bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbiopsy engineered for minimally invasive and suture-free sub-millimetre skin sampling
Authors: Lin Lynlee L , Prow Tarl W , Raphael Anthony P , Harrold III Robert L , Primiero Clare A , Ansaldo Alexander B , Soyer H Peter
Published: May 2013

We describe the development of a sub-millimetre skin punch biopsy device for painless and suture-free skin sampling for molecular diagnosis and research. Conventional skin punch biopsies range from 2-4 mm in diameter. Local anaesthesia is required and sutures are usually used to close the wound. Our microbiopsy is 0.50 mm wide and 0.20 mm thick. The microbiopsy device is fabricated from three stacked medical grade stainless steel plates tapered to a point and contains a chamber within the centre plate to collect the skin sample. We observed that the application of this device resulted in a 0.21 ± 0.04 mm wide puncture site in volunteer skin using reflectance confocal microscopy. Histological sections from microbiopsied skin revealed 0.22 ± 0.12 mm wide and 0.26 ± 0.09 mm deep puncture sites. Longitudinal observation in microbiopsied volunteers showed that the wound closed within 1 day and was not visible after 7 days. Reflectance confocal microscope images from these same sites showed the formation of a tiny crust that resolved by 3 weeks and was completely undetectable by the naked eye. The design parameters of the device were optimised for molecular analysis using sampled DNA mass as the primary end point in volunteer studies. Finally, total RNA was characterized. The optimised device extracted 5.9 ± 3.4 ng DNA and 9.0 ± 10.1 ng RNA. We foresee that minimally invasive molecular sampling will play an increasingly significant role in diagnostic dermatology and skin research.
Pricing Time-Sensitive Services Based on Realized Performance
Authors: Afèche Philipp , Baron Opher , Kerner Yoav
Published: May 2013

Services such as FedEx charge up-front fees but reimburse customers for delays. However, lead-time pricing studies ignore such delay refunds. This paper contributes to filling this gap. It studies revenue-maximizing tariffs that depend on realized lead times for a provider serving multiple time-sensitive customer types. We relax two key assumptions of the standard model in the lead-time pricing literature. First, customers may be risk averse (RA) with respect to payoff uncertainty, where payoff equals valuation, minus delay cost, minus payment. Second, tariffs may be arbitrary functions of realized lead times. The standard model assumes risk-neutral (RN) customers and restricts attention to flat rates. We report three main findings: (1) With RN customers, flat-rate pricing maximizes revenues but leaves customers exposed to payoff variability. (2) With RA customers, flat-rate pricing is suboptimal. If types are distinguishable, the optimal lead-time-dependent tariffs fully insure delay cost risk and yield the same revenue as under optimal flat rates for RN customers. With indistinguishable RA types, the differentiated first-best tariffs may be incentive-compatible even for uniform service, yielding higher revenues than with RN customers. (3) Under price and capacity optimization, lead-time-dependent pricing yields higher profits with less capacity compared to flat-rate pricing.
Variability of Imaging Modalities for Acute Flank Pain in the UK
Authors: Turney BW , Keoghane SR
Published: May 2013

The lifetime prevalence of acute renal colic in the UK has recently been estimated at around 11% and over 80,000 patients per year attend hospital in England with suspected renal colic. This leads to 1–2 presentations of acute flank pain every day to each hospital in the country. Rapid diagnosis will facilitate appropriate management. historically, intravenous urography (IVU) was the 'gold standard' investigation but this has been replaced in recent years by unenhanced computed tomography (CT-KUB). this has well-documented advantages over IVU as the imaging modality of choice in acute flank pain but is still not standard practice in all UK hospitals. the aim of this study was to establish the practical arrangements for imaging suspected stone disease in the UK.
Reconstruction and Financial Remuneration Following Soft Tissue Sarcoma Surgery
Authors: Hassan S , Gale J , Perks AGB , Raurell A , Ashford RU
Published: May 2013

Soft tissue sarcomas are relatively uncommon, with approximately 3,200 new cases per year in the UK, accounting for 1% of all malignancies. They are a heterogeneous group of malignancies that occur anywhere in the body, and arise from the mesenchyme inclusive of muscle, endothelial cells, cartilage and supporting elements. Diagnosis is based on triple assessment with clinical history, imaging and diagnostic biopsy. Histological stage and grade is based on the Trojani classification. Owing to their complex nature, a specialist sarcoma multidisciplinary team (MDT) manages patients. Treatment options include one or more of surgery with wide or planned marginal excision, isolated limb perfusion, chemotherapy or radiotherapy. Long-term follow-up to rule out recurrence of disease is mandatory.
Agenda for change
Authors: Williams Norman
Published: May 2013

