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Abstract Observations over the last few decades from a number of orogenic systems have highlighted the possible importance of tectonic exhumation, i.e., ductile thinning and normal faulting, in exhuming rocks once buried in high-pressure conditions. Taiwan is one of the few active orogens in the world where rocks that once experienced high-pressure metamorphism (> 50 km) are exposed at the Earth’s surface, providing a natural laboratory for advancing our understanding of exhumation processes. We integrate previously published studies of the Taiwan orogen with new structural, geochronological, and fluid inclusion microthermometry data to argue that tectonic extrusion and structural thinning played a critical role in exhuming the metamorphic core of the orogen until very recently, ca. 0.7 Ma. We propose a two-stage process for exhuming the high-pressure metamorphic rocks of the Yuli Belt: an initial stage where exhumation is driven primarily by pressure gradients in a subduction channel and a second stage that is initiated as an orogen-parallel regional-scale strike-slip zone, the Tailuko shear zone, is offset by an orogen-normal strike-slip zone. The offset generates an extensional bend that is filled with extruding high-pressure rocks as the upper crust is structurally thinned. Evidence for tectonic thinning comes primarily from a low-angle penetrative foliation that records significant vertical shortening and a suite of sub-vertical late-stage, mineral-filled veins. Isotopic dating indicates that the second stage started ca. 2.4–3.1 Ma and ended at ca. 0.7 Ma when the northern Backbone Range orocline started to form. We propose the low-angle foliation formed in the footwall of a regional-scale extensional shear zone that rooted to the east, beneath the forearc. Combined tectonic and erosional processes may have limited the topographic growth of the orogen from ~3.0 to

Abstract Industrial designers have a need to acquire knowledge related to physical materials and undertake activities such as materials selection and materials-driven creative design. Chinese indigenous materials (CIMs) and relevant crafts are identified as a significant but currently untapped resource for designers. Existing research lacks systematic organization and classification for this rich resource making it difficult to develop an online materials database for creative design. To enable industrial designers to develop an understanding of CIMs, obtain design inspiration and stimulate creative design activity, this paper reports on the development of a framework for a taxonomy of CIMs. Through literature review and analysis of existing design tools, the purpose, ending conditions, basic methods and framework of a taxonomy were identified. Taking Xuan Paper as an example, a case study was undertaken to establish methods and processes. When combined with expert interviews and user questionnaires, the usefulness, efficiency and acceptability of the research framework were evaluated, optimized and validated. The findings indicate that a CIM taxonomy can support designers to systematically acquire materials and processing information, facilitate materials-driven creative design, material comparison/selection and provide a framework for the construction of CIM-related databases.

BackgroundDetailed and invasive clinical investigations are required to identify the causes of haematuria. Highly unbalanced patient population (predominantly male) and a wide range of potential causes make the ability to correctly classify patients and identify patient-specific biomarkers a major challenge. Studies have shown that it is possible to improve the diagnosis using multi-marker analysis, even in unbalanced datasets, by applying advanced analytical methods. Here, we applied several machine learning algorithms to classify patients from the haematuria patient cohort (HaBio) by analysing multiple biomarkers and to identify the most relevant ones.Materials and methodsWe applied several classification and feature selection methods (k-means clustering, decision trees, random forest with LIME explainer and CACTUS algorithm) to stratify patients into two groups: healthy (with no clear cause of haematuria) or sick (with an identified cause of haematuria e.g., bladder cancer, or infection). The classification performance of the models was compared. Biomarkers identified as important by the algorithms were also analysed in relation to their involvement in the pathological processes.ResultsResults showed that a high unbalance in the datasets significantly affected the classification by random forest and decision trees, leading to the overestimation of the sick class and low model performance. CACTUS algorithm was more robust to the unbalance in the dataset. CACTUS obtained a balanced accuracy of 0.747 for both genders, 0.718 for females and 0.803 for males. The analysis showed that in the classification process for the whole dataset: microalbumin, male gender, and tPSA emerged as the most informative biomarkers. For males: age, microalbumin, tPSA, cystatin C, BTA, HAD and S100A4 were the most significant biomarkers while for females microalbumin, IL-8, pERK, and CXCL16.ConclusionsCACTUS algorithm demonstrated improved performance compared with other methods such as decision trees and random forest. Additionally, we identified the most relevant biomarkers for the specific patient group, which could be considered in the future as novel biomarkers for diagnosis. Our results have the potential to inform future research and provide new personalised diagnostic approaches tailored directly to the needs of the individuals.

Objective The COVID-19 pandemic accelerated changes to clinical research methodology, with clinical studies being carried out via online/remote means. This mixed-methods study aimed to identify which digital tools are currently used across all stages of clinical research by stakeholders in clinical, health and social care research and investigate their experience using digital tools.Design Two online surveys followed by semistructured interviews were conducted. Interviews were audiorecorded, transcribed and analysed thematically.Setting, participants To explore the digital tools used since the pandemic, survey participants (researchers and related staff (n=41), research and development staff (n=25)), needed to have worked on clinical, health or social care research studies over the past 2 years (2020–2022) in an employing organisation based in the West Midlands region of England (due to funding from a regional clinical research network (CRN)). Survey participants had the opportunity to participate in an online qualitative interview to explore their experiences of digital tools in greater depth (n=8).Results Six themes were identified in the qualitative interviews: ‘definition of a digital tool in clinical research’; ‘impact of the COVID-19 pandemic’; ‘perceived benefits/drawbacks of digital tools’; ‘selection of a digital tool’; ‘barriers and overcoming barriers’ and ‘future digital tool use’. The context of each theme is discussed, based on the interview results.Conclusions Findings demonstrate how digital tools are becoming embedded in clinical research, as well as the breadth of tools used across different research stages. The majority of participants viewed the tools positively, noting their ability to enhance research efficiency. Several considerations were highlighted; concerns about digital exclusion; need for collaboration with digital expertise/clinical staff, research on tool effectiveness and recommendations to aid future tool selection. There is a need for the development of resources to help optimise the selection and use of appropriate digital tools for clinical research staff and participants.

