Bioactivity of the cannabigerol cannabinoid and its analogues - the role of 3-dimensional conformation.

Cannabinoids are naturally occurring bioactive compounds with the potential to help treat chronic illnesses including epilepsy, Parkinson's disease, dementia and multiple sclerosis. Their general structures and efficient syntheses are well documented in the literature, yet their quantitative structure-activity relationships (QSARs), particularly 3-dimensional (3-D) conformation-specific bioactivities, are not fully resolved. Cannabigerol (CBG), an antibacterial precursor molecule for the most abundant phytocannabinoids, was characterised herein using density functional theory (DFT), together with selected analogues, to ascertain the influence of the 3D structure on their activity and stability. Results showed that the CBG family's geranyl chains tend to coil around the central phenol ring while its alkyl side-chains form H-bonds with the para-substituted hydroxyl groups as well as CH⋯π interactions with the aromatic density of the ring itself, among other interactions. Although weakly polar, these interactions are structurally and dynamically influential, effectively 'stapling' the ends of the chains to the central ring structure. Molecular docking of the differing 3-D poses of CBG to cytochrome P450 3A4 resulted in lowered inhibitory action by the coiled conformers, relative to their fully-extended counterparts, helping explain the trends in the inhibition of the metabolic activity of the CYP450 3A4. The approach detailed herein represents an effective method for the characterisation of other bioactive molecules, towards improved understanding of their QSARs and in guiding the rational design and synthesis of related compounds.

Aluminium catalysed oligomerisation in cement-forming silicate systems.

Alumino-silicates form the backbone of structural materials including cements and the concrete they form. However, the nanoscale aspects of the oligomerisation mechanisms elongating the (alumino-)silicate chains is not fully clarified; the role of aluminium in particular. Herein, we explore and contrast the growth of silicate and alumino-silicate oligomers by both neutral and anionic mechanisms, with focus on the influence of Al on oligomer structure and stability. Further, the spontaneity of chain lengthening in the absence and presence of Al of differing coordination (Al-IV, V, VI) was characterised. Result trends showed Al-IV facilitating oligomerisation in neutral conditions, with respect to Si only systems, effectively promoting longer chain formation and stabilisation. The anionic pathway similarly showed Al reducing the overall energetic barriers to oligomerisation. In both conditions, Al's coordinative and structural flexibility, at O-Al-O hinge points in particular, was responsible for the lowering of the energetic expense for oligomerisation. The results and implications resolved herein are informative for chain formation and stability for bulk material properties of alumino-silicate materials such as cements, where the aluminosilicate systems are dominated by short chains of 2-5 units in length.

Prospective Multicenter Study of Myocardial Recovery Using Left Ventricular Assist Devices (RESTAGE-HF [Remission from Stage D Heart Failure]): Medium-Term and Primary End Point Results.

