Miracle-dz/UniFAR-FTUs huggingface dataset:
Mediterranean Diet Decreases the Initiation of Use of Vitamin K Epoxide Reductase Inhibitors and Their Associated Cardiovascular Risk: A Randomized Controlled Trial

Our aim is to assess whether following a Mediterranean Diet (MedDiet) decreases the risk of initiating antithrombotic therapies and the cardiovascular risk associated with its use in older individuals at high cardiovascular risk. We evaluate whether participants of the PREvención con DIeta MEDiterránea (PREDIMED) study allocated to a MedDiet enriched in extra-virgin olive oil or nuts (versus a low-fat control intervention) disclose differences in the risk of initiation of: (1) vitamin K epoxide reductase inhibitors (acenocumarol/warfarin; n = 6772); (2) acetylsalicylic acid as antiplatelet agent (n = 5662); and (3) other antiplatelet drugs (cilostazol/clopidogrel/dipyridamole/ditazol/ticlopidine/triflusal; n = 6768). We also assess whether MedDiet modifies the association between the antithrombotic drug baseline use and incident cardiovascular events. The MedDiet intervention enriched with extra-virgin olive oil decreased the risk of initiating the use of vitamin K epoxide reductase inhibitors relative to control diet (HR: 0.68 [0.46–0.998]). Their use was also more strongly associated with an increased risk of cardiovascular disease in participants not allocated to MedDiet interventions (HRcontrol diet: 4.22 [1.92–9.30], HRMedDiets: 1.71 [0.83–3.52], p-interaction = 0.052). In conclusion, in an older population at high cardiovascular risk, following a MedDiet decreases the initiation of antithrombotic therapies and the risk of suffering major cardiovascular events among users of vitamin K epoxide reductase inhibitors.
Suicidality in Patients with Brain Tumors: A Brief Literature Review with Clinical Exemplar

Background: Suicidality and brain tumors are two life-threatening conditions and, somewhat unexpectedly, the associations between them have scarcely been reported. Objective: In this study, we aimed to provide a brief literature review of epidemiological studies on suicidal ideation (SI) and suicidal behavior (SB) in patients with brain tumors. To illustrate various aspects of brain tumors that potentially underlie the emergence of suicidality, the review is supplemented with a clinical exemplar of a long-term survivor of brain tumor (glioblastoma) who experienced persistent SI. Furthermore, we discuss putative both neurobiological (including anatomical and immunological) and psychosocial mechanisms that might be accountable for the development of SI and SB in patients with brain tumors. Conclusions: While the etiology of this phenomenon appears to be multifactorial and still remains a subject of much debate, it is of critical importance to identify patients for which a psychiatric evaluation could recognize, in a timely manner, a possible suicide risk and alleviate the deep related suffering, by appropriate psychopharmacological and supportive and psychotherapeutic interventions.
Reduced Kidney Function and Relative Hypocalciuria—Observational, Cross-Sectional, Population-Based Data

