Linking planetary embryo formation to planetesimal formation II: The impact of pebble accretion in the terrestrial planet zone

The accretion of pebbles on planetary cores has been widely studied in recent years and is found to be a highly effective mechanism for planetary growth. While most studies assume planetary cores as an initial condition in their simulation, the question how, where and when these cores form is often neglected. We study the impact of pebble accretion during the formation phase and subsequent evolution of planetary embryos in the early stages of circumstellar disk evolution. In doing so we aim to quantify the timescales and local dependency of planetary embryo formation, based on the solid evolution of the disk. We connect a one dimensional two population model for solid evolution and pebble flux regulated planetesimal formation to the N-body code LIPAD. In our study we focus on the growth of planetesimals with an initial size of 100 km in diameter by planetesimal collisions and pebble accretion for the first 1 million years of a viscously evolving disk. We compare 18 different N-body simulations in which we vary the total planetesimal mass after 1 million years, the surface density profile of the planetesimal disk, the radial pebble flux and the possibility of pebble accretion. Pebble accretion leads to the formation of fewer, but substantially more massive embryos. The area of possible embryo formation is weakly influenced by the accretion of pebbles and the innermost embryos tend to form slightly earlier compared to the simulations in which pebble accretion is neglected. Pebble accretion strongly enhances the formation of super earths in the terrestrial planet region, but it does not enhance the formation of embryos at larger distances

Linking planetary embryo formation to planetesimal formation I: The impact of the planetesimal surface density in the terrestrial planet zone

The growth time scales of planetary embryos and their formation process are imperative for our understanding on how planetary systems form and develop. They determine the subsequent growth mechanisms during the life stages of a circumstellar disk. We quantify the timescales and spatial distribution of planetary embryos via collisional growth and fragmentation of dynamically forming 100km sized planetesimals. In our study, the formation timescales of viscous disk evolution and planetesimal formation are linked to the formation of planetary embryos in the terrestrial planet zone. We connect a one dimensional model for viscous gas evolution, dust and pebble dynamics and pebble flux regulated planetesimal formation to the N-body code LIPAD. Our framework enables us to study the formation, growth, fragmentation and evolution of planetesimals with an initial size of 100km in diameter for the first million years of a viscous disk. Our study shows the effect of the planetesimal surface density evolution on the preferential location and timescales of planetary embryo formation. A one dimensional analytically derived model for embryo formation based on the local planetesimal surface density evolution is presented. This model manages to reproduce the spatial distribution, formation rate and total number of planetary embryos at a fraction of the computational cost of the N-body simulations. The formation of planetary embryos in the terrestrial planet zone occurs simultaneously to the formation of planetesimals. The local planetesimal surface density evolution and the orbital spacing of planetary embryos in the oligarchic regime serve well as constraints to model planetary embryo formation analytically. Our embryo formation model will be a valuable asset in future studies regarding planet formation

The impact of pebble flux regulated planetesimal formation on giant planet formation

Forming gas giant planets by the accretion of 100 km diameter planetesimals, a typical size that results from self-gravity assisted planetesimal formation, is often thought to be inefficient. Many models therefore use small km-sized planetesimals, or invoke the accretion of pebbles. Furthermore, models based on planetesimal accretion often use the ad hoc assumption of planetesimals distributed radially in a minimum mass solar nebula fashion. We wish to investigate the impact of various initial radial density distributions in planetesimals with a dynamical model for the formation of planetesimals on the resulting population of planets. In doing so, we highlight the directive role of the early stages of dust evolution into pebbles and planetesimals in the circumstellar disk on the following planetary formation. We have implemented a two population model for solid evolution and a pebble flux regulated model for planetesimal formation into our global model for planet population synthesis. This framework is used to study the global effect of planetesimal formation on planet formation. As reference, we compare our dynamically formed planetesimal surface densities with ad-hoc set distributions of different radial density slopes of planetesimals. Even though required, it is not solely the total planetesimal disk mass, but the planetesimal surface density slope and subsequently the formation mechanism of planetesimals, that enables planetary growth via planetesimal accretion. Highly condensed regions of only 100 km sized planetesimals in the inner regions of circumstellar disks can lead to gas giant growth. Pebble flux regulated planetesimal formation strongly boosts planet formation, because it is a highly effective mechanism to create a steep planetesimal density profile. We find this to lead to the formation of giant planets inside 1 au by 100 km already by pure planetesimal accretion

