Airway organoids are polarized 3D epithelial structures that recapitulate the organization and many of the key functions of the in vivo tissue. They present an attractive model that can overcome some ...of the limitations of traditional 2D and Air-Liquid Interface (ALI) models, yet the limited accessibility of the organoids' apical side has hindered their applications in studies focusing on host-pathogen interactions. Here, we describe a scalable, fast and efficient way to generate airway organoids with the apical side externally exposed. These apical-out airway organoids are generated in an Extracellular Matrix (ECM)-free environment from 2D-expanded bronchial epithelial cells and differentiated in suspension to develop uniformly-sized organoid cultures with robust ciliogenesis. Differentiated apical-out airway organoids are susceptible to infection with common respiratory viruses and show varying responses upon treatment with antivirals. In addition to the ease of apical accessibility, these apical-out airway organoids offer an alternative in vitro model to study host-pathogen interactions in higher throughput than the traditional air-liquid interface model.
In this paper an algorithm is developed that combines the capabilities and advantages of several different astrodynamical models of increasing complexity. Splitting these models in a strict ...hierarchical order yields a clearer grasp on what is available. With the effort of developing a comprehensive model overhead, the equations for the spacecraft motion in simpler models can be readily obtained as particular cases. The proposed algorithm embeds the circular and elliptic restricted three-body problems, the four-body bicircular and concentric models, an averaged n-body model, and, at the top hierarchic ladder, the full ephemeris SPICE-based restricted n-body problem. The equations of motion are reduced to the assignment of 13 time-varying coefficients, which multiply the states and the gravitational potential to reproduce the proper vector field. This approach yields an efficient and quick way to check solutions for different dynamics and parameters. We show that in bottom-up applications, a gradual increase of model complexity benefits accuracy, the chances of success and the convergence rate of a continuation algorithm. Case studies are simple periodic orbits and low-energy transfers.
•Astrodynamical models are derived and ordered in a clear hierarchical way.•The dynamics is described with 13 time-varying coefficients.•A new model, based on averaged coefficients, is proposed.•A trajectory refinement algorithm is developed.•Results are given for Earth-Moon L1 halo orbits and low-energy transfers.
Strong evidence for the use of direct oral anticoagulants (DOACs) in the early phase of non valvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) is lacking, because this kind of ...patients were excluded from phase III randomized clinical trials (RCT) and ad hoc RCTs are ongoing. In the latest years a lot of real life studies on this topic have been published. The aim of our review was to focus on these. We reviewed the PubMed databases searching articles reporting on DOACs starting time within 2 weeks from AIS onset. We selected fifteen studies, eight with retrospective, six with prospective observational and one with a prospective, open-label, single arm design. Overall, 2920 patients (47.8% females) were included. In twelve studies median or mean age of patients was over 75 years. Mean or median NIHSS ad hospital admission was ≤ 12 in all studies. About one-third of patients (32.4%) received urgent reperfusion by systemic thrombolysis or mechanical thrombectomy. About one-fifth of patients (22.8%) had large infarct size. Median starting time of DOACs was reported in thirteen studies and it ranged from 2 to 8 days. About one-half of patients (45.9%) received a low dose of DOACs. In studies reporting on median or mean CHA
2
DS
2
-VASC score, it was ≥ 3 in all. In studies reporting on median or mean HAS-BLED score, it was ≥ 2 in all. Ninety-day follow-up was available for nine studies, overall including about 2200 patients. Incidence of 90-day TIA/stroke recurrence, symptomatic haemorrhagic transformation or intracranial bleeding and all cause mortality was 2.25%, 0.90% and 1.5%, respectively. The real life evidence suggests that early starting of DOACs in patients with NVAF-related AIS is safe and associated with low recurrence risk and all-cause mortality.