We are living through perhaps the most significant changes that healthcare in England has undergone since the NHS came into being. These changes are a result of many external factors that are common to most countries in the West – an aging population, greater expectations from the public, and more expensive therapeutic options than ever before to be delivered in a climate of financial constraint. The reorganisation of the NHS brought about by the health and social Care Act and the ramifications of the Francis Report will present the profession with unprecedented challenges that will have profound effects on us and the patients we treat – hopefully for the better. I am sure that surgeons are up to the challenge and will do all they can to make the new system work.
Surgical Simulation: the way ahead
Authors: Cooke Martyn
Published: May 2013

Model-making is nothing new in the medical museum. After all, the great Joseph Towne fashioned dozens of superb-quality wax models during his employment at Guy's Hospital in the 19th century. Over 150 years later, the College's Museums department has begun to reintroduce many previously lost skills.
Psychological governance and behaviour change
Authors: Jones Rhys , Pykett Jessica , Whitehead Mark
Published: May 2013

A suite of ‘behaviour change’ policies has become evident in United Kingdom public policies, informed by insights from the psychological and behavioural sciences. In this article we use Foucauldian conceptions of governmentality and psychological techniques of governance – along with interview and documentary research on contemporary public policy – to examine how such policies re-imagine and address the limitations of neoliberalism, as well as the rationality of subjects. In seeking to address individuals’ irrationality, such policies reframe contemporary forms of neoliberal governance by potentially: re-centring power within the state apparatus; undermining the significance of rational choice; and creating a new breed of passive subject.
Ring of fire: socially perceived necessities in informal urban settlements in South Africa
Authors: Noble Michael , Wright Gemma
Published: May 2013

This paper explores which items people living in South African informal urban settlements regard as essential for an acceptable standard of living, in the context of the high levels of service delivery protests in urban areas. Comparisons are made with people in rural former homeland areas which are shown to have similar levels of deprivation and service delivery dissatisfaction and yet have few such protests. People in informal urban areas rated infrastructure-related items higher than people in rural former homelands. It is argued that inequality and people's reference groups could help explain these attitudinal discrepancies and the locations of protests.
Complex Biological Pattern of Fertility Hormones in Children and Adolescents: A Study of Healthy Children from the CALIPER Cohort and Establishment of Pediatric Reference Intervals
Authors: Konforte Danijela , Shea Jennifer L , Kyriakopoulou Lianna , Colantonio David , Cohen Ashley H , Shaw Julie , Bailey Dana , Chan Man Khun , Armbruster David , Adeli Khosrow
Published: May 2013

BACKGROUND

Pediatric endocrinopathies are commonly diagnosed and monitored by measuring hormones of the hypothalamic-pituitary-gonadal axis. Because growth and development can markedly influence normal circulating concentrations of fertility hormones, accurate reference intervals established on the basis of a healthy, nonhospitalized pediatric population and that reflect age-, gender-, and pubertal stage–specific changes are essential for test result interpretation.

METHODS

Healthy children and adolescents (n = 1234) were recruited from a multiethnic population as part of the CALIPER study. After written informed parental consent was obtained, participants filled out a questionnaire including demographic and pubertal development information (assessed by self-reported Tanner stage) and provided a blood sample. We measured 7 fertility hormones including estradiol, testosterone (second generation), progesterone, sex hormone–binding globulin, prolactin, follicle-stimulating hormone, and luteinizing hormone by use of the Abbott Architect i2000 analyzer. We then used these data to calculate age-, gender-, and Tanner stage–specific reference intervals according to Clinical Laboratory Standards Institute C28-A3 guidelines.

RESULTS

We observed a complex pattern of change in each analyte concentration from the neonatal period to adolescence. Consequently, many age and sex partitions were required to cover the changes in most fertility hormones over this period. An exception to this was prolactin, for which no sex partition and only 3 age partitions were necessary.

CONCLUSIONS

This comprehensive database of pediatric reference intervals for fertility hormones will be of global benefit and should lead to improved diagnosis of pediatric endocrinopathies. The new database will need to be validated in local populations and for other immunoassay platforms as recommended by the Clinical Laboratory Standards Institute.
Advances in Petroleum Refining Processes
Authors: Mochida Isao , Fletcher Ray , Hatanaka Shigeto , Toshima Hiroshi , Inomata Jun , Inomata Makato , Inoue Shinichi , Matsuda Kazuo , Nagamatsu Shigeki , Shimizu Shinichi
Published: May 2013

