bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Digital Twins, Mirrors, and Virtualizations: Frameworks for Model Verification and Validation
Authors: Worden K. , Cross E. J. , Barthorpe R. J. , Wagg D. J. , Gardner P. 
Published: March 2020

Abstract
A powerful new idea in the computational representation of structures is that of the digital twin. The concept of the digital twin emerged and developed over the last decade, and has been identified by many industries as a highly desired technology. The current situation is that individual companies often have their own definitions of a digital twin, and no clear consensus has emerged. In particular, there is no current mathematical formulation of a digital twin. A companion paper to the current one will attempt to present the essential components of the desired formulation. One of those components is identified as a rigorous representation theory of models; most importantly, governing how they are verified and validated, and how validation information can be transferred between models. Unlike its companion, which does not attempt detailed specification of any twin components, this paper will attempt to outline a rigorous representation theory of models, based on the introduction of two new concepts: mirrors and virtualizations. The paper is not intended as a passive wish list; it is intended as a rallying call. The new theory will require the active participation of researchers across a number of domains including: pure and applied mathematics, physics, computer science, and engineering. The paper outlines the main objects of the theory and gives examples of the sort of theorems and hypotheses that might be proved in the new framework.
The Mechanism on Prediction of Transient Maximum Amplitude for Tuned and Mistuned Blisks
Authors: Ouyang Luohui , Shang Hai , Chen Hua , Bi Qingzhen , Zhu Li-Min 
Published: March 2020

Abstract
Blisks are subjected to frequent acceleration and deceleration, which leads to a transient forced response; however, there is limited understanding of this response. In this work, the mechanism on prediction of transient maximum amplitude is found. An analytical link is proposed between the transient maximum amplitude and a fundamental dimensionless parameter which combines the damping ratio, natural frequency, acceleration, and engine order of the system to reveal the mechanism of the transient maximum amplitude. Therefore, the transient maximum amplitudes of tuned and mistuned blisks are predicted analytically. First, a lumped parameter model is used to study the mechanism of the transient maximum amplitude for a tuned blisk, and an approximated analytical expression is derived between the fundamental parameter and the transient amplification factor of a 1DOF (degree-of-freedom) model. The relationship is also applicable to a reduced order, tuned finite element model (FEM). Second, the mechanism of the transient response for a mistuned blisk is studied in the decoupled modal space of the blisk, based on the 1DOF transient relationship. The transient maximum amplitude in a reduced order, mistuned FEM is predicted. Two lumped parameter models and a FEM are employed to validate the prediction.
Progression from ocular hypertension to visual field loss in the English hospital eye service
Authors: Kelly Stephen R , Khawaja Anthony P , Bryan Susan R , Azuara-Blanco Augusto , Sparrow John M , Crabb David P 
Published: March 2020

BackgroundThere are more than one million National Health Service visits in England and Wales each year for patients with glaucoma or ocular hypertension (OHT). With the ageing population and an increase in optometric testing, the economic burden of glaucoma-related visits is predicted to increase. We examined the conversion rates of OHT to primary open-angle glaucoma (POAG) in England and assessed factors associated with risk of conversion.MethodsElectronic medical records of 45 309 patients from five regionally different glaucoma clinics in England were retrospectively examined. Conversion to POAG from OHT was defined by deterioration in visual field (two consecutive tests classified as stage 1 or worse as per the glaucoma staging system 2). Cox proportional hazards models were used to examine factors (age, sex, treatment status and baseline intraocular pressure (IOP)) associated with conversion.ResultsThe cumulative risk of conversion to POAG was 17.5% (95% CI 15.4% to 19.6%) at 5 years. Older age (HR 1.35 per decade, 95% CI 1.22 to 1.50, p<0.001) was associated with a higher risk of conversion. IOP-lowering therapy (HR 0.45, 95% CI 0.35 to 0.57, p<0.001) was associated with a lower risk of conversion. Predicted 5-year conversion rates for treated and untreated groups were 14.0% and 26.9%, respectively.ConclusionLess than one-fifth of OHT patients managed in glaucoma clinics in the UK converted to POAG over a 5-year period, suggesting many patients may require less intensive follow-up. Our study provides real-world evidence for the efficacy of current management (including IOP-lowering treatment) at reducing risk of conversion.
Binocular superior visual field areas associated with driving self-regulation in patients with primary open-angle glaucoma
Authors: Yamasaki Tomoyo , Yuki Kenya , Awano-Tanabe Sachiko , Ono Takeshi , Murata Hiroshi , Tsubota Kazuo , Asaoka Ryo 
Published: March 2020

