bluuebunny/crossref_metadata_2025 huggingface dataset:
Similar Clinical Severity and Outcomes for Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus Pediatric Musculoskeletal Infections
Authors: An Thomas J. , Benvenuti Michael A. , Mignemi Megan E. , Martus Jeffrey , Wood James B. , Thomsen Isaac P. , Schoenecker Jonathan G.
Published: February 2017

Background

Prior studies of pediatric musculoskeletal infection have suggested that methicillin-resistant Staphylococcus aureus (MRSA) infections result in worse outcomes compared with infections with methicillin-susceptible S aureus (MSSA) strains. Based on these results, clinical prediction algorithms have been developed to differentiate between MRSA and MSSA early in a patient’s clinical course. This study compares hospital outcomes for pediatric patients with MRSA and MSSA musculoskeletal infection presenting to the emergency department at a large tertiary care children’s hospital.

Methods

A retrospective study identified pediatric patients with S aureus musculoskeletal infection over a 5-year period (2008–2013) by sequential review of all pediatric orthopedic consults. Relevant demographic information, laboratory values, and clinical outcomes were obtained from the electronic medical record.

Results

Of the 91 identified cases of S aureus pediatric musculoskeletal infection, there were 49 cases of MRSA infection (53%) and 42 cases of MSSA infection (47%). There were no significant differences between MRSA and MSSA infections in median hospital length of stay (4.8 vs 5.7 days, P = .50), febrile days (0.0 vs 1.5 days, P = .10), and antibiotic duration (28 vs 34 days, P = .18). Methicillin-resistant S aureus infections were more likely to require operative intervention than MSSA infection (85% vs 62%, P = .15). A logistic regression model based on C-reactive protein, temperature, white blood cell count, pulse, and respiratory rate at presentation demonstrated poor ability to differentiate between MRSA and MSSA infection.

Conclusions

The results demonstrated no significant differences between MSSA and MRSA musculoskeletal infections for most hospital outcomes measured. However, MRSA infections required more operative interventions than MSSA infections. In addition, a predictive model based on severity markers obtained at presentation was unable to effectively differentiate between MRSA and MSSA infection. The clinical utility and capacity for early differentiation of MRSA and MSSA depends on virulence patterns that may vary temporally and geographically.
Use of Narrow Band Imaging in the Diagnosis of Hypovascular Endobronchial Sarcoidosis
Authors: Hakim Rimoun , Sabath Bruce , Kaplan Tugba , Yung Rex
Published: February 2017

Narrow band imaging (NBI) has been widely applied for the evaluation of numerous disease conditions that present with increased vascularity of the mucosa, most often malignancies. It is increasingly being used in benign conditions as well. We present the first case in which NBI was used, rather, to detect areas of bronchial hypovascularity due to its ability to increase the visual contrast between normal and hypovascular mucosa. Endobronchial biopsy of these nodules led to the diagnosis of sarcoidosis. Had conventional white light alone been utilized, the diagnosis would likely have been missed because not only were these lesions difficult to visualize under white light but transbronchial lung biopsy and transbronchial needle aspiration were unremarkable. We propose that NBI should be considered in the bronchoscopic evaluation of possible sarcoidosis or any other condition that could present with airway hypovascularity.
Generally applicable transcriptome-wide analysis of translational efficiency using anota2seq
Authors: Oertlin Christian , Lorent Julie , Gandin Valentina , Murie Carl , Masvidal Laia , Cargnello Marie , Furic Luc , Topisirovic Ivan , Larsson Ola
Published: February 2017

mRNA translation plays an evolutionarily conserved role in homeostasis and when dysregulated results in various disorders. Optimal and universally applicable analytical methods to study transcriptome-wide changes in translational efficiency are therefore critical for understanding the complex role of translation regulation under physiological and pathological conditions. Techniques used to interrogate translatomes, including polysome- and ribosome-profiling, require adjustment for changes in total mRNA levels to capturebona fidealterations in translational efficiency. Herein, we present the anota2seq algorithm for such analysis using data from ribosome- or polysome-profiling quantified by DNA-microarrays or RNA sequencing, which outperforms current methods for identification of changes in translational efficiency. In contrast to available analytical methods, anota2seq also allows capture of an underappreciated mode for regulation of gene expression whereby translation acts as a buffering mechanism which maintains constant protein levels despite fluctuations in mRNA levels (“translational buffering”). Application of anota2seq shows that insulin affects gene expression at multiple levels, in a largely mTOR-dependent manner. Moreover, insulin induces levels of a subset of mRNAs independently of mTOR that undergo translational buffering upon mTOR inhibition. Thus, the universal anota2seq algorithm allows efficient and hitherto unprecedented interrogation of translatomes and enables studies of translational buffering which represents an unexplored mechanism for regulating of gene expression.
Habitat generalists or specialists, insights from comparative genomic analyses ofThermosipholineages
Authors: Haverkamp Thomas H.A. , Geslin Claire , Lossouarn Julien , Podosokorskaya Olga A. , Kublanov Ilya , Nesbø Camilla L.
Published: February 2017

