Miracle-dz/UniFAR-FTUs huggingface dataset:
Real-world comparative safety and efficacy of tenecteplase versus alteplase in acute ischemic stroke patients with large vessel occlusion

Background and aims: Tenecteplase has recently emerged as an alternative thrombolytic agent in acute ischemic stroke (AIS) patients with large vessel occlusion (LVO), possibly superior in achieving early reperfusion compared with alteplase. We aimed to compare the safety and efficacy of intravenous tenecteplase with intravenous alteplase for AIS patients with LVO in everyday clinical practice settings. Methods: We prospectively evaluated patients with AIS due to LVO, treated with intravenous thrombolysis (IVT) with or without mechanical thrombectomy in two tertiary stroke centers. Patients were treated with standard-dose alteplase (0.9 mg/kg) or 0.25 mg/kg tenecteplase. Safety outcomes included prevalence of symptomatic intracranial hemorrhage (sICH) and mortality. Efficacy outcomes included averted thrombectomy, major neurological improvement at 24 h (defined as decrease in baseline NIHSS score of 8 points or greater) and functional status on discharge and on 3 months assessed by modified Rankin Scale (mRS). Results: Nineteen AIS patients with LVO received tenecteplase and 39 received alteplase. We observed a non-significant higher rate of averted thrombectomies (32% versus 18%, p = 0.243) and a non-significant higher rate of sICH (16% versus 5%, p = 0.201) in the tenecteplase group. The rate of 24 h major neurological improvement was higher in the tenecteplase group (64% versus 33%, p = 0.046) but this was marginally attenuated in multivariable analyses (adjusted OR 10.22, 95% CI: 0.73–142.98; p = 0.084). Discharge mRS, 3-months mRS, and 3-month functional independence (mRS scores of 0–2) did not differ (p > 0.2) between the two groups. The rates of 3-month mortality (11% versus 18%, p = 0.703) were similar in the two groups. No independent association between thrombolytic agent and safety or efficacy outcomes emerged in multivariable regression analyses. Conclusion: The present pilot observational study highlights that AIS patients with LVO treated with 0.25 mg/kg bolus administration of tenecteplase had increased likelihood to achieve early neurological improvement compared with AIS patients treated with alteplase, but this association was attenuated after adjustment for potential confounders. There were no significant differences in 3-month functional or safety outcomes between the two groups. This preliminary real-world observation requires independent confirmation in larger, multicenter studies.
Safety of dried yellow mealworm (Tenebrio molitor larva) as a novel food pursuant to Regulation (EU) 2015/2283

Abstract Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on dried yellow mealworm (Tenebrio molitor larva) as a novel food (NF) pursuant to Regulation (EU) 2015/2283. The term yellow mealworm refers to the larval form of the insect species Tenebrio molitor. The NF is the thermally dried yellow mealworm, either as whole dried insect or in the form of powder. The main components of the NF are protein, fat and fibre (chitin). The Panel notes that the levels of contaminants in the NF depend on the occurrence levels of these substances in the insect feed. The Panel notes that there are no safety concerns regarding the stability of the NF if the NF complies with the proposed specification limits during its entire shelf life. The NF has a high protein content, although the true protein levels in the NF are overestimated when using the nitrogen‐to‐protein conversion factor of 6.25, due to the presence of non‐protein nitrogen from chitin. The applicant proposed to use the NF as whole, dried insect in the form of snacks, and as a food ingredient in a number of food products. The target population proposed by the applicant is the general population. The Panel notes that considering the composition of the NF and the proposed conditions of use, the consumption of the NF is not nutritionally disadvantageous. The submitted toxicity studies from the literature did not raise safety concerns. The Panel considers that the consumption of the NF may induce primary sensitisation and allergic reactions to yellow mealworm proteins and may cause allergic reactions in subjects with allergy to crustaceans and dust mites. Additionally, allergens from the feed may end up in the NF. The Panel concludes that the NF is safe under the proposed uses and use levels.
Identification of Organic Volatile Markers Associated with Aroma during Maturation of Strawberry Fruits

