Evolving Improved Sampling Protocols for Dose-Response Modelling Using Genetic Algorithms with a Profile-Likelihood Metric.

Practical limitations of quality and quantity of data can limit the precision of parameter identification in mathematical models. Model-based experimental design approaches have been developed to minimise parameter uncertainty, but the majority of these approaches have relied on first-order approximations of model sensitivity at a local point in parameter space. Practical identifiability approaches such as profile-likelihood have shown potential for quantifying parameter uncertainty beyond linear approximations. This research presents a genetic algorithm approach to optimise sample timing across various parameterisations of a demonstrative PK-PD model with the goal of aiding experimental design. The optimisation relies on a chosen metric of parameter uncertainty that is based on the profile-likelihood method. Additionally, the approach considers cases where multiple parameter scenarios may require simultaneous optimisation. The genetic algorithm approach was able to locate near-optimal sampling protocols for a wide range of sample number (n = 3-20), and it reduced the parameter variance metric by 33-37% on average. The profile-likelihood metric also correlated well with an existing Monte Carlo-based metric (with a worst-case r > 0.89), while reducing computational cost by an order of magnitude. The combination of the new profile-likelihood metric and the genetic algorithm demonstrate the feasibility of considering the nonlinear nature of models in optimal experimental design at a reasonable computational cost. The outputs of such a process could allow for experimenters to either improve parameter certainty given a fixed number of samples, or reduce sample quantity while retaining the same level of parameter certainty.

A Novel Experimental Approach for the Measurement of Vibration-Induced Changes in the Rheological Properties of Ex Vivo Ovine Brain Tissue.

Increased incidence of traumatic brain injury (TBI) imposes a growing need to understand the pathology of brain trauma. A correlation between the incidence of multiple brain traumas and rates of behavioural and cognitive deficiencies has been identified amongst people that experienced multiple TBI events. Mechanically, repetitive TBIs may affect brain tissue in a similar way to cyclic loading. Hence, the potential susceptibility of brain tissue to mechanical fatigue is of interest. Although temporal changes in ovine brain tissue viscoelasticity and biological fatigue of other tissues such as tendons and arteries have been investigated, no methodology currently exists to cyclically load ex vivo brain tissue. A novel rheology-based approach found a consistent, initial stiffening response of the brain tissue before a notable softening when subjected to a subsequential cyclic rotational shear. History dependence of the mechanical properties of brain tissue indicates susceptibility to mechanical fatigue. Results from this investigation increase understanding of the fatigue properties of brain tissue and could be used to strengthen therapy and prevention of TBI, or computational models of repetitive head injuries.

Analysis of Flow Through Extra-Anatomic Bypasses Between Supra-Aortic Branches Using Particle Image Velocimetry (PIV).

Supra-aortic extra-anatomic debranch (SAD) are prosthetic surgical grafts used to revascularize head and neck arteries that would be blocked during a surgical or hybrid procedure used in treating ascending and arch of the aorta pathologies. However, bypassing the supra-aortic arteries but not occluding their orifice might introduce potential for competitive flow that reduces bypass patency. Competitive flow within the bypasses across the supra-aortic arteries has not previously been identified. This research identified haemodynamics due to prophylactic inclusion of bypasses from the brachiocephalic artery (BCA) to the left common carotid artery (LCCA), and from the LCCA to left subclavian artery (LSA). Four model configurations investigated the risk of competitive flow and the necessity of intentionally blocking the proximal LSA and/or LCCA. Particle image velocimetry (PIV) was used to assess haemodynamics in each model configuration. We found potential for competitive flow in the BCA-LCCA bypass when the LSA was blocked, in the LSA-LCCA bypass, when the LCCA alone or LCCA and LSA were blocked. Flow stagnated at the start of systole within the RCCA-LCCA bypass, along with notable recirculation zones and reciprocating flow occurring throughout systolic flow. Flow also stagnated in the LCCA-LSA bypass when the LCCA was blocked. There was a large recirculation in the LCCA-LSA bypass when both the LCCA and LSA were blocked. The presence of competitive flow in all other configurations indicated that it is necessary to block or ligate the native LCCA and LSA once the debranch is made and the thoracic endovascular aortic repair (TEVAR) completed.

