Proof of Concept: Development of a Mitral Annuloplasty Ring With Crosshatch Net.

OBJECTIVE: Here we report our preclinical, proof-of-concept testing to assess the ability of a novel device to correct mitral regurgitation. The Milwaukee Heart device aims to enable any cardiac surgeon to perform high-quality mitral valve repair using a standard annuloplasty ring with a crosshatch of microporous, monofilament suture. METHODS: Hemodynamic, echocardiographic, and videographic data were collected at baseline, following induction of mitral regurgitation, and after repair using porcine hearts in an ex vivo biosimulator model. A commercially available cardiac prosthesis assessment platform was then used to assess the hydrodynamic characteristics of the study device. RESULTS: Porcine biosimulator pressure and flow metrics exhibited successful correction of mitral regurgitation following device implantation with similar values to baseline. Hydrodynamic results yielded pressure gradients and an effective orifice area comparable to currently approved prostheses. CONCLUSIONS: The study device effectively reduced mitral valve regurgitation and improved hemodynamics in our preclinical model with similar biophysical metrics to currently approved devices. Future in vivo trials are needed to evaluate the efficacy, biocompatibility, and freedom from the most likely adverse events, such as device thrombosis, embolic events, and hemolysis.

Necessary Role of Ceramides in the Human Microvascular Endothelium During Health and Disease.

BACKGROUND: Elevated plasma ceramides and microvascular dysfunction both independently predict adverse cardiac events. Despite the known detrimental effects of ceramide on the microvasculature, evidence suggests that activation of the shear-sensitive, ceramide-forming enzyme NSmase (neutral sphingomyelinase) elicits formation of vasoprotective nitric oxide (NO). Here, we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults (non-coronary artery disease [CAD]) and patients diagnosed with CAD. METHODS: Human arterioles were dissected from discarded surgical adipose tissue (n=166), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO and mitochondrial hydrogen peroxide (H2O2) production were measured in arterioles using fluorescence microscopy. H2O2 fluorescence was assessed in isolated human umbilical vein endothelial cells. RESULTS: Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to NOX-2 (NADPH-oxidase 2)-dependent H2O2-mediated flow-induced dilation. Endothelial dysfunction was prevented by treatment with sphingosine-1-phosphate (S1P) and partially prevented by C2-ceramide and an agonist of S1P-receptor 1 (S1PR1); the inhibition of the S1P/S1PR1 signaling axis induced endothelial dysfunction via NOX-2. Ceramide increased NO production in arterioles from non-CAD adults, an effect that was diminished with inhibition of S1P/S1PR1/S1P-receptor 3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired the overall ability to induce mitochondrial H2O2 production and subsequently dilate to flow, an effect not restored with exogenous S1P. Acute ceramide administration to arterioles from patients with CAD promoted H2O2 as opposed to NO production, an effect dependent on S1P-receptor 3 signaling. CONCLUSION: These data suggest that despite differential downstream signaling between health and disease, NSmase-mediated ceramide formation is necessary for proper functioning of the human microvascular endothelium. Therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.

Subclinical Aortic Insufficiency Causing Cardiogenic Shock Years After Impella Placement.

A 28-year-old male with atrial fibrillation and thyrotoxicosis-induced heart failure underwent multiple interventions, including extracorporeal membrane oxygenation (ECMO), multiple valve repair/replacement, and Impella placement/removal. However, after a period of three years, the patient developed progressive aortic insufficiency (AI), which was attributed to damage caused by the prolonged use of the Impella device. The discussion highlights the importance of adhering to manufacturer guidelines for device use and emphasizes the need for careful examination during placement to minimize potential complications.

Necessary Role of Acute Ceramide Formation in The Human Microvascular Endothelium During Health and Disease.

