Enhanced pre-clinical assessment of total knee replacement using computational modelling with experimental corroboration & probabilistic applications

Demand for Total Knee Replacement (TKR) surgery is high and rising; not just in numbers of procedures, but in the diversity of patient demographics and increase of expectations. Accordingly, greater efforts are being invested into the pre-clinical analysis of TKR designs, to improve their performance in-vivo. A wide range of experimental and computational methods are used to analyse TKR performance pre-clinically. However, direct validation of these methods and models is invariably limited by the restrictions and challenges of clinical assessment, and confounded by the high variability of results seen in-vivo.Consequently, the need exists to achieve greater synergy between different pre-clinical analysis methods. By demonstrating robust corroboration between in-silico and in-vitro testing, and both identifying & quantifying the key sources of uncertainty, greater confidence can be placed in these assessment tools. This thesis charts the development of a new generation of fast computational models for TKR test platforms, with closer collaboration with in-vitro test experts (and consequently more rigorous corroboration with experimental methods) than previously.Beginning with basic tibiofemoral simulations, the complexity of the models was progressively increased, to include in-silico wear prediction, patellofemoral & full lower limb models, rig controller-emulation, and accurate system dynamics. At each stage, the models were compared extensively with data from the literature and experimental tests results generated specifically for corroboration purposes.It is demonstrated that when used in conjunction with, and complementary to, the corresponding experimental work, these higher-integrity in-silico platforms can greatly enrich the range and quality of pre-clinical data available for decision-making in the design process, as well as understanding of the experimental platform dynamics. Further, these models are employed within a probabilistic framework to provide a statistically-quantified assessment of the input factors most influential to variability in the mechanical outcomes of TKR testing. This gives designers a much richer holistic visibility of the true system behaviour than extant 'deterministic' simulation approaches (both computational and experimental).By demonstrating the value of better corroboration and the benefit of stochastic approaches, the methods used here lay the groundwork for future advances in pre-clinical assessment of TKR. These fast, inexpensive models can complement existing approaches, and augment the information available for making better design decisions prior to clinical trials, accelerating the design process, and ultimately leading to improved TKR delivery in-vivo to meet future demands

Lipopolysaccharide-induced interferon response networks at birth are predictive of severe viral lower respiratory infections in the first year of life

Appropriate innate immune function is essential to limit pathogenesis and severity of severe lower respiratory infections (sLRI) during infancy, a leading cause of hospitalization and risk factor for subsequent asthma in this age group. Employing a systems biology approach to analysis of multi-omic profiles generated from a high-risk cohort (n = 50), we found that the intensity of activation of an LPS-induced interferon gene network at birth was predictive of sLRI risk in infancy (AUC = 0.724). Connectivity patterns within this network were stronger among susceptible individuals, and a systems biology approach identified IRF1 as a putative master regulator of this response. These findings were specific to the LPS-induced interferon response and were not observed following activation of viral nucleic acid sensing pathways. Comparison of responses at birth versus age 5 demonstrated that LPS-induced interferon responses but not responses triggered by viral nucleic acid sensing pathways may be subject to strong developmental regulation. These data suggest that the risk of sLRI in early life is in part already determined at birth, and additionally that the developmental status of LPS-induced interferon responses may be a key determinant of susceptibility. Our findings provide a rationale for the identification of at-risk infants for early intervention aimed at sLRI prevention and identifies targets which may be relevant for drug development

Microbes as engines of ecosystem function : When does community structure enhance predictions of ecosystem processes?

FUNDING This work was supported by NSF grant DEB-1221215 to DN, as well as grants supporting the generation of our datasets as acknowledged in their original publications and in Supplementary Table S1. ACKNOWLEDGMENT We thank the USGS Powell Center ‘Next Generation Microbes’ working group, anonymous reviews, Brett Melbourne, and Alan Townsend for valuable feedback on this project.Peer reviewedPublisher PD

IRF7-Associated Immunophenotypes Have Dichotomous Responses to Virus/Allergen Coexposure and OM-85-Induced Reprogramming

