find applications in food, cleaning, cosmetic and pharmaceutical products. Glycolipids are among the best studied surfactants originating from renewable resources and can be obtained by chemical synthesis, fermentation processes as well as by enzymatic syntheses and have gained considerable interest in recent years. The use of suitable enzymes not only facilitates the synthesis of new tailor‐made glycolipids, but also allows targeted modification of known microbial glycolipids. Thereby, novel glycolipids may arise with enhanced surfactant properties, which might exhibit interesting bioactive properties as well. Here we present an overview of the advantages, strategies and important parameters regarding the enzymatic synthesis and modification of surface‐active glycolipids.

Within this article different strategies and advantages of the enzymatic synthesis and modification of glycolipids are discussed.
Formal Intermolecular Hydroamination of Unbiased Olefins for Primary Amine Formation
Authors: Yang Yongsheng , Wong Nurul Imma , Teo Peili
Published: January 2015

A Pd/Ir dual metal tandem catalyst system was found to be active in catalyzing the one‐pot, two‐step formal hydroamination of unbiased olefins such as 1‐dodecene with an ammonia source to give branched primary amines in high yields of >85 % by using only 1 mol‐% of the Ir catalyst. This is the first report of the formal one‐pot intermolecular hydroamination of olefins to obtain primary amines.
A phenomenological contact‐element model considering slight non‐uniform contact for pounding analysis of highway bridges under seismic excitations
Authors: Guo Anxin , Cui Lili , Li Suchao , Li Hui
Published: January 2015

Impact stiffness is an important parameter of the contact‐element models for the analysis and prediction of the pounding responses of highway bridges subjected to seismic excitations. This paper presents a pounding experiment to investigate the inconsistencies between the theoretical and experimental values of the impact stiffness both for the linear impact model and Kelvin impact model presented in literature. The analysis of the impact acceleration and acoustic emission signals indicates that accelerometer performance and the non‐uniform pounding are two important factors that affect the pounding responses. Based on this observation, a phenomenological contact‐element model is proposed based on the actual contact state of highway bridges during the impact. To evaluate the effectiveness of the proposed impact model, a numerical simulation is subsequently conducted. A comparison of the results indicates that the proposed impact model can effectively predict the pounding responses of highway bridges. Copyright © 2015 John Wiley & Sons, Ltd.
The topographic signature of a major typhoon
Authors: Tseng Chih‐Ming , Lin Ching‐Weei , Dalla Fontana Giancarlo , Tarolli Paolo
Published: January 2015

In August 2009, the typhoon Morakot, characterized by a cumulative rainfall up to 2884 mm in about three days, triggered thousands of landslides in Taiwan. The availability of LiDAR surveys before (2005) and after (2010) this event offers a unique opportunity to investigate the topographic signatures of a major typhoon. The analysis considers the comparison of slope–area relationships derived by LiDAR digital terrain models (DTMs). This approach has been successfully used to distinguish hillslope from channelized processes, as a basis to develop landscape evolution models and theories, and understand the linkages between landscape morphology and tectonics, climate, and geology. We considered six catchments affected by a different degree of erosion: three affected by shallow and deep‐seated landslides, and three not affected by erosion. For each of these catchments, 2 m DTMs were derived from LiDAR data. The scaling regimes of local slope versus drainage area suggested that for the catchments affected by landslides: (i) the hillslope‐to‐valley transitions morphology, for a given value of drainage area, is shifted towards higher value of slopes, thus indicating a likely migration of the channelized processes and erosion toward the catchment boundary (the catchment head becomes steeper because of erosion); (ii) the topographic gradient along valley profiles tends to decrease progressively (the valley profile becomes gentler because of sediment deposition after the typhoon). The catchments without any landslides present a statistically indistinguishable slope–area scaling regime. These results are interesting since for the first time, using multi‐temporal high‐resolution topography derived by LiDAR, we demonstrated that a single climate event is able to cause significant major geomorphic changes on the landscape, detectable using slope–area scaling analysis. This provides new insights about landscape evolution under major climate forcing. Copyright © 2015 John Wiley & Sons, Ltd.
Support for Full Disclosure Up Front
Authors: Holzer Felicitas , Mastroleo Ignacio
Published: January 2015

