Self-reported chronic conditions and COVID-19 public health measures among Canadian adults: an analysis of the Canadian longitudinal study on aging.

OBJECTIVES: During the COVID-19 pandemic, public health measures were used to reduce the spread of COVID-19; it is unknown whether people with chronic conditions differentially adhered to public health measures. The objectives of this study were to evaluate the association between chronic conditions and adherence and to explore effect modification by sex, age, and income. STUDY DESIGN: An analysis of data from the Canadian Longitudinal Study on Aging COVID-19 Questionnaires (from April to September 2020) was conducted among middle-aged and older adults aged 50-96 years (n = 28,086). METHODS: Self-reported chronic conditions included lung disease, diabetes, heart disease, cancer, obesity, anxiety, and depression. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between chronic conditions and low, medium, and high levels of adherence. Effect modification was evaluated using statistical interaction and stratification. RESULTS: Most people (n = 17,435; 62%) had at least one chronic condition, and 2866 (10%) had three to seven chronic conditions. Among those with high adherence to public health measures, 69% had one or more chronic condition (n = 2266). Having three to seven chronic conditions, compared with none, was associated with higher adherence to public health measures (OR: 2.14; 95% CI: 1.12-1.42). Higher adherence was also noted across chronic conditions, for example, those with diabetes had higher adherence (OR: 1.72; 95% CI: 1.53-1.93). There was limited evidence of effect modification by sex, age, or income. CONCLUSIONS: Canadians with chronic conditions were more likely to adhere to public health measures; however, future research is needed to understand whether adherence helped to prevent adverse COVID-19 outcomes and if adherence had unintended consequences.

A method to generate perfusable physiologic-like vascular channels within a liver-on-chip model.

The human vasculature is essential in organs and tissues for the transport of nutrients, metabolic waste products, and the maintenance of homeostasis. The integration of vessels in in vitro organs-on-chip may, therefore, improve the similarity to the native organ microenvironment, ensuring proper physiological functions and reducing the gap between experimental research and clinical outcomes. This gap is particularly evident in drug testing and the use of vascularized models may provide more realistic insights into human responses to drugs in the pre-clinical phases of the drug development pipeline. In this context, different vascularized liver models have been developed to recapitulate the architecture of the hepatic sinusoid, exploiting either porous membranes or bioprinting techniques. In this work, we developed a method to generate perfusable vascular channels with a circular cross section within organs-on-chip without any interposing material between the parenchyma and the surrounding environment. Through this technique, vascularized liver sinusoid-on-chip systems with and without the inclusion of the space of Disse were designed and developed. The recapitulation of the Disse layer, therefore, a gap between hepatocytes and endothelial cells physiologically present in the native liver milieu, seems to enhance hepatic functionality (e.g., albumin production) compared to when hepatocytes are in close contact with endothelial cells. These findings pave the way to numerous further uses of microfluidic technologies coupled with vascularized tissue models (e.g., immune system perfusion) as well as the integration within multiorgan-on-chip settings.

Predictive Value of Cardiac CTA, Cardiac MRI, and Transthoracic Echocardiography for Cardioembolic Stroke Recurrence.