This chapter provides an overview of recent advances in several refinery processes, including fluid catalytic cracking (FCC), hydrotreatment of catalytically cracked gasoline to produce low-sulfur gasoline while preserving most of the olefins, isomerization of saturated n-olefins to avoid an octane number penalty, hydroprocessing of gas oil and vacuum gas oil to produce middle and light distillates, and alkylation with solid catalysts to avoid the use of corrosive liquid acids to produce high-octane gasoline. In addition, the chapter reviews upgrading of heavy residua by thermal cracking and integrative schemes for energy sharing between refinery units and across the boundaries of a refinery. A brief history of developments in the FCC process is given along with the future prospects for this important refinery process. This chapter also provides a discussion of potential future developments for the other processes covered here. Recent advances in catalysts used in the refining processes are discussed in Chapter 10 following a parallel outline of this chapter.
Advances in Catalysts for Refining Processes
Authors: Mochida Isao , Fletcher Ray , Hatanaka Shigeto , Toshima Hiroshi , Nagamatsu Shikegi , Inomata Makato , He Rong , Threlkel Richard S. , Dillon Christopher J. , Ida Junko , Matsuhisa Toshio , Inoue Shinichi , Shimizu Shinichi , Shoji Kazuo
Published: May 2013

Catalytic processes play the most significant role in petroleum refineries for changing the molecular architecture of the hydrocarbons to make high-performance fuels in high yields and removing the heteroatoms such as sulfur, nitrogen, and metals to produce environmentally acceptable fuels. Catalysts take part in carbon rejection (e.g., fluid catalytic cracking [FCC]) and hydrogen addition (e.g., hydrocracking) to convert the hydrocarbons in crude oils to desirable light and middle distillates and other chemicals. Catalysts constitute the heart of the catalytic processes, and there have been very significant developments from the days of using natural clays as catalysts for catalytic cracking to designing and producing catalysts with precise control of their structure, composition, and properties for FCC. This chapter introduces new advances in catalysts for selected processes such as FCC, hydrotreatment of FCC gasoline (catalytic cracked gasoline), hydroprocessing of vacuum gas oil, alkylation, processing of heavy bottoms of crude oils, hydrogen production, and the roles of catalyst supports. The chapter follows an outline parallel to the advanced processes discussed in Chapter 7 to focus on the catalysts used in these processes.
Natural Gas Conditioning and Processing
Authors: Migliore Calogero
Published: May 2013

The development of the natural gas industry has been very much influenced by the physical characteristics of natural gas. Although oil, being a liquid at ambient temperature, can be contained and transported relatively easily using simple and less-expensive technologies, natural gas is more complex and generally more expensive to store and transport because of its physical nature, which requires high pressures, very low temperatures, or both. Transportation is a major aspect of the gas industry to ensure the supply of gas to the final users. The main objective of a natural gas supply system is to produce gas from an underground field, send it to a processing facility where the gas is processed to an acceptable quality, and then move it to customers for its final use. This cannot happen without there being a continuous connection from the producing field to the consumer of the gas. This involves the concept of the natural gas value chain. Two chains currently exist in the gas industry. One scheme involves a conventional arrangement in which natural gas is transmitted all of the way from the field to the city gate or consumer facility in high-pressure pipelines. The other one is the LNG scheme, which involves the liquefaction of the gas, its transportation in bulk carriers, the regasification at the point of delivery, and the transportation to the final users, also through highpressure pipelines. This chapter reviews the technologies associated with the processing facilities involved in both existing schemes and their contribution with respect to the natural gas value chain concept. New proposed gas value chains and other technologies to monetize natural gas are also discussed.
Design Aspects of Separation Units and Processing Equipment
Authors: Rodwell M. C. , Riazi M. R.
Published: May 2013

This chapter presents the principles of design and operation of major refinery separation units, including desalting, distillation, absorption and stripping, liquid-liquid extraction, and filtration, along with the heat-transfer equipment, phase separators, pumps, and compressors used in petroleum refining and natural gas processing. With the information presented in this chapter, one can calculate the height, diameter, and thickness of a distillation column, feed entry location, heat requirement for the column, and rate of heat removal in a condenser. Similar calculations for gas absorption and extraction columns are presented. Heat requirements and related design calculations for heat exchangers, furnaces, and heat transfer units are also presented. Some basic calculations and information about pumps and compressors are provided.
Process Control and Instrumentation
Authors: Raman L. , Murthy N. S.
Published: May 2013

