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Recent progresses in intravital imaging have enabled highly-resolved measurements of periarteriolar oxygen gradients (POGs) within the brain parenchyma. POGs are increasingly used as proxies to estimate the local baseline oxygen consumption, which is a hallmark of cell activity. However, the oxygen profile around a given arteriole arises from an interplay between oxygen consumption and delivery, not only by this arteriole but also by distant capillaries. Integrating such interactions across scales while accounting for the complex architecture of the microvascular network remains a challenge from a modelling perspective. This limits our ability to interpret the experimental oxygen maps and constitutes a key bottleneck toward the inverse determination of metabolic rates of oxygen. We revisit the problem of parenchymal oxygen transport and metabolism and introduce a simple, conservative, accurate and scalable direct numerical method going beyond canonical Krogh-type models and their associated geometrical simplifications. We focus on a two-dimensional formulation, and introduce the concepts needed to combine an operator-splitting and a Green's function approach. Oxygen concentration is decomposed into a slowly-varying contribution, discretized by Finite Volumes over a coarse cartesian grid, and a rapidly-varying contribution, approximated analytically in grid-cells surrounding each vessel. Starting with simple test cases, we thoroughly analyze the resulting errors by comparison with highly-resolved simulations of the original transport problem, showing considerable improvement of the computational-cost/accuracy balance compared to previous work. We then demonstrate the model ability to flexibly generate synthetic data reproducing the spatial dynamics of oxygen in the brain parenchyma, with sub-grid resolution. Based on these synthetic data, we show that capillaries distant from the arteriole cannot be overlooked when interpreting POGs, thus reconciling recent measurements of POGs across cortical layers with the fundamental idea that variations of vascular density within the depth of the cortex may reveal underlying differences in neuronal organization and metabolic load. Author summary: The cerebral microvascular network is the logistics system that provides energy to brain cells at the right time and place. Blood flow and oxygen can now be observed dynamically in living rodents, which transformed our knowledge of the system and its role in ageing and disease. However, oxygen concentration at a given location is the result of a subtle balance between local cellular consumption, supply by neighboring vessels and their interconnections to distant ones. Thus, measurements are difficult to interpret without integrating this multi-scale component, which requires advanced computational models. This hinders our ability to bridge the gap between experiments in rodents and clinical applications in humans. In this work, we focus on oxygen transport between vessels, leveraging recent advances in multi-scale modelling and their mathematical foundations. By this way, we formulate for the first time a simple, conservative, accurate and scalable computational model for cerebral oxygen across scales, that is able to integrate the spatially heterogenous distribution of vessels. We illustrate how this model, combined to imaging, will pave the way towards better estimates of oxygen consumption, a hallmark of neural activity that cannot be directly measured. [ABSTRACT FROM AUTHOR]

The microvasculature facilitates gas exchange, provides nutrients to cells, and regulates blood flow in response to stimuli. Vascular abnormalities are an indicator of pathology for various conditions, such as compromised vessel integrity in small vessel disease and angiogenesis in tumors. Traditional immunohistochemistry enables the visualization of tissue cross-sections containing exogenously labeled vasculature. Although this approach can be utilized to quantify vascular changes within small fields of view, it is not a practical way to study the vasculature on the scale of whole organs. Three-dimensional (3D) imaging presents a more appropriate method to visualize the vascular architecture in tissue. Here we describe the complete protocol that we use to characterize the vasculature of different organs in mice encompassing the methods to fluorescently label vessels, optically clear tissue, collect 3D vascular images, and quantify these vascular images with a semi-automated approach. To validate the automated segmentation of vascular images, one user manually segmented one hundred random regions of interest across different vascular images. The automated segmentation results had an average sensitivity of 83±11% and an average specificity of 91±6% when compared to manual segmentation. Applying this procedure of image analysis presents a method to reliably quantify and characterize vascular networks in a timely fashion. This procedure is also applicable to other methods of tissue clearing and vascular labels that generate 3D images of microvasculature. [ABSTRACT FROM AUTHOR]

Contrast transport models are widely used to quantify blood flow and transport in dynamic contrast-enhanced magnetic resonance imaging. These models analyze the time course of the contrast agent concentration, providing diagnostic and prognostic value for many biological systems. Thus, ensuring accuracy and repeatability of the model parameter estimation is a fundamental concern. In this work, we analyze the structural and practical identifiability of a class of nested compartment models pervasively used in analysis of MRI data. We combine artificial and real data to study the role of noise in model parameter estimation. We observe that although all the models are structurally identifiable, practical identifiability strongly depends on the data characteristics. We analyze the impact of increasing data noise on parameter identifiability and show how the latter can be recovered with increased data quality. To complete the analysis, we show that the results do not depend on specific tissue characteristics or the type of enhancement patterns of contrast agent signal. Author summary: In the last decades, study and quantification of tissue perfusion parameters related to blood flow and transport have acquired a significant importance in the analysis of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In fact, concentration time course data derived from DCE-MRI are essential elements for many computational biological applications, ranging from tumor grading assessment to prediction of antiangiogenic treatment response. Contrast agent transport models have been developed and widely used for the analysis of this data, providing diagnostic and prognostic value. Thus, there is a need to ensure reliability and reproducibility of the transport model parameter estimations. Here we propose the analysis of structural and practical model identifiability, combining artificial and real data to study the role of noise in parameter estimation. The results provide a mathematical explanation for the lack of repeatability of DCE-MRI quantification as well as emphasize the need for new DCE-MRI acquisition protocols standards and quantification methods. [ABSTRACT FROM AUTHOR]

This study protocol aims to investigate how localised cooling influences the skin's microvascular, inflammatory, structural, and perceptual tolerance to sustained mechanical loading at the sacrum, evaluating factors such as morphology, physiology, and perceptual responses. The protocol will be tested on individuals of different age, sex, skin tone and clinical status, using a repeated-measure design with three participants cohorts: i) young healthy (n = 35); ii) older healthy (n = 35); iii) spinal cord injured (SCI, n = 35). Participants will complete three testing sessions during which their sacrum will be mechanically loaded (60 mmHg; 45 min) and unloaded (20 min) with a custom-built thermal probe, causing pressure-induced ischemia and post-occlusive reactive hyperaemia. Testing sessions will differ by the probe's temperature, which will be set to either 38°C (no cooling), 24°C (mild cooling), or 16°C (strong cooling). We will measure skin blood flow (via Laser Doppler Flowmetry; 40 Hz); pro- and anti-inflammatory biomarkers in skin sebum (Sebutape); structural skin properties (Optical Coherence Tomography); and ratings of thermal sensation, comfort, and acceptance (Likert Scales); throughout the loading and unloading phases. Changes in post-occlusive reactive hyperaemia will be considered as the primary outcome and data will be analysed for the independent and interactive effects of stimuli's temperature and of participant group on within- and between-subject mean differences (and 95% Confidence Intervals) in peak hyperaemia, by means of a 2-way mixed model ANOVA (or Friedman). Regression models will also be developed to assess the relationship between absolute cooling temperatures and peak hyperaemia. Secondary outcomes will be within- and between-subject mean changes in biomarkers' expression, skin structural and perceptual responses. This analysis will help identifying physiological and perceptual thresholds for the protective effects of cooling from mechanically induced damage underlying the development of pressure ulcers in individuals varying in age and clinical status. [ABSTRACT FROM AUTHOR]

Brain pericytes are one of the critical cell types that regulate endothelial barrier function and activity, thus ensuring adequate blood flow to the brain. The genetic pathways guiding undifferentiated cells into mature pericytes are not well understood. We show here that pericyte precursor populations from both neural crest and head mesoderm of zebrafish express the transcription factor nkx3.1 develop into brain pericytes. We identify the gene signature of these precursors and show that an nkx3.1-, foxf2a-, and cxcl12b-expressing pericyte precursor population is present around the basilar artery prior to artery formation and pericyte recruitment. The precursors later spread throughout the brain and differentiate to express canonical pericyte markers. Cxcl12b-Cxcr4 signaling is required for pericyte attachment and differentiation. Further, both nkx3.1 and cxcl12b are necessary and sufficient in regulating pericyte number as loss inhibits and gain increases pericyte number. Through genetic experiments, we have defined a precursor population for brain pericytes and identified genes critical for their differentiation. Brain pericytes are critical regulators of endothelial barrier function. In this study, the authors reveal that expression of the transcription factor nkx3.1 is critical for the generation of an intermediate precursor cell state necessary for the normal development of brain pericytes. [ABSTRACT FROM AUTHOR]

Ovarian torsion (OT) is a gynecological emergency that can have diverse clinical presentations makings its diagnosis especially challenging. Few studies exist in the literature describing the clinical presentation as well as the management of OT in the emergency department (ED). This study aims to describe the clinical presentation, physical examination, emergency management, radiographic and intraoperative findings, histopathology reports and the time-to-intervention metrics of OT cases presenting to the emergency room of our tertiary care center. Data was collected by a retrospective chart review of all OT cases that presented to our ED over a period of 1 year. A total of 20 cases were included in the final analysis. The incidence of OT in the ED was 157.4 per 100 000 visits of women in the reproductive age group. All patients were women of reproductive age, with a mean age of 27.3 years. A total of 15 patients (78.9%) presented within 24 hours of symptom onset. The most common presenting symptom was abdominal pain (95%, 19/20) with most localizing to the right lower quadrant (60%, 12/20), followed by nausea and vomiting (90%, 18/20). Almost all patients (95%, 19/20) required opioids for pain management. The majority (80%, 16/20) were diagnosed by ultrasound prior to surgery, whereas (20%, 4/20) went straight to surgery based on a high index of clinical suspicion. Among those who underwent ultrasound, ovarian cyst was present in (75%, 12/16) while (68.9%, 11/16) showed ovarian enlargement and (50%, 8/16) showed abnormal ovarian blood flow. All patients except one patient underwent operative management. Out of the 19 patients who underwent surgery, the majority of patients (94.7%, 18/19) had viable ovaries with the exception of 1 patient (5.3%) who required a salpingo-oophorectomy post ovarian detorsion. A total of 13 cases included histopathologic review of specimens out of which 6 (46.2%) had a mature cystic teratoma. The mean time from door to ultrasonography was 1.4 hours and from door to surgery was 11.4 hours. Our study provides valuable insights into the incidence, clinical presentation, physical examination, emergency management, ultrasonographic and intraoperative findings, histopathology reports as well as the time-to-intervention metrics of OT patients presenting to the ED. [ABSTRACT FROM AUTHOR]