High risk for virus-induced asthma exacerbations in children is associated with an IRF7lo immunophenotype, but the underlying mechanisms are unclear. Here, we applied a Systems Biology approach to an animal model comprising rat strains manifesting high (BN) versus low susceptibility (PVG) to experimental asthma, induced by virus/allergen coexposure, to elucidate the mechanism(s)-of-action of the high-risk asthma immunophenotype. We also investigated potential risk mitigation via pretreatment with the immune training agent OM-85. Virus/allergen coexposure in low-risk PVG rats resulted in rapid and transient airways inflammation alongside IRF7 gene network formation. In contrast, responses in high-risk BN rats were characterized by severe airways eosinophilia and exaggerated proinflammatory responses that failed to resolve, and complete absence of IRF7 gene networks. OM-85 had more profound effects in high-risk BN rats, inducing immune-related gene expression changes in lung at baseline and reducing exaggerated airway inflammatory responses to virus/allergen coexposure. In low-risk PVG rats, OM-85 boosted IRF7 gene networks in the lung but did not alter baseline gene expression or cellular influx. Distinct IRF7-associated asthma risk immunophenotypes have dichotomous responses to virus/allergen coexposure and respond differentially to OM-85 pretreatment. Extrapolating to humans, our findings suggest that the beneficial effects OM-85 pretreatment may preferentially target those in high-risk subgroups

Crop Updates 2008 - Lupins, Pulses and Oilseeds

This session covers twenty six papers from different authors: Regional Roundup 1. SOUTH EAST AGRICULTURAL REGION, Mark Seymour Department of Agriculture and Food, and Robert Johnson CBH Group, Esperance 2. CENTRAL AGRICULTURAL REGION, Ian Pritchard, Department of Agriculture and Food 3. GREAT SOUTHERN AND LAKES REGION, Raj Malik, Department of Agriculture and Food 4. NORTHERN AGRICULTURAL REGION, Wayne Parker and Martin Harries, Department of Agriculture and Food LUPINS 5. Cropping lupins in wide rows in Western Australia, Martin Harries and Bob French, Department of Agriculture and Food 6. The effect of sowing time and radish density on lupin yield, Martin Harries and Jo Walker, Department of Agriculture and Food 7. Lupin agronomy affects crop competitiveness with annual ryegrass, Bob French and Laurie Maiolo, Department of Agriculture and Food 8. Identification of lupin mutants with tolerance to isoxaflutole, Leigh Smith, Department of Agriculture and Food PULSES 9. Chickpea 2007 Crop Variety Testing (CVT) and National Variety Testing (NVT), Alan Harris, Rod Hunter, Tanveer Khan and Jenny Garlinge, Department of Agriculture and Food 10. Desi chickpea breeding: Evaluation of advanced lines, Tanveer Khan1, Poran Gaur2, Kadambot Siddique3, Heather Clarke4, Neil Turner4, William MacLeod4, Stuart Morgan1, Alan Harris1, 1Department of Agriculture and Food, 2International Crop Research Institute for the Semi Arid Tropics (ICRISAT); 3The University of Western Australia; 4Centre for Legumes in Mediterranean Agriculture 11. Can wide rows buffer chickpea growth against dry environments? Bob French and Wendy Vance, Department of Agriculture and Food, and School of Environmental Sciences, Murdoch University 12. Field pea 2007 Crop Variety Testing (CVT) and National Variety Testing (NVT), Alan Harris, Rod Hunter, Tanveer Khan and Jenny Garlinge, Department of Agriculture and Food 13. Australian Field Pea improvement Program (AFPIP): Evaluation of advanced breeding lines, Tanveer Khan1, Phillip Chambers1, Chris Veitch1, Stuart Morgan1, Alan Harris1, and Tony Leonforte 2, 1Department of Agriculture and Food, 2Department of Primary Industries, Victoria 14. Ability of semi-leafless field peas to recover after rolling, Mark Seymour and Rodger Beermier, Department of Agriculture and Food 15. Field pea germplasm enhancement for black spot resistance, Tanveer Khan, Stuart Morgan, Alan Harris and Phillip Chambers, Department of Agriculture and Food 16. Application of ‘Blackspot Manager’ model to identifying a low risk sowing date for field pea in South Australia and Western Australia in 2007, Moin Salam1, Jenny Davidson2, Jean Galloway1, Pip Payne2, Tess Humphries2, Bill MacLeod1 and Art Diggle1, 1Department of Agriculture and Food, 2SARDI, South Australia 17. Late post emergent herbicide sprays for field pea, Mark Seymour and Rodger Beermier, Department of Agriculture and Food 18. Adding triasulfuron to croptopping mixes does not affect the yield of field pea, Mark Seymour, Department of Agriculture and Food 18. Herbicide tolerance of field pea varieties, Harmohinder Dhammu and Mark Seymour, Department of Agriculture and Food 19. Breeding highlights of the PBA lentil program, Michael Materne1, Kerry Regan2, Chris Veitch2 and Phil Chambers2, 1Department of Primary Industries, Victoria 2Department of Agriculture and Food CANOLA 20. How late can I sow canola in 2008? Mohammad Amjad, Andy Sutherland and Pat Fels, Department of Agriculture and Food 21. Direct harvesting canola, Glen Riethmuller1, Wallace Cowling2, Milton Sanders2, Eliot Jones2 and Chris Newman1, 1Department of Agriculture and Food, Western Australia, 2Canola Breeders Western Australia Pty Ltd 22. Agronomic performance of new hybrid canola and juncea canola in low, medium and high rainfall environments of Western Australia, Mohammad Amjad, Andy Sutherland and Pat Fels, Department of Agriculture and Food 23. Comparative performance of new canola varieties in commercial-scale field trials of Oilseeds WA – 2007, Mohammad Amjad1, John Duff2 and David Sermon3 1Department of Agriculture and Food, 2Oilseeds Western Australia and John Duff & Associates, Perth; 3ConsultAg, Perth 24. The effect of rotation crops, trash retention and prophylactic sprays on arthropod abundance in a following canola crop, Svetlana Micic, Anthony Dore and Geoff Strickland, Department of Agriculture and Food OATS 25. Fungicide options for controlling disease in oats, Raj Malik and Blakely Paynter, Department of Agriculture and Food 26. Herbicide tolerance of new oat varieties, Harmohinder Dhammu, Vince Lambert and Chris Roberts, Department of Agriculture and Foo

