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This paper investigates the lived experience of alienation as a form of mental strife or pathology as it is connected to the digitalization of modern life. To do so, I deploy the concept of affordances from ecological psychology, phenomenology, and embodied cognition. I propose an affordance-based model for understanding digitalized alienation. First, I argue that the lived sense of alienation is best understood as a fracturing of the affordance space, where possibilities for action are lived as disconnected from one another and therefore from one’s personal development and search for meaning. Using this model, I show how the process of digitalization can lead to a lived sense of alienation for modern subjects. On this model, digitalization is alienating insofar as it fractures the affordance space into disconnected fields that invite determinate, separate, and repeatable tasks—swiping, clicking, scrolling, etc.—rather than offering opportunities for the development of new cognitive and bodily skills that are mutually informing and enriching across different affordance fields.

The Cancer of Unknown Primary (CUP) syndrome is characterized by identifiable metastases while the primary tumor remains hidden. In recent years, various data-driven approaches have been suggested to predict the location of the primary tumor (LOP) in CUP patients promising improved diagnosis and outcome. These LOP prediction approaches use high-dimensional input data like images or genetic data. However, leveraging such data is challenging, resource-intensive and therefore a potential translational barrier. Instead of using high-dimensional data, we analyzed the LOP prediction performance of low-dimensional data from routine medical care. With our findings, we show that such low-dimensional routine clinical information suffices as input data for tree-based LOP prediction models. The best model reached a mean Accuracy of 94% and a mean Matthews correlation coefficient (MCC) score of 0.92 in 10-fold nested cross-validation (NCV) when distinguishing four types of cancer. When considering eight types of cancer, this model achieved a mean Accuracy of 85% and a mean MCC score of 0.81. This is comparable to the performance achieved by approaches using high-dimensional input data. Additionally, the distribution pattern of metastases appears to be important information in predicting the LOP.

Background:. Free flap monitoring is more difficult in patients with dark skin because ischemia and congestion can be masked by pigmentation. For this reason, adjunct methods such as cutaneous near-infrared spectroscopy are of elevated importance in patients with highly pigmented skin. The purpose of this experiment is to determine if ViOpitx T.Ox performance is affected by cutaneous pigmentation. Methods:. Swine with naturally occurring areas of nonpigmented and pigmented skin were used. Pigmentation of each animal was assessed using spectrophotometry and histopathology. During normoxemia, tissue oxygenation (StO2) measurements were taken of nonpigmented and pigmented skin using the T.Ox device. A bicolor pedicled rectus abdominis myocutaneous flap was raised, and T.Ox probe was adhered to adjacent areas of opposite coloration on the same flap. StO2 was measured continuously during reversible episodes of flap ischemia and congestion (n = 4 swine, n = 6 flaps). Results:. There was not a significant difference between baseline StO2 values of nonpigmented (49% ± 7.9%) and pigmented skin (47% ± 6.2%). The absolute change in StO2 was significantly larger during both ischemia (6%) and congestion (16%) in nonpigmented skin compared with adjacent pigmented skin. Conclusions:. T.Ox detects flap ischemia and congestion in both highly pigmented and nonpigmented skin. However, surgeons need to be aware that StO2 changes related to complete flap ischemia or congestion may be much more subtle than what is seen in nonpigmented skin. This study establishes a novel internally controlled porcine model that isolates the impact of skin pigmentation when assessing cutaneous devices measuring tissue oxygenation.