This observational, cross-sectional, epidemiological analysis investigated relationships of kidney function to urine calcium and other variables. The analyses targeted two population-based samples of adults (Gubbio study and Moli-sani study: n = 3508 and 955, respectively). Kidney function was assessed as estimated glomerular filtration rate (eGFR). Calcium/creatinine ratio (Ca/Cr) was used as index of urinary calcium in timed overnight urine under fed condition (Gubbio study), morning urine after overnight fast (Gubbio study), and first-void morning urine (Moli-sani study). Moli-sani study included also data for glomerular filtered calcium load, tubular calcium handling, and serum phosphorus, parathyroid hormone, 1,25-dihydroxyvitamin D, calcium, and 25-hydroxyvitamin D. eGFR positively and independently related to Ca/Cr (p < 0.001). In multivariate analyses, eGFR lower by 10 mL/min × 1.73 m2 related to overnight urine Ca/Cr lower by 14.0 mg/g in men and 17.8 mg/g in women, to morning urine Ca/Cr lower by 9.3 mg/g in men and 11.2 mg/g in women, and to first-void urine Ca/Cr lower by 7.7 mg/g in men and 9.6 mg/g in women (p < 0.001). eGFR independently related to glomerular filtered calcium load (p < 0.001) and did not relate to tubular calcium handling (p ≥ 0.35). In reduced eGFR only (<90 mL/min × 1.73 m2), low urine Ca/Cr independently related to low serum 1,25-dihydroxyvitamin D (p = 0.002) and did not relate to hyperphosphatemia, high serum parathyroid hormone, or hypocalcemia (p ≥ 0.14). Population-based data indicated consistent associations of lower kidney function with lower urine calcium due to reduction in glomerular filtered calcium. In reduced kidney function, relative hypocalciuria associated with higher prevalence of low serum 1,25-dihydroxyvitamin D.
Pharmacokinetic Characterization and External Evaluation of a Quantitative Framework of Sublingual Buprenorphine in Patients with an Opioid Disorder in Puerto Rico

Background: The aim of this analysis was to characterize the pharmacokinetics (PK) of sublingual buprenorphine (BUP) and its metabolites (buprenorphine glucuronide; BUP-g, norbuprenorphine; Nor-BUP, and norbuprenorphine glucuronide; Nor-BUP-g) in opioid use disorder (OUD) patients in Puerto Rico (PR) as a first step of evidence-based BUP dosing strategies in this population. Methods: BUP and metabolites concentrations were measured from 0 to 8 h after the administration of sublingual buprenorphine/naloxone films in 12 stable OUD subjects. Results: PK non-compartmental characteristics showed considerable variability in parameters between the subjects over the 8-h sampling time (tmax = 1.5 ± 0.7 h, Co = 1.6 ± 1.4 ng/mL, Cmax= 7.1 ± 6 ng/mL, and AUC0–8h = 26.8 ± 17.8 h·ng/mL). Subjects had a significantly higher tendency towards CYP-mediated N-demethylation, with the AUC0–8h ratios of the molar concentrations of [Nor-BUP + Nor-BUP-g] to BUP being (3.4 ± 1.9) significantly higher compared with BUP-g to BUP (0.19 ± 0.2). A two-compartment population-PK model with linear absorption (ka = 2.54 h−1), distribution (k12= 2.34 h−1, k14 = 1.29 h−1), metabolism (k24 = 1.28 × 10−1 h−1, k23 = 6.43 × 10−2 h−1, k35 = 1.23 × 10−1 h−1, k45 = 8.73 × 10−1 h−1), and elimination (k30 = 3.81 × 10−3 h−1, k50 = 1.27 × 10−1 h−1) adequately described the time-course of BUP and its metabolites, which has been externally validated using published data. Conclusions: Although limited in sampling time and number of recruited subjects, this study presents specific BUP PK characteristics that evidenced the need for additional PK studies and subsequent modeling of the data for the development of evidence-based dosing approaches in Puerto Rico.
BRCA Methylation Testing Identifies a Subset of Ovarian Carcinomas without Germline Variants That Can Benefit from PARP Inhibitor