BackgroundThe Hypoglycaemia – MEasurement, ThResholds and ImpaCtS (Hypo-METRICS) smartphone app was developed to investigate the impact of hypoglycemia on daily functioning in adults with type 1 diabetes mellitus or insulin-treated type 2 diabetes mellitus. The app uses ecological momentary assessments, thereby minimizing recall bias and maximizing ecological validity. It was used in the Hypo-METRICS study, a European multicenter observational study wherein participants wore a blinded continuous glucose monitoring device and completed the app assessments 3 times daily for 70 days. ObjectiveThe 3 aims of the study were to explore the content validity of the app, the acceptability and feasibility of using the app for the duration of the Hypo-METRICS study, and suggestions for future versions of the app. MethodsParticipants who had completed the 70-day Hypo-METRICS study in the United Kingdom were invited to participate in a brief web-based survey and an interview (approximately 1h) to explore their experiences with the app during the Hypo-METRICS study. Thematic analysis of the qualitative data was conducted using both deductive and inductive methods. ResultsA total of 18 adults with diabetes (type 1 diabetes: n=10, 56%; 5/10, 50% female; mean age 47, SD 16 years; type 2 diabetes: n=8, 44%; 2/8, 25% female; mean age 61, SD 9 years) filled out the survey and were interviewed. In exploring content validity, participants overall described the Hypo-METRICS app as relevant, understandable, and comprehensive. In total, 3 themes were derived: hypoglycemia symptoms and experiences are idiosyncratic; it was easy to select ratings on the app, but day-to-day changes were perceived as minimal; and instructions could be improved. Participants offered suggestions for changes or additional questions and functions that could increase engagement and improve content (such as providing more examples with the questions). In exploring acceptability and feasibility, 5 themes were derived: helping science and people with diabetes; easy to fit in, but more flexibility wanted; hypoglycemia delaying responses and increasing completion time; design, functionality, and customizability of the app; and limited change in awareness of symptoms and impact. Participants described using the app as a positive experience overall and as having a possible, although limited, intervention effect in terms of both hypoglycemia awareness and personal impact. ConclusionsThe Hypo-METRICS app shows promise as a new research tool to assess the impact of hypoglycemia on an individual’s daily functioning. Despite suggested improvements, participants’ responses indicated that the app has satisfactory content validity, overall fits in with everyday life, and is suitable for a 10-week research study. Although developed for research purposes, real-time assessments may have clinical value for monitoring and reviewing hypoglycemia symptom awareness and personal impact.

Summary: Background: Type 1 diabetes is a complex heterogenous autoimmune disease without therapeutic interventions available to prevent or reverse the disease. This study aimed to identify transcriptional changes associated with the disease progression in patients with recent-onset type 1 diabetes. Methods: Whole-blood samples were collected as part of the INNODIA study at baseline and 12 months after diagnosis of type 1 diabetes. We used linear mixed-effects modelling on RNA-seq data to identify genes associated with age, sex, or disease progression. Cell-type proportions were estimated from the RNA-seq data using computational deconvolution. Associations to clinical variables were estimated using Pearson's or point-biserial correlation for continuous and dichotomous variables, respectively, using only complete pairs of observations. Findings: We found that genes and pathways related to innate immunity were downregulated during the first year after diagnosis. Significant associations of the gene expression changes were found with ZnT8A autoantibody positivity. Rate of change in the expression of 16 genes between baseline and 12 months was found to predict the decline in C-peptide at 24 months. Interestingly and consistent with earlier reports, increased B cell levels and decreased neutrophil levels were associated with the rapid progression. Interpretation: There is considerable individual variation in the rate of progression from appearance of type 1 diabetes-specific autoantibodies to clinical disease. Patient stratification and prediction of disease progression can help in developing more personalised therapeutic strategies for different disease endotypes. Funding: A full list of funding bodies can be found under Acknowledgments.

The present study aimed to determine the physical-tactical profiles of elite football teams and individual players according to final league rankings. A total of 50 English Premier League matches (n = 100 match and 583 player observations) were analysed by coding the player’s physical-tactical actions through synchronising tracking data and video. Final league rankings were categorised into Tiers: (A) 1st–5th ranking (n = 25), (B) 6th–10th ranking (n = 26), (C) 11th–15th ranking (n = 26), and (D) 16th–20th ranking (n = 23). One-way analyses of variance were used to compare match performances between different Tiers, and effect size (ES) was determined for the meaningfulness of the difference. Tier A teams covered 39–51% more high-intensity distance for ‘Move to Receive/Exploit Space’ (ES: 1.3–1.6, P < 0.01) and ‘Run with Ball’ (ES: 0.9–1.0, P < 0.05) than Tier C and D, and 23–94% more distance for ‘Over/Underlap’ (ES: 1.0, P < 0.01), ‘Run in Behind/Penetrate’ (ES: 0.7, P < 0.05), and ‘Break into Box’ (ES: 0.9, P < 0.05) compared to Tier C. Central and Wide Defensive Players in Tier A covered 65–551% more high-intensity ‘Move to Receive/Exploit Space’ distance compared to other Tiers (ES: 0.6–1.0, P < 0.01). Moreover, the additional options within the physical-tactical actions and zonal differences unveiled more meaningful insights into ‘HOW’ the top Tier teams physically and tactically perform. Thus, the amalgamated physical-tactical data help improve our understanding of a team’s playing style relative to their competitive standard.