BACKGROUND: Left ventricular assist device (LVAD) unloading and hemodynamic support in patients with advanced chronic heart failure can result in significant improvement in cardiac function allowing LVAD removal; however, the rate of this is generally considered to be low. This prospective multicenter nonrandomized study (RESTAGE-HF [Remission from Stage D Heart Failure]) investigated whether a protocol of optimized LVAD mechanical unloading, combined with standardized specific pharmacological therapy to induce reverse remodeling and regular testing of underlying myocardial function, could produce a higher incidence of LVAD explantation. METHODS: Forty patients with chronic advanced heart failure from nonischemic cardiomyopathy receiving the Heartmate II LVAD were enrolled from 6 centers. LVAD speed was optimized with an aggressive pharmacological regimen, and regular echocardiograms were performed at reduced LVAD speed (6000 rpm, no net flow) to test underlying myocardial function. The primary end point was the proportion of patients with sufficient improvement of myocardial function to reach criteria for explantation within 18 months with sustained remission from heart failure (freedom from transplant/ventricular assist device/death) at 12 months. RESULTS: Before LVAD, age was 35.1±10.8 years, 67.5% were men, heart failure mean duration was 20.8±20.6 months, 95% required inotropic and 20% temporary mechanical support, left ventricular ejection fraction was 14.5±5.3%, end-diastolic diameter was 7.33±0.89 cm, end-systolic diameter was 6.74±0.88 cm, pulmonary artery saturations were 46.7±9.2%, and pulmonary capillary wedge pressure was 26.2±7.6 mm Hg. Four enrolled patients did not undergo the protocol because of medical complications unrelated to the study procedures. Overall, 40% of all enrolled (16/40) patients achieved the primary end point, P<0.0001, with 50% (18/36) of patients receiving the protocol being explanted within 18 months (pre-explant left ventricular ejection fraction, 57±8%; end-diastolic diameter, 4.81±0.58 cm; end-systolic diameter, 3.53±0.51 cm; pulmonary capillary wedge pressure, 8.1±3.1 mm Hg; pulmonary artery saturations 63.6±6.8% at 6000 rpm). Overall, 19 patients were explanted (19/36, 52.3% of those receiving the protocol). The 15 ongoing explanted patients are now 2.26±0.97 years after explant. After explantation survival free from LVAD or transplantation was 90% at 1-year and 77% at 2 and 3 years. CONCLUSIONS: In this multicenter prospective study, this strategy of LVAD support combined with a standardized pharmacological and cardiac function monitoring protocol resulted in a high rate of LVAD explantation and was feasible and reproducible with explants occurring in all 6 participating sites. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01774656.

The infected diabetic foot: Can serum biomarkers predict osteomyelitis after hospital discharge for diabetic foot infections?

The aim of this study is to evaluate serum biomarkers to monitor high-risk patients for reinfection of bone. Thirty-five patients were prospectively enrolled with moderate to severe diabetic foot infections with suspicion of osteomyelitis. Bone samples were obtained for culture and histology. Clinical characteristics and outcomes of patients were compared using χ2 square test. Biomarkers (white blood cell count, erythrocyte sedimentation rate, c-reactive protein, procalcitonin, interleukin-6, interleukin-8, and monocyte chemoattractant protein 1) were assessed at baseline, 3, and 6 weeks after treatment initiation and evaluated for correlation with reinfection of bone. After 6 weeks of antibiotic treatment, ESR at 73.5 mm/h (sensitivity 62.5%, specificity 100%, area under the receiver operating characteristic (AUROC) 0.7839, 95% CI 0.54-1.00, P < .01) and IL-8 at 15.09 mg/dL (sensitivity 42.9%, specificity 92.0% AUROC 0.6286, 95% CI 0.36-0.90, P = .0496) were associated with reinfection of bone. An increase in IL-8 from week 0 to 6 >0.95 mg/dL was associated with reinfection (sensitivity 71%, specificity 72% AUROC 0.7057, 95% CI 0.49-0.92, P = .04). An ESR change from week 0-6 of -16.5% (sensitivity 71.4%, specificity 86.4% AUROC 0.7403, 95% CI 0.48-1.00, P = .02), CRP (-)74.4% (sensitivity 66.7%, specificity 91.3% AUROC 0.7174, 95% CI 0.40-1.00, P = .04), IL-6 (-)49.9% (sensitivity 71.4%, specificity 76% AUROC 0.7371, 95% CI 0.47-1.00, P = .04), and IL-8 29% (sensitivity 85.7%, specificity 56.0% AUROC of 0.7343, 95% CI 0.54-0.93, P = .048) were associated with increased risk of reinfection. Pilot data suggest that serum biomarkers (ESR, IL8 and IL6, MCP-1) may be correlated with developing osteomyelitis and could be used to monitor high-risk patients for reinfection.

Randomized clinical study to compare negative pressure wound therapy with simultaneous saline irrigation and traditional negative pressure wound therapy for complex foot infections.