Refineries and petrochemical units of late have been placed under increasing uncertainties/volatility in feed supply and end product markets. Barring a few “well head” refineries, which process mostly same quality of crude throughout the year, the rest process a wide variety of crude oils. For example, the API of the crude supplies to a refinery varies from 19 to 40 and the sulfur content from 0.1 to 4.7 wt %. Moreover, the cracker plants of petrochemical complexes procure naphtha from different parts of the world that varies in ratio and total paraffin content. On the other hand, downstream processing is becoming very stringent, with refiners required to cater to different grades of fuels; for example, diesel varying in sulfur content from 10 to 5000 ppm, gasoline with different octane ratings, etc. The hydroprocessing industry does this job routinely by producing market-sensitive products from different qualities of feed on any given day. This is an inevitable but “perfect” balancing act. Automation of manufacturing plants, DBN (Debottlenecking) the units to operate them at their maximum capacities, operating processes, and machinery at respective “best and safe operating zones” are essential ingredients to cope with market volatility and realize maximum profits. This is possible only when various instruments that are used for measuring process variables, which are in turn used for controlling the processes, are accurate, precise, reliable, and robust enough within the operating horizon of the manufacturing process. The developments in process control and instrumentation, leveraging computing advancements over years, have made it feasible. In other words, the level of “process maturity” has been raised to a newer benchmark with error-free, self-diagnostic, predictive, and adaptive controls having an elegant man-machine interface.
Corrosion Inspection and Control in Refineries
Authors: Hau Jorge L.
Published: May 2013

Metallic materials used to manufacture equipment for the petroleum refining industry are subjected to a wide variety of potential damage mechanisms, the most common being corrosion and environmental stress corrosion cracking. Safe operation of oil refineries depends on understanding these degradation mechanisms, making the proper material selection, devising corrosion control, inspection programs for earlier detection of problems, and monitoring material performance. This chapter divides corrosion into wet and dry, as applicable to particular refining processes. Wet corrosion occurs in the presence of electrolytes. Stress corrosion cracking mechanisms are associated with wet corrosion processes and the most common ones, affecting metals and alloys used in oil refineries, are described. Dry corrosion affects large areas of refineries; it does not require the presence of water. Dry corrosion also includes oxidation, carburization, and metal dusting, but the most relevant for oil refining is attributed to the presence of sulfur, naphthenic acids, or both. Although they are rather old recognized corrosion mechanisms, the phenomena have not yet been fully comprehended, in particular the complex interaction between these two corrosion processes and the influence of the many factors that seem to play an important role. Some discussion is offered in this respect, based on own research results and experience gained by having been involved in many analyses of failures in oil refineries. Damage mechanisms other than corrosion are also described in their connection with particular refining processes.
Transportation of Crude Oil, Natural Gas, and Petroleum Products
Authors: Ayala H. Luis F.
Published: May 2013

Among all available transportation options, pipelining remains the most popular and customary method of moving hydrocarbon fluids from source to destination for in-land, near-shore, and industrial applications. In the petroleum industry, all producing wells are equipped with tubular fittings that bring wellstream fluids to the production facilities. For onshore and near-shore applications, pipelines are always the most recommendable option to transport fluids to the market. Pipelines are ubiquitous in all refineries and industrial facilities because they provide the connectivity that is needed among all process equipment. Pipeline transportation provides a versatility rarely found in other modes of transportation. Advances in pipeline engineering make it possible to place pipelines in many different environments, including desserts, ocean floors, forest, and mountain ranges. In this chapter, a comprehensive review of transportation of crude oil and natural gas is presented with detailed discussions that include available and applicable standards, design criteria and constraints, analysis of single-phase flow of liquids and gases and multiphase flow, network modeling and temperature effects.
Introduction to Trading, Pricing, and Valuation of Crude Oils and Petroleum Products
Authors: Khor Cheng Seong , Ricardez-Sandoval Luis A. , Elkamel Ali , Shah Nilay
Published: May 2013

This chapter presents a primer on the concepts, systems, and mechanisms of the trading, costing, pricing, and valuation of crude oils and petroleum products. We introduce features of the physical oil and financial paper markets that adopt marker crude oils as pricing benchmarks. To gain a quick appreciation for how the oil markets have evolved, we then present a historical perspective on international crude oil supply, trading, and pricing. Next, we consider the fundamental parameters of the oil markets and the various factors that affect crude oil pricing, including the different sources of price information. We discuss the various mechanisms in which crude oils are priced and how price differentials among different crudes are set to allow the consideration of various important factors. We subsequently extend the analysis to the pricing of petroleum products. Finally, the understanding gained is used to appreciate the roles of costs and profit margins for economic evaluations in the refining industry.
Financial Risk Management in Refinery Operations Planning
Authors: Bagajewicz Miguel
Published: May 2013

This chapter introduces concepts of financial risk as applied to the decision-making associated with refinery operations. Particular focus is given to the use of two-stage programming to make crude purchasing decisions and operational choices such as the throughput of different units. Most models consider the price as an external uncertain parameter. However, because refiners modify retail prices to optimize profit margins and inventory costs, models that include it as a decision variable are also discussed. In addition, techniques to identify decisions that are less profitable, but also less risky, are presented. Finally, we show how commercial software can be used. We conclude that the techniques presented are mature and ready to be adopted in practice.
Future Directions in Petroleum and Natural Gas Refining
Authors: Rana Mohan S. , Ancheyta Jorge , Riazi M. R. , Marafi Meena
Published: May 2013

