An integrated theoretical-experimental approach to accelerate translational tissue engineering

Implantable devices utilizing bioengineered tissue are increasingly showing promise as viable clinical solutions. The design of bioengineered constructs is currently directed according to the results of experiments which are used to test a wide range of different combinations and spatial arrangements of biomaterials, cells and chemical factors. There is an outstanding need to accelerate the design process and reduce financial costs, whilst minimizing the required number of animal-based experiments. These aims could be achieved through the incorporation of mathematical modelling as a preliminary design tool. Here we focus on tissue-engineered constructs for peripheral nerve repair, which are designed to aid nerve and blood vessel growth and repair after peripheral nerve injury. We offer insight into the role that mathematical modelling can play within tissue engineering and motivate the use of modelling as a tool capable of improving and accelerating the design of nerve repair constructs in particular. Specific case studies are presented in order to illustrate the potential of mathematical modelling to direct construct design

Residual erythropoiesis protects against myocardial hemosiderosis in transfusion-dependent thalassemia by lowering labile plasma iron via transient generation of apotransferrin

Cardiosiderosis is a leading cause of mortality in transfusion-dependent thalassemias. Plasma non-transferrin-bound iron and its redox-active component, labile plasma iron, are key sources of iron loading in cardiosiderosis. Risk factors were identified in 73 patients with or without cardiosiderosis. Soluble transferrin receptor-1 levels were significantly lower in patients with cardiosiderosis (odds ratio 21). This risk increased when transfusion-iron loading rates exceeded the erythroid transferrin uptake rate (derived from soluble transferrin receptor-1) by >0.21mg/kg/d (odds ratio 48). Labile plasma iron was >3-fold higher where this uptake rate threshold was exceeded, but non-transferrin-bound iron and transferrin saturation were comparable. Cardiosiderosis risk was also decreased in patients with low liver iron, ferritin and labile plasma iron, or high bilirubin, reticulocyte counts or hepcidin. We hypothesized that high erythroid transferrin uptake rate decreases cardiosiderosis through increased erythroid re-generation of apotransferrin. To test this, iron uptake and intracellular reactive oxygen species were examined in HL-1 cardiomyocytes under conditions modelling transferrin effects on non-transferrin-bound iron speciation with ferric citrate. Intracellular iron and reactive oxygen species increased with ferric citrate concentrations especially where iron-to-citrate ratios exceeded 1:100, i.e. conditions favoring kinetically labile monoferric rather than oligomer species. Excess iron-binding equivalents of apotransferrin inhibited iron uptake, decreased intracellular reactive oxygen species and labile plasma iron, under conditions favoring monoferric species. In conclusion, high transferrin iron utilisation, relative to the transfusion-iron load rate, decreases the cardiosiderotic risk. A putative mechanism is the transient re-generation of apotransferrin by an active erythron, rapidly binding labile plasma iron-detectable ferric monocitrate species

Tackling childhood food poverty in the UK

Actions are needed from national government and local authorities to reduce reliance on emergency food provision, improve take-up of eligible financial support, and develop sustainable food system resilience in diverse communities. Reducing childhood poverty brings life-long benefits to health and wellbeing with economic benefits to society

Country differences in the diagnosis and management of coronary heart disease : a comparison between the US, the UK and Germany

Background The way patients with coronary heart disease (CHD) are treated is partly determined by non-medical factors. There is a solid body of evidence that patient and physician characteristics influence doctors' management decisions. Relatively little is known about the role of structural issues in the decision making process. This study focuses on the question whether doctors' diagnostic and therapeutic decisions are influenced by the health care system in which they take place. This non-medical determinant of medical decision-making was investigated in an international research project in the US, the UK and Germany. Methods Videotaped patients within an experimental study design were used. Experienced actors played the role of patients with symptoms of CHD. Several alternative versions were taped featuring the same script with patients of different sex, age and social status. The videotapes were shown to 384 randomly selected primary care physicians in the three countries under study. The sample was stratified on gender and duration of professional experience. Physicians were asked how they would diagnose and manage the patient after watching the video vignette using a questionnaire with standardised and open-ended questions. Results Results show only small differences in decision making between British and American physicians in essential aspects of care. About 90% of the UK and US doctors identified CHD as one of the possible diagnoses. Further similarities were found in test ordering and lifestyle advice. Some differences between the US and UK were found in the certainty of the diagnoses, prescribed medications and referral behaviour. There are numerous significant differences between Germany and the other two countries. German physicians would ask fewer questions, they would order fewer tests, prescribe fewer medications and give less lifestyle advice. Conclusion Although all physicians in the three countries under study were presented exactly the same patient, some disparities in the diagnostic and patient management decisions were evident. Since other possible influences on doctors treatment decisions are controlled within the experimental design, characteristics of the health care system seem to be a crucial factor within the decision making process

Open Science and Open Innovation in Socio-Political Context: Knowledge Production and Societal Impact in an Age of Populism