Sensor Selection for Tidal Volume Determination via Linear Regression-Impact of Lasso versus Ridge Regression.

The measurement of respiratory volume based on upper body movements by means of a smart shirt is increasingly requested in medical applications. This research used upper body surface motions obtained by a motion capture system, and two regression methods to determine the optimal selection and placement of sensors on a smart shirt to recover respiratory parameters from benchmark spirometry values. The results of the two regression methods (Ridge regression and the least absolute shrinkage and selection operator (Lasso)) were compared. This work shows that the Lasso method offers advantages compared to the Ridge regression, as it provides sparse solutions and is more robust to outliers. However, both methods can be used in this application since they lead to a similar sensor subset with lower computational demand (from exponential effort for full exhaustive search down to the order of O (n2)). A smart shirt for respiratory volume estimation could replace spirometry in some cases and would allow for a more convenient measurement of respiratory parameters in home care or hospital settings.

Comparing Literature- and Subreddit-Derived Laboratory Values in Polycystic Ovary Syndrome (PCOS): Validation of Clinical Data Posted on PCOS Reddit Forums.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a heterogeneous condition that affects 4% to 21% of people with ovaries. Inaccessibility or dissatisfaction with clinical treatment for PCOS has led to some individuals with the condition discussing their experiences in specialized web-based forums. OBJECTIVE: This study explores the feasibility of using such web-based forums for clinical research purposes by gathering and analyzing laboratory test results posted in an active PCOS forum, specifically the PCOS subreddit hosted on Reddit. METHODS: We gathered around 45,000 posts from the PCOS subreddit. A random subset of 5000 posts was manually read, and the presence of laboratory test results was labeled. These labeled posts were used to train a machine learning model to identify which of the remaining posts contained laboratory results. The laboratory results were extracted manually from the identified posts. These self-reported laboratory test results were compared with values in the published literature to assess whether the results were concordant with researcher-published values for PCOS cohorts. A total of 10 papers were chosen to represent published PCOS literature, with selection criteria including the Rotterdam diagnostic criteria for PCOS, a publication date within the last 20 years, and at least 50 participants with PCOS. RESULTS: Overall, the general trends observed in the laboratory test results from the PCOS web-based forum were consistent with clinically reported PCOS. A number of results, such as follicle stimulating hormone, fasting insulin, and anti-Mullerian hormone, were concordant with published values for patients with PCOS. The high consistency of these results among the literature and when compared to the subreddit suggests that follicle stimulating hormone, fasting insulin, and anti-Mullerian hormone are more consistent across PCOS phenotypes than other test results. Some results, such as testosterone, sex hormone-binding globulin, and homeostasis model assessment-estimated insulin resistance index, were between those of PCOS literature values and normal values, as defined by clinical testing limits. Interestingly, other results, including dehydroepiandrosterone sulfate, luteinizing hormone, and fasting glucose, appeared to be slightly more dysregulated than those reported in the literature. CONCLUSIONS: The differences between the forum-posted results and those published in the literature may be due to the selection process in clinical studies and the possibility that the forum disproportionally describes PCOS phenotypes that are less likely to be alleviated with medical intervention. However, the degree of concordance in most laboratory test values implied that the PCOS web-based forum participants were representative of research-identified PCOS cohorts. This validation of the PCOS subreddit grants the possibility for more research into the contents of the subreddit and the idea of undertaking similar research using the contents of other medical internet forums.

Characterisation and Quantification of Upper Body Surface Motions for Tidal Volume Determination in Lung-Healthy Individuals.

Measurement of accurate tidal volumes based on respiration-induced surface movements of the upper body would be valuable in clinical and sports monitoring applications, but most current methods lack the precision, ease of use, or cost effectiveness required for wide-scale uptake. In this paper, the theoretical ability of different sensors, such as inertial measurement units, strain gauges, or circumference measurement devices to determine tidal volumes were investigated, scrutinised and evaluated. Sixteen subjects performed different breathing patterns of different tidal volumes, while using a motion capture system to record surface motions and a spirometer as a reference to obtain tidal volumes. Subsequently, the motion-capture data were used to determine upper-body circumferences, tilt angles, distance changes, movements and accelerations-such data could potentially be measured using optical encoders, inertial measurement units, or strain gauges. From these parameters, the measurement range and correlation with the volume signal of the spirometer were determined. The highest correlations were found between the spirometer volume and upper body circumferences; surface deflection was also well correlated, while accelerations carried minor respiratory information. The ranges of thorax motion parameters measurable with common sensors and the values and correlations to respiratory volume are presented. This article thus provides a novel tool for sensor selection for a smart shirt analysis of respiration.