Thermosiphospecies inhabit various extreme environments such as marine hydrothermal vents, petroleum reservoirs and terrestrial hot springs. A 16S rRNA phylogeny of availableThermosiphospp. sequences suggested habitat specialists adapted to living in hydrothermal vents only, and habitat generalists inhabiting oil reservoirs, hydrothermal vents and hotsprings. Comparative genomics and recombination analysis of the genomes of 15Thermosiphoisolates separated them into three species with different habitat distributions, the widely distributedT. africanusand the more specialized,T. melanesiensisandT. affectus. The threeThermosiphospecies can also be differentiated on the basis of genome content. For instance theT. africanusgenomes had the largest repertoire of carbohydrate metabolism, which could explain why these isolates were obtained from ecologically more divergent habitats. The three species also show different capacities for defense against foreign DNA.T. melanesiensisandT. africanusboth had a complete RM system, while this was missing inT. affectus. These observations also correlated with Pacbio sequencing, which revealed a methylatedT. melanesiensisBI431 genome, while no methylation was detected among twoT. affectusisolates. All the genomes carry CRISPR arrays accompanied by more or less complete CRISPR-cas systems. Interestingly, some isolates of bothT. melanesiensisandT. africanuscarry integrated prophage elements, with spacers matching these in their CRISPR arrays. Taken together, the comparative genomic analyses ofThermosiphospp. revealed genetic variation allowing habitat differentiation within the genus as well as differentiation with respect to invading mobile DNA that is present in subsurface ecosystems.
Broad-spectrum inhibition ofPhytophthora infestansby root endophytes
Authors: de Vries Sophie , von Dahlen Janina K. , Schnake Anika , Ginschel Sarah , Schulz Barbara , Rose Laura E.
Published: February 2017

Phytophthora infestans(Phy. infestans) is a devastating pathogen of tomato and potato. It readily overcomes resistance genes and applied agrochemicals. Fungal endophytes provide a largely unexplored avenue of control againstPhy. infestans. Not only do endophytes produce a wide array of bioactive metabolites, they may also directly compete with and defeat pathogensin planta.

Twelve isolates of fungal endophytes from different plant species were testedin vitrofor their production of metabolites with anti-Phy. infestansactivity. Four well-performing isolates were evaluated for their ability to suppress nine isolates ofPhy. infestanson agar medium andin planta.

Two endophytes reliably inhibited allPhy. infestansisolates on agar medium, of whichPhoma eupatoriiisolate 8082 was the most promising. It nearly abolished infection byPhy. infestans in planta.

Here we present a biocontrol agent, which can inhibit a broad-spectrum ofPhy. infestansisolates. Such broadly acting inhibition is ideal, because it allows for effective control of genetically diverse pathogen isolates and may slow the adaptation ofPhy. infestans.
Robust and Efficient Coding with Grid Cells
Authors: Vágó Lajos , Ujfalussy Balázs B
Published: February 2017

The neuronal code arising from the coordinated population activity of grid cells in the rodent entorhinal cortex can uniquely represent space across large distances but the precise conditions for efficient coding are unknown. Here we present a number-theoretic analysis of grid coding and derive an upper bound on the distance that a population of grid cells can represent without error. We show that in the absence of neuronal noise, the capacity of the system would be extremely sensitive to the choice of the grid periods. However, when the accuracy of the representation is limited by neuronal noise, the capacity becomes gradually more robust against the choice of grid scales as the number of modules increases and remains near optimal even for random scale choices. Our study reveals that robust and efficient coding can be achieved without parameter tuning in the case of grid cell representation.
Division of labor, bet hedging, and the evolution of mixed biofilm investment strategies
Authors: Lowery Nick Vallespir , McNally Luke , Ratcliff William C. , Brown Sam P.
Published: February 2017

Bacterial cells, like many other organisms, face a tradeoff between longevity and fecundity. Planktonic cells are fast growing and fragile, while biofilm cells are often slower growing but stress resistant. Here we ask: why do bacterial lineages invest simultaneously in both fast and slow growing types? We develop a population dynamical model of lineage expansion across a patchy environment, and find that mixed investment is favored across a broad range of environmental conditions, even when transmission is entirely via biofilm cells. This mixed strategy is favored because of a division of labor, where exponentially dividing planktonic cells can act as an engine for the production of future biofilm cells, which grow more slowly. We use experimental evolution to test our predictions, and show that phenotypic heterogeneity is persistent even under selection for purely planktonic or purely biofilm transmission. Furthermore, simulations suggest that maintenance of a biofilm subpopulation serves as a cost-effective hedge against environmental uncertainty, which is also consistent with our experimental findings.
Using constrained inversion of gravity and magnetic field to produce a 3D litho‐prediction model
Authors: Mahmoodi Omid , Smith Richard S. , Spicer Bill
Published: February 2017

