A graphical method for practical and informative identifiability analyses of physiological models: A case study of insulin kinetics and sensitivity

peer reviewedBackground: Derivative based a-priori structural identifiability analyses of mathematical models can offer valuable insight into the identifiability of model parameters. However, these analyses are only capable of a binary confirmation of the mathematical distinction of parameters and a positive outcome can begin to lose relevance when measurement error is introduced. This article presents an integral based method that allows the observation of the identifiability of models with two-parameters in the presence of assay error. Methods: The method measures the distinction of the integral formulations of the parameter coefficients at the proposed sampling times. It can thus predict the susceptibility of the parameters to the effects of measurement error. The method is tested in-silico with Monte Carlo analyses of a number of insulin sensitivity test applications. Results: The method successfully captured the analogous nature of identifiability observed in Monte Carlo analyses of a number of cases including protocol alterations, parameter changes and differences in participant behaviour. However, due to the numerical nature of the analyses, prediction was not perfect in all cases. Conclusions: Thus although the current method has valuable and significant capabilities in terms of study or test protocol design, additional developments would further strengthen the predictive capability of the method. Finally, the method captures the experimental reality that sampling error and timing can negate assumed parameter identifiability and that identifiability is a continuous rather than discrete phenomenon

Parameter Identification Methods in a Model of the Cardiovascular System

To be clinically relevant, mathematical models have to be patient-specific, meaning that their parameters have to be identified from patient data. To achieve real time monitoring, it is important to select the best parameter identification method, in terms of speed, efficiency and reliability. This work presents a comparison of seven parameter identification methods applied to a lumped-parameter cardiovascular system model. The seven methods are tested using in silico and experimental reference data. To do so, precise formulae for initial parameter values first had to be developed. The test results indicate that the trust-region reflective method seems to be the best method for the present model. This method (and the proportional method) are able to perform parameter identification in two to three minutes, and will thus benefit cardiac and vascular monitoring applications

Fabrication of a compliant phantom of the human aortic arch for use in Particle Image Velocimetry (PIV) experimentation

Compliant phantoms of the human aortic arch can mimic patient specific cardiovascular dysfunctions in vitro. Hence, phantoms may enable elucidation of haemodynamic disturbances caused by aortic dysfunction. This paper describes the fabrication of a thin-walled silicone phantom of the human ascending aorta and brachiocephalic artery. The model geometry was determined via a meta-analysis and modelled in SolidWorks before 3D printing. The solid model surface was smoothed and scanned with a 3D scanner. An offset outer mould was milled from Ebalta S-Model board. The final phantom indicated that ABS was a suitable material for the internal model, the Ebalta S-Model board yielded a rough external surface. Co-location of the moulds during silicone pour was insufficient to enable consistent wall thickness. The resulting phantom was free of air bubbles but did not have the desired wall thickness consistency

A Novel Fabrication Method for Compliant Silicone Phantoms of Arterial Geometry for Use in Particle Image Velocimetry of Haemodynamics

Cardiovascular diseases (CVDs) are one of the leading causes of death globally. In-vitro measurement of blood flow in compliant arterial phantoms can provide better insight into haemodynamic states and therapeutic procedures. However, current fabrication techniques are not capable of producing thin-walled compliant phantoms of complex shapes. This study presents a new approach for the fabrication of compliant phantoms suitable for optical measurement. Two 1.5× scaled models of the ascending aorta, including the brachiocephalic artery (BCA), were fabricated from silicone elastomer Sylgard-184. The initial phantom used the existing state of the art lost core manufacturing technique with simple end supports, an acrylonitrile butadiene styrene (ABS) additive manufactured male mould and Ebalta-milled female mould. The second phantom was produced with the same method but used more rigid end supports and ABS male and female moulds. The wall thickness consistency and quality of resulting stereoscopic particle image velocimetry (SPIV) were used to verify the fidelity of the phantom for optical measurement and investigation of physiological flow fields. However, the initial phantom had a rough surface that obscured SPIV analysis and had a variable wall thickness (range = 0.815 mm). The second phantom provided clear particle images and had a less variable wall thickness (range = 0.317 mm). The manufacturing method developed is suitable for fast and cost-effective fabrication of different compliant arterial phantom geometries

