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Purpose Hemophilia B is a bleeding disorder, caused by a factor IX (FIX) deficiency. Recently, FIX concentrates with extended half-life (EHL) have become available. Prophylactic dosing of EHL-FIX concentrates can be optimized by assessment of individual pharmacokinetic (PK) parameters. To determine these parameters, limited sampling strategies (LSSs) may be applied. The study aims to establish adequate LSSs for estimating individual PK parameters of EHL-FIX concentrates using in silico evaluation. Methods Monte Carlo simulations were performed to obtain FIX activity versus time profiles using published population PK models for N9-GP (Refixia), rFIXFc (Alprolix), and rIX-FP (Idelvion). Fourteen LSSs, containing three or four samples taken within 8 days after administration, were formulated. Bayesian analysis was applied to obtain estimates for clearance (CL), half-life (t1/2), time to 1% (Time1%), and calculated weekly dose (Dose1%). Bias and precision of these estimates were assessed to determine which LSS was adequate. Results For all PK parameters of N9-GP, rFIXFc and rIX-FP bias was generally acceptable (range: −5% to 5%). For N9-GP, precision of all parameters for all LSSs was acceptable (1%, except for t1/2 (range: 27.1% to 44.7%) and Dose1% (range: 12% to 29.4%). For rIX-FP, all LSSs showed acceptable bias and precision, except for Dose1% using LSS with the last sample taken on day 3 (LSS 6 and 10). Conclusion Best performing LSSs were LSS with samples taken at days 1, 5, 7, and 8 (N9-GP and rFIXFc) and at days 1, 4, 6, and 8 (rIX-FP), respectively.

Mediastinal masses commonly present in children and may pose diagnostic challenges, particularly with limited sampling. This article aids the pathologist by reviewing the hematologic differential diagnosis of a pediatric mediastinal mass, along with ancillary testing useful for rendering the correct diagnosis. A review of the more common lymphomas is presented, including classic Hodgkin lymphoma, T-lymphoblastic leukemia/lymphoma, and primary mediastinal (thymic) large B-cell lymphoma, along with brief mentions of less common entities such as gray zone lymphoma and thymoma as well as non-neoplastic conditions such as benign cysts and infections.

Background and Objective One approach of therapeutic drug monitoring in the case of mycophenolic acid (MPA) is a limited sampling strategy (LSS), which allows the evaluation of the area under the concentration–time curve (AUC) based on few concentrations. The aim of this systematic review was to review the MPA LSSs and define the most frequent time points for MPA determination in patients with different indications for mycophenolate mofetil (MMF) administration. Methods The literature was comprehensively searched in July 2021 using PubMed, Scopus, and Medline databases. Original articles determining multiple linear regression (MLR)-based LSSs for MPA and its free form (fMPA) were included. Studies on enteric-coated mycophenolic sodium, previously established LSS, Bayesian estimator, and different than twice a day dosing were excluded. Data were analyzed separately for (1) adult renal transplant recipients, (2) adults with other than renal transplantation indication, and (3) for pediatric patients. Results A total of 27, 17, and 11 studies were found for groups 1, 2, and 3, respectively, and 126 MLR-based LSS formulae (n = 120 for MPA, n = 6 for fMPA) were included in the review. Three time-point equations were the most frequent. Four MPA LSSs: 2.8401 + 5.7435 × C0 + 0.2655 × C0.5 + 1.1546 × C1 + 2.8971 × C4 for adult renal transplant recipients, 1.783 + 1.248 × C1 + 0.888 × C2 + 8.027 × C4 for adults after islet transplantation, 0.10 + 11.15 × C0 + 0.42 × C1 + 2.80 × C2 for adults after heart transplantation, and 8.217 + 3.163 × C0 + 0.994 × C1 + 1.334 × C2 + 4.183 × C4 for pediatric renal transplant recipients, plus one fMPA LSS, 34.2 + 1.12 × C1 + 1.29 × C2 + 2.28 × C4 + 3.95 × C6 for adult liver transplant recipients, seemed to be the most promising and should be validated in independent patient groups before introduction into clinical practice. The LSSs for pediatric patients were few and not fully characterized. There were only a few fMPA LSSs although fMPA is a pharmacologically active form of the drug. Conclusions The review includes updated MPA LSSs, e.g., for different MPA formulations (suspension, dispersible tablets), generic form, and intravenous administration for adult and pediatric patients, and emphasizes the need of individual therapeutic approaches according to MMF indication. Five MLR-based MPA LSSs might be implemented into clinical practice after evaluation in independent groups of patients. Further studies are required, e.g., to establish fMPA LSS in pediatric patients.

Objectives Amblyopia is a decrease of visual acuity that cannot be attributed to any structural abnormality of the eye or visual system, causing a partial or complete loss of vision due to inadequate stimulation in early life. Citicoline has been reported to improve visual acuity in amblyopic eyes as adjuvant treatment. This study was aimed to determine the effectiveness of citicoline in pediatric patients with refractive amblyopia in ophthalmology daily practices. Methods This was a retrospective–descriptive study with a time limited sampling method. This study was conducted at Surabaya Eye Clinic, East Java, Indonesia, by reviewing medical records for the period of January 2018 to December 2019. Results A total of 34 eyes were included in the study with the majority aged five years (41.2%) and six years (35.3%). The severity of amblyopia varied among patients, 21 eyes (61.76%) had mild amblyopia, seven eyes (20.59%) had moderate amblyopia, and two eyes (5.88%) had severe amblyopia. The duration of given therapy also varied, 18 eyes (52.94%) were given 3 months therapy, two eyes were given 4 months therapy, 12 eyes were given 6 months therapy, and two eyes were given 8 months therapy. Citicoline was found effective in mild and moderate amblyopia and for the duration of 3 and 6 months (p Conclusions Citicoline therapy resulted in a clinically and statistically improvement in refractive amblyopia patients.

