The nuclear lamina couples mechanical forces to cell fate in the preimplantation embryo via actin organization

During preimplantation development, contractile forces generated at the apical cortex segregate cells into inner and outer positions of the embryo, establishing the inner cell mass (ICM) and trophectoderm. To which extent these forces influence ICM-trophectoderm fate remains unresolved. Here, we found that the nuclear lamina is coupled to the cortex via an F-actin meshwork in mouse and human embryos. Actomyosin contractility increases during development, upregulating Lamin-A levels, but upon internalization cells lose their apical cortex and downregulate Lamin-A. Low Lamin-A shifts the localization of actin nucleators from nucleus to cytoplasm increasing cytoplasmic F-actin abundance. This results in stabilization of Amot, Yap phosphorylation and acquisition of ICM over trophectoderm fate. By contrast, in outer cells, Lamin-A levels increase with contractility. This prevents Yap phosphorylation enabling Cdx2 to specify the trophectoderm. Thus, forces transmitted to the nuclear lamina control actin organization to differentially regulate the factors specifying lineage identity

Enhancement-mode Ga2O3 wrap-gate fin field-effect transistors on native (100) β-Ga2O3 substrate with high breakdown voltage

Sn-doped gallium oxide (Ga2O3) wrap-gate fin-array field-effect transistors (finFETs) were formed by top-down BCl3 plasma etching on a native semi-insulating Mg-doped (100) β-Ga2O3 substrate. The fin channels have a triangular cross-section and are approximately 300 nm wide and 200 nm tall. FinFETs, with 20 nm Al2O3 gate dielectric and ∼2 μm wrap-gate, demonstrate normally-off operation with a threshold voltage between 0 and +1 V during high-voltage operation. The ION/IOFF ratio is greater than 105 and is mainly limited by high on-resistance that can be significantly improved. At VG = 0, a finFET with 21 μm gate-drain spacing achieved a three-terminal breakdown voltage exceeding 600 V without a field-plate

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)

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

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

Cutting edge : Clec9A+ dendritic cells mediate the development of experimental cerebral Malaria

Plasmodium infections trigger strong innate and acquired immune responses, which can lead to severe complications, including the most feared and often fatal cerebral malaria (CM). To begin to dissect the roles of different dendritic cell (DC) subsets in Plasmodium-induced pathology, we have generated a transgenic strain, Clec9A-diphtheria toxin receptor that allows us to ablate in vivo Clec9A+ DCs. Specifically, we have analyzed the in vivo contribution of this DC subset in an experimental CM model using Plasmodium berghei, and we provide strong evidence that the absence of this DC subset resulted in complete resistance to experimental CM. This was accompanied with dramatic reduction of brain CD8 + T cells, and those few cerebral CD8 + T cells present had a less activated phenotype, unlike their wildtype counterparts that expressed IFN-γ and especially granzyme B. This almost complete absence of local cellular responses was also associated with reduced parasite load in the brain.NMRC (Natl Medical Research Council, S’pore

Benefits of Considering More Than Temperature Acceleration for GaN HEMT Life Testing

The purpose of this work was to investigate the validity of Arrhenius accelerated-life testing when applied to gallium nitride (GaN) high electron mobility transistors (HEMT) lifetime assessments, where the standard assumption is that only critical stressor is temperature, which is derived from operating power, device channel-case, thermal resistance, and baseplate temperature. We found that power or temperature alone could not explain difference in observed degradation, and that accelerated life tests employed by industry can benefit by considering the impact of accelerating factors besides temperature. Specifically, we found that the voltage used to reach a desired power dissipation is important, and also that temperature acceleration alone or voltage alone (without much power dissipation) is insufficient to assess lifetime at operating conditions

Induced conductivity in sol-gel ZnO films by passivation or elimination of Zn vacancies

Undoped and Ga- and Al- doped ZnO films were synthesized using sol-gel and spin coating methods and characterized by X-ray diffraction, high-resolution scanning electron microscopy (SEM), optical spectroscopy and Hall-effect measurements. SEM measurements reveal an average grain size of 20 nm and distinct individual layer structure. Measurable conductivity was not detected in the unprocessed films; however, annealing in hydrogen or zinc environment induced significant conductivity (∼10−2 Ω.cm) in most films. Positron annihilation spectroscopy measurements provided strong evidence that the significant enhancement in conductivity was due to hydrogen passivation of Zn vacancy related defects or elimination of Zn vacancies by Zn interstitials which suppress their role as deep acceptors. Hydrogen passivation of cation vacancies is shown to play an important role in tuning the electrical conductivity of ZnO, similar to its role in passivation of defects at the Si/SiO2 interface that has been essential for the successful development of complementary metal–oxide–semiconductor (CMOS) devices. By comparison with hydrogen effect on other oxides, we suggest that hydrogen may play a universal role in oxides passivating cation vacancies and modifying their electronic properties

Report on challenges for SCIs

This report discusses the challenges posed by four types of threats – terrorist attacks, cyber-attacks, extreme weather and social unrest – on the following eight smart critical infrastructure systems:a. ALPHA - Finance (financial system): The analysis focuses on disturbed information flow and disabling/manipulating IT and communication systems, including attacks on the “physical layer” using the example of IEMI/HPEM threats, as well as the software layer.b. BRAVO - Energy supply (system): The analysis focuses on disruption of “smart” energy supply in a “smart city”, caused by natural hazards, in this case flooding, leading to cascading effects and severe consequences for other energy-depending SCIs.c. CHARLIE - Health care (system): Focus of the analysis is on all threats that might cause large increases in the numbers of injuries or sick patients within a densely populated area. This will include indirect impacts, e.g. large numbers of injuries caused by a disaster or terrorist attacks or disease epidemics, but also direct impacts, e.g. service disruptions in critical health infrastructures, such as hospitals, due to attacks or disasters hitting the infrastructure itself.d. DELTA - Transportation (system) – airports: According to the framework situation, threats on Smart Airports will be assessed under circumstances of (i) blocked traffic, (ii) passenger and airplane traffic exceeding capacity (iii) flood.e. ECHO - Industry (in zones in cities) "Industrial Production Plants": The analysis focuses mainly on technological accidents within the refinery complex, but also accidents caused by natural hazards affecting refinery property outside the main refinery complex, e.g. accident on jetty belonging to refinery on the river Danube during unloading/loading oil products from barge to a tank, damages by a gale or storm on process installations (pipes, hoses) resulting in river pollution. Both scenarios could lead to cascading effects for other SCIs in close vicinity.f. FOXTROT - Water supply (systems): The analysis focuses on three cases of local and regional drinking water supply chains, with different kinds of vulnerabilities in terms of climate threats, ICT challenges, security issues and human error.g. GOLF - Urban flood protection (systems): The analysis focuses in the disruption of water and transport caused through tidal and fluvial flooding events.h. HOTEL: City of Helsinki - Flooding underground coal storage. Resilience of the energy infrastructure (city environment). The way this analysis was conducted was by assessing these threats using a 5x5 framework matrix. The two axes of the matrix were phases (understand risks, anticipate/prepare, absorb/withstand, respond/recover, adapt/learn) and dimensions (system/physical, information/data, organizational/business, societal/political, cognitive/decision-making). Each individual matrix block was discussed by subject experts who identified specific challenges and implications for each matrix element and rated its relevance (high, medium, low).In terms of the results, the system/physical dimension received the highest number of important challenges. Overall, the most important singular element was to understand risks in the organizational/business dimension. The least importance was attributed to the adapt/learn phase.SmartResilience: Smart Resilience Indicators for Smart Critical Infrastructure