Objective Reconstructions of the Late Wisconsinan Laurentide Ice Sheet and the Significance of Deformable Beds

A three dimensional steady state plastic ice model; the present surface topography (on a 50 km grid); a recent concensus of the Late Wisconsinan maximum margin (PREST, 1984); and a simple map of ice yield stress are used to model the Laurentide Ice Sheet. A multi-domed, asymmetric reconstruction is computed without prior assumptions about flow lines. The effects of possible deforming beds are modelled by using the very low yield stress values suggested by MATHEWS (1974). Because of low yield stress (deforming beds) the model generates thin ice on the Prairies, Great Lakes area and, in one case, over Hudson Bay. Introduction of low yield stress (deformabie) regions also produces low surface slopes and abrupt ice flow direction changes. In certain circumstances large ice streams are generated along the boundaries between normal yield stress (non-deformable beds) and low yield stress ice (deformabie beds). Computer models are discussed in reference to the geologically-based reconstructions of SHILTS (1980) and DYKE ef al. (1982).À partir d'un modèle théorique tridimensionnel de plasticité de la glace, de la topographie actuelle (sur un canevas de 50 km2), du nouveau consensus quant à la limite maximale de la marge glaciaire (PREST, 1984) et d'une carte des seuils de plasticité de la glace, les auteurs ont élaboré des modèles de la calotte glaciaire laurentidienne. On a donc reconstitué par ordinateur une calotte asymétrique à dômes multiples, sans idée préconçue quant aux directions de l'écoulement des glaces. On a évalué les conséquences de la présence éventuelle de lits non résistants en se fondant sur les très bas seuils de plasticité de la glace proposés par MATHEWS (1974). En raison des bas seuils de plasticité (lits non résistants), les modèles démontrent qu'une glace peu épaisse couvrait les Prairies et la région des Grands Lacs, ainsi que la baie d'Hudson, dans un des deux cas. La prise en considération de régions à bas seuils de plasticité (lits non résistants) montre également la présence de pentes faibles et des changements brusques de direction de l'écoulement glaciaire. Dans certains cas, de grands courants glaciaires se manifestent le long des limites entre les endroits où les seuils de plasticité sont normaux (lits rigides) et les endroits où les seuils de plasticité sont bas (lits non résistants). Les modèles obtenus par ordinateur sont ensuite comparés aux reconstitutions de SHILTS (1980) et de DYKE et al. (1982), élaborées à partir des données géologiques.Ein dreidimensionales konstantes Modell der Eis-Plastizitat, die gegenwàrtige Oberflâchentopographie (auf einem Gitternetz von 50 km), ein neuer Konsensus ùber den maximalen glazialen Rand des spâten Wisconsin (PREST, 1984) und eine einfache Karte der Eis-Plastizitàts-Schwelle werden benutzt, um ein Modell der Laurentischen Eisdecke herzustellen. Eine vielfach gewôlbte, asymmetrische Rekonstruktion ist hergestellt worden, ohne vorgefapte Meinung ùber die Richtung des FlieBens. Die Wirkungen von môglicherweise vorhandenen nachgiebigen Betten werden mittels der sehr niedrigen Eisplastizitàtsschwelle, wie sie von MATHEWS (1974) vorgeschlagen wird, im Modell gestaltet. Wegen der niedrigen Plastizitâtsschwelle (nachgiebige Betten) zeigt das Modell dùnnes Eis in den Prairies, der Gegend der grofien Seen und in einem Fall ùber der Hudson Bay. Die Berùcksichtigung von Gebieten mit niedriger Plastizitàtsschwelle (nachgiebige Betten) fùhrt auch zu niedrigen Hàngen und abrupten Wechseln in der Richtung des EisflieBens. Unter gewissen Bedingungen bilden sich breite Eisstrôme entlang der Grenzèn zwischen Gegenden mit normaler Eisplastizitât (bestândige Betten) und geringer Eisplastizitàt (nachgiebige Betten). Durch Computer erstellte Modelle werden in Bezug auf die geologisch erarbeiteten Rekonstruktionen von SHILTS (1980) und DYKE et al. (1982) diskutiert