The aim of this study was to compare the efficacy of different negative pressure wound therapy (NPWT) devices and NPWT with and without simultaneous irrigation in patients admitted to hospital with moderate and severe foot infections. Ninety patients were randomized in a 12-week prospective, randomized noninferiority trial to compare wound healing in patients with moderate and severe infected foot wounds treated with NPWT after surgery. Inclusion criteria included ABI > 0.5 or toe pressures >30 PVR/mmHg, >18 years of age and exclusion included active Charcot arthropathy, collagen vascular disease, HIV, and hypercoagulable state. We compared two different traditional devices, NPWT-K (KCI, VAC Ulta) and NPWT-C (Cardinal, PRO), and NPWT-I with saline irrigation (Cardinal, PRO). All patients had therapy delivered at 125 mmHg continuous pressure. In patients who received simultaneous saline irrigation (NPWT-I), the administration rate was 15 ml per hour. The primary outcome was the proportion of healed wounds in 12 weeks. Secondary outcomes included surgical wound closure, number of surgeries, length of stay, and time to wound healing. Continuous data was presented as mean ± standard deviation. Analysis of variance was used to compare continuous variables and chi-square to compare dichotomous variables with an alpha of 0.05. There were no differences in outcomes among NPWT-I, NPWT-C, and NPWT-K groups in proportion of healed wounds (63.3%, 50.0%, 46.7% p = 0.39), surgical wound closure (83.3%, 80.0%, 63.3%, p = 0.15), number of surgeries (2.0 ± 0.49, 2.4 ± 0.77, 2.4 ± 0.68, p = 0.06), length of stay (16.3 ± 15.7, 14.7 ± 7.4, 15.3 ± 10.5 days, p = 0.87), time to wound healing (46.2 ± 22.8, 40.9 ± 18.8, 45.9 ± 28.3 days, p = 0.78). We did not identify any significant differences in clinical outcomes or adverse events between patients treated with different NPWT devices or NPWT with and without irrigation.

Lyopreserved amniotic membrane is cellularly and clinically similar to cryopreserved construct for treating foot ulcers.

We compared cellular viability between cryopreserved and lyopreserved amniotic membranes and clinical outcomes of the lyopreserved construct in a prospective cohort study of 40 patients with neuropathic foot ulcers. Patients received weekly application of lyopreserved membrane for 12 weeks with standard weekly debridement and offloading. We evaluated the proportion of foot ulcers that closed, time to closure, closure trajectories, and infection during therapy. We used chi-square tests for dichotomous variables and independent t-tests for continuous variables with an alpha of α = .10. Cellular viability was equivalent between cryo- and lyopreserved amniotic tissues. Clinically, 48% of subjects' wounds closed in an average of 40.0 days. Those that did not close were older (63 vs 59 years, P = .011) and larger ulcers at baseline (7.8 vs 1.6 cm2 , P = .012). Significantly more patients who achieved closure reached a 50% wound area reduction in 4 weeks compared with non-closed wounds (73.7% vs 47.6%, P = .093). There was no difference in the slope of the wound closure trajectories between closed and non-closed wounds (0.124 and 0.159, P = .85), indicating the rate of closure was similar. The rate of closure was 0.60 mm/day (SD = 0.47) for wounds that closed and 0.50 mm/day (SD = 0.58) for wounds that did not close (P = .89).

The effect of continuous diffusion of oxygen treatment on cytokines, perfusion, bacterial load, and healing in patients with diabetic foot ulcers.

To evaluate continuous diffusion of oxygen therapy (CDO) on cytokines, perfusion, and bacterial load in diabetic foot ulcers we evaluated 23 patients for 3 weeks. Tissues biopsies were obtained at each visit to evaluate cytokines and quantitative bacterial cultures. Perfusion was measured with hyperspectral imaging and transcutaneous oxygen. We used paired T tests to compare continuous variables and independent T tests to compare healers and nonhealers. There was an increase from baseline to week 1 in TGF-ß (P = .008), TNF-α (P = .014), VEGF (P = .008), PDGF (P = .087), and IGF-1 (P = .058); baseline to week 2 in TGF-ß (P = .010), VEGF (P = .051), and IL-6 (P = .031); and baseline to week 3 with TGF-ß (P = .055) and IL-6 (P = .054). There was a significant increase in transcutaneous oxygen after 1 week of treatment on both medial and lateral foot (P = .086 and .025). Fifty-three percent of the patients had at least a 50% wound area reduction (healers). At baseline, there were no differences in cytokines between healers and nonhealers. However, there was an increase in CXCL8 after 1 week of treatment (P = .080) and IL-6 after 3 weeks of treatment in nonhealers (P = .099). There were no differences in quantitative cultures in healers and nonhealers.