BACKGROUND Bayesian forecasting-based limited sampling strategies (LSSs) for tacrolimus have not been evaluated for the prediction of subsequent tacrolimus exposure. This study examined the predictive performance of Bayesian forecasting programs/services for the estimation of future tacrolimus area under the curve (AUC) from 0 to 12 hours (AUC0-12) in kidney transplant recipients. METHODS Tacrolimus concentrations were measured in 20 adult kidney transplant recipients, 1 month post-transplant, on 2 occasions one week apart. Twelve samples were taken predose and 13 samples were taken postdose at the specified times on the first and second sampling occasions, respectively. The predicted AUC0-12 (AUCpredicted) was estimated using Bayesian forecasting programs/services and data from both sampling occasions for each patient and compared with the fully measured AUC0-12 (AUCmeasured) calculated using the linear trapezoidal rule on the second sampling occasion. The bias (median percentage prediction error [MPPE]) and imprecision (median absolute prediction error [MAPE]) were determined. RESULTS Three programs/services were evaluated using different LSSs (C0; C0, C1, C3; C0, C1, C2, C4; and all available concentrations). MPPE and MAPE for the prediction of fully measured AUC0-12 were

Therapeutic drug monitoring guided by the area under the concentration-time curve (AUC-guided TDM) is recommended for vancomycin. However, validated efficient software remains elusive to popularize AUC-guided TDM in Japan. The aim of this study was to validate a newly developed web application, PAT, for AUC estimation. PAT was developed on the R ver. 3.6.2 platform for use with mobile phones and personal computers. AUC estimated by PAT (AUCPAT) was evaluated against the reference AUC (AUCREF) calculated with the log-linear trapezoidal rule using eight measured concentrations, or against AUC (AUCBM-P) calculated using an evaluated available software with clinical data. Investigating the best sampling points with limited sampling, PAT produced the least bias using two concentrations at 1 h and 11 h after the end of infusion (slope 1.18, intercept −15.57, median AUCPAT/AUCREF 0.93 [range 0.81–1.24]), where only one estimation (6%) was out of the predetermined acceptable range of 0.8–1.2. Employment of only a trough concentration was more biased (AUCPAT/AUCREF range 0.73–1.30 for 11 h, AUCPAT/AUCREF range 0.62–1.40 for 23 h). In comparison with the evaluated software, AUCPAT was not biased against the AUCBM-P (slope 1.04, intercept −15.80, median AUCPAT/AUCBM-P 1.00 [range 0.86–1.10]). The new application using two concentrations was appropriately validated and might be efficient in popularizing the AUC-guided TDM of vancomycin.

After a heyday in the 1970s and 1980s, probability sampling became much less visible in archaeological literature as it came under assault from the post-processual critique and the widespread adoption of “full-coverage survey.” After 1990, published discussion of probability sampling rarely strayed from sample-size issues in analyses of artifacts along with plant and animal remains, and most textbooks and archaeological training limited sampling to regional survey and did little to equip new generations of archaeologists with this critical aspect of research design. A review of the last 20 years of archaeological literature indicates a need for deeper and broader archaeological training in sampling; more precise usage of terms such as “sample”; use of randomization as a control in experimental design; and more attention to cluster sampling, stratified sampling, and nonspatial sampling in both training and research.

The reason for the rounding error in a measurement system under the condition of a limited sampling period is analysed, and a three-point method based on the difference algorithm (D3P method) is proposed. The effect of the rounding error is reduced by differential approximation of the roundness error and reconstruction of the transfer function. The generalized three-point method (G3P method), the three-point method based on the first-order difference algorithm (I-D3P method) and the three-point method based on the second-order difference algorithm (II-D3P method) are compared and analysed by simulation. The results show that the accuracy of the D3P method is greatly improved compared with that of the G3P method under the restricted sampling period and that the D3P method retains high precision in the case of failed error separation of the G3P method. An experimental system was constructed to realize error separation, and the experimental results show that the D3P method has higher accuracy than the G3P method over a small sampling period.

Background The Web-Accessible Population Pharmacokinetic Service (WAPPS) project generates individually predicted pharmacokinetic (PK) profiles and tailored prophylactic treatment regimens for haemophilic patients, which rely on a set of population PK (PopPK) models providing concentrate-specific priors for the Bayesian forecasting methodology. Aim To describe the predictive performance of the WAPPS PopPK models in use on the WAPPS-Hemo platform. Methods Data for modelling include dense PK data obtained from industry sponsored and independent PK studies, and dense and sparse data accumulated through WAPPS-Hemo. WAPPS PopPK models were developed via non-linear mixed-effect modelling taking into account the effects of covariates and between-individual-and sometimes between-occasion-variability. Model evaluation consisted of (a) prediction-corrected Visual Predictive Check (pcVPC), (b) Limited Sampling Analysis (LSA) and (c) repeated hold-out cross-validation. Results Thirty-three WAPPS PopPK models built on data from 3188 patients (ages 1-78 years) under treatment by factor VIII or IX products (FVIII, FIX) were evaluated. Overall, models exhibit excellent performance characteristics. The pcVPC shows that the observed PK data fall within acceptable 90% interpercentile predictive bands. A slight overprediction beyond the expected half-life, an anticipated result of using sparse data, occurs for some models. The LSA results in lower than 3% of relative error for FVIII and FIX products and 16% for engineered FIX products. Cross-Validation analysis yields relative errors lower than 1.5% and 1.4% in estimates of half-life and time to 0.02 IU/mL, respectively. Conclusion The WAPPS-Hemo models consistently showed excellent performance characteristics for the intended use for Bayesian forecasting of individual PK profiles.

