Microscopic biophysical model of self-organization in tissue due to feedback between cell- and macroscopic-scale forces

We develop a microscopic biophysical model for self-organization and reshaping of artificial tissue, that is codriven by microscopic active forces between cells and an extracellular matrix (ECM), and macroscopic forces that develop within the tissue, finding close agreement with experiment. Microscopic active forces are stimulated by μ m -scale interactions between cells and the ECM within which they exist, and when large numbers of cells act together these forces drive, and are affected by, macroscopic-scale self-organization and reshaping of tissues in a feedback loop. To understand this loop, there is a need to (1) construct microscopic biophysical models that can simulate these processes for the very large number of cells found in tissues, (2) validate and calibrate those models against experimental data, and (3) understand the active feedback between cells and the extracellular matrix, and its relationship to macroscopic self-organization and reshaping of tissue. Our microscopic biophysical model consists of a contractile network representing the ECM, that interacts with a large number of cells via dipole forces, to describe macroscopic self-organization and reshaping of tissue. We solve the model using simulated annealing, finding close agreement with experiments on artificial neural tissue. We discuss the calibration of model parameters. We conclude that feedback between microscopic cell-ECM dipole interactions and tissue-scale forces is a key factor in driving macroscopic self-organization and reshaping of tissue. We discuss the application of the biophysical model to the simulation and rational design of artificial tissues

Adapting tissue-engineered in vitro CNS models for high-throughput study of neurodegeneration

Neurodegenerative conditions remain difficult to treat, with the continuing failure to see therapeutic research successfully advance to clinical trials. One of the obstacles that must be overcome is to develop enhanced models of disease. Tissue engineering techniques enable us to create organised artificial central nervous system tissue that has the potential to improve the drug development process. This study presents a replicable model of neurodegenerative pathology through the use of engineered neural tissue co-cultures that can incorporate cells from various sources and allow degeneration and protection of neurons to be observed easily and measured, following exposure to neurotoxic compounds - okadaic acid and 1-methyl-4-phenylpyridinium. Furthermore, the technology has been miniaturised through development of a mould with 6 mm length that recreates the advantageous features of engineered neural tissue co-cultures at a scale suitable for commercial research and development. Integration of human-derived induced pluripotent stem cells aids more accurate modelling of human diseases, creating new possibilities for engineered neural tissue co-cultures and their use in drug screening

Engineered neural tissue with aligned, differentiated adipose-derived stem cells promotes peripheral nerve regeneration across a critical sized defect in rat sciatic nerve.

Adipose-derived stem cells were isolated from rats and differentiated to a Schwann cell-like phenotype in vitro. The differentiated cells (dADSCs) underwent self-alignment in a tethered type-1 collagen gel, followed by stabilisation to generate engineered neural tissue (EngNT-dADSC). The pro-regenerative phenotype of dADSCs was enhanced by this process, and the columns of aligned dADSCs in the aligned collagen matrix supported and guided neurite extension in vitro. EngNT-dADSC sheets were rolled to form peripheral nerve repair constructs that were implanted within NeuraWrap conduits to bridge a 15 mm gap in rat sciatic nerve. After 8 weeks regeneration was assessed using immunofluorescence imaging and transmission electron microscopy and compared to empty conduit and nerve graft controls. The proportion of axons detected in the distal stump was 3.5 fold greater in constructs containing EngNT-dADSC than empty tube controls. Our novel combination of technologies that can organise autologous therapeutic cells within an artificial tissue construct provides a promising new cellular biomaterial for peripheral nerve repair

Complex circular subsidence structures in tephra deposited on large blocks of ice: Varða tuff cone, Öræfajökull, Iceland

Several broadly circular structures up to 16 m in diameter, into which higher strata have sagged and locally collapsed, are present in a tephra outcrop on southwest Öræfajökull, southern Iceland. The tephra was sourced in a nearby basaltic tuff cone at Varða. The structures have not previously been described in tuff cones, and they probably formed by the melting out of large buried blocks of ice emplaced during a preceding jökulhlaup that may have been triggered by a subglacial eruption within the Öræfajökull ice cap. They are named ice-melt subsidence structures, and they are analogous to kettle holes that are commonly found in proglacial sandurs and some lahars sourced in ice-clad volcanoes. The internal structure is better exposed in the Varða examples because of an absence of fluvial infilling and reworking, and erosion of the outcrop to reveal the deeper geometry. The ice-melt subsidence structures at Varða are a proxy for buried ice. They are the only known evidence for a subglacial eruption and associated jökulhlaup that created the ice blocks. The recognition of such structures elsewhere will be useful in reconstructing more complete regional volcanic histories as well as for identifying ice-proximal settings during palaeoenvironmental investigations

