Endosomal sequestration of lipid-based nanoparticles (LNPs) remains a formidable barrier to delivery. Herein, structure-activity analysis of cholesterol analogues reveals that incorporation of C-24 ...alkyl phytosterols into LNPs (eLNPs) enhances gene transfection and the length of alkyl tail, flexibility of sterol ring and polarity due to -OH group is required to maintain high transfection. Cryo-TEM displays a polyhedral shape for eLNPs compared to spherical LNPs, while x-ray scattering shows little disparity in internal structure. eLNPs exhibit higher cellular uptake and retention, potentially leading to a steady release from the endosomes over time. 3D single-particle tracking shows enhanced intracellular diffusivity of eLNPs relative to LNPs, suggesting eLNP traffic to productive pathways for escape. Our findings show the importance of cholesterol in subcellular transport of LNPs carrying mRNA and emphasize the need for greater insights into surface composition and structural properties of nanoparticles, and their subcellular interactions which enable designs to improve endosomal escape.
A 57-year-old man with nonischemic cardiomyopathy who was dependent on venoarterial extracorporeal membrane oxygenation (ECMO) and was not a candidate for standard therapeutics, including a ...traditional allograft, received a heart from a genetically modified pig source animal that had 10 individual gene edits. Immunosuppression was based on CD40 blockade. The patient was weaned from ECMO, and the xenograft functioned normally without apparent rejection. Sudden diastolic thickening and failure of the xenograft occurred on day 49 after transplantation, and life support was withdrawn on day 60. On autopsy, the xenograft was found to be edematous, having nearly doubled in weight. Histologic examination revealed scattered myocyte necrosis, interstitial edema, and red-cell extravasation, without evidence of microvascular thrombosis - findings that were not consistent with typical rejection. Studies are under way to identify the mechanisms responsible for these changes. (Funded by the University of Maryland Medical Center and School of Medicine.).
Oceanic uptake of anthropogenic carbon dioxide (CO2) is altering the carbonate chemistry of seawater, with potentially negative consequences for many calcifying marine organisms. At the same time, ...increasing fisheries exploitation is impacting on marine ecosystems. Here, using increased benthic‐invertebrate mortality as a proxy for effects of ocean acidification, the potential impact of the two stressors of fishing and acidification on the southeast Australian marine ecosystem to year 2050 was explored. The individual and interaction effects of the two stressors on biomass and diversity were examined for the entire ecosystem and for regional assemblages. For 61 functional groups or species, the cumulative effects of moderate ocean acidification and fishing were additive (30%), synergistic (33%), and antagonistic (37%). Strong ocean acidification resulted in additive (22%), synergistic (40%), and antagonistic (38%) effects. The greatest impact was on the demersal food web, with fishing impacting predation and acidification affecting benthic production. Areas that have been subject to intensive fishing were the most susceptible to acidification effect, although fishing also mitigated some of the decline in biodiversity observed with moderate acidification. The model suggested that ocean acidification and long‐term fisheries exploitation could act synergistically with the increasing sensitivity to change from long‐term (decades) fisheries exploitation potentially causing unexpected restructuring of the pelagic and demersal food webs. Major regime shifts occur around year 2040. Greater focus is needed on how differential fisheries exploitation of marine resources may exacerbate or accelerate effects of environmental changes such as ocean acidification.
Objective More than 200,000 aortic valve replacements are performed annually worldwide. We describe changes in the aortic valve replacement population during 10 years in a large registry and analyze ...outcomes. Methods The Society of Thoracic Surgeons National Database was queried for all isolated aortic valve replacements between January 1, 1997, and December 31, 2006. After exclusion for endocarditis and missing age or sex data, 108,687 isolated aortic valve replacements were analyzed. Time-related trends were assessed by comparing distributions of risk factors, valve types, and outcomes in 1997 versus 2006. Differences in case mix were summarized by comparing average predicted mortality risks with a logistic regression model. Differences across subgroups and time were assessed. Results There was a dramatic shift toward use of bioprosthetic valves. Aortic valve replacement recipients in 2006 were older (mean age 65.9 vs 67.9 years, P < .001) with higher predicted operative mortality risk (2.75 vs 3.25, P < .001); however, observed mortality and permanent stroke rate fell (by 24% and 27%, respectively). Female sex, age older than 70 years, and ejection fraction less than 30% were all related to higher mortality, higher stroke rate and longer postoperative stay. There was a 39% reduction in mortality with preoperative renal failure. Conclusions Morbidity and mortality of isolated aortic valve replacement have fallen, despite gradual increases in patient age and overall risk profile. There has been a shift toward bioprostheses. Women, patients older than 70 years, and patients with ejection fraction less than 30% have worse outcomes for mortality, stroke, and postoperative stay.