Background: Elevated plasma ceramides independently predict adverse cardiac events and we have previously shown that exposure to exogenous ceramide induces microvascular endothelial dysfunction in arterioles from otherwise healthy adults (0-1 risk factors for heart disease). However, evidence also suggests that activation of the shear-sensitive, ceramide forming enzyme neutral sphingomyelinase (NSmase) enhances vasoprotective nitric oxide (NO) production. Here we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults and patients with coronary artery disease (CAD). Methods: Human arterioles were dissected from otherwise discarded surgical adipose tissue (n=123), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO production was measured in arterioles using fluorescence microscopy. Hydrogen peroxide (H2O2) fluorescence was assessed in isolated human umbilical vein endothelial cells. Results: Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to H2O2-mediated flow-induced dilation within 30 minutes. In endothelial cells, NSmase inhibition acutely increased H2O2 production. Endothelial dysfunction in both models was prevented by treatment with C2-ceramide, S1P, and an agonist of S1P-receptor 1 (S1PR1), while the inhibition of S1P/S1PR1 signaling axis induced endothelial dysfunction. Ceramide increased NO production in arterioles from healthy adults, an effect that was diminished with inhibition of S1P/S1PR1/S1PR3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired dilation to flow. This effect was not restored with exogenous S1P. Although, inhibition of S1P/S1PR3 signaling impaired normal dilation to flow. Acute ceramide administration to arterioles from patients with CAD also promoted H2O2 as opposed to NO production, an effect dependent on S1PR3 signaling. Conclusion: These data suggest that despite key differences in downstream signaling between health and disease, acute NSmase-mediated ceramide formation and its subsequent conversion to S1P is necessary for proper functioning of the human microvascular endothelium. As such, therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.

What the geological past can tell us about the future of the ocean's twilight zone.

Paleontological reconstructions of plankton community structure during warm periods of the Cenozoic (last 66 million years) reveal that deep-dwelling 'twilight zone' (200-1000 m) plankton were less abundant and diverse, and lived much closer to the surface, than in colder, more recent climates. We suggest that this is a consequence of temperature's role in controlling the rate that sinking organic matter is broken down and metabolized by bacteria, a process that occurs faster at warmer temperatures. In a warmer ocean, a smaller fraction of organic matter reaches the ocean interior, affecting food supply and dissolved oxygen availability at depth. Using an Earth system model that has been evaluated against paleo observations, we illustrate how anthropogenic warming may impact future carbon cycling and twilight zone ecology. Our findings suggest that significant changes are already underway, and without strong emissions mitigation, widespread ecological disruption in the twilight zone is likely by 2100, with effects spanning millennia thereafter.

Reduced Morbidity and Mortality Associated With Minimally Invasive Single-vessel Coronary Artery Bypass Compared With Conventional Sternotomy.

OBJECTIVE: We aimed to describe the safety and clinical benefits of minimally invasive, nonsternotomy coronary artery bypass grafting (MICABG) using data from The Society of Thoracic Surgeons (STS) National Database. BACKGROUND: MICABG has gained popularity, owing to expected lower perioperative morbidity and shorter recovery. Despite this, concerns remain regarding anastomotic quality and the validity of proposed perioperative benefits. METHODS: We queried the STS National Database for all patients who underwent single-vessel coronary artery bypass grafting (CABG) from January 2014 to December 2016 to compare outcomes of MICABG with conventional CABG. Patients who underwent concomitant or emergent procedures were excluded. Propensity-weighted cohorts were compared by operative approach with adjustment for variability across institutions. RESULTS: Of 12,406 eligible patients, 2688 (21.7%) underwent MICABG, and 9818 (78.3%) underwent conventional CABG. Propensity weighting produced excellent balance in patient characteristics, including completeness of revascularization, body mass index, and STS predictive risk scores. MICABG was associated with significant reduction of in-hospital mortality [odds ratio (OR)=0.32, absolute reduction (AR)=0.91%, P <0.0001]; 30-day mortality (OR=0.51, AR=0.88%, P =0.001), duration of ventilation (8.62 vs 12.6 hours, P <0.0001), prolonged hospitalization (OR=0.77, AR=1.6, P =0.043), deep wound infection (OR=0.33, AR=0.68, P <0.004), postoperative transfusions (OR=0.52, AR=7.7%, P <0.0001), and STS composite morbidity (OR=0.72, AR=1.19%, P =0.008). Subgroup analysis of only off-pump left internal mammary artery-left anterior descending CABG showed similar findings. Major adverse cardiac events and graft occlusion did not differ between groups. CONCLUSIONS: MICABG is associated with lower mortality and perioperative morbidity compared with conventional sternotomy CABG. MICABG may have a role in treating single-vessel disease.