Homologous Recombination Deficiency (HRD) is a frequent feature of high-grade epithelial ovarian carcinoma (EOC), associated with sensitivity to PARP-inhibitors (PARPi). The best characterized causes of HRD in EOCs are germline or somatic mutations in BRCA1 and BRCA2 genes. Although promoter methylation is a well-known mechanism of gene transcriptional repression, few data have been published about BRCA gene methylation in EOCs. In this retrospective study, we quantitatively analyzed by pyrosequencing a selected series of 90 formalin-fixed (FFPE) primary EOCs without BRCA germline mutations. We identified 20/88 (22.7%) EOCs showing BRCA promoter methylation, including 17/88 (19.3%) in BRCA1 and 4/86 (4.6%) in BRCA2 promoters, one of which showing concomitant BRCA1 methylation. Mean methylation levels were 49.6% and 45.8% for BRCA1 and BRCA2, respectively, with methylation levels ≥50% in 10/20 methylated EOCs. Constitutive BRCA methylation was excluded by testing blood-derived DNA. In conclusion, pyrosequencing methylation analysis of BRCA genes is a robust, quantitative and sensitive assay applicable to FFPE samples. Remarkably, a considerable subset of germline BRCA-negative EOCs showed somatic methylation and, likely, HRD. A subpopulation of women with BRCA methylation, even without BRCA mutations, could potentially benefit from PARP-inhibitors; further clinical studies are needed to clarify the predictive role of somatic BRCA methylation of PARP-therapy response.
Feedback Control of a Nonlinear Electrostatic Force Transducer

We document a feedback controller design for a nonlinear electrostatic transducer that exhibits a strong unloaded resonance. Challenging features of this type of transducer include the presence of multiple fixed points (some of which are unstable), nonlinear force-to-deflection transfer, effective spring-constant softening due to electrostatic loading and associated resonance frequency shift. Furthermore, due to the utilization of lowpass filters in the electronic readout circuitry, a significant amount of transport delay is introduced in the feedback loop. To stabilize this electro-mechanical system, we employ an active disturbance-rejecting controller with nonlinear force mapping and delay synchronization. As demonstrated by numerical simulations, the combination of these three control techniques stabilizes the system over a wide range of electrode deflections. The proposed controller shows good setpoint tracking and disturbance rejection, and improved settling time, compared to the sensor alone.
The RNA Architecture of the SARS-CoV-2 3′-Untranslated Region

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. The 3′ untranslated region (UTR) of this β-CoV contains essential cis-acting RNA elements for the viral genome transcription and replication. These elements include an equilibrium between an extended bulged stem-loop (BSL) and a pseudoknot. The existence of such an equilibrium is supported by reverse genetic studies and phylogenetic covariation analysis and is further proposed as a molecular switch essential for the control of the viral RNA polymerase binding. Here, we report the SARS-CoV-2 3′ UTR structures in cells that transcribe the viral UTRs harbored in a minigene plasmid and isolated infectious virions using a chemical probing technique, namely dimethyl sulfate (DMS)-mutational profiling with sequencing (MaPseq). Interestingly, the putative pseudoknotted conformation was not observed, indicating that its abundance in our systems is low in the absence of the viral nonstructural proteins (nsps). Similarly, our results also suggest that another functional cis-acting element, the three-helix junction, cannot stably form. The overall architectures of the viral 3′ UTRs in the infectious virions and the minigene-transfected cells are almost identical.
Transient Receptor Potential Vanilloid 6 (TRPV6) Proteins Control the Extracellular Matrix Structure of the Placental Labyrinth

Calcium-selective transient receptor potential Vanilloid 6 (TRPV6) channels are expressed in fetal labyrinth trophoblasts as part of the feto–maternal barrier, necessary for sufficient calcium supply, embryo growth, and bone development during pregnancy. Recently, we have shown a less- compact labyrinth morphology of Trpv6-deficient placentae, and reduced Ca2+ uptake of primary trophoblasts upon functional deletion of TRPV6. Trpv6-/- trophoblasts show a distinct calcium-dependent phenotype. Deep proteomic profiling of wt and Trpv6-/- primary trophoblasts using label-free quantitative mass spectrometry leads to the identification of 2778 proteins. Among those, a group of proteases, including high-temperature requirement A serine peptidase 1 (HTRA1) and different granzymes are more abundantly expressed in Trpv6-/- trophoblast lysates, whereas the extracellular matrix protein fibronectin and the fibronectin-domain-containing protein 3A (FND3A) were markedly reduced. Trpv6-/- placenta lysates contain a higher intrinsic proteolytic activity increasing fibronectin degradation. Our results show that the extracellular matrix formation of the placental labyrinth depends on TRPV6; its deletion in trophoblasts correlates with the increased expression of proteases controlling the extracellular matrix in the labyrinth during pregnancy.
An Individual Patient Data Meta-Analysis with Colombian Studies on the Effect of Dark Chocolate Consumption on Cardiovascular Risk Parameters