Underground nuclear power plant siting

This study is part of a larger evaluation of the problems associated with siting nuclear power plants in the next few decades. This evaluation is being undertaken by the Environmental Quality Laboratory of the California Institute of Technology in conjunction with The Aerospace Corporation and several other organizations. Current efforts are directed toward novel approaches to siting plants within the State of California. This report contains the results of efforts performed by The Aerospace Corporation to provide input information to the larger evaluation relative to underground siting of large central station nuclear power plants. Projections of electric power demand in California and the country as a whole suggest that a major increase in generating capacity will be required. The problem is complicated beyond that of a large but straightforward extension of capital investment by increased emphasis on environmental factors combined with the early stage of commercial application and regulation of nuclear power sources. Hydroelectric power generation is limited by the availability of suitable sites, and fossil fueled plants are constrained by the availability of high quality fuels and the adverse environmental and/or economic impact from the use of more plentiful fuels. A substantial increase in the number of nuclear power plants is now under way. This source of power is expected to provide the maj or portion of increased capacity. Other power sources such as geothermal and nuclear fusion are unlikely to satisfy the national needs due to technical problems and the lack of a comprehensive development program. There are several problems associated with meeting the projected power demand. Chief among these is the location of acceptable and economic plant sites. Indeed a sufficient number of sites may not be found unless changes occur in the procedures for selecting sites, the criteria for accepting sites, or the type of site required. Placement of a nuclear plant underground has been suggested as an alternative to present siting practices. It is postulated that the advantages of underground siting in some situations may more than compensate for added costs so that such facilities could be preferred even where surface sites are available. By virtue of greater safety, reduced surface area requirements, and improved aesthetics, underground sites might also be found where acceptable surface sites are not available. Four small European reactors have been constructed partially underground but plans for large size commercial plants have not progressed. Consequently, the features of underground power plant siting are not well understood. Gross physical features such as depth of burial, number and size of excavated galleries, equipment layout, and access or exit shafts/tunnels must be specified. Structural design features of the gallery liners, containment structure, foundations, and gallery interconnections must also be identified. Identification of the nuclear, electrical, and support equipment appropriate to underground operation is needed. Operational features must be defined for normal operations, refueling, and construction. Several magazine articles have been published addressing underground concepts. but adequate engineering data is not available to support an evaluation of the underground concept. There also remain several unresolved questions relative to the advantages of underground siting as well as the costs and other possible penalties associated with this novel approach to siting. These include the degree of increased safety through improved containment; the extent and value of isolation from falling objects, e. g. aircraft; the value of isolation from surface storms and tidal waves; the value of protection from vandalism or sabotage; the extent by which siting constraints are relieved through reduced population-distance requirements or aggravated by underground construction requirements; and the value to be placed upon the aesthetic differences of a less visible facility. The study described in this report has been directed toward some of these questions and uncertainties. Within the study an effort has been made to identify viable configurations and structural liners for typical light water reactor nuclear power plants. Three configurations are summarized in Section 3. A discussion of the underground gallery liner design and associated structural analyses is presented in Section 4. Also addressed in the study and discussed in Section 5 are some aspects of containment for underground plants. There it is suggested that the need for large separations between the plant and population centers may be significantly reduced, or perhaps eliminated. Section 6 contains a brief discussion of operational considerations for underground plants. The costs associated with excavation and lining of the underground galleries have been estimated in Section 7. These estimates include an assessment of variations implied by different seismic loading assumptions and differences in geologic media. It is shown that these costs are a small percentage of the total cost of comparable surface plants. Finally, the parameters characterizing an acceptable underground site are discussed in Section 8. Material is also included in the appendices pertaining to foreign underground plants, span limits of underground excavations, potential siting areas for underground plants in the State of California, pertinent data from the Underground Nuclear Test Program, and other supporting technical discussions