Identification and Characterization of ACP-5862, the Major Circulating Active Metabolite of Acalabrutinib: Both Are Potent and Selective Covalent Bruton Tyrosine Kinase Inhibitors .

Acalabrutinib is a covalent Bruton tyrosine kinase (BTK) inhibitor approved for relapsed/refractory mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. A major metabolite of acalabrutinib (M27, ACP-5862) was observed in human plasma circulation. Subsequently, the metabolite was purified from an in vitro biosynthetic reaction and shown by nuclear magnetic resonance spectroscopy to be a pyrrolidine ring-opened ketone/amide. Synthesis confirmed its structure, and covalent inhibition of wild-type BTK was observed in a biochemical kinase assay. A twofold lower potency than acalabrutinib was observed but with similar high kinase selectivity. Like acalabrutinib, ACP-5862 was the most selective toward BTK relative to ibrutinib and zanubrutinib. Because of the potency, ACP-5862 covalent binding properties, and potential contribution to clinical efficacy of acalabrutinib, factors influencing acalabrutinib clearance and ACP-5862 formation and clearance were assessed. rCYP (recombinant cytochrome P450) reaction phenotyping indicated that CYP3A4 was responsible for ACP-5862 formation and metabolism. ACP-5862 formation Km (Michaelis constant) and Vmax were 2.78 µM and 4.13 pmol/pmol CYP3A/min, respectively. ACP-5862 intrinsic clearance was 23.6 µL/min per mg. Acalabrutinib weakly inhibited CYP2C8, CYP2C9, and CYP3A4, and ACP-5862 weakly inhibited CYP2C9 and CYP2C19; other cytochrome P450s, UGTs (uridine 5'-diphospho-glucuronosyltransferases), and aldehyde oxidase were not inhibited. Neither parent nor ACP-5862 strongly induced CYP1A2, CYP2B6, or CYP3A4 mRNA. Acalabrutinib and ACP-5862 were substrates of multidrug resistance protein 1 and breast cancer resistance protein but not OATP1B1 or OATP1B3. Our work indicates that ACP-5862 may contribute to clinical efficacy in acalabrutinib-treated patients and illustrates how proactive metabolite characterization allows timely assessment of drug-drug interactions and potential contributions of metabolites to pharmacological activity. SIGNIFICANCE STATEMENT: This work characterized the major metabolite of acalabrutinib, ACP-5862. Its contribution to the pharmacological activity of acalabrutinib was assessed based on covalent Bruton tyrosine kinase binding kinetics, kinase selectivity, and potency in cellular assays. The metabolic clearance and in vitro drug-drug interaction potential were also evaluated for both acalabrutinib and ACP-5862. The current data suggest that ACP-5862 may contribute to the clinical efficacy observed in acalabrutinib-treated patients and demonstrates the value of proactive metabolite identification and pharmacological characterization.

Authenticating coins of the 'Roman emperor' Sponsian.

The 'Roman emperor' Sponsian is known only from an assemblage of coins allegedly found in Transylvania (Romania) in 1713. They are very unlike regular Roman coins in style and manufacture, with various enigmatic features including bungled legends and historically mixed motifs, and have long been dismissed as poorly made forgeries. Here we present non-destructive imaging and spectroscopic results that show features indicative of authenticity. Deep micro-abrasion patterns suggest extensive circulation-wear. Superficial patches of soil minerals bound by authigenic cement and overlain by oxidation products indicate a history of prolonged burial then exhumation. These observations force a re-evaluation of Sponsian as a historical personage. Combining evidence from the coins with the historical record, we suggest he was most likely an army commander in the isolated Roman Province of Dacia during the military crisis of the 260s CE, and that his crudely manufactured coins supported a functioning monetary economy that persisted locally for an appreciable period.

Correction: Fossil and Genetic Evidence for the Polyphyletic Nature of the Planktonic Foraminifera "Globigerinoides", and Description of the New Genus Trilobatus.