In the present study, organic volatile markers of three strawberry varieties (Albion, Festival and Frontera) during the maturation process were investigated. Forty metabolites associated with aroma in fresh strawberries were monitored during seven stages of maturation using gas chromatography–mass spectrometry (GC-MS) equipped with headspace-solid phase microextraction (HS-SPME). The data were evaluated using multivariate analysis to observe correlations between the organic volatile compound profile and the seven phenological stages of maturation for each strawberry variety. The dynamic levels of butanoic acid methyl ester, hexanoic acid methyl ester, octylcyclohexane, cyclohexane,1,1,2-trimethyl, linalool, tetradecane, and α-muurolene underwent distinctive changes in concentration during the maturation process. The multivariate analysis also allowed the identification of these compounds as possible volatile markers to measure the maturation of strawberry fruits in all three varieties. These findings highlight the importance of the timing of harvest and maturation stage in each variety to preserve or improve the desirable aromatic characteristics of strawberry fruits.
The Added Value of [18F]FDG PET/CT in the Management of Invasive Fungal Infections

Anatomy-based imaging methods are the usual imaging methods used in assessing invasive fungal infections (IFIs). [18F]FDG PET/CT has also been used in the evaluation of IFIs. We assessed the added value of [18F]FDG PET/CT when added to the most frequently used anatomy-based studies in the evaluation of IFIs. The study was conducted in two University Medical Centers in the Netherlands. Reports of [18F]FDG PET/CT and anatomy-based imaging performed within two weeks of the [18F]FDG PET/CT scan were retrieved, and the presence and sites of IFI lesions were documented for each procedure. We included 155 [18F]FDG PET/CT scans performed in 73 patients. A total of 216 anatomy-based studies including 80 chest X-rays, 89 computed tomography studies, 14 magnetic resonance imaging studies, and 33 ultrasound imaging studies were studied. The anatomy-based studies were concordant with the [18F]FDG PET/CT for 94.4% of the scans performed. [18F]FDG PET/CT detected IFI lesions outside of the areas imaged by the anatomy-based studies in 48.6% of the scans. In 74% of the patients, [18F]FDG PET/CT added value in the management of the IFIs.
Evaluating the Role of Anesthesia on Intraoperative Blood Loss and Visibility during Endoscopic Sinus Surgery: A Meta-analysis

Background Previous studies and meta analyses have led to incongruent and incomplete results respectively when total intravenous anesthesia (TIVA) and inhalational anesthesia (IA) are compared in endoscopic sinus surgeries in regards to intraoperative bleeding and visibility. Objective To perform a more comprehensive meta-analysis on randomized controlled trial (RCTs) comparing TIVA with IA in endoscopic sinus surgery to evaluate their effects on intraoperative bleeding and visibility. Methods A systematic review and meta-analysis of studies comparing TIVA and IA in endoscopic sinus surgery for chronic rhinosinusitis was completed in May 2020. Utilizing databases, articles were systematically screened for analysis and 19 studies met our inclusion criteria. The primary outcome included intraoperative visibility scores combining Boezaart, Wormald and Visual Analogue Scale (VAS). Secondary outcomes included rate of blood loss (mL/kg/min), estimated total blood loss (mL), Boezaart, Wormald scores, VAS, heart rate, and mean arterial pressure (MAP). Results 19 RCTs with 1,010 patients were analyzed. TIVA had a significantly lower intraoperative bleeding score indicating better endoscopic visibility (Boezaart, VAS, and Wormald) than IA (−0.514, p = 0.020). IA had a significantly higher average rate of blood loss than TIVA by 0.563 mL/kg/min (p = 0.016). Estimated total blood loss was significantly lower in TIVA than IA (−0.853 mL, p = 0.002). There were no significant differences between TIVA and IA in the mean heart rate (−0.225, p = 0.63) and MAP values (−0.126, p = 0.634). The subgroup analyses revealed no significant difference between TIVA and IA when remifentanil was not utilized and whenever desflurane was the IA agent. Conclusion TIVA seemed to have superior intraoperative visibility scores and blood loss during endoscopic sinus surgery when compared to IA. However, the results are not consistent when stratifying the results based on the use of remifentanil and different inhaled anesthetics. Therefore, the conclusion cannot be made that one approach is superior to the other.
Laser Metal Deposition of Inconel 718 Alloy and As-built Mechanical Properties Compared to Casting

