Prevalence, Characteristics, and Impact on Prognosis of Aortic Stenosis in Patients With Cardiac Amyloidosis.

BACKGROUND: Cardiac amyloidosis (CA) is frequently found in older patients with aortic stenosis (AS). However, the prevalence of AS among patients with CA is unknown. The objective was to study the prevalence and prognostic impact of AS among patients with CA. METHODS AND RESULTS: We conducted a retrospective analysis of a prospective registry comprising 976 patients with native aortic valves who were confirmed with wild type transthyretin amyloid (ATTRwt), hereditary variant transthyretin amyloid (ATTRv), or immunoglobulin light-chain (AL) CA. CA patients' echocardiograms were re-analyzed focusing on the aortic valve. Multivariable Cox regression analysis was performed to assess the mortality risk associated with moderate or greater AS in ATTRwt CA. The crude prevalence of AS among patients with CA was 26% in ATTRwt, 8% in ATTRv, and 5% in AL. Compared with population-based controls, all types of CA had higher age- and sex-standardized rate ratios (SRRs) of having any degree of AS (AL: SRR, 2.62; 95% Confidence Interval (CI) [1.09-3.64]; ATTRv: SRR, 3.41; 95%CI [1.64-4.60]; ATTRwt: SRR, 10.8; 95%CI [5.25-14.53]). Compared with hospital controls, only ATTRwt had a higher SRR of having any degree of AS (AL: SRR, 0.97, 95%CI [0.56-1.14]; ATTRv: SRR, 1.27; 95%CI [0.85-1.44]; ATTRwt: SRR, 4.01; 95%CI [2.71-4.54]). Among patients with ATTRwt, moderate or greater AS was not associated with increased all-cause death after multivariable adjustment (hazard ratio, 0.71; 95%CI [0.42-1.19]; P=0.19). CONCLUSIONS: Among patients with CA, ATTRwt but not ATTRv or AL is associated with a higher prevalence of patients with AS compared with hospital controls without CA, even after adjusting for age and sex. In our population, having moderate or greater AS was not associated with a worse outcome in patients with ATTRwt.

Rationale and design of the FRENch CoHort of myocardial Infarction Evaluation (FRENCHIE) study.

BACKGROUND: Despite major advances in prevention and treatment, cardiovascular diseases - particularly acute myocardial infarction - remain a leading cause of death worldwide and in France. Collecting contemporary data about the characteristics, management and outcomes of patients with acute myocardial infarction in France is important. AIMS: The main objectives are to describe baseline characteristics, contemporary management, in-hospital and long-term outcomes of patients with acute myocardial infarction hospitalized in tertiary care centres in France; secondary objectives are to investigate determinants of prognosis (including periodontal disease and sleep-disordered breathing), to identify gaps between evidence-based recommendations and management and to assess medical care costs for the index hospitalization and during the follow-up period. METHODS: FRENCHIE (FRENch CoHort of myocardial Infarction Evaluation) is an ongoing prospective multicentre observational study (ClinicalTrials.gov Identifier: NCT04050956) enrolling more than 19,000 patients hospitalized for acute myocardial infarction with onset of symptoms within 48hours in 35 participating centres in France since March 2019. Main exclusion criteria are age<18 years, lack of health coverage and procedure-related myocardial infarction (types 4a and 5). Detailed information was collected prospectively, starting at admission, including demographic data, risk factors, medical history and treatments, initial management, with prehospital care pathways and medication doses, and outcomes until hospital discharge. The follow-up period (up to 20 years for each patient) is ensured by linking with the French national health database (Système national des données de santé), and includes information on death, hospital admissions, major clinical events, healthcare consumption (including drug reimbursement) and total healthcare costs. FRENCHIE is also used as a platform for cohort-nested studies - currently three randomized trials and two observational studies. CONCLUSIONS: This nationwide large contemporary cohort with very long-term follow-up will improve knowledge about acute myocardial infarction management and outcomes in France, and provide a useful platform for nested studies and trials.

A Randomized Controlled Trial of Nonfasting vs Fasting Before Interventional Coronary Procedures: The TONIC Trial.