BACKGROUND. Transthoracic echocardiography (TTE) is the standard of care for initial evaluation of patients with suspected cardioembolic stroke. Although TTE is useful for assessing certain sources of cardiac emboli, its diagnostic capability is limited in the detection of other sources, including left atrial thrombus and aortic plaques. OBJECTIVE. The purpose of this article was to investigate sensitivity, specificity, and predictive value of cardiac CTA (CCTA), cardiac MRI (CMRI), and TTE for recurrence in patients with suspected cardioembolic stroke. METHODS. We retrospectively included 151 patients with suspected cardioembolic stroke who underwent TTE and either CMRI (n = 75) or CCTA (n = 76) between January 2013 and May 2017. We evaluated for the presence of left atrial thrombus, left ventricular thrombus, vulnerable aortic plaque, cardiac tumors, and valvular vegetation as causes of cardioembolic stroke. The end point was stroke recurrence. Sensitivity, specificity, PPV, and NPV for recurrent stroke were calculated; the diagnostic accuracy of CMRI, CCTA, and TTE was compared between and within groups using AUC. RESULTS. Twelve and 14 recurrent strokes occurred in the CCTA and CMRI groups, respectively. Sensitivity, specificity, PPV, and NPV were 33.3%, 93.7%, 50.0%, and 88.2% for CCTA; 14.3%, 80.3%, 14.3%, and 80.3% for CMRI; 14.3%, 83.6%, 16.7%, and 80.9% for TTE in the CMRI group; and 8.3%, 93.7%, 20.0%, and 84.5% for TTE in the CCTA group. Accuracy was not different (p > .05) between CCTA (AUC = 0.63; 95% CI, 0.49-0.77), CMRI (0.53; 95% CI, 0.42-0.63), TTE in the CMRI group (0.51; 95% CI, 0.40-0.61), and TTE in the CCTA group (0.51; 95% CI, 0.42-0.59). In the CCTA group, atrial and ventricular thrombus were detected by CCTA in three patients and TTE in one patient; in the CMRI group, thrombus was detected by CMRI in one patient and TTE in two patients. CONCLUSION. CCTA, CMRI, and TTE showed comparably high specificity and NPV for cardioembolic stroke recurrence. CCTA and CMRI may be valid alternatives to TTE. CCTA may be preferred given potentially better detection of atrial and ventricular thrombus. CLINICAL IMPACT. CCTA and CMRI have similar clinical performance as TTE for predicting cardioembolic stroke recurrence. This observation may be especially important when TTE provides equivocal findings.

A fully automated software platform for structural mitral valve analysis.

OBJECTIVE: To evaluate a novel fully automated mitral valve analysis software platform for cardiac computer tomography angiography (CCTA)-based structural heart therapy procedure planning. METHODS: The study included 52 patients (25 women; mean age, 66.9 ± 12.4 years) who had undergone CCTA prior to transcatheter mitral valve replacement (TMVR) or surgical mitral valve intervention (replacement or repair). Therapeutically relevant mitral valve annulus parameters (projected area, circumference, trigone-to-trigone (T-T) distance, anterior-posterior (AP) diameter, and anterolateral-posteromedial (AL-PM) diameter) were measured. Results of the fully automated mitral valve analysis software platform with and without manual adjustments were compared with the reference standard of a user-driven measurement program (3mensio, Pie Medical Imaging). Measurements were compared between the fully automated software, both with and without manual adjustment, and the user-driven program using intraclass correlation coefficients (ICC). A secondary analysis included the time to obtain all measurements. RESULTS: Fully automated measurements showed a good to excellent agreement (circumference, ICC = 0.70; projected area, ICC = 0.81; T-T distance, ICC = 0.64; AP, ICC = 0.62; and AL-PM diameter, ICC = 0.78) compared with the user-driven analysis. There was an excellent agreement between fully automated measurement with manual adjustments and user-driven analysis regarding circumference (ICC = 0.91), projected area (ICC = 0.93), T-T distance (ICC = 0.80), AP (ICC = 0.78), and AL-PM diameter (ICC = 0.79). The time required for mitral valve analysis was significantly lower using the fully automated software with manual adjustments compared with the standard assessment (134.4 ± 36.4 s vs. 304.3 ± 77.7 s) (p < 0.01). CONCLUSION: The fully automated mitral valve analysis software, when combined with manual adjustments, demonstrated a strong correlation compared with the user-driven software while reducing the total time required for measurement. KEY POINTS: • The novel software platform allows for a fully automated analysis of mitral valve structures. • An excellent agreement was found between the fully automated measurement with manual adjustments and the user-driven analysis. • The software showed quicker measurement time compared with the standard analysis of the mitral valve.

Comparison of Artificial Intelligence-Based Fully Automatic Chest CT Emphysema Quantification to Pulmonary Function Testing.