The global energy system is at a junction where current energy demand is soaring while the supply options are unsustainable, and which are limited by environmental legislations as well as economic constraints. Fossil fuel is the world's primary source of energy and will remain so for many years. However, in order to prevent disastrous damage to the global environment, a major decarbonization of world energy sources will be required. Fossil fuel refineries are moving toward heavy or extra-heavy exploration and require new upgrading technologies that lead to cleaner fuel and fulfill the growing demand for the lighter fraction. In addition, demand for natural gas is gradually increasing and hydrogen is proposed to play an important part as an energy carrier whereas the use of biomass will develop, but at a modest level. New techniques for testing that are being developed for fossil-fuel gases are reported along with their consequences such as gas-, biomass-, and even coal-to-liquid technologies with a view to cutting costs and providing better environmental concerns. Biodiesel fuel contains inferior energy density to petroleum diesel fuel, but combusts more thoroughly and reduces the amount of toxic exhaust emissions. The biofuel corresponds to a small but substantial way of breaking total reliance on fossil fuels. In summary, refineries of the future will be more technology-based industries with more valuable products. The objective of this review is to confer a new resource covering all subjects of importance to those who are involved in the energy sector. The data presented on the amount of oil and gas reserves vary from one source to another; however, they provide a general picture of how many hydrocarbon resources remain and how long they will last. The content of this chapter is a compilation by experts in the field of recent advances and processing techniques, plant design, economical issues, environmental considerations, storage and distribution of products, product quality and specifications, market demand and forecasting, inspection and maintenance, safety issues, management of the industry, and international import/export and regulations.
Flow Rate Measurement in Multi-Component Geosynthetic Clay Liners
Authors: Touze-Foltz Nathalie , Barral Camille , Croissant Didier , von Maubeuge K. P.
Published: May 2013

A procedure was developed that combines measuring devices from NF EN 14150 for flow rate measurement through geomembranes and a rigid wall permeameter from NF P84-705. The new procedure aims at measuring flow rates through geosynthetic clay liners (GCLs) in order to measure flow rates through multi-component GCLs. The resulting testing device allows one to measure very small variations in volume with time while applying constant hydraulic pressures. The pressure difference applied on both sides of the multi-component GCL specimens varied between 25 kPa and 100 kPa, with the latter value being equal to the one applied across geomembranes in NF EN 14150. Three different multi-component GCLs from two different manufacturers were tested in order to determine the ability of the testing equipment to quantify the flow rate through multi-component GCLs. The flow rate measurement was performed after a hydration phase under very low hydraulic head and with a 10 kPa normal load on the specimens in accordance with NF P84-705. Details regarding the experimental conditions that could lead to the development of a standard for the measurement of flow rates through multi-component GCLs are given. Results obtained tend to show that flow rates are 1 order of magnitude larger than the ones usually measured for virgin geomembranes (i.e., 10−5 m3/m2/d).
Owl Pellet Paleontology
Authors: McAlpine Lisa K.
Published: May 2013

In this activity for the beginning of a high school Biology 1 evolution unit, students are challenged to reconstruct organisms found in an owl pellet as a model for fossil reconstruction. They work in groups to develop hypotheses about what animal they have found, what environment it inhabited, and what niche it filled. At the end of the activity, the groups participate in a defense and peer review of their findings. This activity develops students’ knowledge of the nature of science, evidence for evolution, and individual thinking and reasoning skills.
Observation of Microorganisms in Milk after the Expiration Date Using Dry Rehydratable Film
Authors: Kim Youngshin , Lim Soo-Min , Lee Il-Sun
Published: May 2013

Cultivation of microorganisms such as fungi and bacteria is often not included in scientific inquiries conducted in school because of the difficulty of manufacturing a suitable medium. A method using dry rehydratable film to reduce the need to manufacture a suitable medium and shorten incubation time was developed as an efficient microbial testing method. Using this method, students can easily perform experiments on microorganisms in schools where time and space are limited. For example, we carried out an inquiry on the possibility of drinking refrigerated milk that is already past its expiration date. Through this activity, we could raise issues related to the current shelf-life labeling system implemented in Korea. In addition, the method can measure microorganisms in several ways through air, direct contact, and indirect contact, making the procedure easier to use in scientific activities at school.
Moving Margins
Authors: McHatton Patricia Alvarez , May Sandy
Published: May 2013