BACKGROUND: Fasting before coronary procedures is currently recommended to reduce complications despite the lack of scientific evidence. OBJECTIVES: The TONIC (Comparison Between Fasting and No Fasting Before Interventional Coronary Intervention on the Occurrence of Adverse Events) noninferiority trial investigated the safety and comfort of a nonfasting strategy (ad libitum food and drinks) vs traditional fasting (>6 hours for solid food and liquids) before coronary procedures. METHODS: In this monocentric, prospective, single-blind randomized controlled trial, 739 patients undergoing coronary procedures were included and randomized to a fasting or a nonfasting strategy. Emergency procedures were excluded. The primary endpoint was a composite of vasovagal reaction, hypoglycemia (defined by blood sugar ≤0.7 g/L), and isolated nausea and/or vomiting. Noninferiority margin was 4%. Secondary endpoints were contrast-induced nephropathy and patients' satisfaction. RESULTS: Among the 739 procedures (697 elective and 42 semiurgent), 517 angiographies, and 222 angioplasties (including complex and high-risk procedures) were performed. The primary endpoint occurred in 30 of 365 nonfasting patients (8.2%) vs 37 of 374 fasting patients (9.9%), demonstrating noninferiority (absolute between-group difference, -1.7%; 1-sided 95% CI upper limit: 1.8%). No food-related adverse event occurred, and contrast-related acute kidney injuries were similar between groups. Overall, procedure satisfaction and perceived pain were similar in both groups, but nonfasting patients reported less hunger and thirst (P < 0.01). In case of redo coronary procedures, most patients (79%) would choose a nonfasting strategy. CONCLUSIONS: The TONIC randomized trial demonstrates the noninferiority of a nonfasting strategy to the usual fasting strategy for coronary procedures regarding safety, while improving patients' comfort.

Three-Year Outcomes With Fractional Flow Reserve-Guided or Angiography-Guided Multivessel Percutaneous Coronary Intervention for Myocardial Infarction.

BACKGROUND: In patients with multivessel disease with successful primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction, the FLOWER-MI trial (Flow Evaluation to Guide Revascularization in Multivessel ST-Elevation Myocardial Infarction) showed that a fractional flow reserve (FFR)-guided strategy was not superior to an angiography-guided strategy for treatment of noninfarct-related artery lesions regarding the 1-year risk of death from any cause, myocardial infarction, or unplanned hospitalization leading to urgent revascularization. The extension phase of the trial was planned using the same primary outcome to determine whether a difference in outcomes would be observed with a longer follow-up. METHODS: In this multicenter trial, we randomly assigned patients with ST-segment-elevation myocardial infarction and multivessel disease with successful percutaneous coronary intervention of the infarct-related artery to receive complete revascularization guided by either FFR (n=586) or angiography (n=577). RESULTS: After 3 years, a primary outcome event occurred in 52 of 498 patients (9.40%) in the FFR-guided group and in 44 of 502 patients (8.17%) in the angiography-guided group (hazard ratio, 1.19 [95% CI, 0.79-1.77]; P=0.4). Death occurred in 22 patients (4.00%) in the FFR-guided group and in 23 (4.32%) in the angiography-guided group (hazard ratio, 0.96 [95% CI, 0.53-1.71]); nonfatal myocardial infarction in 23 (4.13%) and 14 (2.56%), respectively (hazard ratio, 1.63 [95% CI, 0.84-3.16]); and unplanned hospitalization leading to urgent revascularization in 21 (3.83%) and 18 (3.36%; hazard ratio, 1.15 [95% CI, 0.61-2.16]), respectively. CONCLUSIONS: Although event rates in the trial were lower than expected, in patients with ST-segment-elevation myocardial infarction undergoing complete revascularization, an FFR-guided strategy did not have a significant benefit over an angiography-guided strategy with respect to the risk of death, myocardial infarction, or urgent revascularization up to 3 years. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02943954.