High Transpulmonary Artery Gradient Obtained at the Time of Left Ventricular Assist Device Implantation Negatively Affects Survival After Cardiac Transplantation.

AIM: Preoperatively elevated pulmonary vascular resistance (PVR) is a contraindication to heart transplantation (HT). Transpulmonary pressure gradient (TPG) is one of the main variables used in PVR determination (ie, PVR = TPG/cardiac output). Unlike PVR, which is subject to the shortcoming of cardiac output estimation, TPG is directly measured. We aimed to evaluate the relationship of TPG obtained before left ventricular assist device (LVAD) implantation on post-HT survival. METHODS AND RESULTS: A total of 490 patients were implanted with Heartmate II LVADs in the multicenter Heartmate II Bridge-to-Transplantation clinical trial, and 416/490 had pre-LVAD TPG data available. Outcomes during LVAD support and after HT stratified by both PVR and TPG were studied. The median pre-LVAD TPG was 10 mm Hg. Baseline demographic and clinical characteristics were similar for patients with and without TPG >10 mm Hg. Outcomes during LVAD support (ie, recovery to LVAD explantation, HT, or ongoing device support) for patients below and above the median TPG were similar. However, post-HT 1-year survival rate was significantly higher for patients with TPG ≤10 mm Hg compared with those with TPG >10 mm Hg (91% vs 80%; P = .016). Analysis based on the median PVR of 2.68 Wood units did not stratify post-HTx 1-year survival rates between the groups (89% vs 83%; P = .25). CONCLUSIONS: Elevated TPG, rather than high PVR, before LVAD implantation was associated with increased mortality following HT. Pre-LVAD TPG may be useful to identify a cohort that requires close follow-up with serial hemodynamic monitoring before HT.

Preoperative Determinants of Quality of Life and Functional Capacity Response to Left Ventricular Assist Device Therapy.

BACKGROUND: Left ventricular assist devices (LVADs) improve survival, quality of life (QOL), and functional capacity (FC) among patients with end-stage heart failure. Few data are available regarding characteristics associated with QOL and FC response. METHODS AND RESULTS: Patients enrolled in the Heartmate II clinical trials that were alive with ongoing LVAD support at 6 months were included. QOL response criteria included scoring above the lowest quartile on either the Minnesota Living With Heart Failure Questionnaire or the Kansas City Cardiomyopathy Questionnaire. FC responder criteria included improvement in 6-minute walk distance (6MWD) >70 meters from baseline, a 6MWD >220 meters at 6 months, or New York Heart Association functional class I or II. Independent variables associated with QOL nonresponse included history of diabetes (odds ratio [OR] 1.82, 95% confidence interval [CI] 1.20-2.78), lower mean pulmonary arterial pressure (OR 0.97, 95% CI 0.95-0.99), or a Heartmate II right ventricular risk score >2 (OR 1.77, 95% CI 1.00-3.12). Variables associated with FC nonresponse included history of COPD (OR 1.92, 95% CI 1.22-3.03) or diabetes (OR 1.52, 95% CI 1.01-2.27). Compared with responders, QOL and FC nonresponders had reduced long-term survival. CONCLUSIONS: Preoperative comorbidities, including diabetes, COPD, and right heart failure, may limit the QOL and FC response to LVAD therapy and should be considered during the shared decision-making process.

Risk assessment and comparative effectiveness of left ventricular assist device and medical management in ambulatory heart failure patients: design and rationale of the ROADMAP clinical trial.