[This corrects the article DOI: 10.1371/journal.pone.0128108.].

Late recognition of Gore Helex atrial septal occluder fracture and migration.

Patent foramen ovale (PFO) closure is indicated in cryptogenic stroke. Percutaneous PFO closure is both feasible and highly efficacious with low incidence of device-related complications. When complications occur, they are usually discovered within 6 weeks of device deployment. We describe the case of a partially embolised and fractured Gore Helex Septal Occluder device recognised nearly 9 years after placement requiring surgical explant. .

Venovenous Extracorporeal Membrane Oxygenation to Facilitate Removal of Endobronchial Tumors.

Short-term extracorporeal membrane oxygenation is a useful adjunct to thoracic procedures. We report the cases of 2 middle-aged men who were supported with venovenous extracorporeal membrane oxygenation to facilitate tumor debulking and recanalization of the carina and mainstem bronchi. Neither patient had major complications or adverse events. These cases suggest that short-term extracorporeal membrane oxygenation is safe in patients undergoing complex resection or debulking of endobronchial lesions.

Coiling directions in the planktonic foraminifer Pulleniatina: A complex eco-evolutionary dynamic spanning millions of years.

Planktonic foraminifera are heterotrophic sexually reproducing marine protists with an exceptionally complete fossil record that provides unique insights into long-term patterns and processes of evolution. Populations often exhibit strong biases towards either right (dextral) or left (sinistral) shells. Deep-sea sediment cores spanning millions of years reveal that some species show large and often rapid fluctuations in their dominant coiling direction through time. This is useful for biostratigraphic correlation but further work is required to understand the population dynamical processes that drive these fluctuations. Here we address the case of coiling fluctuations in the planktonic foraminifer genus Pulleniatina based on new high-resolution counts from two recently recovered sediment cores from either side of the Indonesian through-flow in the tropical west Pacific and Indian Oceans (International Ocean Discovery Program Sites U1486 and U1483). We use single-specimen stable isotope analyses to show that dextral and sinistral shells from the same sediment samples can show significant differences in both carbon and oxygen isotopes, implying a degree of ecological separation between populations. In one case we detect a significant difference in size between dextral and sinistral specimens. We suggest that major fluctuations in coiling ratio are caused by cryptic populations replacing one another in competitive sweeps, a mode of evolution that is more often associated with asexual organisms than with the classical 'biological species concept'.

Prospective Evaluation of Transseptal TMVR for Failed Surgical Bioprostheses: MITRAL Trial Valve-in-Valve Arm 1-Year Outcomes.

OBJECTIVES: The aim of this study was to assess 1-year clinical outcomes among high-risk patients with failed surgical mitral bioprostheses who underwent transseptal mitral valve-in-valve (MViV) with the SAPIEN 3 aortic transcatheter heart valve (THV) in the MITRAL (Mitral Implantation of Transcatheter Valves) trial. BACKGROUND: The MITRAL trial is the first prospective study evaluating transseptal MViV with the SAPIEN 3 aortic THV in high-risk patients with failed surgical mitral bioprostheses. METHODS: High-risk patients with symptomatic moderate to severe or severe mitral regurgitation (MR) or severe mitral stenosis due to failed surgical mitral bioprostheses were prospectively enrolled. The primary safety endpoint was technical success. The primary THV performance endpoint was absence of MR grade ≥2+ or mean mitral valve gradient ≥10 mm Hg (30 days and 1 year). Secondary endpoints included procedural success and all-cause mortality (30 days and 1 year). RESULTS: Thirty patients were enrolled between July 2016 and October 2017 (median age 77.5 years [interquartile range (IQR): 70.3 to 82.8 years], 63.3% women, median Society of Thoracic Surgeons score 9.4% [IQR: 5.8% to 12.0%], 80% in New York Heart Association functional class III or IV). The technical success rate was 100%. The primary performance endpoint in survivors was achieved in 96.6% (28 of 29) at 30 days and 82.8% (24 of 29) at 1 year. Thirty-day all-cause mortality was 3.3% and was unchanged at 1 year. The only death was due to airway obstruction after swallowing several pills simultaneously 29 days post-MViV. At 1-year follow-up, 89.3% of patients were in New York Heart Association functional class I or II, the median mean mitral valve gradient was 6.6 mm Hg (interquartile range: 5.5 to 8.9 mm Hg), and all patients had MR grade ≤1+. CONCLUSIONS: Transseptal MViV in high-risk patients was associated with 100% technical success, low procedural complication rates, and very low mortality at 1 year. The vast majority of patients experienced significant symptom alleviation, and THV performance remained stable at 1 year.