OBJECTIVE. The purpose of this study was to evaluate an artificial intelligence (AI)-based prototype algorithm for fully automated quantification of emphysema on chest CT compared with pulmonary function testing (spirometry). MATERIALS AND METHODS. A total of 141 patients (72 women, mean age ± SD of 66.46 ± 9.7 years [range, 23-86 years]; 69 men, mean age of 66.72 ± 11.4 years [range, 27-91 years]) who underwent both chest CT acquisition and spirometry within 6 months were retrospectively included. The spirometry-based Tiffeneau index (TI; calculated as the ratio of forced expiratory volume in the first second to forced vital capacity) was used to measure emphysema severity; a value less than 0.7 was considered to indicate airway obstruction. Segmentation of the lung based on two different reconstruction methods was carried out by using a deep convolution image-to-image network. This multilayer convolutional neural network was combined with multilevel feature chaining and depth monitoring. To discriminate the output of the network from ground truth, an adversarial network was used during training. Emphysema was quantified using spatial filtering and attenuation-based thresholds. Emphysema quantification and TI were compared using the Spearman correlation coefficient. RESULTS. The mean TI for all patients was 0.57 ± 0.13. The mean percentages of emphysema using reconstruction methods 1 and 2 were 9.96% ± 11.87% and 8.04% ± 10.32%, respectively. AI-based emphysema quantification showed very strong correlation with TI (reconstruction method 1, ρ = -0.86; reconstruction method 2, ρ = -0.85; both p < 0.0001), indicating that AI-based emphysema quantification meaningfully reflects clinical pulmonary physiology. CONCLUSION. AI-based, fully automated emphysema quantification shows good correlation with TI, potentially contributing to an image-based diagnosis and quantification of emphysema severity.

Value of Machine Learning-based Coronary CT Fractional Flow Reserve Applied to Triple-Rule-Out CT Angiography in Acute Chest Pain.

PURPOSE: To evaluate the additional value of noninvasive artificial intelligence (AI)-based CT-derived fractional flow reserve (CT FFR), derived from triple-rule-out coronary CT angiography for acute chest pain (ACP) in the emergency department (ED) setting. MATERIALS AND METHODS: AI-based CT FFR from triple-rule-out CT angiography data sets was retrospectively obtained in 159 of 271 eligible patients (102 men; mean age, 57.0 years ± 9.7 [standard deviation]) presenting to the ED with ACP. The agreement between CT FFR (≤ 0.80) and stenosis at triple-rule-out CT angiography (≥ 50%), as well as downstream cardiac diagnostic testing, was investigated. Furthermore, the predictive value of CT FFR for coronary revascularization and major adverse cardiac events (MACE) was assessed over a 1-year follow-up period. RESULTS: CT FFR and triple-rule-out CT angiography demonstrated agreement in severity of coronary artery disease (CAD) in 52% (82 of 159) of all cases. CT FFR of 0.80 and less served as a better predictor for coronary revascularization and MACE than stenosis of 50% and greater at triple-rule-out CT angiography (odds ratio, 3.4; 95% confidence interval: 1.4, 8.2 vs odds ratio, 2.2; 95% confidence interval: 0.9, 5.3) (P < .01). In the subgroup of patients with additional noninvasive cardiac testing (94 of 159), there was higher agreement as to the presence or absence of significant disease with CT FFR (55%) than with coronary triple-rule-out CT angiography (47%) (P = .23). CONCLUSION: CT FFR derived from triple-rule-out CT angiography was a better predictor for coronary revascularization and MACE and showed better agreement with additional diagnostic testing than triple-rule-out CT angiography. Therefore, CT FFR may improve the specificity in identifying patients with ACP with significant CAD in the ED setting and reduce unnecessary downstream testing.© RSNA, 2020See also the commentary by Ihdayhid and Ben Zekry in this issue.

Low-kV coronary artery calcium scoring with tin filtration using a kV-independent reconstruction algorithm.