In the last years, powder-based Laser Metal Deposition (LMD) has been attracting attention as a disruptive Additive Manufacturing (AM) technique for both the fabrication and restoration of Inconel 718 components, enabling to overcome current limitations faced by conventional manufacturing processes in terms of manufacturing costs, tool wear, and lead time. Nevertheless, the uncertainty related to the final mechanical performance of the as-built LMD parts limits a wider adoption of such technology at industrial level. This research work focuses on the mechanical characterization of as-built Inconel 718 specimens through split Hopkinson tensile bar tests performed at different strain rate conditions. The influence of laser power on the final mechanical behavior of the as-built tensile samples is discussed and compared with the mechanical response of as-cast ones. The as-built specimens exhibit a high internal density (i.e., 99.92% and 99.90% for 300 W and 400 W, respectively) and a more ductile behavior compared to the as-cast ones for every evaluated strain rate condition. The strain hardening capacity of the as-built samples increases with the laser power involved in the LMD process, reaching an average Yield Strength of 703 MPa for specimens realized at 400 W and tested at 800/s.
The Immunopathological and Histological Landscape of COVID-19-Mediated Lung Injury

A complete understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) physiopathology and related histopathologic lesions is necessary to improve treatment and outcome of coronavirus disease 2019 (COVID-19) patients. Many studies have focused on autopsy findings in COVID-19-related deaths to try and define any possible specific pattern. Histopathologic alterations are principally found within lungs and blood vessels, and these abnormalities also seem to have the highest clinical impact. Nevertheless, many of the morphological data collected so far are non-specific, fickle, and possibly associated with other co-existing factors. The aim of this minireview is to describe the main histopathological features related to COVID-19 and the mechanism known as “cytokine storm”.
Chromatin accessibility dynamics during cell fate reprogramming

Genome architecture and chromatin dynamics govern the fate and identify of a cell. Recent advances in mapping chromatin landscapes offer valuable tools for the acquisition of accurate information regarding chromatin dynamics. Here we discuss recent findings linking chromatin dynamics to cell fate control. Specifically, chromatin undergoes a binary off/on switch during iPSC reprogramming, closing and opening loci occupied by somatic and pluripotency transcription factors, respectively. This logic of a binary off/on switch may also be operational in cell fate control during normal development and implies that further approaches could potentially be developed to direct cell fate changes both in vitro and in vivo.
A scoping review of the utility of self-report and informant-report prospective memory measures

ABSTRACT There has been increased use of self-report prospective memory (PM) scales in recent years, despite uncertainty about their validity. This study reviewed how self-and informant-report PM questionnaires have been used in the assessment of PM. We evaluated relationships between self-report, informant-report, and performance-based PM measures, and the validity of using self-report measures in detecting PM impairments and monitoring intervention outcomes. The scoping review methodology of Arksey and O'Malley (2005. Scoping studies: Towards a methodological framework. International Journal of Social Research Methodology, 8(1), 19–32) was used. Database searches yielded 488 published studies that used the Prospective Memory Questionnaire (PMQ), Prospective and Retrospective Memory Questionnaire (PRMQ), Comprehensive Assessment of PM (CAPM), and Brief Assessment of PM (BAPM). The self-report and informant-report measures of PM had weak- to moderate-strength relationships with performance-based PM measures. Some self-report PM scales could detect PM impairments and monitor intervention outcomes, however few studies had investigated this. The findings indicated that self- and informant-report scales measure different constructs to performance-based measures of PM. It is recommended that these scales be used alongside performance-based measures to provide complementary and comprehensive assessments of PM. Further research into assessment of PM using self-report measures will aid assessment and treatment choices.
Glucosamine displays a potent caloric restriction mimetic effect in senescent rats by activating mitohormesis.