Refractory cor pulmonale under extracorporeal membrane oxygenation for acute respiratory distress syndrome: the role of conversion to veno-pulmonary arterial assist-a case series.

Introduction: Pulmonary vascular dysfunction during severe acute respiratory distress syndrome (ARDS) may lead to right ventricle (RV) dysfunction and acute cor pulmonale (ACP). The occurrence/persistence of ACP despite conventional extracorporeal membrane oxygenation (ECMO) is a challenging situation. We explored the usefulness of a specific dual-lumen cannula that bypasses the RV, and on which a veno-pulmonary arterial assist (V-P ECMO) was mounted, in ARDS patients. Methods: We report a case-series of ARDS patients put on conventional veno-arterial or veno-venous ECMO and presented refractory ACP as an indication for a reconfiguration to V-P ECMO using the ProtekDuo cannula. The primary endpoint was the mitigation of RV and pulmonary vascular dysfunction as assessed by the change in end-diastolic RV/left ventricle (LV) surface ratio. Results: Six patients had their conventional ECMO reconfigured to V-P ECMO to treat refractory ACP. There was a decrease in end-diastolic RV/LV surface ratio, as well as end-systolic LV eccentricity index, and lactatemia immediately after V-P ECMO initiation. The resolution of refractory ACP was immediately achieved in four of our six (66%) patients. The V-P ECMO was weaned after a median of 26 [8-93] days after implantation. All but one patient were discharged home. We detected one case of severe hemolysis with V-P ECMO and two suspected cases of right-sided infective endocarditis. Conclusion: V-P ECMO is useful to mitigate RV overload and to improve hemodynamics in case of refractory ACP despite conventional ECMO.

Exploring the potential effects of forest urbanization on the interplay between small mammal communities and their gut microbiota.

Urbanization significantly impacts wild populations, favoring urban dweller species over those that are unable to adapt to rapid changes. These differential adaptative abilities could be mediated by the microbiome, which may modulate the host phenotype rapidly through a high degree of flexibility. Conversely, under anthropic perturbations, the microbiota of some species could be disrupted, resulting in dysbiosis and negative impacts on host fitness. The links between the impact of urbanization on host communities and their gut microbiota (GM) have only been scarcely explored. In this study, we tested the hypothesis that the bacterial composition of the GM could play a role in host adaptation to urban environments. We described the GM of several species of small terrestrial mammals sampled in forested areas along a gradient of urbanization, using a 16S metabarcoding approach. We tested whether urbanization led to changes in small mammal communities and in their GM, considering the presence and abundance of bacterial taxa and their putative functions. This enabled to decipher the processes underlying these changes. We found potential impacts of urbanization on small mammal communities and their GM. The urban dweller species had a lower bacterial taxonomic diversity but a higher functional diversity and a different composition compared to urban adapter species. Their GM assembly was mostly governed by stochastic effects, potentially indicating dysbiosis. Selection processes and an overabundance of functions were detected that could be associated with adaptation to urban environments despite dysbiosis. In urban adapter species, the GM functional diversity and composition remained relatively stable along the urbanization gradient. This observation can be explained by functional redundancy, where certain taxa express the same function. This could favor the adaptation of urban adapter species in various environments, including urban settings. We can therefore assume that there are feedbacks between the gut microbiota and host species within communities, enabling rapid adaptation.

Microbiota-mediated competition between Drosophila species.

BACKGROUND: The influence of microbiota in ecological interactions, and in particular competition, is poorly known. We studied competition between two insect species, the invasive pest Drosophila suzukii and the model Drosophila melanogaster, whose larval ecological niches overlap in ripe, but not rotten, fruit. RESULTS: We discovered D. suzukii females prevent costly interspecific larval competition by avoiding oviposition on substrates previously visited by D. melanogaster. More precisely, D. melanogaster association with gut bacteria of the genus Lactobacillus triggered D. suzukii avoidance. However, D. suzukii avoidance behavior is condition-dependent, and D. suzukii females that themselves carry D. melanogaster bacteria stop avoiding sites visited by D. melanogaster. The adaptive significance of avoiding cues from the competitor's microbiota was revealed by experimentally reproducing in-fruit larval competition: reduced survival of D. suzukii larvae only occurred if the competitor had its normal microbiota. CONCLUSIONS: This study establishes microbiotas as potent mediators of interspecific competition and reveals a central role for context-dependent behaviors under bacterial influence. Video Abstract.