Background/aimsThe aim of our study was to investigate the associations between driving self-regulation and glaucoma severity, and between driving self-regulation and glaucomatous visual field (VF) defect patterns.MethodsIn 247 patients with primary open-angle glaucoma included in this prospective observational study, a battery of ophthalmic examination was performed, including visual acuity (VA) and VF. Integrated binocular VF was constructed and mean of total deviation (mTD) values in four sectors was calculated (mTDsup-peri, mTDsup-centre, mTDinf-peri and mTDinf-centre). In addition, all participants answered seven questions regarding their avoidance in driving. (1) at night, (2) in rain, (3) in fog, (4) on freeways, (5) lane changing, (6) at high speed and (7) close to the car in front. The associations between these driving behaviours and 10 variables (age, gender, best VA, worst VA, the four sectorial average TD values, years holding a driver’s licence and distance driven per week) were analysed using the generalised linear model with binomial distribution, followed by the model section method using the corrected Akaike information criterion.ResultsAs a result of the model selection, it was suggested that deterioration of mTDsup-peri was associated with (1) avoiding driving at night and (2) avoiding driving in rain. On the other hand, mTDsup-centre was related to (3) avoiding driving in fog.ConclusionDamage in visual function was related with driving behaviours in patients with glaucoma.
Intraoperative iatrogenic retinal breaks in 23-gauge vitrectomy for stage 3 and stage 4 idiopathic macular holes
Authors: Yu Yanping , Qi Biying , Liang Xida , Wang Zengyi , Wang Jing , Liu Wu 
Published: March 2020

AimsTo investigate characteristics of intraoperative iatrogenic retinal breaks in 23-gauge vitrectomy for idiopathic macular hole and classify the breaks based on their causes to analyse the risk factors.MethodsThis retrospective study enrolled patients with stage 3 or 4 idiopathic macular hole who underwent 23-gauge vitrectomy in Beijing Tongren Hospital from July 2015 to August 2018. The intraoperative iatrogenic retinal breaks were classified into three types: by induction of posterior vitreous detachment (type 1), by peripheral vitreous cutting (type 2) and by others (type 3). The types, incidence and distribution of the breaks were analysed, and all clinical features were compared between eyes with and without the breaks.ResultsA total of 364 eyes from 341 patients were recruited. Twenty-five breaks from 24 eyes (6.6%) were encountered, 52% (13/25) of which distributed in the superior region. Type 1 and type 2 breaks contributed 52% (13/25) and 44% (11/25) to all, respectively. Eyes with stage 3 and stage 4 holes showed no significant differences in incidence or distribution in type 2 breaks. No breaks occurred on the surface of lattice degenerations. All clinical features showed no significant differences between eyes with and without the breaks.ConclusionDistribution of intraoperative iatrogenic retinal breaks shows no preference for the superior or inferior region. Induction of posterior vitreous detachment and traction from peripheral vitreous cutting are major causes of the breaks, which classify them into two main types. The presence of lattice may not be one of the risk factors if treated properly.
Retinal blood flow reduction in normal-tension glaucoma with single-hemifield damage by Doppler optical coherence tomography
Authors: Yoshioka Takafumi , Song Youngseok , Kawai Motofumi , Tani Tomofumi , Takahashi Kengo , Ishiko Satoshi , Lavinsky Fabio , Wollstein Gadi , Ishikawa Hiroshi , Schuman Joel S , Yoshida Akitoshi 
Published: March 2020