PURPOSE: To investigate the accuracy of Agatston scoring and potential for radiation dose reduction of a coronary artery calcium scoring (CACS) CT protocol at 100 kV with tin filtration (Sn100kV) and kV-independent iterative reconstruction, compared to standard 120 kV acquisitions. MATERIALS AND METHODS: With IRB approval and in HIPAA compliance, 114 patients (61.8 ± 9.6 years; 66 men) underwent CACS using a standard 120 kV protocol and an additional Sn100kV CACS scan. The two datasets were reconstructed using a medium sharp convolution algorithm and in addition the Sn100kV scans were reconstructed iteratively based on a kV-independent algorithm. Agatston scores and radiation dose values were compared between the Sn100kV and the standard 120 kV protocol. RESULTS: Median Agatston scores derived from the Sn100kV protocol with the kV-independent algorithm and the standard 120 kV were 21.4 (IQR, 0-173.8) and 24.7 (IQR, 0-171.1) respectively, with no significant differences (p=0.18). Agatston scores derived from the two different protocols had an excellent correlation (r = 0.99). The dose-length-product was 11.5 ± 4.1 mGy × cm using Sn100kV and 50.4 ± 24.9 mGy × cm using the standard 120 kV protocol (p < 0.01), resulting in a significantly lower (77%) effective dose at Sn100kV (0.16 ± 0.06 mSv vs. 0.71 ± 0.35 mSv, p < 0.01). Additionally, 99% of the patients were classified into the same risk category (0, 1-10, 11-100, 101-400, or >400) using the Sn100kV protocol. CONCLUSION: CACS at Sn100kV using the kV-independent iterative algorithm is feasible and provides high accuracy when compared to standard 120 kV scanning. Furthermore, radiation dose can be significantly reduced for this screening application in a priori healthy individuals.

Myocardial extracellular volume fraction to differentiate healthy from cardiomyopathic myocardium using dual-source dual-energy CT.

OBJECTIVE: To evaluate the feasibility of dual-energy CT (DECT)-based iodine quantification to estimate myocardial extracellular volume (ECV) fraction in patients with and without cardiomyopathy (CM), as well as to assess its ability to distinguish healthy myocardial tissue from cardiomyopathic, with the goal of defining a threshold ECV value for disease detection. METHODS: Ten subjects free of heart disease and 60 patients with CM (mean age 66.4 ±â€¯9.4; 59 males and 11 females; 40 ischemic and 20 non-ischemic CM) underwent late iodine enhanced DECT imaging. Myocardial iodine maps were obtained using 3-material decomposition. ECV of the left ventricle was estimated from hematocrit levels and the iodine maps using the AHA 16-segment model. Receiver operating characteristic curve analysis was performed, with corresponding area under the curve, along with Youden's index assessment, to establish a threshold for CM detection. RESULTS: The median ECV for healthy myocardium, non-ischemic CM, and ischemic CM were 25.4% (22.9-27.3), 38.3% (33.7-43.0), and 36.9% (32.4-41.1), respectively. Healthy myocardium showed significantly lower ECV values compared to ischemic and non-ischemic CM (p < 0.001). From Youden's index analysis, an ECV>29.5% would indicate the presence of CM in the myocardium (sensitivity = 90.3; specificity = 90.3); the AUC for this criterion was 0.950 (p < 0.001). CONCLUSION: The findings of this study resulted in a statistically significant distinction between healthy myocardium and CM ECVs. This led to the establishment of a promising threshold ECV value that could facilitate the differentiation between healthy and diseased myocardium, and highlights the potential of this DECT methodology to detect cardiomyopathic tissue.

Feasibility of extracellular volume quantification using dual-energy CT.

ObjectiveTo assess the feasibility of dual energy CT (DECT) to derive myocardial extracellular volume (ECV) and detect myocardial ECV differences without a non-contrast acquisition, compared to single energy CT (SECT). MethodsSubjects (n = 35) with focal fibrosis (n = 17), diffuse fibrosis (n = 10), and controls (n = 9) underwent non-contrast and delayed acquisitions to calculate SECT-ECV. DECT-ECV was calculated using the delayed acquisition and the derived virtual non-contrast images. In the control and diffuse fibrotic groups, the entire myocardium of the left ventricle was used to calculate ECV. Two ROIs were placed in the focal fibrotic group, one in normal and one in fibrotic myocardium. ResultsMedian ECV was 33.4% (IQR, 30.1-37.4) using SECT and 34.9% (IQR, 31.2-39.2) using DECT (p = 0.401). For both techniques, focal and diffuse fibrosis had significantly higher ECV values (all p < 0.021) than normal myocardium. There was no systematic bias between DECT and SECT (p = 0.348). SECT had a higher radiation dose (1.1 mSv difference) than DECT (p < 0.001). ConclusionECV can be measured using a DECT approach with only a delayed acquisition. The DECT approach provides similar results at a lower radiation dose compared to SECT.

Extracellular volume quantitation using dual-energy CT in patients with heart failure: Comparison with 3T cardiac MR.

