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Abstract: Obesity is a growing epidemic in the United States (US). Obesity has been recognized as a modifiable risk factor for many diverse diseases including diabetes, cardiovascular disease and cancer burden. Common contributors to obesity include a high fat diet, smoking and physical inactivity. Systemic effects of obesity include increased micro-inflammatory molecules such as nuclear factor kappa B (NF-κB) that influence the both endothelial and epithelial layers as well as the supportive stroma. An emerging risk factor for micro-inflammation also includes periodontal disease. These pro-inflammatory states are hypothesized to contribute to diabetes as well as cardiovascular disease and cancer through the direct activation of NF-κB. Therefore, a comprehensive health care strategy would include reduction of diabetes, cardiovascular and cancer risk through the decrease in micro-inflammation. [Copyright &y& Elsevier]

Motion is vital for life. Currently, the clinical assessment of motion abnormalities is largely qualitative. We previously developed methods to quantitatively assess motion using visual detection systems (around-body) and stretchable electronic sensors (on-body). Here we compare the efficacy of these methods across predefined motions, hypothesizing that the around-body system detects motion with similar accuracy as on-body sensors. Six human volunteers performed six defined motions covering three excursion lengths, small, medium, and large, which were analyzed via both around-body visual marker detection (MoCa version 1.0) and on-body stretchable electronic sensors (BioStamp version 1.0). Data from each system was compared as to the extent of trackability and comparative efficacy between systems. Both systems successfully detected motions, allowing quantitative analysis. Angular displacement between systems had the highest agreement efficiency for the bicep curl and body lean motion, with 73.24% and 65.35%, respectively. The finger pinch motion had an agreement efficiency of 36.71% and chest abduction/adduction had 45.55%. Shoulder abduction/adduction and shoulder flexion/extension motions had the lowest agreement efficiencies with 24.49% and 26.28%, respectively. MoCa was comparable to BioStamp in terms of angular displacement, though velocity and linear speed output could benefit from additional processing. Our findings demonstrate comparable efficacy for non-contact motion detection to that of on-body sensor detection, and offers insight as to the best system selection for specific clinical uses based on the use-case of the desired motion being analyzed.

Background:  Mechanical circulatory support (MCS) is a mainstay of therapy for advanced and end-stage heart failure. Accompanied by systemic anticoagulation, contemporary MCS has become less thrombogenic, with bleeding complications emerging as a major cause of readmission and 1-year mortality. Shear-mediated platelet dysfunction and thrombocytopenia of undefined etiology are primary drivers of MCS-related bleeding. Recently, it has been demonstrated that deprivation of platelet surface glycosylation is associated with the decline of hemostatic function, microvesiculation, and premature apoptosis. We test the hypothesis that shear stress induces remodeling of platelet surface glycosylation via upregulation of glycosidase activity, thus facilitating platelet count decline and intense microvesiculation., Methods:  Human gel-filtered platelets were exposed to continuous shear stress in vitro. Platelets and platelet-derived microparticles (PDMPs) were quantified via flow cytometry using size standard fluorescent nanobeads. Platelet surface glycosylation and NEU1 expression were evaluated using lectin- or immune-staining and multicolor flow cytometry; lectin blotting was utilized to verify glycosylation of individual glycoproteins. Platelet neuraminidase, galactosidase, hexosaminidase, and mannosidase activities were quantified using 4-methylumbelliferone-based fluorogenic substrates., Results:  We demonstrate that shear stress promotes selective remodeling of platelet glycosylation via downregulation of 2,6-sialylation, terminal galactose, and mannose, while 2,3-sialylation remains largely unchanged. Shear-mediated deglycosylation is partially attenuated by neuraminidase inhibitors, strongly suggesting the involvement of platelet neuraminidase in observed phenomena. Shear stress increases platelet NEU1 surface expression and potentiates generation of numerous NEU1+ PDMPs. Platelets exhibit high basal hexosaminidase and mannosidase activities; basal activities of platelet neuraminidase and galactosidase are rather low and are significantly upregulated by shear stress. Shear stress of increased magnitude and duration promotes an incremental decline of platelet count and immense microvesiculation, both being further exacerbated by neuraminidase and partially attenuated by neuraminidase inhibition., Conclusion:  Our data indicate that shear stress accumulation, consistent with supraphysiologic conditions of device-supported circulation, promotes remodeling of platelet glycosylation via selective upregulation of platelet glycosidase activity. Shear-mediated platelet deglycosylation is associated with platelet count drop and increased microvesiculation, thus offering a direct link between deglycosylation and thrombocytopenia observed in device-supported patients. Based on our findings, we propose a panel of molecular markers to be used for reliable detection of shear-mediated platelet deglycosylation in MCS., Competing Interests: None declared., (Thieme. All rights reserved.)

Introduction: Obstructive sleep apnea (OSA) and loud snoring are conditions with increased cardiovascular risk and notably an association with stroke. Central in stroke are thrombosis and thromboembolism, all related to and initiaing with platelet activation. Platelet activation in OSA has been felt to be driven by biochemical and inflammatory means, including intermittent catecholamine exposure and transient hypoxia. We hypothesized that snore-associated acoustic vibration (SAAV) is an activator of platelets that synergizes with catecholamines and hypoxia to further amplify platelet activation. Methods: Gel-filtered human platelets were exposed to snoring utilizing a designed vibro-acoustic exposure device, varying the time and intensity of exposure and frequency content. Platelet activation was assessed via thrombin generation using the Platelet Activity State assay and scanning electron microscopy. Comparative activation induced by epinephrine and hypoxia were assessed individually as well as additively with SAAV, as well as the inhibitory effect of aspirin. Results: We demonstrate that snore-associated acoustic vibration is an independent activator of platelets, which is dependent upon the dose of exposure, i.e., intensity x time. In snoring, acoustic vibrations associated with low-frequency sound content (200 Hz) are more activating than those associated with high frequencies (900 Hz) (53.05% vs. 22.08%, p = 0.001). Furthermore, SAAV is additive to both catecholamines and hypoxia-mediated activation, inducing synergistic activation. Finally, aspirin, a known inhibitor of platelet activation, has no significant effect in limiting SAAV platelet activation. Conclusion: Snore-associated acoustic vibration is a mechanical means of platelet activation, which may drive prothrombosis and thrombotic risk clinically observed in loud snoring and OSA.

Cardiovascular therapeutic devices (CTDs) remain limited by thrombotic adverse events. Current antithrombotic agents limit thrombosis partially, often adding to bleeding. The Impella® blood pump utilizes heparin in 5% dextrose (D5W) as an internal purge to limit thrombosis. While effective, exogenous heparin often complicates overall anticoagulation management, increasing bleeding tendency. Recent clinical studies suggest sodium bicarbonate (bicarb) may be an effective alternative to heparin for local anti-thrombosis. We examined the effect of sodium bicarbonate on human platelet morphology and function to better understand its translational utility. Human platelets were incubated (60:40) with D5W + 25 mEq/L, 50 mEq/L, or 100 mEq/L sodium bicarbonate versus D5W or D5W + Heparin 50 U/mL as controls. pH of platelet-bicarbonate solutions mixtures was measured. Platelet morphology was examined via transmission electron microscopy; activation assessed via P-selectin expression, phosphatidylserine exposure and thrombin generation; and aggregation with TRAP-6, calcium ionophore, ADP and collagen quantified; adhesion to glass measured via fluorescence microscopy. Sodium bicarbonate did not alter platelet morphology but did significantly inhibit activation, aggregation, and adhesion. Phosphatidylserine exposure and thrombin generation were both reduced in a concentration-dependent manner-between 26.6 ± 8.2% (p = 0.01) and 70.7 ± 5.6% (p < 0.0001); and 14.0 ± 6.2% (p = 0.15) and 41.7 ± 6.8% (p = 0.03), respectively, compared to D5W control. Platelet aggregation via all agonists was also reduced, particularly at higher concentrations of bicarb. Platelet adhesion to glass was similarly reduced, between 0.04 ± 0.03% (p = 0.61) and 0.11 ± 0.04% (p = 0.05). Sodium bicarbonate has direct, local, dose-dependent effects limiting platelet activation and adhesion. Our results highlight the potential utility of sodium bicarbonate as a locally acting agent to limit device thrombosis., (© 2023. The Author(s).)