Tumour angiogenesis leads to the formation of blood vessels that are structurally and spatially heterogeneous. Poor blood perfusion, in conjunction with increased hypoxia and oxygen heterogeneity, impairs a tumour's response to radiotherapy. The optimal strategy for enhancing tumour perfusion remains unclear, preventing its regular deployment in combination therapies. In this work, we first identify vascular architectural features that correlate with enhanced perfusion following radiotherapy, using in vivo imaging data from vascular tumours. Then, we present a novel computational model to determine the relationship between these architectural features and blood perfusion in silico. If perfusion is defined to be the proportion of vessels that support blood flow, we find that vascular networks with small mean diameters and large numbers of angiogenic sprouts show the largest increases in perfusion post-irradiation for both biological and synthetic tumours. We also identify cases where perfusion increases due to the pruning of hypoperfused vessels, rather than blood being rerouted. These results indicate the importance of considering network composition when determining the optimal irradiation strategy. In the future, we aim to use our findings to identify tumours that are good candidates for perfusion enhancement and to improve the efficacy of combination therapies. Author summary: Dysregulated tumour vasculature often contains hypoperfused blood vessels which inhibit the delivery of blood-borne anticancer therapies. Radiotherapy, used to treat more than half of all cancer patients, causes DNA damage to vascular endothelial cells, preferentially impacting smaller vessels, leading to their death and vessel pruning. At the same time, experiments measuring changes in tumour perfusion post-irradiation produce varying outcomes and, therefore, the impact of irradiation-induced vessel pruning on network-scale perfusion remains unclear. In this study, we use recent (in vivo) imaging data to identify features of tumour vascular architectures that impact perfusion change post-irradiation. We then use a newly-developed computational framework, directly informed by the experimental observations, to elucidate the relationship between the vascular geometry and topology prior to radiotherapy and the irradiation-induced changes to network perfusion. We find that perfusion increases most significantly for networks of blood vessels with small mean diameters and large numbers of angiogenic sprouts. Our results also distinguish different mechanisms of perfusion increase and we identify cases where rerouting of blood flow causes previously hypoperfused vessels to become perfused. Our study sheds more light on the impact of radiotherapy on tumour blood flow; these insights could be useful for improving anti-cancer treatments. [ABSTRACT FROM AUTHOR]

Background: Recently, we developed a chest compression device that can move the chest compression position without interruption during CPR and be remotely controlled to minimize rescuer exposure to infectious diseases. The purpose of this study was to compare its performance with conventional mechanical CPR device in a mannequin and a swine model of cardiac arrest. Materials and methods: A prototype of a remote-controlled automatic chest compression device (ROSCER) that can change the chest compression position without interruption during CPR was developed, and its performance was compared with LUCAS 3 in a mannequin and a swine model of cardiac arrest. In a swine model of cardiac arrest, 16 male pigs were randomly assigned into the two groups, ROSCER CPR (n = 8) and LUCAS 3 CPR (n = 8), respectively. During 5 minutes of CPR, hemodynamic parameters including aortic pressure, right atrial pressure, coronary perfusion pressure, common carotid blood flow, and end-tidal carbon dioxide partial pressure were measured. Results: In the compression performance test using a mannequin, compression depth, compression time, decompression time, and plateau time were almost equal between ROSCER and LUCAS 3. In a swine model of cardiac arrest, coronary perfusion pressure showed no difference between the two groups (p = 0.409). Systolic aortic pressure and carotid blood flow were higher in the LUCAS 3 group than in the ROSCER group during 5 minutes of CPR (p < 0.001, p = 0.008, respectively). End-tidal CO2 level of the ROSCER group was initially lower than that of the LUCAS 3 group, but was higher over time (p = 0.022). A Kaplan-Meier survival analysis for ROSC also showed no difference between the two groups (p = 0.46). Conclusion: The prototype of a remote-controlled automated chest compression device can move the chest compression position without interruption during CPR. In a mannequin and a swine model of cardiac arrest, the device showed no inferior performance to a conventional mechanical CPR device. [ABSTRACT FROM AUTHOR]

A liquid-based perinatal life support system (PLS) for extremely premature infants (born before 28 week of gestational age) envisions a connection between the infant's native umbilical cord and an artificial placenta system through cannulation. This system mimics a natural mothers' womb to achieve better organ maturations. The objective of this study is to gain insight into the clinical focus points of umbilical cord cannulation and how cannulation should be addressed in extremely premature infants during the transfer from the uterus to an in-utero simulating liquid-based PLS system. We performed an explorative qualitative study. Twelve medical specialists with knowledge of vessel cannulation participated. We collected data through twelve interviews and two focus group discussions. Data were analyzed using inductive content and constant comparison analysis via open and axial coding. Results were derived on the following topics: (1) cannulation technique, (2) cannula fixation, (3) local and systemic anticoagulation, and (4) vasospasm. A side-entry technique is preferred as this may decrease wall damage, stabilizes the vessel better and ensures continuous blood flow. Sutures, especially via an automatic microsurgery instrument, are favored above glue, stents, or balloons as these may be firmer and faster. Medication possibilities for both vasospasm and anticoagulation should function locally since there were uncertainties regarding the systemic effects. According to the findings of this research, the needed umbilical cord cannulation method should include minimal wall damage, improved vascular stability, blood flow maintenance, a strong fixation connection, and local anticoagulation effect. [ABSTRACT FROM AUTHOR]

Intratumoral injection of immunotherapy aims to maximize its activity within the tumor. However, cytokines are cleared via tumor vessels and escape from the tumor periphery into the host-tissue, reducing efficacy and causing toxicity. Thus, understanding the determinants of the tumor and immune response to intratumoral immunotherapy should lead to better treatment outcomes. In this study, we developed a mechanistic mathematical model to determine the efficacy of intratumorally-injected conjugated-cytokines, accounting for properties of the tumor microenvironment and the conjugated-cytokines. The model explicitly incorporates i) the tumor vascular density and permeability and the tumor hydraulic conductivity, ii) conjugated-cytokines size and binding affinity as well as their clearance via the blood vessels and the surrounding tissue, and iii) immune cells—cancer cells interactions. Model simulations show how the properties of the tumor and of the conjugated-cytokines determine treatment outcomes and how selection of proper parameters can optimize therapy. A high tumor tissue hydraulic permeability allows for the uniform distribution of the cytokines into the tumor, whereas uniform tumor perfusion is required for sufficient access and activation of immune cells. The permeability of the tumor vessels affects the blood clearance of the cytokines and optimal values depend on the size of the conjugates. A size >5 nm in radius was found to be optimal, whereas the binding of conjugates should be high enough to prevent clearance from the tumor into the surrounding tissue. In conclusion, development of strategies to improve vessel perfusion and tissue hydraulic conductivity by reprogramming the microenvironment along with optimal design of conjugated-cytokines can enhance intratumoral immunotherapy. Author summary: Cytokines are signaling proteins that can activate the immune response. Intratumoral administration of cytokines has shown promise in improving efficacy of cancer treatment. However, potential toxicity may still result from cytokines release from tumor into systemic circulation. Here, we developed a mechanistic mathematical model of cytokines transport in the tumor and the subsequent immune response. The model investigates the spatiotemporal distribution of intratumorally administered conjugated-cytokines in the tumor and the treatment outcomes, based on the physical and physiological characteristics of the conjugated-cytokines and the tumor microenvironment, respectively. Our results show the importance of tumor blood flow, vascular permeability and tumor tissue hydraulic conductivity in the treatment outcome. Moreover, we found that the size and binding affinity of the conjugated-cytokines are important determinants of the treatment outcome. Our model also shows how reprogramming the tumor microenvironment can improve the treatment outcome of intratumorally-injected cytokines. [ABSTRACT FROM AUTHOR]

Being the largest lymphatic organ in the body, the spleen also constantly controls the quality of red blood cells (RBCs) in circulation through its two major filtration components, namely interendothelial slits (IES) and red pulp macrophages. In contrast to the extensive studies in understanding the filtration function of IES, fewer works investigate how the splenic macrophages retain the aged and diseased RBCs, i.e., RBCs in sickle cell disease (SCD). Herein, we perform a computational study informed by companion experiments to quantify the dynamics of RBCs captured and retained by the macrophages. We first calibrate the parameters in the computational model based on microfluidic experimental measurements for sickle RBCs under normoxia and hypoxia, as those parameters are not available in the literature. Next, we quantify the impact of key factors expected to dictate the RBC retention by the macrophages in the spleen, namely, blood flow conditions, RBC aggregation, hematocrit, RBC morphology, and oxygen levels. Our simulation results show that hypoxic conditions could enhance the adhesion between the sickle RBCs and macrophages. This, in turn, increases the retention of RBCs by as much as four-fold, which could be a possible cause of RBC congestion in the spleen of patients with SCD. Our study on the impact of RBC aggregation illustrates a 'clustering effect', where multiple RBCs in one aggregate can make contact and adhere to the macrophages, leading to a higher retention rate than that resulting from RBC-macrophage pair interactions. Our simulations of sickle RBCs flowing past macrophages for a range of blood flow velocities indicate that the increased blood velocity could quickly attenuate the function of the red pulp macrophages on detaining aged or diseased RBCs, thereby providing a possible rationale for the slow blood flow in the open circulation of the spleen. Furthermore, we quantify the impact of RBC morphology on their tendency to be retained by the macrophages. We find that the sickle and granular-shaped RBCs are more likely to be filtered by macrophages in the spleen. This finding is consistent with the observation of low percentages of these two forms of sickle RBCs in the blood smear of SCD patients. Taken together, our experimental and simulation results aid in our quantitative understanding of the function of splenic macrophages in retaining the diseased RBCs and provide an opportunity to combine such knowledge with the current knowledge of the interaction between IES and traversing RBCs to apprehend the complete filtration function of the spleen in SCD. Author summary: The spleen, the largest organ of the lymphatic system within the abdominal region, is positioned adjacent to the greater curvature of the stomach and is ensconced within the omentum. It constantly controls the quality of red blood cells (RBCs) in circulation. Erythrophagocytosis is one of the critical processes to remove senescent and diseased red blood cells (RBCs) from circulation in the spleen. In this study, we aim to quantify the influence of key factors that are expected to govern the retention of RBCs by macrophages in the spleen. These factors include blood flow conditions, RBC aggregation, hematocrit levels, RBC morphology, and oxygen levels. Our simulation results show that hypoxic conditions could enhance the adhesion between the sickle RBCs and macrophages. Taken together, our experimental and simulation results aid in our quantitative understanding of the function of splenic macrophages in retaining the diseased RBCs and provide an opportunity to combine such knowledge with the current knowledge of the interaction between IES and traversing RBCs to apprehend the complete filtration function of the spleen in SCD. [ABSTRACT FROM AUTHOR]