Marginalia is the practice of writing notes in the margins of texts as a way to capture ones’ thoughts and feelings about the text during reading. It is the giving in to the impulse, based on what was read, to stop and record a comment. In this manuscript, we make the connection between marginalia and the visceral responses to text felt by one doctoral student (the second author) taking a course examining language as a “place of struggle” (hooks, 2004, p. 153). We also demonstrate how marginalia can be used as a qualitative method to document and investigate the way textual interaction facilitates learning. A found poem developed from the marginalia compiled throughout the semester is shared exemplifying the way a critical analysis of personal marginalia can facilitate awareness of transformative processes and highlighting the margins as a transformative space.
Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules?
Authors: Xu Shuhang , Chen Guofang , Peng Wen , Renko Kostja , Derwahl Michael
Published: May 2013

Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. This study analysed whether both differentiated thyroid cells and thyroid stem and progenitor cells are targets of oestrogen action. In thyroid stem/progenitor cells derived from nodular goitres, the ability of 17β-oestradiol (E2) to induce the formation of thyrospheres and the expression of oestrogen receptors (ERs) and the effect of E2 on the growth and expression of markers of stem cells and thyroid differentiation (TSH receptor, thyroperoxidase, thyroglobulin and sodium iodide symporter (NIS)) were analysed. E2 induced thyrosphere formation, albeit to a lower extent than other growth factors. Thyroid stem and progenitor cells expressed ERα (ESR1) and ERβ (ESR2) with eight times higher expression levels of ERα mRNA compared with the differentiated thyrocytes. E2 was a potent stimulator of the growth of thyroid stem/progenitor cells. In contrast, TSH-induced differentiation of progenitor cells, in particular, the expression of NIS, was significantly inhibited by E2. In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females.
Rare Variant Association Testing Under Low-Coverage Sequencing
Authors: Navon Oron , Sul Jae Hoon , Han Buhm , Conde Lucia , Bracci Paige M , Riby Jacques , Skibola Christine F , Eskin Eleazar , Halperin Eran
Published: May 2013

Deep sequencing technologies enable the study of the effects of rare variants in disease risk. While methods have been developed to increase statistical power for detection of such effects, detecting subtle associations requires studies with hundreds or thousands of individuals, which is prohibitively costly. Recently, low-coverage sequencing has been shown to effectively reduce the cost of genome-wide association studies, using current sequencing technologies. However, current methods for disease association testing on rare variants cannot be applied directly to low-coverage sequencing data, as they require individual genotype data, which may not be called correctly due to low-coverage and inherent sequencing errors. In this article, we propose two novel methods for detecting association of rare variants with disease risk, using low coverage, error-prone sequencing. We show by simulation that our methods outperform previous methods under both low- and high-coverage sequencing and under different disease architectures. We use real data and simulation studies to demonstrate that to maximize the power to detect associations for a fixed budget, it is desirable to include more samples while lowering coverage and to perform an analysis using our suggested methods.
The Aurora B Kinase Promotes Inner and Outer Kinetochore Interactions in Budding Yeast
Authors: Akiyoshi Bungo , Nelson Christian R , Biggins Sue
Published: May 2013

The kinetochore is the macromolecular protein complex that mediates chromosome segregation. The Dsn1 component is crucial for kinetochore assembly and is phosphorylated by the Aurora B kinase. We found that Aurora B phosphorylation of Dsn1 promotes the interaction between outer and inner kinetochore proteins in budding yeast.
Priors in Whole-Genome Regression: The Bayesian Alphabet Returns
Authors: Gianola Daniel
Published: May 2013

Whole-genome enabled prediction of complex traits has received enormous attention in animal and plant breeding and is making inroads into human and even Drosophila genetics. The term “Bayesian alphabet” denotes a growing number of letters of the alphabet used to denote various Bayesian linear regressions that differ in the priors adopted, while sharing the same sampling model. We explore the role of the prior distribution in whole-genome regression models for dissecting complex traits in what is now a standard situation with genomic data where the number of unknown parameters (p) typically exceeds sample size (n). Members of the alphabet aim to confront this overparameterization in various manners, but it is shown here that the prior is always influential, unless n ≫ p. This happens because parameters are not likelihood identified, so Bayesian learning is imperfect. Since inferences are not devoid of the influence of the prior, claims about genetic architecture from these methods should be taken with caution. However, all such procedures may deliver reasonable predictions of complex traits, provided that some parameters (“tuning knobs”) are assessed via a properly conducted cross-validation. It is concluded that members of the alphabet have a room in whole-genome prediction of phenotypes, but have somewhat doubtful inferential value, at least when sample size is such that n ≪ p.
Prospective Head and Neck Cancer Research: A Four-Decade Bibliometric Perspective
Authors: Sun Gordon H. , Houlton Jeffrey J. , Moloci Nicholas M. , MacEachern Mark P. , Bradford Carol R. , Prince Mark E. , Jagsi Reshma
Published: May 2013