The present study aimed to contextualise physical metrics with tactical actions according to general and specialised tactical roles. A total of 244 English Premier League players were analysed by coding player’s physical-tactical actions via the fusion of tracking data and video. Data were analysed across 5 general (Central Defensive Players = CDP, Wide Defensive Players = WDP, Central Midfield Players = CMP, Wide Offensive Players = WOP, Central Offensive Players = COP) and 11 specialised positions (Centre Backs = CB, Full-Backs = FB, Wing-Backs = WB, Box-to-Box Midfielders = B2BM, Central Defensive Midfielders = CDM, Central Attacking Midfielders = CAM, Wide Midfielders = WM, Wide Forwards = WF, Centre Forwards = CF). COP covered more distance at high-intensity (> 19.8 km· h-1) when performing actions such as ‘Break into Box’, Run in Behind/Penetrate’, and ‘Close Down/Press’ than other positions (ES: 0.6–5.2, P < 0.01). WOP covered more high-intensity ‘Run with Ball’ distance (ES: 0.7–1.7, P < 0.01) whereas WDP performed more ‘Over/Underlap’ distance than other positions (ES: 0.9–1.4, P < 0.01). CDP and WDP covered more high-intensity ‘Covering’ distances than other positions (ES: 0.4–2.4, P < 0.01). Nonetheless, data demonstrated that implementing specialised positional analysis relative to a generalised approach is more sensitive in measuring physical-tactical performances of players with the latter over or underestimating the match demands of the players compared to the former. A contextualised analysis may assist coaches and practitioners when designing position or even player-specific training drills since the data provides unique physical-tactical trends across specialised roles.

IntroductionThe aim of this study was to determine the acceptability and psychometric properties of the Hypo-METRICS (Hypoglycemia MEasurement, ThResholds and ImpaCtS) application (app): a novel tool designed to assess the direct impact of symptomatic and asymptomatic hypoglycemia on daily functioning in people with insulin-treated diabetes.Materials and methods100 adults with type 1 diabetes mellitus (T1DM, n = 64) or insulin-treated type 2 diabetes mellitus (T2DM, n = 36) completed three daily 'check-ins' (morning, afternoon and evening) via the Hypo-METRICs app across 10 weeks, to respond to 29 unique questions about their subjective daily functioning. Questions addressed sleep quality, energy level, mood, affect, cognitive functioning, fear of hypoglycemia and hyperglycemia, social functioning, and work/productivity. Completion rates, structural validity, internal consistency, and test-retest reliability were explored. App responses were correlated with validated person-reported outcome measures to investigate convergent (rs>±0.3) and divergent (rsResultsParticipants' mean±SD age was 54±16 years, diabetes duration was 23±13 years, and most recent HbA1c was 56.6±9.8 mmol/mol. Participants submitted mean±SD 191±16 out of 210 possible 'check-ins' (91%). Structural validity was confirmed with multi-level confirmatory factor analysis showing good model fit on the adjusted model (Comparative Fit Index >0.95, Root-Mean-Square Error of Approximation ConclusionHigh completion rates and satisfactory psychometric properties demonstrated that the Hypo-METRICS app is acceptable to adults with T1DM and T2DM, and a reliable and valid tool to explore the daily impact of hypoglycemia.

The present study aimed to determine the physical-tactical trends of elite players/teams during peak 1-, 3- and 5-min periods of match-play. A total of 50 English Premier League matches (n = 583 player observations) were analysed by coding the players’ physical-tactical activities through the synchronisation of tracking data and video. The contextualised data showed that during the peak periods (i.e., the most demanding passage of play), players/teams covered the largest distances for ‘Recovery Run’ (28–37%) out of possession and ‘Support Play’ (9–13%) in possession. In the following periods, players covered less high-intensity distance versus the average with a more pronounced decline in the next 1-min period than longer duration 3- and 5-min periods (48% vs ~25–30%, ES: 0.4–0.5, P < 0.01); team data showed similar trends with different relative patterns (31% vs 17–30%, ES: 0.5–0.8, P < 0.01). After peak periods, players/teams performed 20–53% less high-intensity distances for ‘Covering’ and ‘Recovery Run’ (ES: 0.2–0.7, P < 0.01) out of possession. However, players covered 28–91% less distance for ‘Run with Ball’ (ES: 0.1–0.5, P < 0.05) when in possession. Some physical-tactical actions exhibited inconsistency in different time durations of the next periods; however, these physical-tactical data were position-specific. This may signify that each position has certain physical-tactical actions to execute even after the peak periods, especially when they are tactically required to do so. As the data demonstrates unique physical-tactical trends of players/teams during the peak and next periods of play, this could help practitioners prescribe position- and player-specific drills, and better understand transient decrements in high-intensity running after intense passages of play.

IntroductionHaematuria is a common red flag symptom of urinary tract cancer. Bladder cancer (BC) is the most common cancer to present with haematuria. Women presenting with haematuria are often underdiagnosed. Currently, no gender-specific tests are utilized in clinical practice. Considerable healthcare resources are needed to investigate causes of haematuria and this study was set up to help identify markers of BC. The aim of the study was to define biomarker algorithms in haematuria patients using an expanded panel of biomarkers to diagnose BC and investigate if the algorithms are gender-specific.Materials and MethodsA total of n=675 patients with a history of haematuria were recruited from Northern Ireland hospitals. Patients were collected on a 2:1 ratio, non-BC (control) n=474: BC n=201. A detailed clinical history, urine and blood samples were collected. Biomarkers, known to be involved in the pathobiology underlying bladder carcinogenesis were investigated. Biomarkers differentially expressed between groups were investigated using Wilcoxon rank sum and linear regression.ResultsBiomarkers were gender specific. Two biomarker-algorithms were identified to triage haematuria patients; male – u_NSE, s_PAI-1/tPA, u_midkine, u_NGAL, u_MMP-9/TIMP-1 and s_prolactin (u=urine; s=serum); sensitivity 71.8%, specificity 72.8%; AUROC 0.795; and female urine biomarkers - IL-12p70, IL-13, midkine and clusterin; sensitivity 83.7%, specificity 79.7%; AUROC 0.865. Addition of the clinical variable infection to both algorithms increased both AUROC to 0.822 (DeLong p=0.014) and to 0.923 (DeLong p=0.004) for males and females, respectively. Combining clinical risk factors with biomarker algorithms would enable application of the algorithms to triage haematuria patients.ConclusionUsing gender-specific biomarker algorithms in combination with clinical risks that are associated with BC would allow clinicians to better manage haematuria patients and potentially reduce underdiagnosis in females. In this study, we demonstrate, for the first time, that blood and urine biomarkers are gender-specific when assessing risk of BC in patients who present with blood in their urine. Combining biomarker data with clinical factors could improve triage when referring patients for further investigations.

