Relative contribution of canopy and soil effects between plants with different metal tolerance along a metal pollution gradient.

Multiple effects, operating either on the long-term (soil-engineering effects) or on the short-term during plant life (microclimate modification or resources pre-emption), can act simultaneously and determine the outcome of plant-plant interactions. These diverse effects have not been disentangled along a gradient of metal/metalloid pollution, although this is crucial for understanding the dominant species turnover along the gradient, and thus the driving processes of facilitation recurrently found in metalliferous ecosystems, which could help improving ecological restoration of these degraded ecosystems. Here, we experimentally assessed different short-term effects of two dominant forbs of highly polluted habitats (Hutchinsia alpina and Arenaria multicaulis, tolerant to metal stress) and two grasses of less polluted habitats (Agrostis capillaris and Festuca rubra, less tolerant to metal stress) on target plant species (the same as the dominant species mentioned above) transplanted along a large metal pollution gradient. Additionally, in highly polluted environments, we differentiated short- from long-term effects of the two metallicolous forbs, which had different abilities to concentrate metals in their leaves. In line with other studies along metal gradients, variation of short-term interactions appeared to follow the Stress Gradient Hypothesis for plants less adapted to metal pollution (p = 0.030), with positive interactions dominating in most severe areas. Regarding long-term effects, the species with highest leaf metal-accumulation showed no negative effect contrary to the Elemental allelopathy Hypothesis. Long-term effects of the species with lower leaf-metal accumulation could not be determined because of the occurrence of an unexpected difference in micro-habitat conditions (soil depth and humidity) for this species along the metal pollution gradient. Increasing short-term facilitation along metal pollution gradients, which confirmed previous studies, is promising for improving conditions and restoring the most polluted environments. However, long-term results stressed the difficulty to quantify these effects given that these areas are highly fragmented and heterogeneous.

The role of ecotypic variation for plant facilitation in a metal-polluted system: Stress-intolerant target ecotypes are the best beneficiaries and stress-tolerant nurse ecotypes the best benefactors.

Disentangling competitive-response and -effect abilities has strongly improved our understanding of the role of competition for the diversity and composition of plant communities. Much less is known about the relative importance of facilitative-effect and -response abilities in harsh ecosystems. Here, we aim to fill this gap by simultaneously assessing the facilitative-response and -effect abilities of different species and ecotypes in former mining sites in the French Pyrenees, both in naturally occurring communities and in a common-garden designed on a slag heap. The response of two ecotypes of the target species Festuca rubra with contrasting metal-stress tolerances and the facilitative effects of two ecotypes with contrasting metal-stress tolerances of four different metallicolous nurse species were assessed. The results revealed that the response of the Festuca ecotype with lower metal-stress tolerance shifted from competitive (RII = -0.24) to facilitative (RII = 0.29) as pollution increased, consistently with the stress-gradient-hypothesis. The Festuca ecotype with high metal-stress tolerance did not show any facilitative response. Regarding facilitative effect ability assessed in the common-garden, nurse ecotypes from highly polluted habitats (RII = 0.04) had a significantly higher facilitative effects than ecotypes from less polluted habitats (RII = -0.05). Metal-intolerant target ecotypes of Festuca rubra were the most sensitive to the positive effects of neighbours, while metal-tolerant nurse ecotypes were the best benefactors. Facilitative-response ability appeared to be driven by a trade-off between stress-tolerance and facilitative response of target ecotypes. In contrast, facilitative-effect ability was positively correlated to the stress-tolerance of nurse plants. The results of this study show that the highest restoration success of highly metal-stressed systems should be found when highly stress-tolerant nurse ecotypes are associated with less stress-tolerant target ecotypes.

Junctional Tachycardia: A Critical Reassessment.