Learning Objectives

Outline trends in the gender and continent of origin of first and corresponding authors of prospective head and neck cancer treatment research. Identify trends in the presence of pharmacotherapy, radiotherapy, and surgery in prospective head and neck cancer treatment research.
Real-World Effectiveness of Systemic Agents Approved for Advanced Non-Small Cell Lung Cancer: A SEER–Medicare Analysis
Authors: Owonikoko Taofeek K. , Ragin Camille , Chen Zhengjia , Kim Sungjin , Behera Madhusmita , Brandes Johann C. , Saba Nabil F. , Pentz Rebecca , Ramalingam Suresh S. , Khuri Fadlo R.
Published: May 2013

Objectives.

Disparity exists between patients with lung cancer enrolled in clinical trials and patients treated in the community setting. This study assessed the real-world effectiveness of cytotoxic agents that became available for the treatment of non-small cell lung cancer (NSCLC) in the last 2 decades.

Methods.

We employed the linked Surveillance, Epidemiology, and End Results (SEER)–Medicare database for patients diagnosed with stage IIIB/IV NSCLC between 1988 and 2005 to assess the effectiveness of newly approved agents. Effectiveness of specific agents was assessed at time periods immediately following the approval of the agent for NSCLC: baseline, 1988–1994; platinum, 1995–1999; docetaxel, 1999–2003; pemetrexed and bevacizumab, 2004–2005. Significant associations between specific drug treatment and survival improvement were determined using the Kaplan-Meier method, Cox proportional hazard model, and propensity score analyses. Significant differences were established by log-rank test.

Results.

This analysis employed data from 143,548 patients by sex (58% male, 42% female), cancer stage (35% stage IIIB, 65% stage IV), and age (12% 20–64 years, 22% 65–69 years, 45% 70–79 years, 22% 80 years and older). There was temporal improvement in survival for patients treated with newly approved chemotherapy (1-year survival rates: 32.41% in 1988–1994, 32.95% in 1995–1998, 37.40% in 1999–2003, and 39.55% in 2004–2005). Patients treated with a newly approved drug during the relevant treatment era had a significant reduction in the risk of death when compared with patients treated with chemotherapy other than the newly approved agent (hazard ratios [95% confidence interval] were 0.76 [0.71–0.81] for platinum, 0.73 [0.70–0.75] for docetaxel, 0.40 [0.37–0.44] for pemetrexed, and 0.33 [0.27–0.40] for bevacizumab; p < .001). Propensity score adjustment did not significantly alter these results.

Conclusions.

Currently approved drugs for the treatment of advanced NSCLC are associated with improved survival in the U.S. Medicare patient population. Our findings support the effectiveness of these agents in the real-world oncology practice.
Adlatipora, a Distinctive New Acanthocladiid Bryozoan from the Permian of the Glass Mountains, Texas, U.S.A., and its Bearing on Fenestrate Astogeny and Growth
Authors: Gautier T. Gary , Jackson Patrick N. Wyse , McKinney Frank K.
Published: May 2013

A new acanthocladiid bryozoan genus from the Permian of the Glass Mountains of Texas, U.S.A., reveals a distinctive morphology and a growth pattern unique amongst members of the extinct stenolaemate Order Fenestrata. Adlatipora fossulata n. gen. n. sp. forms small pinnate expansions with moderately robust main stems and shorter laterally placed pinnae. Colonies developed from small basal discs that exhibit a unique multilayered skeletal structure, from which a circlet of first generation autozooids bud from the ancestrula; these become the bases of branches. In Adlatipora autozooecia are organized into diagonal rows that alternate along branches and are separated into right-handed or left-handed forms. A fossula is developed from the distal margin of autozooecial apertures. Proximal pores are located adjacent to autozooecial apertures and are remnants of fossulae. These pores probably acted as an anal pore providing a passageway for fecal products.
Geotechnical stability analysis
Authors: SLOAN S.W.
Published: May 2013

This paper describes recent advances in stability analysis that combine the limit theorems of classical plasticity with finite elements to give rigorous upper and lower bounds on the failure load. These methods, known as finite-element limit analysis, do not require assumptions to be made about the mode of failure, and use only simple strength parameters that are familiar to geotechnical engineers. The bounding properties of the solutions are invaluable in practice, and enable accurate limit loads to be obtained through the use of an exact error estimate and automatic adaptive meshing procedures. The methods are very general, and can deal with heterogeneous soil profiles, anisotropic strength characteristics, fissured soils, discontinuities, complicated boundary conditions, and complex loading in both two and three dimensions. A new development, which incorporates pore water pressures in finite-element limit analysis, is also described. Following a brief outline of the new techniques, stability solutions are given for several practical problems, including foundations, anchors, slopes, excavations and tunnels.
The subnivium: a deteriorating seasonal refugium
Authors: Pauli Jonathan N , Zuckerberg Benjamin , Whiteman John P , Porter Warren
Published: May 2013

