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Background and Objective: In clinical practice, injectable drug combination (IDC) usually provides good therapeutic effects for patients. Numerous clinical studies have directly indicated that inappropriate IDC generates adverse drug events (ADEs). The clinical application of injections is increasing, and many injections lack relevant combination information. It is still a significant need for experienced clinical pharmacists to participate in evidence-based drug decision making, monitor medication safety, and manage drug interactions. Meanwhile, a large number of injection pairs and dosage combinations limit exhaustive screening. Here, we present a prediction framework, called DeepIDC, that can expediently screen the feasibility of IDCs using heterogeneous information with deep learning. This is the first specific prediction framework to identify IDCs. Methods: Since the interaction between the injected drugs may occur in the direct physical and chemical reactions at the time of mixing or may be the indirect interaction of their drug targets and pathways, we used molecular fingerprints, drug-target associations, and drug-pathway associations to convert injections into a string of digital vectors. Then, based on these injection vectors, we combined a bidirectional long short-term memory and a feed-forward neural network to build a prediction model for accurate and instructive prediction of IDC. Results: In three realistic evaluation scenarios, DeepIDC has achieved ideal prediction results. Furthermore, compared with the other five machine-learning methods, the proposed predictor is more efficient and robust. Among the top 30 potential IDCs of each IDC class predicted by DeepIDC, we found that 9 cases were experimentally verified in the literature or available on Drug.com. Conclusion: The information we extracted in vivo and in vitro can effectively characterize injectable drugs. DeepIDC developed based on deep learning algorithm provides a valuable unified framework for new IDC discovery, which can make up for the lack of IDC information and predict potential IDC events. [ABSTRACT FROM AUTHOR]

Solid contact ion selective electrodes are extensively utilized owing to their marvelous performance over traditional liquid contact ones. The main drawback of those solid contact electrodes is aqueous layer formation which affects their constancy. Herein and to overcome this common drawback, a carbon paste electrode containing poly(3,4-ethylenedioxythiophene) was constructed and used for determination of probenecid at variant pH values. This modification decreased the potential drift down to 0.8 mV/h and improved its stability over 30 days. A Nernstian slope of − 57.8 mV/decade associated with a linear range of 1.0 × 10−6–1.0 × 10−2 mol/L was obtained. The modified carbon paste electrode successfully detected up to 8.0 × 10−7 mol/L probenecid. Results of this modified carbon paste electrode were also compared to unmodified one. [ABSTRACT FROM AUTHOR]

Affective immunology of the skin is a growing area; however, established protocols for measuring individual differences in cutaneous inflammation are lacking. To address this, we present a preliminary validation of Precision Implementation of Minimal Erythema Dose (PI-MED) testing as a method for measuring cutaneous inflammation. PI-MED is a recently adapted protocol, optimized for reproducibility and individual differences research, that uses ultraviolet (UV) light to evoke cutaneous erythema, or inflammatory skin reddening. PI-MED's novel UV dosage schedule produces standardized erythema responses across different skin pigmentation types and shows strong internal consistency within person and good test–retest reliability across 8–10 weeks. In line with predictions, increased PI-MED erythema was associated with heightened anhedonia, across several measures, beyond influences of non-affective covariates. While future work should further refine the dosage schedule for the lightest and darkest skin types, overall, evidence supports PI-MED as a protocol for inducing and measuring individual differences in cutaneous inflammation. Further, PI-MED-induced erythema can expand psychoneuroimmunology research by offering a complementary assessment for general inflammatory tone. This work adds to a growing body of evidence demonstrating a distinct relationship between inflammation and anhedonia. [ABSTRACT FROM AUTHOR]

