The accurate prediction of human pharmacokinetics is critically important in modern drug discovery since it drives both pharmacological and toxicological effects. Although significant progress has ...been made in predicting drug disposition by hepatic drug-metabolizing enzymes, predicting transporter-mediated clearance is still highly uncertain. Furthermore, different approaches are often used to predict clearance with and without transporter involvement, hence the major clearance pathway for a compound must first be determined to know which approach to use. As a result of these challenges, a novel unified method has been developed using cryopreserved suspended human hepatocytes to predict human hepatic clearance for both enzyme- and transporter-mediated mechanisms. This method hypothesizes that, once in vitro metabolic stability is scaled by partition coefficients between hepatocytes and buffer with 4% bovine serum albumin, in vivo clearance can be better predicted. With this method, good in vitro-in vivo correlation of human hepatic clearance has been obtained for a set of 32 structurally diverse compounds, including such transporters as organic anion-transporting polypeptide substrates. The clearance predictions for most compounds are within 3-fold of observed values. This is the first time that multiple compounds result in good in vitro-in vivo extrapolation using an entirely "bottom-up" approach without any empirical scaling factor when transporter-mediated clearance is involved. Potential exceptions are compounds with significant biliary and/or extra-hepatic clearance. The method offers an alternative approach to more accurately predict human hepatic clearance when multiple complex mechanisms are involved.
The first record of the Early Toarcian Oceanic Anoxic Event (c. 183 Ma) from the Southern Hemisphere is described from the Neuquen Basin, Argentina, identified chemostratigraphically on the basis of ...a relative increase in marine organic carbon and a characteristic negative carbon-isotope excursion (δ13Corg) in bulk rock and fossil wood. The negative excursion of -6 per mil in bulk organic carbon (falling to -31.3 per mil) crosses the boundary of the tenuicostatum-hoelderi Andean ammonite Zones, equivalent to the tenuicostatum-falciferum/serpentinum zones of Europe. These data indicate that the Early Toarcian Oceanic Anoxic Event was a global phenomenon.
Rocky tide pools are transition environments whose communities are affected by sudden temperature, salinity and nutrient fluctuations. Furthermore, these environments are exposed to multiple ...stressors and can be easily altered by human trampling. In particular, specific studies on rock pool heterobranchs communities are lacking for the Mediterranean Sea. In this study, the community of Heterobranchia (Mollusca: Gastropoda) living in an anthropized rock pools system in western Adriatic (Ancona, Italy) has been investigated and a first checklist of the sea slugs in this urbanized areas is provided. During the four months survey, a total of 452 specimens, belonging to 19 species and 12 families was recorded. Notable findings were the first record of Placida dendritica for the Conero Riviera, and the first records of Doto cervicenigra and Ercolania viridis for the western Adriatic Sea. Identification of trophic categories showed a diversified assemblage in terms of food sources mirroring a surprising species diversity. Moreover, we provide here the description of a peculiar behavior possibly used by sea slugs to cope with the stressful conditions within this semi-closed system.
This paper presents different approaches to optimize wind turbine airfoils in an uncertain scenario. The approaches are specifically applied to the aerodynamic design optimization of a wind turbine ...airfoil accounting for the uncertainty in setting up the XFOIL's NCRIT constant: a parameter that is considered affected by a chain of aleatory and epistemic uncertainty. Subject to a set of aerodynamic and structural constraints, the uncertain response of the airfoil is optimized by means of both probability- and imprecise probability-based approaches. These solutions are compared with a reference airfoil optimized with a conventional design approach, in which the treatment of uncertainty is carried out in a simplistic fashion. Once evaluated in the probabilistic scenario, the airfoil designed with the conventional approach still achieves the largest aerodynamic efficiency mean. This airfoil is however affected by the largest performance sensitivity to NCRIT variations. The airfoils optimized by means of uncertainty-based approaches instead achieve larger performance robustness and reliability than the airfoil optimized with the conventional approach.
Background
Systemic lupus erythematosus is associated with an increased risk of cardiovascular disease. Low-dose aspirin, hydroxychloroquine and statins have been suggested to play a prophylactic ...role of cardiovascular events. This study is devoted to reviewing the literature on the topic and assessing the effects of these drugs in preventing a first cardiovascular event in a two-centre Italian series.
Methods
A PubMed search on cardiovascular prevention in systemic lupus erythematosus was performed. Moreover, systemic lupus erythematosus patients admitted to two centres from 2000–2015, who at admission had not experienced any cardiovascular event, were investigated. Aspirin, hydroxychloroquine and statin use, and the occurrence of any cardiovascular event, were recorded at each visit. Kaplan-Meier and Cox regression analyses were performed to evaluate the role of traditional, disease-related cardiovascular risk factors and of each of the three drugs in the occurrence of new cardiovascular events.