Geologically constrained inversion of gravity and magnetic field data of the Victoria property (located in Sudbury, Canada) was undertaken in order to update the present three‐dimensional geological model. The initial and reference model was constructed based on geological information from over 950 drillholes to constrain the inversion. In addition, downhole density and magnetic susceptibility measured in six holes were statistically analysed to derive lower and upper bounds on the physical properties attributed to the lithological units in the reference model. Constrained inversion of the ground gravity and the airborne magnetic data collected at the Victoria property were performed using GRAV3D and MAG3D, respectively. A neural network was trained to predict lithological units from the physical properties measured in six holes. Then, the trained network was applied on the three‐dimensional distribution of physical properties derived from the inversion models to produce a three‐dimensional litho‐prediction model. Some of the features evident in the lithological model are remnants of the constraints, where the data did not demand a significant change in the model from the initial constraining model (e.g., the thin pair of diabase dykes). However, some important changes away from the initial model are evident; for example, a larger body was predicted for quartz diorite, which may be related to the prospective offset dykes; a new zone was predicted as sulfide, which may represent potential mineralisation; and a geophysical subcategory of metabasalt was identified with high magnetic susceptibility and high density. The litho‐prediction model agrees with the geological expectation for the three‐dimensional structure at Victoria and is consistent with the geophysical data, which results in a more holistic understanding of the subsurface lithology.
Functional outcomes of fungal community shifts driven by tree genotype and spatial‐temporal factors in Mediterranean pine forests
Authors: Pérez‐Izquierdo Leticia , Zabal‐Aguirre Mario , Flores‐Rentería Dulce , González‐Martínez Santiago C. , Buée Marc , Rincón Ana
Published: February 2017

Fungi provide relevant ecosystem services contributing to primary productivity and the cycling of nutrients in forests. These fungal inputs can be decisive for the resilience of Mediterranean forests under global change scenarios, making necessary an in‐deep knowledge about how fungal communities operate in these ecosystems. By using high‐throughput sequencing and enzymatic approaches, we studied the fungal communities associated with three genotypic variants of Pinus pinaster trees, in 45‐year‐old common garden plantations. We aimed to determine the impact of biotic (i.e., tree genotype) and abiotic (i.e., season, site) factors on the fungal community structure, and to explore whether structural shifts triggered functional responses affecting relevant ecosystem processes. Tree genotype and spatial‐temporal factors were pivotal structuring fungal communities, mainly by influencing their assemblage and selecting certain fungi. Diversity variations of total fungal community and of that of specific fungal guilds, together with edaphic properties and tree's productivity, explained relevant ecosystem services such as processes involved in carbon turnover and phosphorous mobilization. A mechanistic model integrating relations of these variables and ecosystem functional outcomes is provided. Our results highlight the importance of structural shifts in fungal communities because they may have functional consequences for key ecosystem processes in Mediterranean forests.
Back on the water margin: the ethical fixes of sustainable water provisions in rural China
Authors: Pia Andrea E.
Published: February 2017

The classical Chinese novelThe water margintells the story of a group of petty officials who take a collective stance against the widespread corruption and unfairness of imperial Chinese society. At the root of this story lies the deeply ethical conundrum of redressing injustice when unchecked power prevails. This article draws from this insight to explore some of the ethical dilemmas Chinese state bureaucrats in Yunnan face today when provisioning drinking water to rural communities. Yunnanese officials are burdened with these dilemmas by the state's conspicuous retreat from rural public services in favour of market‐based supply. Through their ethical interventions, Chinese bureaucrats are able to temporarily defer the collapsing of rural water provisions which is caused by the contradictions introduced by the marketization of water. However, such interventions may be followed by further damage to the environment.
Determination of Time since Death using Vitreous Humor Tryptophan
Authors: Ansari Niha , Menon Shobhana K.
Published: February 2017

Determination of time since death (TSD) plays very important role in forensic examination as it narrows down field of suspects and aids in deceased identification. This study utilizes the fluorescence property of vitreous humor (VH) tryptophan to determine TSD using o‐phthalaldehyde (OPA). The detection limit of these fluorometric studies was found to be 8 ppb indicating sensitivity and high accuracy in TSD determination. The study was performed on selected 76 cadaver with known TSD ranging from 3 to 90 h. Excellent correlation between VH tryptophan and TSD was obtained with a coefficient of correlationR2= 0.9590. Results showed statistically significant increase in vitreous tryptophan with TSD up to 90 h, and the proposed method was efficaciously applied for prediction of TSD as no systematic error exist. The regression equation obtained from the study is [Trp] = 2.21 + 2.98 * TSD.
Masculinity, Age and Life Cycle in the Age of Reform
Authors: Gleadle Kathryn
Published: February 2017

The 1867 Reform Act created a polity in which, for 50 years, age and householding status were frequently more important than class in determining British men's right to vote. In the debates leading up to the act, both age and householder status were deployed to manage fears of greater democratisation. This essay traces some of the associative connections parliamentarians made between the sexual and family status of potential voters; their relationship to their fathers or sons; the kinds of houses in which they dwelt; and their personal decisions to delay or undertake marriage. The claim that the new male voter was distinguished for his ‘independence’ has been much discussed. However, it is suggested here that it was equally the figure of the settled citizen which emerged as significant during parliamentary debate. This was a category which could be interlaced with a stream of connected ideas concerning attachment to the ‘hearth’, the community, and to Anglo‐Saxon heritage itself. During the age of reform, calls to raise the age of suffrage frequently surfaced. This contributed to a climate of opinion which legitimised arguments denigrating the political abilities of the young and which helped to make possible age‐related political structures. Analysed alongside debates over the merits of an education clause in 1866 and the amendment to enfranchise lodgers the following year, the essay considers how class‐specific distinctions of age and life cycle helped to uphold an enduring model of hegemonic masculinity, centring on the mature, householding male.
The Second Reform Act and the Politics of Empire
Authors: Middleton Alex
Published: February 2017

