Computational modelling and experimental tank testing of the multi float WaveSub under regular wave forcing

A submerged wave device generates energy from the relative motion of floating bodies. In 1 WaveSub, three floats are joined to a reactor; each connected to a spring and generator. Electricity generated 2 damps the orbital movements of the floats. The forces are non-linear and each float interacts with the others. 3 Tuning to the wave climate is achieved by changing the line lengths so there is a need to understand the 4 performance trade-offs for a large number of configurations. This requires an efficient, large displacement, 5 multidirectional, multi-body numerical scheme. Results from a 1/25 scale wave basin experiment are described. 6 Here we show that a time domain linear potential flow formulation (Nemoh, WEC-Sim) can match the tank 7 testing provided that suitably tuned drag coefficients are employed. Inviscid linear potential models can match 8 some wave device experiments, however, additional viscous terms generally provide better accuracy. Scale 9 experiments are also prone to mechanical friction and we estimate friction terms to improve the correlation 10 further. The resulting error in mean power between numerical and physical models is approximately 10%. 11 Predicted device movement shows a good match. Overall, drag terms in time domain wave energy modelling 12 will improve simulation accuracy in wave renewable energy device design

Computational modelling and experimental tank testing of the multi float WaveSub under regular wave forcing

A submerged wave device generates energy from the relative motion of floating bodies. In WaveSub, three floats are joined to a reactor; each connected to a spring and generator. Electricity generated damps the orbital movements of the floats. The forces are non-linear and each float interacts with the others. Tuning to the wave climate is achieved by changing the line lengths, so there is a need to understand the performance trade-offs for a large number of configurations. This requires an efficient, large displacement, multidirectional, multi-body numerical scheme. Results from a 1/25 scale wave basin experiment are described. Here, we show that a time domain linear potential flow formulation (Nemoh, WEC-Sim) can match the tank testing provided that suitably tuned drag coefficients are employed. Inviscid linear potential models can match some wave device experiments; however, additional viscous terms generally provide better accuracy. Scale experiments are also prone to mechanical friction, and we estimate friction terms to improve the correlation further. The resulting error in mean power between numerical and physical models is approximately 10%. Predicted device movement shows a good match. Overall, drag terms in time domain wave energy modelling will improve simulation accuracy in wave renewable energy device design

AZD8055 enhances in vivo efficacy of afatinib in chordomas

Chordomas are primary bone tumors that arise in the cranial base, mobile spine, and sacrococcygeal region, affecting patients of all ages. Currently, there are no approved agents for chordoma patients. Here, we evaluated the anti-tumor efficacy of small molecule inhibitors that target oncogenic pathways in chordoma, as single agents and in combination, to identify novel therapeutic approaches with the greatest translational potential. A panel of small molecule compounds was screened in vivo against patient-derived xenograft (PDX) models of chordoma, and potentially synergistic combinations were further evaluated using chordoma cell lines and xenograft models. Among the tested agents, inhibitors of EGFR (BIBX 1382, erlotinib, and afatinib), c-MET (crizotinib), and mTOR (AZD8055) significantly inhibited tumor growth in vivo but did not induce tumor regression. Co-inhibition of EGFR and c-MET using erlotinib and crizotinib synergistically reduced cell viability in chordoma cell lines but did not result in enhanced in vivo activity. Co-inhibition of EGFR and mTOR pathways using afatinib and AZD8055 synergistically reduced cell viability in chordoma cell lines. Importantly, this dual inhibition completely suppressed tumor growth in vivo, showing improved tumor control. Together, these data demonstrate that individual inhibitors of EGFR, c-MET, and mTOR pathways suppress chordoma growth both in vitro and in vivo. mTOR inhibition increased the efficacy of EGFR inhibition on chordoma growth in several preclinical models. The insights gained from our study potentially provide a novel combination therapeutic strategy for patients with chordoma. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland

Focused wave interactions with floating structures: A blind comparative study

The paper presents results from the Collaborative Computational Project in Wave Structure Interaction (CCP-WSI) Blind Test Series 2. Without prior access to the physical data, participants, with numerical methods ranging from low-fidelity linear models to fully non-linear Navier-Stokes (NS) solvers, simulate the interaction between focused wave events and two separate, taut-moored, floating structures: a hemispherical-bottomed cylinder and a cylinder with a moonpool. The 'blind' numerical predictions for heave, surge, pitch and mooring load, are compared against physical measurements. Dynamic time warping is used to quantify the predictive capability of participating methods. In general, NS solvers and hybrid methods give more accurate predictions; however, heave amplitude is predicted reasonably well by all methods; and a WEC-Sim implementation, with CFD-informed viscous terms, demonstrates comparable predictive capability to even the stronger NS solvers. Large variations in the solutions are observed (even among similar methods), highlighting a need for standardisation in the numerical modelling of WSI problems

Targeted Doxorubicin Delivery to Brain Tumors via Minicells: Proof of Principle Using Dogs with Spontaneously Occurring Tumors as a Model

