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BackgroundStatins are frequently prescribed with direct oral anticoagulants (DOACs), and previous studies have raised concerns about the increased risk of intracerebral hemorrhage or other major bleeding in concurrent statins and DOACs use. The objective of this study is to evaluate the risk of major bleeding in non-valvular atrial fibrillation patients taking DOACs with or without statins.MethodsThis nationwide, retrospective cohort study used data from the Taiwan National Health Insurance Research Database, enrolled a total of 90,731 non-valvular atrial fibrillation patients receiving rivaroxaban, dabigatran, apixaban or edoxaban from January 1st, 2012 to December 31st, 2017. Major bleeding was defined as a hospitalization or emergency department visit with a primary diagnosis of intracerebral hemorrhage, gastrointestinal tract bleeding, urogenital tract bleeding, or other sites of bleeding. Adjusted incidence rate ratios (IRR) and differences of major bleeding between person-quarters of DOACs with or without statins were estimated using a Poisson regression and inverse probability of treatment weighting using the propensity score.Results50,854 (56.0%) of them were male with a mean age of 74.9 (SD, 10.4) years. Using DOACs without statins as a reference, the adjusted IRR for all major bleedings in concurrent use of DOACs and statins was 0.8 (95% CI 0.72–0.81). Lower major bleeding risk was seen in both low-to-moderate-intensity statins (IRR: 0.8, 95% CI 0.74–0.84) and high-intensity statins (IRR: 0.8, 95% CI 0.74–0.88). Concurrent use of DOACs and statins decreased the risk for intracerebral hemorrhage with an IRR of 0.8 (95% CI 0.66–0.93), and gastrointestinal tract bleeding with an IRR of 0.7 (95% CI 0.69–0.79). The protective effect of statins on intracerebral hemorrhage was observed only in female patients (IRR 0.67, 95% CI 0.51–0.89), but not in male patients (IRR 0.87, 95% CI 0.70–1.08).ConclusionsAmong non-valvular atrial fibrillation patients who were taking DOACs, concurrent use of statins decreased major bleeding risk, including intracerebral hemorrhage and gastrointestinal tract bleeding. Considering this and other cardioprotective effects, statins should be considered in all eligible patients prescribed with DOACs.

Using type-x spin-orbit torque (SOT) switching scheme, in which the easy axis (EA) of the ferromagnetic (FM) layer and the charge current flow direction are collinear, is possible to realize a lower-power-consumption, higher-density, and better-performance SOT magnetoresistive random access memory (SOT-MRAM) as compared to the conventional type-y design. Here, we systematically investigate type-x SOT switching properties by both macrospin and micromagnetic simulations. The out-of-plane external field and anisotropy field dependence of the switching current density ($J_{sw}$) is first examined in the ideal type-x configuration. Next, we study the FM layer canting angle ($\phi_{EA}$) dependence of $J_{sw}$ through macrospin simulations and experiments, which show a transformation of switching dynamics from type-x to type-y with increasing $\phi_{EA}$. By further integrating field-like torque (FLT) into the simulated system, we find that a positive FLT can assist type-x SOT switching while a negative one brings about complex dynamics. More crucially, with the existence of a sizable FLT, type-x switching mode results in a lower critical switching current than type-y at current pulse width less than ~ 10 ns, indicating the advantage of employing type-x design for ultrafast switching using materials systems with FLT. Our work provides a thorough examination of type-x SOT scheme with various device/materials parameters, which can be informative for designing next-generation SOT-MRAM.

Over the past few years, with the rapid growth of deep-sequencing technology and the development of computational prediction algorithms, a large number of long non-coding RNAs (lncRNAs) have been identified in various types of human cancers. Therefore, it has become critical to determine how to properly annotate the potential function of lncRNAs from RNA-sequencing (RNA-seq) data and arrange the robust information and analysis into a useful system readily accessible by biological and clinical researchers. In order to produce a collective interpretation of lncRNA functions, it is necessary to integrate different types of data regarding the important functional diversity and regulatory role of these lncRNAs. In this study, we utilized transcriptomic sequencing data to systematically observe and identify lncRNAs and their potential functions from 5034 The Cancer Genome Atlas RNA-seq datasets covering 24 cancers. Then, we constructed the ‘lncExplore’ database that was developed to comprehensively integrate various types of genomic annotation data for collective interpretation. The distinctive features in our lncExplore database include (i) novel lncRNAs verified by both coding potential and translation efficiency score, (ii) pan-cancer analysis for studying the significantly aberrant expression across 24 human cancers, (iii) genomic annotation of lncRNAs, such as cis-regulatory information and gene ontology, (iv) observation of the regulatory roles as enhancer RNAs and competing endogenous RNAs and (v) the findings of the potential lncRNA biomarkers for the user-interested cancers by integrating clinical information and disease specificity score. The lncExplore database is to our knowledge the first public lncRNA annotation database providing cancer-specific lncRNA expression profiles for not only known but also novel lncRNAs, enhancer RNAs annotation and clinical analysis based on pan-cancer analysis. lncExplore provides a more complete pathway to highly efficient, novel and more comprehensive translation of laboratory discoveries into the clinical context and will assist in reinterpreting the biological regulatory function of lncRNAs in cancer research. Database URL http://lncexplore.bmi.nycu.edu.tw