Background: Significant complications of diabetes include pain and the loss of sensation in peripheral limbs. Pain management of diabetic symmetric peripheral neuropathy (DSPN) remains challenging. This study reports on utilizing pulsed electromagnetic field therapy (PEMF) to reduce pain and improve skin perfusion pressure (SPP) in subjects with DSPN., Methods: A randomized, sham-controlled, double-blind, clinical trial was conducted on subjects afflicted with foot pain associated with DSPN. Following informed consent, 182 subjects with diabetes and confirmed DSPN were entered into the trial for a period of 18 weeks. Subjects were randomized into active PEMF treatment or nonactive sham and instructed to treat to their feet for 30 minutes, twice daily and report daily pain scores. Some patients in the active arm experienced a transient low field strength notification (LFSN) due to improper pad placement during treatment. Skin perfusion pressure measurements were also collected at two and seven weeks to assess peripheral arterial disease effects via measurement of local microcirculatory flow and blood pressure., Results: Patients in the active arm who did not receive an LFSN experienced a clinically significant 30% reduction in pain from baseline compared to sham ( P < .05). Though not statistically significant, SPP in the active group trended toward improvement compared to sham., Conclusions: Pulsed electromagnetic field therapy appears effective as a nonpharmacological means for reduction of pain associated with diabetic peripheral neuropathy and holds promise for improvement of vascular physiology in microcirculatory dysfunction associated with diabetic peripheral arterial disease., Competing Interests: Declaration of Conflicting InterestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Erica E. Tassone is a full-time employee of Regenesis Biomedical Inc., Jeffrey C. Page is a member of the medical advisory board of Regenesis Biomedical Inc., Marvin J. Slepian is a member of the board of directors of Regenesis Biomedical Inc.

Background: The Impella® microaxial blood pumps utilize purge fluid containing heparin to prevent biofouling of internal surfaces. Purge fluid interfaces with blood or blood components at two notable internal locations: (1) 5-8 μm radial gap ("Radial Gap" or "Gap 1") between the motor shaft and bearing, a site accessible by blood proteins or small molecules; and (2) 100 μm axial gap ("Axial Gap" or "Gap 2") between the impeller rotor and bearing, the site of mixing with larger circulating blood components. Despite its efficacy, heparin in the purge fluid complicates overall patient anticoagulation management. Here, we investigate sodium bicarbonate as an alternative to heparin in the purge fluid in a simulated purge gap micro-environment., Methods: To assess protein stability simulated at Gap 1, human serum albumin (HSA; 40 mg/ml) species were quantified utilizing size exclusion liquid chromatography (SEC-HPLC) after stirring with purge fluid (5% dextrose in water (D5W) with heparin (25 U/ml) or sodium bicarbonate (25 or 50 mEq/L)) over a 24-h period. pH measurements were taken immediately prior to stirring. Mixing between blood and purge fluid at Gap 2 was mimicked in vitro utilizing a 60:40 blood: purge fluid ratio. Purge fluid consisted of D5W with or without sodium bicarbonate (25 or 50 mEq/L). Human citrated blood samples were freshly collected with or without the addition of heparin (5 U/ml). Coagulability was determined via thromboelastography (TEG). pH measurements of blood mixtures were taken immediately before and after TEG analysis., Results: Sodium bicarbonate alone or synergistically with heparin was effective in increasing protein stability, increasing pH, and reducing coagulability. In the Gap 1 model, sodium bicarbonate led to preservation of HSA monomer after 24 h mixing, with monomer composing 88.3 ± 2.3% and 88.6 ± 0.9% of total HSA species for 25 or 50 mEq/L sodium bicarbonate, respectively. Only 60.4 ± 4.3% monomer was observed with D5W alone (p < 0.005). HSA aggregates and fragments were evident in heparin and D5W purge mixtures, but absent in sodium bicarbonate (25 and 50 mEq/L). pH of HSA mixtures significantly increased in the presence of sodium bicarbonate. In the Gap 2 model, combined heparin (5 U/ml) and sodium bicarbonate prolonged clotting time (TEG-ACT), leading to an average increase of 795 ± 275 s (p = 0.04) and 846 243 s (p = 0.03). This trend of reduced coagulability was similarly observed in clot initiation time (R time), clot formation time (K time), and clotting rate (α angle). Blood mixture pH measurements increased with addition of sodium bicarbonate in both heparinized and non-heparinized blood samples., Conclusion: Sodium bicarbonate in the purge fluid has the potential to significantly increase protein stability and reduce protein denaturation at the Impella® radial gap (Gap 1), while reducing blood coagulation at the Impella® axial gap (Gap 2). The influence of sodium bicarbonate on the biochemical environment of the purge fluid may ensure stable purge flow resistance and play a synergistic or supportive role in the purge gap micro-environment when used with systemic anticoagulation., (© 2023 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Artificial intelligence (AI) has the potential to improve diagnostic accuracy. Yet people are often reluctant to trust automated systems, and some patient populations may be particularly distrusting. We sought to determine how diverse patient populations feel about the use of AI diagnostic tools, and whether framing and informing the choice affects uptake. To construct and pretest our materials, we conducted structured interviews with a diverse set of actual patients. We then conducted a pre-registered (osf.io/9y26x), randomized, blinded survey experiment in factorial design. A survey firm provided n = 2675 responses, oversampling minoritized populations. Clinical vignettes were randomly manipulated in eight variables with two levels each: disease severity (leukemia versus sleep apnea), whether AI is proven more accurate than human specialists, whether the AI clinic is personalized to the patient through listening and/or tailoring, whether the AI clinic avoids racial and/or financial biases, whether the Primary Care Physician (PCP) promises to explain and incorporate the advice, and whether the PCP nudges the patient towards AI as the established, recommended, and easy choice. Our main outcome measure was selection of AI clinic or human physician specialist clinic (binary, "AI uptake"). We found that with weighting representative to the U.S. population, respondents were almost evenly split (52.9% chose human doctor and 47.1% chose AI clinic). In unweighted experimental contrasts of respondents who met pre-registered criteria for engagement, a PCP's explanation that AI has proven superior accuracy increased uptake (OR = 1.48, CI 1.24-1.77, p < .001), as did a PCP's nudge towards AI as the established choice (OR = 1.25, CI: 1.05-1.50, p = .013), as did reassurance that the AI clinic had trained counselors to listen to the patient's unique perspectives (OR = 1.27, CI: 1.07-1.52, p = .008). Disease severity (leukemia versus sleep apnea) and other manipulations did not affect AI uptake significantly. Compared to White respondents, Black respondents selected AI less often (OR = .73, CI: .55-.96, p = .023) and Native Americans selected it more often (OR: 1.37, CI: 1.01-1.87, p = .041). Older respondents were less likely to choose AI (OR: .99, CI: .987-.999, p = .03), as were those who identified as politically conservative (OR: .65, CI: .52-.81, p < .001) or viewed religion as important (OR: .64, CI: .52-.77, p < .001). For each unit increase in education, the odds are 1.10 greater for selecting an AI provider (OR: 1.10, CI: 1.03-1.18, p = .004). While many patients appear resistant to the use of AI, accuracy information, nudges and a listening patient experience may help increase acceptance. To ensure that the benefits of AI are secured in clinical practice, future research on best methods of physician incorporation and patient decision making is required., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Robertson et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Implantable Cardiovascular Therapeutic Devices (CTD), while lifesaving, impart supraphysiologic shear stress to platelets, resulting in thrombotic and bleeding coagulopathy. We previously demonstrated that shear-mediated platelet dysfunction is associated with downregulation of platelet GPIb-IX-V and αIIbβ3 receptors via generation of Platelet-Derived MicroParticles (PDMPs). Here, we test the hypothesis that sheared PDMPs manifest phenotypical heterogeneity of morphology and receptor surface expression and modulate platelet hemostatic function. Human gel-filtered platelets were exposed to continuous shear stress. Alterations of platelet morphology were visualized using transmission electron microscopy. Surface expression of platelet receptors and PDMP generation were quantified by flow cytometry. Thrombin generation was quantified spectrophotometrically, and platelet aggregation was measured by optical aggregometry. Shear stress promotes notable alterations in platelet morphology and ejection of distinctive types of PDMPs. Shear-mediated microvesiculation is associated with the remodeling of platelet receptors, with PDMPs expressing significantly higher levels of adhesion receptors (α IIb β 3 , GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist receptors (P 2 Y 12 and PAR1). Sheared PDMPs promote thrombin generation and inhibit platelet aggregation induced by collagen and ADP. Sheared PDMPs demonstrate phenotypic heterogeneity as to morphology and defined patterns of surface receptors and impose a bidirectional effect on platelet hemostatic function. PDMP heterogeneity suggests that a range of mechanisms are operative in the microvesiculation process, contributing to CTD coagulopathy and posing opportunities for therapeutic manipulation.

In recent years, the treatment of aortic stenosis with TAVR has rapidly expanded to younger and lower-risk patients. However, persistent thrombotic events such as stroke and valve thrombosis expose recipients to severe clinical complications that hamper TAVR's rapid advance. We presented a novel methodology for establishing a link between commonly acceptable mild paravalvular leak (PVL) levels through the device and increased thrombogenic risk. It utilizes in vitro patient-specific TAVR 3D-printed replicas evaluated for hydrodynamic performance. High-resolution µCT scans are used to reconstruct in silico FSI models of these replicas, in which multiple platelet trajectories are studied through the PVL channels to quantify thrombogenicity, showing that those are highly dependent on patient-specific flow conditions within the PVL channels. It demonstrates that platelets have the potential to enter the PVL channels multiple times over successive cardiac cycles, increasing the thrombogenic risk. This cannot be reliably approximated by standard hemodynamic parameters. It highlights the shortcomings of subjectively ranked PVL commonly used in clinical practice by indicating an increased thrombogenic risk in patient cases otherwise classified as mild PVL. It reiterates the need for more rigorous clinical evaluation for properly diagnosing thrombogenic risk in TAVR patients.

Bicuspid aortic valve (BAV), the most common congenital heart malformation, is characterized by the presence of only two valve leaflets with asymmetrical geometry, resulting in elliptical systolic opening. BAV often leads to early onset of calcific aortic stenosis (AS). Following the rapid expansion of transcatheter aortic valve replacement (TAVR), designed specifically for treating conventional tricuspid AS, BAV patients with AS were initially treated "off-label" with TAVR, which recently gained FDA and CE regulatory approval. Despite its increasing use in BAV, pathological BAV anatomy often leads to complications stemming from mismatched anatomical features. To mitigate these complications, a novel eccentric polymeric TAVR valve incorporating asymmetrical leaflets was designed specifically for BAV anatomies. Computational modeling was used to optimize its asymmetric leaflets for lower functional stresses and improved hemodynamic performance. Deployment and flow were simulated in patient-specific BAV models (n = 6) and compared to a current commercial TAVR valve (Evolut R 29 mm), to assess deployment and flow parameters. The novel eccentric BAV-dedicated valve demonstrated significant improvements in peak systolic orifice area, along with lower jet velocity and wall shear stress (WSS). This feasibility study demonstrates the clinical potential of the first known BAV-dedicated TAVR design, which will foster advancement of patient-dedicated valvular devices., (© 2022. The Author(s) under exclusive licence to Biomedical Engineering Society.)

Objective . Platelets are small, mechanosensitive blood cells responsible for maintaining vascular integrity and activatable on demand to limit bleeding and facilitate thrombosis. While circulating in the blood, platelets are exposed to a range of mechanical and chemical stimuli, with the platelet membrane being the primary interface and transducer of outside-in signaling. Sensing and modulating these interface signals would be useful to study mechanochemical interactions; yet, to date, no methods have been defined to attach adducts for sensor fabrication to platelets without triggering platelet activation. We hypothesized that DNA origami, and methods for its attachment, could be optimized to enable nonactivating instrumentation of the platelet membrane. Approach and Results . We designed and fabricated multivalent DNA origami nanotile constructs to investigate nanotile hybridization to membrane-embedded single-stranded DNA-tetraethylene glycol cholesteryl linkers. Two hybridization protocols were developed and validated (Methods I and II) for rendering high-density binding of DNA origami nanotiles to human platelets. Using quantitative flow cytometry, we showed that DNA origami binding efficacy was significantly improved when the number of binding overhangs was increased from two to six. However, no additional binding benefit was observed when increasing the number of nanotile overhangs further to 12. Using flow cytometry and transmission electron microscopy, we verified that hybridization with DNA origami constructs did not cause alterations in the platelet morphology, activation, aggregation, or generation of platelet-derived microparticles. Conclusions . Herein, we demonstrate that platelets can be successfully instrumented with DNA origami constructs with no or minimal effect on the platelet morphology and function. Our protocol allows for efficient high-density binding of DNA origami to platelets using low quantities of the DNA material to label a large number of platelets in a timely manner. Nonactivating platelet-nanotile adducts afford a path for advancing the development of DNA origami nanoconstructs for cell-adherent mechanosensing and therapeutic agent delivery.

Background: We reviewed our experience with 505 patients with confirmed coronavirus disease-2019 (COVID-19) supported with extracorporeal membrane oxygenation (ECMO) at 45 hospitals and estimated risk factors for mortality., Methods: A multi-institutional database was created and used to assess all patients with COVID-19 who were supported with ECMO. A Bayesian mixed-effects logistic regression model was estimated to assess the effect on survival of multiple potential risk factors for mortality, including age at cannulation for ECMO as well as days between diagnosis of COVID-19 and intubation and days between intubation and cannulation for ECMO., Results: Median time on ECMO was 18 days (interquartile range, 10-29 days). All 505 patients separated from ECMO: 194 patients (38.4%) survived and 311 patients (61.6%) died. Survival with venovenous ECMO was 184 of 466 patients (39.5%), and survival with venoarterial ECMO was 8 of 30 patients (26.7%). Survivors had lower median age (44 vs 51 years, P < .001) and shorter median time interval from diagnosis to intubation (7 vs 11 days, P = .001). Adjusting for several confounding factors, we estimated that an ECMO patient intubated on day 14 after the diagnosis of COVID-19 vs day 4 had a relative odds of survival of 0.65 (95% credible interval, 0.44-0.96; posterior probability of negative effect, 98.5%). Age was also negatively associated with survival: relative to a 38-year-old patient, we estimated that a 57-year-old patient had a relative odds of survival of 0.43 (95% credible interval, 0.30-0.61; posterior probability of negative effect, >99.99%)., Conclusions: ECMO facilitates salvage and survival of select critically ill patients with COVID-19. Survivors tend to be younger and have shorter time from diagnosis to intubation. Survival of patients supported with only venovenous ECMO was 39.5%., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Cardiac conduction abnormality (CCA)- one of the major persistent complications associated with transcatheter aortic valve replacement (TAVR) may lead to permanent pacemaker implantation. Localized stresses exerted by the device frame on the membranous septum (MS) which lies between the aortic annulus and the bundle of His, may disturb the cardiac conduction and cause the resultant CCA. We hypothesize that the area-weighted average maximum principal logarithmic strain (AMPLS) in the MS region can predict the risk of CCA following TAVR., Methods: Rigorous finite element-based analysis was conducted in two patients (Balloon expandable TAVR recipients) to assess post-TAVR CCA risk. Following the procedure one of the patients required permanent pacemaker (PPM) implantation while the other did not (control case). Patient-specific aortic root was modeled, MS was identified from the CT image, and the TAVR deployment was simulated. Mechanical factors in the MS region such as logarithmic strain, contact force, contact pressure, contact pressure index (CPI) and their time history during the TAVR deployment; and anatomical factors such as MS length, implantation depth, were analyzed., Results: Maximum AMPLS (0.47 and 0.37, respectively), contact force (0.92 N and 0.72 N, respectively), and CPI (3.99 and 2.86, respectively) in the MS region were significantly elevated in the PPM patient as compared to control patient., Conclusion: Elevated stresses generated by TAVR devices during deployment appear to correlate with CCA risk, with AMPLS in the MS region emerging as a strong predictor that could be used for preprocedural planning in order to minimize CCA risk., (© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Tissue-based transcatheter aortic valve (AV) replacement (TAVR) devices have been a breakthrough approach for treating aortic valve stenosis. However, with the expansion of TAVR to younger and lower risk patients, issues of long-term durability and thrombosis persist. Recent advances in polymeric valve technology facilitate designing more durable valves with minimal in vivo adverse reactions. We introduce our second-generation polymeric transcatheter aortic valve (TAV) device, designed and optimized to address these issues. We present the optimization process of the device, wherein each aspect of device deployment and functionality was optimized for performance, including unique considerations of polymeric technologies for reducing the volume of the polymer material for lower crimped delivery profiles. The stent frame was optimized to generate larger radial forces with lower material volumes, securing robust deployment and anchoring. The leaflet shape, combined with varying leaflets thickness, was optimized for reducing the flexural cyclic stresses and the valve's hydrodynamics. Our first-generation polymeric device already demonstrated that its hydrodynamic performance meets and exceeds tissue devices for both ISO standard and patient-specific in vitro scenarios. The valve already reached 900 × 106 cycles of accelerated durability testing, equivalent to over 20 years in a patient. The optimization framework and technology led to the second generation of polymeric TAV design- currently undergoing in vitro hydrodynamic testing and following in vivo animal trials. As TAVR use is rapidly expanding, our rigorous bio-engineering optimization methodology and advanced polymer technology serve to establish polymeric TAV technology as a viable alternative to the challenges facing existing tissue-based TAV technology., (Copyright © 2022 by ASME.)

Background: The role of extracorporeal membrane oxygenation (ECMO) in the management of patients with COVID-19 continues to evolve. The purpose of this analysis is to review our multi-institutional clinical experience involving 200 consecutive patients at 29 hospitals with confirmed COVID-19 supported with ECMO., Methods: This analysis includes our first 200 COVID-19 patients with complete data who were supported with and separated from ECMO. These patients were cannulated between March 17 and December 1, 2020. Differences by mortality group were assessed using χ 2 tests for categoric variables and Kruskal-Wallis rank sum tests and Welch's analysis of variance for continuous variables., Results: Median ECMO time was 15 days (interquartile range, 9 to 28). All 200 patients have separated from ECMO: 90 patients (45%) survived and 110 patients (55%) died. Survival with venovenous ECMO was 87 of 188 patients (46.3%), whereas survival with venoarterial ECMO was 3 of 12 patients (25%). Of 90 survivors, 77 have been discharged from the hospital and 13 remain hospitalized at the ECMO-providing hospital. Survivors had lower median age (47 versus 56 years, P < .001) and shorter median time from diagnosis to ECMO cannulation (8 versus 12 days, P = .003). For the 90 survivors, adjunctive therapies on ECMO included intravenous steroids (64), remdesivir (49), convalescent plasma (43), anti-interleukin-6 receptor blockers (39), prostaglandin (33), and hydroxychloroquine (22)., Conclusions: Extracorporeal membrane oxygenation facilitates survival of select critically ill patients with COVID-19. Survivors tend to be younger and have a shorter duration from diagnosis to cannulation. Substantial variation exists in drug treatment of COVID-19, but ECMO offers a reasonable rescue strategy., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Supraphysiological shear stress and surface-contact are recognized as driving mechanisms of platelet activation (PA) in blood contacting devices (BCDs). However, the competing role of these mechanisms in triggering thrombogenic events is poorly understood. Here, we characterized the dynamics of PA in response to the combined effect of shear stress and material exposure. Human platelets were stimulated with different levels of shear stress (500, 750, 1000 dynes/cm 2 ) over a range of exposure times (10, 20, and 30 min) within capillary tubes made of various polymeric materials. Polyethylene (PE), polytetrafluoroethylene (PTFE), ethylene tetrafluoroethylene (ETFE), and polyether ether ketone (PEEK), used for BCDs fabrication, were investigated as compared to glass and thromboresistant Sigma™-coated glass. PA was quantified using the Platelet Activity State assay. Our results indicate that mechanical stimulation and polymer surface-contact both significantly contribute to PA. Notably, the contribution of the mechanical stimulus ranges between +36% and +43%, while that associated with polymer surface-contact ranges from +48% to +59%, depending on the exposure time. In more detail, our results indicate that: (i) PA increases with increasing shear stress magnitude; (ii) PA has a non-linear, time-dependent relationship to exposure time; (iii) PA is largely influenced by biomaterials, with PE and PEEK having respectively the lowest and highest prothrombotic potential; (iv) the effects of polymer surface-contact and shear stress are not correlated and can be studied separately. Our results suggest the importance of incorporating the evaluation of platelet activation driven by the combined effect of shear stress and polymer surface-contact for the comprehensive assessment, and eventually minimization, of BCDs thrombogenic potential.

Probiotic strains from the Bifidobacterium or Lactobacillus genera improve health outcomes in models of metabolic and cardiovascular disease. Yet, underlying mechanisms governing these improved health outcomes are rooted in the interaction of gut microbiota, intestinal interface, and probiotic strain. Central to defining the underlying mechanisms governing these improved health outcomes is the development of adaptable and non-invasive tools to study probiotic localization and colonization within the host gut microbiome. The objective of this study was to test labeling and tracking efficacy of Bifidobacterium animalis subspecies lactis 420 (B420) using a common clinical imaging agent, indocyanine green (ICG). ICG was an effective in situ labeling agent visualized in either intact mouse or excised gastrointestinal (GI) tract at different time intervals. Quantitative PCR was used to validate ICG visualization of B420, which also demonstrated that B420 transit time matched normal murine GI motility (~8 hours). Contrary to previous thoughts, B420 did not colonize any region of the GI tract whether following a single bolus or daily administration for up to 10 days. We conclude that ICG may provide a useful tool to visualize and track probiotic species such as B420 without implementing complex molecular and genetic tools. Proof-of-concept studies indicate that B420 did not colonize and establish residency align the murine GI tract., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented., Competing Interests: Disclosures: The authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

Introduction: Platelet activation by mechanical means such as shear stress exposure, is a vital driver of thrombotic risk in implantable blood-contacting devices used in the treatment of heart failure. Lipids are essential in platelets activation and have been studied following biochemical activation. However, little is known regarding lipid alterations occurring with mechanical shear-mediated platelet activation., Methods: Here, we determined if shear-activation of platelets induced lipidome changes that differ from those associated with biochemically-mediated platelet activation. We performed high-resolution lipidomic analysis on purified platelets from four healthy human donors. For each donor, we compared the lipidome of platelets that were non-activated or activated by shear, ADP, or thrombin treatment., Results: We found that shear activation altered cell-associated lipids and led to the release of lipids into the extracellular environment. Shear-activated platelets released 21 phospholipids and sphingomyelins at levels statistically higher than platelets activated by biochemical stimulation., Conclusions: We conclude that shear-mediated activation of platelets alters the basal platelet lipidome. Further, these alterations differ and are unique in comparison to the lipidome of biochemically activated platelets. Many of the released phospholipids contained an arachidonic acid tail or were phosphatidylserine lipids, which have known procoagulant properties. Our findings suggest that lipids released by shear-activated platelets may contribute to altered thrombosis in patients with implanted cardiovascular therapeutic devices., Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-021-00692-x., Competing Interests: Conflicts of interestAlice Sweedo, Lisa M. Wise, Yana Roka-Moiia, Fernando Teran Arce, S. Scott Saavedra, Jawaad Sheriff, Danny Bluestein, Marvin J. Slepian, and John G. Purdy declare that they have no conflicts of interest., (© Biomedical Engineering Society 2021.)

Background: Patients' responses to antiplatelet therapy significantly vary, with individuals showing high residual platelet reactivity associated with thrombosis. To personalize thrombosis management, platelet function testing has been suggested as a promising tool able to monitor the antithrombotic effect of antiplatelet agents in real-time. We have prototyped the MICELI, a miniature and easy-to-use electrical impedance aggregometer (EIA), measuring platelet aggregation in whole blood. Here, we tested the capability of the MICELI aggregometer to quantify platelet reactivity on antiplatelet agents, as compared with conventional light-transmission aggregometry (LTA)., Methods: Platelet aggregation in ACD-anticoagulated whole blood and platelet-rich plasma of healthy donors (n = 30) was evaluated. The effect of clopidogrel, ticagrelor, cangrelor, cilostazol, and tirofiban on ADP-induced aggregation was tested, while aspirin was evaluated with arachidonic acid and collagen. Platelet aggregation was recorded using the MICELI or BioData PAP-8E (Bio/Data Corp.) aggregometers., Results: The MICELI aggregometer detected an adequate and comparable dose-dependent decrease of platelet aggregation in response to increments of drugs' concentrations, as compared to LTA (the inter-device R 2  = 0.79-0.93). Platelet aggregation in platelet-rich plasma recorded by LTA showed higher sensitivity to antiplatelet agents, but it couldn't distinguish between different drug doses as indicated by saturation of the aggregatory response., Conclusion: Platelet aggregation in whole blood as recorded by EIA represents a better model system for evaluation of platelet reactivity as compared with platelet aggregation in platelet-rich plasma as recorded by LTA, since EIA takes into consideration the modulatory effect of other blood cells on platelet hemostatic function and pharmacodynamics of antiplatelet drugs in vivo. As such, the MICELI impedance aggregometer could be potentially employed for the point-of-care monitoring of platelet function in patients on-treatment for personalized tailoring of their antiplatelet regimen., (Copyright © 2021. Published by Elsevier Ltd.)

Competing Interests: Disclosures: The authors have no conflicts of interest to report.

A growing body of evidence supports the modulation of pain by light exposure. As such, phototherapy is being increasingly utilized for the management of a variety of pain conditions. The modes of delivery, and hence applications of phototherapy, vary by wavelength, intensity, and route of exposure. As such, differing mechanisms of action exist depending upon those parameters. Cutaneous application of red light (660 nm) has been shown to reduce pain in neuropathies and complex regional pain syndrome-I, whereas visual application of the same wavelength of red light has been reported to exacerbate migraine headache in patients and lead to the development of functional pain in animal models. Interestingly visual exposure to green light can result in reduction in pain in variety of pain conditions such as migraine and fibromyalgia. Cutaneous application typically requires exposure on the order of minutes, whereas visual application requires exposure on the order of hours. Both routes of exposure elicit changes centrally in the brainstem and spinal cord, and peripherally in the dorsal root ganglia and nociceptors. The mechanisms of photobiomodulation of pain presented in this review provide a foundation in furtherance of exploration of the utility of phototherapy as a tool in the management of pain. PERSPECTIVE: This review synopsizes the pathways and mechanisms through which light modulates pain and the therapeutic utility of different colors and exposure modalities of light on pain. Recent advances in photobiomodulation provide a foundation for understanding this novel treatment for pain on which future translational and clinical studies can build upon., (Copyright © 2021 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Contemporary centrifugal continuous-flow left ventricular assist devices (LVADs) incorporate dynamic speed modulation algorithms. Hemocompatibility of these periodic unsteady pump operating conditions has been only partially explored. We evaluated whether speed modulation induces flow alterations associated with detrimental prothrombotic effects. For this aim, we evaluated the thrombogenic profile of the HeartWare ventricular assist device (HVAD) Lavare Cycle (LC) and HeartMate3 (HM3) artificial pulse (AP) via comprehensive numerical evaluation of (i) pump washout, (ii) stagnation zones, (iii) shear stress regimens, and (iv) modeling of platelet activation status via the platelet activity state (PAS) model. Data were compared between different simulated operating scenarios, including: (i) constant rotational speed and pump pressure head, used as reference; (ii) unsteady pump pressure head as induced by cardiac pulsatility; and (iii) unsteady rotor speed modulation of the LC (HVAD) and AP (HM3). Our results show that pump washout did not improve across the different simulated scenarios in neither the HVAD nor the HM3. The LC reduced but did not eliminate flow stagnation (-57%) and did not impact metrics of HVAD platelet activation (median PAS: +0.4%). The AP reduced HM3 flow stagnation by up to 91% but increased prothrombotic shear stress and simulated platelet activation (median PAS: +124%). Our study advances understanding of the pathogenesis of LVAD thrombosis, suggesting mechanistic implications of rotor speed modulation. Our data provide rationale criteria for the future design optimization of next generation LVADs to further reduce hemocompatibility-related adverse events., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2020.)

Shear-mediated platelet activation (SMPA) in the "free flow" is the net result of a range of cell mechanobiological mechanisms. Previously, we outlined three main groups of mechanisms including: 1) mechano-destruction - i.e. additive platelet (membrane) damage; 2) mechano-activation - i.e. activation of shear-sensitive ion channels and pores; and 3) mechano-transduction - i.e. "outside-in" signaling via a range of transducers. Here, we report on recent advances since our original report which describes additional features of SMPA. A clear "signature" of SMPA has been defined, allowing differentiation from biochemically-mediated activation. Notably, SMPA is characterized by mitochondrial dysfunction, platelet membrane eversion, externalization of anionic phospholipids, and increased thrombin generation on the platelet surface. However, SMPA does not lead to integrin αIIbβ3 activation or P-selectin exposure due to platelet degranulation, as is commonly observed in biochemical activation. Rather, downregulation of GPIb, αIIbβ3, and P-selectin surface expression is evident. Furthermore, SMPA is accompanied by a decrease in overall platelet size coupled with a concomitant, progressive increase in microparticle generation. Shear-ejected microparticles are highly enriched in GPIb and αIIbβ3. These observations indicate the enhanced diffusion, migration, or otherwise dispersion of platelet adhesion receptors to membrane zones, which are ultimately shed as receptor-rich PDMPs. The pathophysiological consequence of this progressive shear accumulation phenomenon is an associated dyscrasia of remaining platelets - being both reduced in size and less activatable via biochemical means - a tendency to favor bleeding, while concomitantly shed microparticles are highly prothrombotic and increase the tendency for thrombosis in both local and systemic milieu. These mechanisms and observations offer direct clinical utility in allowing measurement and guidance of the net balance of platelet driven events in patients with implanted cardiovascular therapeutic devices., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

A critical component of tissue engineering is the ability to functionally replace native tissue stroma. Electrospinning is a technique capable of forming fibrous constructs with a high surface area for increased cell-material interaction and enhanced biocompatibility. However, physical and biological properties of electrospun scaffolds are limited by design controllability on a macroscale. We developed a methodology for generating electrospun scaffolds with defined patterns and topographic features to influence physical properties and biological interactions. Five unique design electrospinning target collectors were fabricated to allow for generation of defined polymeric scaffold patterns including lines, sinusoids, squares, zigzags, and solid. Poly(lactic- co -glycolic) acid was electrospun under identical conditions utilizing these varied targets, and constructs generated were examined as to their physical configuration, mechanical and chemical properties, and their ability to foster vascular smooth muscle cell adhesion and retention at 24 h. Modifying collector designs led to significant differences in fiber target coverage ranging from 300 mm 2 for solid (100% of the target area) to 217.8 mm 2 for lines (72.6% of the target area). Measured fiber excess, residual open area, and contact angle (hydrophobicity) followed the same trend as fiber target coverage with respect to the collector pattern: lines > sinusoids > squares > zigzags > solid. Similarly, the line design allowed for the greatest cell adhesion and retention (258 ± 31 cells), whereas solid exhibited the lowest (150 ± 15 cells); p < 0.05. There was a strong direct correlation of cell adhesion to construct residual open area ( R 2 = 0.94), normalized fiber excess ( R 2 = 0.99), and fiber grammage ( R 2 = 0.72), with an inverse relationship to fiber target coverage ( R 2 = 0.94). Our results demonstrate the ability to utilize patterned collectors for modifying macroscopic and microscopic electrospun scaffold features, which directly impact cell adhesion and retention, offering translational utility for designing specific tissue constructs.

The role of extracorporeal membrane oxygenation (ECMO) in the management of severely ill patients with coronavirus disease 2019 (COVID-19) continues to evolve. The purpose of this study is to review a multi-institutional clinical experience in 100 consecutive patients, at 20 hospitals, with confirmed COVID-19 supported with ECMO. This analysis includes our first 100 patients with complete data who had confirmed COVID-19 and were supported with ECMO. The first patient in the cohort was placed on ECMO on March 17, 2020. Differences by the mortality group were assessed using χ2 tests for categorical variables and Kruskal-Wallis rank-sum tests and Welch's analysis of variance for continuous variables. The median time on ECMO was 12.0 days (IQR = 8-22 days). All 100 patients have since been separated from ECMO: 50 patients survived and 50 patients died. The rate of survival with veno-venous ECMO was 49 of 96 patients (51%), whereas that with veno-arterial ECMO was 1 of 4 patients (25%). Of 50 survivors, 49 have been discharged from the hospital and 1 remains hospitalized at the ECMO-providing hospital. Survivors were generally younger, with a lower median age (47 versus 56.5 years, p = 0.014). In the 50 surviving patients, adjunctive therapies while on ECMO included intravenous steroids (26), anti-interleukin-6 receptor blockers (26), convalescent plasma (22), remdesivir (21), hydroxychloroquine (20), and prostaglandin (15). Extracorporeal membrane oxygenation may facilitate salvage and survival of selected critically ill patients with COVID-19. Survivors tend to be younger. Substantial variation exists in the drug treatment of COVID-19, but ECMO offers a reasonable rescue strategy., Competing Interests: Disclosure: Dr. Jacobs has received funds from SpecialtyCare. Dr. Firstenberg has received funds from Maquet Cardiovascular and Medtronic. Mr. Stammers, Ms. Mongero, Dr. Tesdahl, Mr. Patel, Mr. Coley, and Dr. Sestokas are paid employees of SpecialtyCare, Inc. The remaining authors have no conflicts of interest to report., (Copyright © ASAIO 2021.)

[Figure: see text].

Following in vitro tests established for surgical prosthetic heart valves, transcatheter aortic valves (TAV) are similarly tested in idealized geometries-excluding effects that may hamper TAVR performance in situ. Testing in vitro in pulse duplicator systems that incorporated patient-specific replicas would enhance the testing veracity by bringing it closer to the clinical scenario. To that end we compare TAV hemodynamic performance tested in idealized geometries according to the ISO standard (baseline performance) to that obtained by testing the TAVs following deployment in patient-specific replicas. Balloon-expandable (n = 2) and self-expandable (n = 3) TAVs were tested in an idealized geometry in mock-circulation system (following ISO 5840-3 guidelines) and compared to the measurements in a dedicated mock-circulation system adapted for the five patient-specific replicas. Patient-specific deployments resulted in a decline in performance as compared to the baseline idealized testing, as well as a variation in performance that depended on the design features of each device that was further correlated with the radial expansion and eccentricity of the deployed TAV stent (obtained with CT-scans of the deployed valves). By excluding the deployment effects in irregular geometries, the current idealized ISO testing is limited to characterize the baseline device performance. Utilizing patient-specific anatomic contours provides performance indicators under more stringent conditions likely encountered in vivo. It has the potential to enhance testing and development complementary to the ISO standard, for improved TAV safety and effectiveness., (© 2020 International Center for Artificial Organs and Transplantation and Wiley Periodicals LLC.)

Flow-induced platelet activation prompts complex filopodial formation. Continuum methods fail to capture such molecular-scale mechanisms. A multiscale numerical model was developed to simulate this activation process, where a Dissipative Particle Dynamics (DPD) model of viscous blood flow is interfaced with a Coarse Grained Molecular Dynamics (CGMD) platelet model. Embedded in DPD blood flow, the macroscopic dynamic stresses are interactively transferred to the CGMD model, inducing intra-platelet associated events. The platelets activate by a biomechanical transductive linkage chain and dynamically change their shape in response. The models are fully coupled via a hybrid-potential interface and multiple time-stepping (MTS) schemes for handling the disparity between the spatiotemporal scales. Cumulative hemodynamic stresses that may lead to platelet activation are mapped on the surface membrane and simultaneously transmitted to the cytoplasm and cytoskeleton. Upon activation, the flowing platelets lose their quiescent discoid shape and evolve by forming filopodia. The model predictions were validated by a set of in vitro experiments, Platelets were exposed to various combinations of shear stresses and durations in our programmable hemodynamic shearing device (HSD). Their shape change was measured at multiple time points using scanning electron microscopy (SEM). The CGMD model parameters were fine-tuned by interrogating a parameter space established in these experiments. Segmentation of the SEM imaging streams was conducted by a deep machine learning system. This model can be further employed to simulate shear mediated platelet activation thrombosis initiation and to study the effects of modulating platelet properties to enhance their shear resistance via mechanotransduction pathways., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Chronic disease or injury of the vasculature impairs the functionality of vascular wall cells particularly in their ability to migrate and repair vascular surfaces. Under pathologic conditions, vascular endothelial cells (ECs) lose their non-thrombogenic properties and decrease their motility. Alternatively, vascular smooth muscle cells (SMCs) may increase motility and proliferation, leading to blood vessel luminal invasion. Current therapies to prevent subsequent blood vessel occlusion commonly mechanically injure vascular cells leading to endothelial denudation and smooth muscle cell luminal migration. Due to this dichotomous migratory behavior, a need exists for modulating vascular cell growth and migration in a more targeted manner. Here, we examine the efficacy of utilizing small direct current electric fields to influence vascular cell-specific migration ("galvanotaxis"). We designed, fabricated, and implemented an in vitro chamber for tracking vascular cell migration direction, distance, and displacement under galvanotactic influence of varying magnitude. Our results indicate that vascular ECs and SMCs have differing responses to galvanotaxis; ECs exhibit a positive correlation of anodal migration while SMCs exhibit minimal change in directional migration in relation to the electric field direction. SMCs exhibit less motility response (i.e. distance traveled in 4 h) compared to ECs, but SMCs show a significantly higher motility at low electric potentials (80 mV/cm). With further investigation and translation, galvanotaxis may be an effective solution for modulation of vascular cell-specific migration, leading to enhanced endothelialization, with coordinate reduced smooth muscle in-migration., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic has revealed deep gaps in our understanding of the clinical nuances of this extremely infectious viral pathogen. In order for public health, care delivery systems, clinicians, and other stakeholders to be better prepared for the next wave of SARS-CoV-2 infections, which, at this point, seems inevitable, we need to better understand this disease-not only from a clinical diagnosis and treatment perspective-but also from a forecasting, planning, and advanced preparedness point of view. To predict the onset and outcomes of a next wave, we first need to understand the pathologic mechanisms and features of COVID-19 from the point of view of the intricacies of clinical presentation, to the nuances of response to therapy. Here, we present a novel approach to model COVID-19, utilizing patient data from related diseases, combining clinical understanding with artificial intelligence modeling. Our process will serve as a methodology for analysis of the data being collected in the ASAIO database and other data sources worldwide., Competing Interests: Disclosure: Drs Rahman and Slepian report no conflict of interest. Drs Meyer and Kriak are consultants to Goldblatt Systems. Dr Goldblatt is the founder of Goldblatt Systems., (Copyright © ASAIO 2020.)

Despite growing use of mechanical circulatory support, limitations remain related to hemocompatibility. Here, we performed a head-to-head comparison of the hemocompatibility of a centrifugal cardiac assist system-the Centrimag, with that of the latest generation of an intravascular microaxial system-the Impella 5.5. Specifically, hemolysis, platelet activation, microparticle (MP) generation, and von Willebrand factor (vWF) degradation were evaluated for both devices. Freshly obtained porcine blood was recirculated within device propelled mock loops for 4 hours, and alteration of the hemocompatibility parameters was monitored over time. We found that the Impella 5.5 and Centrimag exhibited low levels of hemolysis, as indicated by minor increase in plasma free hemoglobin. Both devices did not induce platelet degranulation, as no alteration of β-thromboglobulin and P-selectin in plasma occurred, rather minor downregulation of platelet surface P-selectin was detected. Furthermore, blood exposure to shear stress via both Centrimag and Impella 5.5 resulted in a minor decrease of platelet count with associated ejection of procoagulant MPs, and a decrease of vWF functional activity (but not plasma level of vWF-antigen). Greater MP generation was observed with the Centrimag relative to the Impella 5.5. Thus, the Impella 5.5 despite having a lower profile and higher impeller rotational speed demonstrated good and equivalent hemocompatibility, in comparison with the predicate Centrimag, with the advantage of lower generation of MPs.

Though mechanical circulatory support (MCS) devices, such as ventricular assist devices and total artificial hearts (TAH), provide heart failure patients with bridges to heart transplantation or are alternatives to transplantation, device performance, and corresponding control strategies are often difficult to evaluate. Difficulties arise due to the complex interaction of multiple domains-i.e., biological, hydraulic, hemodynamics, electromechanical, system dynamics, and controls. In an attempt to organize, integrate and clarify these interactions, a technique often used in hydraulic pump design and robotics, called "bond graph modeling," is applied to describe the performance and functionality of MCS devices and the interaction between the cardiovascular (CV) system and the MCS device. This technical brief demonstrates the advantages of this tool in formulating a model for the systemic circulation interacting with the left side of a TAH, adopting the fundamental structure of either a hydraulic mechanism (i.e., AbioCor/Carmat) or a pneumatic mechanism (i.e., SynCardia), combined with a systemic circulation loop. The model captures the dynamics of the membrane, the hydraulic source or pneumatic source, and the systemic circulation. This multidisciplinary cross-pollination of an analytical tool from the field of dynamic systems may provide important insight to further aid and improve the design and control of future MCS systems., (Copyright © 2020 by ASME.)

As coronavirus disease 2019 (COVID-19) cases surge worldwide, an urgent need exists to enhance our understanding of the role of extracorporeal membrane oxygenation (ECMO) in the management of severely ill patients with COVID-19 who develop acute respiratory and cardiac compromise refractory to conventional therapy. The purpose of this manuscript is to review our initial clinical experience in 32 patients with confirmed COVID-19 treated with ECMO. A multi-institutional registry and database was created and utilized to assess all patients who were supported with ECMO provided by SpecialtyCare. Data captured included patient characteristics, pre-COVID-19 risk factors and comorbidities, confirmation of COVID-19 diagnosis, features of ECMO support, specific medications utilized to treat COVID-19, and short-term outcomes through hospital discharge. This analysis includes all of our patients with COVID-19 supported with ECMO, with an analytic window starting March 17, 2020, when our first COVID-19 patient was placed on ECMO, and ending April 9, 2020. During the 24 days of this study, 32 consecutive patients with COVID-19 were placed on ECMO at nine different hospitals. As of the time of analysis, 17 remain on ECMO, 10 died before or shortly after decannulation, and five are alive and extubated after removal from ECMO, with one of these five discharged from the hospital. Adjunctive medication in the surviving patients while on ECMO was as follows: four of five survivors received intravenous steroids, three of five survivors received antiviral medications (Remdesivir), two of five survivors were treated with anti-interleukin-6-receptor monoclonal antibodies (Tocilizumab or Sarilumab), and one of five survivors received hydroxychloroquine. Analysis of these 32 COVID-19 patients with severe pulmonary compromise supported with ECMO suggests that ECMO may play a useful role in salvaging select critically ill patients with COVID-19. Additional patient experience and associated clinical and laboratory data must be obtained to further define the optimal role of ECMO in patients with COVID-19 and acute respiratory distress syndrome (ARDS). These initial data may provide useful information to help define the best strategies to care for these challenging patients and may also provide a framework for much-needed future research about the use of ECMO to treat patients with COVID-19.

Mechanical circulatory support (MCS) devices continue to be hampered by thrombotic adverse events (AEs), a consequence of device-imparted supraphysiologic shear stresses, leading to shear-mediated platelet activation (SMPA). In advancing MCS devices from design to clinical use, in vitro circulatory loops containing the device under development and testing are utilized as a means of assessing device thrombogenicity. Physical characteristics of these test circulatory loops may also contribute to inadvertent platelet activation through imparted shear stress, adding inadvertent error in evaluating MCS device thrombogenicity. While investigators normally control for the effect of a loop, inadvertent addition of what are considered innocuous connectors may impact test results. Here, we tested the effect of common, additive components of in vitro circulatory test loops, that is, connectors and loop geometry, as to their additive contribution to shear stress via both in silico and in vitro models. A series of test circulatory loops containing a ventricular assist device (VAD) with differing constituent components, were established in silico including: loops with 0~5 Luer connectors, a loop with a T-connector creating 90° angulation, and a loop with 90° angulation. Computational fluid dynamics (CFD) simulations were performed using a k - ω shear stress transport turbulence model to platelet activation index (PAI) based on a power law model. VAD-operated loops replicating in silico designs were assembled in vitro and gel-filtered human platelets were recirculated within (1 hour) and SMPA was determined. CFD simulations demonstrated high shear being introduced at non-smooth regions such as edge-connector boundaries, tubing, and at Luer holes. Noticeable peaks' shifts of scalar shear stress (sss) distributions toward high shear-region existed with increasing loop complexity. Platelet activation also increased with increasing shear exposure time, being statistically higher when platelets were exposed to connector-employed loop designs. The extent of platelet activation in vitro could be successfully predicted by CFD simulations. Loops employing additional components (non-physiological flow pattern connectors) resulted in higher PAI. Loops with more components (5-connector loop and 90° T-connector) showed 63% and 128% higher platelet activation levels, respectively, versus those with fewer (0-connector (P = .023) and a 90° heat-bend loop (P = .0041). Our results underscore the importance of careful consideration of all component elements, and suggest the need for standardization in designing in vitro circulatory loops for MCS device evaluation to avoid inadvertent additive SMPA during device evaluation, confounding overall results. Specifically, we caution on the use and inadvertent introduction of additional connectors, ports, and other shear-generating elements which introduce artifact, clouding primary device evaluation via introduction of additive SMPA., (© 2019 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

The severe acute respiratory syndrome (SARS)-CoV-2 is an emerging viral pathogen responsible for the global coronavirus disease 2019 (COVID)-19 pandemic resulting in significant human morbidity and mortality. Based on preliminary clinical reports, hypoxic respiratory failure complicated by acute respiratory distress syndrome is the leading cause of death. Further, septic shock, late-onset cardiac dysfunction, and multiorgan system failure are also described as contributors to overall mortality. Although extracorporeal membrane oxygenation and other modalities of mechanical cardiopulmonary support are increasingly being utilized in the treatment of respiratory and circulatory failure refractory to conventional management, their role and efficacy as support modalities in the present pandemic are unclear. We review the rapidly changing epidemiology, pathophysiology, emerging therapy, and clinical outcomes of COVID-19; and based on these data and previous experience with artificial cardiopulmonary support strategies, particularly in the setting of infectious diseases, provide consensus recommendations from ASAIO. Of note, this is a "living document," which will be updated periodically, as additional information and understanding emerges.