This essay examines the place of imperial issues in the debates over the Second Reform Act. It argues that contemporaries did not readily associate the British empire with domestic constitutional reform in the 1860s; that relatively few references were made to imperial questions in the course of the debates; and that those references were of limited significance to the framing and interpretation of the legislation. It suggests, furthermore, that the act exercised minimal influence on the ways in which the empire was discussed immediately after 1867. The essay goes on to argue that this separation between visions of domestic constitutional reform and visions of empire in the 1860s had a number of causes, but that it was in large part a consequence of the resolution of specific anxieties about imperial policy, which had made imperial government a topic of sustained debate at home between the late 1820s and early 1850s.
The Irish Reform Act of 1868
Authors: Barr Colin
Published: February 2017

From the Act of Union until 1884, the Irish electoral franchise was different from that in England or Scotland. The history of its reform also followed a different calendar: 1829, 1832, 1850, and 1868 were the waypoints on the path to homogenisation with the rest of the United Kingdom. But the Irish Reform Act of 1868 has received little attention, and is usually dismissed as a minor technical alteration of minimal political or social importance. When set against the changes in England the year before, this is true. But it is worthy of study, and this essay is the first to examine the 1860s campaign for Irish reform, its relationship to events in Britain, the expectations for the act, its various drafts, and its political consequences. It traces the short‐lived alliance between the Catholic Church, the Irish Liberal Party and often secular working‐class radicals in both Ireland and England, as well as the parallel, but quite distinct, campaign for reform on the part of working‐class northern protestants, many associated with the Orange Order. Although political circumstance resulted in the abandonment of most of the projected reforms, the drafting process and accompanying debates reveal important aspects of Irish political realities and expectations, as well as the limits of parliamentary interest in Ireland. Even in its abbreviated form, the act had a significant impact on Irish politics, substantially increasing the borough electorate across the island and dramatically so in Ulster.
‘Pressure from Without’: Karl Marx and 1867
Authors: Jones Gareth Stedman
Published: February 2017

The period 1864 to 1867 was among the most fruitful of Karl Marx's life. As well as writing up the manuscript of Capital, he was an active participant in the International Working Men's Association (IWMA), which had been founded in London in 1864. It was Marx who composed its ‘Inaugural Address’ and the ‘Rules’ of the Association, helping to define the new social democratic language of the 1860s. Internationally, the civil war in America, the Polish Rising and the achievements of Mazzini and Garibaldi in Italy provided a new context for radical thought in Britain, contributing to a new political activism among trade unionists. Marx was closely engaged in these debates, as well as with the leading figures in the campaign for reform of parliament. He followed the reform debates closely, debating both the goals and tactics of reformers as well as the potential for ‘pressure from without’. As such, the reform struggle provides an important case study in Marx's evolving political thought and in his understanding of the means by which political change might be achieved. It is important to remember that, until the eve of publication, his intention was to publish the whole of Capital in two volumes. This would have established a far closer connection between his ‘Critique of Political Economy’ and his concurrent conception of ‘pressure from without’. Had this happened, it would have led to a significantly different conception of the relationship between the politics and economics of ‘Marxism’.
Inhibitory Effects of Red Wine on Lipid Oxidation in Fish Oil Emulsion and Angiogenesis in Zebrafish Embryo
Authors: Sun Haiyan , Zhang Yulin , Shen Yixiao , Zhu Yongchao , Wang Hua , Xu Zhimin
Published: February 2017

The capabilities of red wine against lipid oxidation and angiogenesis were evaluated by using a fish oil emulsion system and an in vivo zebrafish embryos model, respectively. The red wine contained 12 different antioxidant phenolics which levels were led by anthocyanins (140.46 mg/L), catechin (55.08 mg/L), and gallic acid (46.76 mg/L). The diversity of the phenolics in red wine was greater than the tea, coffee, or white wine selected as a peer control in this study. The total phenolics concentration of red wine was 305.53 mg/L, although the levels of tea, coffee, and white wine were 85.59, 76.85, and 26.57 mg/L, respectively. The activity of red wine in scavenging DPPH (2,2‐diphenyl‐1‐picrylhydrazyl) free radicals was approximately 4 times higher than the tea and 8 times than the coffee or white wine. The red wine showed the highest capability in preventing long chain PUFA oxidation in the fish oil emulsion. Because of the outstanding antioxidant activity of red wine, the red wine dried extract was used to monitor its inhibitory effect against angiogenesis by using transgenic zebrafish embryos (Tg[fli1:egfp]y1) with fluorescent blood vessels. After incubated in 100 μg/mL of the extract solution for 26 h pf, each of the embryos had a lower number of intersegmental vessel than the control embryo. The inhibition rate of red wine extract against growing of angiogenic blood vessel reached 100%.
Characterizing change points and continuous transitions in movement behaviours using wavelet decomposition
Authors: Soleymani Ali , Pennekamp Frank , Dodge Somayeh , Weibel Robert
Published: February 2017

Individual behaviour, that is, the reaction of an organism to internal state, conspecifics and individuals of other species as well as the environment, is a crucial building block of their ecology. Modern tracking techniques produce high‐frequency observations of spatial positions of animals and accompanying speed and tortuosity measurements. However, inferring behavioural modes from movement trajectories remains a challenge.