Skeletal dysplasia (SD) is a complex group of bone and cartilage disorders often detectable by fetal ultrasound, but the definitive diagnosis remains challenging because the phenotypes are highly variable and often overlap among different disorders. The molecular mechanisms underlying this condition are also diverse. Hundreds of genes are involved in the pathogenesis of SD, but most of them are yet to be elucidated, rendering genotyping almost infeasible except those most common such as fibroblast growth factor receptor 3 (FGFR3), collagen type I alpha 1 chain (COL1A1), collagen type I alpha 2 chain (COL1A2), diastrophic dysplasia sulfate transporter (DTDST), and SRY-box 9 (SOX9). Here, we report the use of trio-based whole exome sequencing (trio-WES) with comprehensive gene set analysis in two Taiwanese non-consanguineous families with fetal SD at autopsy. A biparental-origin homozygous c.509G&gt, A(p.G170D) mutation in peptidylprolyl isomerase B (PPIB) gene was identified. The results support a diagnosis of a rare form of autosomal recessive SD, osteogenesis imperfecta type IX (OI IX), and confirm that the use of a trio-WES study is helpful to uncover a genetic explanation for observed fetal anomalies (e.g., SD), especially in cases suggesting autosomal recessive inheritance. Moreover, the finding of an identical PPIB mutation in two non-consanguineous families highlights the possibility of the founder effect, which deserves future investigations in the Taiwanese population.

Additional file 2: Supplementary Figure 1. The illustration of path analyses models. We used path analyses to evaluate whether Z-SUM scores of 18F-THK-5351 uptake intensity mediated the associations between stroke volume and cognitive performance. We selected cognitive functions showing significant correlations with both stroke volume and Z-sum scores as the endogenous variables. Further, we adjusted for age, education, and depressive symptoms (a) and anxiety (b) co-variables.

Additional file 5. Inferences of selected genes to Marbach, TRRUSTv2 and ENCODE TF-Targets dataset.

Additional file 14: Supplementary Table 12. Clinical characteristics of patients with hemorrhagic and ischemic stroke

Additional file 3. Monotonic descending pattern genes with DE ≤ 4.

Additional file 6: Supplementary Table 5. Associations of total Z-SUM scores of 18F-THK-5351 uptake intensity with cognitive function in model II

Additional file 8. TO-GCN robustness analysis.

Additional file 1. MDS plot and heatmap.

Additional file 10: Supplementary Figure 2. Path analyses of stroke effects on cognition via total or ipsilateral Z-SUM-4 scores after age, education and anxiety adjustment. Stroke volume contributes significantly to cognitive function as well as total and ipsilateral Z-SUM-4 scores in patients with either left-hemispheric (a, b) or right-hemispheric (c, d) stroke. Further, ipsilateral Z-SUM-4 scores can partly mediate language influence from stroke volume in patients with left-hemispheric stroke (b). Likewise, total and ipsilateral Z-SUM-4 scores can partly mediate executive influence from stroke volume in patients with right-hemispheric stroke (c, d)

Additional file 4. Monotonic ascending pattern genes with DE ≤ 4.

Additional file 12: Supplementary Table 10. Comparisons of the contralateral Z-SUM scores of stroke patients with the average Z-SUM scores of bilateral hemispheres of healthy subjects

Additional file 2. TF in TO-GCN.

Additional file 6. List of enriched pathways in each level.