Introduction The aim of this study was to determine the psychometric properties of the 12-Item Hypoglycemia Impact Profile (HIP12), a brief measure of the impact of hypoglycemia on quality of life (QoL) among adults with type 1 (T1D) or type 2 diabetes (T2D).Research design and methods Adults with T1D (n=1071) or T2D (n=194) participating in the multicountry, online study, ‘Your SAY: Hypoglycemia’, completed the HIP12. Psychometric analyses were undertaken to determine acceptability, structural validity, internal consistency, convergent/divergent validity, and known-groups validity.Results Most (98%) participants completed all items on the HIP12. The expected one-factor solution was supported for T1D, T2D, native English speaker, and non-native English speaker groups. Internal consistency was high across all groups (ω=0.91–0.93). Convergent and divergent validity were satisfactory. Known-groups validity was demonstrated for both diabetes types, by frequency of severe hypoglycemia (0 vs ≥1 episode in the past 12 months) and self-treated episodes (

This study aimed to: (1) develop an integrated approach to quantifying match physical-tactical performance and (2) comprehensively examine the validity and reliability of this novel approach. Both UEFA qualified coaches and performance analysts (n = 30) participated to verify the scientific robustness of this new method. The percentage of correct responses were used to verify the validity of the integrated approach and the minimum acceptable agreement was set at 80%. Two well-trained groups of observers analysed a randomly selected English Premier League match for inter- and intra-observer reliability using the kappa statistic. A high degree of validity was demonstrated as the mean percentage of correct responses by all participants, accounting for 91.8 ± 4.3% for all, 92.2 ± 4.7% for out-of-possession, and 91.6 ± 5.7% for in-possession physical-tactical variables. Inter- and intra-observer reliability were found to be strong (κ = 0.81) to almost perfect (κ = 0.94), respectively. Additional analyses demonstrated that there was a nearly perfect correlation between data derived from the novel filter used for the present study to capture high-intensity running and those obtained from the filter of the commercial data provider (r = 0.99; P < 0.01). The data demonstrates that the integrated approach is valid and reliable regarding the quantification of physical-tactical performances. Therefore, it is now possible to unveil unique high-intensity profiles of elite players related to key tactical actions. This may help coaches and practitioners better understand the physical-tactical performances of players, as well as effectively translate physical metrics into training.

Introduction Optimising glycaemic control in type 1 diabetes (T1D) remains challenging. Flash glucose monitoring with FreeStyle Libre 2 (FSL2) is a novel alternative to the current standard of care self-monitoring of blood glucose (SMBG). No randomised controlled trials to date have explored the potential benefits of FSL2 in T1D. We aim to assess the impact of FSL2 in people with suboptimal glycaemic control T1D in comparison with SMBG.Methods This open-label, multicentre, randomised (via stochastic minimisation), parallel design study conducted at eight UK secondary and primary care centres will aim to recruit 180 people age ≥16 years with T1D for >1 year and glycated haemoglobin (HbA1c) 7.5%–11%. Eligible participants will be randomised to 24 weeks of FSL2 (intervention) or SMBG (control) periods, after 2-week of blinded sensor wear. Participants will be assessed virtually or in-person owing to the COVID-19 pandemic. HbA1c will be measured at baseline, 12 and 24 weeks (primary outcome). Participants will be contacted at 4 and 12 weeks for glucose optimisation. Control participants will wear a blinded sensor during the last 2 weeks. Psychosocial outcomes will be measured at baseline and 24 weeks. Secondary outcomes include sensor-based metrics, insulin doses, adverse events and self-report psychosocial measures. Utility, acceptability, expectations and experience of using FSL2 will be explored. Data on health service resource utilisation will be collected.Analysis Efficacy analyses will follow intention-to-treat principle. Outcomes will be analysed using analysis of covariance, adjusted for the baseline value of the corresponding outcome, minimisation factors and other known prognostic factors. Both within-trial and life-time economic evaluations, informed by modelling from the perspective of the National Health Service setting, will be performed.Ethics The study was approved by Greater Manchester West Research Ethics Committee (reference 19/NW/0081). Informed consent will be sought from all participants.Trial registration number NCT03815006.Protocol version 4.0 dated 29 June 2020.

Information security recognised the human as the weakest link. Despite numerous international or sector-specific standards and frameworks, the information security community has not yet adopted formal mechanisms to manage human errors that cause information security breaches. Such techniques have been however established within the safety field where human reliability analysis (HRA) techniques are widely applied. In previous work we developed Information Security Core Human Error Causes (IS-CHEC) to fill this gap. This case study presents empirical research that uses IS-CHEC over a 12 month period within two participating public and private sector organisations in order to observe and understand how the implementation of the IS-CHEC information security HRA technique affected the respective organisations. The application of the IS-CHEC technique enabled the proportions of human error related information security incidents to be understood as well as the underlying causes of these incidents. The study captured the details of the incidents in terms of the most common underlying causes, selection of remedial and preventative measures, volumes of reported information security incidents, proportions of human error, common tasks undertaken at the time the incident occurred, as well as the perceptions of key individuals within the participating organisations through semi-structured interviews. The study confirmed in both cases that the vast majority of reported information security incidents relate to human error, and although the volumes of human error related incidents pertaining to both participating organisations fluctuated over the 12 month period, the proportions of human error remained consistently as the majority root cause.

