Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation ...Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs).
BOADICEA incorporates the effects of truncating variants in BRCA1, BRCA2, PALB2, CHEK2, and ATM; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information.
Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17-<30% (moderate risk according to National Institute for Health and Care Excellence NICE guidelines) and 1.1% a lifetime risk of ≥30% (high risk).
This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.
To assess the pharmacokinetics of linezolid in septic patients undergoing continuous renal replacement therapy (CRRT) and investigate whether residual renal function affects the probability of ...attaining the pharmacokinetic/pharmacodynamic (PK/PD) target.
Prospective study conducted in three Spanish hospitals. Linezolid concentrations were measured in plasma and effluent samples and pharmacokinetic parameters were calculated. The probability of target attainment (PTA) and the cumulative fraction of response (CFR) were calculated considering AUC24/MIC>80 and %T>MIC > 85% as the PK/PD indexes related to efficacy.
In anuric patients (CrCl<10 mL/min), the contribution of extracorporeal Cl to total Cl was higher (47% vs 16%) than in patients with residual renal function (CrCl≥10 mL/min). For an MIC of 2 mg/L, AUC24/MIC>80 was achieved in >85% of the anuric patients, but in <15% of the patients with residual renal function.
The standard dose (600 mg q12h) ensures a moderately high probability of treatment success in anuric patients when the infection is due to microorganisms with MIC≤2 mg/L; although higher doses increase the probability of treatment success, the safety is compromised. In patients with residual renal function, the standard dose is insufficient, but 900 mg q8h provide higher probability of treatment success without compromising the safety.
•In acute renal failure, CRRT conditions the total clearance of linezolid.•The contribution of extracorporeal to total clearance is 3 times higher in anurics.•For MIC≤2 mg/L, 600 mg q12h provide high probability of success in anuric patients.•600 mg q12h is deficient for patients with residual renal function receiving CRRT.•900 mg q8h improve the probability of success in nonanuric patients receiving CRRT.
Pistachio (Pistacia vera L.) is a drought-tolerant species grown under the semiarid conditions of the Mediterranean basin. For this reason, it is essential to make an exhaustive quantification of ...yield and quality benefits of the kernels because the regulated deficit irrigation will allow significant water savings with a minimum impact on yield while improving kernel quality. The goal of this scientific work was to study the influence of the rootstock, water deficit during pit hardening, and kernel roasting on pistachio (P. vera, cv. Kerman) fruit yield, fruit size, and kernel content of fatty acids phytoprostanes (PhytoPs) and phytofurans (PhytoFs) for the first time. Water stress during pit hardening did not affect the pistachio yield. The kernel cultivar showed a lower oleic acid and a higher linoleic acid contents than other cultivars. Kernels from plants grafted on the studied rootstocks showed very interesting characteristics. P. integerrima led to the highest percentage of monounsaturated fatty acids. Regarding the plant oxylipins, P. terebinthus led to the highest contents of PhytoPs and PhytoFs (1260 ng/100 g and 16.2 ng/100 g, respectively). In addition, nuts from trees cultivated under intermediate water deficit during pit hardening showed increased contents of the 9-series F1-phytoprostanes and ent-16(RS)-9-epi-ST-Δ14-10-phytofuran. However, roasting of pistachios led to PhytoP degradation. Therefore, plant cultivar, deficit irrigation, rootstock, and roasting must be considered to enhance biosynthesis of these secondary metabolites. New tools using agricultural strategies to produce hydroSOS pistachios have been opened thanks to the biological properties of these prostaglandin-like compounds linking agriculture, nutrition, and food science technology for further research initiatives.
Recently, new bioactive compounds were identified in olive oil, lipophenols, which are composed of a fatty acid (FA) and a phenolic core, such as HT (HT-FA). However, their bioaccessibility remains ...unknown. Thus, the present study uncovers the impact of the separate phases of gastrointestinal digestion on the release and stability of HT-FAs from oily matrices under in vitro simulated conditions. Accordingly, it was found that the bioaccessibility of HT derivatives is largely dependent on the type of FA that esterifies HT, as well as the food matrix. Also, the generation of HT-FAs during intestinal digestion was observed, with pancreatin being the enzyme responsible, to a higher extent, for the de novo formation of lipophenolic derivatives. These findings prompt us to identify new applications to oily matrices and their byproducts as potential functional ingredients for the promotion of health, where the possible formation of new lipophenols during digestion should be taken into consideration.
•Augmented renal clearance (ARC) significantly increases linezolid clearance.•ARC leads to a high risk of suboptimal linezolid exposure at a dose of 600 mg every 12 h.•Continuous infusion increases ...the probability of attaining the pharmacokinetic/pharmacodynamic target.•In patients with ARC, continuous infusion of 75 mg/h ensures concentrations ≥2 mg/ml.•Therapeutic drug monitoring may help to optimize linezolid dosing.
The aim of this study was to assess the influence of renal function, in particular the presence of augmented renal clearance (ARC), on the pharmacokinetics of linezolid in critically ill patients. The effect of continuous infusion on the probability of therapeutic success from a pharmacokinetic/pharmacodynamic (PK/PD) perspective was also evaluated.
Seventeen patients received linezolid (600 mg every 12 h) as a 30-min infusion and 26 as a continuous infusion (50 mg/h). The PK parameters were calculated and the probability of PK/PD target attainment (PTA) was estimated by Monte Carlo simulation (MCS) for different doses administered by intermittent (600 mg every 12 h or 600 mg every 8 h) or continuous infusion (50 mg/h or 75 mg/h).