Contains fulltext : 220736.pdf (Publisher’s version ) (Closed access) Background Amlodipine is a widely used antihypertensive agent for the treatment of paediatric hypertension, but the commercially available tablets are not suitable to treat young patients, who need lower, flexible dosages and a liquid formulation. Objective To determine the pharmacokinetic properties of amlodipine and the acceptability of a standardised, extemporaneous oral solution. Method A newly developed liquid formulation of amlodipine was administered to hypertensive children between the age of 6 months and 11 years. Using a limited sampling strategy, population PK analysis was performed using nonlinear mixed effects modelling. Results Nine children, with a median age of 2.9 years (IQR 1.8-8.4), receiving stable amlodipine therapy in a median dose of 0.15 mg kg(-1) day(-1) (IQR 0.11-0.18), were switched to study medication. The population pharmacokinetic model was able to accurately predict the clearance of amlodipine in the study population. Based on the final model, clearance was reduced by 31.2% (RSE: 10%) in females. Patient reported outcomes on taste from a five-point hedonic scale were available for five patients, who scored the taste from positive to slightly negative. Conclusion The results from the PK study and the acceptability assessment show that the amlodipine oral solution presented in this study offers an appropriate treatment option for young children.

Purpose Pemetrexed is a widely used cytostatic agent with an established exposure–response relationship. Although dosing is based on body surface area (BSA), large interindividual variability in pemetrexed plasma concentrations is observed. Therapeutic drug monitoring (TDM) can be a feasible strategy to reduce variability in specific cases leading to potentially optimized pemetrexed treatment. The aim of this study was to develop a limited sampling schedule (LSS) for the assessment of pemetrexed pharmacokinetics. Methods Based on two real-life datasets, several limited sampling designs were evaluated on predicting clearance, using NONMEM, based on mean prediction error (MPE %) and normalized root mean squared error (NRMSE %). The predefined criteria for an acceptable LSS were: a maximum of four sampling time points within 8 h with an MPE and NRMSE ≤ 20%. Results For an accurate estimation of clearance, only four samples in a convenient window of 8 h were required for accurate and precise prediction (MPE and NRMSE of 3.6% and 5.7% for dataset 1 and of 15.5% and 16.5% for dataset 2). A single sample at t = 24 h performed also within the criteria with MPE and NRMSE of 5.8% and 8.7% for dataset 1 and of 11.5% and 16.4% for dataset 2. Bias increased when patients had lower creatinine clearance. Conclusions We presented two limited sampling designs for estimation of pemetrexed pharmacokinetics. Either one can be used based on preference and feasibility.

PURPOSE OF REVIEW: Transbronchial lung cryobiopsy has shown promise in several studies in providing meaningful histological information in the multidisciplinary team diagnosis of fibrotic interstitial lung diseases. The purpose of this review is to describe recent literature providing support for the formal integration of cryobiopsy into the algorithm for interstitial lung disease diagnosis. RECENT FINDINGS: Histopathological concordance between cryobiopsy and surgical biopsy and diagnostic agreement at multidisciplinary discussion have been reported good; furthermore, cryobiopsy may provide an increased diagnostic confidence to a level likely to influence management. Finally, although cryobiopsy is more likely to provide a probable usual interstitial pneumonia (UIP) pattern than a definite UIP pattern, given the limited sampling of sub-pleural lung parenchyma in most cases, finding of a probable UIP pattern at cryobiopsy samples is strongly predictive of a definite UIP pattern in the corresponding surgical biopsy and when a UIP pattern is found on cryobiopsy sample, this is associated with higher mortality compared with other histological patterns. SUMMARY: Cryobiopsy is becoming a valid alternative to surgical lung biopsy for making histopathological diagnosis in patients with interstitial lung diseases of undetermined type in experienced centres, with standardized protocols, in order to have the best risks/diagnostic yields ratio.

It is important to monitor the plasma concentration degree in kidney transplantation and adjust drug dosages accordingly. The selection of plasma concentration sampling time points is a challenging task and the limited sampling strategy is used traditionally. The existing solutions have not considered characteristics of individual patients and had room for improvement. In this work, we propose a new deep learning model, Deep Personalized Prediction of Mycophenolic Acid Area Under Curve with Attentive Interactions (DPMPA-AUC) to select the plasma concentration sampling time points. This model has the capability to take account of the factors of individual patients. We use the soft attention method to select the sampling time points for the plasma concentration. We analyze the correlation between plasma concentration degree and the Mycophenolic Acid density distribution after kidney transplantation. We consider 2 to 4 sampling time points in this work. We use individual factors as the attention weights of the plasma concentration degree. We develop a Long Short Term Memory Dilated Convolutional Neural Networks with the soft attention mechanism to predict Mycophenolic Acid density during 12 hours after taking the drug. The experimental results show that our solution has better performance comparing with existing solutions.