Changes in behavioural modes occur at different temporal and spatial scales and may take two forms: abrupt, representing distinct change points; or continuous, representing smooth transitions between movement modes. The multi‐scale nature of these behavioural changes necessitates development of methods that can pinpoint behavioural states across spatial and temporal scales.

We propose a novel segmentation method based on the discrete wavelet transform (DWT), where the movement signal is decomposed into low‐frequency approximation and high‐frequency detail sub‐bands to screen for behavioural changes at multiple scales. Approximation sub‐bands characterizes broad changes by taking the continuous variations between behavioural modes into account, whereas detail sub‐bands are employed to detect abrupt, finer scale change points.

We tested the ability of our method to identify behavioural modes in simulated trajectories by comparing it to three state‐of‐the‐art methods from the literature. We further validated the method using an annotated dataset of turkey vultures (Cathartes aura) relating extracted segments to the expert knowledge of migratory vs. non‐migratory patterns. Our results show that the proposed DWT segmentation is more versatile than other segmentation methods, as it can be applied to different movement parameters, performs better or equally well on the simulated data, and correctly identifies behavioural modes identified by the experts. It is hence a valuable addition to the toolbox of land managers and conservation practitioners to understand the behavioural patterns expressed by animals in natural and human‐dominated landscapes.
Grain spilled from moving trains create a substantial wildlife attractant in protected areas
Authors: Gangadharan A. , Pollock S. , Gilhooly P. , Friesen A. , Dorsey B. , St. Clair C. C.
Published: February 2017

Transportation corridors can attract threatened wildlife via habitat enhancement and foraging opportunities, leading to collisions with vehicles. But wildlife may also be attracted to energy‐dense food products that are spilled or discarded from moving vehicles, which is rarely studied. Therefore, we quantified train‐spilled attractants in Banff and Yoho National Parks, Canada, where agricultural products (hereafter, grain) are transported along 134 km of railway and may contribute to wildlife mortality. We measured grain deposition from 2012 to 2015 at 19 sites and assessed the performance of three structures developed to measure spilled grain. We then modeled grain deposition with respect to four types of spatial and temporal variables: those related to grain shipment, physical habitat characteristic, train‐related characteristics and variables specific to the study site. Grain was spilled at a mean rate of 1.64 g m−2 day−1 (sd = 3.60) from April to October (n = 3 years) and 1.52 (sd = 2.37) from November to March (n = 1 year). Extrapolating annual deposition across the study area yielded enough grain (110 tons) to provide 4.77 × 108 kcal of gross energy, which is equivalent to the average annual caloric needs of 42–54 grizzly bears Ursus arctos horribilis; the regional population is estimated at 50–73 animals. Much of this energy will not be accessible or available to bears; however, their attraction to it could contribute to rising and unsustainable rates of mortality. Models explained 9–31% of the variance in deposition for each grain type, primarily via coarse temporal variables of shipping rates and month. The absence of more specific predictive variables suggests that mitigation should target broader policies, such as prompt reporting and repair of leaky hopper cars, and limits to train stoppage in protected areas. We encourage more global assessment of the under‐studied issue of food attractants spilled by vehicles along transportation corridors.
Is There a Right to the Death of the Foetus?
Authors: Mathison Eric , Davis Jeremy
Published: February 2017

At some point in the future – perhaps within the next few decades – it will be possible for foetuses to develop completely outside the womb. Ectogenesis, as this technology is called, raises substantial issues for the abortion debate. One such issue is that it will become possible for a woman to have an abortion, in the sense of having the foetus removed from her body, but for the foetus to be kept alive. We argue that while there is a right to an abortion, there are reasons to doubt that there is a right to the death of the foetus. Our strategy in this essay is to consider and reject three arguments in favour of this latter right. The first claims that women have a right not to be biological mothers, the second that women have a right to genetic privacy, and the third that a foetus is one's property. Furthermore, we argue that it follows from rejecting the third claim that genetic parents also lack a right to the destruction of cryopreserved embryos used for in vitro fertilization. The conclusion that a woman possesses no right to the death of the foetus builds upon the claims that other pro‐choice advocates, such as Judith Jarvis Thomson, have made.
Ways Out of the Patenting Prohibition? Human Parthenogenetic and Induced Pluripotent Stem Cells
Authors: Schickl Hannah , Braun Matthias , Dabrock Peter
Published: February 2017