Development of a Head Acceleration Event Classification Algorithm for Female Rugby Union.

Instrumented mouthguards have been used to detect head accelerations and record kinematic data in numerous sports. Each recording requires validation through time-consuming video verification. Classification algorithms have been posed to automatically categorise head acceleration events and spurious events. However, classification algorithms must be designed and/or validated for each combination of sport, sex and mouthguard system. This study provides the first algorithm to classify head acceleration data from exclusively female rugby union players. Mouthguards instrumented with kinematic sensors were given to 25 participants for six competitive rugby union matches in an inter-university league. Across all instrumented players, 214 impacts were recorded from 460 match-minutes. Matches were video recorded to enable retrospective labelling of genuine and spurious events. Four machine learning algorithms were trained on five matches to predict these labels, then tested on the sixth match. Of the four classifiers, the support vector machine achieved the best results, with area under the receiver operator curve (AUROC) and area under the precision recall curve (AUPRC) scores of 0.92 and 0.85 respectively, on the test data. These findings represent an important development for head impact telemetry in female sport, contributing to the safer participation and improving the reliability of head impact data collection within female contact sport.

Analysing multi-perspective patient-related data during laparoscopic gynaecology procedures.

Fusing data from different medical perspectives inside the operating room (OR) sets the stage for developing intelligent context-aware systems. These systems aim to promote better awareness inside the OR by keeping every medical team well informed about the work of other teams and thus mitigate conflicts resulting from different targets. In this research, a descriptive analysis of data collected from anaesthesiology and surgery was performed to investigate the relationships between the intra-abdominal pressure (IAP) and lung mechanics for patients during laparoscopic procedures. Data of nineteen patients who underwent laparoscopic gynaecology were included. Statistical analysis of all subjects showed a strong relationship between the IAP and dynamic lung compliance (r = 0.91). Additionally, the peak airway pressure was also strongly correlated to the IAP in volume-controlled ventilated patients (r = 0.928). Statistical results obtained by this study demonstrate the importance of analysing the relationship between surgical actions and physiological responses. Moreover, these results form the basis for developing medical decision support models, e.g., automatic compensation of IAP effects on lung function.

A review of the hormones involved in the endocrine dysfunctions of polycystic ovary syndrome and their interactions.

Polycystic ovary syndrome (PCOS) affects up to 20% of women but remains poorly understood. It is a heterogeneous condition with many potential comorbidities. This review offers an overview of the dysregulation of the reproductive and metabolic systems associated with PCOS. Review of the literature informed the development of a comprehensive summarizing 'wiring' diagram of PCOS-related features. This review provides a justification for each diagram aspect from the relevant academic literature, and explores the interactions between the hypothalamus, ovarian follicles, adipose tissue, reproductive hormones and other organ systems. The diagram will provide an efficient and useful tool for those researching and treating PCOS to understand the current state of knowledge on the complexity and variability of PCOS.

Particle Image Velocimetry Evaluation of Hemodynamics Proximal to the Kissing Stent Configuration in the Aorto-Iliac Bifurcation.