Over the last two decades, mitochondrial DNA (mtDNA) sequence data, as well as analyses of nuclear DNA based on the multispecies coalescent model, have increasingly been used to delimit species, sometimes based on limited sampling and without other supporting evidence. We have argued elsewhere that the uncritical use of these approaches has resulted in unnecessary and unwarranted taxonomic changes that have real and long-lasting consequences for science and society. Unfortunately, these arguments have been misrepresented by Burbrink and Ruane's Point of View on “contemporary” species delimitation in this issue. Here, we discuss the role of models in species delimitation research, and again argue that careful consideration of model assumptions (and their potential violation) is necessary when inferring population history and delimiting species. We echo recent calls for targeted, thorough geographic sampling across contact zones and into parapatric ranges to test for reproductive isolation and draw inferences about the evolutionary independence (or lack thereof) of populations that exchange genes. Finally, despite our very different views on how best to identify species and when to make taxonomic changes, we end by highlighting areas where we agree with Burbrink and Ruane's Point of View and offer suggestions for future research.

In this letter, a novel angular sampling method–random offset sampling (ROS) is proposed for the simulation of ray-based physical reference channel models. This new method employs an asymmetrical random angular offset to the equal power sampling method, which makes the simulated channel match the spatial–temporal characteristics of the reference channel model more exactly. It is shown that this new method can make better utilization of the symmetrical property of power angular spectrum distributions with very limited sampling sinusoids, especially performing pretty well in case of small angular spread. With small modifications, ROS can be directly embedded in the state-of-the-art standardized channel simulation models.

On the Ground • The use of science to inform conservation practices is limited by broad generalities generated from limited sampling alongside narrow ecosystem service perspectives. • Collaborative science approaches featuring “social-ecological system” perspectives are being used as a means to improve the utility of science. • We review our approach to collaborative science to improve brush management outcomes in rangelands in the Chihuahuan Desert. • Expanding the use and utility of collaborative science requires stable support via targeted funding and technical expertise, as well as web-based tools and mobile applications that link specific locations to science information and conservation practice guidelines.

Silvanidae is a small group of cucujoid beetles, and their fossil record is poorly documented. The two recently described genera from Burmese amber, Cretoliota Liu et al. and Protoliota Liu et al. , are distinctive among all known Silvanidae, displaying markedly long antennae and mandibular horns in males, as found in the extant Uleiota Latreille. Due to the limited sampling of fossil specimens, the morphological variations of male mandibular horns remain a mystery. Here we report six well-preserved specimens of Protoliota with both male and female genitalia exposed from mid-Cretaceous Burmese amber. Our discovery confirms the presence of remarkable sexual dimorphism in Protoliota . Males of Protoliota antennatus Liu et al. display short to very long mandibular horns and much longer antennae. Interesting morphological convergence of the beetles (Silvanidae and Staphylinidae) living under the bark of dead trees is briefly discussed. Our discovery represents the first definitive sexual dimorphism in beetles from Burmese amber.

Limited sampling strategy (LSS) is a precise and relatively convenient therapeutic drug monitoring method. We evaluated LSSs for mycophenolic acid (MPA) in children with nephrotic syndrome treated with mycophenolic mofetil (MMF) and validated the LSSs using two different approaches. We measured MPA plasma concentrations in 31 children using HPLC-UV method and received 37 MPA pharmacokinetic profiles (0–12 h). For six children, MPA profiles were estimated twice after two MMF doses. LSSs were developed using multilinear regression with STATISTICA and R software and validated using validation group and bootstrap method, respectively. The best three time point equations included C1, C3, C6 (good guess 83%, bias − 2.78%; 95% confidence interval (CI) − 9.85–0.46); C1, C2, C6 (good guess 72%, bias 0.72%; 95% CI − 5.33–7.69); and C1, C2, C4 (good guess 72%, bias 2.05%; 95% CI − 4.92–13.01) for STATISTICA software. For R software, the best equations consisted of C1, C3, C6 (good guess 92%, bias − 2.69%; 95% CI − 27.18–33.75); C0, C1, C3 (good guess 84%, bias − 2.11%; 95% CI − 24.19–22.29); and C0, C1, C2 (good guess 84%, bias − 0.48%; 95% CI − 30.77–54.07). During validation, better results were obtained for R evaluations, i.e., bootstrap method. The most useful equations included C0, C1, C3 and C0, C1, C2 time points; however, the most precise included C1, C3, C6 time points because of MPA enterohepatic recirculation. Better results were obtained for bootstrap validation due to greater number of patients. Validated LSS should be used only in the population for which it was developed. As there is growing evidence that underexposure of MPA is associated with insufficient treatment response, we recommend the introduction of therapeutic drug monitoring for MPA in children with nephrotic syndrome.

One of the causes of limited sampling on concrete structures is that there are reinforcement in the concrete structure, so that when using a large diameter drill core, can damage the concrete structure. Therefore a study of small diameter concrete was conducted to predict the compressive strength of cylindrical concrete. Test specimens in the form of concrete cylinders with dimension 10 cm x 20 cm, 2 concrete plates with dimension 45cm x 45cm x 13cm and 4 concrete beams with dimensions 70 cm x 30 cm x 15 cm by taking concrete using a drill core diameter of 2" and 1". Two concrete slabs and two concrete beams with concrete strength (f'c) 20 MPa (MSA 20mm and 10mm) while two concrete concrete slabs and two concrete beams with concrete strength (f'c) 30 MPA (MSA 20mm and 10mm). Types of tests carried out include testing the compressive strength of concrete, core concrete normality test, modulus of elasticity and compressive strength of the core concrete. From test results, can be concluded that the compressive strength of core concrete with sample in the direction of casting for a diameter of 2 inches and concrete strength of 20 MPa (MSA 20 mm and 10 mm) meets the requirements and can be recommended with number samples of 25, whereas for diameter 1" the number of samples must be added.