Assessment of coronary microcirculation alterations in a porcine model of no-reflow using ultrasound localization microscopy: a proof of concept study.

BACKGROUND: Coronary microvascular obstruction also known as no-reflow phenomenon is a major issue during myocardial infarction that bears important prognostic implications. Alterations of the microvascular network remains however challenging to assess as there is no imaging modality in the clinics that can image directly the coronary microvascular vessels. Ultrasound Localization Microscopy (ULM) imaging was recently introduced to map microvascular flows at high spatial resolution (∼10 µm). In this study, we developed an approach to image alterations of the microvascular coronary flow in ex vivo perfused swine hearts. METHODS: A porcine model of myocardial ischemia-reperfusion was used to obtain microvascular coronary alterations and no-reflow. Four female hearts with myocardial infarction in addition to 6 controls were explanted and placed immediately in a dedicated preservation and perfusion box manufactured for ultrasound imaging. Microbubbles (MB) were injected into the vasculature to perform Ultrasound Localization Microscopy (ULM) imaging and a linear ultrasound probe mounted on a motorized device was used to scan the heart on multiple slices. The coronary microvascular anatomy and flow velocity was reconstructed using dedicated ULM algorithms and analyzed quantitatively. FINDINGS: We were able to image the coronary microcirculation of ex vivo swine hearts at a resolution of tens of microns and measure flow velocities ranging from 10 mm/s in arterioles up to more than 200 mm/s in epicardial arteries. Under different aortic perfusion pressures, we measured in large arteries of a subset of control hearts an increase of flow velocity from 31 ± 11 mm/s at 87 mmHg to 47 ± 17 mm/s at 132 mmHg (N = 3 hearts, P < 0.05). This increase was compared with a control measurement with a flowmeter in the aorta. We also compared 6 control hearts to 4 hearts in which no-reflow was induced by the occlusion and reperfusion of a coronary artery. Using average MB velocity and average density of MB per unit of surface as two ULM quantitative markers of perfusion, we were able to detect areas of coronary no-reflow in good agreement with a control anatomical pathology analysis of the cardiac tissue. In the no-reflow zone, we measured an average perfusion of 204 ± 305 MB/mm2 compared to 3182 ± 1302 MB/mm2 in the surrounding re-perfused area. INTERPRETATION: We demonstrated this approach can directly image and quantify coronary microvascular obstruction and no-reflow on large mammal perfused hearts. This is a first step for noninvasive, quantitative and affordable assessment of the coronary microcirculation function and particularly coronary microvascular anatomy in the infarcted heart. This approach has the potential to be extended to other clinical situations characterized by microvascular dysfunction. FUNDING: This study was supported by the French National Research Agency (ANR) under ANR-21-CE19-0002 grant agreement.

Three-vessel coronary infusion of cardiosphere-derived cells for the treatment of heart failure with preserved ejection fraction in a pre-clinical pig model.

Heart failure with preserved ejection fraction (HFpEF) is a major public health concern. Its outcome is poor and, as of today, barely any treatments have been able to decrease its morbidity or mortality. Cardiosphere-derived cells (CDCs) are heart cell products with anti-fibrotic, anti-inflammatory and angiogenic properties. Here, we tested the efficacy of CDCs in improving left ventricular (LV) structure and function in pigs with HFpEF. Fourteen chronically instrumented pigs received continuous angiotensin II infusion for 5 weeks. LV function was investigated through hemodynamic measurements and echocardiography at baseline, after 3 weeks of angiotensin II infusion before three-vessel intra-coronary CDC (n = 6) or placebo (n = 8) administration and 2 weeks after treatment (i.e., at completion of the protocol). As expected, arterial pressure was significantly and similarly increased in both groups. This was accompanied by LV hypertrophy that was not affected by CDCs. LV systolic function remained similarly preserved during the whole protocol in both groups. In contrast, LV diastolic function was impaired (increases in Tau, LV end-diastolic pressure as well as E/A, E/E'septal and E/E'lateral ratios) but CDC treatment significantly improved all of these parameters. The beneficial effect of CDCs on LV diastolic function was not explained by reduced LV hypertrophy or increased arteriolar density; however, interstitial fibrosis was markedly reduced. Three-vessel intra-coronary administration of CDCs improves LV diastolic function and reduces LV fibrosis in this hypertensive model of HFpEF.