BACKGROUNDS: Cardiac magnetic resonance (CMR) T1 mapping and the extracellular volume (ECV) have been developed to quantitative analysis of diffusely abnormal myocardial fibrosis (MF). However, dual-energy CT (DECT) has a potential for calculation of ECV. The aim of this study is to evaluate the feasibility and accuracy of DECT technique in determining the ECV in patients with heart failure, with 3T CMR as the reference. METHODS: Thirty-five patients with various reasons of heart failure were enrolled in this study. Both DECT and CMR exams were completed within 24 h. ECVs were calculated, and the relationship between DECT-ECV, CMR-ECV, and other heart function parameters, including left ventricular end systolic and diastolic volume, cardiac output and ejection fraction (LVESV, LVEDV, CO, LVEF), Brain natriuretic peptide (BNP) was determined. All participants gave informed consent, and the study was approved by the institutional review board. RESULTS: The median ECVs on DECT and CMR were 33% (95%CI: 32%-36%) and 30% (95%CI: 30% - 32%), respectively. A good correlation between myocardial ECV at DECT and that at CMR (r = 0.945, P < 0.001) was observed. Bland-Altman analysis between DECT and CMR showed a small bias (2.6%), with 95% limits of agreement of -0.4% and 5.6%. Interobserver agreement for ECV at DECT was excellent (ICC = 0.907). Both ECVs, for DECT and CMR, were inversely associated with LVEF and CO. CONCLUSION: DECT-based ECV could be an alternative non-invasive imaging tool for myocardial tissue characterization. However, overestimation of the extent of diffuse MF is observed with use of DECT.

Non-contrast-enhanced magnetic resonance angiography: a reliable clinical tool for evaluating transplant renal artery stenosis.

PURPOSE: To evaluate image quality of non-contrast-enhanced magnetic resonance angiography (MRA) and compare transplant renal artery stenosis (TRAS) seen by non-contrast-enhanced MRA with digital subtraction angiography (DSA) as the gold standard. MATERIALS AND METHODS: 330 patients receiving 369 non-contrast-enhanced MRA examinations from July 2014 to June 2017 were included. Thirty patients received at least two MRA examinations. Image quality was independently assessed by two radiologists. Inter-observer agreement was analyzed. Transplant renal artery anatomy and complications were evaluated and compared with DSA. If possible, accuracy was calculated on a per-artery basis. RESULTS: Good or excellent image quality was found in 95.4 % (352/369) of examinations with good inter-observer agreement (K=0.760). Twenty-two patients with DSA had 28 non-contrast-enhanced MRA examinations within a 2-month period. Of these, 19 patients had TRAS, two patients had pseudoaneurysms, and one patient had a normal transplant renal artery but an occluded external iliac artery. Non-contrast-enhanced MRA correctly detected 19 TRAS and nine normal arteries, giving 96.6 % accuracy on a per-artery basis. CONCLUSIONS: Non-contrast-enhanced MRA demonstrates a good depiction of the transplanted renal artery and shows good correlation with DSA in cases where there was TRAS. KEY POINTS: • Good or excellent image quality was found in 95.4 % of examinations. • Non-contrast-enhanced MRA can clearly map transplant renal artery anatomy. • Non-contrast-enhanced MRA is a reliable tool to detect TRAS.

Nonbinary quantification technique accounting for myocardial infarct heterogeneity: Feasibility of applying percent infarct mapping in patients.