Thymulin inhibits monocrotaline-induced pulmonary hypertension modulating interleukin-6 expression and suppressing p38 pathway

The pathogenesis of pulmonary hypertension (PH) includes an inflammatory response. Thymulin, a zinc-dependent thymic hormone, has important immunobiological effects by inhibiting various proinflammatory cytokines and chemokines. We investigated morphological and hemodynamic effects of thymulin administration in a rat model of monocrotaline (MCT)-induced PH, as well as the pattern of proinflammatory cytokine gene expression and the intracellular pathways involved. Adult Wistar rats received an injection of MCT (60 mg/kg, sc) or an equal volume of saline. One day after, the animals randomly received during 3 wk an injection of saline, vehicle (zinc plus carboxymethyl cellulose), or thymulin (100 ng/kg, sc, daily). At d 23-25, the animals were anesthetized for hemodynamic recordings, whereas heart and lungs were collected for morphometric and molecular analysis. Thymulin prevented morphological, hemodynamic, and inflammatory cardiopulmonary profile characteristic of MCT-induced PH, whereas part of these effects were also observed in MCT-treated animals injected with the thymulin's vehicle containing zinc. The pulmonary thymulin effect was likely mediated through suppression of p38 pathway.Portuguese Foundation for Science and Technology (No. POCI/SAVFCF/60803/2004; POCTI/SAV-MMO/61547/2004 and PTDC/SAV-FCF/65793/2006) through Cardiovascular R&D Unit (FCT No. 51/94). R.S.M. was supported by Fundação para a Ciência e a Tecnologia (reference SFRH/BPD/15408/2005

New perspectives for the treatment of pulmonary hypertension

Pulmonary hypertension (PH) is a debilitating disease with a poor prognosis. Therapeutic options remain limited despite the introduction of prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors within the last 15 years; these interventions address predominantly the endothelial and vascular dysfunctionS associated with the condition, but simply delay progression of the disease rather than offer a cure. In an attempt to improve efficacy, emerging approaches have focused on targeting the pro-proliferative phenotype that underpins the pulmonary vascular remodelling in the lung and contributes to the impaired circulation and right heart failure. Many novel targets have been investigated and validated in animal models of PH, including modulation of guanylate cyclases, phosphodiesterases, tyrosine kinases, Rho kinase, bone morphogenetic proteins signalling, 5-HT, peroxisome proliferator activator receptors and ion channels. In addition, there is hope that combinations of such treatments, harnessing and optimizing vasodilator and anti-proliferative properties, will provide a further, possibly synergistic, increase in efficacy; therapies directed at the right heart may also offer an additional benefit. This overview highlights current therapeutic options, promising new therapies, and provides the rationale for a combination approach to treat the disease

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Improved risk stratification of patients with atrial fibrillation: an integrated GARFIELD-AF tool for the prediction of mortality, stroke and bleed in patients with and without anticoagulation.

OBJECTIVES: To provide an accurate, web-based tool for stratifying patients with atrial fibrillation to facilitate decisions on the potential benefits/risks of anticoagulation, based on mortality, stroke and bleeding risks. DESIGN: The new tool was developed, using stepwise regression, for all and then applied to lower risk patients. C-statistics were compared with CHA2DS2-VASc using 30-fold cross-validation to control for overfitting. External validation was undertaken in an independent dataset, Outcome Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). PARTICIPANTS: Data from 39 898 patients enrolled in the prospective GARFIELD-AF registry provided the basis for deriving and validating an integrated risk tool to predict stroke risk, mortality and bleeding risk. RESULTS: The discriminatory value of the GARFIELD-AF risk model was superior to CHA2DS2-VASc for patients with or without anticoagulation. C-statistics (95% CI) for all-cause mortality, ischaemic stroke/systemic embolism and haemorrhagic stroke/major bleeding (treated patients) were: 0.77 (0.76 to 0.78), 0.69 (0.67 to 0.71) and 0.66 (0.62 to 0.69), respectively, for the GARFIELD-AF risk models, and 0.66 (0.64-0.67), 0.64 (0.61-0.66) and 0.64 (0.61-0.68), respectively, for CHA2DS2-VASc (or HAS-BLED for bleeding). In very low to low risk patients (CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)), the CHA2DS2-VASc and HAS-BLED (for bleeding) scores offered weak discriminatory value for mortality, stroke/systemic embolism and major bleeding. C-statistics for the GARFIELD-AF risk tool were 0.69 (0.64 to 0.75), 0.65 (0.56 to 0.73) and 0.60 (0.47 to 0.73) for each end point, respectively, versus 0.50 (0.45 to 0.55), 0.59 (0.50 to 0.67) and 0.55 (0.53 to 0.56) for CHA2DS2-VASc (or HAS-BLED for bleeding). Upon validation in the ORBIT-AF population, C-statistics showed that the GARFIELD-AF risk tool was effective for predicting 1-year all-cause mortality using the full and simplified model for all-cause mortality: C-statistics 0.75 (0.73 to 0.77) and 0.75 (0.73 to 0.77), respectively, and for predicting for any stroke or systemic embolism over 1 year, C-statistics 0.68 (0.62 to 0.74). CONCLUSIONS: Performance of the GARFIELD-AF risk tool was superior to CHA2DS2-VASc in predicting stroke and mortality and superior to HAS-BLED for bleeding, overall and in lower risk patients. The GARFIELD-AF tool has the potential for incorporation in routine electronic systems, and for the first time, permits simultaneous evaluation of ischaemic stroke, mortality and bleeding risks. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF (NCT01090362) and for ORBIT-AF (NCT01165710)