Phosphorus (P) deficiency in agricultural soil is a worldwide concern. P modification of biochar, a common soil conditioner produced by pyrolysis of wastes and residues, can increase P availability and improve soil quality. This study aims to investigate the effects of P-modified biochar as a soil amendment on the growth and quality of a medicinal plant (Pseudostellaria heterophylla). P. heterophylla were grown for 4 months in lateritic soil amended with P-modified and unmodified biochar (peanut shell) at dosages of 0, 3% and 5% (by mass). Compared with unmodified biochar, P-modified biochar reduced available heavy metal Cd in soil by up to 73.0% and osmotic suction in the root zone by up to 49.3%. P-modified biochar application at 3% and 5% promoted the tuber yield of P. heterophylla significantly by 68.6% and 136.0% respectively. This was different from that in unmodified biochar treatment, where tuber yield was stimulated at 3% dosage but inhibited at 5% dosage. The concentrations of active ingredients (i.e., polysaccharides, saponins) in tuber were increased by 2.9–78.8% under P-modified biochar amendment compared with control, indicating the better tuber quality. This study recommended the application of 5% P-modified biochar for promoting the yield and quality of P. heterophylla. [ABSTRACT FROM AUTHOR]

Unlike artificial nanosystems, biological systems are ideally engineered to respond to their environment. As such, natural molecular buffers ensure precise and quantitative delivery of specific molecules through self-regulated mechanisms based on Le Chatelier's principle. Here, we apply this principle to design self-regulated nucleic acid molecular buffers for the chemotherapeutic drug doxorubicin and the antimalarial agent quinine. We show that these aptamer-based buffers can be programmed to maintain any specific desired concentration of free drug both in vitro and in vivo and enable the optimization of the chemical stability, partition coefficient, pharmacokinetics and biodistribution of the drug. These programmable buffers can be built from any polymer and should improve patient therapeutic outcome by enhancing drug activity and minimizing adverse effects and dosage frequency. Natural buffer molecules ensure the controlled and precise delivery of specific molecules in biology. Here, the authors replicate the natural buffer systems using aptamers with controlled binding efficiency to control and maintain the levels of free drugs both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Purpose: Successful drug therapy in children is contingent upon hassle-free administration of pediatric dosage forms. Pediatric patients suffer from difficulty in swallowing due to weak esophagus muscles in their early age. Considering this challenge liquid formulations are preferred over solid dosage form among pediatric patients to avoid the possibility of choking which can be a serious life-threatening condition in children. The main aim of the present research work was to develop a reconstitutable amorphous acetaminophen spray-dried milk powder (ASDM) as novel pediatric formulation. Methods: ASDM was prepared by spray drying process and the spray drying process was optimized using Box-Behnken design to study the effect of spray drying process parameters at X1 [inlet temperature], X2 [aspiration rate] and X3 [feed rate] to Y1 [% yield], Y2 [angle of repose], Y3 [Hausner's Ratio] and Y4 [Carr's Index] as dependent variables of ASDM. In addition, each batch was characterized for particle size by polarized light microscopy and drug entrapment. Results: Predicted parameters from optimized spray drying process model were successfully employed to manufacture a scale up cum validation batch of ASDM, which showed notably improved yield and desirable flow properties. The scale-up validation batch was further characterized using thermal analysis, diffraction studies, spectroscopic analysis, dispersion studies, stability APAP in dispersion formulation and formulation stability studies to confirm the physico-chemical stability of ASDM. Conclusions: Thus, ASDM for oral use can serve as a promising pediatric formulation and the developed prototype formulation can be further extended to future newly discovered drugs with similar characteristics. [ABSTRACT FROM AUTHOR]

