Morphology and pattern of Quaternary sedimentation in the North Sea Basin

The Quaternary North Sea Basin, which extends from northwest mainland Europe in the south (52°N) to the Norwegian Sea in the north (62°N), contains a thick (up to 1 km) sedimentary succession that records the changing nature of sediment supply from surrounding land areas during the last c.2.6 Ma. We use an extensive 2D and 3D seismic database to correlate major Quaternary seismo-stratigraphic surfaces and units across the North Sea and reconstruct the broad-scale infill pattern of the entire Quaternary North Sea Basin. The total volume of Quaternary sediments in the North Sea (350,000 km²) is c.140,000 km3, while the area inside the 500 m contour of the base-Quaternary surface has a volume of 109,000 km3. Two largely independent depocentres developed in the North Sea Basin during the early Quaternary: the southern and central sub-basin was infilled by shelf fluvio-deltaic and prodeltaic sediments delivered from the east and south-east, whilst the northern sub-basin was infilled mainly by prograding glacigenic debris-flows deposited from an ice mass centred on the Norwegian mainland. Contour currents were an important mechanism of sediment deposition and reworking, with water circulation in the basin probably occurring in an anti-clockwise direction. Whilst most of the southern North Sea Basin was infilled by around 1.6-1.7 Ma, a depression persisted in the central North Sea until around 1 Ma. The analysis of landforms on 3D seismic data suggests that the Fennoscandian Ice Sheet (FIS) extended intermittently to the palaeo-shelf break in the northern North Sea during the earliest Quaternary and expanded into the central North Sea prior to the excavation of the Norwegian Channel

Quaternary and Neogene Reservoirs of the Norwegian Continental Shelf and the Faroe-Shetland Basin

Glaciogenic reservoirs host important hydrocarbon resources across the globe. Examples such as the Peon and Aviat discoveries in the North Sea show that Quaternary and Neogene reservoirs can be prospective in the region. In this study, we interpret 2D and 3D reflection seismic data combined with borehole information to document unconventional play models from the shallow subsurface of the Norwegian Continental Shelf and the Faroe-Shetland Basin. These plays include (i) glacial sands in ice-marginal outwash fans, sealed by stiff subglacial tills (the Peon discovery), (ii) meltwater turbidites, (iii) contouritic fine-grained glacimarine sands sealed by gas hydrates, (iv) remobilized oozes above large evacuation craters which are sealed by megaslides and glacial muds, and (v) Neogene sand injectites. The hydrocarbon reservoirs are characterized by negative-polarity reflections with anomalously high amplitudes in the reflection seismic data as well as density and velocity decreases in the borehole data. Extensive new 3D reflection seismic data are crucial to correctly interpret glacial processes and distinguish shallow reservoirs from shallow seals. These data document a variety of play models with the potential for gas in large quantities and enable the identification of optimal drilling targets at stratigraphic levels which have so far been overlooked

Neuroendocrine Stress Response in Female and Male Youths With Conduct Disorder and Associations With Early Adversity

Objective: Conduct disorder (CD) involves aggressive and antisocial behavior and is associated with blunted cortisol stress response in male youths. Far less is known about cortisol stress responsivity in female youths with CD or other neuroendocrine responses in both sexes. Although CD is linked to early adversity, the possibility that neuroendocrine alterations may mediate the relationship between early adversity and CD has not been systematically investigated. Method: Within the European FemNAT-CD multi-site study, salivary cortisol, testosterone, the testosterone/cortisol ratio, oxytocin, and psychological stress response to a standardized psychosocial stress test (the Trier Social Stress Test [TSST]), together with common pre- and postnatal environmental risk factors, were investigated in 130 pubertal youths with CD (63% female, 9-18 years of age) and 160 sex-, age-, and puberty-matched healthy controls (HCs). Results: The TSST induced psychological stress in both CD and HCs. In contrast, female and male youths with CD showed blunted cortisol, testosterone, oxytocin, and testosterone/cortisol stress responses compared to HCs. These blunted stress responses partly mediated the relationship between environmental risk factors and CD. Conclusion: Findings from this unique sample, including many female youths with CD, provide evidence for a widespread attenuated stress responsivity of not only stress hormones, but also sex hormones and neuropeptides in CD and its subgroups (eg, with limited prosocial emotions). Results are the first to demonstrate blunted neuroendocrine stress responses in both female and male youths with CD. Early adversity may alter neuroendocrine stress responsivity. Biological mechanisms should be investigated further to pave the way for personalized intervention, thereby improving treatments for CD.</p

