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The aim of this study was to assess health inequalities by sexual attraction in the 2016-2017 Barcelona population, stratifying by sex. Methods: Data came from the 2016-2017 Barcelona Health Survey, where 3362 adults answered among other instruments the EuroQol-5 dimensions-5 levels (EQ-5D-5L), which measures five dimensions and summarizes health-related quality of life into a single utility index score. To assess health differences by sexual attraction, we constructed Tobit models for the EQ-5D index score and Poisson regression models for the EQ-5D dimensions. Nested models were constructed to examine the mediating role of discrimination and health-related variables. Results: After adjusting for sociodemographic variables, women feeling attraction to more than one sex showed a lower EQ-5D index score (worse health) than those with only other sex attraction (-0.042, p = 0.012), and higher prevalence of problems with mobility, usual activities, and anxiety/depression with the following adjusted prevalence ratios (aPR) and confidence intervals (CIs): 1.79 (95% CI 1.05-3.05), 1.84 (95% CI 1.05-3.21), and 1.76 (95% CI 1.27-2.43). Women feeling attraction only to their same sex also presented higher prevalence of anxiety/depression (aPR = 1.46, CI 95% 1.10-1.92). In contrast, differences were not observed for men. Conclusion: Women, but not men, feeling attraction to more than one sex and only same-sex attraction in Barcelona in 2016-2017 presented worse health than those feeling only other sex attraction, with discrimination playing a mediating role in explaining such inequalities. These results among women indicate the need to develop public health strategies in Barcelona addressed to lesbian and bisexual women, considering the intersection of gender and sexual orientation.

Seeking to fabricate B4C composites that are even more superhard (>30 GPa) at lower cost, B4C was transient liquid-phase assisted spark-plasma-sintered, somewhat counterintuitively, at lower temperature ( 15 vol.%) than ever before. It was found that just 20 vol.% MoSi2 aid enables the full densification of B4C at 1700 °C, thereby avoiding the deleterious transformation β-MoB2→α-MoB2, having consumed the entire MoSi2 to form MoB2 and SiC. This maximizes the hardness (∼33 GPa) of these novel triplex-particulate B4C-SiC-MoB2 composites without penalizing their toughness (∼4.1 MPa⋅m0.5). Also importantly, the dry sliding-wear of these novel composites was investigated for the first time, showing that they undergo only mild wear (specific wear rate of ∼10−8 mm³/(N⋅m)) by plasticity-dominated two-body abrasion. Moreover, it was demonstrated that they are much more wear resistant than porous B4C monolithics fabricated under both the same and more demanding conditions, and at least as equally wear resistant as fully-dense B4C monolithics and composites fabricated under more demanding conditions.

An ultrahard ZrC–Co cemented carbide was fabricated by high-energy ball-milling (HEBM) of micrometric starting powders and spark plasma sintering (SPS), whose ultrafine-grained microstructure makes it comparatively more sliding-wear resistant. First, it is shown that prolonged HEBM activates mechanically the ZrC+Co powder mixture, enhancing markedly its SPS densifiability (notable reduction of the SPS temperature attributable to the lowered eutectic temperature and speeded kinetics of solution-reprecipitation). The combination of refined particle sizes and enhanced sinterability yields ultrafine-grained ZrC–Co cemented carbides with ultrahigh hardness (~18 GPa) and sufficient fracture toughness (~6 MPa·m1/2). And second, it is shown that dry wear of the ZrC–Co cemented carbides is, regardless of the microstructure, mild (10−7 mm3/(N·m)) and occurs essentially by plasticity-dominated abrasion, but also that their microstructural refinement makes them comparatively much more wear resistant and therefore attractive for tribological applications.