For many terrestrial organisms in the Northern Hemisphere, winter is a period of resource scarcity and energy deficits, survivable only because a seasonal refugium – the “subnivium” – exists beneath the snow. The warmer and more stable conditions within the subnivium are principally driven by snow duration, density, and depth. In temperate regions, the subnivium is important for the overwintering success of plants and animals, yet winter conditions are changing rapidly worldwide. Throughout the Northern Hemisphere, the impacts of climate change are predicted to be most prominent during the winter months, resulting in a shorter snow season and decreased snow depth. These climatic changes will likely modify the defining qualities of the subnivium, resulting in broad‐scale shifts in distributions of species that are dependent on these refugia. Resultant changes to the subnivium, however, will be spatially and temporally variable. We believe that ecologists and managers are overlooking this widespread, crucial, and vulnerable seasonal refugium, which is rapidly deteriorating due to global climate change.
Creating Portfolio Insights by a Practical Multimethod Optimization Approach
Authors: Willigers B.J.A.. J.A. , Weis F.. , Majou F..
Published: May 2013

This study demonstrates how portfolio insights can be created by combining well-known optimization methods that are generally used individually—genetic algorithm (GA), linear programming (LP), and portfolio filtering (PF). An integrated optimization approach combines the advantages of individual methods while mitigating their shortcomings.

Effective portfolio management requires a comprehensive understanding of the tradeoffs between different portfolio choices. Given a set of constraints, portfolio-optimization techniques based on LP and GAs can be applied to identify an optimal portfolio. However, this optimal portfolio might not be the preferred portfolio. Decision makers have to understand the tradeoffs between generally conflicting objectives and constraints before one portfolio can be identified as the preferred option. Such assessment of the overall search space is not made with LP and GAs when used to identify a single best solution, and many portfolio options will have been eliminated before an understanding of these alternatives has been developed.

Markowitz's mean-variance (M-V) approach and the traditional “rank and cut” approach are used typically to establish a relationship between a portfolio's value and its variance or associated development cost. Although these methods enable decision makers to compare and contrast different options, the optimization is limited to the portfolio value measure and a single other metric. This latter limitation is overcome by the more recently developed PF approach. This method is practical and transparent and allows for a quick development of strategic portfolio alternatives while considering a large number of portfolio attributes. Its main drawback is that the analyzed set of portfolios generally represents a subset of the total search space. Thus, as the number of feasible portfolio options increases, so does the chance that the optimal portfolio is not present in the population of sampled portfolios.
Randomized Trial of Continuous Subcutaneous Delivery of Exenatide by ITCA 650 Versus Twice-Daily Exenatide Injections in Metformin-Treated Type 2 Diabetes
Authors: Henry Robert R. , Rosenstock Julio , Logan Douglas K. , Alessi Thomas R. , Luskey Kenneth , Baron Michelle A.
Published: May 2013

OBJECTIVE

To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes.

RESEARCH DESIGN AND METHODS

We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 μg/day of ITCA 650 or Ex-BID 5→10 μg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 μg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24.

RESULTS

HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9–8.0% was −0.98, −0.95, and −0.72% for the 20 and 40 μg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (∼1.4% from baseline) were achieved with 60 and 80 μg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤7% at 24 weeks; respectively. Weight was reduced by 2.8–3.7 kg (P < 0.05) at 24 weeks in all except the 20→20 μg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 μg/day relative to Ex-BID; and 60 μg/day had the best profile of tolerability and HbA1c lowering.

CONCLUSIONS

ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20→60 μg/day regimen was considered the best dose for further examination in phase 3.
A Critical Analysis of the Clinical Use of Incretin-Based Therapies
Authors: Nauck Michael A.
Published: May 2013

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to an increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk.

—William T. Cefalu, MD Editor in Chief, Diabetes Care
The influence of position in overlap joints of Mg and Al alloys on microstructure and hardness of laser welds
Authors: Bannour S. , Abderrazak K. , Mattei S. , Masse J. E. , Autric M. , Mhiri H.
Published: May 2013

Structure and properties of laser beam welding zone of dissimilar materials, AZ31 magnesium alloy and A5754 Aluminum alloy, are investigated. The microstructure and quality of the Mg/Al weld were studied by metallography, microhardness, and optical microscopy. Differences in physical and mechanical properties of both materials, magnesium and aluminum, affect weldability and resistance of this combination, and lead to the formation of intermetallic compounds in the welded metal.