Low-intensity endurance exercise with blood flow restriction (KAATSU) is under consideration for use in cardiac rehabilitation. However, the physiological responses to such exercise have not yet been fully characterized. In an initial effort in healthy males (n = 11, age: 26.3±4.6 y), we compared the physiological responses to low-intensity endurance exercise with and without a thigh KAATSU. Participants performed maximal graded exercise testing using a cycle ergometer with or without KAATSU. We examined responses to cycling exercise at ventilatory threshold (VT) in heart rate (HR), oxygen consumption (VO2), dyspnea, ratings of perceived exertion (RPE), blood pressure (BP), and rectus femoris activation. Participants reached VT at a lower mechanical load, HR, VO2, dyspnea, and double product (HR×systolic BP) with KAATSU vs. no-KAATSU. At VT, RPE, and rectus femoris activity did not differ between the two conditions. These results suggest that KAATSU reduced exercise intensity to reach VT and the physiological responses to exercise at VT without changes in knee extensor muscle activation. Results from this pilot study in healthy males suggest that KAATSU aerobic exercise at VT intensity has the potential to be an effective and low-burden adjuvant to cycling in cardiac rehabilitation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate the effect of a 1% brinzolamide and 0.1% brimonidine fixed combination (BBFC) on ONH blood flow (BF) in rabbits. Methods: A crossover study was conducted on pigmented rabbits; a physiological saline solution, brinzolamide, or BBFC was administered for eight days. ONH BF, intraocular pressure (IOP) and systemic parameters were measured before the eighth day's first dose and at 6, 9, 12, and 14 hours after the dose. ONH BF was assessed using laser speckle flowgraphy, and mean blur rate (MBR) values were calculated. The percentage against baseline of each parameter was calculated, and intergroup comparisons were performed at each time point. Results: There were no significant differences in the percentage change in systemic parameters. At 6 hours after administration, the BBFC group showed a significantly higher percentage change in large vessel area-MBR (%MV) compared to the control group (98.6±16.8%MV vs. 81.3±7.9%MV, P = 0.03). On the other hand, the brinzolamide group did not show a significant difference. Both the brinzolamide and BBFC groups had significantly lower percentage change in IOP (%IOP) compared to the control group (90.6±5.0%IOP, 93.3±2.9%IOP, and 99.2±1.7%IOP, respectively, P < 0.01). Conclusion: BBFC effectively reduces IOP and mitigates diurnal fluctuation-induced decreases in ONH BF. [ABSTRACT FROM AUTHOR]

The development of a functional cardiovascular system ensures a sustainable oxygen, nutrient and hormone delivery system for successful embryonic development and homeostasis in adulthood. While early vessels are formed by biochemical signaling and genetic programming, the onset of blood flow provides mechanical cues that participate in vascular remodeling of the embryonic vascular system. The zebrafish is a prolific animal model for studying the quantitative relationship between blood flow and vascular morphogenesis due to a combination of favorable factors including blood flow visualization in optically transparent larvae. In this study, we have developed a cell-and-plasma blood transport model using computational fluid dynamics (CFD) to understand how red blood cell (RBC) partitioning affect lumen wall shear stress (WSS) and blood pressure in zebrafish trunk blood vascular networks with altered rheology and morphology. By performing live imaging of embryos with reduced hematocrit, we discovered that cardiac output and caudal artery flow rates were maintained. These adaptation trends were recapitulated in our CFD models, which showed reduction in network WSS via viscosity reduction in the caudal artery/vein and via pressure gradient weakening in the intersegmental vessels (ISVs). Embryos with experimentally reduced lumen diameter showed reduced cardiac output and caudal artery flow rate. Factoring in this trend into our CFD models, simulations highlighted that lumen diameter reduction increased vessel WSS but this increase was mitigated by flow reduction due to the adaptive network pressure gradient weakening. Additionally, hypothetical network CFD models with different vessel lumen diameter distribution characteristics indicated the significance of axial variation in lumen diameter and cross-sectional shape for establishing physiological WSS gradients along ISVs. In summary, our work demonstrates how both experiment-driven and hypothetical CFD modeling can be employed for the study of blood flow physiology during vascular remodeling. Author summary: During angiogenesis, new blood vessels grow into larger networks to expand the cardiovascular system that delivers nutrients to tissue and organs vital for the organism's survival. How the forces of blood flow guide the initial stages of network expansion can be studied with zebrafish embryos due to their optical transparency. However, a key challenge is quantifying the forces of blood flow, which cannot be easily measured from experiments. For this, we have employed computational fluid dynamics (CFD) modeling to predict blood flow forces based on vessel network geometries and blood flow parameters imaged from zebrafish experiments. By combining CFD with experiments on normal zebrafish and zebrafish with genetically transformed blood vessels, we studied how blood flow and its associated forces adapt to such changes. Our analysis highlights that force gradients and distributions in a network follow closely the flow distribution patterns that are in turn adapting to the network geometry and patterning. Through this work, we have demonstrated CFD as a useful quantitative tool for vascular biologists who may employ CFD to complement existing experiment techniques in order to construct or support mechanistic theories of blood flow regulation and vessel remodeling during angiogenesis. [ABSTRACT FROM AUTHOR]

Leptomeningeal collaterals (LMCs) connect the main cerebral arteries and provide alternative pathways for blood flow during ischaemic stroke. This is beneficial for reducing infarct size and reperfusion success after treatment. However, a better understanding of how LMCs affect blood flow distribution is indispensable to improve therapeutic strategies. Here, we present a novel in silico approach that incorporates case-specific in vivo data into a computational model to simulate blood flow in large semi-realistic microvascular networks from two different mouse strains, characterised by having many and almost no LMCs between middle and anterior cerebral artery (MCA, ACA) territories. This framework is unique because our simulations are directly aligned with in vivo data. Moreover, it allows us to analyse perfusion characteristics quantitatively across all vessel types and for networks with no, few and many LMCs. We show that the occlusion of the MCA directly caused a redistribution of blood that was characterised by increased flow in LMCs. Interestingly, the improved perfusion of MCA-sided microvessels after dilating LMCs came at the cost of a reduced blood supply in other brain areas. This effect was enhanced in regions close to the watershed line and when the number of LMCs was increased. Additional dilations of surface and penetrating arteries after stroke improved perfusion across the entire vasculature and partially recovered flow in the obstructed region, especially in networks with many LMCs, which further underlines the role of LMCs during stroke. Author summary: Cerebral ischaemic strokes are a leading cause of death and disability worldwide. Among other factors, the outcome of stroke treatment is determined by the existence and extent of collateral flow paths, which sustain residual blood supply to the obstructed brain region. To improve therapeutic strategies and to reduce reperfusion injuries during treatment, an in-depth understanding of the role of collaterals for maintaining blood supply is indispensable. We performed numerical simulations to quantify how leptomeningeal collaterals impact blood flow redistribution in response to middle cerebral artery occlusion. Our studies have the unique feature that they are consistent with the topology of case-specific pial arterial networks from mouse brains and aligned with sparse in vivo blood flow measurements. This allows the valuable joint interpretation of numerical studies and in vivo experiments. We observed that maintaining perfusion to the obstructed region comes at the cost of reduced blood supply in other areas. Moreover, dilation of arterial vessels improved perfusion in the entire vasculature. Importantly, flow changes vary significantly across and even within vessel types, which underlines the benefits of numerical models with single vessel resolution. Taken together, our framework establishes a strong link between experimental and numerical studies necessary to advance our understanding of perfusion changes in response to stroke and after clot removal. [ABSTRACT FROM AUTHOR]

The heart is widely acknowledged as the unique driver of blood circulation. Recently, we discovered a flow-driving mechanism that can operate without imposed pressure, using infrared (IR) energy to propel flow. We considered the possibility that, by exploiting this mechanism, blood vessels, themselves, could propel flow. We verified the existence of this driving mechanism by using a three-day-old chick-embryo model. When the heart was stopped, blood continued to flow for approximately 50 minutes, albeit at a lower velocity. When IR was introduced, the postmortem flow increased from ~41.1 ± 25.6 μm/s to ~153.0 ± 59.5 μm/s (n = 6). When IR energy was diminished under otherwise physiological conditions, blood failed to flow. Hence, this IR-dependent, vessel-based flow-driving mechanism may indeed operate in the circulatory system, complementing the action of the heart. [ABSTRACT FROM AUTHOR]

Spatial patterns of elevated wall shear stress and pressure due to blood flow past aortic stenosis (AS) are studied using GPU-accelerated patient-specific computational fluid dynamics. Three cases of moderate to severe AS, one with a dilated ascending aorta and two within the normal range (root diameter less than 4cm) are simulated for physiological waveforms obtained from echocardiography. The computational framework is built based on sharp-interface Immersed Boundary Method, where aortic geometries segmented from CT angiograms are integrated into a high-order incompressible Navier–Stokes solver. The key question addressed here is, given the presence of turbulence due to AS which increases wall shear stress (WSS) levels, why some AS patients undergo much less aortic dilation. Recent case studies of AS have linked the existence of an elevated WSS hotspot (due to impingement of AS on the aortic wall) to the dilation process. Herein we further investigate the WSS distribution for cases with and without dilation to understand the possible hemodynamics which may impact the dilation process. We show that the spatial distribution of elevated WSS is significantly more focused for the case with dilation than those without dilation. We further show that this focal area accommodates a persistent pocket of high pressure, which may have contributed to the dilation process through an increased wall-normal forcing. The cases without dilation, on the contrary, showed a rather oscillatory pressure behaviour, with no persistent pressure "buildup" effect. We further argue that a more proximal branching of the aortic arch could explain the lack of a focal area of elevated WSS and pressure, because it interferes with the impingement process due to fluid suction effects. These phenomena are further illustrated using an idealized aortic geometry. We finally show that a restored inflow eliminates the focal area of elevated WSS and pressure zone from the ascending aorta. Author summary: Dilation of the aorta can be a precursor to fatal events such as aortic dissection. Aortic dilation is an involved process which depends on the biological properties of the aorta as well as on the aortic blood flow features. Recent flow imaging studies suggest that a stenotic (i.e., narrowed) aortic valve leads to a turbulent flow character which elevates the fluid stresses applied onto the aortic wall. These excessive stresses are then linked to dilation of the aorta through weakening of the vessel wall tissue. Not all patients with stenotic aortic valves develop aortic dilation, however. Aortic geometry may be a key factor in whether or not a stenotic valve leads to dilation, as it affects the way the restricted aortic flow jet interacts with the vessel wall. We investigate the role of this factor by studying three aortic stenosis patients with and without aortic dilation. To this end, we set up and use a high-fidelity image-based computational framework for detailed simulation of the turbulent flow states and show that certain geometrical layouts of the aorta may be more likely to lead to dilation, because they create persisting and focused areas of excessive blood flow stress on the aortic wall. [ABSTRACT FROM AUTHOR]