The densifiability by spark plasma sintering (SPS) and the dry sliding-wear behaviour of novel cemented carbides based on micrometre-sized ZrC with 16.7 vol.% Co binder (ZrC–Co), compositionally equivalent to the typical WC–10 wt%Co but with ZrC in place of WC, were investigated. Firstly, detailed analysis of both the densification and the shrinkage-rate curves registered during SPS (at 50 MPa) showed that ~1275 °C is the onset SPS temperature for liquid-phase sintering, and ~1600 °C that of full densification. Hardness measurements by Vickers indentation tests confirmed the gradual densification with increasing SPS temperature up to 1600 °C, a condition yielding an extra-coarse-grained (~7–8 μm grain size), ultrahard (~18.2 ± 0.3 GPa) ZrC–Co cemented carbide that is also sufficiently tough (~6.1 ± 0.2 MPa m1/2). And secondly, pin-on-disk tribological tests (at both 20 N for 1000 m and 40 N for 2000 m) and subsequent characterization of the worn surfaces indicated that, under sliding contact, these ZrC–Co cemented carbides wear essentially by two-body abrasion dominated by plastic deformation. Wear increases with increasing severity of the contact conditions, but is nonetheless mild due to the high hardness of these ZrC–Co cemented carbides and to the formation of discontinuous oxide tribolayers.

Because cardiotoxicity is one of the leading causes of drug failure and attrition, the design of new protocols and technologies to assess proarrhythmic risks on cardiac cells is in continuous development by different laboratories. Current methodologies use electrical, intracellular Ca2+, or contractility assays to evaluate cardiotoxicity. Increasingly, the human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are the in vitro tissue model used in commercial assays because it is believed to recapitulate many aspects of human cardiac physiology. In this work, we demonstrate that the combination of a contractility and voltage measurements, using video-based imaging and fluorescence microscopy, on hiPSC-CMs allows the investigation of mechanistic links between electrical and mechanical effects in an assay design that can address medium throughput scales necessary for drug screening, offering a view of the mechanisms underlying drug toxicity. To assess the accuracy of this novel technique, 10 commercially available inotropic drugs were tested (5 positive and 5 negative). Included were drugs with simple and specific mechanisms, such as nifedipine, Bay K8644, and blebbistatin, and others with a more complex action such as isoproterenol, pimobendan, digoxin, and amrinone, among others. In addition, the results provide a mechanism for the toxicity of itraconazole in a human model, a drug with reported side effects on the heart. The data demonstrate a strong negative inotropic effect because of the blockade of L-type Ca2+ channels and additional action on the cardiac myofilaments. We can conclude that the combination of contractility and action potential measurements can provide wider mechanistic knowledge of drug cardiotoxicity for preclinical assays.

A wide suite of powder mixtures of ZrB2 with five different additions of transition metal disilicides (MeSi2; 5, 17.5, or 30 vol% MoSi2; 17.5 vol% TaSi2; or 17.5 vol% ZrSi2) were prepared by high-energy ball-milling (HEBM) for different times, and their optimal densification temperatures were evaluated by dilatometric spark-plasma-sintering (SPS) tests to compare their sinterability. SPS densification tests at the so-determined optimal densification temperatures were also performed in selected cases. It was found that HEBM progressively enhanced the sinterability, especially once the ZrB2 particle sizes were refined to the ultrafine range or below (

An effective way to obtain the optimal parameters of a process or experiment is the response surface method. Using the Box–Behnken design further decreases the number of experiments needed to obtain sufficient data to obtain a reliable equation. From the equation, it is possible to predict the behavior of the response with respect to the combination of variables involved. In this study we evaluated the photocatalytic activity of the synthesized TiO2 for the degradation of acetaminophen, a frequently used and uncontrolled drug that has been detected with increasing frequency in wastewater effluents. The variables used for this study were pH, contaminant concentration (acetaminophen) and catalyst dose. We found, with a 95% confidence level, that 99% of the contaminant can be degraded to pH 10, contaminant to 35 mg/L and a catalyst dose of 0.15 g TiO2.

Aims Endurance training improves aerobic fitness and cardiac function in individuals with heart failure. However, the underlying mechanisms are not well characterized. Exercise training could therefore act as a tool to discover novel targets for heart failure treatment. We aimed to associate changes in Ca2+ handling and electrophysiology with micro-RNA (miRNA) profile in exercise trained heart failure rats to establish which miRNAs induce heart failure-like effects in Ca2+ handling and electrophysiology. Methods and results Post-myocardial infarction (MI) heart failure was induced in Sprague Dawley rats. Rats with MI were randomized to sedentary control (sed), moderate (mod)- or high-intensity (high) endurance training for 8 weeks. Exercise training improved cardiac function, Ca2+ handling and electrophysiology including reduced susceptibility to arrhythmia in an exercise intensity-dependent manner where high intensity gave a larger effect. Fifty-five miRNAs were significantly regulated (up or down) in MI-sed, of which 18 and 3 were changed towards Sham-sed in MI-high and MI-mod, respectively. Thereafter we experimentally altered expression of these “exercise-miRNAs” individually in human induced pluripotent stem cell-derived cardiomyocytes (hIPSC-CM) in the same direction as they were changed in MI. Of the “exercise-miRNAs”, miR-214-3p prolonged AP duration, whereas miR-140 and miR-208a shortened AP duration. miR-497-5p prolonged Ca2+ release whereas miR-214-3p and miR-31a-5p prolonged Ca2+ decay. Conclusion Using exercise training as a tool, we discovered that miR-214-3p, miR-497-5p, miR-31a-5p contribute to heart-failure like behaviour in Ca2+ handling and electrophysiology and could be potential treatment targets.