Aging is strongly correlated with several non-communicable disorders such as diabetes, obesity, cardiovascular disease, and neurodegenerative conditions. Glucosamine (2-amino-2-deoxy-D-glucose, GlcN) is a naturally occurring amino sugar and is reported to act as a caloric restriction mimetic (CRM). In young and D-galactose-induced accelerated rat aging models, we tested a persistent oral dietary dose of GlcN and evaluated various aging biomarkers in erythrocytes and plasma. A significant increase in the reactive oxygen species (ROS) was observed in GlcN treated young and accelerated senescent rat model. Increased value of Ferric Reducing Antioxidant Potential (FRAP), Superoxide Dismutase (SOD), Catalase (CAT), and Plasma membrane reduced system (PMRS) was observed. We suggest that GlcN induces a mitohormetic impact by a transient increase in ROS. Our findings indicate that GlcN may be a successful CRM.
Blood plasma metabolomics of children and adolescents with sickle cell anaemia treated with hydroxycarbamide: a new tool for uncovering biochemical alterations

Sickle cell anaemia (SCA) is a debilitating genetic haemoglobinopathy predominantly affecting the disenfranchised strata of society in Africa and the Americas. The most common pharmacological treatment for this disease is the administration of hydroxycarbamide (HC) for which questions remain regarding its mechanism of action, efficacy and long‐term toxicity specifically in paediatric individuals. A multiplatform metabolomics approach was used to assess the metabolome of plasma samples from a population of children and adolescents with SCA with and without HC treatment along with non‐SCA individuals. Fifty‐three metabolites were identified by ultra‐high performance liquid chromatography coupled to high‐resolution mass spectrometry (UHPLC‐HRMS) and 1H nuclear magnetic resonance (NMR) with a predominance of membrane lipids, amino acids and organic acids. The partial least‐squares discriminant analysis (PLS‐DA) analysis allowed a clear discrimination between the different studied groups, revealing clear effects of the HC treatment in the patients’ metabolome including rescue of specific metabolites to control levels. Increased creatine/creatinine levels under HC treatment suggests a possible increase in the arginine pool and increased NO synthesis, supporting existing models for HC action in SCA. The metabolomics results extend the current knowledge on the models for SCA pathophysiology including impairment of Lands’ cycle and increased synthesis of sphingosine 1‐phosphate. Putative novel biomarkers are suggested.
Identification of a Dexamethasone Mediated Radioprotection Mechanism Reveals New Therapeutic Vulnerabilities in Glioblastoma

Simple Summary The standard of care for patients with newly diagnosed glioblastoma (GBM) comprises surgery followed by radio- and chemotherapy. In addition, dexamethasone is used to manage the development of inflammation within the brain in general, and particularly during treatment. The effects of dexamethasone on patient survival however remain controversial because several clinical studies suggest that dexamethasone could potentially restrict effective radiotherapy. With the idea to improve GBM therapy, we set out to identify small molecule inhibitors that could improve the killing of GBM cells when applied together with radiotherapy. We have identified a novel dexamethasone-induced mechanism that can directly protect GBM cells from radiotherapy and thus may contribute to the adverse effects observed in the clinic. Strikingly, this mechanism also sensitises GBM cells to tyrosine kinase inhibitors, thus encouraging the revision of the use of these inhibitors for the treatment of GBM, potentially in an adjuvant setting. Abstract (1) Background: Despite the indisputable effectiveness of dexamethasone (DEXA) to reduce inflammation in glioblastoma (GBM) patients, its influence on tumour progression and radiotherapy response remains controversial. (2) Methods: We analysed patient data and used expression and cell biological analyses to assess effects of DEXA on GBM cells. We tested the efficacy of tyrosine kinase inhibitors in vitro and in vivo. (3) Results: We confirm in our patient cohort that administration of DEXA correlates with worse overall survival and shorter time to relapse. In GBM cells and glioma stem-like cells (GSCs) DEXA down-regulates genes controlling G2/M and mitotic-spindle checkpoints, and it enables cells to override the spindle assembly checkpoint (SAC). Concurrently, DEXA up-regulates Platelet Derived Growth Factor Receptor (PDGFR) signalling, which stimulates expression of anti-apoptotic regulators BCL2L1 and MCL1, required for survival during extended mitosis. Importantly, the protective potential of DEXA is dependent on intact tyrosine kinase signalling and ponatinib, sunitinib and dasatinib, all effectively overcome the radio-protective and pro-proliferative activity of DEXA. Moreover, we discovered that DEXA-induced signalling creates a therapeutic vulnerability for sunitinib in GSCs and GBM cells in vitro and in vivo. (4) Conclusions: Our results reveal a novel DEXA-induced mechanism in GBM cells and provide a rationale for revisiting the use of tyrosine kinase inhibitors for the treatment of GBM.
Combined Effects of Methylated Cytosine and Molecular Crowding on the Thermodynamic Stability of DNA Duplexes