Background: Cytochrome P450 3A is the most relevant drug-metabolizing enzyme in humans as it is involved in the elimination of 50% of marketed drugs. Nothing is known about the activity of cytochrome P450 3A in palliative care patients who have complicated symptoms often associated with a terminal illness. Aim: In order to improve drug dosing in end-of-life care and to avoid drug interactions, cytochrome P450 3A activity was determined in patients of a palliative care unit under real-life clinical conditions. Design: As midazolam is an established marker substance for cytochrome P450 3A activity, this single-arm prospective trial was designed to obtain a 4-h pharmacokinetic profile of midazolam after oral administration of a 10-µg dose from each enrolled patient. Plasma concentrations of midazolam and its primary metabolite 1′-hydroxy-midazolam were quantified by mass spectrometry techniques. Cytochrome P450 3A activity was calculated as partial metabolic clearance from a limited sampling area under the curve. All other drugs taken by the participating patients were considered, as well as recent blood test results and patients’ diagnoses. The trial was registered at German Clinical Trials Register ( www.drks.de ): DRKS00011753. Setting/participants: The trial was carried out at a university palliative care unit under real-life clinical conditions. Every patient admitted to the ward was screened for possible participation, independent of the individual performance status. Results: Partial metabolic clearance of midazolam in palliative care patients was 31.7 ± 32.1 L/h. This was a highly significant 40% reduction ( p Conclusion: Dosing of cytochrome P450 3A substrate drugs (e.g. macrolide antibiotics, benzodiazepines, calcium channel blockers) needs to be adjusted in palliative care patients; otherwise, escalation of debilitating symptoms due to drug interactions might occur.

International audience; This article is concerned with the control of a Semi-Active suspension system of a 7DOF Full Vehicle model, equipped with four Electro Rheological (ER) dampers, taking into account their incipient dissipativity constraints. Herein, a Real-Time, fast, advanced control structure is presented within the Model Predictive Control framework for Linear Parameter Varying (LPV) systems. The control algorithm is developed to provide a suitable trade-off between comfort and handling performances of the vehicle in a very limited sampling period (T s = 5 ms), in the view of a possible realtime implementation on a real vehicle. The control structure is tested and compared to other standard fast control approaches. Full nonlinear realistic simulation results illustrate the overall good operation and behaviour of the proposed control approach.

Introduction: Personalised pharmacokinetics (PK) using Bayesian analysis with limited sampling is assumed to help to optimise prophylaxis in haemophilia A (HA) patients. Materials and methods: Our prospective, observational study analysed the influence of PK parameters on clinical variables (bleeding rates, joint status, adherence, and consumption) using myPKFiT (R) in a cohort of twenty-one severe and moderate HA patients on prophylaxis with recombinant FVIII (Advate (R)) in two periods of one year, the first before PK-based tailoring and the second after PK-guided prophylaxis. Intra-individual and inter-individual coefficients of variation (CV) of half-life (t(1/2)) were calculated. Results: A total of 73 PK estimations were performed in both periods, resulting in 17.2% inter-individual CV in mean t(1/2), and 4.9% intra-individual CV. Before PK-based tailoring a significant association between joint bleeds and t(1/2) was found (P = 0.010), especially in patients with short t(1/2). This finding was reproduced (P = 0.013) after withdrawal of two patients with bleeding phenotype related to their advanced arthropathy but normal t(1/2) and trough levels. Patients with joint bleeds weighed less (P = 0.039) and required higher doses (P = 0.032) than patients with zero joint bleeds. These associations were not observed in the second period after the adoption of PK-guided prophylaxis. There were no differences between the two periods, although a tendency to fewer spontaneous bleeds was suggested after PK-based tailoring. Conclusions: PK-guided prophylaxis facilitates an adequate level of bleeding control in patients with HA, maintaining clinical variables and patient convenience in an integrative manner, without increasing FVIII consumption.

Bilastine is a non-sedating second-generation H1 antihistamine approved for treatment of allergic rhinoconjunctivitis (AR) and urticaria (U) in adults at the oral (p.o.) dose of 20 mg once daily (OD). Optimal attributes can be anticipated for its clinical use in pediatrics due to its favorable safety and tolerability and age-independent PD profile. The aim of this work was to characterize bilastine PK in children through population modeling of data from a limited sampling confirmatory clinical trial in children with AR or U. The objective was also to ascertain whether the proposed dose (10 mg/day) in the target pediatric subset aged 2– A popPK model characterizing bilastine PK behavior in children aged from 4 to The achievement of comparable PK (i.e., within the range) to that observed in adults after the therapeutic dose of 20 mg, together with the achievement of similar PD and additional integrative analysis, served to confirm the validity of the 10 mg daily dose for the target pediatric subset (2 to

In this paper, we study the problem of low-rank tensor recovery from limited sampling with noisy observations for third-order tensors. A tensor nuclear norm method based on a convex relaxation of t...