Background It is postulated that cocoa solids possess cardioprotective capacity by various mechanisms. In the different cocoa studies evaluating cardiovascular disease, there are no conclusive data on the role it plays in controlling the lipid profile and anthropometric variables, perhaps because the concentration of cocoa, the geographical origin of the population, and the different concentrations supplied lead to a high heterogeneity of results. This study aims to estimate the effect of consuming cocoa-rich chocolate compared to placebo on the lipid profile and anthropometric variables based on data from three clinical trials conducted in Colombia. Methods Meta-analysis of individual data from three randomized clinical trials conducted in Colombia. The entire population of the primary studies was included, which was reassigned into intervention groups if they consumed 50 grams of 70% concentrated cocoa or placebo, which was considered to be cocoa-free or with a concentration less than 50 grams. The variables at the beginning of the study were analyzed with medians, interquartile ranges, means, and deviations according to whether they met the normality assumption. Multiple imputations were used to manage missing data and were analyzed using the two approaches proposed for this type of study, that of one and two stages. In the two-stage approach, the data were weighted on a conventional Forrest plot, while in the one-stage approach, linear regressions with mixed models were applied. This study is governed by the regulations described in the 2013 Declaration of Helsinki and by article 11 of Resolution 8430 of 1993, which classifies it as a risk-free study. Results A total of 275 participants were included, who consumed cocoa or placebo for 81 days on average; 52.7% were female and few smoked at the time of the intervention (31/275). Physical activity performed in number of hours per week was comparable between the intervention groups. When evaluating total cholesterol, low-density cholesterol (LDL), high-density cholesterol (HDL), triglycerides, abdominal circumference, and final body mass index with both the one-stage and two-stage approaches, there were no significant differences between the two groups. Conclusions According to the results obtained in the meta-analysis, the consumption of cocoa in the Colombian population does not seem to significantly modify variables such as lipid profile, abdominal circumference, and body mass index. This conclusion according to the quality of the evidence has a weak recommendation and a low-to-moderate certainty. However, the analysis through the two proposed approaches yielded similar results.
NAMPT Over-Expression Recapitulates the BRAF Inhibitor Resistant Phenotype Plasticity in Melanoma

Simple Summary Malignant melanoma (MM) is the most fatal skin cancer due to its high metastatic potential. Treatment strategies are dramatically changing due to the introduction of BRAF/MEK inhibitors (i) and immunotherapy; however, multiple resistant mechanisms rapidly occur including metabolic rewiring. This study aimed to establish the driver role of the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) in BRAFi resistance development. We defined that NAMPT over-expressing MM cells were strikingly similar to cells that acquired resistance to BRAFi in terms of growth, invasion, and phenotype plasticity. These findings confirmed NAMPT as a key factor in melanoma progression and in the onset of BRAFi resistance in melanoma patients, opening new therapeutic possibilities for this subset of patients. Abstract Serine–threonine protein kinase B-RAF (BRAF)-mutated metastatic melanoma (MM) is a highly aggressive type of skin cancer. Treatment of MM patients using BRAF/MEK inhibitors (BRAFi/MEKi) eventually leads to drug resistance, limiting any clinical benefit. Herein, we demonstrated that the nicotinamide adenine dinucleotide (NAD)-biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) is a driving factor in BRAFi resistance development. Using stable and inducible NAMPT over-expression systems, we showed that forced NAMPT expression in MM BRAF-mutated cell lines led to increased energy production, MAPK activation, colony-formation capacity, and enhance tumorigenicity in vivo. Moreover, NAMPT over-expressing cells switched toward an invasive/mesenchymal phenotype, up-regulating expression of ZEB1 and TWIST, two transcription factors driving the epithelial to mesenchymal transition (EMT) process. Consistently, within the NAMPT-overexpressing cell line variants, we observed an increased percentage of a rare, drug-effluxing stem cell-like side population (SP) of cells, paralleled by up-regulation of ABCC1/MRP1 expression and CD133-positive cells. The direct correlation between NAMPT expression and gene set enrichments involving metastasis, invasiveness and mesenchymal/stemness properties were verified also in melanoma patients by analyzing The Cancer Genome Atlas (TCGA) datasets. On the other hand, CRISPR/Cas9 full knock-out NAMPT BRAFi-resistant MM cells are not viable, while inducible partial silencing drastically reduces tumor growth and aggressiveness. Overall, this work revealed that NAMPT over-expression is both necessary and sufficient to recapitulate the BRAFi-resistant phenotype plasticity.
Comparison of Contemporary Feature Selection Algorithms: Application to the Classification of ABC-Transporter Substrates