Few data are available on age-related burden and characteristics of embolic stroke of undetermined source (ESUS) in the real world clinical practice. The aim of our study was to provide information ...about it. We retrospectively analyzed data of patients consecutively admitted to our Stroke Unit along 1 year (2017, November 1st–2018, October 31st). The etiology of ischemic stroke was defined at hospital discharge; ESUS was considered as a subset of cryptogenic stroke, and defined according to the 2014 international criteria. In the analyzed period, 306 patients, 52.3% females, mean age ± SD 77.9 ± 11.9 years, were discharged with diagnosis of ischemic stroke. Ischemic strokes of cardioembolic and lacunar origin were the most frequent subtypes: 30.1% and 29.4%, respectively. Cardioembolic strokes were particularly frequent in patients ≥ 75 years, and almost always associated with atrial fibrillation. Overall, in 80 patients (26.1%) the etiology of stroke was undetermined; in 25 (8.2%) it remained undefined because of death or severe comorbidity, making further diagnostic work-up not worthy. Cryptogenic stroke occurred in 55 patients (18%), and ESUS criteria were satisfied in 39 of them (12.7%). According to age, cryptogenic stroke was diagnosed in 21.1% (21.1% ESUS) of patients < 65 years, 24.2% (19.4% ESUS) of patients aged 65–74 years, 15.5% (9.2% ESUS) of patients ≥ 75 years. After diagnostic work-up, patent foramen ovale was most commonly associated with ESUS (17.9%), especially in patients < 65 years (62.5%); covert paroxysmal atrial fibrillation was detected in 10.5% of ESUS patients ≥ 75 years. In the real world clinical practice, the frequency of ischemic strokes of undetermined etiology, and of those satisfying ESUS criteria, is not negligible, especially in younger patients. A thorough diagnostic work-up, with an age-specific approach, is therefore necessary and of the utmost importance for the identification of stroke etiology, in order to optimize secondary stroke prevention strategies.
DESTINY+ is an upcoming JAXA Epsilon medium-class mission to fly by the Geminids meteor shower parent body (3200) Phaethon. It will be the world’s first spacecraft to escape from a near-geostationary ...transfer orbit into deep space using a low-thrust propulsion system. In doing so, DESTINY+ will demonstrate a number of technologies that include a highly efficient ion engine system, lightweight solar array panels, and advanced asteroid flyby observation instruments. These demonstrations will pave the way for JAXA’s envisioned low-cost, high-frequency space exploration plans. Following the Phaethon flyby observation, DESTINY+ will visit additional asteroids as its extended mission. The mission design is divided into three phases: a spiral-shaped apogee-raising phase, a multi-lunar-flyby phase to escape Earth, and an interplanetary and asteroids flyby phase. The main challenges include the optimization of the many-revolution low-thrust spiral phase under operational constraints; the design of a multi-lunar-flyby sequence in a multi-body environment; and the design of multiple asteroid flybys connected via Earth gravity assists. This paper shows a novel, practical approach to tackle these complex problems, and presents feasible solutions found within the mass budget and mission constraints. Among them, the baseline solution is shown and discussed in depth; DESTINY+ will spend two years raising its apogee with ion engines, followed by four lunar gravity assists, and a flyby of asteroids (3200) Phaethon and (155140) 2005 UD. Finally, the flight operations plan for the spiral phase and the asteroid flyby phase are presented in detail.
•Mission design and space flight operations of JAXA’s DESTINY+ mission is introduced.•A novel approach to tackle complex low-thrust trajectory design is proposed.•Low-thrust many-revolution trajectory design approach is presented.•High-fidelity moon flyby database is utilized to patch the entire trajectory.•A new asteroid flyby cycler method is applied for Phaethon flyby trajectory design.
