Miracle-dz/UniFAR-FTUs huggingface dataset:
Efficacy and Safety of Vorapaxar With and Without a Thienopyridine for Secondary Prevention in Patients With Previous Myocardial Infarction and No History of Stroke or Transient Ischemic Attack: Results from TRA 2°P-TIMI 50

Background— Vorapaxar antagonizes protease-activated receptor 1, the primary receptor for thrombin on human platelets, and reduces recurrent thrombotic events in stable patients with a previous myocardial infarction (MI). We wished to determine whether the efficacy and safety of antiplatelet therapy with vorapaxar was modified by concurrent thienopyridine use. Methods and Results— The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50 (TRA 2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with previous atherothrombosis. This prespecified analysis included 16 897 patients who qualified with a MI in the preceding 2 weeks to 12 months and was restricted to patients without a history of stroke or transient ischemic attack given its contraindication in that population. Randomization was stratified on the basis of planned thienopyridine use. Thienopyridine was planned at randomization in 12 410 (73%). Vorapaxar significantly reduced the composite of cardiovascular death, MI, and stroke in comparison with placebo regardless of planned thienopyridine therapy (planned thienopyridine, hazard ratio, 0.80, 0.70–0.91, P<0.001; no planned thienopyridine, hazard ratio, 0.75; 0.60–0.94, P=0.011; P-interaction=0.67). Findings were similar when patients were stratified by actual thienopyridine use at baseline (P-interaction=0.82) and through 18 months (P-interaction=0.44). Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate or severe bleeding risk was increased with vorapaxar and was not significantly altered by planned thienopyridine (planned, hazard ratio, 1.50; 1.18–1.89, P<0.001; no planned, hazard ratio, 1.90, 1.17–3.07, P=0.009; P-interaction=0.37) or actual thienopyridine use (P-interaction=0.24). Conclusions— Vorapaxar reduced cardiovascular death, MI, or stroke in stable patients with a history of previous MI, whether treated concomitantly with a thienopyridine or not. The relative risk of moderate or severe bleeding was similarly increased irrespective of thienopyridine use. Clinical Trial Registration— URL: http://www.clinicaltrials. gov. Unique identifier: NCT00526474.
Effects of concentration of CRISPR/Cas9 components on genetic mosaicism in cytoplasmic microinjected porcine embryos

Cytoplasmic microinjection (CI) of the CRISPR/Cas9 system enabled the induction of site-specific mutations in porcine zygotes and resulting pigs. However, mosaicism is a serious problem for genetically modified pigs. In the present study, we investigated suitable timing and concentration of CRISPR/Cas9 components for introduction into oocytes/zygotes by CI, to reduce mosaicism in the resulting blastocysts. First, we introduced 20 ng/μl of Cas9 protein and guide RNA (gRNA), targeting the α-1,3-galactosyltransferase (GalT) gene in oocytes before in vitro fertilization (IVF), in zygotes after IVF, or in oocytes/zygotes before and after IVF, twice. CI treatment had no detrimental effects on blastocyst formation rates. The highest value of the rate of mutant blastocysts was observed in zygotes injected after IVF. Next, we injected Cas9 protein and gRNA into zygotes after IVF at a concentration of 20 ng/μl each (20 ng/μl group) or 100 ng/μl each (100 ng/μl group). The ratio of the number of blastocysts that carried mutations to the total number of blastocysts examined in the 100 ng/μl group was significantly higher (P < 0.05) than that in the 20 ng/μl group. Although no blastocysts from the 20 ng/μl group carried a biallelic mutation, 16.7% of blastocysts from the 100 ng/μl group carried a biallelic mutation. In conclusion, increasing the concentration of Cas9 protein and gRNA is effective in generating biallelic mutant blastocysts. To reduce mosaicism, however, further optimization of the timing of CI, and the concentration of CRISPR/Cas9 components, is needed.
Efficient Congestion Mitigation Using Congestion-Aware Steiner Trees and Network Coding Topologies