AimsTo evaluate the associations between retinal blood flow (RBF) and optical coherence tomography (OCT) structural measurements in normal-tension glaucoma (NTG) eyes with single-hemifield visual field (VF) damage by the Doppler OCT.MethodsThe Doppler OCT was used to measure temporal artery (TA) RBF and temporal vein (TV) RBF. Retinal nerve fibre layer thickness (RNFLT) was measured by spectral-domain OCT.ResultsForty-three consecutive eyes of 43 patients with NTG with VF defect confined to a single hemifield and 24 eyes of 24 age-matched healthy subjects were studied. TA and TV RBF and RNFLT were reduced in the damaged hemisphere compared with the normal hemisphere (mean (SD), 3.61 (1.68) vs 5.86 (2.59) µL/min, p<0.001; 5.61 (2.51) vs 6.94 (2.83) µL/min, p=0.010; 69.0 (19.7) vs 99.7 (22.8) µm, p<0.001). Those values in the normal hemisphere of NTG eyes also decreased compared with the healthy hemisphere of the healthy eyes (8.40 (3.36) µL/min, p<0.001; 9.28 (4.47) µL/min, p<0.002; 122.8 (20.2) µm, p<0.001). Multivariate model showed that normal and damaged hemispheres and RNFLT were associated with RBF reduction. In addition, the RBF in the normal hemisphere was lower than that in the healthy hemisphere even after adjusting for RNFLT.ConclusionIn NTG eyes with single-hemifield damage, the RBF was significantly reduced in the damaged hemisphere compared with the normal one. The RBF decreased in the normal and damaged hemispheres of NTG eyes compared with the healthy hemisphere independent from RNFLT.
Retinoblastoma in Finland, 1964–2014: incidence and survival
Authors: Nummi Kalle , Kivelä Tero T 
Published: March 2020

AimsTo determine the incidence of retinoblastoma (Rb) and subsequent survival in the Finnish population during five decades.MethodsThis retrospective observational cohort study comprised all patients with Rb born in Finland during 1964–2014 and diagnosed in 2018 (birth cohort analysis) or diagnosed in 1964–2014 (standard annual analysis), identified from the Finnish Cancer Registry and the national referral centre. We report age-adjusted incidences and survival according to cause of death.ResultsOf children born in 1964–2014, 205 developed Rb, whereas 204 Rbs were diagnosed during these years; 196 belonged to both cohorts. Altogether 80 (38%) of the 213 children had heritable Rb and 19 (9%) had familial disease. The sex ratio was 1.34, suggesting male preponderance. Birth cohort analysis showed a median incidence of 6.2 per 100 000 live births (1:16 130) and less variability as compared with standard annual analysis (12.1, 6.5 and 4.4 per million children 0–4, 0–9 and 0–14 years of age, respectively). The incidence of heritable Rb increased with time, reflecting the increase in familial tumours. Five-year mortality rates from Rb were 6.2% and 7.6% for non-heritable and heritable diseases, respectively, and 35-year mortality rates from second malignancies were 0% and 14.3%, respectively. Family history predicted improved survival, whereas the period of diagnosis did not.ConclusionThe incidence of familial Rb has increased, along with improvement in survival in Finland in 1964–2014, whereas the overall incidence of Rb was stable. Long-term risk of dying of second malignancies after heritable Rb was in line with other countries.
Fracture union rates across a century of war: a systematic review of the literature
Authors: Stewart Sarah K , Tenenbaum O , Higgins C , Masouros S , Ramasamy A 
Published: March 2020

IntroductionFractures have been a common denominator of the injury patterns observed over the past century of warfare. The fractures typified by the blast and ballistic injuries of war lead to high rates of bone loss, soft tissue injury and infection, greatly increasing the likelihood of non-union. Despite this, no reliable treatment strategy for non-union exists. This literature review aims to explore the rates of non-union across a century of conflict, in order to determine whether our ability to heal the fractures of war has improved.MethodsA systematic review of the literature was conducted, evaluating the rates of union in fractures sustained in a combat environment over a 100-year period. Only those fractures sustained through a ballistic or blast mechanism were included. The review was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Quality and bias assessment was also undertaken.ResultsThirty studies met the inclusion criteria, with a total of 3232 fractures described across 15 different conflicts from the period 1919–2019. Male subjects made up 96% of cases, and tibial fractures predominated (39%). The lowest fracture union rate observed in a series was 50%. Linear regression analysis demonstrated that increasing years had no statistically significant impact on union rate.ConclusionsFailure to improve fracture union rates is likely a result of numerous factors, including greater use of blast weaponry and better survivability of casualties. Finding novel strategies to promote fracture healing is a key defence research priority in order to improve the rates of fractures sustained in a combat environment.
Physical prognostic factors predicting outcome following anterior cruciate ligament reconstruction: protocol for a systematic review
Authors: Middlebrook Andrew , Bekker Sheree , Middlebrook Nicola , Rushton Alison B 
Published: March 2020