PURPOSE: The kissing stent (KS) method is low-risk compared with open surgery techniques. It is often used to treat aorto-iliac occlusive disease (AIOD). Deployment of the KS geometry has a high technical success rate. However, stent patency reduces in the first 5 years potentially due to deleterious flow behavior. Potentially harmful hemodynamics due to the KS were investigated in vitro. METHODOLOGY: A compliant phantom of the aorto-iliac bifurcation was manufactured. Two surrogate stent-grafts were deployed into the phantom in the KS configuration to investigate effects of the presence of the stents, including the compliance mismatch they cause, on the hemodynamics proximal and distal to the KS. The investigation used pulsatile flow through a flow circuit to simulate abdominal aortic flow. Particle image velocimetry (PIV) was used to quantify the hemodynamics. RESULTS: PIV identified peak proximal and distal velocity in vitro was 0.71 and 1.40m·s-1, respectively, which were within physiological ranges. Throughout systole, flow appeared normal and undisturbed. A lumen wall collapse in the sagittal plane formed during late systole and continued to early diastole proximal to the aorto-iliac bifurcation, distal to the inlet stent position. The wall collapse led to disturbed flow proximal to the stented region in early diastole producing potential recirculation zones and abnormal flow patterns. CONCLUSION: The normal systolic flow behavior indicates the KS configuration is unlikely to cause an inflammatory response of the arterial walls. The collapse has not been previously identified and may potentially cause long-term patency reduction. It requires further investigation. CLINICAL IMPACT: The role of this article is to provide further insight into the haemodynamic behavior through a stented aorto-iliac artery. The results of this investigation will improve the understanding of the effects that using the kissing stent method may have on a patient and help to identify high risk regions that may require more detailed monitoring. This paper also develops the in vitro modelling techniques that will enable further research that cannot be carried out within patients.

The Effects of Additional Local-Mixing Compartments in the DISST Model-Based Assessment of Insulin Sensitivity.

BACKGROUND: The identification of insulin sensitivity in glycemic modelling can be heavily obstructed by the presence of outlying data or unmodelled effects. The effect of data indicative of local mixing is especially problematic with models assuming rapid mixing of compartments. Methods such as manual removal of data and outlier detection methods have been used to improve parameter ID in these cases, but modelling data with more compartments is another potential approach. METHODS: This research compares a mixing model with local depot site compartments with an existing, clinically validated insulin sensitivity test model. The Levenberg-Marquardt (LM) parameter identification method was implemented alongside a modified version (aLM) capable of operator-independent omission of outlier data in accordance with the 3 standard deviation rule. Three cases were tested: LM where data points suspected to be affected by incomplete mixing at the depot site were removed, aLM, and LM with the more complex mixing model. RESULTS: While insulin parameters identified in the mixing model differed greatly from those in the DISST model, there were strong Spearman correlations of approximately 0.93 for the insulin sensitivity values identified across all 3 methods. The 2 models also showed comparable identification stability in insulin sensitivity estimation through a Monte Carlo analysis. However, the mixing model required modifications to the identification process to improve convergence, and still failed to converge to feasible parameters on 5 of the 212 trials. CONCLUSIONS: The mixing compartment model effectively captured the dynamics of mixing behavior, but with no significant improvement in insulin sensitivity identification.

The Impact of Exogenous Insulin Input on Calculating Hepatic Clearance Parameters.

OBJECTIVE: Model-based metabolic tests require accurate identification of subject-specific parameters from measured assays. Insulin assays are used to identify insulin kinetics parameters, such as general and first-pass hepatic clearances. This study assesses the impact of intravenous insulin boluses on parameter identification precision. METHOD: Insulin and C-peptide data from two intravenous glucose tolerance test (IVGTT) trials of healthy adults (N = 10 × 2; denoted A and B), with (A) and without (B) insulin modification, were used to identify insulin kinetics parameters using a grid search. Monte Carlo analysis (N = 1000) quantifies variation in simulation error for insulin assay errors of 5%. A region of parameter values around the optimum was identified whose errors are within variation due to assay error. A smaller optimal region indicates more precise practical identifiability. Trial results were compared to assess identifiability and precision. RESULTS: Trial B, without insulin modification, has optimal parameter regions 4.7 times larger on average than Trial A, with 1-U insulin bolus modification. Ranges of optimal parameter values between trials A and B increase from 0.04 to 0.12 min-1 for hepatic clearance and from 0.07 to 0.14 for first-pass clearance on average. Trial B's optimal values frequently lie outside physiological ranges, further indicating lack of distinct identifiability. CONCLUSIONS: A small 1-U insulin bolus improves identification of hepatic clearance parameters by providing a smaller region of optimal parameter values. Adding an insulin bolus in metabolic tests can significantly improve identifiability and outcome test precision. Assay errors necessitate insulin modification in clinical tests to ensure identifiability and precision.

Review of the Development of Hemodynamic Modeling Techniques to Capture Flow Behavior in Arteries Affected by Aneurysm, Atherosclerosis, and Stenting.