In the advent of smaller devices, a significant increase in the density of on-chip components has raised congestion and overflow as critical issues in VLSI physical design automation. In this paper, we present novel techniques for reducing congestion and minimizing overflows. Our methods are based on ripping up nets that go through the congested areas and replacing them with congestion-aware topologies. Our contributions can be summarized as follows. First, we present several efficient algorithms for finding congestion-aware Steiner trees that is, trees that avoid congested areas of the chip. Next, we show that the novel technique of network coding can lead to further improvements in routability, reduction of congestion, and overflow avoidance. Finally, we present an algorithm for identifying efficient congestion-aware network coding topologies. We evaluate the performance of the proposed algorithms through extensive simulations.
Disruption of Endolysosomal RAB5/7 Efficiently Eliminates Colorectal Cancer Stem Cells.

Given that cancer stem cells (CSC) play a key role in drug resistance and relapse, targeting CSCs remains promising in cancer therapy. Here we show that RAB5/7, which are involved in the endolysosomal pathway, play key roles in the maintenance of CSC survival via regulation of the mitophagic pathway. Inhibition of RAB5/7 efficiently eliminated colorectal CSCs and disrupted cancer foci. In addition, we identified mefloquine hydrochloride, an antimalarial drug, as a novel RAB5/7 inhibitor and promising colorectal CSC-targeting drug. Endolysosomal RAB5/7 and LAMP1/2 mediated parkin-dependent mitochondrial clearance and modulated mitophagy through lysosomal dynamics. In a patient-derived xenograft (PDX) model of colon cancer, treatment with mefloquine resulted in suppression of mitophagic PINK1/PARKIN and increased mitochondrial disorder and mitochondria-induced apoptosis without apparent side effects. These results suggest that the combination of mefloquine with chemotherapeutic agents in the PDX model potentially disrupts the hierarchy of colorectal cancer cells and identify endolysosomal RAB5/7 and LAMP1/2 as promising therapeutic targets in CSCs. SIGNIFICANCE: These findings show that endosomal/lysosomal RAB5 and RAB7, which regulate mitophagy, are essential for the survival of colon cancer stem cells.Graphical Abstract: http://cancerres.aacrjournals. org/content/canres/79/7/1426/F1.large. jpg.
Determinants and prognostic implications of left ventricular mechanical dispersion in aortic stenosis

Abstract Aims The present study aimed at investigating the association between left ventricular (LV) mechanical dispersion measured with speckle tracking echocardiography and severity of aortic stenosis (AS) and its impact on prognosis. Methods and results This retrospective study included 630 patients [age 72 (62–78) years, 61.4% men] with various grades of AS (mild AS, 19.8%; moderate AS, 37.0%; severe AS, 43.2%). LV mechanical dispersion (defined as standard deviation of time from Q/R on electrocardiogram to peak longitudinal strain in 17 LV segments) was assessed by speckle tracking echocardiography. Clinical, electrocardiographic, and echocardiographic determinants of increased LV mechanical dispersion were evaluated. During a follow-up of 107 (43–133) months, the independent association between LV mechanical dispersion and all-cause mortality (n = 302, 48%) was evaluated including aortic valve replacement as time-dependent co-variate. LV mechanical dispersion increased significantly with increasing severity of AS (mild AS, 54.5 ± 17.2 ms; moderate AS, 56.7 ± 19.3 ms; severe AS, 70.9 ± 24.3 ms; P < 0.001). Independent determinants of increased mechanical dispersion included older age (β = 0.28; P = 0.003), lower LV ejection fraction (β = −0.24; P = 0.020), smaller aortic valve area (β = −8.55; P = 0.001), larger LV mass index (β = 0.20; P < 0.001), and longer QRS duration (β = 1.12 per each 10 ms increase; P = 0.012). LV mechanical dispersion showed incremental prognostic value for all-cause mortality (hazard ratio 1.10 per each 10 ms increase, 95% confidence interval 1.04–1.15; P < 0.001). Conclusion LV mechanical dispersion assessed by speckle tracking echocardiography increases significantly with severity of AS and is significantly associated with all-cause mortality.
An integrated analysis to predict micro‐RNAs targeting both stemness and metastasis in breast cancer stem cells