Junctional tachycardia (JT) is typically considered to have an automatic mechanism originating from the distal atrioventricular node. When there is 1:1 retrograde conduction via the fast pathway, JT would resemble the typical form of atrioventricular nodal re-entrant tachycardia (AVNRT). Atrial pacing maneuvers have been proposed to exclude AVNRT and suggest a diagnosis of JT. However, after excluding AVNRT, one should consider the possibility of an infra-atrial narrow QRS re-entrant tachycardia, which can exhibit features that resemble AVNRT as well as JT. Pacing maneuvers and mapping techniques should be performed to assess for infra-atrial re-entrant tachycardia before concluding that JT is the mechanism of a narrow QRS tachycardia. Distinguishing JT from typical AVNRT or infra-atrial re-entrant tachycardia has notable implications regarding the approach to ablation of the tachycardia. Ultimately, a contemporary review of the evidence on JT raises some questions as to the mechanism and source of what has traditionally been considered JT.

Cardiac resynchronisation therapy in anthracycline-induced cardiomyopathy.

INTRODUCTION: Chemotherapy-induced cardiomyopathy has been increasingly recognised as patients are living longer with more effective treatments for their malignancies. Anthracyclines are known to cause left ventricular (LV) dysfunction. While heart failure medications are frequently used, some patients may need consideration for device-based therapies such as cardiac resynchronisation therapy (CRT). However, the role of CRT in anthracycline-induced cardiomyopathy (AIC) is not well understood. METHODS: We performed a retrospective review of all patients undergoing CRT implantation at our centre from 2003 to 2019 with a diagnosis of AIC. The LV remodelling and survival outcomes of this population were obtained and then compared with consecutive patients with other aetiologies of non-ischaemic cardiomyopathy (NICM). RESULTS: A total of 34 patients underwent CRT implantation with a diagnosis of AIC with a mean age of 60.5±12.7 years, left ventricular ejection fraction (LVEF) of 21.7%±7.4%, and 11.3±7.5 years and 10.2±7.4 years from cancer diagnosis and last anthracycline exposure, respectively. At 9.6±8.1 months after CRT implantation, there was an increase of LVEF from 21.8%±7.6% to 30.4%±13.0% (p<0.001). Patients whose LVEF increased by at least 10% post-CRT implant (42.5% of cohort) survived significantly longer than patients who failed to improve their LVEF by that amount (p=0.01). A propensity matched analysis between patients with AIC and 369 consecutive patients with other aetiologies of NICM who underwent CRT implantation during the same period revealed no significant differences in improvement in LVEF or long-term survival. CONCLUSIONS: Patients with AIC undergo LV remodelling with CRT at rates similar to other aetiologies of NICM. Furthermore, AIC post-CRT responders have a favourable long-term mortality compared with non-responders.

CHA2DS2-VASc score stratifies mortality risk in patients with and without atrial fibrillation.

OBJECTIVES: The CHA2DS2-VASc score is the preferred risk model for anticoagulation decision-making in atrial fibrillation (AF) patients. Recent studies have found this score to have prognostic value in other cardiovascular diseases. We assessed the relationships between CHA2DS2-VASc score and long-term mortality in adults referred for stress testing, METHODS: 165 184 consecutive patients from January 1991 to December 2014 from a prospective registry were studied, with CHA2DS2-VASc score calculated for all patients, and AF and anticoagulation status were recorded. The primary endpoint was all-cause mortality. RESULTS: In this cohort, 12 450 (7.5%) patients had AF and mean CHA2DS2-VASc score was 2.2±1.2. There were 22 152 (18.4%) deaths during mean follow-up of 6.1±4.8 years. In multivariable analysis, CHA2DS2-VASc score, presence of AF and anticoagulation use, along with end-stage renal failure and smoking were all independently associated with mortality with HRs (95% CIs) of 1.23 (1.21 to 1.25), 1.18 (1.10 to 1.27) and 1.50 (1.40 to 1.60), respectively. Higher CHA2DS2-VASc score was incrementally associated with worse survival both in patients with and without AF (log-rank p<0.001). Anticoagulation use was associated with reduced survival in non-AF patients with alternative anticoagulation indications at all CHA2DS2-VASc score categories, and AF patients with lower CHA2DS2-VASc score 0-2, but was protective in AF patients with higher CHA2DS2-VASc score 4-9. CONCLUSION: Incrementally higher CHA2DS2-VASc score, a simple clinical tool, is associated with mortality in patients regardless of presence of AF and anticoagulation status. Anticoagulation use was associated with worse survival in non-AF patients and AF patients with low CHA2DS2-VASc scores, but was protective in AF patients with high CHA2DS2-VASc scores.