This conceptual paper traces the origins and progress of Open Science and proposes its generative coupling to Open Innovation in the contemporary socio-political context; where universities are re-imaging their civic missions in the face of anti-establishment populist politics. This setting is one of changing knowledge production regimes and institutional pressures that create contradictions identifiable through the prism of the series of scientific norms conceptualised by Robert K. Merton. This paper privileges a sociological perspective to proffer scientific knowledge production as a societally embedded process, which is well illustrated by scholarship in the Science and Technology Studies (STS) and Science in Society fields. In doing so, it identifies the co-evolution, co-existence and co-production of Open Science with Open Innovation; and notes how it shares the attributes of other recent diagnoses of changing knowledge production regimes; in particular Mode 2, post-normal science and the Quadruple Helix. It also argues that Open Science can be coupled with Open Innovation to catalyse positive societal change, but that the rise of a populist post-truth era opposed to objectivity, expertise and technocratic political solutions gives the demand for openness and participation a different complexion. Merton’s norms provide a useful lens to observe recent shifts in the delivery of science, knowledge and innovation in society towards more inclusive, ethical and sustainable outcomes; and expose the limited reflection on how the appropriation and exploitation of open scientific knowledge encounters industrial R&D and Open Innovation

A Holder Continuous Nowhere Improvable Function with Derivative Singular Distribution

We present a class of functions $\mathcal{K}$ in $C^0(\R)$ which is variant of the Knopp class of nowhere differentiable functions. We derive estimates which establish \mathcal{K} \sub C^{0,\al}(\R) for 0<\al<1 but no $K \in \mathcal{K}$ is pointwise anywhere improvable to C^{0,\be} for any \be>\al. In particular, all $K$'s are nowhere differentiable with derivatives singular distributions. $\mathcal{K}$ furnishes explicit realizations of the functional analytic result of Berezhnoi. Recently, the author and simulteously others laid the foundations of Vector-Valued Calculus of Variations in $L^\infty$ (Katzourakis), of $L^\infty$-Extremal Quasiconformal maps (Capogna and Raich, Katzourakis) and of Optimal Lipschitz Extensions of maps (Sheffield and Smart). The "Euler-Lagrange PDE" of Calculus of Variations in $L^\infty$ is the nonlinear nondivergence form Aronsson PDE with as special case the $\infty$-Laplacian. Using $\mathcal{K}$, we construct singular solutions for these PDEs. In the scalar case, we partially answered the open $C^1$ regularity problem of Viscosity Solutions to Aronsson's PDE (Katzourakis). In the vector case, the solutions can not be rigorously interpreted by existing PDE theories and justify our new theory of Contact solutions for fully nonlinear systems (Katzourakis). Validity of arguments of our new theory and failure of classical approaches both rely on the properties of $\mathcal{K}$.Comment: 5 figures, accepted to SeMA Journal (2012), to appea

Excavating the 'Rutland Sea Dragon': The largest ichthyosaur skeleton ever found in the UK (Whitby Mudstone Formation, Toarcian, Lower Jurassic)

An almost complete ichthyosaur skeleton 10 m long was discovered in January 2021 at the Rutland Water Nature Reserve in the county of Rutland, UK. This was excavated by a small team of palaeontologists in the summer of the same year. Nicknamed ‘The Rutland Sea Dragon’, this almost fully articulated skeleton is an example of the large-bodied Early Jurassic ichthyosaur Temnodontosaurus. The specimen was analysed in situ, recorded (including a 3D scan using photogrammetry), excavated and removed from the site in a series of large plaster field jackets to preserve taphonomic information. Significantly, the specimen is the largest ichthyosaur skeleton to have been found in the UK and it may be the first recorded example of Temnodontosaurus trigonodon to be found in the country, extending its known geographic range significantly. It also represents the most complete skeleton of a large prehistoric reptile to have been found in the UK. We provide an account of the discovery and describe the methods used for excavating, recording and lifting the large skeleton which will aid palaeontologists facing similar challenges when collecting extensive remains of large and fragile fossil vertebrates. We also discuss the preliminary research findings and the global impact this discovery has had through public engagement

Readmission after discharge from acute mental healthcare among 231 988 people in England: cohort study exploring predictors of readmission including availability of acute day units in local areas

Background: In the UK, acute mental healthcare is provided by in-patient wards and crisis resolution teams. Readmission to acute care following discharge is common. Acute day units (ADUs) are also provided in some areas. Aims: To assess predictors of readmission to acute mental healthcare following discharge in England, including availability of ADUs. Method: We enrolled a national cohort of adults discharged from acute mental healthcare in the English National Health Service (NHS) between 2013 and 2015, determined the risk of readmission to either in-patient or crisis teams, and used multivariable, multilevel logistic models to evaluate predictors of readmission. Results: Of a total of 231 998 eligible individuals discharged from acute mental healthcare, 49 547 (21.4%) were readmitted within 6 months, with a median time to readmission of 34 days (interquartile range 10–88 days). Most variation in readmission (98%) was attributable to individual patient-level rather than provider (trust)-level effects (2.0%). Risk of readmission was not associated with local availability of ADUs (adjusted odds ratio 0.96, 95% CI 0.80–1.15). Statistically significant elevated risks were identified for participants who were female, older, single, from Black or mixed ethnic groups, or from more deprived areas. Clinical predictors included shorter index admission, psychosis and being an in-patient at baseline. Conclusions: Relapse and readmission to acute mental healthcare are common following discharge and occur early. Readmission was not influenced significantly by trust-level variables including availability of ADUs. More support for relapse prevention and symptom management may be required following discharge from acute mental healthcare