We evaluated mycophenolic acid (MPA) limited sampling strategies (LSSs) established using multiple linear regression (MLR) in children with nephrotic syndrome treated with mycophenolate mofetil (MMF). MLR-LSS is an easy-to-determine approach of therapeutic drug monitoring (TDM). We assessed the practicability of different LSSs for the estimation of MPA exposure as well as the optimal time points for MPA TDM. The literature search returned 29 studies dated 1998–2020. We applied 53 LSSs (n = 48 for MPA, n = 5 for free MPA [fMPA]) to predict the area under the time-concentration curve (AUCpred) in 24 children with nephrotic syndrome, for whom we previously determined MPA and fMPA concentrations, and compare the results with the determined AUC (AUCtotal). Nine equations met the requirements for bias and precision ±15%. The MPA AUC in children with nephrotic syndrome was predicted the best by four time-point LSSs developed for renal transplant recipients. Out of five LSSs evaluated for fMPA, none fulfilled the ±15% criteria for bias and precision probably due to very high percentage of bound MPA (99.64%). MPA LSS for children with nephrotic syndrome should include blood samples collected 1 h, 2 h and near the second MPA maximum concentration. MPA concentrations determined with the high performance liquid chromatography after multiplying by 1.175 may be used in LSSs based on MPA concentrations determined with the immunoassay technique. MPA LSS may facilitate TDM in the case of MMF, however, more studies on fMPA LSS are required for children with nephrotic syndrome.

Some songbirds produce only one or a few song types, but others sing large repertoires with many different song types. Birds with large repertoires can arrange these songs in a variety of distinct singing patterns that add a layer of complexity to their vocal production. Both large repertoires and singing patterns may communicate important information to conspecific males and females. Previous estimates of repertoire size of Red-eyed Vireos (Vireo olivaceus) range from 39 to 59. These estimates were based on a small number of recorded phrases per individual, and on single recordings of most individuals. I have made lengthy, multiple recordings over periods of days and weeks of 46 Red-eyed Vireos to revisit the question of their repertoire size. Repertoire size estimated for the birds I recorded varied between 17 and 341 phrase types, with a mean of 91. Fourteen birds for which I recorded at least 1,000 phrases had a mean repertoire of 154 phrase types. Previous estimates may have been low by a factor of 2–3 because of limited sampling. Plotting of phrase type vs. phrases sung for each bird showed a variety of singing patterns. Six birds sang a single limited repertoire of 17–47 phrase types. Nineteen birds sang a single repertoire, but new phrases continued to be added as more recordings were made, so these repertoires had no clear size limits. Twenty birds sang multiple groups or sub-repertoires of phrase types at different times, often changing between sub-repertoires during a single continuous bout of singing. Five birds sang frequent repetitions of a small number of phrase types selected from larger repertoires. The mean singing rate of the birds studied climbed from a low of 33 phrases/min at the beginning of the breeding season to a high of 46 phrases/min at the peak, and declined to 34 phrases/ min at the end of the breeding season. My study shows that Red-eyed Vireo repertoires are significantly larger than previously estimated, that singing patterns vary widely among individual birds, and that many birds group phrase types into multiple sub-repertoires, sung at different times.

Aims: Recently a limited sampling strategy (LSS) for determination of metformin' pharmacokinetics was developed. The LSS utilizes the plasma concentration of metformin 3 and 10 hours after oral intake of a single dose to estimate the area under the concentration–time curve up to 24 hours (AUC 0–24h). The main purpose of this study was to support the feasibility of this strategy in a large prospective trial. Methods: Volunteers orally ingested two 500-mg tablets of metformin hydrochloride. A blood sample was drawn three and ten hours after the ingestion. Urine was collected for 0–10 and 10–24 hours and urine volumes recorded. The AUC 0–24h was calculated using the equation AUC 0–24h = 4.779 * C 3 + 13.174 * C 10. Additionally, all participants were genotyped for the single-nucleotide polymorphism A270S in OCT2, g.-66 T > C in MATE1, R61C, G465R, G401S and the deletion M420del in OCT1. Results: In total, 212 healthy volunteers participated. The median (25th - 75th interquartile range) AUC 0 − 24h, CL renal, C 3 and C 10, were 10 600 (8470–12 500) ng* hr* mL −1, 29 (24–34) L* hour −1, 1460 (1180–1770) and 260 (200–330) ng* mL −1, respectively, which is in agreement with our previous results. GFR i was correlated with metformin AUC and CL renal (P 0 − 24h. We were unable to reproduce our previous finding of a gene–gene interaction (OCT2 and MATE1) effect on CL renal in this cohort. Conclusion: This study further supports the use of the 2-point LSS algorithm in large pharmacokinetic trials.

International audience; The 2020 COVID-19 pandemic had a profound impact on the publishing landscape. The 'pre-peer-review' publication model is likely to become common as a lag in publishing is not acceptable in a pandemic or other time! Mycopathologia is well placed to adopt such changes with its improved editorial processes, article formats, author engagements, and published articles' access and citation. Mycopathologia had an improved journal impact factor and article downloads in 2018-2019. A limited sampling suggested a slight decrease in the total submissions in 2019 (352 articles) compared to 2018 (371 articles). However, the acceptance rate improved to 30% in 2019 from 19% in 2018. Nearly half of all submissions in 2019 were rejected before peer-review or transferred to other Springer Nature journals. The published articles were contributed from 34 different countries, with authors from China, the USA, and Brazil among the top three contributors. An enhanced editorial oversight allowed peer-reviewers to focus on fewer articles that were well-matched to their expertise, which led to lower rejection rates post-peer-review. The introduction of MycopathologiaGENOME and MycopathologiaIMAGE article types received a good reception with notable downloads and citations.