According to the judgement of the European Court of Justice in 2014, human parthenogenetic stem cells are excluded from the patenting prohibition of procedures based on hESC by the European Biopatent Directive, because human parthenotes are not human embryos. This article is based on the thesis that in light of the technological advances in the field of stem cell research, the attribution of the term ‘human embryo’ to certain entities on a descriptive level as well as the attribution of a normative protection status to certain entities based on the criterion of totipotency, are becoming increasingly unclear. The example of human parthenotes in particular demonstrates that totipotency is not at all a necessary condition for the attribution of the term ‘human embryo’. Furthermore, the example of hiPSC and somatic cells particularly shows that totipotency is also not a sufficient condition for the attribution of a normative protection status to certain entities. Therefore, it is not a suitable criterion for distinguishing between human embryos worthy of protection and human non‐embryos not worthy of protection. Consequently, this conclusion has repercussions for the patenting question. The strict delineation between an ethically problematic commercial use of human embryos and the concomitant patenting prohibition of hESC‐based procedures and an ethically unproblematic commercial use of human non‐embryos and the therefore either unrestrictedly permitted (cf. human parthenotes) or even unregulated (cf. hiPSC) patenting of procedures based on these alleged alternatives becomes increasingly blurred.
Human Dignity and Human Enhancement: A Multidimensional Approach
Authors: Kirchhoffer David G.
Published: February 2017

In the debates concerning the ethics of human enhancement through biological or technological modifications, there have been several appeals to the concept of human dignity, both by those favouring such enhancement and by those opposing it. The result is the phenomenon of ‘dignity talk', where opposing sides both appeal to the concept of human dignity to ground their arguments resulting in a moral impasse. This article examines the use of the concept of human dignity in the enhancement debates and reveals that the problem of dignity talk arises because proponents of various positions tend to ground human dignity in different features of the human individual. These features include species‐membership, possession of a particular capacity, a sense of self‐worth, and moral behaviour. The article proposes a solution to this problem by appealing to another feature of human beings, namely their being‐in‐relationship‐over‐time. Doing so enables us to understand dignity as a concept that affirms the worth of human individuals as complex, multidimensional wholes, rather than as isolated features. Consequently, the concept of human dignity can serve both a descriptive and a normative function in the enhancement debates. At a descriptive level, asking what advocates of a position mean when they refer to human dignity will reveal what aspects of being human they deem to be most valuable. The debate can then focus on these values. The normative function, although it cannot proscribe or prescribe all enhancement, approves only those enhancements that contribute to the flourishing of human individuals as multidimensional wholes.
Maximin Optimal Designs for Cluster Randomized Trials
Authors: Wu Sheng , Wong Weng Kee , Crespi Catherine M.
Published: February 2017

We consider design issues for cluster randomized trials (CRTs) with a binary outcome where both unit costs and intraclass correlation coefficients (ICCs) in the two arms may be unequal. We first propose a design that maximizes cost efficiency (CE), defined as the ratio of the precision of the efficacy measure to the study cost. Because such designs can be highly sensitive to the unknown ICCs and the anticipated success rates in the two arms, a local strategy based on a single set of best guesses for the ICCs and success rates can be risky. To mitigate this issue, we propose a maximin optimal design that permits ranges of values to be specified for the success rate and the ICC in each arm. We derive maximin optimal designs for three common measures of the efficacy of the intervention, risk difference, relative risk and odds ratio, and study their properties. Using a real cancer control and prevention trial example, we ascertain the efficiency of the widely used balanced design relative to the maximin optimal design and show that the former can be quite inefficient and less robust to mis-specifications of the ICCs and the success rates in the two arms.
Controlling the False Discoveries in LASSO
Authors: Huang Hanwen
Published: February 2017

The LASSO method estimates coefficients by minimizing the residual sum of squares plus a penalty term. The regularization parameter in LASSO controls the trade-off between data fitting and sparsity. We derive relationship between and the false discovery proportion (FDP) of LASSO estimator and show how to select so as to achieve a desired FDP. Our estimation is based on the asymptotic distribution of LASSO estimator in the limit of both sample size and dimension going to infinity with fixed ratio. We use a factor analysis model to describe the dependence structure of the design matrix. An efficient majorization–minimization based algorithm is developed to estimate the FDP at fixed value of . The analytic results are compared with those of numerical simulations on finite-size systems and are confirmed to be correct. An application to the high-throughput genomic riboavin data set also demonstrates the usefulness of our method.
Proton beam therapy for bone sarcomas of the skull base and spine: A retrospective nationwide multicenter study in Japan
Authors: Demizu Yusuke , Mizumoto Masashi , Onoe Tsuyoshi , Nakamura Naoki , Kikuchi Yasuhiro , Shibata Tetsushi , Okimoto Tomoaki , Sakurai Hideyuki , Akimoto Tetsuo , Ono Kota , Daimon Takashi , Murayama Shigeyuki
Published: February 2017