Cardiac Resynchronization Therapy With or Without Defibrillation in Patients With Nonischemic Cardiomyopathy: A Systematic Review and Meta-Analysis.

[Figure: see text].

Comparative Analysis of Procedural Outcomes and Complications Between De Novo and Upgraded Cardiac Resynchronization Therapy.

OBJECTIVES: This study compared rates of procedural success and complications between de novo cardiac resynchronization therapy (CRT) implantation versus upgrade, including characterization of technical challenges. BACKGROUND: CRT upgrade is common, but data are limited on the incidence of procedural success and complications as compared to de novo implantation. METHODS: All patients who underwent a transvenous CRT procedure at a single institution between 2013 and 2018 were reviewed for procedure outcome, 90-day complications, reasons for unsuccessful left ventricular lead delivery, and the presence of venous occlusive disease (VOD) that required a modified implantation technique. RESULTS: Among 1,496 patients, 947 (63%) underwent de novo implantation and 549 (37%) underwent device upgrade. Patients who received a device upgrade were older (70 ± 12 years vs. 68 ± 13 years; p < 0.01), with a male predominance (75% vs. 66%; p < 0.01) and greater prevalence of comorbidities. There was no difference in the rate of procedural success between de novo and upgrade CRT procedures (97% vs. 96%; p = 0.28) or 90-day complications (5.1% vs. 4.6%; p = 0.70). VOD was present in 23% of patients who received a device upgrade and was more common among patients with a dual-chamber versus a single-chamber device (26% vs. 9%; p < 0.001). Patients with and without VOD had a similar composite outcome of procedural failure or complication (8.0% vs. 7.8%; p = 1.0). CONCLUSIONS: Rates of procedural success and complications were no different between de novo CRT implantations and upgrades. VOD frequently increased procedural complexity in upgrades, but alternative management strategies resulted in similar outcomes. Routine venography before CRT upgrade may aid in procedural planning and execution of these strategies.

Clinical Characteristics and Outcomes of Non-ICU Hospitalization for COVID-19 in a Nonepicenter, Centrally Monitored Healthcare System.

BACKGROUND: The clinical characteristics and outcomes associated with non-intensive care unit (non-ICU) hospitalizations for coronavirus disease 2019 (COVID-19) outside disease epicenters remain poorly characterized. METHODS: Systematic analysis of all non-ICU patient hospitalizations for COVID-19 completing discharge between March 13 and May 1, 2020, in a large US health care system utilizing off-site central monitoring. Variables of interest were examined in relation to a composite event rate of death, ICU transfer, or increased oxygen requirement to high-flow nasal cannula, noninvasive ventilation, or mechanical ventilation. RESULTS: Among 350 patients (age, 64 ± 16 years; 55% male), most (73%) required 3 L/min or less of supplemental oxygen during admission. Telemetry was widely utilized (79%) yet arrhythmias were uncommon (14%) and were predominantly (90%) among patients with abnormal troponin levels or known cardiovascular disease. Ventricular tachycardia was rare (5%), nonsustained, and not associated with hydroxychloroquine/azithromycin treatment. Adverse events occurred in 62 patients (18%), including 22 deaths (6%), 48 ICU transfers (14%), and 49 patients with increased oxygen requirement (14%) and were independently associated with elevated C-reactive protein (odds ratio, 1.09 per 1 mg/dL; 95% CI, 1.01-1.18; P = .04) and lactate dehydrogenase (OR, 1.006 per 1U/L; 95% CI, 1.001-1.012; P = .03) in multivariable analysis. CONCLUSION: Among non-critically ill patients hospitalized within a nonepicenter health care system, overall survival was 94% with the development of more severe illness or death independently associated with higher levels of C-reactive protein and lactate dehydrogenase on admission. Clinical decompensation was largely respiratory-related, while serious cardiac arrhythmias were rare, which suggests that telemetry can be prioritized for high-risk patients.

Postoperative bridging anticoagulation and left ventricular assist system thrombosis.