BACKGROUND: Binary threshold-based quantification techniques ignore myocardial infarct (MI) heterogeneity, yielding substantial misquantification of MI. PURPOSE: To assess the technical feasibility of MI quantification using percent infarct mapping (PIM), a prototype nonbinary algorithm, in patients with suspected MI. STUDY TYPE: Prospective cohort POPULATION: Patients (n = 171) with suspected MI referred for cardiac MRI. FIELD STRENGTH/SEQUENCE: Inversion recovery balanced steady-state free-precession for late gadolinium enhancement (LGE) and modified Look-Locker inversion recovery (MOLLI) T1 -mapping on a 1.5T system. ASSESSMENT: Infarct volume (IV) and infarct fraction (IF) were quantified by two observers based on manual delineation, binary approaches (2-5 standard deviations [SD] and full-width at half-maximum [FWHM] thresholds) in LGE images, and by applying the PIM algorithm in T1 and LGE images (PIMT1 ; PIMLGE ). STATISTICAL TEST: IV and IF were analyzed using repeated measures analysis of variance (ANOVA). Agreement between the approaches was determined with Bland-Altman analysis. Interobserver agreement was assessed by intraclass correlation coefficient (ICC) analysis. RESULTS: MI was observed in 89 (54.9%) patients, and 185 (38%) short-axis slices. IF with 2, 3, 4, 5SDs and FWHM techniques were 15.7 ± 6.6, 13.4 ± 5.6, 11.6 ± 5.0, 10.8 ± 5.2, and 10.0 ± 5.2%, respectively. The 5SD and FWHM techniques had the best agreement with manual IF (9.9 ± 4.8%) determination (bias 1.0 and 0.2%; P = 0.1426 and P = 0.8094, respectively). The 2SD and 3SD algorithms significantly overestimated manual IF (9.9 ± 4.8%; both P < 0.0001). PIMLGE measured significantly lower IF (7.8 ± 3.7%) compared to manual values (P < 0.0001). PIMLGE , however, showed the best agreement with the PIMT1 reference (7.6 ± 3.6%, P = 0.3156). Interobserver agreement was rated good to excellent for IV (ICCs between 0.727-0.820) and fair to good for IF (0.589-0.736). DATA CONCLUSION: The application of the PIMLGE technique for MI quantification in patients is feasible. PIMLGE , with its ability to account for voxelwise MI content, provides significantly smaller IF than any thresholding technique and shows excellent agreement with the T1 -based reference. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.

Closed-loop feedback control for microfluidic systems through automated capacitive fluid height sensing.

Precise fluid height sensing in open-channel microfluidics has long been a desirable feature for a wide range of applications. However, performing accurate measurements of the fluid level in small-scale reservoirs (<1 mL) has proven to be an elusive goal, especially if direct fluid-sensor contact needs to be avoided. In particular, gravity-driven systems used in several microfluidic applications to establish pressure gradients and impose flow remain open-loop and largely unmonitored due to these sensing limitations. Here we present an optimized self-shielded coplanar capacitive sensor design and automated control system to provide submillimeter fluid-height resolution (∼250 µm) and control of small-scale open reservoirs without the need for direct fluid contact. Results from testing and validation of our optimized sensor and system also suggest that accurate fluid height information can be used to robustly characterize, calibrate and dynamically control a range of microfluidic systems with complex pumping mechanisms, even in cell culture conditions. Capacitive sensing technology provides a scalable and cost-effective way to enable continuous monitoring and closed-loop feedback control of fluid volumes in small-scale gravity-dominated wells in a variety of microfluidic applications.

Quantitative Assessment of Population Variability in Hepatic Drug Metabolism Using a Perfused Three-Dimensional Human Liver Microphysiological System.

In this work, we first describe the population variability in hepatic drug metabolism using cryopreserved hepatocytes from five different donors cultured in a perfused three-dimensional human liver microphysiological system, and then show how the resulting data can be integrated with a modeling and simulation framework to accomplish in vitro-in vivo translation. For each donor, metabolic depletion profiles of six compounds (phenacetin, diclofenac, lidocaine, ibuprofen, propranolol, and prednisolone) were measured, along with metabolite formation, mRNA levels of 90 metabolism-related genes, and markers of functional viability [lactate dehydrogenase (LDH) release, albumin, and urea production]. Drug depletion data were analyzed with mixed-effects modeling. Substantial interdonor variability was observed with respect to gene expression levels, drug metabolism, and other measured hepatocyte functions. Specifically, interdonor variability in intrinsic metabolic clearance ranged from 24.1% for phenacetin to 66.8% for propranolol (expressed as coefficient of variation). Albumin, urea, LDH, and cytochrome P450 mRNA levels were identified as significant predictors of in vitro metabolic clearance. Predicted clearance values from the liver microphysiological system were correlated with the observed in vivo values. A population physiologically based pharmacokinetic model was developed for lidocaine to illustrate the translation of the in vitro output to the observed pharmacokinetic variability in vivo. Stochastic simulations with this model successfully predicted the observed clinical concentration-time profiles and the associated population variability. This is the first study of population variability in drug metabolism in the context of a microphysiological system and has important implications for the use of these systems during the drug development process.

A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties.