We conducted a retrospective, nationwide multicenter study to evaluate the clinical outcomes of proton beam therapy for bone sarcomas of the skull base and spine in Japan. Eligibility criteria included: (i) histologically proven bone sarcomas of the skull base or spine; (ii) no metastases; (iii) ≥20 years of age; and (iv) no prior treatment with radiotherapy. Of the 103 patients treated between January 2004 and January 2012, we retrospectively analyzed data from 96 patients who were followed‐up for >6 months or had died within 6 months. Seventy‐two patients (75.0%) had chordoma, 20 patients (20.8%) had chondrosarcoma, and four patients (7.2%) had osteosarcoma. The most frequent tumor locations included the skull base in 68 patients (70.8%) and the sacral spine in 13 patients (13.5%). Patients received a median total dose of 70.0 Gy (relative biological effectiveness). The median follow‐up was 52.6 (range, 6.3–131.9) months. The 5‐year overall survival, progression‐free survival, and local control rates were 75.3%, 49.6%, and 71.1%, respectively. Performance status was a significant factor for overall survival and progression‐free survival, whilst sex was a significant factor for local control. Acute Grade 3 and late toxicities of ≥Grade 3 were observed in nine patients (9.4%) each (late Grade 4 toxicities [n = 3 patients; 3.1%]). No treatment‐related deaths occurred. Proton beam therapy is safe and effective for the treatment of bone sarcomas of the skull base and spine in Japan. However, larger prospective studies with a longer follow‐up are warranted.
Children, Poverty and the Sustainable Development Goals
Authors: Dornan Paul
Published: February 2017

The Sustainable Development Goals (SDGs) came into force in January 2016, taking over from the Millennium Development Goals (MDGs). Significant human development progress has occurred in recent decades. Nevertheless, theMDGs have been criticised not least for failing to prioritise inequality and gains for the poorest people. TheSDGs create a much more comprehensive agenda and support many key child rights concerns. WhileSDGs reflect an important global consensus, their delivery depends upon national action.
Resection of synchronous liver metastases between radiotherapy and definitive surgery for locally advanced rectal cancer: short‐term surgical outcomes, overall survival and recurrence‐free survival
Authors: Labori K. J. , Guren M. G. , Brudvik K. W. , Røsok B. I. , Waage A. , Nesbakken A. , Larsen S. , Dueland S. , Edwin B. , Bjørnbeth B. A.
Published: February 2017

Aim

There is debate as to the correct treatment algorithm sequence for patients with locally advanced rectal cancer with liver metastases. The aim of the study was to assess safety, resectability and survival after a modified ‘liver‐first’ approach.

Method

This was a retrospective study of patients undergoing preoperative radiotherapy for the primary rectal tumour, followed by liver resection and, finally, resection of the primary tumour. Short‐term surgical outcome, overall survival and recurrence‐free survival are reported.

Results

Between 2009 and 2013, 45 patients underwent liver resection after preoperative radiotherapy. Thirty‐four patients (76%) received neoadjuvant chemotherapy, 24 (53%) concomitant chemotherapy during radiotherapy and 17 (43%) adjuvant chemotherapy. The median time interval from the last fraction of radiotherapy to liver resection and rectal surgery was 21 (range 7–116) and 60 (range 31–156) days, respectively. Rectal resection was performed in 42 patients but was not performed in one patient with complete response and two with progressive metastatic disease. After rectal surgery three patients did not proceed to a planned second stage liver (n = 2) or lung (n = 1) resection due to progressive disease. Clavien–Dindo ≥Grade III complications developed in 6.7% after liver resection and 19% after rectal resection. The median overall survival and recurrence‐free survival in the patients who completed the treatment sequence (n = 40) were 49.7 and 13.0 months, respectively. Twenty of the 30 patients who developed recurrence underwent further treatment with curative intent.

Conclusion

The modified liver‐first approach is safe and efficient in patients with locally advanced rectal cancer and allows initial control of both the primary tumour and the liver metastases.
Prediction model for cardiac allograft vasculopathy: Comparison of three multivariable methods
Authors: Kransdorf Evan P. , Loghmanpour Natasha A. , Kanwar Manreet K. , Temkit M'hamed H. , Stehlik Josef
Published: February 2017

Background

Cardiac allograft vasculopathy (CAV) remains an important cause of graft failure after heart transplantation (HT). Although many risk factors for CAV have been identified, there are no clinical prediction models that enable clinicians to determine each recipient's risk of CAV.

Methods

We studied a cohort of 14 328 heart transplant recipients whose data were reported to the International Society for Heart and Lung Transplantation Registry between 2000 and 2010. The cohort was divided into training (75%) and test (25%) sets. Multivariable modeling was performed in the test set using variables available at the time of heart transplant using three methods: (i) stepwise Cox proportional hazard, (ii) regularized Cox proportional hazard, and (iii) Bayesian network.

Results

Cardiac allograft vasculopathy developed in 4259 recipients (29.7%) at a median time of 3.0 years after HT. The regularized Cox proportional hazard model yielded the optimal performance and was also the most parsimonious. We deployed this model as an Internet‐based risk calculator application.