BACKGROUND: Cytotoxic chemotherapy can be very effective for the treatment of cancer but toxicity on normal tissues often limits patient tolerance and often causes long-term adverse effects. The objective of this study was to assist in the preclinical development of using modified, non-living bacterially-derived minicells to deliver the potent chemotherapeutic doxorubicin via epidermal growth factor receptor (EGFR) targeting. Specifically, this study sought to evaluate the safety and efficacy of EGFR targeted, doxorubicin loaded minicells (designated EGFRminicellsDox) to deliver doxorubicin to spontaneous brain tumors in 17 companion dogs; a comparative oncology model of human brain cancers. METHODOLOGY/PRINCIPLE FINDINGS: EGFRminicellsDox were administered weekly via intravenous injection to 17 dogs with late-stage brain cancers. Biodistribution was assessed using single-photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI). Anti-tumor response was determined using MRI, and blood samples were subject to toxicology (hematology, biochemistry) and inflammatory marker analysis. Targeted, doxorubicin-loaded minicells rapidly localized to the core of brain tumors. Complete resolution or marked tumor regression (>90% reduction in tumor volume) were observed in 23.53% of the cohort, with lasting anti-tumor responses characterized by remission in three dogs for more than two years. The median overall survival was 264 days (range 49 to 973). No adverse clinical, hematological or biochemical effects were observed with repeated administration of EGFRminicellsDox (30 to 98 doses administered in 10 of the 17 dogs). CONCLUSIONS/SIGNIFICANCE: Targeted minicells loaded with doxorubicin were safely administered to dogs with late stage brain cancer and clinical activity was observed. These findings demonstrate the strong potential for clinical applications of targeted, doxorubicin-loaded minicells for the effective treatment of patients with brain cancer. On this basis, we have designed a Phase 1 clinical study of EGFR-targeted, doxorubicin-loaded minicells for effective treatment of human patients with recurrent glioblastoma

What is important to people with dementia living at home? A set of core outcome items for use in the evaluation of non-pharmacological community-based health and social care interventions

YesObjectives: Inconsistency in outcome measurement in dementia care trials impedes the comparisons of effectiveness between trials. The key aim of this study is to establish an agreed standardised core outcome set (COS) for use when evaluating non-pharmacological health and social care interventions for people with dementia living at home. Method: We used a mixed-methods research design, including substantive qualitative research with five key stakeholders groups. We consulted with people living with dementia for many aspects of this research. We applied a modified two-round 54 item Delphi approach to attain consensus on core outcomes. The COS was finalised in a face-to-face consensus meeting in 2018. Results: Of the 288 who completed round 1 (21 people living with dementia, 58 care partners, 137 relevant health and social care professionals, 60 researchers, 12 policy makers), 246 completed round 2 (85% response rate). Twenty participants attended the consensus meeting. We reached consensus for the inclusion of 13 outcome items. Conclusion: We identified 13 outcome items which are considered core; many relate to social health. Providing there are adequate measures, measuring these core outcome items will enhance comparisons for effectiveness making trial evidence more useful. The items will provide commissioners and service planners with information on what types of interventions are most likely to be valued highly by people living with dementia.This study was funded jointly by the Economic and Social Research Council (ESRC) and the National Institute for Health Research (NIHR). ESRC is part of UK Research and Innovation

Prescriptive variability of drugs by general practitioners

<div><p>Prescription drug spending is growing faster than any other sector of healthcare. However, very little is known about patterns of prescribing and cost of prescribing between general practices. In this study, we examined variation in prescription rates and prescription costs through time for 55 GP surgeries in Northern Ireland Western Health and Social Care Trust. Temporal changes in variability of prescribing rates and costs were assessed using the Mann–Kendall test. Outlier practices contributing to between practice variation in prescribing rates were identified with the interquartile range outlier detection method. The relationship between rates and cost of prescribing was explored with Spearman's statistics. The differences in variability and mean number of prescribing rates associated with the practice setting and socioeconomic deprivation were tested using t-test and <i>F</i>-test respectively. The largest between-practice difference in prescribing rates was observed for Apr-Jun 2015, with the number of prescriptions ranging from 3.34 to 8.36 per patient. We showed that practices with outlier prescribing rates greatly contributed to between-practice variability. The largest difference in prescribing costs was reported for Apr-Jun 2014, with the prescription cost per patient ranging from £26.4 to £64.5. In addition, the temporal changes in variability of prescribing rates and costs were shown to undergo an upward trend. We demonstrated that practice setting and socio-economic deprivation accounted for some of the between-practice variation in prescribing. Rural practices had higher between practice variability than urban practices at all time points. Practices situated in more deprived areas had higher prescribing rates but lower variability than those located in less deprived areas. Further analysis is recommended to assess if variation in prescribing can be explained by demographic characteristics of patient population and practice features. Identification of other factors contributing to prescribing variability can help us better address potential inappropriateness of prescribing.</p></div

Crossing Eurasia: trans-regional Afghan trading networks in China and beyond

An expanding body of literature in the field of Central Asian studies has brought attention to the problems of considering the region's complex dynamics through the lens of its nation-states. Comparatively less attention has been paid to the role played by trans-regional circulations in connecting parts of Central Asia to the wider world. This paper situates ethnographic work on trans-regional networks of Afghan traders in China, Central Asia, Russia, Ukraine and the UK in relation to the literature on trans-regional connections and circulation societies. Ethnographically it demonstrates the multi-polar nature of these trans-regional networks, and the importance of trading nodes, especially the Chinese city of Yiwu, to their formation and ongoing vitality