Reduced emphasis on early postoperative bridging anticoagulation is one explanation for the increased incidence of HeartMate II (HM II) pump thrombosis. We conducted a single-center analysis of initial postoperative anticoagulation practices and their impact on the incidence of HM II pump thrombosis. Data was collected on 105 patients undergoing primary HM II implant from 2009 to 2014. A parenteral bridge was defined as use of parenteral anticoagulation prior to attainment of an international normalized ratio ≥ 2 on warfarin. A parenteral bridge was further characterized as early if initiated ≤ 3 days of implant and therapeutic if a manufacturer-specified goal partial thromboplastin time (PTT) was achieved during each of the first 3 days of administration. Pump thrombosis was "suspected" based upon suggestive clinical parameters leading to hospital admission with parenteral anticoagulant administration and "confirmed" by direct visualization of thrombus in the device. A majority of patients (70%) were treated with an initial parenteral bridge, which was started within 3 days of device implantation in 68% of cases. Therapeutic PTT levels were achieved in 52% of patients treated with a parenteral bridge. Patients who were bridged had lower Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profiles (p = 0.039) and longer intensive care unit stay (p = 0.005). Pump thrombosis was suspected in 25% and confirmed in 13% of patients within 6 months of implant. Point estimates of pump thrombosis incidence demonstrated a lower event rate at 6 months in patients who received a therapeutic bridge (15.8%, 95% CI 6.3-29.1% for suspected; 7.9%, 95% CI 2.0-19.3% for confirmed) compared to those who did not receive a therapeutic bridge (29.9%, CI 19.3-41.1% for suspected; 16.4%, 95% CI 8.7-26.3% for confirmed). This trend was not sustained at 12 and 24 months. Cumulative incidence analyses showed no significant difference in the overall incidence of pump thrombosis between patients who did and did not receive a parenteral bridge. In patients undergoing HM II implantation, the use of initial postoperative parenteral bridging anticoagulation is common but frequently sub-therapeutic. Use of a parenteral bridge reaching therapeutic targets may decrease the 6-month but not the overall incidence of pump thrombosis.

Adoptive Transfer of Invariant NKT Cells as Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial.

Purpose: Invariant NKT cells (iNKT) are innate-like CD1d-restricted T cells with immunoregulatory activity in diseases including cancer. iNKT from advanced cancer patients can have reversible defects including IFNγ production, and iNKT IFNγ production may stratify for survival. Previous clinical trials using iNKT cell activating ligand α-galactosylceramide have shown clinical responses. Therefore, a phase I clinical trial was performed of autologous in vitro expanded iNKT cells in stage IIIB-IV melanoma.Experimental Design: Residual iNKT cells [<0.05% of patient peripheral blood mononuclear cell (PBMC)] were purified from autologous leukapheresis product using an antibody against the iNKT cell receptor linked to magnetic microbeads. iNKT cells were then expanded with CD3 mAb and IL2 in vitro to obtain up to approximately 109 cells.Results: Expanded iNKT cells produced IFNγ, but limited or undetectable IL4 or IL10. Three iNKT infusions each were completed on 9 patients, and produced only grade 1-2 toxicities. The 4th patient onward received systemic GM-CSF with their second and third infusions. Increased numbers of iNKT cells were seen in PBMCs after some infusions, particularly when GM-CSF was also given. IFNγ responses to α-galactosylceramide were increased in PBMCs from some patients after infusions, and delayed-type hypersensitivity responses to Candida increased in 5 of 8 evaluated patients. Three patients have died, three were progression-free at 53, 60, and 65 months, three received further treatment and were alive at 61, 81, and 85 months. There was no clear correlation between outcome and immune parameters.Conclusions: Autologous in vitro expanded iNKT cells are a feasible and safe therapy, producing Th1-like responses with antitumor potential. Clin Cancer Res; 23(14); 3510-9. ©2017 AACR.

Variability in Antithrombotic Therapy Regimens Peri-TAVR: A Single Academic Center Experience.