Temperature controls carbon cycling and biological evolution in the ocean twilight zone.

Theory suggests that the ocean's biological carbon pump, the process by which organic matter is produced at the surface and transferred to the deep ocean, is sensitive to temperature because temperature controls photosynthesis and respiration rates. We applied a combined data-modeling approach to investigate carbon and nutrient recycling rates across the world ocean over the past 15 million years of global cooling. We found that the efficiency of the biological carbon pump increased with ocean cooling as the result of a temperature-dependent reduction in the rate of remineralization (degradation) of sinking organic matter. Increased food delivery at depth prompted the development of new deep-water niches, triggering deep plankton evolution and the expansion of the mesopelagic "twilight zone" ecosystem.

Author Correction: Large-scale mass wasting in the western Indian Ocean constrains onset of East African rifting.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Large-scale mass wasting in the western Indian Ocean constrains onset of East African rifting.

Faulting and earthquakes occur extensively along the flanks of the East African Rift System, including an offshore branch in the western Indian Ocean, resulting in remobilization of sediment in the form of landslides. To date, constraints on the occurrence of submarine landslides at margin scale are lacking, leaving unanswered a link between rifting and slope instability. Here, we show the first overview of landslide deposits in the post-Eocene stratigraphy of the Tanzania margin and we present the discovery of one of the biggest landslides on Earth: the Mafia mega-slide. The emplacement of multiple landslides, including the Mafia mega-slide, during the early-mid Miocene is coeval with cratonic rifting in Tanzania, indicating that plateau uplift and rifting in East Africa triggered large and potentially tsunamigenic landslides likely through earthquake activity and enhanced sediment supply. This study is a first step to evaluate the risk associated with submarine landslides in the region.

Comparative pharmacokinetics and pharmacodynamics of the advanced Retinol-Binding Protein 4 antagonist in dog and cynomolgus monkey.

Accumulation of lipofuscin bisretinoids in the retina contributes to pathogenesis of macular degeneration. Retinol-Binding Protein 4 (RBP4) antagonists reduce serum retinol concentrations thus partially reducing retinol delivery to the retina which decreases bisretinoid synthesis. BPN-14136 is a novel RBP4 antagonist with good in vitro potency and selectivity and optimal rodent pharmacokinetic (PK) and pharmacodynamic (PD) characteristics. To select a non-rodent species for regulatory toxicology studies, we conducted PK and PD evaluation of BPN-14136 in dogs and non-human primates (NHP). PK properties were determined following oral and intravenous administration of BPN-14136 in beagle dogs and cynomolgus monkeys. Dynamics of plasma RBP4 reduction in response to compound administration was used as a PD marker. BPN-14136 exhibited favorable PK profile in both species. Dose-normalized exposure was significantly higher in NHP than in dog. Baseline concentrations of RBP4 were considerably lower in dog than in NHP, reflecting the atypical reliance of canids on non-RBP4 mechanisms of retinoid trafficking. Oral administration of BPN-14136 to NHP induced a strong 99% serum RBP4 reduction. Dynamics of RBP4 lowering in both species correlated with compound exposure. Despite adequate PK and PD characteristics of BPN-14136 in dog, reliance of canids on non-RBP4 mechanisms of retinoid trafficking precludes evaluation of on-target toxicities for RBP4 antagonists in this species. Strong RBP4 lowering combined with good PK attributes and high BPN-14136 exposure achieved in NHP, along with the biology of retinoid trafficking that is similar to that of humans, support the choice of NHP as a non-rodent safety species.