T follicular helper cells (Tfh) have been recognised in minor salivary glands (MSG) of patients with primary Sjögren's syndrome (pSS). Nevertheless, if the Tfh1, Tfh2, Tfh17, Tfr phenotype is different when comparing pSS and associated SS in systemic lupus erythematosus (SLE) is unknown.We included MSG biopsies from 8 pSS, 8 SLE/SS patients, 7 SLE patients, and 2 non-SS sicca patients. To determine the subpopulation of Tfh, a double-staining procedure for transcription factor B cell lymphoma 6 (Bcl-6)+/IL-17A+, Bcl6+/IL-4+, Bcl6+/IFN-γ+, and Bcl6+/Foxp3+ cells was performed. We estimated the mean percentage of positively staining cells in four fields per sample.Tfh1, Tfh2, and Tfh17 cells were highly expressed in pSS compared with the rest of the groups; conversely, in patients with SLE/SS predominated, the Tfh17 and in SLE patients the Tfh1 cells. Regulatory Tfh cells (Tfr) were similar in pSS and the rest of the patients. However, the lowest frequency was found in the SLE group. A positive correlation was observed between anti-Ro/SSA autoantibody and Tfh17 subset (r=0.726, p=0.0001); and with the (Tfh2+Tfh17)/Tfh1 ratio (r=0.844, p0.0001) in the MSG of patients with pSS.We showed a differential Tfh profile in primary SS and SLE with associated SS. Whether this Tfh differential profile participates in the increased risk of lymphoproliferative disease in pSS compared with associated SS, or other outcomes, is yet to be determined in future studies.

Objective The clinical significance of anti-phosphatidylserine/prothrombin (aPS/PT) in antiphospholipid syndrome (APS) is still controversial. We assessed the prevalence of aPS/PT antibodies, their association with other anti-phospholipid antibodies (aPL) and with different APS clinical phenotypes. Methods We included 95 primary APS patients according to the Sydney classification criteria, and patients with thrombocytopenia and/or hemolytic anemia who also fulfilled the serological APS criteria. We tested aCL, anti-β2GP-I and aPS/PT antibodies (both IgG and IgM isotypes) and lupus anticoagulant (LA). We used χ2 test, Spearman's correlation coefficient, Mann-Whitney U test and logistic regression. Results Seventy-seven percent of patients had thrombosis, 50% hematologic involvement and 25% obstetric events (non-exclusive groups). Twenty patients had only hematologic features. The prevalence of IgG and IgM aPS/PT antibodies was 61% and 60%, respectively. Patients with LA+ had a higher prevalence and higher titers of IgG and IgM aPS/PT antibodies. aPS/PT antibodies correlated with aPL antibodies including LA. IgG aPS/PT antibodies were associated with thrombosis (OR 8.6 [95% CI 2.13–33.8, p = 0.002]) and pure hematologic features (OR 0.2, CI 95% 0.05–0.97, p = 0.004). IgM anti-β2GP-I antibodies conferred high risk for both hematologic (OR 7.9, 95% CI 1.88–34.61, p = 0.006) and thrombotic involvement (OR 7.4, 95% CI 1.76–31.12, p = 0.006). Conclusions aPS/PT antibodies were highly prevalent and correlated with other aPL antibodies. IgG aPTS/PT conferred a high risk for thrombosis, but not for pure hematologic involvement. aPS/PT antibodies may be a useful serological tool in the diagnosis and phenotypic characterization of APS patients.