Integration of biorelevant pediatric dissolution methodology into PBPK modeling to predict in vivo performance and bioequivalence of generic drugs in pediatric populations : a carbamazepine case study

This study investigated the impact of gastro-intestinal fluid volume and bile salt (BS) concentration on the dissolution of carbamazepine (CBZ) immediate release (IR) 100 mg tablets and to integrate these in vitro biorelevant dissolution profiles into physiologically based pharmacokinetic modelling (PBPK) in pediatric and adult populations to determine the biopredictive dissolution profile. Dissolution profiles of CBZ IR tablets (100 mg) were generated in 50–900 mL biorelevant adult fasted state simulated gastric and intestinal fluid (Ad-FaSSGF and Ad-FaSSIF), also in three alternative compositions of biorelevant pediatric FaSSGF and FaSSIF medias at 200 mL. This study found that CBZ dissolution was poorly sensitive to changes in the composition of the biorelevant media, where dissimilar dissolution (F2 = 46.2) was only observed when the BS concentration was changed from 3000 to 89 μM (Ad-FaSSIF vs Ped-FaSSIF 50% 14 BS). PBPK modeling demonstrated the most predictive dissolution volume and media composition to forecast the PK was 500 mL of Ad-FaSSGF/Ad-FaSSIF media for adults and 200 mL Ped-FaSSGF/FaSSIF media for pediatrics. A virtual bioequivalence simulation was conducted by using Ad-FaSSGF and/or Ad-FaSSIF 500 mL or Ped-FaSSGF and/or Ped-FaSSIF 200 mL dissolution data for CBZ 100 mg (reference and generic test) IR product. The CBZ PBPK models showed bioequivalence of the product. This study demonstrates that the integration of biorelevant dissolution data can predict the PK profile of a poorly soluble drug in both populations. Further work using more pediatric drug products is needed to verify biorelevant dissolution data to predict the in vivo performance in pediatrics. Graphical Abstract

The Translational Medicine Ontology and Knowledge Base: driving personalized medicine by bridging the gap between bench and bedside

Background: Translational medicine requires the integration of knowledge using heterogeneous data from health care to the life sciences. Here, we describe a collaborative effort to produce a prototype Translational Medicine Knowledge Base (TMKB) capable of answering questions relating to clinical practice and pharmaceutical drug discovery. Results: We developed the Translational Medicine Ontology (TMO) as a unifying ontology to integrate chemical, genomic and proteomic data with disease, treatment, and electronic health records. We demonstrate the use of Semantic Web technologies in the integration of patient and biomedical data, and reveal how such a knowledge base can aid physicians in providing tailored patient care and facilitate the recruitment of patients into active clinical trials. Thus, patients, physicians and researchers may explore the knowledge base to better understand therapeutic options, efficacy, and mechanisms of action. Conclusions: This work takes an important step in using Semantic Web technologies to facilitate integration of relevant, distributed, external sources and progress towards a computational platform to support personalized medicine. Availability: TMO can be downloaded from http://code.google.com/p/translationalmedicineontology and TMKB can be accessed at http://tm.semanticscience.org/sparql

Anvers-Hugo Trough palaeo-ice stream, Antarctic Peninsula: geomorphological evidence for the role of subglacial water in facilitating ice stream flow

We will present new multibeam bathymetry data that make the Anvers-Hugo Trough west of the Antarctic Peninsula one of the most completely surveyed palaeo-ice stream pathways in Antarctica. We interpret landforms revealed by these data as indicating that subglacial water availability played an important role in facilitating ice stream flow in the trough during late Quaternary glacial periods. Specifically, we observe a set of northward-shoaling valleys that are eroded into the upstream edge of a sedimentary basin, extend northwards from a zone containing landforms typical of erosion by subglacial water flow, and coincide spatially with the onset of mega-scale glacial lineations. Water was likely supplied to the ice stream bed episodically as a result of outbursts from a subglacial lake previously hypothesized to have been located in the Palmer Deep basin on the inner continental shelf. In a palaeo-ice stream confluence area, close juxtaposition of mega-scale glacial lineations with landforms that are characteristic of slow, dry-based ice flow, suggests that water availability was also an important control on the lateral extent of these palaeo-ice streams. These interpretations are consistent with the hypothesis that subglacial lakes or areas of elevated geothermal heat flux play a critical role in the onset of many large ice streams. The interpretations also have implications for the dynamic behaviour of the Anvers-Hugo Trough palaeo-ice stream and, potentially, of several other Antarctic palaeo-ice streams. Keywords: multibeam bathymetry, ice stream, subglacial water, landfor