A commentary on “Models of Consent to Return of Incidental Findings in Genomic Research,” by Paul S. Appelbaum, Erik Parens, Cameron R. Waldman, Robert Klitzman, Abby Fyer, Josue Martinez, W. Nicholson Price II, and Wendy K. Chung, in the July‐August 2014 issue.
Microethics: The Ethics of Everyday Clinical Practice
Authors: Truog Robert D. , Brown Stephen D. , Browning David , Hundert Edward M. , Rider Elizabeth A. , Bell Sigall K. , Meyer Elaine C.
Published: January 2015

Over the past several decades, medical ethics has gained a solid foothold in medical education and is now a required course in most medical schools. Although the field of medical ethics is by nature eclectic, moral philosophy has played a dominant role in defining both the content of what is taught and the methodology for reasoning about ethical dilemmas. Most educators largely rely on the case‐based method for teaching ethics, grounding the ethical reasoning in an amalgam of theories drawn from moral philosophy, including consequentialism, deontology, and principlism.

In this article we hope to make a case for augmenting the focus of education in medical ethics. We propose complementing the traditional approach to medical ethics with a more embedded approach, one that has been described by others as “microethics,” the ethics of everyday clinical practice.
Should All Research Subjects Be Treated the Same?
Authors: Brody Baruch , Migueles Stephen A. , Wendler David
Published: January 2015

One of the founding principles of research ethics is that subjects should be treated equally. In the words of the Belmont Report, “equals ought to be treated equally.” This principle does not imply that all subjects should be treated exactly the same. Rather, subjects who are similar in relevant respects should receive similar treatment. Clinical status is clearly relevant to determining how subjects should be treated. Greater resources should be devoted to subjects who have worse diseases. In contrast, fame is irrelevant. Subjects should not receive greater resources simply because they are famous. A more challenging question, one that pervades clinical research yet has received almost no attention in the literature, is whether subjects' level of scientific importance is relevant to determining how much support they should receive.
SUPPORT: Risks, Harms, and Equipoise
Authors: Nelson Robert M.
Published: January 2015

The debate about the ethics of the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT) often focuses on the assumptions made by the different parties involved, failing to note the lack of a necessary connection between those assumptions and the main criticism of the study—that the parents appear to have been poorly informed. The fact that the target ranges of oxygen saturation (SpO2) used in SUPPORT were within the range recommended as an appropriate “standard of care” does not mean that the infants randomized to one of two restricted SpO2 ranges received the same treatment they would have received outside of the trial. The corresponding observation that randomization altered the potential harms to which an individual infant was exposed does not mean that the risks of being in SUPPORT were greater than or in addition to the risks associated with usual care. The argument that parents should have been better informed about these potential harms does not entail the (incorrect) assumption that neonatal clinicians make individualized treatment decisions rather than follow a standardized protocol when adjusting the level of oxygen a preterm infant receives. The fact that parents are unaware of the trade‐off clinicians make between these potential harms when establishing such a protocol does not justify the failure to adequately inform parents about the purpose of SUPPORT and the risks and harms that were involved.
The Controversy over SUPPORT Continues and the Hyperbole Increases
Authors: Fleischman Alan R.
Published: January 2015

Two articles in this issue of the Hastings Center Report address the continuing controversy over the Surfactant, Positive Pressure, and Oxygenation Randomized Trial (SUPPORT). This controversy is part of a larger discussion about the appropriate regulatory framework for protecting human research participants in comparative effectiveness research (CER), a group of studies that aims to compare two “usual” or “standard” treatments in order to provide evidence of which treatment is most effective.
On the Destructiveness of Scientism
Authors: Cassell Eric J.
Published: January 2015