The role of aspirin in the prevention of ovarian, endometrial and cervical cancers

Drug repurposing is the application of an existing licenced drug for a new indication and potentially provides a faster and cheaper approach to developing new anti-cancer agents. Gynaecological cancers contribute significantly to the global cancer burden, highlighting the need for low cost, widely accessible therapies. A large body of evidence supports the role of aspirin as an anti-cancer agent, and a number of randomized trials are currently underway aiming to assess the potential benefit of aspirin in the treatment of cancer. This review summarizes the evidence underpinning aspirin use for the prevention of the development and recurrence of gynaecological cancers (ovarian, endometrial and cervical) and potential mechanisms of action

Statins as Potential Chemoprevention or Therapeutic Agents in Cancer: a Model for Evaluating Repurposed Drugs

Purpose of Review: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. Recent Findings: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with “target” trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. Summary: We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer

The relative contribution of common and rare genetic variants to ADHD

Attention deficit hyperactivity disorder (ADHD) is highly heritable. Genome-wide molecular studies show an increased burden of large, rare copy-number variants (CNVs) in children with ADHD compared with controls. Recent polygenic risk score analyses have also shown that en masse common variants are enriched in ADHD cases compared with population controls. The relationship between these common and rare variants has yet to be explored. In this study, we tested whether children with ADHD with (N = 60) a large (4500 kb), rare (o1% frequency) CNV differ by polygenic risk scores for ADHD to children with ADHD without such CNVs (N = 421). We also compared ADHD polygenic scores in ADHD children with and without CNVs with a group of population controls (N = 4670; of whom N = 397 had CNVs). The results show that children with ADHD with large, rare CNVs have lower polygenic scores than children without such CNVs (odds ratio (OR) = 0.73, P = 0.023). Although ADHD children without CNVs had higher scores than controls (OR = 1.18, P = 0.0031), this difference was not observed for ADHD children with CNVs (OR = 0.86, P = 0.27). These results are consistent with a polygenic liability threshold model of ADHD with both common and rare variants involved

The effect of maternal undernutrition on the rat placental transcriptome: protein restriction up-regulates cholesterol transport

Fetal exposure to a maternal low protein diet during rat pregnancy is associated with hypertension, renal dysfunction and metabolic disturbance in adult life. These effects are present when dietary manipulations target only the first half of pregnancy. It was hypothesised that early gestation protein restriction would impact upon placental gene expression and that this may give clues to the mechanism which links maternal diet to later consequences. Pregnant rats were fed control or a low protein diet from conception to day 13 gestation. Placentas were collected and RNA Sequencing performed using the Illumina platform. Protein restriction down-regulated 67 genes and up-regulated 24 genes in the placenta. Ingenuity pathway analysis showed significant enrichment in pathways related to cholesterol and lipoprotein transport and metabolism, including atherosclerosis signalling, clathrin-mediated endocytosis, LXR/RXR and FXR/RXR activation. Genes at the centre of these processes included the apolipoproteins ApoB, ApoA2 and ApoC2, microsomal triglyceride transfer protein (Mttp), the clathrin-endocytosis receptor cubilin, the transcription factor retinol binding protein 4 (Rbp4) and transerythrin (Ttr; a retinol and thyroid hormone transporter). Real-time PCR measurements largely confirmed the findings of RNASeq and indicated that the impact of protein restriction was often striking (cubilin up-regulated 32-fold, apoC2 up-regulated 17.6-fold). The findings show that gene expression in specific pathways is modulated by maternal protein restriction in the day-13 rat placenta. Changes in cholesterol transport may contribute to altered tissue development in the fetus and hence programme risk of disease in later life

Cell Cycle Regulation and Cytoskeletal Remodelling Are Critical Processes in the Nutritional Programming of Embryonic Development