On-going collaborative priority-setting for research activity: a method of capacity building to reduce the research-practice translational gap

Background: International policy suggests that collaborative priority setting (CPS) between researchers and end users of research should shape the research agenda, and can increase capacity to address the research-practice translational gap. There is limited research evidence to guide how this should be done to meet the needs of dynamic healthcare systems. One-off priority setting events and time-lag between decision and action prove problematic. This study illustrates the use of CPS in a UK research collaboration called Collaboration and Leadership in Applied Health Research and Care (CLAHRC). Methods: Data were collected from a north of England CLAHRC through semi-structured interviews with 28 interviewees and a workshop of key stakeholders (n = 21) including academics, NHS clinicians, and managers. Documentary analysis of internal reports and CLAHRC annual reports for the first two and half years was also undertaken. These data were thematically coded. Results: Methods of CPS linked to the developmental phase of the CLAHRC. Early methods included pre-existing historical partnerships with on-going dialogue. Later, new platforms for on-going discussions were formed. Consensus techniques with staged project development were also used. All methods demonstrated actual or potential change in practice and services. Impact was enabled through the flexibility of research and implementation work streams; ‘matched’ funding arrangements to support alignment of priorities in partner organisations; the size of the collaboration offering a resource to meet project needs; and the length of the programme providing stability and long term relationships. Difficulties included tensions between being responsive to priorities and the possibility of ‘drift’ within project work, between academics and practice, and between service providers and commissioners in the health services. Providing protected ‘matched’ time proved difficult for some NHS managers, which put increasing work pressure on them. CPS is more time consuming than traditional approaches to project development. Conclusions: CPS can produce needs-led projects that are bedded in services using a variety of methods. Contributing factors for effective CPS include flexibility in use and type of available resources, flexible work plans, and responsive leadership. The CLAHRC model provides a translational infrastructure that enables CPS that can impact on healthcare systems

MRI-derived g-ratio and lesion severity in newly diagnosed multiple sclerosis

Myelin loss is associated with axonal damage in established multiple sclerosis. This relationship is challenging to study in vivo in early disease. Here, we ask whether myelin loss is associated with axonal damage at diagnosis, by combining non-invasive neuroimaging and blood biomarkers. We performed quantitative microstructural MRI and single molecule ELISA plasma neurofilament measurement in 73 patients with newly diagnosed, immunotherapy naïve relapsing-remitting multiple sclerosis. Myelin integrity was evaluated using aggregate g-ratios, derived from magnetization transfer saturation (MTsat) and neurite orientation dispersion and density imaging (NODDI) diffusion data. We found significantly higher g-ratios within cerebral white matter lesions (suggesting myelin loss) compared with normal-appearing white matter (0.61 vs 0.57, difference 0.036, 95% CI 0.029 to 0.043, p &amp;lt; 0.001). Lesion volume (Spearman’s rho rs= 0.38, p &amp;lt; 0.001) and g-ratio (rs= 0.24 p &amp;lt; 0.05) correlated independently with plasma neurofilament. In patients with substantial lesion load (n = 38), those with higher g-ratio (defined as greater than median) were more likely to have abnormally elevated plasma neurofilament than those with normal g-ratio (defined as less than median) (11/23 [48%] versus 2/15 [13%] p &amp;lt; 0.05). These data suggest that, even at multiple sclerosis diagnosis, reduced myelin integrity is associated with axonal damage. MRI-derived g-ratio may provide useful additional information regarding lesion severity, and help to identify individuals with a high degree of axonal damage at disease onset. York, Martin et al. simultaneously measured g-ratio and plasma neurofilament in 73 relapsing-remitting multiple sclerosis patients at diagnosis using advanced MRI and single molecule ELISA. They demonstrate that g-ratio of cerebral white matter lesions varies at diagnosis, and show that high g-ratio of lesions is associated with elevated plasma neurofilament