BACKGROUND: Mechanical circulatory support is now a proven therapy for the treatment of patients with advanced heart failure and cardiogenic shock. The role for this therapy in patients with less severe heart failure is unknown. OBJECTIVE: The objective of this study is to examine the impact of mechanically assisted circulation using the HeartMate II left ventricular assist device in patients who meet current US Food and Drug Administration-defined criteria for treatment but are not yet receiving intravenous inotropic therapy. METHODS: This is a prospective, nonrandomized clinical trial of 200 patients treated with either optimal medical management or a mechanical circulatory support device. CLINICAL CONTEXT: This trial will be the first prospective clinical evaluation comparing outcomes of patients with advanced ambulatory heart failure treated with either ongoing medical therapy or a left ventricular assist device. It is anticipated to provide novel insights regarding relative outcomes with each treatment and an understanding of patient and provider acceptance of the ventricular assist device therapy. This trial will also provide information regarding the risk of events in "stable" patients with advanced heart failure and guidance for the optimal timing of left ventricular assist device therapy.

Principles of HeartMate II implantation to avoid pump malposition and migration.

Proper left ventricular assist device (LVAD) insertion will help maximize LVAD flow and may reduce adverse events such as right heart failure and pump thrombosis. Although no standardized insertion technique has been universally accepted, the goals are: unobstructed inflow cannula, unobstructed outflow graft with avoidance of right ventricular compression, and prevention of pump migration. To achieve these objectives for the HeartMate II LVAD, we delineate four principles: proper pump pocket creation, optimized positioning of inflow cannula and outflow graft, proper pump position in the body, and fixation. These basic principles are easy to implement and have been beneficial in our patients, assuring long-term unobstructed LVAD flow.

Incidence, risk, and consequences of atrial arrhythmias in patients with continuous-flow left ventricular assist devices.

BACKGROUND: Although atrial arrhythmias (AAs) are common in heart failure, the incidence of AAs subsequent to the placement of left ventricular assist devices (LVADs) has not been elucidated. METHODS: Patients receiving a HeartMate II LVAD in the bridge to transplant (n = 490) and destination therapy (n = 634) trials were included (n = 1125). AAs requiring treatment were recorded, regardless of symptoms. Using Cox models with and without a 60-day blanking period, risk factors for early and late AAs were determined. RESULTS: In total, there were 271 AAs in 231 patients (21%), most of which occurred within the first 60 days. Patients with and without AAs had similar survival (p = 0.16). Serum creatinine (hazard ratio [HR] = 1.49 per unit increase, 1.18 to 1.88; p < 0.001) and ejection fraction (HR = 0.98 per 1% increase, 0.95 to 0.999; p = 0.04) were associated with AAs in a multivariable model. Although quality of life (QoL) and functional status improved in all patients, those with AAs had worse unadjusted QoL (p < 0.001) and a decreased rate of improvement in six-minute walk distance over six to 24 months postimplant (p = 0.016). CONCLUSIONS: Approximately one-fifth of LVAD patients have AAs, most commonly within the first 60 days of support. Preoperative creatinine is a strong risk factor for early and late AAs. Although AAs do not impact survival, they are associated with decreased functional status and QoL improvements during LVAD support.

Identification of ADB-5'Br-BINACA in plant material and analytical characterization using GC-MS, LC-QTOF-MS, NMR and ATR-FTIR.

Synthetic cannabinoids are a class of novel psychoactive substances that emerged in the drug market in the early 2010s. Since then, a wide range of different synthetic cannabinoids has been detected in drug materials and in biological specimens collected from intoxication cases. In general, synthetic cannabinoids are reported first in seized materials. In this study, the identification of the novel synthetic cannabinoid, ADB-5'Br-BINACA is reported. A plant material suspected to contain a synthetic cannabinoid was extracted and analyzed. Analyses were performed using gas chromatography-mass spectrometry (GC-MS), liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS), attenuated total reflectance Fourier transform infrared spectroscopy (ATR-FTIR) and one dimensional and two-dimensional nuclear magnetic resonance (NMR) spectroscopy. An aliquot of the sample was extracted using methanol and deuterated chloroform, and analyzed via GC-MS and NMR, respectively. Further dilution of the methanolic extract was analyzed via LC-QTOF-MS. For ATR-FTIR analyses, a few drops of the extract in deuterated chloroform were analyzed. GC-MS, LC-QTOF-MS, and 1H NMRwere successfully used to elucidate and confirm the structure of ADB-5'Br-BINACA in the drug sample. ATR-FTIR and 13C NMR analyses of the extracts did not result in significant information for the confirmation of ADB-5'Br-BINACA in the plant material likely due to low amount of drug material and high background noise. The chemical characterization of ADB-5'Br-BINACA in an authentic sample is reported herein, and chromatographic, mass spectrometric and spectroscopic data are provided for use in future analysis of this drug in suspected samples.