Surgery for delayed leaflet impingement after transcatheter closure of a paravalvular leak associated with an aortic pseudoaneurysm.

Background: Paravalvular leak (PVL) is a recognized and challenging complication after surgical or transcatheter valve replacement. The transcatheter closure of PVL has become the first-line treatment in clinical practice when the procedure is not contraindicated. Transcatheter PVL closure rests on a complex procedure and complications still occur in approximately 9% of patients. Case Report: We describe the case of a delayed mechanical prosthetic leaflet impingement after transcatheter closure of a paravalvular leak associated with a Valsalva pseudoaneurysm that required an urgent surgery. Conclusion: Aorta-left ventricle communication could be a relative contraindication to be assessed on a case-by-case basis, but transcatheter closure does not preclude subsequent attempt for surgical repair and outcome.

Predictors of Clinical Success After Transcatheter Paravalvular Leak Closure: An International Prospective Multicenter Registry.

BACKGROUND: Transcatheter closure of a symptomatic prosthetic paravalvular leak (PVL) is feasible, but there is presently no conclusive evidence to show consistent efficacy. We aimed to identify predictors of clinical success after transcatheter PVL closure. METHODS: Consecutive patients referred to 24 European centers for transcatheter PVL closure in 2017 to 2019 were included in a prospective registry (Fermeture de Fuite ParaProthétique, FFPP). Clinical success was absence of any of the following within 1 month: re-admission for heart failure, blood transfusion, open-heart valvular surgery, and death. RESULTS: We included 216 symptomatic patients, who underwent 238 percutaneous PVL closure procedures on the mitral (64.3%), aortic (34.0%), or tricuspid (1.7%) valve. Symptoms were heart failure, hemolytic anemia, or both in 48.9%, 7.8%, and 43.3% of patients, respectively. One, 2, and 3 leaks were treated during the same procedure in 69.6%, 26.6%, and 3.8% of patients, respectively. The PVL was pinpoint or involved 1/8 or 1/4 of the valve circumference in 18.6%, 52.4%, and 28.1% of cases, respectively. The most frequently used devices were the Vascular Plug 3, Ventricular Septal Defect Occluder, Vascular Plug 2, and Paravalvular Leak Device (45.0%, 16.6%, 14.2%, and 13.6% of cases, respectively). Successful device(s) implantation with leak reduction to ≤grade 2 was obtained in 85.0% of mitral and 91.4% of aortic procedures, respectively (P=0.164); with major periprocedural adverse event rates of 3.3% and 1.2%, respectively (P=0.371); and clinical success rates of 70.3% and 88.0%, respectively (P=0.004). By multivariate analysis, technical failure, mechanical valve, and hemolytic anemia were independently associated with absence of clinical success (odds ratios [95% CIs], 7.7 [2.0-25.0]; P=0.002; 3.6 [1.1-11.1]; P=0.036; and 3.7 [1.2-11.9]; P=0.025; respectively). CONCLUSIONS: Transcatheter PVL closure is efficient and safe in symptomatic patients but is associated with a lower clinical success rate in patients with hemolysis and/or a mechanical valve. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifiers: NCT05089136.

Immediate versus staged complete myocardial revascularization in patients with ST-segment elevation myocardial infarction and multivessel disease: A post hoc analysis of the randomized FLOWER-MI trial.