Multidrug ABC-transporters are highly polyspecific in their substrate recognition pattern and influence the pharmacokinetics of a broad variety of structurally diverse compounds. Thus, prediction of ABC-transporter substrate properties of compound libraries is of major interest. In this study, we use k-nearest neighbor (kNN) classification in combination with five different feature subset selection (FS) algorithms to create predictive models for classification of ABCB1, ABCC1, and ABCG2 substrates. Our results show that FS methods that incorporate the classification algorithm give the best results and contain only a small subset of descriptors. For ABCB1 and ABCG2 cross validated accuracies of higher than 80% were achieved. The interpretation of the best performing feature subsets showed that descriptors consisting of simple counts as well as of projections of physicochemical properties on subdivided surface areas have highest contribution to the models.
Mathematical evaluation of process schedules for aseptic processing of low-acid foods containing discrete particulates

A quantitative methodology was developed for evaluating thermal process schedules for low-acid foods containing particulates of any shape. The methodology uses finite element analysis to determine temperature distributions within particulate foods subjected to timevarying boundary conditions. Simulations were conducted to study the effects of particle size, residence time distributions within heat exchanger and holding tube, and convective heat transfer coefficients. Results indicate that all these factors have significant effects on the thermal process schedule required to achieve commercial sterility. For large particles, simulations indicate that little credit can be given for lethality within the heating section.
On the Fidelity of NS-3 Simulations of Wireless Multipath TCP Connections

The multipath transmission control protocol (MPTCP) is considered a promising wireless multihoming solution, and the 3rd generation partnership project (3GPP) includes it as a standard feature in the fifth-generation (5G) networks. Currently, ns-3 (Network Simulator-3) is widely used to evaluate the performance of wireless networks and protocols, including the emerging MPTCP protocol. This paper investigates the fidelity of the Linux kernel implementation of MPTCP in the ns-3 direct code execution module. The fidelity of MPTCP simulation is tested by comparing its performance with a real Linux stack implementation of MPTCP using a hardware testbed for two different setups. One setup emulates the existence of a bottleneck link between the sending and receiving networks, whereas the other setup does not have such a bottleneck. The fidelity of ns-3’s simulation is tested for four congestion control algorithms, namely Cubic, linked-increases algorithm (LIA), opportunistic LIA (OLIA) and wVegas for relatively short and long data flows. It is found that the uplink MPTCP throughput performance exhibited by the ns-3 simulator matches the hardware testbed results only if the flows are long-lived and share no common bottleneck link. Likewise, the MPTCP throughput achieved during a downlink scenario using the ns-3 simulator and the hardware testbed are close to each other across all algorithms except wVegas regardless of the flow size if there is no bottleneck link. Moreover, it is observed that the impact of LTE handover on MPTCP throughput is less significant in the simulator than the real hardware testbed, and it is setup-dependent.
Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT.