Vibro-Acoustic Platelet Activation: An Additive Mechanism of Prothrombosis with Applicability to Snoring and Obstructive Sleep Apnea.

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.

Assessing the Effects of Pulsed Electromagnetic Therapy on Painful Diabetic Distal Symmetric Peripheral Neuropathy: A Double-Blind Randomized Controlled Trial.

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.

Sodium bicarbonate as a local adjunctive agent for limiting platelet activation, aggregation, and adhesion within cardiovascular therapeutic devices.

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.

Diverse patients' attitudes towards Artificial Intelligence (AI) in diagnosis.

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.

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function.

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 αIIbß3 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 (αIIbß3, GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist receptors (P2Y12 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.

Shear-Mediated Platelet Microparticles Demonstrate Phenotypic Heterogeneity as to Morphology, Receptor Distribution, and Hemostatic Function.

Objective: Implantable cardiovascular therapeutic devices (CTD) including stents, percutaneous heart valves and ventricular assist devices, while lifesaving, impart supraphysiologic shear stress to platelets resulting in thrombotic and bleeding device-related coagulopathy. We previously demonstrated that shear-mediated platelet dysfunction is associated with downregulation of platelet GPIb-IX-V and αIIbß3 receptors via generation of platelet-derived microparticles (PDMPs). Here, we test the hypothesis that shear-generated PDMPs manifest phenotypical heterogeneity of their morphology and surface expression of platelet receptors, and modulate platelet hemostatic function. Approach and Results: Human gel-filtered platelets were exposed to continuous shear stress and sonication. 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 in plasma was measured by optical aggregometry. We demonstrate that platelet exposure to shear stress promotes notable alterations in platelet morphology and ejection of several distinctive types of PDMPs. Shear-mediated microvesiculation is associated with the differential remodeling of platelet receptors with PDMPs expressing significantly higher levels of both adhesion (α IIb ß 3 , GPIX, PECAM-1, P-selectin, and PSGL-1) and agonist-evoked receptors (P 2 Y 12 & PAR1). Shear-mediated PDMPs have a bidirectional effect on platelet hemostatic function, promoting thrombin generation and inhibiting platelet aggregation induced by collagen and ADP. Conclusions: Shear-generated PDMPs demonstrate phenotypic heterogeneity as to morphologic features and defined patterns of surface receptor alteration, 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.

Mild Paravalvular Leak May Pose an Increased Thrombogenic Risk in Transcatheter Aortic Valve Replacement (TAVR) Patients-Insights from Patient Specific In Vitro and In Silico Studies.

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.

Sodium bicarbonate alters protein stability and blood coagulability in a simulated Impella purge gap model.

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.

Designing a Novel Asymmetric Transcatheter Aortic Valve for Stenotic Bicuspid Aortic Valves Using Patient-Specific Computational Modeling.

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.

DNA Origami-Platelet Adducts: Nanoconstruct Binding without Platelet Activation.

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.

Visions of TAVR Future: Development and Optimization of a Second Generation Novel Polymeric TAVR.

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.

Multi-institutional Analysis of 505 Patients With Coronavirus Disease-2019 Supported With Extracorporeal Membrane Oxygenation: Predictors of Survival.

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%.

A computational framework for post-TAVR cardiac conduction abnormality (CCA) risk assessment in patient-specific anatomy.

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.

Multi-institutional Analysis of 200 COVID-19 Patients Treated With Extracorporeal Membrane Oxygenation: Outcomes and Trends.

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 χ2 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.

Shear-Mediated Platelet Activation is Accompanied by Unique Alterations in Platelet Release of Lipids.

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.

An adaptable and non-invasive method for tracking Bifidobacterium animalis subspecies lactis 420 in the mouse gut.

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.

Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology.

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.