The objective of the research was to establish data relating to underlying causes of human error which are the most common cause of information security incidents within a private sector healthcare organization. A survey questionnaire was designed to proactively apply the IS-CHEC information security human reliability analysis (HRA) technique. The IS-CHEC technique questionnaire identified the most likely core human error causes that could result in incidents, their likelihood, the most likely tasks that could be affected, suggested remedial and preventative measures, systems or processes that would be likely to be affected by human error and established the levels of risk exposure. The survey was operational from 15th November 2018 to 15th December 2018. It achieved a response rate of 65% which equated to 485 of 749 people targeted by the research. The research found that, in the case of this particular participating organization, the application of the IS-CHEC technique through a questionnaire added beneficial value as an enhancement to a standard approach of holistic risk assessment. The research confirmed that the IS-CHEC in questionnaire form can be successfully applied within a private sector healthcare organization and also that a distributed approach for information security human error assessment can be successfully undertaken in order to add beneficial value. The results of this paper indicate, from the questionnaire responses supplied by employees, that organizational focus on its people and their working environment can improve information security posture and reduce the likelihood of associated information security incidents through a reduction in human error.

Four isolated sauropod axial elements from the Oxford Clay Formation (Callovian, Middle Jurassic) of Peterborough, UK, are described. Two associated posterior dorsal vertebrae show a dorsoventrally elongated centrum and short neural arch, and nutrient or pneumatic foramina, most likely belonging to a non-neosauropod eusauropod, but showing ambiguous non-neosauropod eusauropod and neosauropod affinities. An isolated anterior caudal vertebra displays a ventral keel, a ‘shoulder’ indicating a wing-like transverse process, along with a possible prespinal lamina. This, together with an overall high complexity of the anterior caudal transverse process (ACTP) complex, indicates that this caudal could have belonged to a neosauropod. A second isolated middle-posterior caudal vertebra also shows some diagnostic features, despite the neural spine and neural arch not being preserved and the neurocentral sutures being unfused. The positioning of the neurocentral sutures on the anterior one third of the centrum indicates a middle caudal position, and the presence of faint ventrolateral crests, as well as a rhomboid anterior articulation surface, suggest neosauropod affinities. The presence of possible nutrient foramina are only tentative evidence of a neosauropod origin, as they are also found in Late Jurassic non-neosauropod eusauropods. As the caudals from the two other known sauropods from the Peterborough Oxford Clay, Cetiosauriscus stewarti and an indeterminate non-neosauropod eusauropod, do not show the features seen on either of the new elements described, both isolated caudals indicate a higher sauropod species diversity in the faunal assemblage than previously recognised. An exploratory phylogenetic analysis using characters from all four isolated elements supports a basal neosauropod placement for the anterior caudal, and a diplodocid origin for the middle caudal. The dorsal vertebrae are an unstable OTU, and therefore remain part of an indeterminate eusauropod of uncertain affinities. Together with Cetiosauriscus, and other material assigned to different sauropod groups, this study indicates the presence of a higher sauropod biodiversity in the Oxford Clay Formation than previously recognised. This study shows that it is still beneficial to examine isolated elements, as these may be indicators for higher species richness in deposits that are otherwise poor in terrestrial fauna.

The industrial revolution created a rise in mass manufacture, increasing consumption to current unsustainable levels and marking a decline in hands-on craft practice. In contemporary practice, designers frequently employ digital ways of working and, whilst this may create opportunities and efficiencies, it can limit the working of materials by hand. In contrast, hands-on craft processes can develop in-depth knowledge and understanding to help solve complex and novel design problems. With increasing use of digital design methods, it is timely to reflect on the role and value of hands-on craft practices. The study explores the use of craft-based approaches to support design practice in relation to novelty and quality and considers its future potential to contribute towards design for sustainability. A design project that integrated hand weaving with sandal design was undertaken and qualitative data were collected. This was analysed through data reduction, coding, clustering and display and is presented as a case study. The findings indicate that a craft-based approach can contribute to a heightened control of materials, construction and awareness of wider design issues such as the development process, production methods and environmental impact. Difficulties were identified in inefficient use of time and a knowledge/skills gap between specialist design and craft disciplines. This work is licensed under Creative Commons Attribution (CC BY). To view a copy of the licence, visit https://creativecommons.org/licenses/by/4.0/