The definition of a brain state remains elusive, with varying interpretations across different sub-fields of neuroscience—from the level of wakefulness in anaesthesia, to activity of individual neurons, voltage in EEG, and blood flow in fMRI. This lack of consensus presents a significant challenge to the development of accurate models of neural dynamics. However, at the foundation of dynamical systems theory lies a definition of what constitutes the 'state' of a system—i.e., a specification of the system's future. Here, we propose to adopt this definition to establish brain states in neuroimaging timeseries by applying Dynamic Causal Modelling (DCM) to low-dimensional embedding of resting and task condition fMRI data. We find that ~90% of subjects in resting conditions are better described by first-order models, whereas ~55% of subjects in task conditions are better described by second-order models. Our work calls into question the status quo of using first-order equations almost exclusively within computational neuroscience and provides a new way of establishing brain states, as well as their associated phase space representations, in neuroimaging datasets. Author summary: There is a deceptively simple question that remains unasked at the heart of computational neuroscience—what exactly is a 'brain state'? This question is motivated by the various and seemingly unrelated definitions of brain states: ranging from the level of wakefulness in anaesthesia, to activity of individual neurons, voltage in EEG, and blood flow in fMRI. There is, however, a precise definition of the state of a dynamical system that often remains overlooked: some piece(s) of information that allow us to say what the system does next. Here, we show that this same definition can be used to quantify the information required to predict the future in neuroimaging timeseries. We demonstrate, with the aid of simulations, that this theoretical framework can be used to extract the characteristic features constituting dynamical system states in a range of scenarios. We then apply the same methodology to fMRI datasets and show that task conditions require more information about a neural system's history to constitute a brain state, as compared with rest conditions. [ABSTRACT FROM AUTHOR]

Shame can be defined as the emotional response to one's violations of rules being exposed to others. However, it is difficult to objectively measure this concept. This study examined the psychophysiological indicators of shame in young children using behavioral methods and thermography, which measures facial temperatures that reflect blood flow changes related to emotions. Four- to six-year-old children participated in an "animal guessing game," in which they lied about having violated a rule. They were assigned to either the exposure or the non-exposure group. In the exposure group, participants' lies were exposed by the experimenter, whereas in the non-exposure group, their lies were not. Results showed that at the behavioral level, participants in the exposure group expressed characteristic behaviors of shame (e.g., embarrassed smiles) more often than those in the non-exposure group. Moreover, the nasal temperatures of participants in the exposure group were higher than those of participants in the other group after the lie was exposed. These results suggest that participants' lies being exposed induced psychophysiological responses and consequently raised their nasal temperature. This finding indicates that psychophysiological responses can enable us to objectively measure higher-order emotions in young children. [ABSTRACT FROM AUTHOR]

Background: Left-sided breast cancer patients receiving adjuvant radiotherapy are at risk for coronary artery disease, and/or radiation mediated effects on the microvasculature. Previously our laboratory demonstrated in canines with hybrid 18FDG/PET a progressive global inflammatory response during the initial one year following treatment. In this study, the objective is to evaluate corresponding changes in perfusion, in the same cohort, where resting myocardial blood flow (MBF) was quantitatively measured. Method: In five canines, Ammonia PET (13NH3) derived MBF was measured at baseline, 1-week, 1, 3, 6 and 12-months after cardiac external beam irradiation. MBF measurements were correlated with concurrent 18FDG uptake. Simultaneously MBF was measured using the dual bolus MRI method. Results: MBF was significantly increased at all time points, in comparison to baseline, except at 3-months. This was seen globally throughout the entire myocardium independent of the coronary artery territories. MBF showed a modest significant correlation with 18FDG activity for the entire myocardium (r = 0.51, p = 0.005) including the LAD (r = 0.49, p = 0.008) and LCX (r = 0.47, p = 0.013) coronary artery territories. Conclusion: In this canine model of radiotherapy for left-sided breast cancer, resting MBF increases as early as 1-week and persists for up to one year except at 3-months. This pattern is similar to that of 18FDG uptake. A possible interpretation is that the increase in resting MBF is a response to myocardial inflammation. [ABSTRACT FROM AUTHOR]

Objectives: The present paper aims to characterize the Angiotensin-converting enzyme (ACE) genotype, with particular emphasis on its association with arterial oxygen saturation, arterial blood pressure, hemoglobin [Hb] concentration, and ventilatory measures among the Tawang Monpa, a high-altitude native population of the Eastern Himalaya, India. Methods: A cross-sectional sample of 168Monpa participants from Tawang town, Arunachal Pradesh, India, was selected who live at an altitude of ∼3,200 meters (m) above sea level. For each participant, height, weight, and skinfold thickness were measured, based on which body mass index (BMI, kg/m2) and percentage of body fat (%BF) were calculated. Physiological measures, such as the transcutaneous arterial oxygen saturation (SaO2), hemoglobin [Hb] concentration, forced vital capacity (FVC), forced expiratory volume in 1-second (FEV1), and systemic arterial blood pressure were measured. First, the peripheral venous blood samples (four ml) were drawn, and then white blood cells were separated for the ACE genotyping of each participant. Results: Unlike high-altitude natives from Peru and Ladakh, who exhibit high frequencies of II homozygotes, the Tawang Monpa shows a significantly high frequency of ID heterozygotes (p<0.0001). In addition, no significant association was identified between ACE gene polymorphism and arterial blood pressure, oxygen saturation at rest, vital capacity, or [Hb] concentration. Discussion: The results suggest that the association of the ACE gene with resting SaO2 is inconsistent across native populations living under hypobaric hypoxia. Further, ACE I/D gene polymorphism may not be under natural selection in specific native populations, including Tawang Monpa, for their adaptation to high-altitude hypoxia. [ABSTRACT FROM AUTHOR]

Purpose: To examine whether extended interscan time (IST) on optical coherence tomography angiography (OCTA) can detect slow retinal blood flow, which is undetectable on default IST, in the healthy macula. Methods: OCTA (OCT-A1, Canon Inc.) scanning of a macular area measuring 4 × 4 mm2 of 14 healthy eyes of 14 healthy volunteers with no history or evidence of systemic and macular diseases was performed. ISTs were set at 7.6 (IST7.6, default setting), 12.0 (IST12.0), and 20.6 msec (IST20.6). Ten OCTA images were acquired at each IST, and an averaged image was created. For each averaged OCTA image obtained at IST7.6, IST12.0, and IST20.6, we defined the area surrounded by the innermost capillary ring as the foveal avascular zone (FAZ). We qualitatively evaluated the delineation of the capillaries consisting of the FAZ and quantitatively measured the FAZ area at each IST. Results: Extensions from IST7.6 to IST12.0 and IST20.6 could newly delineated retinal capillaries that were undetectable at the default IST; new capillaries were detected in 10 (71%) eyes at IST12.0 and 11 (78%) eyes at IST20.0. The FAZ areas were 0.334 ± 0.137 mm2, 0.320 ± 0.132 mm2, and 0.319 ± 0.129 mm2 for IST7.6, IST12.0, and IST20.0, respectively; the FAZ areas at IST12.0 and IST20.0 were significantly decreased compared with that at IST7.6 (p = 0.004 and 0.002, respectively). Conclusion: In OCTA for healthy participants, extensions of the ISTs newly detected retinal capillaries with slow blood flow around FAZ. The FAZ shapes varied with different ISTs. Thus, the blood flow dynamics are not physiologically uniform around FAZ. Compared with conventional OCTA, this protocol enables a more detailed evaluation of retinal circulation and provides a better understanding of the physiological circulatory status of the healthy retina, and may enable the assessment of circulation in the very early stages in diseased eyes. [ABSTRACT FROM AUTHOR]

The cerebral arterial network covering the brain cortex has multiscale anastomosis structures with sparse intermediate anastomoses (O[102] μm in diameter) and dense pial networks (O[101] μm in diameter). Recent studies indicate that collateral blood supply by cerebral arterial anastomoses has an essential role in the prognosis of acute ischemic stroke caused by large vessel occlusion. However, the physiological importance of these multiscale morphological properties—and especially of intermediate anastomoses—is poorly understood because of innate structural complexities. In this study, a computational model of multiscale anastomoses in whole-brain-scale cerebral arterial networks was developed and used to evaluate collateral blood supply by anastomoses during middle cerebral artery occlusion. Morphologically validated cerebral arterial networks were constructed by combining medical imaging data and mathematical modeling. Sparse intermediate anastomoses were assigned between adjacent main arterial branches; the pial arterial network was modeled as a dense network structure. Blood flow distributions in the arterial network during middle cerebral artery occlusion simulations were computed. Collateral blood supply by intermediate anastomoses increased sharply with increasing numbers of anastomoses and provided one-order-higher flow recoveries to the occluded region (15%–30%) compared with simulations using a pial network only, even with a small number of intermediate anastomoses (≤10). These findings demonstrate the importance of sparse intermediate anastomoses, which are generally considered redundant structures in cerebral infarction, and provide insights into the physiological significance of the multiscale properties of arterial anastomoses. Author summary: The collateral blood supply in the cerebral arterial network that covers the brain cortex has an essential role in the prognosis of acute ischemic stroke caused by large vessel occlusion. However, these physiological functions remain poorly understood because of the structural complexities of cerebral arterial anastomoses (the source of collateral blood supply), which have multiscale properties (diameters 50–400 μm). Thus, we aimed to estimate the potential function of multiscale anastomoses in collateral blood supply during acute ischemic stroke using computational modeling. A sparse intermediate scale of anastomoses (O[102] μm in diameter) and a dense pial arterial network (O[101] μm in diameter) were constructed in the morphologically validated arterial network model (whole-brain scale); blood flow distributions in this arterial network were then computed using numerous patterns of intermediate anastomoses in the MCA occlusion. Obtained results successfully demonstrate that sparse numbers of intermediate anastomoses primarily provide collateral blood supply toward upstream and downstream regions and provide one-order-higher flow recoveries to the occlusion region compared with simulations with a pial network only. We hope that our findings stimulate further clinical and anatomical measurements of multiscale cerebral anastomoses. [ABSTRACT FROM AUTHOR]

Models of arterial injury in rodents have been invaluable to our current understanding of vessel restenosis and play a continuing role in the development of endovascular interventions for cardiovascular disease. Mechanical distention of the vessel wall and denudation of the vessel endothelium are the two major modes of vessel injury observed in most clinical pathologies and are critical to the reproducible modelling of progressive neointimal hyperplasia. The current models which have dominated this research area are the mouse wire carotid or femoral injury and the rat carotid balloon injury. While these elicit simultaneous distension of the vessel wall and denudation of the luminal endothelium, each model carries limitations that need to be addressed using a complementary injury model. Wire injuries in mice are highly technical and procedurally challenging due to small vessel diameters, while rat balloon injuries require permanent blood vessel ligation and disruption of native blood flow. Complementary models of vascular injury with reproducibility, convenience, and increased physiological relevance to the pathophysiology of endovascular injury would allow for improved studies of neointimal hyperplasia in both basic and translational research. In this study, we developed a new surgical model that elicits vessel distention and endothelial denudation injury using sequential steps using microforceps and a standard needle catheter inserted via arteriotomy into a rat common carotid artery, without requiring permanent ligation of branching arteries. After 2 weeks post-injury this model elicits highly reproducible neointimal hyperplasia and rates of re-endothelialisation similar to current wire and balloon injury models. Furthermore, evaluation of the smooth muscle cell phenotype profile, inflammatory response and extracellular matrix within the developing neointima, showed that our model replicated the vessel remodelling outcomes critical to restenosis and those becoming increasingly focused upon in the development of new anti-restenosis therapies. [ABSTRACT FROM AUTHOR]