In patients without ARC, the standard dose was adequate to attain the PK/PD target. However, linezolid clearance was significantly higher in ARC patients, leading to sub-therapeutic concentrations. Continuous infusion (50 mg/h) provided concentrations ≥2 mg/l in 70% of the ARC patients. MCS revealed that concentrations ≥2 mg/l would be reached in >90% of patients receiving 75 mg/h.
ARC increases linezolid clearance and leads to a high risk of underexposure with the standard dose. Continuous infusion increases the PTA, but an infusion rate of 75 mg/h should be considered to ensure concentrations ≥2 mg/ml.
To evaluate the pharmacokinetics of piperacillin/tazobactam in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to assess the success of the therapy against ...susceptible bacteria.
Sixteen patients undergoing CRRT with different degrees of renal function were included in the study. Blood and ultrafiltrate samples were drawn after administration of piperacillin/tazobactam (4/0.5 g) every 4, 6 or 8 h. The data were analysed by a population approach using NONMEM 7.2. The probability of target attainment (PTA) of maintaining free piperacillin levels above the MIC during the entire dosing interval was estimated by simulation of intermittent and continuous infusions.
The pharmacokinetics of piperacillin and tazobactam were best described by two-compartment models where the elimination of both drugs was conditioned by renal dependent on creatinine clearance (CLCR), non-renal and extracorporeal clearances. A 20 min infusion of piperacillin/tazobactam administered every 6 h provided high PTAs against MICs ≤ 32 mg/L in patients with severe renal failure. In patients with normal or moderate renal function PTAs ≥ 90% were only obtained up to MICs ≤ 8 mg/L with short infusions. However, simulating continuous infusion, higher probabilities of success were obtained against MICs of 32 and 16 mg/L when CLCR was 50 and 100 mL/min, respectively.
Population pharmacokinetic models have been developed and validated for piperacillin and tazobactam. Based on the pharmacokinetic/pharmacodynamic analysis, dosing recommendations are given considering the residual renal function of the patient and the MIC for the isolated bacteria.
A new versatile and geometrically reconfigurable ultrasonic tomography system (UTS) has been designed to inspect and obtain information about the internal structure and inner damage of columns in ...heritage buildings. This nondestructive system is considered innovative because it aims to overcome common limitations of existing systems. Tomographic inspections are typically carried out manually and are thus limited to small portions of construction elements. The proposed UTS allows the automatization of the inspection and the generation of numerous tomographic slices along the height of the column. It is valid for multiple types of columns and materials. In the present work, the system was tested on two limestone columns of the north façade of the Convent of Carmo in Lisbon, Portugal. The UTS is composed of a mechanical and an electronic system. The mechanical system consists of four linear motion subsystems mounted in a square setup. A transducer is placed on each of the axes, acting as emitter or receiver of the ultrasonic signals. The mechanical system also includes a guide system to adapt the inspections to the complex geometry of the columns. The electronic system allows the control and the synchronization of the movements and the emission/reception configuration of the four ultrasonic transducers.
Levetiracetam pharmacokinetics is extensively altered in critically ill patients with augmented renal clearance (ARC). Consequently, the dosage regimens commonly used in clinical practice may not be ...sufficient to achieve target plasma concentrations. The aim of this study is to propose alternative dosage regimens able to achieve target concentrations in this population. Furthermore, the feasibility of the proposed dosing regimens will be discussed from a clinical point of view.
Different dosage regimens for levetiracetam were evaluated in critically ill patients with ARC. Monte Carlo simulations were conducted with extended or continuous infusions and/or high drug doses using a previously developed population pharmacokinetic model. To assess the clinical feasibility of the proposed dosages, we carried out a literature search to evaluate the information on toxicity and efficacy of continuous administration or high doses, as well as the post-dilution stability of levetiracetam.
According to the simulations, target concentrations in patients with CrCl of 160 or 200 mL/min can be achieved with the 3000 mg daily dose by prolonging the infusion time of levetiracetam. For patients with CrCl of 240 mL/min, it would be necessary to administer doses higher than the maximum recommended. Available evidence suggests that levetiracetam administration in continuous infusion or at higher doses than those approved seems to be safe. It would be desirable to re-examinate the current recommendations about drug stability and to achieve a consensus in this issue.
Conventional dosage regimens of levetiracetam (500-1500 mg twice daily in a short infusion) do not allow obtaining drug plasma concentrations among the defined target in critically ill patients with ARC. Therefore, new dosing guidelines with specific recommendations for patients in this subpopulation are needed. This study proposes new dosages for levetiracetam, including extended (4 or 6 h) infusions, continuous infusions or the administration of doses higher than the recommended in the summary of product characteristics (> 3000 mg). These new dosage recommendations take into account biopharmaceutical and pharmacokinetic aspects and meet feasibility criteria, which allow them to be transferred to the clinical environment with safety and efficacy. Nevertheless, further clinical studies are needed to confirm these results.
This study explores the feasibility of using transmission tomographic images based on attenuation measures in transmission to detect and estimate the most common materials that are embedded in ...concrete, reinforcements and natural and artificial voids. A limited set of concrete specimens have been made in which cylindrical objects such as bars/tubes of steel, PVC and aluminium have been embedded to analyse the effect of size and material. The methodology and scope of this study is presented and numerical simulations are carried out to optimize the emitter-receiver configuration and to understand the complex physical propagation phenomena of ultrasonic signals that travel through concrete with embedded inclusions. Experimental tomographic images are obtained by using an ultrasonic tomographic system, which has the advantage of needing only two ultrasonic transducers. Both the software simulation tool and the tomographic inspection system are developed by the authors. The obtained results show that PVC tubes and steel bars of diameters higher than 19 mm and embedded in cylindrical specimens, can be detected and their sizes estimated using segmented tomographic images.
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