Results
The literature search produced conflicting results. Two hundred and ninety-one systemic lupus erythematosus patients were included in the study and followed for a median of eight years. During follow-up, 16 cardiovascular events occurred. At multivariate analysis, taking aspirin (hazard ratio: 0.24) and hydroxychloroquine for more than five years (hazard ratio: 0.27) reduced, while antiphospholipid antibody positivity (hazard ratio: 4.32) increased, the risk of a first cardiovascular event. No effect of statins emerged.
Conclusion
Our study confirms an additive role of aspirin and hydroxychloroquine in the primary prophylaxis of cardiovascular events in Italian patients with systemic lupus erythematosus. The lack of any detected effect in previous reports may depend on the design of studies and their short follow-up period.
Objective
To evaluate the impact of duration of remission on the health-related quality of life (HRQoL) of patients with systemic lupus erythematosus (SLE).
Methods
We conducted a 5-year ...retrospective study on two Italian cohorts. Remission was defined as a continuative period of no clinical disease activity, according to the Systemic Lupus Erythematosus Disease Activity Index 2 K, and a permitted maximum prednisone dose of 5 mg/day. HRQoL was measured using the 36-Item Short-Form Health Survey (SF36) during the last visit.
Results
We enrolled 136 female SLE patients. During observation, 15 (11%) patients had been in remission for ≥1 and <2 years, 15 (11%) for ≥2 and <3 years, 19 (14%) for ≥3 and <4 years, 9 (7%) for ≥4 and <5 years, and 53 (39%) had been in prolonged remission for ≥5 years. In the multivariate model, considering depression and fatigue as covariates, patients in prolonged remission showed significantly better scores in the physical functioning (p = 0.039), role physical (p = 0.029), bodily pain (p = 0.0057), general health (p = 0.0033) and social functioning (p = 0.0085) components of the SF36, compared with those in remission <5 years or unremitted. Subsequent mediation analyses found that these effects were partly influenced by depression.
Conclusion
Lupus remission could improve the HRQoL of SLE patients, particularly when associated with appropriate management of depression and fatigue.
By offering fast and flexible solutions to create 3D models, handheld scanners are currently under the focus of many research activities in various 3D data processing fields. The real-time constraint ...is still challenging to achieve especially when it comes with concurrent needs, such as level of accuracy in the data acquisition, easiness of recovering from scanning interruptions or loop closure abilities... Among them, object/scene tracking quality is one of the most critical. In this work, we describe two issues that affects its performance, focusing on the robustness of the process. Specifically, we encounter such issues at to two different steps while moving through the working pipeline of a prototype handheld scanner, i.e. (1) the data pre-processing before running a pairwise alignment between a frame and the model representation, called key-frame, and (2) the temporal and quality criteria that govern key-frame updates. Our approach simply consists in substituting the use of a rigid (uniform) pattern for sampling, with a random distribution of points. We then implement an adaptive statistical method to select suitable timing steps for key-frames refreshing, comparing this solution with a previous static one based on regular updating rate. We run experiments on a dataset created with our own scanner and we show that the adoption of such alternatives reduce the number of tracking failures, consequently increasing the robustness of the system, improving the quality of the alignments and preserving the real-time behavior of the device.
Physiologically based pharmacokinetic (PBPK) models provide a framework useful for generating credible human pharmacokinetic predictions from data available at the earliest, preclinical stages of ...pharmaceutical research. With this approach, the pharmacokinetic implications of in vitro data are contextualized via scaling according to independent physiological information. However, in many cases these models also require model-based estimation of additional empirical scaling factors (SFs) in order to accurately recapitulate known human pharmacokinetic behavior. While this practice clearly improves data characterization, the introduction of empirically derived SFs may belie the extrapolative power commonly attributed to PBPK. This is particularly true when such SFs are compound dependent and/or when there are issues with regard to identifiability. As such, when empirically-derived SFs are necessary, a critical evaluation of parameter estimation and model structure are prudent. In this study, we applied a global optimization method to support model-based estimation of a single set of empirical SFs from intravenous clinical data on seven OATP substrates within the context of a previously published PBPK model as well as a revised PBPK model. The revised model with experimentally measured unbound fraction in liver, permeability between liver compartments, and permeability limited distribution to selected tissues improved data characterization. We utilized large-sample approximation and resampling approaches to estimate confidence intervals for the revised model in support of forward predictions that reflect the derived uncertainty. This work illustrates an objective approach to estimating empirically-derived SFs, systematically refining PBPK model performance and conveying the associated confidence in subsequent forward predictions.
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