Cancer risk among tetrafluoroethylene synthesis and polymerization workers.

Tetrafluoroethylene (TFE), a compound used for the production of fluorinated polymers including polytetrafluoroethylene, increases the incidence of liver and kidney cancers and leukemia in rats and mice. This is the first time the cancer risk in humans has been explored comprehensively in a cohort mortality study (1950-2008) that included all polytetrafluoroethylene production sites in Europe and North America at the time it was initiated. A job-exposure matrix (1950-2002) was developed for TFE and ammonium perfluoro-octanoate, a chemical used in the polymerization process. National reference rates were used to calculate standardized mortality ratios (SMRs) and 95% confidence intervals. Among 4,773 workers ever exposed to TFE, we found a lower rate of death from most causes, as well as increased risks for cancer of the liver (SMR = 1.27; 95% confidence interval: 0.55, 2.51; 8 deaths) and kidney (SMR = 1.44; 95% confidence interval: 0.69, 2.65; 10 deaths) and for leukemia (SMR = 1.48; 95% confidence interval: 0.77, 2.59; 12 deaths). A nonsignificant upward trend (P = 0.24) by cumulative exposure to TFE was observed for liver cancer. TFE and ammonium perfluoro-octanoate exposures were highly correlated, and therefore their separate effects could not be disentangled. This pattern of findings narrows the range of uncertainty on potential TFE carcinogenicity but cannot conclusively confirm or refute the hypothesis that TFE is carcinogenic to humans.

Enhanced Thrombin Formation in Patients With Ventricular Assist Devices Experiencing Bleeding: Insights From the Multicenter PREVENT Study.

The aim of this investigation was to characterize the hemostatic status of heart failure patients with implanted left ventricular assist devices (LVADs) to propose a mechanism associated with bleeding. Patients (n = 300) from 23 US hospitals were enrolled in the PREVENtion of HeartMate II Pump Thrombosis through Clinical Management (PREVENT) study. A biobank was established with serum and plasma samples prospectively collected from a cohort of 175 patients preimplant baseline (BL) and 3 months (3M) postimplant. Outcomes were collected for 6 months. Thrombin (prothrombin fragment 1.2 [F1.2], functional thrombin generation [TG]) and fibrinolytic activity (D-dimer, plasminogen activator inhibitor-1 [PAI-1]), but not contact activation (complement C5a), were elevated in heart failure patients at BL. F1.2, TG, and PAI-1 levels decreased 3M after LVAD implantation ( p < 0.01) but did not revert to normal in all patients; conversely, D-dimer increased BL to 3M ( p < 0.01). Compared with patients without events, thrombin activity (F1.2) was increased in patients with late bleeding (3-4 months postimplant) ( p = 0.06) and in those with late gastrointestinal (GI) bleeding ( p = 0.01). Patients with 3M F1.2 levels above the cohort mean had a higher incidence of bleeding ( p < 0.001) and GI bleeding ( p < 0.001) compared with those with below mean F1.2. Patients experiencing multiple bleeding events were more likely to have 3M F1.2 greater than the cohort mean. Despite anticoagulation with aspirin and warfarin, LVAD implanted patients exhibit hemostatic activation. Excess thrombin formation, particularly shown by increased F1.2, was demonstrated in association with bleeding in LVAD implanted patients.

Association of Angiopoetin-2 and TNF-α With Bleeding During Left Ventricular Assist Device Support: Analysis From the PREVENT Biorepository.