Cardiovascular diseases (CVDs) are the leading cause of death in the developed world. CVD can include atherosclerosis, aneurysm, dissection, or occlusion of the main arteries. Many CVDs are caused by unhealthy hemodynamics. Some CVDs can be treated with the implantation of stents and stent grafts. Investigations have been carried out to understand the effects of stents and stent grafts have on arteries and the hemodynamic changes post-treatment. Numerous studies on stent hemodynamics have been carried out using computational fluid dynamics (CFD) which has yielded significant insight into the effect of stent mesh design on near-wall blood flow and improving hemodynamics. Particle image velocimetry (PIV) has also been used to capture behavior of fluids that mimic physiological hemodynamics. However, PIV studies have largely been restricted to unstented models or intra-aneurysmal flow rather than peri or distal stent flow behaviors. PIV has been used both as a standalone measurement method and as a comparison to validate the CFD studies. This article reviews the successes and limitations of CFD and PIV-based modeling methods used to investigate the hemodynamic effects of stents. The review includes an overview of physiology and relevant mechanics of arteries as well as consideration of boundary conditions and the working fluids used to simulate blood for each modeling method along with the benefits and limitations introduced.

Investigating Torque-Speed Relationship of Self-Tapping Screws.

Correctly torquing bone screws is important to prevent fixation failures and ensure positive patient outcomes. It has been proposed that an automatic model-based method may be able to determine the patient-specific material properties of bone, and provide objective and quantitative torquing recommendations. One major part of developing this system is the modelling of the bone-screwing process, and the self-tapping screwing process in general. In this paper, we investigate the relationship between screw insertion torque (Nm) and speed of insertion (RPM). A weak positive correlation was found below approximately 30 RPM. Further research should focus on increasing the precision of the methodology, and this testing must be extended to ex-vivo animal bone testing in addition to the polyurethane foam substitute used here.Clinical relevance: To maximise the accuracy of torque recommendations, the model should account for all important factors. This study investigates and attempts to quantify the relationship between screw insertion speed and torque for later inclusion in modelling if significant.

Geometric Generalization of Self Tapping Screw Insertion Model.

Bone screws are used in orthopaedic procedures to fix implants and stabilise fractures. These procedures require care, as improperly torquing the screws can lead to implant failure or tissue damage, potentially requiring revision surgery or causing further disability. It was proposed that automated torque-limit identification may allow clinical decision support to control the screw torque, and lead to improved patient outcomes. This work extends a previous model of the screw insertion process to model complex thread geometries used for bone screws; consideration was made for the variable material properties and behaviours of bone to allow further tuning in the future. The new model was simulated and compared with the original model. The model was found to be in rough agreement with the earlier model, but was distinct, and could model thread features that the earlier model could not, such as the fillets and curves on the bone screw profile. The new model shows promise in modelling the more advanced thread geometries of bone screws with higher accuracy.Clinical relevance: This work extends a self tapping screw model to support complex thread shapes, as common in bone screws, allowing more accurate modelling of the clinically relevant geometries.

Quantifying Accuracy of Self-Tapping Screw Models.

Correct torquing of bone screws is important to prevent fixation failures and ensure positive patient outcomes. It has been proposed that an automatic model-based method may be able to determine the patient-specific material properties of bone, and provide objective and quantitative torquing recommendations. Models have been previously proposed for identifying the bone material properties, but have not been experimentally tested for accuracy. Here we used these models to perform parameter identification on experimental data using a variety of materials (rigid polyurethane foams) and screws. The identified values were then compared to the values from the datasheet, and matched with a reasonable accuracy for medium-density foam. It was found that for the lower-density foam, the model slightly under-predicted the strength, and for the highest density foam there was a large under-prediction. This suggests that with appropriate calibration, this method is good, but may only be applicable to lower-to-medium strength materials. More thorough testing is required to confirm this and determine the reliable density range.Clinical relevance: Accurate material property identification is required to provide effective torque recommendations for bone screws. This work quantifies the accuracy of two proposed models for material property identification.

In vitro pulsatile flow study in compliant and rigid ascending aorta phantoms by stereo particle image velocimetry.