Healers: Extraordinary Clinicians at Work, by David Schenck and Larry R. Churchill, and What Patients Teach: The Everyday Ethics of Health Care, by Churchill, Joseph B. Fanning, and Schenck are both important and thought‐inspiring books. For the first, Schenck and Churchill recruited fifty practitioners, mostly physicians but some clinicians who practice alternative therapies, “identified by their peers as excellent healers,” and interviewed them to find out what they did to establish a good relationship with their patients. The results of their interviews and how they wrote their book makes this the best and most concrete understanding of a necessary step to healing that I have read. What Patients Teach examines the patients’ perspective about forming relationships with their clinicians. The patients’ clinicians were asked to nominate patients to be interviewed to help answer the question. This volume, while important, is less extraordinary than the first because we hear less what the patients want to say and more what the authors want to tell us. That aside, taken together, these two books are a major advance in the literature of healing.
Lateralization of brain activity pattern during unilateral movement in Parkinson's disease
Authors: Wu Tao , Hou Yanan , Hallett Mark , Zhang Jiarong , Chan Piu
Published: January 2015

We investigated the lateralization of brain activity pattern during performance of unilateral movement in drug‐naïve Parkinson's disease (PD) patients with only right hemiparkinsonian symptoms. Functional MRI was obtained when the subjects performed strictly unilateral right hand movement. A laterality index was calculated to examine the lateralization. Patients had decreased activity in the left putamen and left supplementary motor area, but had increased activity in the right primary motor cortex, right premotor cortex, left postcentral gyrus, and bilateral cerebellum. The laterality index was significantly decreased in PD patients compared with controls (0.41 ± 0.14 vs. 0.84 ± 0.09). The connectivity from the left putamen to cortical motor regions and cerebellum was decreased, while the interactions between the cortical motor regions, cerebellum, and right putamen were increased. Our study demonstrates that in early PD, the lateralization of brain activity during unilateral movement is significantly reduced. The dysfunction of the striatum–cortical circuit, decreased transcallosal inhibition, and compensatory efforts from cortical motor regions, cerebellum, and the less affected striatum are likely reasons contributing to the reduced motor lateralization. The disruption of the lateralized brain activity pattern might be a reason underlying some motor deficits in PD, like mirror movements or impaired bilateral motor coordination. Hum Brain Mapp 36:1878–1891, 2015. © 2015 Wiley Periodicals, Inc.
Osteoblast-Specific γ-Glutamyl Carboxylase-Deficient Mice Display Enhanced Bone Formation With Aberrant Mineralization
Authors: Azuma Kotaro , Shiba Sachiko , Hasegawa Tomoka , Ikeda Kazuhiro , Urano Tomohiko , Horie-Inoue Kuniko , Ouchi Yasuyoshi , Amizuka Norio , Inoue Satoshi
Published: January 2015