BACKGROUND: In patients with ST-segment elevation myocardial infarction and multivessel disease, percutaneous coronary intervention for non-culprit lesions is superior to treatment of the culprit lesion alone. The optimal timing for non-infarct-related artery revascularization - immediate versus staged - has not been investigated adequately. AIM: We aimed to assess clinical outcomes at 1 year in patients with ST-segment elevation myocardial infarction with multivessel disease using immediate versus staged non-infarct-related artery revascularization. METHODS: Outcomes were analysed in patients from the randomized FLOWER-MI trial, in whom, after successful primary percutaneous coronary intervention, non-culprit lesions were assessed using fractional flow reserve or angiography during the index procedure or during a staged procedure during the initial hospital stay, ≤5 days after the index procedure. The primary outcome was a composite of all-cause death, non-fatal myocardial infarction and unplanned hospitalization with urgent revascularization at 1year. RESULTS: Among 1171 patients enrolled in this study, 1119 (96.2%) had complete revascularization performed during a staged procedure, and 44 (3.8%) at the time of primary percutaneous coronary intervention. During follow-up, a primary outcome event occurred in one of the patients (2.3%) with an immediate strategy and in 55 patients (4.9%) with a staged strategy (adjusted hazard ratio 1.44, 95% confidence interval 0.39-12.69; P=0.64). CONCLUSIONS: Staged non-infarct-related artery complete revascularization was the strategy preferred by investigators in practice in patients with ST-segment elevation myocardial infarction with multivessel disease. This strategy was not superior to immediate revascularization, which, in the context of this trial, was used in a small proportion of patients. Further randomized studies are needed to confirm these observational findings.

3D-Printing to Plan Complex Transcatheter Paravalvular Leaks Closure.

BACKGROUND: Percutaneous closure of paravalvular leak (PVL) has emerged as an alternative to surgical management in selected cases. Achieving complete PVL occlusion, while respecting prosthesis function remains challenging. A multimodal imaging analysis of PVL morphology before and during the procedure is mandatory to select an appropriate device. We aim to explore the additional value of 3D printing in predicting device related adverse events including mechanical valve leaflet blockade, risk of device embolization and residual shunting. METHODS: From the FFPP registries (NCT05089136 and NCT05117359), we included 11 transcatheter PVL closure procedures from three centers for which 3D printed models were produced. Cardiac CT was used for segmentation for 3D printed models (3D-heartmodeling, Caissargues, France). Technology used a laser to fuse very fine powders (TPU Thermoplastic polyurethane) into a final part-laser sintering technology (SLS) with an adapted elasticity. A simulation on 3D printed model was performed using a set of occluders. RESULTS: PVLs were located around aortic prostheses in six cases, mitral prostheses in four cases and tricuspid ring in one case. The device chosen during the simulation on the 3D printed model matched the one implanted in eight cases. In the three other cases, a similar device type was chosen during the procedures but with a different size. A risk of prosthesis leaflet blockade was identified on 3D printed models in four cases. During the procedure, the occluder was removed before release in one case. In another case the device was successfully repositioned and released. In two patients, leaflet impingement was observed post-operatively and surgical device removal had to be performed. CONCLUSION: In a case-series of complex transcatheter PVL closure procedures, hands-on simulation testing on 3D printed models proved its usefulness to plan and facilitate these challenging procedures.

Coronary Flow Assessment Using 3-Dimensional Ultrafast Ultrasound Localization Microscopy.