Background: Insulin is generally administered to people with type 1 diabetes mellitus (T1DM) using multiple daily injections (MDIs), but can also be delivered using infusion pumps. In the UK, pumps are recommended for patients with the greatest need and adult use is less than in comparable countries. Previous trials have been small, of short duration and have failed to control for training in insulin adjustment. Objective: To assess the clinical effectiveness and cost-effectiveness of pump therapy compared with MDI for adults with T1DM, with both groups receiving equivalent structured training in flexible insulin therapy. Design: Pragmatic, multicentre, open-label, parallel-group cluster randomised controlled trial, including economic and psychosocial evaluations. After participants were assigned a group training course, courses were randomly allocated in pairs to either pump or MDI. Setting: Eight secondary care diabetes centres in the UK. Participants: Adults with T1DM for > 12 months, willing to undertake intensive insulin therapy, with no preference for pump or MDI, or a clinical indication for pumps. Interventions: Pump or MDI structured training in flexible insulin therapy, followed up for 2 years. MDI participants used insulin analogues. Pump participants used a Medtronic Paradigm® VeoTM (Medtronic, Watford, UK) with insulin aspart (NovoRapid, Novo Nordisk, Gatwick, UK). Main outcome measures: Primary outcome – change in glycated haemoglobin (HbA1c) at 2 years in participants whose baseline HbA1c was ≥ 7.5% (58 mmol/mol). Key secondary outcome – proportion of participants with HbA1c ≤ 7.5% at 2 years. Other outcomes at 6, 12 and 24 months – moderate and severe hypoglycaemia; insulin dose; body weight; proteinuria; diabetic ketoacidosis; quality of life (QoL); fear of hypoglycaemia; treatment satisfaction; emotional well-being; qualitative interviews with participants and staff (2 weeks), and participants (6 months); and ICERs in trial and modelled estimates of cost-effectiveness. Results: We randomised 46 courses comprising 317 participants: 267 attended a Dose Adjustment For Normal Eating course (132 pump; 135 MDI); 260 were included in the intention-to-treat analysis, of which 235 (119 pump; 116 MDI) had baseline HbA1c of ≥ 7.5%. HbA1c and severe hypoglycaemia improved in both groups. The drop in HbA1c% at 2 years was 0.85 on pump and 0.42 on MDI. The mean difference (MD) in HbA1c change at 2 years, at which the baseline HbA1c was ≥ 7.5%, was –0.24% [95% confidence interval (CI) –0.53% to 0.05%] in favour of the pump (p = 0.098). The per-protocol analysis showed a MD in change of –0.36% (95% CI –0.64% to –0.07%) favouring pumps (p = 0.015). Pumps were not cost-effective in the base case and all of the sensitivity analyses. The pump group had greater improvement in diabetes-specific QoL diet restrictions, daily hassle plus treatment satisfaction, statistically significant at 12 and 24 months and supported by qualitative interviews. Limitation: Blinding of pump therapy was not possible, although an objective primary outcome was used. Conclusion: Adding pump therapy to structured training in flexible insulin therapy did not significantly enhance glycaemic control or psychosocial outcomes in adults with T1DM. Research priority: To understand why few patients achieve a HbA1c of

Much of the global canine population is now overweight, and this can adversely affect health, lifespan and quality of life. Undesirable behaviours are also common in pet dogs, and these can adversely affect welfare, as well as being stressful to owners. However, links between obesity and behavioural disorders have never previously been explored. An online survey was conducted between June and August in 2014, coinciding with the broadcast of a National UK television programme, exploring dog health, welfare and behaviour. Information gathered included signalment, overweight status and the prevalence of a range of undesirable behaviours. Fisher's exact test and OR were used to determine associations between overweight status and owner-reported behaviours. A total of 17 028 responses were received. After data verification, the final dataset comprised 11 154 dogs, 1801 (16·1 %) of which were reported by owners to be overweight. Owners of overweight dogs were more likely to see them as ‘a baby’ (P

Regular physical activity is an important means of promoting health, both in people and their pets. Walking is the most common method used for dogs, but there is a lack of clarity on how much daily activity different breeds of dog require. Data from an online survey of UK dog owners were collected between June and August in 2014. The University of Liverpool Ethics Committee approved the project, and owners consented to data use. The initial dataset (17 028 dogs) was first cleaned to remove erroneous data, and then edited to remove mixed breed dogs, leaving a total of 12 314 dogs from known pedigree breeds. Other information collected included sex, age, neuter status, breed, and amount and frequency of exercise. Exercise frequency and duration were estimated across different breeds, and compared with Kennel Club recommendations, using χ 2 tests and binary logistic regression. The online survey data indicated differences amongst breeds in the amount of walking reported (P

Canine obesity is now the number one health concern in dogs worldwide. Regular physical activity can improve health, and owners are advised to exercise their dogs on a regular basis. However, limited information exists about associations between overweight status of dogs and walking activity. An online survey was conducted between June and August in 2014, coinciding with the broadcast of a national UK television programme, exploring dog behaviour. Information gathered included signalment, overweight status, and owner-reported information on duration and frequency of dog walking. The University of Liverpool Ethics Committee approved the project, and owners consented to data use. Simple and multiple logistic regression analyses were used to determine associations between overweight status and dog walking activity. Data were available from 11 154 adult dogs, and 1801 (16·1 %) of these were reported as overweight by their owners. Dogs reported to be overweight dogs were more likely to be neutered (P

The classical concept of estrogen receptor (ER) activation is that steroid passes the cell membrane, binds to its specific protein receptor in the cell′s cytoplasm and the steroid-receptor complex travels to the nucleus where it activates responsive genes. This basic idea has been challenged by results of experiments demonstrating insulin-like growth factor 1 (IGF-1) activation of the ER in the complete absence of estrogen suggesting at least one other mechanism of ER activation not involving steroid. One explanation is that activation of the cell surface IGF-1 receptor leads to synthesis of an intracellular protein(s) able to bind to and stimulate the ER. Based on results using the two-hybrid system, coimmunoprecipitation and transfection-luciferase assays, we herein show that one of these proteins could well be receptor for activated C kinase 1 (RACK-1). Using the human ER type α (ER-α) as bait, a cloned complementary deoxyribonucleic acid (cDNA) library from IGF-1 treated human breast cancer MCF-7 cells was screened for ER-α - protein interactions. Many positive clones were obtained which contained the RACK-1 cDNA sequence. Coimmunoprecipitation of in-vitro translation products of the ER-α and RACK-1 confirmed the interaction between the two proteins. Transfection studies using the estrogen response element spliced to a luciferase reporter gene revealed that constitutive RACK-1 expression was able to powerfully stimulate ER-α activity under estrogen-free conditions. This effect could be enhanced by 17β-estradiol (E2) and blocked by tamoxifen, an E2 antagonist. These results show that RACK-1 is able to activate the ER-α in the absence of E2, although together with the latter, enhanced effects occur. Since RACK-1 gene expression is stimulated by IGF-1, it is distinctly possible that RACK-1 is the mediator of the stimulatory effects of IGF-1 on ER-α.

BackgroundInterleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs.Methods and findingsTo define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only.ConclusionsThe DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.Trial registrationISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

Expertise, connoisseurship, and experiential knowledge have been discussed as integral to professional practice by professionals and scholars inside and outside their professional domains. However, the notions of expertise, connoisseurship, and experiential knowledge have not been discussed explicitly in relation to practical activities. This special issue, “Experiential Knowledge, Expertise, and Connoisseurship,” explores the nature of experiential knowledge as relating to expertise and connoisseurship in practical activities within design and other professional domains. This editorial article discusses how the two types of specialist knowledge—contributory and interactional expertise, and connoisseurship—gained from experience, can be utilized to judge practice and outputs within the framework of research inquiry. The nine articles included in the special issue serve as examples, demonstrating ways in which these forms of knowledge are understood in research relating to professional practice.

Producing predictions of the probabilistic risks of operating materials for given lengths of time at stated operating conditions requires the assimilation of existing deterministic creep life prediction models (that only predict the average failure time) with statistical models that capture the random component of creep. To date, these approaches have rarely been combined to achieve this objective. The first half of this paper therefore provides a summary review of some statistical models to help bridge the gap between these two approaches. The second half of the paper illustrates one possible assimilation using 1Cr1Mo-0.25V steel. The Wilshire equation for creep life prediction is integrated into a discrete hazard based statistical model—the former being chosen because of its novelty and proven capability in accurately predicting average failure times and the latter being chosen because of its flexibility in modelling the failure time distribution. Using this model it was found that, for example, if this material had been in operation for around 15 years at 823 K and 130 MPa, the chances of failure in the next year is around 35%. However, if this material had been in operation for around 25 years, the chance of failure in the next year rises dramatically to around 80%.

Pliosaurids were a long-lived and cosmopolitan group of marine predators that spanned 110 million years and occupied the upper tiers of marine ecosystems from the Middle Jurassic until the early Late Cretaceous. A well-preserved giant pliosaurid skull from the Late Jurassic Kimmeridge Clay Formation of Dorset, United Kingdom, represents a new species, Pliosaurus kevani. This specimen is described in detail, and the taxonomy and systematics of Late Jurassic pliosaurids is revised. We name two additional new species, Pliosaurus carpenteri and Pliosaurus westburyensis, based on previously described relatively complete, well-preserved remains. Most or all Late Jurassic pliosaurids represent a globally distributed monophyletic group (the genus Pliosaurus, excluding 'Pliosaurus' andrewsi). Despite its high species diversity, and geographically widespread, temporally extensive occurrence, Pliosaurus shows relatively less morphological and ecological variation than is seen in earlier, multi-genus pliosaurid assemblages such as that of the Middle Jurassic Oxford Clay Formation. It also shows less ecological variation than the pliosaurid-like Cretaceous clade Polycotylidae. Species of Pliosaurus had robust skulls, large body sizes (with skull lengths of 1.7-2.1 metres), and trihedral or subtrihedral teeth suggesting macropredaceous habits. Our data support a trend of decreasing length of the mandibular symphysis through Late Jurassic time, as previously suggested. This may be correlated with increasing adaptation to feeding on large prey. Maximum body size of pliosaurids increased from their first appearance in the Early Jurassic until the Early Cretaceous (skull lengths up to 2360 mm). However, some reduction occurred before their final extinction in the early Late Cretaceous (skull lengths up to 1750 mm).

Since 2002 the Initial Teacher Education Program at the Ontario Institute for Studies in Education, University of Toronto, has run a series of professional learning partnership projects between university instructors and K-12 educators. The Inquiry Into Practice Series, based on a collaborative inquiry approach, has strengthened the commitment to program principles and benefited the participants by deepening understanding about a range of educational questions and issues and improving practice. In this article we review key features and principles of this multi-year initiative and discuss challenges, lessons learned, and outcomes. We also provide reflections regarding the importance of high quality professional learning models that support teaching and learning and that are responsive to changing and complex educational pressures and contexts both in higher education and K-12 education.

Invasion of the open ocean by tetrapods represents a major evolutionary transition that occurred independently in cetaceans, mosasauroids, chelonioids (sea turtles), ichthyosaurs and plesiosaurs. Plesiosaurian reptiles invaded pelagic ocean environments immediately following the Late Triassic extinctions. This diversification is recorded by three intensively-sampled European fossil faunas, spanning 20 million years (Ma). These provide an unparalleled opportunity to document changes in key macroevolutionary parameters associated with secondary adaptation to pelagic life in tetrapods. A comprehensive assessment focuses on the oldest fauna, from the Blue Lias Formation of Street, and nearby localities, in Somerset, UK (Earliest Jurassic: 200 Ma), identifying three new species representing two small-bodied rhomaleosaurids (Stratesaurus taylori gen et sp. nov.; Avalonnectes arturi gen. et sp. nov) and the most basal plesiosauroid, Eoplesiosaurus antiquior gen. et sp. nov. The initial radiation of plesiosaurs was characterised by high, but short-lived, diversity of an archaic clade, Rhomaleosauridae. Representatives of this initial radiation were replaced by derived, neoplesiosaurian plesiosaurs at small-medium body sizes during a more gradual accumulation of morphological disparity. This gradualistic modality suggests that adaptive radiations within tetrapod subclades are not always characterised by the initially high levels of disparity observed in the Paleozoic origins of major metazoan body plans, or in the origin of tetrapods. High rhomaleosaurid diversity immediately following the Triassic-Jurassic boundary supports the gradual model of Late Triassic extinctions, mostly predating the boundary itself. Increase in both maximum and minimum body length early in plesiosaurian history suggests a driven evolutionary trend. However, Maximum-likelihood models suggest only passive expansion into higher body size categories.