Several evidences support the idea that a small population of tumour cells representing self‐renewal potential are involved in initiation, maintenance, metastasis, and outcomes of cancer therapy. Elucidation of microRNAs/genes regulatory networks activated in cancer stem cells (CSCs) is necessary for the identification of new targets for cancer therapy. The aim of the present study was to predict the miRNAs pattern, which can target both metastasis and self‐renewal pathways using integration of literature and data mining. For this purpose, mammospheres derived from MCF‐7, MDA‐MB231, and MDA‐MB468 were used as breast CSCs model. They had higher migration, invasion, and colony formation potential, with increasing in stemness‐ and EMT‐related genes expression. Our results determined that miR‐204, ‐200c, ‐34a, and ‐10b contemporarily could target both self‐renewal and EMT pathways. This core regulatory of miRNAs could increase the survival rate of breast invasive carcinoma via up‐regulation of OCT4, SOX2, KLF4, c‐MYC, NOTCH1, SNAI1, ZEB1, and CDH2 and down‐regulation of CDH1. The majority of those target genes were involved in the regulation of pluripotency, MAPK, WNT, Hedgehog, p53, and transforming growth factor β pathways. Hence, this study provides novel insights for targeting core regulatory of miRNAs in breast CSCs to target both self‐renewal and metastasis potential and eradication of breast cancer.
A Paradigm to Enhance Motor Imagery Using Rubber Hand Illusion Induced by Visuo-Tactile Stimulus

Enhancing motor imagery (MI) results in amplified event-related desynchronization (ERD) and is important for MI-based rehabilitation and brain–computer interface (BCI) applications. Many attempts to enhance the MI by providing a visual guidance have been reported. We believe that the rubber hand illusion (RHI), which induces body ownership over an external object, can provide better guidance to enhance MI; thus, an RHI-based paradigm with motorized moving rubber hand was proposed. To validate the proposed MI enhancing paradigm, we conducted an experimental comparison among paradigms with 20 healthy subjects. The peak amplitude and arrival times of ERD were compared at contralateral and ipsilateral electroencephalogram channels. We found significantly amplified ERD caused by the proposed paradigm, which is similar to the ERD caused by motor execution. In addition, the arrival time suggests that the proposed paradigm is applicable for BCI. In conclusion, the proposed paradigm can significantly enhance the MI with better characteristics for use with BCI.
Metabolic Costs During Backward Running with Body Weight Support

Abstract We investigated metabolic costs, rating of perceived exertion (RPE), stride frequency (SF), and preferred speed (PS) during forward and backward running at different levels of body weight support (BWS). Participants completed forward and backward running on a lower body positive pressure treadmill at their preferred speed for forward and backward running at 0%BWS, 20%BWS, and 50%BWS. Oxygen uptake (V̇O2), heart rate (HR), RPE, SF, and PS were measured. HR, RPE, and SF during forward and backward running decreased with increasing BWS (P<0.05). V̇O2 during both forward and backward running at 50%BWS was significantly lower than when running at 0%BWS (P<0.01). However, PS during forward and backward running increased with increasing BWS (P<0.01). Furthermore,V̇O2 was different between running directions only when running at 0%BWS (P<0.01). HR and RPE were not different between running directions (P>0.05). SF during backward running was higher than that of forward running (P<0.01). PS during backward running was lower than when running forward (P<0.001). Our observations suggest that individuals may select PS and SF during running with BWS in a way that resulted in similar metabolic costs, regardless of direction of locomotion.
Imaging of Patients with Suspected Large-Vessel Occlusion at Primary Stroke Centers: Available Modalities and a Suggested Approach