Car accidents are one of the top ten causes of death and are produced mainly by driver distractions. ADAS (Advanced Driver Assistance Systems) can warn the driver of dangerous scenarios, improving road safety, and reducing the number of traffic accidents. However, having a system that is continuously sounding alarms can be overwhelming or confusing or both, and can be counterproductive. Using the driver"s attention to build an efficient ADAS is the main contribution of this work. To obtain this 'attention value” the use of a Gaze tracking is proposed. Driver"s gaze direction is a crucial factor in understanding fatal distractions, as well as discerning when it is necessary to warn the driver about risks on the road. In this paper, a real-time gaze tracking system is proposed as part of the development of an ADAS that obtains and communicates the driver"s gaze information. The developed ADAS uses gaze information to determine if the drivers are looking to the road with their full attention. This work gives a step ahead in the ADAS based on the driver, building an ADAS that warns the driver only in case of distraction. The gaze tracking system was implemented as a model-based system using a Kinect v2.0 sensor and was adjusted on a set-up environment and tested on a suitable-features driving simulation environment. The average obtained results are promising, having hit ratios between 96.37% and 81.84% This work has been supported by the Spanish Government under projects TRA2016-78886-C3-1-R, PID2019-104793RB-C31, RTI2018-096036-B-C22, PEAVAUTO-CM-UC3M and by the Region of Madrid Excellence Program (EPUC3M17)

Background The aim of this systematic review is to assess the impact of primary treatments with curative intention in patients with localized prostate cancer, measured with Patient-Reported Outcomes (PROs), and to examine differences among modalities within treatments. Methods We conducted a systematic literature search for January 2005-March 2017 following PRISMA guidelines, including longitudinal studies measuring disease-specific PROs in localized prostate cancer patients with a follow-up from pre- to post-treatment (≥1 year). Two reviewers independently extracted data and assessed risk of bias. The study is registered in PROSPERO: CRD42015019747. Results Of 148 identified studies, 60 were included in the meta-analyses. At the 1st year, radical prostatectomy patients showed small urinary irritative-obstructive improvement (0.37SD 95%CI 0.30, 0.45), but large deterioration for sexual function and incontinence with high heterogeneity (I2 = 77% and 93%). Moderate worsening in external radiotherapy patients for sexual function (−0.46SD 95%CI −0.55, −0.36), small urinary incontinence (−0.16SD 95%CI −0.23, −0.09) and bowel impairment (−0.31SD 95%CI −0.39, −0.23). Brachytherapy patients presented small deterioration in urinary incontinence (−0.29SD 95%CI −0.39, −0.19), irritative obstructive symptoms (−0.35SD 95%CI −0.47, −0.23), sexual function (−0.12SD 95%CI −0.24, −0.002), and bowel bother (−0.27SD 95%CI −0.42, −0.11). These patterns persisted up to the 5th year. High-intensity focused ultrasound and active surveillance only have results at 1st year, showing no statistically significant worsening. Conclusions No remarkable differences in PRO appeared between modalities within each treatment. Nowadays, available evidence supports brachytherapy as possible alternative to radical prostatectomy for patients seeking an attempted curative treatment limiting the risk for urinary incontinence and sexual dysfunction.

Many drugs designed to inhibit kinases have their clinical utility limited by cardiotoxicity-related label warnings or prescribing restrictions. While this liability is widely recognized, designing safer kinase inhibitors (KI) requires knowledge of the causative kinase(s). Efforts to unravel the kinases have encountered pharmacology with nearly prohibitive complexity. At therapeutically relevant concentrations, KIs show promiscuity distributed across the kinome. Here, to overcome this complexity, 65 KIs with known kinome-scale polypharmacology profiles were assessed for effects on cardiomyocyte (CM) beating. Changes in human iPSC-CM beat rate and amplitude were measured using label-free cellular impedance. Correlations between beat effects and kinase inhibition profiles were mined by computation analysis (Matthews Correlation Coefficient) to identify associated kinases. Thirty kinases met criteria of having (1) pharmacological inhibition correlated with CM beat changes, (2) expression in both human-induced pluripotent stem cell-derived cardiomyocytes and adult heart tissue, and (3) effects on CM beating following single gene knockdown. A subset of these 30 kinases were selected for mechanistic follow up. Examples of kinases regulating processes spanning the excitation–contraction cascade were identified, including calcium flux (RPS6KA3, IKBKE) and action potential duration (MAP4K2). Finally, a simple model was created to predict functional cardiotoxicity whereby inactivity at three sentinel kinases (RPS6KB1, FAK, STK35) showed exceptional accuracy in vitro and translated to clinical KI safety data. For drug discovery, identifying causative kinases and introducing a predictive model should transform the ability to design safer KI medicines. For cardiovascular biology, discovering kinases previously unrecognized as influencing cardiovascular biology should stimulate investigation of underappreciated signaling pathways.

Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the comprehensive in vitro proarrhythmia assay (CiPA). We studied the effects of 26 drugs and 3 drug combinations on 2 commercially available iPSC-CM types using high-throughput voltage-sensitive dye and microelectrode-array assays being studied for the CiPA initiative and compared the results with clinical QT prolongation and torsade de pointes (TdP) risk. Concentration-dependent analysis comparing iPSC-CMs to clinical trial results demonstrated good correlation between drug-induced rate-corrected action potential duration and field potential duration (APDc and FPDc) prolongation and clinical trial QTc prolongation. Of 20 drugs studied that exhibit clinical QTc prolongation, 17 caused APDc prolongation (16 in Cor.4U and 13 in iCell cardiomyocytes) and 16 caused FPDc prolongation (16 in Cor.4U and 10 in iCell cardiomyocytes). Of 14 drugs that cause TdP, arrhythmias occurred with 10 drugs. Lack of arrhythmic beating in iPSC-CMs for the four remaining drugs could be due to differences in relative levels of expression of individual ion channels. iPSC-CMs responded consistently to human ether-a-go-go potassium channel blocking drugs (APD prolongation and arrhythmias) and calcium channel blocking drugs (APD shortening and prevention of arrhythmias), with a more variable response to late sodium current blocking drugs. Current results confirm the potential of iPSC-CMs for proarrhythmia prediction under CiPA, where iPSC-CM results would serve as a check to ion channel and in silico modeling prediction of proarrhythmic risk. A multi-site validation study is warranted.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) and higher throughput platforms have emerged as potential tools to advance cardiac drug safety screening. This study evaluated the use of high bandwidth photometry applied to voltage-sensitive fluorescent dyes (VSDs) to assess drug-induced changes in action potential characteristics of spontaneously active hiPSC-CM. Human iPSC-CM from 2 commercial sources (Cor.4U and iCell Cardiomyocytes) were stained with the VSD di-4-ANEPPS and placed in a specialized photometry system that simultaneously monitors 2 wavebands of emitted fluorescence, allowing ratiometric measurement of membrane voltage. Signals were acquired at 10 kHz and analyzed using custom software. Action potential duration (APD) values were normally distributed in cardiomyocytes (CMC) from both sources though the mean and variance differed significantly (APD90: 229 ± 15 ms vs 427 ± 49 ms [mean ± SD, P < 0.01]; average spontaneous cycle length: 0.99 ± 0.02 s vs 1.47 ± 0.35 s [mean ± SD, P < 0.01], Cor.4U vs iCell CMC, respectively). The 10-90% rise time of the AP (Trise) was ∼6 ms and was normally distributed when expressed as 1/[Formula: see text] in both cell preparations. Both cell types showed a rate dependence analogous to that of adult human cardiac cells. Furthermore, nifedipine, ranolazine, and E4031 had similar effects on cardiomyocyte electrophysiology in both cell types. However, ranolazine and E4031 induced early after depolarization-like events and high intrinsic firing rates at lower concentrations in iCell CMC. These data show that VSDs provide a minimally invasive, quantitative, and accurate method to assess hiPSC-CM electrophysiology and detect subtle drug-induced effects for drug safety screening while highlighting a need to standardize experimental protocols across preparations.