The FeOOH polymers commonly existing in nature are potential adsorbent materials for phosphate ions (P). In this work, five synthesized isomeric α-, β-, γ-FeOOH (goethite, akaganéite and lepidocrocite samples of Gth1 and Gth2, Aka1 and Aka2, and Lep, respectively) were used to investigate their P adsorption characteristics and mechanisms, under various times, the levels of phosphate and FeOOH, solution pH, temperatures, and coexisting anions. Under 1.0 g/L of dosage and 20 mg/L of P, Lagergren second order rate model could describe well kinetic behaviors of P adsorptions for FeOOH (R2 being 0.999) at pH 7. Phosphate adsorption behaviors could be described well by both Langmuir (R2 being 0.968 − 0.999) and Freundlich (R2 being 0.945 − 0.988). The maximum adsorption capacities (mg/g) were 8.09(Gth1), 6.5(Gth2), 5.49(Aka1), 12.9(Aka2), and 7.36(Lep). In addition, P adsorptions presented the better capacities in a pH range of 3 − 8. The SO42− had the stronger effects on P adsorptions, while the other anions (Cl−, NO3− and CO32−) had little effects. The possible P adsorption mechanisms by FTIR and XPS results for FeOOH mainly were electrostatic attractions and ion exchanges. It is obvious that isomeric FeOOH are the promising adsorbents for P removal. [ABSTRACT FROM AUTHOR]

Rabeprazole, antiulcer drug, was labeled with Tc to obtain an agent for ulcer imaging. The radiochemical yield of Tc-rabeprazole reaches approximately 98.5 ± 0.4%.The optimum conditions are as follows: pH 9, 50 μg of SnCl·2HO, 30 min, and 3 mg of the substrate.Tc-rabeprazole was stable for 6 h. Intravenous biodistribution studies of Tc-rabeprazole revealed high concentration in the stomach ulcer, reaching about 33.4% of the total injected dose at 30 min post injection. This concentration of Tc-rabeprazole in stomach ulcer makes this agent promising for stomach ulcer imaging. [ABSTRACT FROM AUTHOR]

Allopolyploidy greatly expands the range of possible regulatory interactions among functionally redundant homoeologous genes. However, connection between the emerging regulatory complexity and expression and phenotypic diversity in polyploid crops remains elusive. Here, we use diverse wheat accessions to map expression quantitative trait loci (eQTL) and evaluate their effects on the population-scale variation in homoeolog expression dosage. The relative contribution of cis- and trans-eQTL to homoeolog expression variation is strongly affected by both selection and demographic events. Though trans-acting effects play major role in expression regulation, the expression dosage of homoeologs is largely influenced by cis-acting variants, which appear to be subjected to selection. The frequency and expression of homoeologous gene alleles showing strong expression dosage bias are predictive of variation in yield-related traits, and have likely been impacted by breeding for increased productivity. Our study highlights the importance of genomic variants affecting homoeolog expression dosage in shaping agronomic phenotypes and points at their potential utility for improving yield in polyploid crops. The connection between expression variation and phenotypic diversity in the populations of polyploid crops remains elusive. Here, the authors reveal the impact of genetic variants leading to biased expression of homoeologous genes in hexaploid wheat on agronomic traits. [ABSTRACT FROM AUTHOR]

Meiotic crossovers are limited in number and are prevented from occurring close to each other by crossover interference. In many species, crossover number is subject to sexual dimorphism, and a lower crossover number is associated with shorter chromosome axes lengths. How this patterning is imposed remains poorly understood. Here, we show that overexpression of the Arabidopsis pro-crossover protein HEI10 increases crossovers but maintains some interference and sexual dimorphism. Disrupting the synaptonemal complex by mutating ZYP1 also leads to an increase in crossovers but, in contrast, abolishes interference and disrupts the link between chromosome axis length and crossovers. Crucially, combining HEI10 overexpression and zyp1 mutation leads to a massive and unprecedented increase in crossovers. These observations support and can be predicted by, a recently proposed model in which HEI10 diffusion along the synaptonemal complex drives a coarsening process leading to well-spaced crossover-promoting foci, providing a mechanism for crossover patterning. During meiosis, the number and distribution of crossovers (COs) are tightly controlled, but the mechanistic basis of this control is unclear. Here, by combining experimental data and mathematical modeling, the study advocates a CO patterning model via coarsening through the diffusion of HEI10 along the synaptonemal complex. [ABSTRACT FROM AUTHOR]