Category: Ankle Arthritis; Ankle; Hindfoot; Other Introduction/Purpose: End-stage ankle osteoarthritis (EOA) causes severe pain and chronic disability. Once non operative measures have been exhausted the two main surgical treatments include total ankle replacement (TAR) and ankle fusion (AF). Systematic reviews have confirmed that both procedures are effective but there has never been a robust randomised multicentre level I study comparing the two treatments. Our objective was to investigate and compare the clinical and cost effectiveness of TAR against AF in the treatment of end-stage ankle osteoarthritis in patients aged 50-85 years. Methods: TARVA is a multi-centre, parallel-group, open label randomised trial. Patients with EOA, aged 50-85, suitable for either procedure were recruited at 17 UK hospitals. Randomisation was carried out using a secure on-line service and was stratified by surgeon and the presence or absence of adjacent joint OA (based on an independently reviewed preoperative MRI scan). Participants were randomised 1:1 to either TAR or ankle arthrodesis. The primary outcome was the change in the Manchester Oxford Foot & Ankle Questionnaire (MOXFQ) walking/standing domain scores between pre-operation and 52 weeks post- operation. Secondary outcomes measures included FAAM; FAAM (ADL); and Sport subscale scores. Quality of life was measured using the EQ-5D-5L. Total range of tibia to floor motion was measured using a validated method. Health economic analysis used mean incremental cost per quality-adjusted life years (QALY) gained. Analysis was by intention to treat. The trial registration is ISRCTN60672307. Results: Of 933 eligible patients 303 were randomised. 282 underwent surgery. Mean age 68 (71% male). Aetiology was post- trauma in 55.3%, and inflammatory in 7.1%. Groups were well balanced at baseline on all parameters. 54% TARs were fixed bearing. 61% of fusions were performed arthroscopically. At 2 years the adjusted mean difference in the change in MOXFQ W/S between TAR & AF was -4.4(95% CI -11.38 to 2.68, p=0∙23). Post hoc analysis of the commonest implant type (fixed bearing TAR) did show a statistically significant improvement over AF (p=0∙04, -8.9, 95% CI -17.2 to -0.6). Secondary outcomes, EQ5D-VAS and FAAM were significant. Complications included wound healing issues (13.8% vs 5.5%); nerve injuries (4.3% vs 0.7%). 11.8% of AF patients had plain radiographic evidence of non-union but only 6.9% had symptoms. Reoperation rate was 7.2% for TAR vs 5.2% for AF; and revision rate was 0.7% for TAR vs 2.8% for AF. Conclusion: Patients improved in all outcomes in both arms. We did not show a significant difference in our primary outcome measure between TAR and AF overall(p=0.23), but did show significance when fixed bearing TAR alone was compared against AF(p=0.04). Secondary outcomes did show significance. Adjacent joint arthritis increases the size of effect noted between arms. There were more wound healing issues and nerve injuries in TAR group. The symptomatic non-union rate for AF is 6.9%. TAR is likely to be cost-effective compared to AF at the NICE cost-effectiveness threshold of £20,000 per Quality Adjusted Life Year gained over the patients' lifetime.

Abstract Objective Skeletal dysplasias, cartilaginous or skeletal disorders that sometimes result in abnormal bone development, are seldom reported in free-ranging wild animals. Here, we use photogrammetry and comparative morphometric analyses to describe cases of abnormal appendicular skeletal proportions of free-ranging giraffe in two geographically distinct taxa: a Nubian giraffe (Giraffa camelopardalis camelopardalis) in Murchison Falls National Park, Uganda and an Angolan giraffe (Giraffa giraffa angolensis) on a private farm in central Namibia. Results These giraffe exhibited extremely shortened radius and metacarpal bones relative to other similarly aged giraffe. Both giraffe survived to at least subadult life stage. This report documents rare occurrences of these apparent skeletal dysplasias in free-ranging wild animals and the first records in giraffe.