Methylated cytosine within CpG dinucleotides is a key factor for epigenetic gene regulation. It has been revealed that methylated cytosine decreases DNA backbone flexibility and increases the thermal stability of DNA. Although the molecular environment is an important factor for the structure, thermodynamics, and function of biomolecules, there are few reports on the effects of methylated cytosine under a cell-mimicking molecular environment. Here, we systematically investigated the effects of methylated cytosine on the thermodynamics of DNA duplexes under molecular crowding conditions, which is a critical difference between the molecular environment in cells and test tubes. Thermodynamic parameters quantitatively demonstrated that the methylation effect and molecular crowding effect on DNA duplexes are independent and additive, in which the degree of the stabilization is the sum of the methylation effect and molecular crowding effect. Furthermore, the effects of methylation and molecular crowding correlate with the hydration states of DNA duplexes. The stabilization effect of methylation was due to the favorable enthalpic contribution, suggesting that direct interactions of the methyl group with adjacent bases and adjacent methyl groups play a role in determining the flexibility and thermodynamics of DNA duplexes. These results are useful to predict the properties of DNA duplexes with methylation in cell-mimicking conditions.
A modular framework for early-phase seamless oncology trials

Background: As our understanding of the etiology and mechanisms of cancer becomes more sophisticated and the number of therapeutic options increases, phase I oncology trials today have multiple primary objectives. Many such designs are now “seamless,” meaning that the trial estimates both the maximum tolerated dose and the efficacy at this dose level. Sponsors often proceed with further study only with this additional efficacy evidence. However, with this increasing complexity in trial design, it becomes challenging to articulate fundamental operating characteristics of these trials, such as (1) what is the probability that the design will identify an acceptable, that is. , safe and efficacious, dose level? or (2) how many patients will be assigned to an acceptable dose level on average? Methods: In this manuscript, we propose a new modular framework for designing and evaluating seamless oncology trials. Each module is comprised of either a dose assignment step or a dose-response evaluation, and multiple such modules can be implemented sequentially. We develop modules from existing phase I/II designs as well as a novel module for evaluating dose-response using a Bayesian isotonic regression scheme. Results: We also demonstrate a freely available R package called seamlesssim to numerically estimate, by means of simulation, the operating characteristics of these modular trials. Conclusions: Together, this design framework and its accompanying simulator allow the clinical trialist to compare multiple different candidate designs, more rigorously assess performance, better justify sample sizes, and ultimately select a higher quality design.
The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases

Brain-derived neurotrophic factor (BDNF) is one of the most abundantneurotrophins in the central nervous system. Numerous studies suggestthat BDNF has extensive roles by binding to its specific receptor, tropomyosin-related kinase receptor B (TrkB), and thereby triggering downstream signaling pathways. Recently, growing evidence highlightsthat the BDNF/TrkB pathway is expressed in the cardiovascular system andclosely associated with the development and outcome of cardiovascular diseases (CVD), including coronary artery disease, heart failure, cardiomyopathy, hypertension, and metabolic diseases. Furthermore, circulating BDNF has also been revealed as a new potential biomarker for both diagnosis and prognosis of CVD. In this review, we discuss the current evidence of the emerging role of BDNF/TrkBsignalingand address the challenges that remain in translating these discoveries to novel therapeutic strategies for CVD.