Elevations of plasma creatinine are common after major surgery, but their pathophysiology is poorly understood. To identify possible contributing mechanisms, we pooled data from eight prospective studies performed in four different countries to study circumstances during which elevation of plasma creatinine occurs. We included 642 patients undergoing mixed major surgeries, mostly open gastrointestinal. Plasma and urinary creatinine and a composite index for renal fluid conservation (Fluid Retention Index, FRI) were measured just before surgery and on the first postoperative morning. Urine flow was measured during the surgery. The results show that patients with a postoperative increase in plasma creatinine by >25% had a high urinary creatinine concentration (11.0±5.9 vs. 8.3±5.6 mmol/L; P< 0001) and higher FRI value (3.2±1.0 vs. 2.9±1.1; P< 0.04) already before surgery was initiated. Progressive increase of plasma creatinine was associated with a gradually lower urine flow and larger blood loss during the surgery (Kruskal-Wallis test, P< 0.001). The patients with an elevation > 25% also showed higher creatinine and a higher FRI value on the first postoperative morning (P< 0.001). Elevations to > 50% of baseline were associated with slightly lower mean arterial pressure (73 ± 10 vs. 80 ± 12 mmHg; P< 0.005). We conclude that elevation of plasma creatinine in the perioperative period was associated with low urine flow and greater blood loss during surgery and with concentrated urine both before and after the surgery. Renal water conservation-related mechanisms seem to contribute to the development of increased plasma creatinine after surgery. [ABSTRACT FROM AUTHOR]

Background: Automatic chest compression devices (ACCDs) can promote high-quality cardiopulmonary resuscitation (CPR) and are widely used worldwide. Early application of automated external defibrillators (AEDs) along with high-quality CPR is crucial for favorable outcomes in patients with cardiac arrest. Here, we developed an automated CPR (A-CPR) apparatus that combines ACCD and AED and evaluated its performance in a pilot animal-based study. Methods: Eleven pigs (n = 5, A-CPR group; n = 6, ACCD CPR and AED [conventional CPR (C-CPR)] group) were enrolled in this study. After 2 min observation without any treatment following ventricular fibrillation induction, CPR with a 30:2 compression/ventilation ratio was performed for 6 min, mimicking basic life support (BLS). A-CPR or C-CPR was applied immediately after BLS, and resuscitation including chest compression and defibrillation, was performed following a voice prompt from the A-CPR device or AED. Hemodynamic parameters, including aortic pressure, right atrial pressure, coronary perfusion pressure, carotid blood flow, and end-tidal carbon dioxide, were monitored during resuscitation. Time variables, including time to start rhythm analysis, time to charge, time to defibrillate, and time to subsequent chest compression, were also measured. Results: There were no differences in baseline characteristics, except for arterial carbon dioxide pressure (39 in A-CPR vs. 33 in C-CPR, p = 0.034), between the two groups. There were no differences in hemodynamic parameters between the groups. However, time to charge (28.9 ± 5.6 s, A-CPR group; 47.2 ± 12.4 s, C-CPR group), time to defibrillate (29.1 ± 7.2 s, A-CPR group; 50.5 ± 12.3 s, C-CPR group), and time to subsequent chest compression (32.4 ± 6.3 s, A-CPR group; 56.3 ± 10.7 s, C-CPR group) were shorter in the A-CPR group than in the C-CPR group (p = 0.015, 0.034 and 0.02 respectively). Conclusions: A-CPR can provide effective chest compressions and defibrillation, thereby shortening the time required for defibrillation. [ABSTRACT FROM AUTHOR]

Duplex ultrasound (DUS) is the most widely used method for surveillance of arteriovenous fistulae (AVF) created for dialysis. However, DUS is poor at predicting AVF outcomes and there is a need for novel methods that can more accurately evaluate multidirectional AVF flow. In this study we aimed to evaluate the feasibility of detecting AVF stenosis using a novel method combining tensor-decomposition of B-mode ultrasound cine loops (videos) of blood flow and machine learning classification. Classification of stenosis was based on the DUS assessment of blood flow volume, vessel diameter size, flow velocity, and spectral waveform features. Real-time B-mode cine loops of the arterial inflow, anastomosis, and venous outflow of the AVFs were analysed. Tensor decompositions were computed from both the 'full-frame' (whole-image) videos and 'cropped' videos (to include areas of blood flow only). The resulting output were labelled for the presence of stenosis, as per the DUS findings, and used as a set of features for classification using a Long Short-Term Memory (LSTM) neural network. A total of 61 out of 66 available videos were used for analysis. The whole-image classifier failed to beat random guessing, achieving a mean area under the receiver operating characteristics (AUROC) value of 0.49 (CI 0.48 to 0.50). In contrast, the 'cropped' video classifier performed better with a mean AUROC of 0.82 (CI 0.66 to 0.96), showing promising predictive power despite the small size of the dataset. The combined application of tensor decomposition and machine learning are promising for the detection of AVF stenosis and warrant further investigation. [ABSTRACT FROM AUTHOR]

Hemodynamics is crucial for the activation and aggregation of platelets in response to flow-induced shear. In this paper, a novel image-based computational model simulating blood flow through and around platelet aggregates is presented. The microstructure of aggregates was captured by two different modalities of microscopy images of in vitro whole blood perfusion experiments in microfluidic chambers coated with collagen. One set of images captured the geometry of the aggregate outline, while the other employed platelet labelling to infer the internal density. The platelet aggregates were modelled as a porous medium, the permeability of which was calculated with the Kozeny-Carman equation. The computational model was subsequently applied to study hemodynamics inside and around the platelet aggregates. The blood flow velocity, shear stress and kinetic force exerted on the aggregates were investigated and compared under 800 s−1, 1600 s−1 and 4000 s−1 wall shear rates. The advection-diffusion balance of agonist transport inside the platelet aggregates was also evaluated by local Péclet number. The findings show that the transport of agonists is not only affected by the shear rate but also significantly influenced by the microstructure of the aggregates. Moreover, large kinetic forces were found at the transition zone from shell to core of the aggregates, which could contribute to identifying the boundary between the shell and the core. The shear rate and the rate of elongation flow were investigated as well. The results imply that the emerging shapes of aggregates are highly correlated to the shear rate and the rate of elongation. The framework provides a way to incorporate the internal microstructure of the aggregates into the computational model and yields a better understanding of the hemodynamics and physiology of platelet aggregates, hence laying the foundation for predicting aggregation and deformation under different flow conditions. Author summary: The initial step in the formation of an arterial thrombus is the rapid aggregation of the tiny blood particles called platelets. This process significantly influences the formation and structure of the resulting thrombi. The mechanical properties of the aggregates depend on their microstructure, which in turn is dictated by their interaction with the flow during formation. However, due to currently existing technological limitations, it is not possible to measure these interactions in sufficient detail experimentally. In this paper, an image-based computational model is proposed based on two different modalities of experimental images, that can complement the experiments and give detailed information on hemodynamics during the aggregation. The image sets are captured from whole blood perfused microfluidic chambers coated with collagen. One modality of images captured the shape of the aggregate outline with high contrast, while the other employed platelet labeling to infer the internal density. The platelet aggregates are considered as porous media in the simulations, informed by the images. This framework incorporates the internal microstructure of the aggregates into the computational model and yields a better understanding of the hemodynamics and physiology of platelet aggregates, hence laying the foundation for predicting aggregation and deformation under different flow conditions. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to compare choroidal adjusted flow index (AFI) in healthy, hypertensive & preeclamptic pregnancies using optical coherence tomography angiography (OCTA). Methods: In this prospective study, healthy, hypertensive & preeclamptic third trimester pregnant women underwent OCTA imaging. 3x3 & 6x6 mm choriocapillaris slabs were exported and the parafoveal area was marked by two concentric ETDRS circles at 1 & 3 mm, centered on the foveal avascular zone. Parafoveal AFI was calculated as a parameter of choroidal blood flow. Results: Fifteen eyes of fifteen women per group were recruited (45 eyes). AFI was significantly lower in the preeclamptic compared to the healthy & hypertensive groups (Tukey HSD: <0.001 in both groups on 3x3 mm, and 0.02 & 0.04 in 6x6 mm scans), and in the hypertensive compared to the healthy group (0.005 & 0.03 in 3x3 & 6x6 mm scans respectively). Conclusions: Pregnancies complicated with preeclampsia revealed the lowest choroidal blood flow on OCTA followed by pregnancies with systemic hypertension compared to healthy pregnancies. We provide in-vivo documentation of choroidal ischemia, highlighting its culpability in hypertensive and preeclamptic retinochoroidal pathology, and the possibility of utilizing choroidal blood flow on OCTA as a precursor for disease progression. [ABSTRACT FROM AUTHOR]

Background: Healthcare simulators have been demonstrated to be a valuable resource for training several technical and nontechnical skills. A gap in the fidelity of tissues has been acknowledged as a barrier to application for current simulators; especially for interventional procedures. Inaccurate or unrealistic mechanical response of a simulated tissue to a given surgical tool motion may result in negative training transfer and/or prevents the "suspension of disbelief" necessary for a trainee to engage in the activity. Thus, where it is relevant to training outcomes, there should be an effort to create healthcare simulators with simulated tissue mechanical responses that match or represent those of biological tissues. Historically, this data is most often gathered from preserved (post mortem) tissue; however, there is a concern that the mechanical properties of preserved tissue, that lacks blood flow, may lack adequate accuracy to provide the necessary training efficacy of simulators. Methods and findings: This work explores the effect of the "state" of the tissue testing status on liver and peritoneal tissue by using a customized handheld grasper to measure the mechanical responses of representative porcine (Sus domesticus) tissues in n = 5 animals across five test conditions: in vivo, post mortem (in-situ), ex vivo (immediately removed from fresh porcine cadaver), post-refrigeration, and post-freeze-thaw cycle spanning up to 72 hours after death. No statistically significant difference was observed in the mechanical responses due to grasping between in vivo and post-freeze conditions for porcine liver and peritoneum tissue samples (p = 0.05 for derived stiffness at grasping force values F = 5N and 6.5N). Furthermore, variance between in vivo and post-freeze conditions within each animal, was comparable to the variance of the in vivo condition between animals. Conclusions: Results of this study further validate the use of preserved tissue in the design of medical simulators via observing tissue mechanical responses of post-freeze tissue comparable to in vivo tissue. Therefore, the use of thawed preserved tissue for the further study and emulation of mechanical perturbation of the liver and peritoneum can be considered. Further work in this area should investigate these trends further, particularly in regard to other tissues and the potential effects varying preservation methods may yield. [ABSTRACT FROM AUTHOR]