Conclusions

We have developed a clinical prediction model for assessing a recipient's risk of CAV using variables available at the time of HT. Application of this model may allow clinicians to determine which recipients will benefit from interventions to reduce the risk of development and progression of CAV.
Evaluation of the safety of endoscopic radiofrequency ablation for malignant biliary stricture using a digital peroral cholangioscope (with videos)
Authors: Ogura Takeshi , Onda Saori , Sano Tatsushi , Takagi Wataru , Okuda Atsushi , Miyano Akira , Nishioka Nobu , Imanishi Miyuki , Amano Mio , Masuda Daisuke , Higuchi Kazuhide
Published: February 2017

Background and Aim

The clinical impact of catheter‐based radiofrequency ablation (RFA) under endoscopic retrograde cholangiopancreatography (ERCP) guidance has recently been reported; however, severe adverse events have also been noted. If tumor is not present in the biliary tract, severe adverse events such as perforation or bleeding as a result of vessel injury around the biliary tract may occur. In addition, the effectiveness of RFA may not be sufficient based solely on radiographic guidance. The aim of the present study was to evaluate the actual feasibility of intraductal RFA by peroral cholangioscope (POCS) evaluation before/after RFA.

Methods

In this retrospective study carried out between July and September 2016, consecutive patients who underwent RFA for malignant biliary stricture and POCS evaluation before/after RFA were enrolled. Primary endpoint of this study was technical feasibility of RFA, which was evaluated by POCS. Secondary endpoints were rates and types of adverse event.

Results

A total of 12 consecutive patients were retrospectively enrolled in this study. Stent placement using uncovered metal stents had been previously done in six patients before RFA. Tumor was seen in the biliary tract in all patients. RFA was technically successful in all patients, and clinical success was confirmed in all patients by POCS imaging. Adverse events were seen in only one patient. Median stent patency was 154 days.

Conclusions

RFA for malignant biliary stricture may be safe. To confirm the feasibility and efficacy of RFA, additional cases, prospective studies, and a comparison study between with and without endobiliary RFA are needed.
Efficacy of midazolam‐ versus propofol‐based sedations by non‐anesthesiologists during therapeutic endoscopic retrograde cholangiopancreatography in patients aged over 80 years
Authors: Han Su Jung , Lee Tae Hoon , Park Sang‐Heum , Cho Young Sin , Lee Yun Nah , Jung Yunho , Choi Hyun Jong , Chung Il‐Kwun , Cha Sang‐Woo , Moon Jong Ho , Cho Young Deok , Kim Sun‐Joo
Published: February 2017

Background and Aim

As society ages, the need for endoscopic retrograde cholangiopancreatography (ERCP) is increasing. This prospective comparative study evaluated the safety and efficacy of midazolam‐ versus propofol‐based sedations by non‐anesthesiologists during therapeutic ERCP in patients over 80 years of age.

Methods

A total of 100 patients over 80 years of age who required therapeutic ERCP were enrolled and randomly received midazolam + fentanyl (MF group) or propofol + fentanyl (PF group) sedation. Endoscopic sedation was titrated to a moderate level and carried out by trained registered nurses. Main outcome measurements were sedation safety in terms of cardiopulmonary components and efficacy measured on a 10‐point visual analogue scale (VAS).

Results

Regarding safety, hypoxia occurred in seven (14%) in the MF group and in eight patients (16%) in the PF group (P = 0.779). Increased O2 supply was more frequent in the PF group (32% vs 42%), albeit not significantly so. There were no differences in the frequency of hypotension, bradycardia or tachycardia between the two groups. Mean VAS score for overall satisfaction with sedation by patients, endoscopists, and nurses and the scores for pain during the procedures were not different between the two groups. There was no significant difference in the procedure outcomes or rate of ERCP‐related complications.

Conclusions

There were no significant differences of safety and efficacy between midazolam‐ and propofol‐based sedation in patients over 80 years of age. Increased O2 supply was more frequent in the propofol group, but the prevalence of hypoxia did not differ significantly.
Chronic liraglutide therapy induces an enhanced endogenous glucagon‐like peptide‐1 secretory response in early type 2 diabetes
Authors: Kramer Caroline K. , Zinman Bernard , Choi Haysook , Connelly Philip W. , Retnakaran Ravi
Published: February 2017

Sustained exogenous stimulation of a hormone‐specific receptor can affect endogenous hormonal regulation. In this context, little is known about the impact of chronic treatment with glucagon‐like peptide‐1 (GLP‐1) agonists on the endogenous GLP‐1 response. We therefore evaluated the impact of chronic liraglutide therapy on endogenous GLP‐1 and glucose‐dependent insulinotropic polypeptide (GIP) response to an oral glucose challenge. A total of 51 people with type 2 diabetes of 2.6 ± 1.9 years’ duration were randomized to daily subcutaneous liraglutide or placebo injection and followed for 48 weeks, with an oral glucose tolerance test (OGTT) every 12 weeks. GLP‐1 and GIP responses were assessed according to their respective area under the curve (AUC) from measurements taken at 0, 30, 60, 90 and 120 minutes during each OGTT. There were no differences in AUCGIP
between the groups. By contrast, although fasting GLP‐1 was unaffected, the liraglutide arm had ~2‐fold higher AUCGLP

‐1 at 12 weeks (
P
 < .001), 24 weeks (
P
 < .001), 36 weeks (
P
 = .03) and 48 weeks (
P
 = .03), as compared with placebo. Thus, chronic liraglutide therapy induces a previously unrecognized, robust and durable enhancement of the endogenous GLP‐1 response, highlighting the need for further study of the long‐term effects of incretin mimetics on L‐cell physiology.