The incorporation of Advance Driver Assistance Systems (ADAS) is a growing trend in active safety systems. The current outlook of passive ADAS that, exclusively warning the driver, presents a reactive interaction model in which each system acts independently. The increasing of the amount of in-vehicle passive ADASs arises an interoperability issue against conflict situations that could affect driver's decision-making process negatively, diminishing their attention level. This paper proposes an architecture based on the multi-agent paradigm for designing driver-centered ADASs that operates through the data fusion. The principal goal is to design a hierarchical structure which can manage the knowledge acquisition process of all aspects involved in the driving scene such as the environment as well as the driver's behavior and state, providing support for building and testing reasoning models. An experimental method was performed to verify the feasibility of the proposed approach using the deployment of a warning ADAS which involves the interaction of several developed systems. Besides, the staging of one set of specific hazardous driving situations was designed to conduct an experimental assay with ten drivers in a driving simulation system. Regarding evaluation measurements, the analysis of the reaction time performed by the drivers and user questionnaires collected after each experimental session has shown promising results.

The clinical significance of anti-phosphatidylserine/prothrombin (aPS/PT) in antiphospholipid syndrome (APS) is still controversial. We assessed the prevalence of aPS/PT antibodies, their association with other anti-phospholipid antibodies (aPL) and with different APS clinical phenotypes.We included 95 primary APS patients according to the Sydney classification criteria, and patients with thrombocytopenia and/or hemolytic anemia who also fulfilled the serological APS criteria. We tested aCL, anti-β2GP-I and aPS/PT antibodies (both IgG and IgM isotypes) and lupus anticoagulant (LA). We used χ2 test, Spearman's correlation coefficient, Mann-Whitney U test and logistic regression.Seventy-seven percent of patients had thrombosis, 50% hematologic involvement and 25% obstetric events (non-exclusive groups). Twenty patients had only hematologic features. The prevalence of IgG and IgM aPS/PT antibodies was 61% and 60%, respectively. Patients with LA+ had a higher prevalence and higher titers of IgG and IgM aPS/PT antibodies. aPS/PT antibodies correlated with aPL antibodies including LA. IgG aPS/PT antibodies were associated with thrombosis (OR 8.6 [95% CI 2.13-33.8, p = 0.002]) and pure hematologic features (OR 0.2, CI 95% 0.05-0.97, p = 0.004). IgM anti-β2GP-I antibodies conferred high risk for both hematologic (OR 7.9, 95% CI 1.88-34.61, p = 0.006) and thrombotic involvement (OR 7.4, 95% CI 1.76-31.12, p = 0.006).aPS/PT antibodies were highly prevalent and correlated with other aPL antibodies. IgG aPTS/PT conferred a high risk for thrombosis, but not for pure hematologic involvement. aPS/PT antibodies may be a useful serological tool in the diagnosis and phenotypic characterization of APS patients.

Human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) have applications in disease modeling, cell therapy, drug screening and personalized medicine. Computational models can be used to interpret experimental findings in iPSC-CMs, provide mechanistic insights, and translate these findings to adult cardiomyocyte (CM) electrophysiology. However, different cell lines display different expression of ion channels, pumps and receptors, and show differences in electrophysiology. In this exploratory study, we use a mathematical model based on iPSC-CMs from Cellular Dynamic International (CDI, iCell), and compare its predictions to novel experimental recordings made with the Axiogenesis Cor.4U line. We show that tailoring this model to the specific cell line, even using limited data and a relatively simple approach, leads to improved predictions of baseline behavior and response to drugs. This demonstrates the need and the feasibility to tailor models to individual cell lines, although a more refined approach will be needed to characterize individual currents, address differences in ion current kinetics, and further improve these results.

The effect of a 2 wt% addition of particulate graphite on the spark-plasma sintering (SPS) kinetics of both ZrB2 and ZrB2+30 vol% SiC was investigated using to that end two broad sets of powder mixtures prepared by high-energy co-ball-milling. It was observed that the particulate graphite addition enhances the SPS kinetics of both systems, and it was identified that, contrary to the case in conventional sintering, this improvement in sinterability is not due to the carbothermal reduction of oxides in situ during SPS but to the lubrication imposed by the graphite flakes inducing a greater green-body densification. Consequently, the graphite is not consumed during SPS but remains in the microstructure of the resulting ultra-high-temperature ceramics (UHTCs) as flaky particles dispersed homogeneously at grain boundaries. Implications of interest for the UHTC community are discussed.