Many mechanisms purport to explain how nutritional signals during early development are manifested as disease in the adult offspring. While these describe processes leading from nutritional insult to development of the actual pathology, the initial underlying cause of the programming effect remains elusive. To establish the primary drivers of programming, this study aimed to capture embryonic gene and protein changes in the whole embryo at the time of nutritional insult rather than downstream phenotypic effects. By using a cross-over design of two well established models of maternal protein and iron restriction we aimed to identify putative common “gatekeepers” which may drive nutritional programming

Pathological regression of primary tumour and metastatic lymph nodes following chemotherapy in resectable OG cancer: pooled analysis of two trials

Background: No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. / Methods: Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. / Results: Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. / Conclusions: Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further

Mapping the spatiotemporal dynamics of calcium signaling in cellular neural networks using optical flow

An optical flow gradient algorithm was applied to spontaneously forming net- works of neurons and glia in culture imaged by fluorescence optical microscopy in order to map functional calcium signaling with single pixel resolution. Optical flow estimates the direction and speed of motion of objects in an image between subsequent frames in a recorded digital sequence of images (i.e. a movie). Computed vector field outputs by the algorithm were able to track the spatiotemporal dynamics of calcium signaling pat- terns. We begin by briefly reviewing the mathematics of the optical flow algorithm, and then describe how to solve for the displacement vectors and how to measure their reliability. We then compare computed flow vectors with manually estimated vectors for the progression of a calcium signal recorded from representative astrocyte cultures. Finally, we applied the algorithm to preparations of primary astrocytes and hippocampal neurons and to the rMC-1 Muller glial cell line in order to illustrate the capability of the algorithm for capturing different types of spatiotemporal calcium activity. We discuss the imaging requirements, parameter selection and threshold selection for reliable measurements, and offer perspectives on uses of the vector data.Comment: 23 pages, 5 figures. Peer reviewed accepted version in press in Annals of Biomedical Engineerin

Acceptability of bisphosphonates among patients, clinicians and managers: a systematic review and framework synthesis

Objective: To explore the acceptability of different bisphosphonate regimens for the treatment of osteoporosis among patients, clinicians and managers, payers and academics. Design: A systematic review of primary qualitative studies. Seven databases were searched from inception to July 2019. Screening, data extraction and quality assessment of full-articles selected for inclusion were performed independently by two authors. A framework synthesis was applied to extracted data based on the theoretical framework of acceptability (TFA). The TFA includes seven domains relating to sense-making, emotions, opportunity costs, burden, perceived effectiveness, ethicality and self-efficacy. Confidence in synthesis findings was assessed. Setting: Any developed country healthcare setting. Participants: Patients, healthcare professionals, managers, payers and academics. Intervention: Experiences and views of oral and intravenous bisphosphonates. Results: Twenty-five studies were included, mostly describing perceptions of oral bisphosphonates. We identified, with high confidence, how patients and healthcare professionals make sense (coherence) of bisphosphonates by balancing perceptions of need against concerns, how uncertainty prevails about bisphosphonate perceived effectiveness and a number of individual and service factors that have potential to increase self-efficacy in recommending and adhering to bisphosphonates. We identified, with moderate confidence, that bisphosphonate taking induces concern, but has the potential to engender reassurance, and that both side effects and special instructions for taking oral bisphosphonates can result in treatment burden. Finally, we identified with low confidence that multimorbidity plays a role in people’s perception of bisphosphonate acceptability. Conclusion: By using the lens of acceptability, our findings demonstrate with high confidence that a theoretically informed, whole-system approach is necessary to both understand and improve adherence. Clinicians and patients need supporting to understand the need for bisphosphonates, and clinicians need to clarify to patients what constitutes bisphosphonate treatment success. Further research is needed to explore perspectives of male patients and those with multimorbidity receiving bisphosphonates, and patients receiving intravenous treatment