Endovascular thrombectomy has proven efficacy for a wide range of patients with large-vessel occlusion stroke and in selected cases up to 24 hours from onset. While primary stroke centers have increased the proportion of patients withstroke receiving thrombolytic therapy, delays can be encountereduntil patients with LVO are identified and transferred from the primary stroke center to acomprehensive stroke center. Therefore, any extra steps need to be carefullyweighed. The use of CTA (especially multiphase) at the primary stroke center levelhas many advantages in expediting the transfer of appropriate patients to a comprehensive center. SUMMARY: The overwhelming benefit of endovascular therapy in patients with large-vessel occlusions suggests that more patients will be screened than treated. Some of those patients will be evaluated first at primary stroke centers; this type of evaluation calls for standardizing the imaging approach to minimize delays in assessing, transferring, and treating these patients. Here, we propose that CT angiography (performed at the same time as head CT) should be the minimum imaging approach for all patients with stroke with suspected large-vessel occlusion presenting to primary stroke centers. We discuss some of the implications of this approach and how to facilitate them.
Palliative care in paramedic practice: A retrospective cohort study

Background: Paramedics may be involved in the care of patients experiencing a health crisis associated with palliative care. However, little is known about the paramedic’s role in the care of these patients. Aim: To describe the incidence and nature of cases attended by paramedics and the care provided where the reason for attendance was associated with a history of palliative care. Design: This is a retrospective cohort study. Setting/participants: Adult patients (aged >17 years) attended by paramedics in the Australian state of Victoria between 1 July 2015 and 30 June 2016 where terms associated with palliative care or end of life were recorded in the patient care record. Secondary transfers including inter-hospital transport cases were excluded. Results: A total of 4348 cases met inclusion criteria. Median age was 74 years (interquartile range 64–83). The most common paramedic assessments were ‘respiratory’ (20.1%), ‘pain’ (15.8%) and ‘deceased’ (7.9%); 74.4% (n = 3237) were transported, with the most common destination being a hospital (99.5%, n = 3221). Of those with pain as the primary impression, 359 (53.9%) received an analgesic, morphine, fentanyl or methoxyflurane, and 356 (99.2%) were transported following analgesic administration. Resuscitation was attempted in 98 (29.1%) of the 337 cases coded as cardiac arrest. Among non-transported cases, there were 105 (9.6%) cases where paramedics re-attended the patient within 24 h of the previous attendance. Conclusion: Paramedics have a significant role in caring for patients receiving palliative care. These results should inform the design of integrated systems of care that involve ambulance services in the planning and delivery of community-based palliative care.
Early Subthreshold Aerobic Exercise for Sport-Related Concussion: A Randomized Clinical Trial

Importance Sport-related concussion (SRC) is a significant public health problem without an effective treatment. Objective To assess the effectiveness of subsymptom threshold aerobic exercise vs a placebo-like stretching program prescribed to adolescents in the acute phase of recovery from SRC. Design, Setting, and Participants This multicenter prospective randomized clinical trial was conducted at university concussion centers. Male and female adolescent athletes (age 13-18 years) presenting within 10 days of SRC were randomly assigned to aerobic exercise or a placebo-like stretching regimen. Interventions After systematic determination of treadmill exercise tolerance on the first visit, participants were randomly assigned to a progressive subsymptom threshold aerobic exercise or a progressive placebo-like stretching program (that would not substantially elevate heart rate). Both forms of exercise were performed approximately 20 minutes per day, and participants reported daily symptoms and compliance with exercise prescription via a website. Main Outcomes and Measures Days from injury to recovery; recovery was defined as being asymptomatic, having recovery confirmed through an assessment by a physician blinded to treatment group, and returning to normal exercise tolerance on treadmill testing. Participants were also classified as having normal (<30 days) or delayed (≥30 days) recovery. Results A total of 103 participants were included (aerobic exercise: n = 52; 24 female [46%]; stretching, n = 51; 24 female [47%]). Participants in the aerobic exercise group were seen a mean (SD) of 4.9 (2.2) days after the SRC, and those in the stretching group were seen a mean (SD) of 4.8 (2.4) days after the SRC. There were no differences in age, sex, previous concussions, time from injury, initial symptom severity score, or initial exercise treadmill test and physical examination results. Aerobic exercise participants recovered in a median of 13 (interquartile range [IQR], 10-18.5) days, whereas stretching participants recovered in 17 (IQR, 13-23) days (P = .009 by Mann-Whitney test). There was a nonsignificant lower incidence of delayed recovery in the aerobic exercise group (2 participants [4%] in the aerobic group vs 7 [14%] in the placebo group; P = .08). Conclusions and Relevance This is, to our knowledge, the first RCT to show that individualized subsymptom threshold aerobic exercise treatment prescribed to adolescents with concussion symptoms during the first week after SRC speeds recovery and may reduce the incidence of delayed recovery. Trial Registration ClinicalTrials.gov identifier: NCT02710123
Some observations on the liquid crystalline and gel behaviors of aqueous dispersions of a prodrug