Neuroendocrine tumors (NET) include a spectrum of malignancies arising from neuroendocrine cells throughout the body. The objective of this clinical investigation of retrospectively and prospectively collected data was to describe the prevalence, demographic data, clinical symptoms and methods of diagnosis of NET and the treatment and long-term follow-up of patients with NET. Data were provided by the participating centers and assessed for consistency by internal reviewers. All the cases were centrally evaluated (when necessary) by the pathologists in our group. The tissue samples were reviewed by hematoxylin and eosin and immunohistochemical staining techniques to confirm the diagnosis of NET. In total, 532 cases were documented: 461 gastroenteropancreatic-NET (GEP-NET) and 71 bronchial NET (BNET). All the tumors were immunohistochemically defined according to the World Health Organization (WHO) and European Neuroendocrine Tumor Society criteria. The most common initial symptoms in GEP-NET were abdominal pain, diarrhea, bowel obstruction, flushing, gastrointestinal bleeding and weight loss. The most common tumor types were carcinoid (58.0%), non-functional pancreatic tumor (23.0%), metastatic NET of unknown primary (16.0%) and functional pancreatic tumor (3.0%). Of the BNET, 89.0% were typical and 11.0% atypical carcinoids. Of the patients with GEP-NET, 59.2% had distant metastasis at diagnosis. The locations of the primary tumors in GEP-NET were the small bowel (26.9%), pancreas (25.2%), colon-rectum (12.4%), appendix (7.6%), stomach (6.9%), esophagus (2.8%), duodenum (2.0%) and unknown primary (16.3%). The histological subtypes based on the WHO classification were well-differentiated NET (20.1%), well-differentiated neuroendocrine carcinomas (66.5%) and poorly differentiated neuroendocrine carcinomas (10.3%). Overall, 67.3% of the patients underwent surgery, 41.2% with curative intent and 26.1% for palliative purposes. The 5-year survival rates were 65.1% (95% confidence interval, 58.0-71.4%) in GEP-NET and 100.0% in typical carcinoid of the lung. This observational, non-interventional, longitudinal study aimed to accumulate relevant information regarding the epidemiology, clinical presentation and current practices in the treatment of NET patients in Argentina, providing insight into regional differences and patterns of care in this heterogeneous disease.

Introduction:\ud \ud Voltage-sensitive optical (VSO) sensors offer a minimally invasive method to study the time course of repolarization of the cardiac action potential (AP). This Comprehensive in vitro Proarrhythmia Assay (CiPA) cross-platform study investigates protocol design and measurement variability of VSO sensors for preclinical cardiac electrophysiology assays.\ud \ud Methods:\ud \ud Three commercial and one academic laboratory completed a limited study of the effects of 8 blinded compounds on the electrophysiology of 2 commercial lines of human induced pluripotent stem-cell derived cardiomyocytes (hSC-CMs). Acquisition technologies included CMOS camera and photometry; fluorescent voltage sensors included di-4-ANEPPS, FluoVolt and genetically encoded QuasAr2. The experimental protocol was standardized with respect to cell lines, plating and maintenance media, blinded compounds, and action potential parameters measured. Serum-free media was used to study the action of drugs, but the exact composition and the protocols for cell preparation and drug additions varied among sites.\ud \ud Results:\ud \ud Baseline AP waveforms differed across platforms and between cell types. Despite these differences, the relative responses to four selective ion channel blockers (E-4031, nifedipine, mexiletine, and JNJ 303 blocking IKr, ICaL, INa, and IKs, respectively) were similar across all platforms and cell lines although the absolute changes differed. Similarly, four mixed ion channel blockers (flecainide, moxifloxacin, quinidine, and ranolazine) had comparable effects in all platforms. Differences in repolarisation time course and response to drugs could be attributed to cell type and experimental method differences such as composition of the assay media, stimulated versus spontaneous activity, and single versus cumulative compound addition.\ud \ud Discussion:\ud \ud In conclusion, VSOs represent a powerful and appropriate method to assess the electrophysiological effects of drugs on iPSC-CMs for the evaluation of proarrhythmic risk. Protocol considerations and recommendations are provided toward standardizing conditions to reduce variability of baseline AP waveform characteristics and drug responses.

The spark-plasma sintering (SPS) kinetics of ZrB2-SiC powder mixtures was investigated as a function of the degree of high-energy co-ball-milling and of the SiC content (5, 17.5, or 30 vol%). As in ...