Mechanically assisted circulation (MAC) sustains the blood circulation in the body of a patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) or on ventricular assistance with a ...ventricular assist device (VAD) or on extracorporeal membrane oxygenation (ECMO) with a pump-oxygenator system. While MAC provides short-term (days to weeks) support and long-term (months to years) for the heart and/or lungs, the blood is inevitably exposed to non-physiological shear stress (NPSS) due to mechanical pumping action and in contact with artificial surfaces. NPSS is well known to cause blood damage and functional alterations of blood cells. In this review, we discussed shear-induced platelet adhesion, platelet aggregation, platelet receptor shedding, and platelet apoptosis, shear-induced acquired von Willebrand syndrome (AVWS), shear-induced hemolysis and microparticle formation during MAC. These alterations are associated with perioperative bleeding and thrombotic events, morbidity and mortality, and quality of life in MCS patients. Understanding the mechanism of shear-induce hemostatic disorders will help us develop low-shear-stress devices and select more effective treatments for better clinical outcomes.
Carbon cycling in the coastal zone affects global carbon budgets and is critical for understanding the urgent issues of hypoxia, acidification, and tidal wetland loss. However, there are no regional ...carbon budgets spanning the three main ecosystems in coastal waters: tidal wetlands, estuaries, and shelf waters. Here we construct such a budget for eastern North America using historical data, empirical models, remote sensing algorithms, and process‐based models. Considering the net fluxes of total carbon at the domain boundaries, 59 ± 12% (± 2 standard errors) of the carbon entering is from rivers and 41 ± 12% is from the atmosphere, while 80 ± 9% of the carbon leaving is exported to the open ocean and 20 ± 9% is buried. Net lateral carbon transfers between the three main ecosystem types are comparable to fluxes at the domain boundaries. Each ecosystem type contributes substantially to exchange with the atmosphere, with CO2 uptake split evenly between tidal wetlands and shelf waters, and estuarine CO2 outgassing offsetting half of the uptake. Similarly, burial is about equal in tidal wetlands and shelf waters, while estuaries play a smaller but still substantial role. The importance of tidal wetlands and estuaries in the overall budget is remarkable given that they, respectively, make up only 2.4 and 8.9% of the study domain area. This study shows that coastal carbon budgets should explicitly include tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.
Plain Language Summary
A carbon budget for a particular site or region describes the inputs and outputs of carbon to that site or region as well as the processes that change carbon from one form to another. A carbon budget is needed to fully understand many important issues facing coastal waters. We constructed the carbon budget for coastal waters of eastern North America. We found that about 60% of the carbon entering the domain is from rivers and about 40% is from the atmosphere, while about 80% of the carbon leaving the domain goes to the open ocean and about 20% is buried. Transfers of carbon from wetlands to estuaries and from estuaries to the ocean were as important as transfers of carbon at the domain boundaries. Tidal wetlands and estuaries were found to be important to the carbon budget despite making up only 2.4 and 8.9% of the study domain area, respectively. This study shows that coastal carbon budgets should explicitly consider tidal wetlands, estuaries, shelf waters, and the linkages between them; ignoring any of them may produce a biased picture of coastal carbon cycling.
Key Points
Tidal wetlands, estuaries, and shelf waters each contribute substantially to the carbon budget of eastern North American coastal waters
Study region net ecosystem production, atmospheric uptake, and burial are 20.2 ± 4.4, 5.1 ± 2.4, and 2.5 ± 0.7 Tg C yr−1, respectively
Net lateral carbon fluxes between tidal wetlands, estuaries, and shelf waters are large terms in the carbon budget of eastern North American coastal waters
Ventricular assist devices (VADs) have already helped many patients with heart failure but have the potential to assist more patients if current problems with blood damage (hemolysis, platelet ...activation, thrombosis and emboli, and destruction of the von Willebrand factor (vWf)) can be eliminated. A step towards this goal is better understanding of the relationships between shear stress, exposure time, and blood damage and, from there, the development of numerical models for the different types of blood damage to enable the design of improved VADs. In this study, computational fluid dynamics (CFD) was used to calculate the hemodynamics in three clinical VADs and two investigational VADs and the shear stress, residence time, and hemolysis were investigated. A new scalar transport model for hemolysis was developed. The results were compared with in vitro measurements of the pressure head in each VAD and the hemolysis index in two VADs. A comparative analysis of the blood damage related fluid dynamic parameters and hemolysis index was performed among the VADs. Compared to the centrifugal VADs, the axial VADs had: higher mean scalar shear stress (sss); a wider range of sss, with larger maxima and larger percentage volumes at both low and high sss; and longer residence times at very high sss. The hemolysis predictions were in agreement with the experiments and showed that the axial VADs had a higher hemolysis index. The increased hemolysis in axial VADs compared to centrifugal VADs is a direct result of their higher shear stresses and longer residence times. Since platelet activation and destruction of the vWf also require high shear stresses, the flow conditions inside axial VADs are likely to result in more of these types of blood damage compared with centrifugal VADs.