Category: Ankle Arthritis; Ankle; Other Introduction/Purpose: Both ankle replacement and ankle arthrodesis are offered as treatments to patients with end stage ankle osteoarthritis. Systematic reviews have confirmed that both procedures are effective but there has never been a robust randomised multicentre level I study comparing the two treatments. Our objective was to investigate and compare the clinical and cost effectiveness and complication rates of ankle replacement against ankle arthrodesis in the treatment of end-stage ankle osteoarthritis in patients aged 50-85 years. Methods: 17 NHS centres and 35 surgeons across the United Kingdom participated. Formal Ethics committee approvals were obtained. A Trial Management Group was overseen by a Trial Steering Committee, and an Independent Data Monitoring Committee. Randomisation was carried out using a secure on-line service and was stratified by surgeon and the presence or absence of adjacent joint OA (based on an independently reviewed preoperative MRI scan). Participants were randomised 1:1 to either TAR or ankle fusion. The primary outcome was the change in the Manchester Oxford Foot & Ankle Questionnaire (MOXFQ) walking/standing domain scores between pre-operation and 52 weeks post-operation. Secondary outcomes measures included FAAM; FAAM (ADL); and Sport subscale scores. Quality of life was measured using the EQ-5D-5L. Total range of motion was measured using a validated method. Radiological parameters and adverse events were captured. Health economic analysis used mean incremental cost per quality-adjusted life years (QALY) gained. Results: 1600 patients were screened for eligibility. 330 participants were consented and 303 were randomised; 282 underwent surgery and attended follow-up visits. Mean age was 68 years (71% male). The aetiology of OA was post-trauma in 60%, with 6% patients having inflammatory OA. 42% had MRI evidence of OA in the adjacent joints. The groups were well balanced at baseline on all other parameters including deformity, range of motion and baseline clinical and quality of life scores.42% had MRI evidence of OA in the adjacent joints. 54% TARs used were fixed bearing; 46% were mobile bearing. 61% of fusions were performed arthroscopically. We present all outcomes including adverse effects (death; thromboembolic events; reoperation and revision); radiological findings; and range of motion. We also present subgroup analyses looking at the performance of fixed versus mobile bearing implants; differences by age; and by the presence or absence of adjacent joint OA. Conclusion: This is the first publicly funded, multicentre, prospective, randomised clinical trial comparing the clinical and cost effectiveness of ankle replacement against ankle fusion. It is also the first study in surgery to have detailed prospectively captured health economic data to be able to feed into the reimbursement discussions on these life transforming treatments. Due to contractual requirements of the funders the formal results cannot be released until the final report has been submitted for peer review which will not happen until the end of April 2021. The paper is submitted on behalf of the TARVA Study Group.

Correct operation of many critical systems is dependent on the data consistency and integrity properties of underlying databases. Therefore, a verifiable and rigorous database design process is highly desirable. This research aims to investigate and deliver a comprehensive and practical approach for modelling databases in formal methods through layered refinements. The methodology is being guided by a number of case studies, using abstraction and refinement in UML-B and verification with the Rodin tool. UML-B is a graphical representation of the Event-B formalism and the Rodin tool supports verification for Event-B and UML-B. Our method guides developers to model relational databases in UML-B through layered refinement and to specify the necessary constraints and operations on the database.

En español La geografía, el carácter nacional y el proceso político norteamericano conforman la política exterior de los Estados Unidos de diversas formas que frecuentemente resultan desconocidas para el observador extranjero. Protegido de los conflictos de Europa por el Océano Atlántico, los Estados Unidos desarrolló una tradición diplomática que acentuó el desarrollo y los asuntos del continente americano; cuando Estados Unidos abandonó su tradición aislacionista, su ubicación geografica lo hizo partícipe del mundo europeo, del americano y del Pacífico. La composición étnica norteamericana y su sistema de ideas políticas dieron lugar a una diplomacia que hizo hincapié en la protección de los derechos humanos y civiles individuales en contra de los Estados opresores y que apoyó a organismos internacionales tales como las Naciones Unidas. Por último, el sistema político de los Estados Unidos ha abierto el proceso de formulación de políticas externas a un grado tal que probablemente no sea igualado en ningún otro lugar del mundo. Dichos factores hacen que la diplomacia norteamericana resulte compleja y que el proceso de formulación de políticas sea complicado. Ellos han creado, no obstante, un amplio consenso de apoyo a los principales objetivos diplomáticos que permanece constante a pesar de los cambios en la política interna. En inglés Geography, national character and the American political process all shape the United States'foreign policy in ways that are often unfamiliar to the foreign observer. Protected by the Atlantic Ocean from Europe's discords, the United States developed a diplomatic tradition that emphasized the development of and affairs within the American continent; when the United State abandoned its isolationist tradition, its geographical location made it a participant in the European, American and Pacific worlds. The American ethnic make-up and system of political beliefs gave rise to a diplomacy that emphasidez the protection of individual human and civil rights againts oppressor states and supported multinational organizations such as the United Nations. Finally, the American political system has opened the foreign policy-making process to a degree probably unmatched anywhere in the world. These factors make American diplomacy complex, and the policy-making process a complicated one. They have, however, also created a broad consensus in support of major diplomatic goals that remains constant despite changes in domestic politics.