Introduction. The optimal timing for starting anticoagulation in the early phase of nonvalvular atrial fibrillation (NVAF)-related acute ischemic stroke (AIS) remains a challenge, especially in ...patients undergoing urgent reperfusion by systemic thrombolysis or mechanical thrombectomy. The aim of our study was to review the literature evidence reporting on safety of direct oral anticoagulants (DOACs) starting in the early phase of NVAF-related AIS undergoing systemic thrombolysis and/or mechanical thrombectomy. Materials and Methods. We reviewed the PubMed databases searching articles reporting on efficacy and safety of DOACs starting time within two weeks from AIS onset in patients undergoing systemic thrombolysis and/or mechanical thrombectomy. Results. Three studies were selected, overall including one hundred and six patients (62 females, 58.4%). Median National Institute of Health Stroke Scale (NIHSS) score at hospital admission ranged from 9 to 13 points. Median DOACs starting time ranged from 2 to 6 days. Median CHA2DS2-VASC score ranged from 4 to 6 points. Follow-up was limited to 14 days in one study, 30 days in another, and 90 days in a third one. Overall, stroke recurrence and/or intracranial bleeding occurred in two patients (1.9%) and no patient died at follow-up. Conclusion. Small sample size real life studies seem to demonstrate that the introduction of DOACs in the early phase of NVAF-related AIS undergoing urgent reperfusion is efficacious and safe. Prospective RCTs are necessary to confirm these findings.
The balance between the risk of early stroke recurrence and hemorrhagic transformation represents the cornerstone of practical management of non-valvular atrial fibrillation (NVAF)-related acute ...ischemic stroke (AIS). Patients who receive antithrombotic therapy as secondary prevention in the early phase of NVAF-related AIS have a better prognosis compared with patients who do not receive antithrombotic treatment. Recently, the RAF study showed that the best efficacy/safety profile was associated with anticoagulation started between 4 and 14 days from stroke onset. Based on the RAF study, the 2018 American Heart Association/American Stroke Association (AHA/ASA) guidelines suggest starting anticoagulants between 4 and 14 days from stroke onset with a class of recommendation IIa. Strong evidence for the use of direct oral anticoagulants (DOACs) in the early phase of NVAF-related AIS is lacking, because this kind of patients were excluded from phase III randomized clinical trials (RCT) and ad hoc RCTs are ongoing. However, the real life evidence suggests that early starting time of DOACs in patients with NVAF-related AIS is safe and associated with low recurrence risk and all-cause mortality. In the present review the Authors provide an update on anticoagulation in the early phase of NVAF-related AIS with focus on DOACs.
•The optimal starting time of anticoagulation in the early phase of NVAF-related AIS is unclear•Balancing the risk of early stroke recurrence and hemorrhagic transformation is the key-point of ...NVAF-related AIS management•Patients with acute stroke were excluded from randomized clinical trials of DOACs on stroke prevention in atrial fibrillation•Real life studies showed an optimal efficacy/safety profile of DOACs in the early phase of NVAF-related AIS•Results of randomized clinical trials on DOACs aimed to confirm the real life evidence in this clinical setting are awaited
Subclinical paroxysmal atrial fibrillation (AF) is one of the main occult causative mechanisms of embolic stroke of undetermined source (ESUS). Aim of this study was to identify AF predictors, and to ...develop a score to predict the probability of AF detection in ESUS.
We retrospectively analyzed ESUS patients undergoing 2-week external electrocardiographic monitoring. Patients with and without AF detection were compared. On the basis of multivariate analysis, predictors of AF were identified and used to develop a predictive score, which was then compared with other existing literature scores.
Eighty-two patients, 48 females, mean age±SD 72±10 years, were included. In 36 patients (43.9%) AF was detected. The frequency of age 75 years or above and arterial hypertension, and the median CHA 2 DS 2 -VASc score were significantly higher in patients with AF compared with those without. National Institutes of Health Stroke Scale (NIHSS) score ≥8 was the only independent variable associated with AF detection. We derived the Empoli ESUS-AF (E 2 AF) score (NIHSS ≥8 5 points, arterial hypertension 3 points, age 75 years or above 2 points, age 65 to 74 years 1 point, history of coronary/peripheral artery disease 1 point, left atrial enlargement 1 point, posterior lesion 1 point, cortical or cortical-subcortical lesion 1 point), whose predictive power in detecting AF was good (area under the curve: 0.746, 95% confidence interval: 0.638-0.836) and higher than that of CHA 2 DS 2 -VASc and other scores.
In our study NIHSS score ≥8 was the only independent predictor of post-ESUS-AF detection. The E 2 AF score appears to have a good predictive power for detecting AF. External validations are required.
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