INTRODUCTION: The aim of this study was to describe peri-procedural antithrombotic use in patients undergoing transcatheter aortic valve replacement (TAVR) at a single academic medical center. METHODS: Retrospective collection of antiplatelet and anticoagulant use during the index hospitalization for all patients undergoing TAVR at our institution from April 2009 through March 2014. RESULTS: Of a total of 255 patients undergoing the procedure, 132 (51%) had an indication for anticoagulation pre-TAVR and 92 (70% of those with an indication) were on treatment. On discharge, 106 patients (44% of total surviving to discharge, 73% of those surviving with an indication for anticoagulation) were treated with oral anticoagulation. Of these patients, 89 (84%) were discharged on aspirin and an oral anticoagulant without clopidogrel. Only 122 (51% of total patients) were discharged on the regimen of aspirin and clopidogrel alone. CONCLUSION: Peri-procedural antithrombotic regimens vary greatly following TAVR. More than half of patients have an indication for anticoagulation following the procedure. Most patients at our institution who require anticoagulation are discharged on aspirin and an oral anticoagulant, though the optimal regimen requires further investigation.

Biologic Activity of Autologous, Granulocyte-Macrophage Colony-Stimulating Factor Secreting Alveolar Soft-Part Sarcoma and Clear Cell Sarcoma Vaccines.

PURPOSE: Alveolar soft-part sarcoma (ASPS) and clear cell sarcoma (CCS) are rare mesenchymal malignancies driven by chromosomal translocations that activate members of the microphthalmia transcription factor (MITF) family. However, in contrast to malignant melanoma, little is known about their immunogenicity. To learn more about the host response to ASPS and CCS, we conducted a phase I clinical trial of vaccination with irradiated, autologous sarcoma cells engineered by adenoviral-mediated gene transfer to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). EXPERIMENTAL DESIGN: Metastatic tumors from ASPS and CCS patients were resected, processed to single-cell suspensions, transduced with a replication-defective adenoviral vector encoding GM-CSF, and irradiated. Immunizations were administered subcutaneously and intradermally weekly three times and then every other week. RESULTS: Vaccines were successfully manufactured for 11 of the 12 enrolled patients. Eleven subjects received from three to 13 immunizations. Toxicities were restricted to grade 1-2 skin reactions at inoculation sites. Vaccination elicited local dendritic cell infiltrates and stimulated T cell-mediated delayed-type hypersensitivity reactions to irradiated, autologous tumor cells. Antibody responses to tissue-type plasminogen activator (tTPA) and angiopoietins-1/2 were detected. Tumor biopsies showed programmed death-1 (PD-1)-positive CD8(+) T cells in association with PD ligand-1 (PD-L1)-expressing sarcoma cells. No tumor regressions were observed. CONCLUSIONS: Vaccination with irradiated, GM-CSF-secreting autologous sarcoma cell vaccines is feasible, safe, and biologically active. Concurrent targeting of angiogenic cytokines and antagonism of the PD-1-negative regulatory pathway might intensify immune-mediated tumor destruction.

The Mll partial tandem duplication: differential, tissue-specific activity in the presence or absence of the wild-type allele.

The partial tandem duplication of MLL (MLL-PTD) is found in 5% to 10% of patients with acute myeloid leukemia (AML) and normal cytogenetics. Its expression in leukemic blasts is coincident with a silenced wild-type (WT) MLL allele. We therefore generated mice expressing the Mll-PTD in the absence of Mll-WT. These Mll(PTD/-) mice die at birth unlike the normal life expectancy of Mll(PTD/WT), Mll(WT/-), and Mll(WT/WT) mice. Using Mll(WT/WT) fetal liver cells (FLC) as baseline, we compared Mll(PTD/-) with Mll(PTD/WT) FLC and found both had increased HoxA gene expression and granulocyte-macrophage colony-forming progenitor cells (CFU-GM); in contrast, only Mll(PTD/WT) FLC had increased pluripotent hemopoietic progenitors (CFU-GEMM). The similarities between Mll(PTD/WT) and Mll(PTD/-) mice suggest that the Mll-PTD mutation can up-regulate target genes in a dominant, gain-of-function fashion. The differences between these 2 genotypes suggest that in select tissues the Mll-PTD requires cooperation with the Mll-WT in the genesis of the observed abnormality.