Additional file 9: Supplementary Table 8. Correlations of contralateral Z-SUM scores with cognitive performance in patients with left and right hemisphere stroke

Additional file 11: Supplementary Table 9. Effects of stroke volume and Z-SUM-4 score on cognitive function after adjustment for age, education and depressive symptoms (A~D) and anxiety (E~H)

Additional file 8: Supplementary Table 7. Demographic data, imaging findings and cognitive results between patients with left and right hemisphere stroke

Additional file 1: Supplementary Table 1. Tests for neuropsychological function and stroke severity evaluation

Additional file 7: Supplementary Table 6. Associations of total Z-SUM scores of 18F-THK-5351 uptake intensity with cognitive function in model III

Additional file 13: Supplementary Table 11. The correlations between total Z-SUM scores and cognitive function in ischemic stroke patients

Additional file 3: Supplementary Table 2. The comparisons of total Z-SUM scores between the presence and absence of vascular risk factors in stroke patients and healthy subjects

Additional file 4: Supplementary Table 3. Correlations of total Z-SUM scores with demographic, vascular and neurodegenerative features

The adaptive cellular response to low oxygen tensions is mediated by the hypoxia‐inducible factors (HIFs), a family of heterodimeric transcription factors composed of HIF‐α and HIF‐β subunits. Prolonged HIF expression is a key contributor to cellular transformation, tumorigenesis and metastasis. As such, HIF degradation under hypoxic conditions is an essential homeostatic and tumour‐suppressive mechanism. LIMD1 complexes with PHD2 and VHL in physiological oxygen levels (normoxia) to facilitate proteasomal degradation of the HIF‐α subunit. Here, we identify LIMD1 as a HIF‐1 target gene, which mediates a previously uncharacterised, negative regulatory feedback mechanism for hypoxic HIF‐α degradation by modulating PHD2‐LIMD1‐VHL complex formation. Hypoxic induction of LIMD1 expression results in increased HIF‐α protein degradation, inhibiting HIF‐1 target gene expression, tumour growth and vascularisation. Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator. Taken together, our data open a new field of research into the aetiology, diagnosis and prognosis of LIMD1‐negative lung cancers.

Table S1. The standardized uptake value ratios (SUVRs) of 18F-THK-5351 PET and diffusion tensor imaging parameters in the bilateral cerebral hemispheres. (DOCX 45Â kb)

In this paper, a novel single stage step up/down AC/DC converter is proposed for small wind power BLDC generators. Basically, the proposed converter is derived by integrating a brushless DC generator (BLDCG), a full diode bridge, and a C'uk DC to DC converter to achieve same robustness as a traditional diode rectifier but without incurring large torque ripple trouble. Also, it can not only generate continuous output current but also can step up/down the generator terminal voltage to cope with the wind speed variation flexibly for achieving larger operation range of the system. Moreover, a unique scalar dynamic model of the BLDCG is proposed for simplifying the dynamic control of the system. Finally, some simulation results are given for demonstrating the feasibility of the proposed converter.

In this paper, a new module structure of phase locked loop (PLL) speed controller is first proposed for permanent magnet brushless dc (PMBLDC) motor drives to achieve both fast response and high accuracy. The proposed standard module renders the controller design rather simple and straightforward. In addition, in order to reduce the drive cost, a phase current sensing scheme is adopted to properly integrate with the PWM control of the PLL controller. A prototype is also constructed to verify the feasibility of the proposed variable speed drive. It is seen that the proposed drive is rather suitable for practical applications.

In this paper, first, an equivalent scalar dynamic model for the three-phase brushless dc (BLDC) motor is derived to simplify the control of the electric vehicle (EV) drive. Then, an equivalent armature current sensing technique is proposed for synthesizing the three-phase line current by using the low-side switches of the inverter as current sensors. No additional current sensors are required and no extra power loss is generated. Third, the proposed equivalent current sensing technique is dedicatedly integrated with the PWM control for convenient closed-loop torque control implementation. Finally, a prototype EV drive system is constructed by using a 36V, 100A, 8-poles BLDC motor and a CPLD. Experimental results show that the proposed EV drive can indeed achieve the desired performance. Moreover, it is seen that with the above simplification and integration, the proposed EV drive controller circuit can be easily integrated into a single chip.

Due to the sinusoidal air gap flux waveform of interior permanent magnet (IPM) motors, an expensive encoder is usually required for the drive. In this paper, a robust and low cost hall-sensor-based rotor position signal synthesizer is first proposed for traction motor drives. Then, a double-band hysteresis current controller is adopted for the inverter to further reduce switching loss. Also, a digital signal processor, namely TI TMS320F240 is used to implement the speed controller. Experimental results show that, for common traction motor applications, the proposed IPM traction motor drive can satisfy the desired performance without using an expensive and delicate encoder.