BACKGROUND: Direct assessment of the coronary microcirculation has long been hampered by the limited spatial and temporal resolutions of cardiac imaging modalities. OBJECTIVES: The purpose of this study was to demonstrate 3-dimensional (3D) coronary ultrasound localization microscopy (CorULM) of the whole heart beyond the acoustic diffraction limit (<20 µm resolution) at ultrafast frame rate (>1000 images/s). METHODS: CorULM was performed in isolated beating rat hearts (N = 6) with ultrasound contrast agents (Sonovue, Bracco), using an ultrasonic matrix transducer connected to a high channel-count ultrafast electronics. We assessed the 3D coronary microvascular anatomy, flow velocity, and flow rate of beating hearts under normal conditions, during vasodilator adenosine infusion, and during coronary occlusion. The coronary vasculature was compared with micro-computed tomography performed on the fixed heart. In vivo transthoracic CorULM was eventually assessed on anaesthetized rats (N = 3). RESULTS: CorULM enables the 3D visualization of the coronary vasculature in beating hearts at a scale down to microvascular structures (<20 µm resolution). Absolute flow velocity estimates range from 10 mm/s in tiny arterioles up to more than 300 mm/s in large arteries. Fitting to a power law, the flow rate-radius relationship provides an exponent of 2.61 (r2 = 0.96; P < 0.001), which is consistent with theoretical predictions and experimental validations of scaling laws in vascular trees. A 2-fold increase of the microvascular coronary flow rate is found in response to adenosine, which is in good agreement with the overall perfusion flow rate measured in the aorta (control measurement) that increased from 8.80 ± 1.03 mL/min to 16.54 ± 2.35 mL/min (P < 0.001). The feasibility of CorULM was demonstrated in vivo for N = 3 rats. CONCLUSIONS: CorULM provides unprecedented insights into the anatomy and function of coronary arteries at the microvasculature level in beating hearts. This new technology is highly translational and has the potential to become a major tool for the clinical investigation of the coronary microcirculation.

Gene copy number variations at the within-host population level modulate gene expression in a multipartite virus.

Multipartite viruses have a segmented genome, with each segment encapsidated separately. In all multipartite virus species for which the question has been addressed, the distinct segments reproducibly accumulate at a specific and host-dependent relative frequency, defined as the 'genome formula'. Here, we test the hypothesis that the multipartite genome organization facilitates the regulation of gene expression via changes of the genome formula and thus via gene copy number variations. In a first experiment, the faba bean necrotic stunt virus (FBNSV), whose genome is composed of eight DNA segments each encoding a single gene, was inoculated into faba bean or alfalfa host plants, and the relative concentrations of the DNA segments and their corresponding messenger RNAs (mRNAs) were monitored. In each of the two host species, our analysis consistently showed that the genome formula variations modulate gene expression, the concentration of each genome segment linearly and positively correlating to that of its cognate mRNA but not of the others. In a second experiment, twenty parallel FBNSV lines were transferred from faba bean to alfalfa plants. Upon host switching, the transcription rate of some genome segments changes, but the genome formula is modified in a way that compensates for these changes and maintains a similar ratio between the various viral mRNAs. Interestingly, a deep-sequencing analysis of these twenty FBNSV lineages demonstrated that the host-related genome formula shift operates independently of DNA-segment sequence mutation. Together, our results indicate that nanoviruses are plastic genetic systems, able to transiently adjust gene expression at the population level in changing environments, by modulating the copy number but not the sequence of each of their genes.

Diuretic vs. placebo in intermediate-risk acute pulmonary embolism: a randomized clinical trial.

AIMS: The role of diuretics in patients with intermediate-risk pulmonary embolism (PE) is controversial. In this multicentre, double-blind trial, we randomly assigned normotensive patients with intermediate-risk PE to receive either a single 80 mg bolus of furosemide or a placebo. METHODS AND RESULTS: Eligible patients had at least a simplified PE Severity Index (sPESI) ≥1 with right ventricular dysfunction. The primary efficacy endpoint assessed 24 h after randomization included (i) absence of oligo-anuria and (ii) normalization of all sPESI items. Safety outcomes were worsening renal function and major adverse outcomes at 48 hours defined by death, cardiac arrest, mechanical ventilation, or need of catecholamine. A total of 276 patients underwent randomization; 135 were assigned to receive the diuretic, and 141 to receive the placebo. The primary outcome occurred in 68/132 patients (51.5%) in the diuretic and in 49/132 (37.1%) in the placebo group (relative risk = 1.30, 95% confidence interval 1.04-1.61; P = 0.021). Major adverse outcome at 48 h occurred in 1 (0.8%) patients in the diuretic group and 4 patients (2.9%) in the placebo group (P = 0.19). Increase in serum creatinine level was greater in diuretic than placebo group [+4 µM/L (-2; 14) vs. -1 µM/L (-11; 6), P < 0.001]. CONCLUSION: In normotensive patients with intermediate-risk PE, a single bolus of furosemide improved the primary efficacy outcome at 24 h and maintained stable renal function. In the furosemide group, urine output increased, without a demonstrable improvement in heart rate, systolic blood pressure, or arterial oxygenation.ClinicalTrials.gov identifier NCT02268903.