IntroductionInjuries of the anterior cruciate ligament (ACL) are a common musculoskeletal complication and can cause significant reduction in patient function and quality of life. Many undergo ACL reconstruction, with high-quality rehabilitation key to successful outcome. Knowledge of physical prognostic factors, such as quadriceps strength, is crucial to inform rehabilitation and has important implications for outcome following ACL reconstruction. However, these factors predicting outcome are poorly defined. Therefore, the aim of this systematic review is to establish physical prognostic factors predictive of outcome in adults following ACL reconstruction. Outcome will be subdivided into two groups of outcome measures, patient-reported and performance-based. Physical prognostic factors of interest will reflect a range of domains and may be modifiable/non-modifiable. Results will help decide most appropriate management and assist in planning and tailoring preoperative and postoperative rehabilitation.Methods and analysisThis systematic review protocol is reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols. MEDLINE, CINAHL and EMBASE databases, key journals and grey literature will be searched from inception to July 2019. Prospective cohort studies including participants aged ≥16 years who have undergone ACL reconstruction will be included, with articles focusing on multi-ligament reconstructions and ACL repair surgery, or not published in English excluded. Two independent reviewers will conduct searches, assess study eligibility, extract data, assess risk of bias (Quality in Prognostic Studies tool) and quantify overall quality of evidence (modified Grading of Recommendations, Assessment, Development and Evaluation guidelines). If possible, a meta-analysis will be conducted, otherwise a narrative synthesis will ensue focusing on prognostic factors, risk of bias of included studies and strength of association with outcomes.Ethics and disseminationFindings will be published in a peer-reviewed journal, presented at conferences and locally to physiotherapy departments. Ethical approval is not required for this systematic review.PROSPERO registration numberCRD42019127732.
Trends in disease incidence and survival and their effect on mortality in Scotland: nationwide cohort study of linked hospital admission and death records 2001–2016
Authors: Timmers Paul R H J , Kerssens Joannes J , Minton Jon , Grant Ian , Wilson James F , Campbell Harry , Fischbacher Colin M , Joshi Peter K 
Published: March 2020

ObjectivesIdentify causes and future trends underpinning Scottish mortality improvements and quantify the relative contributions of disease incidence and survival.DesignPopulation-based study.SettingLinked secondary care and mortality records across Scotland.Participants1 967 130 individuals born between 1905 and 1965 and resident in Scotland from 2001 to 2016.Main outcome measuresHospital admission rates and survival within 5 years postadmission for 28 diseases, stratified by sex and socioeconomic status.Results‘Influenza and pneumonia’, ‘Symptoms and signs involving circulatory and respiratory systems’ and ‘Malignant neoplasm of respiratory and intrathoracic organs’ were the hospital diagnosis groupings associated with most excess deaths, being both common and linked to high postadmission mortality. Using disease trends, we modelled a mean mortality HR of 0.737 (95% CI 0.730 to 0.745) from one decade of birth to the next, equivalent to a life extension of ~3 years per decade. This improvement was 61% (30%–93%) accounted for by improved disease survival after hospitalisation (principally cancer) with the remainder accounted for by lowered hospitalisation incidence (principally heart disease and cancer). In contrast, deteriorations in infectious disease incidence and survival increased mortality by 9% (~3.3 months per decade). Disease-driven mortality improvements were slightly greater for men than women (due to greater falls in disease incidence), and generally similar across socioeconomic deciles. We project mortality improvements will continue over the next decade but slow by 21% because much progress in disease survival has already been achieved.ConclusionMorbidity improvements broadly explain observed mortality improvements, with progress on prevention and treatment of heart disease and cancer contributing the most. The male–female health gaps are closing, but those between socioeconomic groups are not. Slowing improvements in morbidity may explain recent stalling in improvements of UK period life expectancies. However, these could be offset if we accelerate improvements in the diseases accounting for most deaths and counteract recent deteriorations in infectious disease.
Hypoxia is not the primary mechanism contributing to exercise-induced proteinuria
Authors: Joyce Kelsley E , Delamere John , Bradwell Susie , Myers Stephen David , Ashdown Kimberly , Rue Carla , Lucas Samuel JE , Thomas Owen D , Fountain Amy , Edsell Mark , Myers Fiona , Malein Will , Imray Chris , Clarke Alex , Lewis Chrisopher T , Newman Charles , Johnson Brian , Cadigan Patrick , Wright Alexander , Bradwell Arthur 
Published: March 2020