Abstract BMS-830216 is a diprotic acid prodrug of two pKa values (<2 and 6.8) with high apparent solubility at pH ≥ 7. At ∼ pH 4 solutions of BMS-830216 appear to be surface active, in which their surface tension can be reduced from 72 to 65 dynes when its concentrations is above the critical aggregation concentration (CAC∼0.2 mM). Additionally, at this pH, BMS-830216 tends to form liquid crystalline phases (at ≥ 2 mg/mL) in acetate buffer when using tris salt. Furthermore, after raising the concentration beyond 20 mg/g, formation of gel-like dispersions was noted. These gel-like dispersions exhibited a strong elastic strength, significantly impacting the dissolution behavior of the tris salt. Mechanistically, it is likely that BMS-830216 tris salt in solution first forms a lamellar phase followed by formation of a gel phase at higher concentrations (≥20 mg/mL). As indicated by SAXS, the lamellar phase formed seems to have two d-spacing values (∼5 nm and ∼10 nm (weak), which seems to correspond to two molecules connected tail by tail (5 nm). Further investigation is needed for phase identification, as their properties can affect the physical behavior of BMS-830216 in the development of pharmaceutical dosage forms.
Laminations and Microgranule Formation in Pediatric Glomerular Basement Membranes

Glomerular basement membrane (GBM) splitting, laminations, and microgranular formation are classically encountered with Alport disease, but can be found in other glomerular diseases. We found moderate to marked GBM laminations/microgranular formations in 51 of 724 (7%) pediatric diagnostic renal biopsies. These included 12 Alport disease, 12 thin basement membrane disease (TBM), 13 mesangial hypercellularity (MH), 6 focal segmental glomerulosclerosis (FSGS), and 8 other diseases. Follow-up demonstrated progression in most of the Alport disease and FSGS, as expected, but also in 40% of TBM and 30% of MH. Basement membrane laminations/microgranular formations are not specific for Alport disease, may represent a non-specific injury, and may herald a progressive clinical course.
Does juvenile hormone prompt oxidative stress in male damselflies?

ABSTRACT In invertebrates, it has recently been reported that secondary sexual characteristics (SSCs) reflect the antioxidant defense of their bearers, but it is not known what physiological link maintains the honesty of those signals. Here, we used the damselfly Hetaerina americana to test whether juvenile hormone plays such a role. First, we analyzed whether oxidative damage is a real threat in natural damselfly populations by examining the accumulation of oxidized guanines as a function of age in males. Then, we injected paraquat (a pro-oxidant agent) and added the juvenile hormone analog methoprene (JHa) to the experimental group and the JHa vehicle (acetone) to the control group, to determine whether JHa increases the levels of pro-oxidants and antioxidants. We found that DNA oxidation increased with age, and that levels of hydrogen peroxide and superoxide dismutase, but not catalase or glutathione, were elevated in the JHa group compared with the control group. We propose that juvenile hormone is a mediator of the relationship between SSCs and antioxidant capacity and, based on the literature, we know that JHa suppresses the immune response. We therefore suggest that juvenile hormone is a molecular mediator of the general health of males, which is reflected in their SSCs. Summary: We propose that in invertebrates, juvenile hormone is a molecular mediator of the relationship between oxidative stress status and secondary sexual characteristics.