Drugs foresight 2020: a Delphi expert panel study

Peer reviewe

Implications for registry-based vaccine effectiveness studies from an evaluation of an immunization registry: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Population-based electronic immunization registries create the possibility of using registry data to conduct vaccine effectiveness studies which could have methodological advantages over traditional observational studies. For study validity, the base population would have to be clearly defined and the immunization status of members of the population accurately recorded in the registry. We evaluated a city-wide immunization registry, focusing on its potential as a tool to study pertussis vaccine effectiveness, especially in adolescents.</p> <p>Methods</p> <p>We conducted two evaluations – one in sites that were active registry participants and one in sites that had implemented an electronic medical record with plans for future direct data transfer to the registry – of the ability to match patients' medical records to registry records and the accuracy of immunization records in the registry. For each site, records from current pediatric patients were chosen randomly. Data regarding pertussis-related immunizations, clinic usage, and demographic and identifying information were recorded; for 11–17-year-old subjects, information on MMR, hepatitis B, and varicella immunizations was also collected. Records were then matched, when possible, to registry records. For records with a registry match, immunization data were compared.</p> <p>Results</p> <p>Among 350 subjects from sites that were current registry users, 307 (87.7%) matched a registry record. Discrepancies in pertussis-related data were common for up-to-date status (22.6%), number of immunizations (34.7%), dates (10.2%), and formulation (34.4%). Among 442 subjects from sites that planned direct electronic transfer of immunization data to the registry, 393 (88.9%) would have matched a registry record; discrepancies occurred frequently in number of immunizations (11.9%), formulation (29.1%), manufacturer (94.4%), and lot number (95.1%.) Inability to match and immunization discrepancies were both more common in subjects who were older at their first visit to the provider site. For 11–17-year-old subjects, discrepancies were also common for MMR, hepatitis B, and varicella vaccination data.</p> <p>Conclusion</p> <p>Provider records frequently could not be matched to registry records or had discrepancies in key immunization data. These issues were more common for older children and were present even with electronic data transfer. These results highlight general challenges that may face investigators wishing to use registry-based immunization data for vaccine effectiveness studies, especially in adolescents.</p

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Predation on an Upper Trophic Marine Predator, the Steller Sea Lion: Evaluating High Juvenile Mortality in a Density Dependent Conceptual Framework

The endangered western stock of the Steller sea lion (Eumetopias jubatus) – the largest of the eared seals – has declined by 80% from population levels encountered four decades ago. Current overall trends from the Gulf of Alaska to the Aleutian Islands appear neutral with strong regional heterogeneities. A published inferential model has been used to hypothesize a continuous decline in natality and depressed juvenile survival during the height of the decline in the mid-late 1980's, followed by the recent recovery of juvenile survival to pre-decline rates. However, these hypotheses have not been tested by direct means, and causes underlying past and present population trajectories remain unresolved and controversial. We determined post-weaning juvenile survival and causes of mortality using data received post-mortem via satellite from telemetry transmitters implanted into 36 juvenile Steller sea lions from 2005 through 2011. Data show high post-weaning mortality by predation in the eastern Gulf of Alaska region. To evaluate the impact of such high levels of predation, we developed a conceptual framework to integrate density dependent with density independent effects on vital rates and population trajectories. Our data and model do not support the hypothesized recent recovery of juvenile survival rates and reduced natality. Instead, our data demonstrate continued low juvenile survival in the Prince William Sound and Kenai Fjords region of the Gulf of Alaska. Our results on contemporary predation rates combined with the density dependent conceptual framework suggest predation on juvenile sea lions as the largest impediment to recovery of the species in the eastern Gulf of Alaska region. The framework also highlights the necessity for demographic models based on age-structured census data to incorporate the differential impact of predation on multiple vital rates