The purpose of this study was to describe the changes in plasma levels of angiogenic and inflammatory biomarkers, specifically Ang-2 and TNF-α, in patients receiving HeartMate II (HMII) left ventricular assist device (LVAD) and correlate them with nonsurgical bleeding. It has been shown that angiopoietin-2 (Ang-2) and tissue necrosis factor-α (TNF-α) may be linked to bleeding in LVAD patients. This study utilized biobanked samples prospectively collected from the PREVENT study, a prospective, multicenter, single-arm, nonrandomized study of patients implanted with HMII. Paired serum samples were obtained in 140 patients before implantation and at 90 days postimplantation. Baseline demographics were as follows: age 57 ± 13 years, 41% had ischemic etiology, 82% male, and 75% destination therapy indication. In the 17 patients with baseline elevation of both TNF-α and Ang-2, 10 (60%) experienced a significant bleeding event within 180 days postimplant compared with 37 of 98 (38%) patients with Ang-2 and TNF-α below the mean ( p = 0.02). The hazard ratio for a bleeding event was 2.3 (95% CI: 1.2-4.6) in patients with elevated levels of both TNF-α and Ang-2. In the PREVENT multicenter study, patients with elevations in serum Angiopoietin-2 and TNF-α at baseline before LVAD implantation demonstrated increased bleeding events after LVAD implantation.

Use of a Pulmonary Artery Pressure Sensor to Manage Patients With Left Ventricular Assist Devices.

BACKGROUND: Hemodynamic-guided management with a pulmonary artery pressure sensor (CardioMEMS) is effective in reducing heart failure hospitalization in patients with chronic heart failure. This study aims to determine the feasibility and clinical utility of the CardioMEMS heart failure system to manage patients supported with left ventricular assist devices (LVADs). METHODS: In this multicenter prospective study, we followed patients with HeartMate II (n=52) or HeartMate 3 (n=49) LVADs and with CardioMEMS PA Sensors and measured pulmonary artery pressure, 6-minute walk distance, quality of life (EQ-5D-5 L scores), and heart failure hospitalization rates through 6 months. Patients were stratified as responders (R) and nonresponders to reductions in pulmonary artery diastolic pressure (PAD). RESULTS: There were significant reductions in PAD from baseline to 6 months in R (21.5-16.5 mm Hg; P<0.001), compared with an increase in NR (18.0-20.3; P=0.002), and there was a significant increase in 6-minute walk distance among R (266 versus 322 meters; P=0.025) compared with no change in nonresponder. Patients who maintained PAD <20 compared with PAD ≥20 mm Hg for more than half the time throughout the study (averaging 15.6 versus 23.3 mm Hg) had a statistically significant lower rate of heart failure hospitalization (12.0% versus 38.9%; P=0.005). CONCLUSIONS: Patients with LVAD managed with CardioMEMS with a significant reduction in PAD at 6 months showed improvements in 6-minute walk distance. Maintaining PAD <20 mm Hg was associated with fewer heart failure hospitalizations. Hemodynamic-guided management of patients with LVAD with CardioMEMS is feasible and may result in functional and clinical benefits. Prospective evaluation of ambulatory hemodynamic management in patients with LVAD is warranted. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03247829.

CO2-mineralization and carbonation reactor rig: Design and validation for in situ neutron scattering experiments-Engineering and lessons learned.

CO2 mineralization via aqueous Mg/Ca/Na-carbonate (MgCO3/CaCO3/Na2CO3) formation represents a huge opportunity for the utilization of captured CO2. However, large-scale mineralization is hindered by slow kinetics due to the highly hydrated character of the cations in aqueous solutions (Mg2+ in particular). Reaction conditions can be optimized to accelerate carbonation kinetics, for example, by the inclusion of additives that promote competitive dehydration of Mg2+ and subsequent agglomeration, nucleation, and crystallization. For tracking mineralization and these reaction steps, neutron scattering presents unprecedented advantages over traditional techniques for time-resolved in situ measurements. However, a setup providing continuous solution circulation to ensure reactant system homogeneity for industrially relevant CO2-mineralization is currently not available for use on neutron beamlines. We, therefore, undertook the design, construction, testing and implementation of such a self-contained reactor rig for use on selected neutron beamlines at the ISIS Neutron and Muon Source (Harwell, UK). The design ensured robust attachment via suspension from the covering Tomkinson flange to stabilize the reactor assembly and all fittings (~25 kg), as well as facilitating precise alignment of the entire reactor and sample (test) cell with respect to beam dimension and direction. The assembly successfully accomplished the principal tasks of providing a continuous flow of the reaction mixture (~500 mL) for homogeneity, quantitative control of CO2 flux into the mixture, and temperature and pressure regulation throughout the reaction and measurements. The design is discussed, with emphasis placed on the reactor, including its geometry, components, and all technical specifications. Descriptions of the off-beamline bench tests, safety, and functionality, as well as the installation on beamlines and trial experimental procedure, are provided, together with representative raw neutron scattering results.