Vitamin K is a fat-soluble vitamin that is necessary for blood coagulation. In addition, it has bone-protective effects. Vitamin K functions as a cofactor of γ-glutamyl carboxylase (GGCX), which activates its substrates by carboxylation. These substrates are found throughout the body and examples include hepatic blood coagulation factors. Furthermore, vitamin K functions as a ligand of the nuclear receptor known as steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR). We have previously reported on the bone-protective role of SXR/PXR signaling by demonstrating that systemic Pxr-knockout mice displayed osteopenia. Because systemic Ggcx-knockout mice die shortly after birth from severe hemorrhage, the GGCX-mediated effect of vitamin K on bone metabolism has been difficult to evaluate. In this work, we utilized Ggcx-floxed mice to generate osteoblast-specific GGCX-deficient (GgcxΔobl/Δobl) mice by crossing them with Col1-Cre mice. The bone mineral density (BMD) of GgcxΔobl/Δobl mice was significantly higher than that of control Col1-Cre (Ggcx+/+) mice. Histomorphometrical analysis of trabecular bones in the proximal tibia showed increased osteoid volume and a higher rate of bone formation in GgcxΔobl/Δobl mice. Histomorphometrical analysis of cortical bones revealed a thicker cortical width and a higher rate of bone formation in GgcxΔobl/Δobl mice. Electron microscopic examination revealed disassembly of mineralized nodules and aberrant calcification of collagen fibers in GgcxΔobl/Δobl mice. The mechanical properties of bones from GgcxΔobl/Δobl mice tended to be stronger than those from control Ggcx+/+ mice. These results suggest that GGCX in osteoblasts functions to prevent abnormal mineralization in bone formation, although this function may not be a prerequisite for the bone-protective effect of vitamin K. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.
Progradation rates of coastal barriers estimated from the 14C age of soil organic matter
Authors: BOSKI T. , ANGULO R.J. , SOUZA M.C. , BARBOZA E.G. , KNICKER H. , GONZÁLEZ‐PÉREZ J.A. , GONZÁLEZ‐VILA F.J.
Published: January 2015

The antecedent geomorphological and structural framework combined with nearshore dynamics and sediment budget provided the conditions necessary for the formation of coastal plains along the southern Brazilian littoral during the Holocene. To establish a temporal framework for littoral accretion, we applied 14C dating of humic organic material from the B‐horizon of spodosols. The dated soils developed under Atlantic tropical forest, which covers the coastal barriers along the Santa Catarina shoreline of south‐east Brazil. The obtained ages point to a highly coherent trend in barrier accretion and indicate that the transfer of organic matter from the surface to the B‐horizon has largely been occurring vertically at the same time as the sediment surface was colonized by Atlantic forest. Accretion of the strandplain in the coastal cell of Volta Velha began ca. 6800 cal a BP, initially at a rate of ca. 22 cm a−1 and reaching 58 cm a−1 during the last 3 ka. Structural analysis of the dated humic material was by analytical pyrolysis and solid‐state 13C nuclear magnetic resonance spectroscopy. Both techniques revealed marked compositional differences between the organic matter of different ages, which are discussed in terms of time‐dependent degradation processes.
Landscape sensitivity and ecological change in western Zambia: The long‐term perspective from dambo cut‐and‐fill sediments
Authors: BURROUGH S. L. , THOMAS D. S. G. , ORIJEMIE E. A. , WILLIS K. J.
Published: January 2015

A series of small, shallow seasonally, or interannually, waterlogged depressions (dambos) in the upper Zambezi Valley in western Zambia hold shallow peat deposits and are bounded on their western margin by sandy lunette dunes. Using luminescence dating of sands, fossil pollen analyses and the macrocharcoal record from cored peat, the long‐term stability of these landforms and the vegetation they now support is investigated at a site east of the upper Zambezi. Although the upper lunette dune sediments accumulated between 14 ± 2 and 6 ± 1 ka, the onset of peat accumulation and preservation within the dambo did not occur until 2800 cal a BP, suggesting that only from this point onwards were conditions stable and wet enough year‐round to allow the formation and preservation of peat during this time. Results from this study indicate that the long‐term behaviour of the dambo conforms to a cut‐and‐fill dynamic, where under more arid conditions the dambo becomes a dry pan, providing a sediment source for the adjacent lunette dune. In contrast, during wetter times, when the dambo holds surface water year‐round, it becomes an organic‐rich sediment repository preserving a fossil pollen record of long‐term vegetation change.
Hydrological variations on the Central Tibetan Plateau since the Last Glacial Maximum and their teleconnection to inter‐regional and hemispheric climate variations
Authors: KASPER THOMAS , HABERZETTL TORSTEN , WANG JUNBO , DAUT GERHARD , DOBERSCHÜtz STEFAN , ZHU LIPING , MÄUSBACHER ROLAND
Published: January 2015