Introduction Human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) are emerging as new and human-relevant source in vitro model for cardiac safety assessment that allow us to investigate a set of 20 reference drugs for predicting cardiac arrhythmogenic liability using optical action potential (oAP) assay. Methods Here, we describe our examination of the oAP measurement using a voltage sensitive dye (Di-4-ANEPPS) to predict adverse compound effects using hiPS-CMs and 20 cardioactive reference compounds. Fluorescence signals were digitized at 10 kHz and the records subsequently analyzed off-line. Cells were exposed to 30 min incubation to vehicle or compound (n = 5/dose, 4 doses/compound) that were blinded to the investigating laboratory. Action potential parameters were measured, including rise time (Trise) of the optical action potential duration (oAPD). Results Significant effects on oAPD were sensitively detected with 11 QT-prolonging drugs, while oAPD shortening was observed with ICa-antagonists, IKr-activator or ATP-sensitive K+ channel (KATP)-opener. Additionally, the assay detected varied effects induced by 6 different sodium channel blockers. The detection threshold for these drug effects was at or below the published values of free effective therapeutic plasma levels or effective concentrations by other studies. Discussion The results of this blinded study indicate that OAP is a sensitive method to accurately detect drug-induced effects (i.e., duration/QT-prolongation, shortening, beat rate, and incidence of early after depolarizations) in hiPS-CMs; therefore, this technique will potentially be useful in predicting drug-induced arrhythmogenic liabilities in early de-risking within the drug discovery phase.

We have explored the feasibility of reducing the spark-plasma-sintering (SPS) temperature of additive-free ZrB 2 ultra-high-temperature ceramics (UHTCs) via crystal size refinement of the starting powder down to the low nanoscale. We found that under otherwise the same SPS conditions (75 MPa pressure, and 100 °C/min heating ramp) nanoscale ZrB 2 can be densified at temperatures about 450 °C lower than for the typical micrometre and submicrometre ZrB 2 powders, and at least 250 °C below the ultra-fine powder temperature. Furthermore, the nanoscale crystal refinement also promotes the production of fine-grained ZrB 2 UHTCs. We also found that elimination of the B 2 O 3 impurities plays an important role in the complete densification. The unequalled sinterability of the nanoscale ZrB 2 powders highlights the need to use high-energy ball-milling for the comminution of the typical commercially available ZrB 2 powders.

Oxide impurities in ZrB2 powders promote coarsening, resulting in lower sinterability. Given its importance for sintering, we studied the oxidation of ZrB2 powders during high-energy ball-milling (the form of milling able to refine ZrB2 powders to the nanoscale) with the aid of various characterization techniques, namely fusion in inert gas, X-ray diffractometry, helium pycnometry, transmission electron microscopy, and Fourier-transform infrared, Raman, and X-ray photoemission spectroscopy. It was found that high-energy ball-milling in air introduces twice as much oxygen into the ZrB2 powders as the more conventional attrition milling. Also, this oxygen does not form solid-solutions with ZrB2, but amorphous oxides (i.e., ZrO2 and B2O3) that locate preferentially on the surface of the ultra-fine agglomerates resulting from cold-welding of the primary nano-particles that form during the ball-milling.

The in situ formation is reported of a fine-grained ZrB2 ultra-high-temperature ceramic (UHTC) containing evenly distributed ZrO2 of uniform size located at triple joints and grain boundaries of the ZrB2 grains, discovered during the spark-plasma sintering of ZrB2 powders subjected to high-energy ball-milling in air. It is found that this type of microstructure forms because the oxide film of ZrO2, developed on the surface of the ZrB2 particles during the high-energy ball-milling in air, creeps towards the ZrB2 multigrain joints under the application of pressure during sintering, and then crystallizes there during the fast cooling down to room-temperature. Together with the mechanism by which these dense ZrB2–ZrO2 UHTC composites form, it is also shown that they are simultaneously harder and much tougher than their ZrB2 monolith counterpart.

The crystal-size dependence of the spark-plasma-sintering (SPS) kinetics of ZrB2 ultra-high-temperature ceramics (UHTCs) was investigated. It was found that refining the starting powder enhances the SPS kinetics, reducing the onset temperatures of sintering and of the intermediate and final sintering regimes, as well as promoting a greater maximum shrinkage rate at lower temperatures. This enhancement was only relevant with reduction in crystal size to the nanoscale. Finally, the implications for low-temperature sintering of ZrB2 UHTCs are discussed.