Percutaneous angio-guided versus surgical veno-arterial ECLS implantation in patients with cardiogenic shock or cardiac arrest.

BACKGROUND: Veno-arterial Extracorporeal Life Support (V-A ECLS) has gained increasing place into the management of patients with refractory cardiogenic shock or cardiac arrest. Both surgical and percutaneous approach can be used for cannulation, but percutaneous approach has been associated with fewer complications. Angio-guided percutaneous cannulation and decannulation may further decrease the rate of complication. We aimed to compare outcome and complication rates in patients supported with V-A ECLS through percutaneous angio-guided versus surgical approach. METHODS: We included all patients with emergent peripheral femoro-femoral V-A ECLS implantation for refractory cardiogenic shock or cardiac arrest in our center from March 2018 to March 2021. Survival and major complications (major bleeding, limb ischemia and groin infection) rates were compared between the percutaneous angio-guided and the surgical groups. RESULTS: One hundred twenty patients received V-A ECLS, 59 through surgical approach and 61 through angio-guided percutaneous approach. Patients' baseline characteristics and severity scores were equally balanced between the 2 groups. Thirty-day mortality was not significantly different between the 2 approaches. However, angio-guided percutaneous cannulation was associated with fewer major vascular complications (42% vs. 11%, p > 0.0001) and a higher rate of V-A ECLS decannulation. In multivariate analysis, percutaneous angio-guided implantation of V-A ECLS was independently associated with a lower probability of major complications. CONCLUSION: Compared to surgical approach, angio-guided percutaneous V-A ECLS implantation is associated with fewer major vascular complications. Larger studies are needed to confirm those results and address their impact on mortality.

Effects of an Alphasatellite on the Life Cycle of the Nanovirus Faba Bean Necrotic Yellows Virus.

Nanoviruses are plant viruses with a multipartite single-stranded DNA (ssDNA) genome. Alphasatellites are commonly associated with nanovirus infections, but their putative impact on their helper viruses is unknown. In this study, we investigated the role of subterranean clover stunt alphasatellite 1 (here named SCSA 1) on various important traits of Faba bean necrotic yellows virus (FBNYV) in its host plant Vicia faba and aphid vector Acyrthosiphon pisum, including disease symptoms, viral accumulation, and viral transmission. The results indicate that SCSA 1 does not affect the severity of symptoms nor overall FBNYV accumulation in V. faba, but it does change the relative amounts of its different genomic segments. Moreover, the association of SCSA 1 with FBNYV increases the rate of plant-to-plant transmission by a process seemingly unrelated to the simple increase of viral accumulation in the vector. These results represent the first study on the impact of an alphasatellite on the biology of its helper nanovirus. They suggest that SCSA 1 may benefit FBNYV, but the genericity of this conclusion is discussed and questioned. IMPORTANCE Alphasatellites are circular single-stranded DNA molecules frequently found in association with natural isolates of nanoviruses and some geminiviruses, the two ssDNA plant-infecting virus families. While the implications of alphasatellite presence in geminivirus infections are relatively well documented, comparable studies on alphasatellites associated with nanoviruses are not available. Here, we confirm that subterranean clover stunt alphasatellite 1 affects different traits of its helper nanovirus, Faba bean necrotic yellows virus, both in the host plant and aphid vector. We show that the frequencies of the virus segments change in the presence of alphasatellite, in both the plant and the vector. We also confirm that although within-plant virus load and symptoms are not affected by alphasatellite, the presence of alphasatellite decreases within-aphid virus load but significantly increases virus transmission rate, and thus it may confer a possible evolutionary advantage for the helper virus.