Decadal to sub‐decadal variability of inflow, evaporation and biological productivity derived from Lake Nam Co was used to reconstruct hydrological changes for the past ca. 24 k cal a BP. The timing of these variations corresponds to known climatic shifts on the Northern Hemisphere. After a dry and cold Last Glacial Maximum the lake level of Nam Co initially rose at ca. 20 k cal a BP. Moist but further cold conditions between ca. 16.2 and 14 k cal a BP correspond to Heinrich Event 1. A warm and moist phase between ca. 14 and 13 k cal a BP is expressed as a massive enhancement in inflow and biological productivity and might be associated with a first intensification of the Indian Ocean Summer Monsoon coinciding with the Bølling–Allerød complex. A two‐step decrease in inflow and a contemporaneous decline in biological productivity until ca. 11.8 k cal a BP points to cool and dry conditions during the Younger Dryas. Lake levels peak at ca. 9.4 k cal a BP, although hydrological conditions remain relatively stable during the Holocene with only low‐amplitude variations observed.
A test of the cosmogenic 3He production rate in the south‐west Pacific (39°S)
Authors: EAVES SHAUN R. , WINCKLER GISELA , SCHAEFER JOERG M. , VANDERGOES MARCUS J. , ALLOWAY BRENT V. , MACKINTOSH ANDREW N. , TOWNSEND DOUGAL B. , RYAN MATTHEW T. , LI XUN
Published: January 2015

Calculation of surface exposure ages, using in situ cosmogenic nuclides, requires accurate knowledge of local production rates. Here, we report the first attempt to calibrate cosmogenic 3He production in the south‐west Pacific region. We present a new radiocarbon chronology that precisely dates the emplacement of the Murimotu Formation, a large debris avalanche deposit in central North Island, New Zealand (ca. 830 m asl; 39°S), which occurred 10.4–10.6 cal ka BP. Measurements of cosmogenic 3He in pyroxene separated from large andesitic blocks exposed during this event yield a sea‐level high‐latitude production rate of 120 ± 12 atoms g−1 a−1 (‘Lm’ scaling). This is consistent with a recent global compilation, comprised predominantly of calibration sites located in the Northern Hemisphere. Thus, we conclude that the globally compiled cosmogenic 3He production rate is valid in the south‐west Pacific. Using independent, proximal calibrations of cosmogenic isotopes 10Be and 14C from quartz in New Zealand, we derive cosmogenic 3He/10Be and 3He/14C production ratios of 32.2 ± 3.2 and 10.6 ± 1.6, respectively.
Low‐cost modular phonosurgery training station: Development and validation
Authors: Holliday Michael A. , Bones Victoria M. , Malekzadeh Sonya , Grant Nazaneen N.
Published: January 2015

Objective

Phonosurgery requires technical precision and careful tissue handling. Typically, phonosurgical procedures require single‐operator techniques, making it difficult for novice residents to develop necessary skills. We developed a low‐cost phonosurgery simulator to allow practice and acquisition of microlaryngeal skills.

Study Design

Validation study assessing the simulator's face and content validity in surgical education.

Methods

For construction, the simulator is composed of a simulation station and laryngeal modules, each constructed with inexpensive, easily accessible materials including plywood and polyvinyl chloride pipe. Laryngeal modules were constructed using rubber bands, bacitracin, and plastic wrap to simulate layers of the true vocal fold. Three separate modules were developed to address specific skills: 1) basic instrumentation; 2) papilloma debulking; 3) subepithelial and epithelial lesion excision. Papillomas, subepithelial, and epithelial lesions were simulated with grapefruit, caulk, and suture, respectively. The Kantor‐Berci video laryngoscope was used for visualization.

For validation, face and content validity were assessed by attending otolaryngologists (n = 16), who performed the three specific skills using the simulation station and completed a 5‐point Likert‐type postsimulation questionnaire.