This cross-sectional study compared optical coherence tomography angiography (OCTA) parameters between older Black and White adults with systemic comorbidities in an effort to further understand racial differences in the retinal microvasculature. We analyzed vessel density at the superficial (SCP), intermediate (ICP), and deep capillary plexuses (DCP), foveal avascular zone (FAZ) parameters, and blood flow area (BFA) at the choriocapillaris. We used a mixed-effects linear regression model, controlling for hypertension and two eyes from the same subject, to compare OCTA parameters. Black subjects had lower foveal vessel density at the SCP and ICP, while no differences were observed at the parafovea or 3x3 mm macular area of any capillary layer. Black subjects had greater FAZ area, perimeter, and FD-300, a measurement of vessel density in a 300 μm wide ring around the FAZ. Black subjects also had lower BFA at the choriocapillaris. Within a cohort of subjects without hypertension, these differences remained statistically significant, with the exception of foveal vessel density at the SCP and foveal BFA of the choriocapillaris. These findings suggest that normative databases of OCTA parameters must strive to be diverse in nature to adequately capture differences across patient populations. Further study is required to understand if baseline differences in OCTA parameters contribute to epidemiological disparities in ocular diseases. [ABSTRACT FROM AUTHOR]

Demixing signals in transcranial videos of neuronal calcium flux across the cerebral hemispheres is a key step before mapping features of cortical organization. Here we demonstrate that independent component analysis can optimally recover neural signal content in widefield recordings of neuronal cortical calcium dynamics captured at a minimum sampling rate of 1.5×106 pixels per one-hundred millisecond frame for seventeen minutes with a magnification ratio of 1:1. We show that a set of spatial and temporal metrics obtained from the components can be used to build a random forest classifier, which separates neural activity and artifact components automatically at human performance. Using this data, we establish functional segmentation of the mouse cortex to provide a map of ~115 domains per hemisphere, in which extracted time courses maximally represent the underlying signal in each recording. Domain maps revealed substantial regional motifs, with higher order cortical regions presenting large, eccentric domains compared with smaller, more circular ones in primary sensory areas. This workflow of data-driven video decomposition and machine classification of signal sources can greatly enhance high quality mapping of complex cerebral dynamics. Author summary: Researchers have been able to record from a large population of neurons across the cortex using calcium indicators in awake, behaving mice; however, many confounding neuronal signals (ie. neurons from different depths) or tissue dynamics (ie. blood flow) influence these recordings. Our custom pipeline utilizes algorithms to identify distinct signals and spatially segment the signal sources into components that can then be characterized. From these components, we show that neuronal signals are distinct from non-neuronal artifacts; further, we are able to remove the artifacts to clean the neuronal signal. The remaining components are spatial segments of the neuronal signals; we use them to create a data-driven map of functional units, which we call domains. We characterize these domains between subsequent recordings and show that they are highly similar within the same animal, given a long enough recording. This data-driven map can provide information about the limitations one can make from the specific recordings. Furthermore, it will enhance our ability to understand the effects on functional maps from animals that do not have a reference map, including mapping functional changes in development, differences between genetically mutated or varying strains of mice. [ABSTRACT FROM AUTHOR]

Laser therapeutic applications, such as the use of high energy lasers (HILT), are widely used in physical therapy, but basic studies on the mechanisms of action of HILT on tendinous/ligamentous tissue are largely lacking. The aim of this study was to investigate microcirculatory changes of the patellar tendon by HILT. 21 healthy volunteers were included in the present investigation. Before and after HILT, as well as 10 minutes later, the microcirculation was measured by noninvasive laser Doppler and white light spectroscopy (O2C device). Tissue temperature was recorded at the measurement time points using thermography. Blood flow increased significantly by 86.38 arbitrary units (AU; p < 0.001) after the intervention and by 25.76 AU (p < 0.001) at follow-up. Oxygen saturation increased by 20.14% (p < 0.001) and 13.48%, respectively (p < 0.001), whereas relative hemoglobin decreased by 6.67 AU and 7.90 AU, respectively. Tendon temperature increased by 9.45° and 1.94° Celsius, respectively. Acceleration of blood flow by improving the flow properties of erythrocytes and platelets may have caused the results. HILT could be a therapeutic perspective for tendon pathologies with impaired microcirculation, although further studies are needed to validate the experimental results. [ABSTRACT FROM AUTHOR]

Purpose: To determine the blood flow pattern of eyes before the development of type 3 macular neovascularization (MNV) by optical coherence tomography angiography (OCTA). Study design: Retrospective study. Subjects: Ten eyes of 10 patients (4 men and 6 women, mean age 80.4 years) diagnosed with unilateral Type 3 MNV who developed type 3 MNV in the fellow normal eye during the follow-up period were studied. Methods: The time of onset of type 3 MNV was defined as the time when retinal exudation was detected by OCT. The blood flow of a 3 x 3 mm or 6 x 6 mm area in the deep capillary plexus (DCP) and the outer retina (OR) including the central fovea were assessed at the onset and at 6 months prior to the onset of the type 3 MNV. Results: All MNVs that developed in the fellow eye were type 3 MNVs. Abnormal blood flow signals in the MNVs were detected in the DCP and/or the OR by OCTA at the onset in all cases. Eight of the 10 eyes had OCTA recordings prior to the development of the MNV: 3 eyes had non-exudative MNVs only in the DCP and 5 eyes had non-exudative MNVs in the DCP and OR. The exudation appeared on the average 3.5 months after the non-exudative MNV was observed in the fellow eyes. Conclusions: A non-exudative MNV in the fellow eyes can already be observed by OCTA in eyes before the onset of the exudation. Knowing this will help clinicians not only how to treat these eyes appropriately but will also help in determining the origin of the MNV. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the association of systemic oxidative stress markers and optic nerve head (ONH) blood flow in normal-tension glaucoma (NTG) patients, as well as sex differences in this association. Methods: This was a cross-sectional study of 235 eyes with NTG of 134 patients (56 male, 78 female; mean age, 60.9±14.1 years). Laser speckle flowgraphy (LSFG) was used to measure ONH blood flow (mean blur rate in the tissue area of the ONH; MBR-T) and LSFG pulse-waveform parameters, including flow acceleration index in the tissue area of the ONH (FAI-T). Oxidative stress markers, diacron-reactive oxygen metabolites (d-ROMs), and biological antioxidant potential (BAP) were measured with a free radical elective evaluator. Spearman's rank correlation test and a multivariate linear mixed-effect model were used to investigate factors associated with ONH blood flow. Results: MBR-T was significantly correlated with age (rs = -0.28, p < 0.001), mean arterial pressure (rs = -0.20, p = 0.002), intraocular pressure (rs = 0.24, p < 0.001), peripapillary retinal nerve fiber layer thickness (rs = 0.62, p < 0.001), and disc area (rs = -0.26, p < 0.001), but not with serum d-ROM level. Separate analyses of the subjects divided by sex showed that BAP was positively correlated to MBR-T (rs = 0.21, p = 0.036) and FAI-T (rs = 0.36, p < 0.001) only in male subjects. Similarly, BAP was significantly associated with MBR-T (β = 0.25, p = 0.026) and FAI-T (β = 0.37, p < 0.001) in male subjects in a multivariate linear mixed-effect model. Conclusion: A lower serum antioxidant level, as indicated by BAP, was associated with reduced ONH blood flow only in male NTG patients. Our findings suggest that there are sex differences in the involvement of oxidative stress in the pathogenesis of reduced ocular blood flow in NTG. [ABSTRACT FROM AUTHOR]

This paper presents a numerical analysis of blood flow in a diseased vessel within the presence of an external magnetic field. The blood flow was considered to be incompressible and fully developed, in that the non-Newtonian nature of the fluid was characterised as a generalised power law model for shear-thinning, Newtonian, and shear-thickening fluids. The impact of a transverse directed external magnetic field on blood flow through a stenosed bifurcated artery was investigated. The arterial geometry was considered as a bifurcated channel with overlapping shaped stenosis. The problem was treated mathematically using the Galerkin Least-Squares (GLS) method. The implementation of this numerical method managed to overcome the numerical instability faced by the classical Galerkin technique when adopted to a highly viscous flow. The benefit of GLS in circumventing the Ladyzhenskaya-Babuška-Brezzi (LBB) condition was utilized by evaluating both the velocity and pressure components at corner nodes of a unstructured triangular element. The non-linearity that emerged from the convective terms was then treated using the Newton-Raphson method, while the numerical integrals were computed using a Gaussian quadrature rule with six quadrature points. The findings obtained from this study were then compared with available results from the literature as well as Comsol multiphysics software to verify the accuracy and validity of the numerical algorithms. It was found that the application of magnetic field was able to overcome flow reversal by 39% for a shear-thinning fluid, 26% for a Newtonian fluid, and 27% for a shear-thickening fluid. The negative pressure and steep wall shear stress which occurs at the extremities of an overlapping stenosis throat were diminished by rise in magnetic intensity. This prevented thrombosis occurrence and produced a uniform calm flow. [ABSTRACT FROM AUTHOR]

Introduction: The newly introduced Cellular Oxygen METabolism (COMET®) monitor enables the measurement of mitochondrial oxygen tension (mitoPO2) using the protoporphyrin IX triplet state lifetime technique (PpIX-TSLT). This study aims to investigate the feasibility and applicability of the COMET® measurements in the operating theatre and study the behavior of the new parameter mitoPO2 during stable operating conditions. Methods: In this observational study mitochondrial oxygenation was measured in 20 patients during neurosurgical procedures using the COMET® device. Tissue oxygenation and local blood flow were measured by the Oxygen to See (O2C). Primary outcomes included mitoPO2, skin temperature, mean arterial blood pressure, local blood flow and tissue oxygenation. Results: All patients remained hemodynamically stable during surgery. Mean baseline mitoPO2 was 60 ± 19 mmHg (mean ± SD) and mean mitoPO2 remained between 40–60 mmHg during surgery, but tended to decrease over time in line with increasing skin temperature. Conclusion: This study presents the feasibility of mitochondrial oxygenation measurements as measured by the COMET® monitor in the operating theatre and shows the parameter mitoPO2 to behave in a stable and predictable way in the absence of notable hemodynamic alterations. The results provide a solid base for further research into the added value of mitochondrial oxygenation measurements in the perioperative trajectory. [ABSTRACT FROM AUTHOR]