BACKGROUND: Extended half-life (EHL) factor VIII (FVIII) products may decrease the burden of prophylactic treatment in hemophilia A by reducing infusion frequency. However, these products still exhibit wide inter-patient variability and benefit from pharmacokinetic (PK) tailoring. OBJECTIVE: Identify limited sampling strategies for rFVIIIFc, an EHL FVIII product, that produce accurate estimates of PK parameters and relevant troughs. METHODS: We performed a limited sampling analysis on simulated populations of adults, adolescents, and children based on published population PK data. Sampling strategies were evaluated by comparing the error in estimates of half-life, clearance, and trough levels, to a full 6-sample design. Furthermore, we assessed the impact of incorporating knowledge about prior doses, and the day of the PK study within the regimen. We also evaluated the potential inappropriate dose adjustment rate (IDAR) among the modeled sampling strategies. RESULTS: Many sampling strategies, including several 2-sample designs, accurately predicted the PK and exposure measures (median absolute error 20% to ~5% for adults/adolescents. In this same scenario, appropriate scheduling of the PK study decreases likelihood of unmeasurable predose samples, reducing median error on the 72-hour trough from 25% to

Several inflammatory or inflammatory-like lesions that involve the breast have an overall spindle cell appearance or may develop focal areas with spindled or histiocytoid morphology. Such lesions can present diagnostic challenges given the broad differential that arises from their often overlapping histologies, especially on the limited sampling of a core needle biopsy. Some of these lesions are specific to the breast, while others are more ubiquitous and are known to involve multiple anatomic sites. As such, remembering that they may occur in the breast is key in their diagnosis and subsequent appropriate management which is especially relevant as the biologic behavior of this group ranges from benign to malignant.

Blackening waxcaps (Hygrocybe subsect. Hygrocybe) are a group of colorful and attractive mushrooms. However, the species diversity of subsect. Hygrocybe in China is still poorly known due to the limited sampling. In this study, three new species of this group from Guangdong Province, China are described and illustrated based on their morphological characteristics and molecular analyses of the internal transcribed spacer and large subunit ribosomal DNA regions. Hygrocybe debilipes from grasslands of South China Sea islands is mainly characterized by its orange red to vivid red pileus, fragile stipe, and ellipsoid to oblong basidiospores; H. griseonigricans from woodlands is characterized by its whitish to dull yellow pileus, quick black discoloration and the globose, subglobose to broadly ovoid basidiospores; H. rubroconica from woodlands is characterized by the hemispheric to plano-convex pileus when mature, semitranslucent fibrose stipe, and globose to ellipsoid basidiospores.

Coronavirus disease 2019 (COVID-19) has become a severe threat to human health worldwide. Early etiological diagnosis plays a critical role in controlling COVID-19 pandemic. However, etiological diagnosis has been largely compromised by high “false-negative” rates of viral nucleic acid testing, resulting from limited sampling efficiency using conventional oropharyngeal swabs. Here, we engineer regular swabs by using a microneedle (MN) patch to significantly improve the quality and quantity of virus collection. The combination of MNs with different crosslinking levels endows the patches with dual capability of mucus penetration and virus extraction. Moreover, the antibody (Ab) against viral spike protein was integrated into the patch, conferring MNs with an active virus capture potential. By taking advantage of the biological and engineered species, we believe that the designed MN/Ab swabs could serve as a promising tool to improve current sampling efficiency with fewer false negatives, contributing to the containment of the COVID-19 pandemic., Graphical Abstract, Highlights • Well-designed microneedles were introduced onto the oropharyngeal swab • Different crosslinked microneedles indicated distinct functions • Virus-specific antibody integration in the swab facilitated virus capture • Highly effective sampling significantly reduced “false negatives”, Progress and Potential The epidemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to most countries of the world, causing severe respiratory illness (coronavirus disease 2019). To combat the disease, early tests on viral nucleic acid act as the standard method, but this results in a high rate of “false negatives,” which may mislead the doctor's response. Aiming to reduce these false negatives, we fabricated a chemically engineered oropharyngeal swab by introducing a microneedle structure and integrating virus-specific antibodies. Importantly, the modified swab could provide effective penetration and active virus capture, achieving high-efficiency sampling by synergizing the advantages of biological and engineered species, which widen the difference between positive and negative samples. With current advances, we believe that the designed swab could serve as a promising candidate for other oral or respiratory disease diagnostics, suggesting the generalizability of the strategy., A well-designed microneedle patch was invented to modify the heads of regular oropharyngeal swabs to improve sampling efficiency during COVID-19 detection. The microneedle patch consists of two different crosslinked clusters capable of both tissue penetration and virus capture. In combination with virus-specific antibodies, the swab achieved high-efficiency sampling by synergizing the advantages of biological and engineered species, facilitating accurate virus detection to significantly reduce “false negatives” during COVID-19 diagnostics.

Fibroepithelial lesions (FEL) of the breast are biphasic neoplasms consisting of proliferative epithelial and stromal components and include fibroadenoma, phyllodes tumour and periductal stromal tumour. Core needle biopsy (CNB) is a commonly used diagnostic modality for investigation of breast lesions. As the accurate diagnosis of FEL requires integrated assessment of both epithelial and stromal components, this may create problems in small biopsies with limited sampling. In this review, common problems encountered in CNB of FEL are discussed, including establishing a diagnosis of borderline/malignant phyllodes tumour in a biopsy consisting of malignant spindle cells, differentiating phyllodes tumour from fibroadenoma on CNB, grading of phyllodes tumour of intermediate histological grade and assessment of periductal stromal tumours. The approaches are detailed systematically based on histology, immunohistochemistry and molecular characterisation. This comprehensive approach may aid in dealing with the overlapping histological appearance of FEL and sampling limitations of CNB.