Objectives Cardiogenic shock after cardiac surgery is accompanied by a high mortality rate. Early institution of hemodynamic support with a versatile, easy to insert left ventricular assist device ...might help bridge patients to recovery or to the next therapy, and improve the outcomes. Methods Patients developing cardiogenic shock or low cardiac output syndrome after being weaned off cardiopulmonary bypass were enrolled in a prospective single-arm feasibility study (RECOVER I). The primary safety endpoint was the frequency of major adverse events (death, stroke) at 30 days or discharge, whichever was longer. The primary efficacy endpoint was survival of the patient to implementation of the next therapy, which included recovery at 30 days after device removal and bridge-to-other-therapy. Results Sixteen patients provided informed consent and were enrolled in the study. Hemodynamics improved immediately after the initiation of mechanical support: cardiac index, 1.65 versus 2.7 L/min/m2 ( P = .0001); mean arterial pressure, 71.4 versus 83.1 mm Hg ( P = .01); and pulmonary artery diastolic pressure, 28.0 versus 19.8 mm Hg ( P < .0001). The pump provided an average of 4.0 ± 0.6 L/min of flow for an average duration of 3.7 ± 2.9 days (range, 1.7–12.6). The primary safety endpoint occurred in 2 patients (13%; 1 stroke and 1 death). For the primary efficacy endpoint, recovery of the native heart function was obtained in 93% of the patients discharged, with bridge-to-other-therapy in 7%. Survival to 30 days, 3 months, and 1 year was 94%, 81%, and 75%, respectively. Conclusions The use of the Impella 5.0/left direct device is safe and feasible in patients presenting with postcardiotomy cardiogenic shock. The device was rapidly inserted, enabled early support, and yielded favorable outcomes.
The aim of this study was to evaluate the impact of virtual monoenergetic imaging (VMI) and quantum iterative reconstruction (QIR) on the accuracy of coronary artery calcium scoring (CACS) using a ...virtual noniodine (VNI) reconstruction algorithm on a first-generation, clinical, photon counting detector computed tomography system.
Coronary artery calcium scoring was evaluated in an anthropomorphic chest phantom simulating 3 different patient sizes by using 2 extension rings (small: 300 × 200 mm, medium: 350 × 250 mm, large: 400 × 300 mm) and in patients (n = 61; final analyses only in patients with coronary calcifications n = 34; 65.4 ± 10.0 years; 73.5% male), who underwent nonenhanced and contrast-enhanced, electrocardiogram-gated, cardiac computed tomography on a photon counting detector system. Phantom and patient data were reconstructed using a VNI reconstruction algorithm at different VMI (55-80 keV) and QIR (strength 1-4) levels (CACS VNI ). True noncontrast (TNC) scans at 70 keV and QIR "off" were used as reference for phantom and patient studies (CACS TNC ).
In vitro and in vivo CACS VNI showed strong correlation ( r > 0.9, P < 0.001 for all) and excellent agreement (intraclass correlation coefficient > 0.9 for all) with CACS TNC at all investigated VMI and QIR levels. Phantom and patient CACS VNI significantly increased with decreasing keV levels (in vitro: from 475.2 ± 26.3 at 80 keV up to 652.5 ± 42.2 at 55 keV; in vivo: from 142.5 7.4/737.7 at 80 keV up to 248.1 31.2/1144 at 55 keV; P < 0.001 for all), resulting in an overestimation of CACS VNI at 55 keV compared with CACS TNC at 70 keV in some cases (in vitro: 625.8 ± 24.4; in vivo: 225.4 35.1/959.7). In vitro CACS increased with rising QIR at low keV. In vivo scores were significantly higher at QIR 1 compared with QIR 4 only at 60 and 80 keV (60 keV: 220.3 29.6-1060 vs 219.5 23.7/1048; 80 keV: 152.0 12.0/735.6 vs 142.5 7.4/737.7; P < 0.001). CACS VNI was closest to CACS TNC at 60 keV, QIR 2 (+0.1%) in the small; 55 keV, QIR 1 (±0%) in the medium; 55 keV, QIR 4 (-0.1%) in the large phantom; and at 60 keV, QIR 1 (-2.3%) in patients.
Virtual monoenergetic imaging reconstructions have a significant impact on CACS VNI . The effects of different QIR levels are less consistent and seem to depend on several individual conditions, which should be further investigated.
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