Results

Most participants (89%) strongly agreed that the simulator incorporates essential phonosurgery skills and that portions of the model simulated an actual case (content validity). All participants (100%) agreed that the simulator is an adequate training device to increase resident competency and would be interested in using it to train residents (face validity).

Conclusion

This simulator has the potential to be an important component of phonosurgical education and preoperative preparation. Advantages include a realistic experience, modular design, and inexpensive construction.

Level of Evidence

N/A. Laryngoscope, 125:1409–1413, 2015
Less Heat — More Power
Authors: Rattunde Marcel , Berndt Michael
Published: January 2015

We demonstrate a diode laser pumped semiconductor disk laser (SDL) at 2 μm wavelength of increased efficiency. By employing a novel pumping concept at a wavelength of 1470 nm, we optimize the power conversion efficiency of the 2 μm SDL. This is exemplarily shown for an SDL with an output power of over 20 W in continuous wave operation. This sets a new benchmark regarding efficiency and output power for these SDLs.
Direct Metal Laser Sintering
Authors: Grünberger Thomas , Domröse Robert
Published: January 2015

A few years ago, 3D printing and additive manufacturing (AM) were next generation technologies and well known as methods for rapid prototyping. Less rapid manufacturing applications were on the market (e. g. manufacturing of dental crowns and bridges). Today, AM is on the step to serial production, industries ranging from aerospace and medical to energy and automotive benefit from the possibility to design and manufacture products in a completely new way. These industries require a detailed documentation of the process including automated in‐process quality inspection. Several technologies are used for quality assurance of the process and quality inspection of the parts. This paper describes how to setup an in‐process monitoring system to detect a process phenomenon called “splashy process” for the DMLS process.
Depressive symptoms in Parkinson's disease are related to decreased hippocampus and amygdala volume
Authors: van Mierlo Tom J. , Chung Chin , Foncke Elisabeth M. , Berendse Henk W. , van den Heuvel Odile A.
Published: January 2015

Depression and anxiety are common in Parkinson's disease (PD), and are among the non‐motor symptoms that interfere with quality of life dramatically. Motor, cognitive, and affective features overlap in PD, hampering diagnosis. To shed more light on the contribution of structural brain changes to the presence of PD‐related depressive symptoms, we conducted a Voxel‐Based Morphometry (VBM) study. We hypothesized that depressive symptoms in PD are related to regional gray matter (GM) volume loss within the limbic circuit. We analyzed the T1‐weigthed magnetic resonance imaging (MRI) images of 67 PD patients with a mean disease duration of 2.95 (±3.39) years. Scores on the Beck Depression Inventory (BDI) and GM probability maps were analyzed by regression analysis to study the association between GM volume and severity of depressive symptoms. Results are reported at both the uncorrected and the family‐wise error (FWE) corrected level for multiple comparisons. The BDI scores correlated negatively with bilateral hippocampus and right amygdala volume and positively with the volume of the anterior cingulate cortex. These findings confirm the hypothesized involvement of the limbic circuit in PD‐related depressive symptoms. We speculate that non‐dopaminergic changes are essential in the pathophysiology of depressive symptoms in PD, because our findings suggest the involvement of extra‐striatal brain regions. © 2015 International Parkinson and Movement Disorder Society
An efficient algebraic multigrid method for quadratic discretizations of linear elasticity problems on some typical anisotropic meshes in three dimensions
Authors: Xiao Yingxiong , Zhou Zhiyang , Shu Shi
Published: January 2015