Short bouts of occlusion of blood flow can induce a preconditioning response that reduces subsequent damage from longer periods of ischemia. It has been shown that ischemic preconditioning (IPC) can be elicited remotely (RIPC) through limitation of blood flow and as recently described via only pain sensation. Non-obstructive banding (NOB) through the donning of tefillin (a box with sacred texts attached to a leather strap that is traditionally bound to the non-dominant arm of Jewish adults during morning prayers) has been shown to elicit an RIPC response at least partially through pain sensation. This study evaluated the effects of NOB on heart rate variability (HRV) dependent factors that are known to be affected by various RIPC stimuli. We recruited 30 healthy subjects and subjected them to NOB versus control and found various HRV markers associated with RIPC to be changed in the NOB group. This finding provides further evidence that tefillin, likely through NOB induced RIPC changes, may still be a viable clinical pathway to prevent and decrease the morbidity associated with ischemic events. [ABSTRACT FROM AUTHOR]

Neurons regulate the activity of blood vessels through the neurovascular coupling (NVC). A detailed understanding of the NVC is critical for understanding data from functional imaging techniques of the brain. Many aspects of the NVC have been studied both experimentally and using mathematical models; various combinations of blood volume and flow, local field potential (LFP), hemoglobin level, blood oxygenation level-dependent response (BOLD), and optogenetics have been measured and modeled in rodents, primates, or humans. However, these data have not been brought together into a unified quantitative model. We now present a mathematical model that describes all such data types and that preserves mechanistic behaviors between experiments. For instance, from modeling of optogenetics and microscopy data in mice, we learn cell-specific contributions; the first rapid dilation in the vascular response is caused by NO-interneurons, the main part of the dilation during longer stimuli is caused by pyramidal neurons, and the post-peak undershoot is caused by NPY-interneurons. These insights are translated and preserved in all subsequent analyses, together with other insights regarding hemoglobin dynamics and the LFP/BOLD-interplay, obtained from other experiments on rodents and primates. The model can predict independent validation-data not used for training. By bringing together data with complementary information from different species, we both understand each dataset better, and have a basis for a new type of integrative analysis of human data. Author summary: The neurovascular coupling (NVC) is the basis for functional magnetic resonance imaging (fMRI), since the NVC connects neural activity with the observed hemodynamic changes. This connection is highly complex, which warrants a model-based analysis. However, even though NVC-data from several species and many relevant variables are available, a mathematical model for all these data is still missing. Herein, we combine experimental data from mice, monkeys, and humans, to develop a comprehensive model for NVC. Importantly, our new approach to modelling propagates the qualitative insights from each species to the subsequent analysis of data from other species. In mice, we unravel the role of different neuronal sub-populations when producing a biphasic response to prolonged sensory stimulations. The qualitative role of these sub-populations is preserved when analysing primate data. These primate data add knowledge on the interplay between local field potential (LFP) and vascular changes. Similarly, these pre-clinical qualitative insights are propagated to analysis of human data, which contain additional insights regarding blood flow and volume in arterioles and venules, during both positive and negative responses. This work illustrates how data with complementary information from different species can be combined, so that qualitative insights from animals are preserved in the quantitative analysis of human data. [ABSTRACT FROM AUTHOR]

This study assessed the acute effect of adding blood flow restriction (BFR) to quad sets on muscle-cross sectional area (mCSA), muscle thickness (MT), echo intensity (EI), and subcutaneous fat-normalized EI (EINORM) of the superficial quadriceps muscles. Twelve males and 12 females (mean±SD; age (yrs): 21.4±2.9; stature (m): 1.76±0.1; body mass (kg): 77.7±2.9) performed 70 repetitions (one set of 30, three sets of 15 repetitions) of bodyweight quad sets separately on each leg, with or without BFR (CON) applied. Rating of perceived exertion was recorded following each set. Panoramic ultrasound images of the vastus lateralis (VL), vastus medialis (VM), and rectus femoris (RF) were captured prior to (PRE), immediately after (IMM-POST), 30- (30-POST), and 60-minutes after (60-POST) after exercise. Sex x condition x time repeated measures ANOVAs assessed differences at p<0.05 for each muscle and dependent variable separately. Although males had larger VM and VL mCSA and VL MT (p<0.05), there were no acute changes from PRE to IMM-POST (p>0.05). There was a 3-way interaction in VL mCSA (p = 0.025) which indicated BFR was greater than CON at IMM-POST by 7.6% (p = 0.019) for males only. Females had greater EI in the VM and VL than males (p<0.05), yet males had greater EINORM for each muscle (p>0.05) and EINORM did not change over time or treatment (p>0.05). The lack of changes in MT, EI, and EINORM indicate that unloaded quad sets do not provide a stimulus to promote fluid shifts or acute changes in muscle size with the exception of IMM-POST in the VL for males. Future research should attempt to elucidate the acute muscular responses of BFR application for lightly loaded rehabilitation exercises in the clinical populations for which they are prescribed. [ABSTRACT FROM AUTHOR]

The neurovascular and neurometabolic couplings (NVC and NMC) connect cerebral activity, blood flow, and metabolism. This interconnection is used in for instance functional imaging, which analyses the blood-oxygen-dependent (BOLD) signal. The mechanisms underlying the NVC are complex, which warrants a model-based analysis of data. We have previously developed a mechanistically detailed model for the NVC, and others have proposed detailed models for cerebral metabolism. However, existing metabolic models are still not fully utilizing available magnetic resonance spectroscopy (MRS) data and are not connected to detailed models for NVC. Therefore, we herein present a new model that integrates mechanistic modelling of both MRS and BOLD data. The metabolic model covers central metabolism, using a minimal set of interactions, and can describe time-series data for glucose, lactate, aspartate, and glutamate, measured after visual stimuli. Statistical tests confirm that the model can describe both estimation data and predict independent validation data, not used for model training. The interconnected NVC model can simultaneously describe BOLD data and can be used to predict expected metabolic responses in experiments where metabolism has not been measured. This model is a step towards a useful and mechanistically detailed model for cerebral blood flow and metabolism, with potential applications in both basic research and clinical applications. Author summary: The neurovascular and neurometabolic couplings are highly central for several clinical imaging techniques since these frequently use blood oxygenation (the BOLD signal) as a proxy for neuronal activity. This relationship is described by the highly complex neurovascular and neurometabolic couplings, which describe the balancing between increased metabolic demand and blood flow, and which involve several cell types and regulatory systems, which all change dynamically over time. While there are previous works that describe the neurovascular coupling in detail, neither we nor others have developed connections to corresponding mechanistic models for the third aspect, the metabolic aspect. Furthermore, magnetic resonance spectroscopy (MRS) data for such modelling readily is available. In this paper we present a minimal mechanistic model that can describe the metabolic response to visual stimuli. The model is trained to describe experimental data for the relative change in metabolic concentrations of several metabolites in the visual cortex during stimulation. The model is also validated against independent validation data, that was not used for model training. Finally, we also connect this metabolic model to a detailed mechanistic model of the neurovascular coupling. Showing that the model can describe both the metabolic response and a neurovascular response simultaneously. [ABSTRACT FROM AUTHOR]

Pulsatile arterial blood flow plays an important role in vascular system mechanobiology, especially in the study of mechanisms of pathology. Limitations in cost, time, sample size, and control across current in-vitro and in-vivo methods limit future exploration of novel treatments. Presented is the verification of a novel reciprocating positive displacement pump aimed at resolving these issues through the simulation of human ocular, human fingertip and skin surface, human cerebral, and rodent spleen organ systems. A range of pulsatile amplitudes, frequencies, and flow rates were simulated using pumps made of 3D printed parts incorporating a tubing system, check valve and proprietary software. Volumetric analysis of 430 total readings across a flow range of 0.025ml/min to 16ml/min determined that the pump had a mean absolute error and mean relative error of 0.041 ml/min and 1.385%, respectively. Linear regression analysis compared to expected flow rate across the full flow range yielded an R2 of 0.9996. Waveform analysis indicated that the pump could recreate accurate beat frequency for flow ranges above 0.06ml/min at 70BPM. The verification of accurate pump output opens avenues for the development of novel long-term in-vitro benchtop models capable of looking at fluid flow scenarios previously unfeasible, including low volume-high shear rate pulsatile flow. [ABSTRACT FROM AUTHOR]

Background: Obstructive sleep apnea (OSA) has been associated with incidence of cardiovascular disease and with nocturnal angina, but evidence of a link with coronary atherosclerosis and myocardial ischemia is limited and previous studies may have been affected by selection bias or unmeasured confounding factors. Methods: We performed overnight polysomnography in 178 older male twins. The Apnea/Hypopnea Index (AHI) was calculated to assess OSA from the overnight sleep evaluation. AHI ≥15 was used as indicator of moderate/severe OSA. The following day, twins underwent myocardial perfusion imaging with [82Rb]-chloride positron emission tomography. Quantitative and semiquantitative measures of myocardial perfusion and absolute myocardial blood flow were obtained. Results: The mean age was 68 years and 40% of the sample had an AHI≥15, which indicates moderate to severe OSA. Abnormal myocardial perfusion, both with stress and at rest, was more common in twins with elevated AHI. After adjusting for clinical, lifestyle and behavioral factors, and previous history of cardiovascular disease, twins with AHI ≥15 had 3.6 higher odds (95% CI, 1.5–8.9) of an abnormal total severity score, defined as a score ≥100, and for each 5-point increment in AHI, the odds of abnormality increased by 20% (95% CI, 7%-34%). Twin pairs where both twins had OSA exhibited the greatest risk. There were no differences in measures of ischemia and absolute myocardial blood flow and flow reserve by AHI status. Conclusions: OSA is associated with myocardial perfusion abnormalities that suggest prior subclinical myocardial scarring or infarction. Early environmental factors that affect both twins equally may play a role and should be further explored. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the choriocapillaris changes associated with pachychoroid pigment epitheliopathy (PPE) in comparison with healthy eyes. Methods: Nine 3 × 3 mm macular optical coherence tomography angiography images were acquired in patients with PPE and age-matched healthy participants. Multiple en face image averaging of the choriocapillaris was binarized for quantitative image analysis of the flow voids. In PPE eyes, we evaluated the presence of pachyvessels and the association between the location of the choriocapillaris flow deficit and pachyvessels. Results: Thirty-two eyes with PPE and 30 eyes of healthy participants were included. In PPE eyes, the mean total area (1.16 ± 0.18 vs. 0.91 ± 0.16, p < 0.001) and average size of the flow voids (790 ± 144 vs. 520 ± 138; p < 0.001) were significantly larger than those in control eyes. Composite images of the choriocapillaris and choroid showed choriocapillaris flow deficits just above and outside the pachyvessels. The mean proportion of the flow void area overlying the pachyvessels against the whole flow void area of the choriocapillaris was 21.3% ± 10.2% (9.38%-44.42%) in PPE eyes. Conclusions: In PPE eyes, the blood flow area of the choriocapillaris decreased diffusely within the macular area compared to control eyes, and the choriocapillaris flow deficit was not necessarily related to pachyvessel location. [ABSTRACT FROM AUTHOR]