IntroductionProteinuria increases at altitude and with exercise, potentially as a result of hypoxia. Using urinary alpha-1 acid glycoprotein (α1-AGP) levels as a sensitive marker of proteinuria, we examined the impact of relative hypoxia due to high altitude and blood pressure-lowering medication on post-exercise proteinuria.MethodsTwenty individuals were pair-matched for sex, age and ACE genotype. They completed maximal exercise tests once at sea level and twice at altitude (5035 m). Losartan (100 mg/day; angiotensin-receptor blocker) and placebo were randomly assigned within each pair 21 days before ascent. The first altitude exercise test was completed within 24–48 hours of arrival (each pair within ~1 hour). Acetazolamide (125 mg two times per day) was administrated immediately after this test for 48 hours until the second altitude exercise test.ResultsWith placebo, post-exercise α1-AGP levels were similar at sea level and altitude. Odds ratio (OR) for increased resting α1-AGP at altitude versus sea level was greater without losartan (2.16 times greater). At altitude, OR for reduced post-exercise α1-AGP (58% lower) was higher with losartan than placebo (2.25 times greater, p=0.059) despite similar pulse oximetry (SpO2) (p=0.95) between groups. Acetazolamide reduced post-exercise proteinuria by approximately threefold (9.3±9.7 vs 3.6±6.0 μg/min; p=0.025) although changes were not correlated (r=−0.10) with significant improvements in SpO2(69.1%±4.5% vs 75.8%±3.8%; p=0.001).DiscussionProfound systemic hypoxia imposed by altitude does not result in greater post-exercise proteinuria than sea level. Losartan and acetazolamide may attenuate post-exercise proteinuria, however further research is warranted.
Organoid cultures of early-onset colorectal cancers reveal distinct and rare genetic profiles
Authors: Yan Helen H N , Siu Hoi Cheong , Ho Siu Lun , Yue Sarah S K , Gao Yang , Tsui Wai Yin , Chan Dessy , Chan April S , Wong Jason W H , Man Alice H Y , Lee Bernard C H , Chan Annie S Y , Chan Anthony K W , Hui Ho Sang , Cheung Arthur K L , Law Wai Lun , Lo Oswens S H , Yuen Siu Tsan , Clevers Hans , Leung Suet Yi 
Published: March 2020

ObjectiveSporadic early-onset colorectal cancer (EOCRC) has bad prognosis, yet is poorly represented by cell line models. We examine the key mutational and transcriptomic alterations in an organoid biobank enriched in EOCRCs.DesignWe established paired cancer (n=32) and normal organoids (n=18) from 20 patients enriched in microsatellite-stable EOCRC. Exome and transcriptome analysis was performed.ResultsWe observed a striking diversity of molecular phenotypes, including PTPRK-RSPO3 fusions. Transcriptionally, RSPO fusion organoids resembled normal colon organoids and were distinct from APC mutant organoids, with high BMP2 and low PTK7 expression. Single cell transcriptome analysis confirmed the similarity between RSPO fusion organoids and normal organoids, with a propensity for maturation on Wnt withdrawal, whereas the APC mutant organoids were locked in progenitor stages. CRISPR/Cas9 engineered mutation of APC in normal human colon organoids led to upregulation of PTK7 protein and suppression of BMP2, but less so with an engineered RNF43 mutation. The frequent co-occurrence of RSPO fusions with SMAD4 or BMPR1A mutation was confirmed in TCGA database searches. RNF43 mutation was found in organoid from a leukaemia survivor with a novel mutational signature; and organoids with POLE proofreading mutation displayed ultramutation. The cancer organoid genomes were stable over long culture periods, while normal human colon organoids tended to be subject to clonal dominance over time.ConclusionsThese organoid models enriched in EOCRCs with linked genomic data fill a gap in existing CRC models and reveal distinct genetic profiles and novel pathway cooperativity.