Two-year outcomes of patients with newly diagnosed atrial fibrillation: results from GARFIELD-AF.

AIMS: The relationship between outcomes and time after diagnosis for patients with non-valvular atrial fibrillation (NVAF) is poorly defined, especially beyond the first year. METHODS AND RESULTS: GARFIELD-AF is an ongoing, global observational study of adults with newly diagnosed NVAF. Two-year outcomes of 17 162 patients prospectively enrolled in GARFIELD-AF were analysed in light of baseline characteristics, risk profiles for stroke/systemic embolism (SE), and antithrombotic therapy. The mean (standard deviation) age was 69.8 (11.4) years, 43.8% were women, and the mean CHA2DS2-VASc score was 3.3 (1.6); 60.8% of patients were prescribed anticoagulant therapy with/without antiplatelet (AP) therapy, 27.4% AP monotherapy, and 11.8% no antithrombotic therapy. At 2-year follow-up, all-cause mortality, stroke/SE, and major bleeding had occurred at a rate (95% confidence interval) of 3.83 (3.62; 4.05), 1.25 (1.13; 1.38), and 0.70 (0.62; 0.81) per 100 person-years, respectively. Rates for all three major events were highest during the first 4 months. Congestive heart failure, acute coronary syndromes, sudden/unwitnessed death, malignancy, respiratory failure, and infection/sepsis accounted for 65% of all known causes of death and strokes for <10%. Anticoagulant treatment was associated with a 35% lower risk of death. CONCLUSION: The most frequent of the three major outcome measures was death, whose most common causes are not known to be significantly influenced by anticoagulation. This suggests that a more comprehensive approach to the management of NVAF may be needed to improve outcome. This could include, in addition to anticoagulation, interventions targeting modifiable, cause-specific risk factors for death. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Exploring multiple generations of planetary embryos

Context. Global models of planet formation tend to begin with an initial set of planetary embryos for the sake of simplicity. While this approach gives valuable insights into the evolution of the initial embryos, the initial distribution itself is staked on a bold assumption. Limiting the study to an initial distribution may neglect essential physics that either precedes or follows such an initial distribution. Aims. We wish to investigate the effect of dynamic planetary embryo formation on the formation of planetary systems. Methods. The presented framework begins with an initial disk of gas, dust, and pebbles. The disk evolution, the formation of plan-etesimals and the formation of planetary embryos is modeled consistently. Embryos then grow by pebble accretion, followed by planetesimal and, eventually, gas accretion. Planet-disk interactions and N-body dynamics, along with a consideration of other simultaneously growing embryos, are included in the framework. Results. We show that the formation of planets can occur in multiple consecutive phases. Earlier generations grow massive by pebble accretion but are subject to fast type I migration and, thus, by accretion to the star. The later generations of embryos that form grow too much smaller masses by planetesimal accretion, as the amount of pebbles in the disk has vanished. Conclusions. The formation history of planetary systems may be far more complex than an initial distribution of embryos could reflect. The dynamic formation of planetary embryos needs to be considered in global models of planet formation to allow for a complete picture of the system’s evolution