The quality of the mesh used in the finite element discretizations will affect the efficiency of solving the discreted linear systems. The usual algebraic solvers except multigrid method do not consider the effect of the grid geometry and the mesh quality on their convergence rates. In this paper, we consider the hierarchical quadratic discretizations of three‐dimensional linear elasticity problems on some anisotropic hexahedral meshes and present a new two‐level method, which is weakly independent of the size of the resulting problems by using a special local block Gauss–Seidel smoother, that is LBGS_v iteration when used for vertex nodes or LBGS_m iteration for midside nodes. Moreover, we obtain the efficient algebraic multigrid (AMG) methods by applying DAMG (AMG based on distance matrix) or DAMG‐PCG (PCG with DAMG as a preconditioner) to the solution of the coarse level equation. The resulting AMG methods are then applied to a practical example as a long beam. The numerical results verify the efficiency and robustness of the proposed AMG algorithms. Copyright © 2015 John Wiley & Sons, Ltd.
Chaotic dynamics and convergence analysis of temporal difference algorithms with bang‐bang control
Authors: Tutsoy Onder , Brown Martin
Published: January 2015

Reinforcement learning is a powerful tool used to obtain optimal control solutions for complex and difficult sequential decision making problems where only a minimal amount of a priori knowledge exists about the system dynamics. As such, it has also been used as a model of cognitive learning in humans and applied to systems, such as humanoid robots, to study embodied cognition. In this paper, a different approach is taken where a simple test problem is used to investigate issues associated with the value function's representation and parametric convergence. In particular, the terminal convergence problem is analyzed with a known optimal control policy where the aim is to accurately learn the value function. For certain initial conditions, the value function is explicitly calculated and it is shown to have a polynomial form. It is parameterized by terms that are functions of the unknown plant's parameters and the value function's discount factor, and their convergence properties are analyzed. It is shown that the temporal difference error introduces a null space associated with the finite horizon basis function during the experiment. The learning problem is only non‐singular when the experiment termination is handled correctly and a number of (equivalent) solutions are described. Finally, it is demonstrated that, in general, the test problem's dynamics are chaotic for random initial states and this causes digital offset in the value function learning. The offset is calculated, and a dead zone is defined to switch off learning in the chaotic region. Copyright © 2015 John Wiley & Sons, Ltd.
Absorption threshold extended to 1.15 eV using InGaAs/GaAsP quantum wells for over‐50%‐efficient lattice‐matched quad‐junction solar cells
Authors: Toprasertpong Kasidit , Fujii Hiromasa , Thomas Tomos , Führer Markus , Alonso‐Álvarez Diego , Farrell Daniel J. , Watanabe Kentaroh , Okada Yoshitaka , Ekins‐Daukes Nicholas J. , Sugiyama Masakazu , Nakano Yoshiaki
Published: January 2015

Bandgap engineering of strain‐balanced InGaAs/GaAsP multiple quantum wells (MQWs) allows high‐quality materials with an absorption edge beyond GaAs to be epitaxially grown in Ge/GaAs‐based multijunction solar cells. We demonstrate MQW solar cells with effective bandgaps ranging from 1.31 eV to as low as 1.15 eV. The bandgap‐voltage‐offset of MQWs is found to be independent of effective bandgaps and superior to a bulk reference by approximately 0.1 V. This implies the merit of high photovoltage as compared with bulk cells with the same bandgap in addition to their widely bandgap‐tunable property. Towards the realization of fully lattice‐matched quad‐junction devices, we demonstrate a 70‐period, 1.15‐eV bandgap MQW cell as a promising material in 0.66/1.15/1.51/1.99‐eV quad‐junction cells, whose practical efficiency has a potential to achieve over 50%. With such a large period number of MQWs, the reverse‐biased external quantum efficiency reaches an average of over 60% in the spectral region corresponding to a 1.15‐eV subcell; this is achieved with only a‐few‐percent drop at short‐circuit condition. The device presented here reaches the target open‐circuit voltage and over 75% of the current density required for realizing a 1.15‐eV subcell in a 50%‐efficient quad‐junction solar cell. We believe that future devices which exploit light‐trapping structures and enhanced carrier extraction will be able to reach the desired target. Copyright © 2015 John Wiley & Sons, Ltd.