This prospective observational study analyzed the pharmacokinetics of busulfan in Japanese children and evaluated the predicting accuracy of previous pediatric PPK models of busulfan. This study enrolled five patients (aged 2-12 years, BW 14-48 kg) receiving a busulfan-based conditioning regimen for hematopoietic stem cell transplantation at our hospital between January 2017 and December 2018. All patients received a 2-hour intravenous busulfan infusion four times daily for a total of 16 doses. After the infusions, 51 plasma samples were collected with the plasma busulfan concentration measured by liquid chromatography-tandem mass spectrometry. PPK model fitting was analyzed using the (%MPE) and the (%MAPE). Limited sampling strategies for estimating busulfan AUC were also evaluated. High interpatient variability was observed in the PK parameters. The most suitable PPK model that reflected our data was McCune's two-compartment model (%MPE -8.7, %MAPE 19.3). A combination sampling method using the busulfan concentration at 2 and 6 hours after the start of the first busulfan dose was found to be able to estimate AUC4 day . These results provide useful information on busulfan therapeutic drug monitoring in the Japanese pediatric population.

The CoViD-19 outbreak has escalated to a pandemic in the last few months. Pharmaceutical solutions based upon virologic studies, at this point, remain inconclusive, with no proven pharmaceutical solution so far. In contrast, this paper looks towards creating more accurate epidemiological models during this phase of viral growth in order to provide better feedback measures to public health officials and agencies, in particular, by providing a responsive, timely model of the R value based on the previous few days’ results. Such an R value, although bearing less statistical precision due to limited sampling, could allow R to become a more effective, responsive standalone measure of infectious transmission. It demonstrates that the R value can be used as a dynamic, time-dependent indicator without the use of curve-fitting, and also estimates the most recent R-value of the CoViD-19 outbreak to be between 1.32 and 1.35.

As pessoas costumam tentar gastar o minimo possivel ao fazer compras em um supermercado. Muitas pessoas nao podem reduzir seus custos ao comprar, devido a falta de tempo para pesquisar ou devido a grande variedade de produtos e precos. Este artigo apresenta o software Superpagg, cujo principal objetivo e ajudar as pessoas a gastar menos em compras em supermercados, comparando os precos de diferentes produtos em diferentes supermercados, para que o usuario possa ver onde pagar menos pelos mesmos produtos, permitindo que eles paguem menos. faca suas compras com mais economia. Os resultados obtidos foram que as informacoes apresentadas pelo software, utilizando uma amostragem limitada, e que o consumidor economiza de 2,01% a 17,64% mensalmente por produto adquirido.

Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with JDM and optimize the limited sampling strategy (LSS).Fifteen JDM patients treated with MMF, at a median age of 7.35 (range, 3.09–16.1) years, were included. Blood samples were collected at 30 minutes pre-dose, 20 minutes, 60 minutes and 180 minutes post-dose to measure the MPA concentrations. Data were retrospectively collected from the electronic medical records. A two-compartment model with first-order absorption, lag time in absorption, and first-order elimination was developed. Height and co-administered cotrimoxazole were added as the covariates to the model.Concentrations at different time points were simulated and area under the concentration–time curve (AUC0–12 h) was calculated. By removing one sampling point at a time, AUC0–12 h from three-point sampling strategy was re-calculated via Bayesian approach. AUC0–12 h from the three-point sampling strategy (by removing the point at 20 minutes post-dose) had the strongest correlation with AUC0–12 h from the four-point sampling strategy (Pearson’s r = 0.971). Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease specifically affecting children. Mycophenolate mofetil (MMF) is an immunosuppressant used to treat JDM. Mycophenolic acid (MPA) is an active metabolite of MMF. This study aimed to develop a population pharmacokinetic (PPK) model of MPA in children with JDM and optimize the limited sampling strategy (LSS). Fifteen JDM patients treated with MMF, at a median age of 7.35 (range, 3.09–16.1) years, were included. Blood samples were collected at 30 minutes pre-dose, 20 minutes, 60 minutes and 180 minutes post-dose to measure the MPA concentrations. Data were retrospectively collected from the electronic medical records. A two-compartment model with first-order absorption, lag time in absorption, and first-order elimination was developed. Height and co-administered cotrimoxazole were added as the covariates to the model. Concentrations at different time points were simulated and area under the concentration–time curve (AUC0–12 h) was calculated. By removing one sampling point at a time, AUC0–12 h from three-point sampling strategy was re-calculated via Bayesian approach. AUC0–12 h from the three-point sampling strategy (by removing the point at 20 minutes post-dose) had the strongest correlation with AUC0–12 h from the four-point sampling strategy (Pearson’s r = 0.971).

The background of the writing of this study because the freight is often encounteredsome obstacles gas which is then encapsulated in a few issues, while the problemsencountered, among others, how is the role of the temperature outside propane tank in theloading process and any attempt to do when the temperature outside is different tanks withthe temperature in the cargo tank. In this study using qualitative methods, the research aimsto explain the phenomenon of the deepest data collection. This study does not give priority topopulation size or sampling, even a very limited sampling. If the data collected has beenprofound and could explain the phenomenon under study, then no need to look for othersampling. Qualitative research is more pressing on the issue of depth (quality) of data, notthe number (quantity) of data.It can be concluded that the change in temperature outside thevessel can greatly affect the handling of loading and unloading activities, especially in thecourse of loading, at which time the temperature outside is very cold or heat can affect thecondition of the cargo and the tank.