Background:  Implantable cardiovascular therapeutic devices, while hemodynamically effective, remain limited by thrombosis. A driver of device-associated thrombosis is shear-mediated platelet activation (SMPA). Underlying mechanisms of SMPA, as well as useful biomarkers able to detect and discriminate mechanical versus biochemical platelet activation, are poorly defined. We hypothesized that SMPA induces a differing pattern of biomarkers compared with biochemical agonists., Methods:  Gel-filtered human platelets were subjected to mechanical activation via either uniform constant or dynamic shear; or to biochemical activation by adenosine diphosphate (ADP), thrombin receptor-activating peptide 6 (TRAP-6), thrombin, collagen, epinephrine, or arachidonic acid. Markers of platelet activation (P-selectin, integrin αIIbβ3 activation) and apoptosis (mitochondrial membrane potential, caspase 3 activation, and phosphatidylserine externalization [PSE]) were examined using flow cytometry. Platelet procoagulant activity was detected by chromogenic assay measuring thrombin generation. Contribution of platelet calcium flux in SMPA was tested employing calcium chelators, ethylenediaminetetraacetic acid (EDTA), and BAPTA-AM., Results:  Platelet exposure to continuous shear stress, but not biochemical agonists, resulted in a dramatic increase of PSE and procoagulant activity, while no integrin αIIbβ3 activation occurred, and P-selectin levels remained barely elevated. SMPA was associated with dissipation of mitochondrial membrane potential, but no caspase 3 activation was observed. Shear-mediated PSE was significantly decreased by chelation of extracellular calcium with EDTA, while intracellular calcium depletion with BAPTA-AM had no significant effect. In contrast, biochemical agonists ADP, TRAP-6, arachidonic acid, and thrombin were potent inducers of αIIbβ3 activation and/or P-selectin exposure. This differing pattern of biomarkers seen for SMPA for continuous uniform shear was replicated in platelets exposed to dynamic shear stress via circulation through a ventricular assist device-propelled circulatory loop., Conclusion:  Elevated shear stress, but not biochemical agonists, induces a differing pattern of platelet biomarkers-with enhanced PSE and thrombin generation on the platelet surface. This differential biomarker phenotype of SMPA offers the potential for early detection and discrimination from that mediated by biochemical agonists., Competing Interests: Y.R.-M., D.B., and M.J.S. have a patent PCT/US2019/037528 pending to University of Arizona.J. I. reports personal fees from Platelet BioGenesis, outside the submitted work., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The characterization of limb biomechanics has broad implications for analyzing and managing motion in aging, sports, and disease. Motion capture videography and on-body wearable sensors are powerful tools for characterizing linear and angular motions of the body, though are often cumbersome, limited in detection, and largely non-portable. Here we examine the feasibility of utilizing an advanced wearable sensor, fabricated with stretchable electronics, to characterize linear and angular movements of the human arm for clinical feedback. A wearable skin-adhesive patch with embedded accelerometer and gyroscope (BioStampRC, MC10 Inc.) was applied to the volar surface of the forearm of healthy volunteers. Arms were extended/flexed for the range of motion of three different regimes: 1) horizontal adduction/abduction 2) flexion/extension 3) vertical abduction. Data were streamed and recorded revealing the signal "pattern" of movement in three separate axes. Additional signal processing and filtering afforded the ability to visualize these motions in each plane of the body; and the 3-dimensional motion envelope of the arm., Results: Each of the three motion regimes studied had a distinct pattern - with identifiable qualitative and quantitative differences. Integration of all three movement regimes allowed construction of a "motion envelope," defining and quantifying motion (range and shape - including the outer perimeter of the extreme of motion - i.e. the envelope) of the upper extremity. The linear and rotational motion results from multiple arm motions match measurements taken with videography and benchtop goniometer., Conclusions: A conformal, stretchable electronic motion sensor effectively captures limb motion in multiple degrees of freedom, allowing generation of characteristic signatures which may be readily recorded, stored, and analyzed. Wearable conformal skin adherent sensor patchs allow on-body, mobile, personalized determination of motion and flexibility parameters. These sensors allow motion assessment while mobile, free of a fixed laboratory environment, with utility in the field, home, or hospital. These sensors and mode of analysis hold promise for providing digital "motion biomarkers" of health and disease., Competing Interests: Competing interestsAll authors report no competing interests, with exception of MJS who reports receiving equipment support (Biostamps) for research from MC10, Inc. Study was conducted at arms length from MC10, with MC10 having no role in design of the study, nor in collection, analysis, and interpretation of data or writing of the manuscript., (© The Author(s) 2020.)

As key cellular elements of hemostasis, platelets represent a primary target for thrombosis and bleeding management. Currently, therapeutic manipulations of platelet function (antithrombotic drugs) and count (platelet transfusion) are performed with limited or no real-time monitoring of the desired outcome at the point-of-care. To address the need, we have designed and fabricated an easy-to-use, accurate, and portable impedance aggregometer called "MICELI" (MICrofluidic, ELectrical, Impedance). It improves on current platelet aggregation technology by decreasing footprint, assay complexity, and time to obtain results. The current study aimed to optimize the MICELI protocol; validate sensitivity to aggregation agonists and key blood parameters, i.e., platelet count and hematocrit; and verify the MICELI operational performance as compared to commercial impedance aggregometry. We demonstrated that the MICELI aggregometer could detect platelet aggregation in 250 μL of whole blood or platelet-rich plasma, stimulated by ADP, TRAP-6, collagen, epinephrine, and calcium ionophore. Using hirudin as blood anticoagulant allowed higher aggregation values. Aggregation values obtained by the MICELI strongly correlated with platelet count and were not affected by hematocrit. The operational performance comparison of the MICELI and the Multiplate ® Analyzer demonstrated strong correlation and similar interdonor distribution of aggregation values obtained between these devices. With the proven reliability of the data obtained by the MICELI aggregometer, it can be further translated into a point-of-care diagnostic device aimed at monitoring platelet function in order to guide pharmacological hemostasis management and platelet transfusions., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Transcatheter aortic valve replacement (TAVR) has emerged as an effective therapy for the unmet clinical need of inoperable patients with severe aortic stenosis (AS). Current clinically used tissue TAVR valves suffer from limited durability that hampers TAVR's rapid expansion to younger, lower risk patients. Polymeric TAVR valves optimized for hemodynamic performance, hemocompatibility, extended durability, and resistance to calcific degeneration offer a viable solution to this challenge. We present extensive in vitro durability and stability testing of a novel polymeric TAVR valve (PolyNova valve) using 1) accelerated wear testing (AWT, ISO 5840); 2) calcification susceptibility (in the AWT)-compared with clinically used tissue valves; and 3) extended crimping stability (valves crimped to 16 Fr for 8 days). Hydrodynamic testing was performed every 50M cycles. The valves were also evaluated visually for structural integrity and by scanning electron microscopy for evaluation of surface damage in the micro-scale. Calcium and phosphorus deposition was evaluated using micro-computed tomography (μCT) and inductive coupled plasma spectroscopy. The valves passed 400M cycles in the AWT without failure. The effective orifice area kept stable at 1.8 cm with a desired gradual decrease in transvalvular pressure gradient and regurgitation (10.4 mm Hg and 6.9%, respectively). Calcium and phosphorus deposition was significantly lower in the polymeric valve: down by a factor of 85 and 16, respectively-as compared to a tissue valve. Following the extended crimping testing, no tears nor surface damage were evident. The results of this study demonstrate the potential of a polymeric TAVR valve to be a viable alternative to tissue-based TAVR valves.

At the nanoscale, pushing, pulling, and shearing forces drive biochemical processes in development and remodeling as well as in wound healing and disease progression. Research in the field of mechanobiology investigates not only how these loads affect biochemical signaling pathways but also how signaling pathways respond to local loading by triggering mechanical changes such as regional stiffening of a tissue. This feedback between mechanical and biochemical signaling is increasingly recognized as fundamental in embryonic development, tissue morphogenesis, cell signaling, and disease pathogenesis. Historically, the interdisciplinary field of mechanobiology has been driven by the development of technologies for measuring and manipulating cellular and molecular forces, with each new tool enabling vast new lines of inquiry. In this review, we discuss recent advances in the manufacturing and capabilities of molecular-scale force and strain sensors. We also demonstrate how DNA nanotechnology has been critical to the enhancement of existing techniques and to the development of unique capabilities for future mechanosensor assembly. DNA is a responsive and programmable building material for sensor fabrication. It enables the systematic interrogation of molecular biomechanics with forces at the 1- to 200-pN scale that are needed to elucidate the fundamental means by which cells and proteins transduce mechanical signals.

Infections are a serious health concern worldwide, particularly in vulnerable populations such as the immunocompromised, elderly, and young. Advances in metagenomic sequencing availability, speed, and decreased cost offer the opportunity to supplement or even replace culture-based identification of pathogens with DNA sequence-based diagnostics. Adopting metagenomic analysis for clinical use requires that all aspects of the workflow are optimized and tested, including data analysis and computational time and resources. We tested the accuracy, sensitivity, and resource requirements of three top metagenomic taxonomic classifiers that use fast k-mer based algorithms: Centrifuge, CLARK, and KrakenUniq. Binary mixtures of bacteria showed all three reliably identified organisms down to 1% relative abundance, while only the relative abundance estimates of Centrifuge and CLARK were accurate. All three classifiers identified the organisms present in their default databases from a mock bacterial community of 20 organisms, but only Centrifuge had no false positives. In addition, Centrifuge required far less computational resources and time for analysis. Centrifuge analysis of metagenomes obtained from samples of VAP, infected DFUs, and FN showed Centrifuge identified pathogenic bacteria and one virus that were corroborated by culture or a clinical PCR assay. Importantly, in both diabetic foot ulcer patients, metagenomic sequencing identified pathogens 4-6 weeks before culture. Finally, we show that Centrifuge results were minimally affected by elimination of time-consuming read quality control and host screening steps., Competing Interests: The authors have declared that no competing interests exist.