Advanced heart failure treated with continuous-flow left ventricular assist device.

BACKGROUND: Patients with advanced heart failure have improved survival rates and quality of life when treated with implanted pulsatile-flow left ventricular assist devices as compared with medical therapy. New continuous-flow devices are smaller and may be more durable than the pulsatile-flow devices. METHODS: In this randomized trial, we enrolled patients with advanced heart failure who were ineligible for transplantation, in a 2:1 ratio, to undergo implantation of a continuous-flow device (134 patients) or the currently approved pulsatile-flow device (66 patients). The primary composite end point was, at 2 years, survival free from disabling stroke and reoperation to repair or replace the device. Secondary end points included survival, frequency of adverse events, the quality of life, and functional capacity. RESULTS: Preoperative characteristics were similar in the two treatment groups, with a median age of 64 years (range, 26 to 81), a mean left ventricular ejection fraction of 17%, and nearly 80% of patients receiving intravenous inotropic agents. The primary composite end point was achieved in more patients with continuous-flow devices than with pulsatile-flow devices (62 of 134 [46%] vs. 7 of 66 [11%]; P<0.001; hazard ratio, 0.38; 95% confidence interval, 0.27 to 0.54; P<0.001), and patients with continuous-flow devices had superior actuarial survival rates at 2 years (58% vs. 24%, P=0.008). Adverse events and device replacements were less frequent in patients with the continuous-flow device. The quality of life and functional capacity improved significantly in both groups. CONCLUSIONS: Treatment with a continuous-flow left ventricular assist device in patients with advanced heart failure significantly improved the probability of survival free from stroke and device failure at 2 years as compared with a pulsatile device. Both devices significantly improved the quality of life and functional capacity. (ClinicalTrials.gov number, NCT00121485.)

Young patients with nonischemic cardiomyopathy have higher likelihood of left ventricular recovery during left ventricular assist device support.

BACKGROUND: Recovery of ventricular function during left ventricular assist device (LVAD) support allowing device explantation occurs infrequently. We explored the hypothesis that certain patient profiles are more likely to exhibit LV recovery during LVAD support. METHODS AND RESULTS: A retrospective analysis of data from the HeartMate II bridge to transplant (BTT) and destination therapy (DT) trials was conducted, including 490 BTT, 600 DT, and 18 compassionate-use patients. Of the 1,108 patients, 20 (1.8%; 10 BTT, 10 DT) were explanted owing to LV recovery. The median age was 33 years, and 12 patients (60%) were <40 years of age. History of heart failure was <1 year for 11 patients (61%), and the primary etiology was nonischemic (90%). Of the patients with nonischemic etiologies and <1-year history of heart failure, 13% were explanted. Three patients required LVAD reimplantation; of the remaining 17, 16 remain alive. At follow-up (median 510 days), the mean ejection fraction was 42% (20%-67%) and the mean left ventricular end-diastolic diameter was 55 ± 8 mm. At the 2-year follow-up (n = 13), patients were New York Heart Association functional class I or II and overall survival rate was 85 ± 11%. CONCLUSIONS: The results of this study suggest that LV recovery is most likely to occur in young patients (<40 years) with nonischemic cardiomyopathy of <1 year duration. Two-year postexplant survival was excellent.