The Science Performance of JWST as Characterized in Commissioning

This paper characterizes the actual science performance of the James Webb Space Telescope (JWST), as determined from the six month commissioning period. We summarize the performance of the spacecraft, telescope, science instruments, and ground system, with an emphasis on differences from pre-launch expectations. Commissioning has made clear that JWST is fully capable of achieving the discoveries for which it was built. Moreover, almost across the board, the science performance of JWST is better than expected; in most cases, JWST will go deeper faster than expected. The telescope and instrument suite have demonstrated the sensitivity, stability, image quality, and spectral range that are necessary to transform our understanding of the cosmos through observations spanning from near-earth asteroids to the most distant galaxies.Comment: 5th version as accepted to PASP; 31 pages, 18 figures; https://iopscience.iop.org/article/10.1088/1538-3873/acb29

BHPR research: qualitative1. Complex reasoning determines patients' perception of outcome following foot surgery in rheumatoid arhtritis

Background: Foot surgery is common in patients with RA but research into surgical outcomes is limited and conceptually flawed as current outcome measures lack face validity: to date no one has asked patients what is important to them. This study aimed to determine which factors are important to patients when evaluating the success of foot surgery in RA Methods: Semi structured interviews of RA patients who had undergone foot surgery were conducted and transcribed verbatim. Thematic analysis of interviews was conducted to explore issues that were important to patients. Results: 11 RA patients (9 ♂, mean age 59, dis dur = 22yrs, mean of 3 yrs post op) with mixed experiences of foot surgery were interviewed. Patients interpreted outcome in respect to a multitude of factors, frequently positive change in one aspect contrasted with negative opinions about another. Overall, four major themes emerged. Function: Functional ability & participation in valued activities were very important to patients. Walking ability was a key concern but patients interpreted levels of activity in light of other aspects of their disease, reflecting on change in functional ability more than overall level. Positive feelings of improved mobility were often moderated by negative self perception ("I mean, I still walk like a waddling duck”). Appearance: Appearance was important to almost all patients but perhaps the most complex theme of all. Physical appearance, foot shape, and footwear were closely interlinked, yet patients saw these as distinct separate concepts. Patients need to legitimize these feelings was clear and they frequently entered into a defensive repertoire ("it's not cosmetic surgery; it's something that's more important than that, you know?”). Clinician opinion: Surgeons' post operative evaluation of the procedure was very influential. The impact of this appraisal continued to affect patients' lasting impression irrespective of how the outcome compared to their initial goals ("when he'd done it ... he said that hasn't worked as good as he'd wanted to ... but the pain has gone”). Pain: Whilst pain was important to almost all patients, it appeared to be less important than the other themes. Pain was predominately raised when it influenced other themes, such as function; many still felt the need to legitimize their foot pain in order for health professionals to take it seriously ("in the end I went to my GP because it had happened a few times and I went to an orthopaedic surgeon who was quite dismissive of it, it was like what are you complaining about”). Conclusions: Patients interpret the outcome of foot surgery using a multitude of interrelated factors, particularly functional ability, appearance and surgeons' appraisal of the procedure. While pain was often noted, this appeared less important than other factors in the overall outcome of the surgery. Future research into foot surgery should incorporate the complexity of how patients determine their outcome Disclosure statement: All authors have declared no conflicts of interes

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Pathological chemotherapy response score is prognostic in tubo-ovarian high-grade serous carcinoma: A systematic review and meta-analysis of individual patient data

There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT.This article is freely available via Open Access. Click on the Publisher URL to access the full-text via the publisher's site