Distant metastasis is the major cause of breast cancer-related mortality, commonly emerging clinically after 5 or more years of seeming 'cure' of the primary tumor, indicating a quiescent dormancy. The lack of relevant accessible model systems for metastasis that recreate this latent stage has hindered our understanding of the molecular basis and the development of therapies against these lethal outgrowths. We previously reported on the development of an all-human 3D ex vivo hepatic microphysiological system that reproduces several features of liver physiology and enables spontaneous dormancy in a subpopulation of breast cancer cells. However, we observed that the dormant cells were localized primarily within the 3D tissue, while the proliferative cells were in contact with the polystyrene scaffold. As matrix stiffness is known to drive inflammatory and malignant behaviors, we explored the occurrence of spontaneous tumor dormancy and inflammatory phenotype. The microphysiological system was retrofitted with PEGDa-SynKRGD hydrogel scaffolding, which is softer and differs in the interface with the tissue. The microphysiological system incorporated donor-matched primary human hepatocytes and non-parenchymal cells (NPCs), with MDA-MB-231 breast cancer cells. Hepatic tissue in hydrogel scaffolds secreted lower levels of pro-inflammatory analytes, and was more responsive to inflammatory stimuli. The proportion of tumor cells entering dormancy was markedly increased in the hydrogel-supported tissue compared to polystyrene. Interestingly, an unexpected differential response of dormant cells to varying chemotherapeutic doses was identified, which if reflective of patient pathophysiology, has important implications for patient dosing regimens. These findings highlight the metastatic microphysiological system fitted with hydrogel scaffolds as a critical tool in the assessment and development of therapeutic strategies to target dormant metastatic breast cancer.

Quantitative Systems Pharmacology Approaches Applied to Microphysiological Systems (MPS): Data Interpretation and Multi-MPS Integration.

Our goal in developing Microphysiological Systems (MPS) technology is to provide an improved approach for more predictive preclinical drug discovery via a highly integrated experimental/computational paradigm. Success will require quantitative characterization of MPSs and mechanistic analysis of experimental findings sufficient to translate resulting insights from in vitro to in vivo. We describe herein a systems pharmacology approach to MPS development and utilization that incorporates more mechanistic detail than traditional pharmacokinetic/pharmacodynamic (PK/PD) models. A series of studies illustrates diverse facets of our approach. First, we demonstrate two case studies: a PK data analysis and an inflammation response--focused on a single MPS, the liver/immune MPS. Building on the single MPS modeling, a theoretical investigation of a four-MPS interactome then provides a quantitative way to consider several pharmacological concepts such as absorption, distribution, metabolism, and excretion in the design of multi-MPS interactome operation and experiments.

Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system.

BACKGROUND: Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. METHODS: Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. RESULTS: The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU(-) or Ki67(-)). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. CONCLUSIONS: These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy.

The effect of collection and extension on tarsal flexion and fetlock extension at trot.

A recent epidemiological study indicated that various factors may be related to injury in dressage horses, but the mechanism by which these injuries occur has yet to be determined. The suspensory ligament (SL) is a frequent site of injury, and it is assumed that greatest strain is placed on this structure in collected trot; this has yet to be proved conclusively. The study aimed to investigate the effect of collected and extended trot on the hindlimb movement pattern. Four dressage horses were fitted with markers and inertial motion sensors (IMS). High-speed video was obtained for 2 strides on each rein in collected and extended trot on 3 different surfaces: waxed outdoor; sand/plastic granules; and waxed indoor. Maximal tarsal flexion during stance and distal metatarsal coronary band ratio (MTCR), representing fetlock extension, were determined. Inertial motion sensor data determined stride duration, speed and stride length. Data were compared between collection and extension within horses on each surface, and compared between surfaces. Collected trot had significantly lower speed and stride length but longer stride duration than extended trot on all surfaces. All horses had less tarsal flexion and fetlock extension in collected compared with extended trot (P<0.05), which is likely to increase SL loading. The study findings indicate that extended trot may increase SL strain, providing a possible explanation for the high incidence of SL injury in horses trained for extravagant movement. It is possible that substantial use of extended trot could be a risk factor for development of suspensory desmitis, which might be one contributory factor in the prevalence of suspensory desmitis in young horses repeatedly undertaking extravagant movement.