DISTq: An Iterative Analysis of Glucose Data for Low-Cost, Real-Time and Accurate Estimation of Insulin Sensitivity

Insulin sensitivity (SI) estimation has numerous uses in medical and clinical situations. However, highresolution tests that are useful for clinical diagnosis and monitoring are often too intensive, long and costly for regular use. Simpler tests that mitigate these issues are not accurate enough for many clinical diagnostic or monitoring scenarios. The gap between these tests presents an opportunity for new approaches

In-vitro particle image velocimetry assessment of the endovascular haemodynamic features distal of stent-grafts that are associated with development of limb occlusion

Aneurysms are common vascular diseases which affect normal haemodynamics in the aorta. Endovascular aortic repair (EVAR) using stent-grafts is a common treatment that excludes the aneurysm from the circulation, preventing further growth and eventual rupture. However, complications such as endoleak, dislocation or limb occlusion have been reported after EVAR. This study hypothesized that the compliance mismatch between the graft and parent artery causes haemodynamic disturbances at the distal edge of the graft. Therefore, the potential for the graft to cause limb occlusion was assessed. A compliant phantom was fabricated. A circulatory loop was developed to run the fluid and generate a physiological flow waveform. Particle Image Velocimetry was utilised to capture fluid dynamics in the replica. The result showed a low velocity region at the graft trailing edge wall. The low velocity boundary layer thickness decreased downstream of the graft. A flow recirculation was initiated and increased in size during the mid-acceleration at the low velocity region. Shear stresses fluctuated at the trailing edge of the graft which is a risk factor for intimal thickening followed by graft or limb occlusion. It was concluded that this haemodynamic behaviour was due to the graft and parent artery compliance mismatch

The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review

The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response

Association between multimorbidity and mortality in a cohort of patients admitted to hospital with COVID-19 in Scotland

Funding: BREATHE - The Health Data Research Hub for Respiratory Health, which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK (MC_PC_19004); CSO Rapid Research in Covid-19 Programme (COV/SAN/20/06); HDR UK Measuring and Understanding Multi-morbidity using Routine Data in the UK (MurMuRUK) (HDR-9006-9006; CFC0110); Medical Research Council (MR/R008345/1).Objectives We investigated the association between multimorbidity among patients hospitalised with COVID-19 and their subsequent risk of mortality. We also explored the interaction between the presence of multimorbidity and the requirement for an individual to shield due to the presence of specific conditions and its association with mortality. Design We created a cohort of patients hospitalised in Scotland due to COVID-19 during the first wave (between 28 February 2020 and 22 September 2020) of the pandemic. We identified the level of multimorbidity for the patient on admission and used logistic regression to analyse the association between multimorbidity and risk of mortality among patients hospitalised with COVID-19. Setting Scotland, UK. Participants Patients hospitalised due to COVID-19. Main outcome measures Mortality as recorded on National Records of Scotland death certificate and being coded for COVID-19 on the death certificate or death within 28 days of a positive COVID-19 test. Results Almost 58% of patients admitted to the hospital due to COVID-19 had multimorbidity. Adjusting for confounding factors of age, sex, social class and presence in the shielding group, multimorbidity was significantly associated with mortality (adjusted odds ratio 1.48, 95%CI 1.26–1.75). The presence of multimorbidity and presence in the shielding patients list were independently associated with mortality but there was no multiplicative effect of having both (adjusted odds ratio 0.91, 95%CI 0.64–1.29). Conclusions Multimorbidity is an independent risk factor of mortality among individuals who were hospitalised due to COVID-19. Individuals with multimorbidity could be prioritised when making preventive policies, for example, by expanding shielding advice to this group and prioritising them for vaccination.Publisher PDFPeer reviewe