Busana et al. (doi.org/10.1152/japplphysiol.00871.2020) published 5 patients with COVID-19 in whom the fraction of non-aerated lung tissue had been quantified by computed tomography. They assumed that shunt flow fraction was proportional to the non-aerated lung fraction, and, by randomly generating 106 different bimodal distributions for the ventilation-perfusion (V˙/Q˙) ratios in the lung, specified as sets of paired values { V˙i,Q˙i }, sought to identify as solutions those that generated the observed arterial partial pressures of CO2 and O2 (PaCO2 and PaO2). Our study sought to develop a direct method of calculation to replace the approach of randomly generating different distributions, and so provide more accurate solutions that were within the measurement error of the blood-gas data. For the one patient in whom Busana et al. did not find solutions, we demonstrated that the assumed shunt flow fraction led to a non-shunt blood flow that was too low to support the required gas exchange. For the other four patients, we found precise solutions (prediction error < 1x10-3 mmHg for both PaCO2 and PaO2), with distributions qualitatively similar to those of Busana et al. These distributions were extremely wide and unlikely to be physically realisable, because they predict the maintenance of very large concentration gradients in regions of the lung where convection is slow. We consider that these wide distributions arise because the assumed value for shunt flow is too low in these patients, and we discuss possible reasons why the assumption relating to shunt flow fraction may break down in COVID-19 pneumonia. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is a systemic vascular disease of the legs that results in a blockage of blood flow from the heart to the lower extremities. Now one of the most common causes of mortality in the U.S., the first line of therapy for PAD is to mechanically open the blockages using balloon angioplasty. Coating the balloons with antiproliferative agents can potentially reduce vessel re-narrowing, or restenosis after surgical intervention, but current drug-coated balloons releasing chemotherapy agents like paclitaxel have in some cases shown increased mortality long-term. Our aim was to design a novel drug-coated balloon using a polymeric nanodelivery system for a sustained release of polyphenols that reduce restenosis but with reduced toxicity compared to chemotherapy agents. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles with entrapped quercetin, a dimethoxy quercetin (rhamnazin), as well as quercetin covalently attached to PLGA, were developed. Balloon catheters were coated with polymeric nanoparticles using an ultrasonic method, and nanoparticle characteristics, drug loading, coating uniformity and drug release were determined. The adhesion of nanoparticles to vascular smooth muscle cells and the antiproliferative effect of nano-delivered polyphenols were also assessed. Of the nanoparticle systems tested, those with covalently attached quercetin provided the most sustained release over a 6-day period. Although these particles adhered to cells to a smaller extent compared to other nanoparticle formulations, their attachment was resistant to washing. These particles also exhibited the greatest anti-proliferative effect. In addition, their attachment was not altered when the cells were grown in calcifying conditions, and in PAD tissue calcification is typically a condition that impedes drug delivery. Moreover, the ultrasonic coating method generated a uniform balloon coating. The polymeric nanoparticle system with covalently attached quercetin developed herein is thus proposed as a promising platform to reduce restenosis post-angioplasty. [ABSTRACT FROM AUTHOR]

Objective: Measures of Doppler blood flow velocity profiles are an integral part of monitoring fetal well-being during pregnancy. These examinations are performed at different times of the day and at different maternal meal states. In uncomplicated pregnancies, we assessed the effect of a standardized maternal meal on middle cerebral artery (MCA) and umbilical artery (UA) Doppler blood flow velocity pulsatility indices (PIs) and MCA peak systolic velocity (PSV). Methods: In this prospective single-blinded crossover study 25 healthy women were examined at 36 weeks of pregnancy. The first examination was performed in the morning following overnight fast, and repeated after extended fast (state A), and after a standard breakfast meal (state B). Results: Irrespective of maternal prandial status, the MCA-PI values were lower in the 2nd compared to the 1st examination (-0.187; p = 0.071, and -0.113; p = 0.099, state A and B, respectively). Compared to the values in the 1st examination, the UA-PI values, were higher after extended fast (0.014; p = 0.436), and lower post-prandially (-0.036; p = 0.070). The difference (state B minus state A) between the meal states were not significant (0.074; p = 0.487 and -0.050; p = 0.058, for MCA-PI and UA-PI, respectively). Adjusting for the possible influence of fetal heart rate on MCA-PI and UA-PI, the differences between meal states remained non-significant (p = 0.179, p = 0.064, respectively). The MCA-PSV values increased after the meal (6.812; p = 0.035), whereas no increase was observed following extended fast (0.140; p = 0.951). The difference in MCA-PSV values between the two meal states was not significant (6.672; p = 0.055). Conclusion: Our results demonstrate possible diurnal variations in MCA-PI and UA-PI, with and without adjustment for fetal heart rate, that seem to be unaffected by maternal meal intake in healthy pregnancies. [ABSTRACT FROM AUTHOR]

The microvasculature plays a key role in oxygen transport in the mammalian brain. Despite the close coupling between cerebral vascular geometry and local oxygen demand, recent experiments have reported that microvascular occlusions can lead to unexpected distant tissue hypoxia and infarction. To better understand the spatial correlation between the hypoxic regions and the occlusion sites, we used both in vivo experiments and in silico simulations to investigate the effects of occlusions in cerebral penetrating arteriole trees on tissue hypoxia. In a rat model of microembolisation, 25 μm microspheres were injected through the carotid artery to occlude penetrating arterioles. In representative models of human cortical columns, the penetrating arterioles were occluded by simulating the transport of microspheres of the same size and the oxygen transport was simulated using a Green's function method. The locations of microspheres and hypoxic regions were segmented, and two novel distance analyses were implemented to study their spatial correlation. The distant hypoxic regions were found to be present in both experiments and simulations, and mainly due to the hypoperfusion in the region downstream of the occlusion site. Furthermore, a reasonable agreement for the spatial correlation between hypoxic regions and occlusion sites is shown between experiments and simulations, which indicates the good applicability of in silico models in understanding the response of cerebral blood flow and oxygen transport to microemboli. Author summary: The brain function depends on the continuous oxygen supply through the bloodstream inside the microvasculature. Occlusions in the microvascular network will disturb the oxygen delivery in the brain and result in hypoxic tissues that can lead to infarction and cognitive dysfunction. To aid in understanding the formation of hypoxic tissues caused by micro-occlusions in the penetrating arteriole trees, we use rodent experiments and simulations of human vascular networks to study the spatial correlations between the hypoxic regions and the occlusion locations. Our results suggest that hypoxic regions can form distally from the occlusion site, which agrees with the previous observations in the rat brain. These distant hypoxic regions are primarily due to the lack of blood flow in the brain tissues downstream of the occlusion. Moreover, a reasonable agreement of the spatial relationship is found between the experiments and the simulations, which indicates the applicability of in silico models to study the effects of microemboli on the brain tissue. [ABSTRACT FROM AUTHOR]

Collateral circulation in the circle of Willis (CoW), closely associated with disease mechanisms and treatment outcomes, can be effectively investigated using one-dimensional–zero-dimensional hemodynamic simulations. As the entire cardiovascular system is considered in the simulation, it captures the systemic effects of local arterial changes, thus reproducing collateral circulation that reflects biological phenomena. The simulation facilitates rapid assessment of clinically relevant hemodynamic quantities under patient-specific conditions by incorporating clinical data. During patient-specific simulations, the impact of clinical data uncertainty on the simulated quantities should be quantified to obtain reliable results. However, as uncertainty quantification (UQ) is time-consuming and computationally expensive, its implementation in time-sensitive clinical applications is considered impractical. Therefore, we constructed a surrogate model based on machine learning using simulation data. The model accurately predicts the flow rate and pressure in the CoW in a few milliseconds. This reduced computation time enables the UQ execution with 100 000 predictions in a few minutes on a single CPU core and in less than a minute on a GPU. We performed UQ to predict the risk of cerebral hyperperfusion (CH), a life-threatening condition that can occur after carotid artery stenosis surgery if collateral circulation fails to function appropriately. We predicted the statistics of the postoperative flow rate increase in the CoW, which is a measure of CH, considering the uncertainties of arterial diameters, stenosis parameters, and flow rates measured using the patients' clinical data. A sensitivity analysis was performed to clarify the impact of each uncertain parameter on the flow rate increase. Results indicated that CH occurred when two conditions were satisfied simultaneously: severe stenosis and when arteries of small diameter serve as the collateral pathway to the cerebral artery on the stenosis side. These findings elucidate the biological aspects of cerebral circulation in terms of the relationship between collateral flow and CH. Author summary: Cerebral arteries generate a ring-like network that provides alternative routes for blood supply in the case of carotid artery stenosis. This collateral circulation is closely associated with the potential risk of stroke and treatment outcomes in patients with stenosis. In this study, we propose a method to elucidate the cerebral circulation of individual patients using a blood flow simulation that incorporates the patient's clinical data. A key feature of our approach is its capability to obtain the probability of the different outputs using simulation, considering the uncertainty of patient conditions. Although this capability is essential for obtaining reliable results, the process is time-consuming and requires numerous computer resources. We solved this problem by combining the blood flow simulation with machine learning to perform predictions 43 000 times faster than conventional simulations. We applied the proposed method to predict cerebral circulation following surgery in three patients with stenosis and verified that the method can assess the surgical risk almost in real-time, even on a desktop computer. Additionally, extensive prediction results (100 000 cases for each patient) obtained using this method clarify the relationship between collateral circulation and life-threatening surgical outcomes. [ABSTRACT FROM AUTHOR]

Arterial stenosis is a common cardiovascular disease that restricts blood flow. A stenotic blood vessel creates tangent stress pressure, which lessens the arterial side and causes an aneurysm. The primary purpose of this study is to investigate blood flowing via an inclination pipe with stricture and expansion after stricture (widening) underneath the influence of a constant incompressible Casson liquid flowing with the magnetism field. The relations for surface shearing stress, pressure drop, flow resistance, and velocity are calculated analytically by applying a mild stenosis approximation. The effect of different physical characteristics on liquid impedance to flowing, velocity, and surface shearing stress are studied. With a non-Newtonian aspect of the Casson liquid, the surface shearing stress declines, and an impedance upturn. Side resistivity and shear-stress increase with the elevations of stricture, whilst together decreasing with a dilatation height. [ABSTRACT FROM AUTHOR]