This article considers the potential for a researcher to use their own creative practice as a method of data collection. Much of the published material in this field focuses on more theoretical positions, with limited use being made of specific PhDs that illustrate the context in which practice was undertaken by the researcher. It explores strategies for data collection and researcher motivation during what the author identifies as "researcher practice." This is achieved through the use of three PhD case studies. Methods of data collection focus on: (a) the use of output from practice for quantitative data collection (i.e., for comparative analysis), (b) the use of output from practice for qualitative data collection (i.e., reflection on new working practice), and (c) the use of output from practice for data translation (i.e., using research output to produce a creative design solution for a tool that can be used for further data collection and validation). The article discusses the methodologies employed in the case studies to identify themes which enable the definition of a generic researcher practitioner methodology. It notes the significance of creative practice in support of data collection and the differences between researcher practice and commercial practice, and emphasises the contribution of researcher practice towards personal motivation.

Herein we demonstrate how nanojunctions between lysosomes and sarcoplasmic reticulum (L-SR junctions) serve to couple lysosomal activation to regenerative, ryanodine receptor-mediated cellular Ca 2+ waves. In pulmonary artery smooth muscle cells (PASMCs) it has been proposed that nicotinic acid adenine dinucleotide phosphate (NAADP) triggers increases in cytoplasmic Ca 2+ via L-SR junctions, in a manner that requires initial Ca 2+ release from lysosomes and subsequent Ca 2+-induced Ca 2+ release (CICR) via ryanodine receptor (RyR) subtype 3 on the SR membrane proximal to lysosomes. L-SR junction membrane separation has been estimated to be < 400 nm and thus beyond the resolution of light microscopy, which has restricted detailed investigations of the junctional coupling process. The present study utilizes standard and tomographic transmission electron microscopy to provide a thorough ultrastructural characterization of the L-SR junctions in PASMCs. We show that L-SR nanojunctions are prominent features within these cells and estimate that the junctional membrane separation and extension are about 15 nm and 300 nm, respectively. Furthermore, we develop a quantitative model of the L-SR junction using these measurements, prior kinetic and specific Ca 2+ signal information as input data. Simulations of NAADP-dependent junctional Ca 2+ transients demonstrate that the magnitude of these signals can breach the threshold for CICR via RyR3. By correlation analysis of live cell Ca 2+ signals and simulated Ca 2+ transients within L-SR junctions, we estimate that “trigger zones” comprising 60–100 junctions are required to confer a signal of similar magnitude. This is compatible with the 110 lysosomes/cell estimated from our ultrastructural observations. Most importantly, our model shows that increasing the L-SR junctional width above 50 nm lowers the magnitude of junctional [Ca 2+] such that there is a failure to breach the threshold for CICR via RyR3. L-SR junctions are therefore a pre-requisite for efficient Ca 2+signal coupling and may contribute to cellular function in health and disease.

Part 1: Middle True A Young Woman. An empty space with an unmade bed and white linens; they'd be 'crisp white linens' if they weren't so rumpled. Dark. Silence. Low [...]

Rationale: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, but the precise molecular mechanisms of this phenomenon remain controversial. Among the genes influenced by natural selection in high-altitude populations is one for the adenosine monophosphate-activated protein kinase (AMPK) α1-catalytic subunit, which governs cell-autonomous adaptations during metabolic stress.Objectives: We investigated whether AMPK-α1 and/or AMPK-α2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.Methods: We used plethysmography, electrophysiology, functional magnetic resonance imaging, and immediate early gene (c-fos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-α1 and/or AMPK-α2 genes in catecholaminergic cells, which compose the hypoxia-responsive respiratory network from carotid body to brainstem.Measurements and Main Results: AMPK-α1 and AMPK-α2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-α1 and AMPK-α2 exhibited hypoventilation and apnea during hypoxia, with the primary precipitant being loss of AMPK-α1 expression. However, the carotid bodies of AMPK-knockout mice remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is determined solely by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and c-fos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.Conclusions: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks, and deficiencies in AMPK expression precipitate hypoventilation and apnea, even when carotid body afferent input is normal. [ABSTRACT FROM AUTHOR]

The article discusses the history of "rube" characters, or unsophisticated rural persons, in American performance. It argues that rubes were depicted as both yeomen and barbarians. The author considers rubes in American theater from the mid-nineteenth century, particularly in vaudeville and variety shows, and considers ties to minstrelsy and popular depictions of Yankee characters. Actors who performed rube characters are considered, including Cal Stewart and Frank Bell. Later rube representations in the film "Mr. Deeds Goes to Town" and the television show "The Beverly Hillbillies" are also explored.

The article discusses the book "Vom Musikalisch-Schönen" (On the Musically Beautiful) by Eduard Hanslick as a means to explore Hanslick's notion of absolute music. More specifically, Hanslick's belief in a connection between nature and music is detailed, with emphasis given to his idea that musical sounds are closely related to the type of motion described by natural physics and cosmological motion.

As policing enters an era of financial austerity and increased public scrutiny against the backdrop of an increasingly global criminal economy, this paper describes the value of crime intelligence as a component of future policing strategies. It proposes the Integrated Crime Intelligence Analysis Framework (The Diamond Matrix) as a way of ‘shrinking the crime triangle’ by supporting and educating intelligence practitioners to generate the actionable ideas necessary to drive targeted, coordinated policing. Moreover, it provides the foundations for a wider programme focused on intelligence specialists/advanced specialists, decision-makers, and managers/leaders—a scientifically driven approach to the use and application of crime intelligence to underpin the requirements of a future-focused professional policing service. [ABSTRACT FROM PUBLISHER]

The article focuses on the personal investigation of the play Cato, produced by Joseph Addison and staged at the Valley Forge, Pennsylvania cantonment of the U.S. military leader George Washington's Continental Army. It mentions that the investigation is based on the letter written by theatre enthusiast and amateur dramatist William Bradford after he attended the play. It states that the author tried to investigate the facts such as what is the context of the act and its impact.