The aorta is a high risk region for cardiovascular disease (CVD). Haemodynamic patterns leading to CVD are not well established despite numerous experimental and numerical studies. Most overlook effects of arterial compliance and pulsatile flow. However, rigid wall assumptions can lead to overestimation of wall shear stress; a key CVD determinant. This work investigates the effect of compliance on aortic arch haemodynamics experiencing pulsatility. Rigid and compliant phantoms of the arch and brachiocephalic branch (BCA) were manufactured. Stereoscopic particle image velocimetry was used to observe velocity fields. Higher velocity magnitude was observed in the rigid BCA during acceleration. However, during deceleration, the compliant phantom experienced higher velocity. During deceleration, a low velocity region initiated and increased in size in the BCA of both phantoms with irregular shape in the compliant. At mid-deceleration, considerably larger recirculation was observed under compliance compared to rigid. Another recirculation region formed and increased in size on the inner wall of the arch in the compliant during late deceleration, but not rigid. The recirculation regions witnessed identify as high risk areas for atherosclerosis formation by a previous ex-vivo study. The results demonstrate necessity of compliance and pulsatility in haemodynamic studies to obtain highly relevant clinical outcomes.

Methoxyflurane toxicity: historical determination and lessons for modern patient and occupational exposure.

AIM: Historically methoxyflurane was used for anaesthesia. Evidence of nephrotoxicity led to abandonment of this application. Subsequently, methoxyflurane, in lower doses, has re-emerged as an analgesic agent, typically used via the Penthrox inhaler in the ambulance setting. We review the literature to consider patient and occupational risks for methoxyflurane. METHOD: Articles were located via PubMed, ScienceDirect, Google Scholar, Anesthesiology journal and the Cochrane Library. RESULTS: Early studies investigated pharmacokinetics and considered the resulting effects to pose minimal risk. Pre-clinical rodent studies utilised a species not vulnerable to the nephrotoxic fluoride metabolite of methoxyflurane, so nephrotoxicity was not identified until almost a decade after its introduction, and was initially met with scepticism. Further evidence of nephrotoxicity led to abandonment of methoxyflurane use for anaesthesia. Subsequent research suggested there are additional risks potentially relevant to recurrent patient or occupational exposure. Specifically, greater than expected fluoride production after repeated low-dose exposure, increased fluoride production due to medication-caused hepatic enzyme induction, fluoride deposition in bone potentially acting as a slow-release fluoride compartment, which suggests a risk of skeletal fluorosis, and hepatotoxicity. Gestational risk is unclear. CONCLUSIONS: Methoxyflurane poses a potentially substantial health risk in high (anaesthetic) doses, and there are a number of pathways whereby repeated exposure to methoxyflurane in lower doses may pose a risk. Single analgesic doses in modern use generally appear safe for patients. However, the safety of recurrent patient or occupational healthcare-worker exposure has not been confirmed, and merits further investigation.

PIV Analysis of Haemodynamics Distal to the Frozen Elephant Trunk Stent Surrogate.

PURPOSE: The Frozen Elephant Trunk (FET) stent is a hybrid endovascular device that may be implemented in the event of an aneurysm or aortic dissection of the aortic arch or superior descending aorta. A Type 1B endoleak can lead to intrasaccular flow during systole and has been identified as a known failure of the FET stent graft. The purpose was to develop in-vitro modelling techniques to enable the investigation of the known failure. METHODS: A silicone aortic phantom and 3D printed surrogate stent graft were manufactured to investigate the haemodynamics of a Type 1B endoleak. Physiological pulsatile flow dynamics distal to the surrogate stent graft were investigated in-vitro using Particle Image Velocimetry (PIV). RESULTS: PIV captured recirculation zones and an endoleak distal to the surrogate stent graft. The endoleak was developed at the peak of systole and sustained until the onset of diastole. The endoleak was asymmetric, indicating a potential variation in the phantom artery wall thickness or stent alignment. Recirculation was identified on the posterior dorsal line during late systole. CONCLUSIONS: The identification of the Type 1B endoleak proved that in-vitro modelling can be used to investigate complex compliance changes and wall motions. The recirculation may indicate the potential for long term intimal layer inflammatory issues such as atherosclerosis. These results may aid future remediation techniques or stent design. Further development of the methods used in this experiment may assist with the future testing of stents prior to animal or human trial.