This paper provides an overview of the CODA framework for modelling and refinement of component-based embedded systems. CODA is an extension of Event-B and UML-B and is supported by a plug-in for the Rodin toolset. CODA augments Event-B with constructs for component-based modelling including components, communications ports, port connectors, timed communications and timing triggers. Component behaviour is specified through a combination of UML-B state machines and Event-B. CODA communications and timing are given an Event-B semantics through translation rules. Refinement is based on Event-B refinement and allows layered construction of CODA models in a consistent way.

Term rewriting has a significant presence in various areas, not least in automated theorem proving where it is used as a proof technique. Many theorem provers employ specialised proof tactics for rewriting. This results in an interleaving between deduction and computation (i.e., rewriting) steps. If the logic of reasoning supports partial functions, it is necessary that rewriting copes with potentially ill-defined terms. In this paper, we provide a basis for integrating rewriting with a deductive proof system that deals with well-definedness. The definitions and theorems presented in this paper are the theoretical foundations for an extensible rewriting-based prover that has been implemented for the set theoretical formalism Event-B.

Highly pathogenic avian influenza H5N1 viruses can result in poultry and occasionally in human mortality. A safe and effective H5N1 vaccine is urgently needed to reduce the pandemic potential. Hemagglutinin (HA), a major envelope protein accounting for approximately 80% of spikes in influenza virus, is often used as a major antigen for subunit vaccine development. In this study, we conducted a systematic study of the immune response against influenza virus infection following immunization with recombinant HA proteins expressed in insect (Sf9) cells, insect cells that contain exogenous genes for elaborating N-linked glycans (Mimic) and mammalian cells (CHO). While the antibody titers are higher with the insect cell derived HA proteins, the neutralization and HA inhibition titers are much higher with the mammalian cell produced HA proteins. Recombinant HA proteins containing tri- or tetra-antennary complex, terminally sialylated and asialyated-galactose type N-glycans induced better protective immunity in mice to lethal challenge. The results are highly relevant to issues that should be considered in the production of fragment vaccines.

This work investigated the replication kinetics of the four dengue virus serotypes (DEN-1 to DEN-4), including dengue virus type 4 (DEN-4) recovered from an infectious cDNA clone, in Vero cells and in MRC-5 cells grown on Cytodex 1 microcarriers. DEN-1 strain Hawaii, DEN-2 strain NGC, DEN-3 strain H-87, and DEN-4 strain H-241 , and DEN-4 strain 814669 derived from cloned DNA, were used to infect Vero cells and MRC-5 cells grown in serum-free or serum-containing microcarrier cultures. Serum-free and serum-containing cultures were found to yield comparable titers of these viruses. The cloned DNA-derived DEN-4 started genetically more homogeneous was used to investigate the genetic stability of the virus propagated in Vero cells and MRC-5 cells. Sequence analysis revealed that the DEN-4 propagated in MRC-5 cells maintained a high genetic stability, compared to the virus propagated in Vero cells. Amino acid substitutions of Gly(104)Cys and Phe(108)Ile were detected at 70%, 60%, respectively, in the envelope (E) protein of DEN-4 propagated in Vero cells, whereas a single mutation of Glu(345)Lys was detected at 50% in E of the virus propagated in MRC-5 cells. Sequencing of multiple clones of three separate DNA fragments spanning 40% of the genome also indicated that DEN-4 propagated in Vero cells contained a higher number of mutations than the virus growing in MRC-5 cells. Although Vero cells yielded a peak virus titer approximately 1 to 17 folds higher than MRC-5 cells, cloned DEN-4 from MRC-5 cells maintained a greater stability than the virus from Vero cells. Serum-free microcarrier cultures of MRC-5 cells offer a potentially valuable system for the large-scale production of live-attenuated DEN vaccines.