Purpose: We conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy of different doses of intravenous tranexamic acid (TXA) in spinal surgery.Methods: We searched relevant academic articles from PubMed, Embase, the Cochrane Library, and CNKI. Two reviewers independently selected studies, assessed quality, extracted data, and evaluated the risk of bias. RevMan 5.4 was used for data analysis.Results: Ten randomized controlled trials (RCTs) met the inclusion criteria and were identified, including 740 patients. According to the different dose regimens of intravenous TXA, the included studies' patients were divided into the high dose of intravenous TXA group and the low dose of intravenous TXA group. Compared with the low-dose group, the high-dose group can reduce the intraoperative blood loss (MD = - 100.87, 95% CI: [- 147.81, - 53.92], P < 0.0001). For the postoperative Hb and HCT, the high-dose group can separately maintain 4.54 g/dL (MD = 4.54, 95% CI: [2.08, 6.99], P = 0.003) and 1.27% (MD = 1.27, 95% CI: [0.59, 1.94], P = 0.0002). There were no statistically significant differences in total blood loss, preoperative Hb and HCT, operative time, and blood transfusion rate between the high-dose group and the low-dose group.Conclusions: Based on the present meta-analysis, compared with the low-dose of intravenous TXA in spinal surgery, the high dose of intravenous TXA decreases the intraoperative blood loss and preserves higher postoperative Hb and HCT levels without increasing the operative time and blood transfusion rate. [ABSTRACT FROM AUTHOR]

A medicine can be administered in varied dosage forms which are having different environmental impacts. Two dosage forms of paracetamol (tablet and syrup) have the same function but are prepared and packaged differently, meaning that the environmental impacts arising out of their production will be of different magnitude. This study utilizes the life cycle assessment technique to find and compare the environmental impacts of two dosage forms of the paracetamol. Life cycle assessment software 'GaBi' v 8.0 has been utilized to carry out this study. Midpoint and endpoint impact assessment methods from 'ReCiPe' impact assessment method are used to carry out the life cycle impact assessment. The midpoint impact assessment results show that syrup production has 90% contribution in climate change impact category and more than 50% environment impact in fine particulate matter formation, fossil depletion, freshwater consumption, freshwater eutrophication, freshwater ecotoxicity, ionizing radiation, photochemical ozone formation, stratospheric ozone depletion, and terrestrial ecotoxicity midpoint impact categories. Tablet production has major impacts in 3 midpoint impact categories that are human toxicity, ionizing radiation, and metal depletion. Syrup production has major impacts (more than 70%) in 8 out of the 11 endpoint impact categories considered, while tablet production has a major impact in 3 impact categories that are human toxicity and ionizing radiation endpoint impact categories. Syrup production has a visibly higher impact in more number of midpoint as well as endpoint impact categories considered. The environmental hotspot is, however, dependent on the individual impact categories. The results of the study add to the existing knowledge of environmental sustainability assessment in the pharmaceutical sector and will benefit the environmental managers to better manage the environmental sustainability of pharmaceutical products. [ABSTRACT FROM AUTHOR]

Three simple, sensitive, precise, and rapid spectrophotometric methods are developed and optimized for the assay of vardenafil in pharmaceutical formulations. The procedures are ascertained on the oxidation of vardenafil with a slight excess of N-bromosuccinimide (NBS), and the unreacted oxidant is estimated by evaluating the amount of the unconsumed NBS by reacting with a fixed amount of safranin (method A), crystal violet (method B), and aniline blue (method C) in an acidic medium by measuring the absorbance at 530, 600, and 610 nm, respectively. In all the methods, the amount of NBS consumed corresponds to the amount of the drug. Beer's law range, Sandell's sensitivity, and the corresponding molar absorptivity values of 1.1104 × 104, 1.0305 × 104, and 6.217 × 103 L/mol × cm for methods A, B, and C are calculated. The limits of detection and quantification are evaluated. The methods are also evaluated statistically by means of Student's t-test and F-test. The results show excellent agreement and insignificant difference between the proposed methods and the reference method. The developed methods are successfully applied to the assay of Vardenafil in pure and dosage forms, and no interference is observed from common excipients present in pharmaceutical formulations. [ABSTRACT FROM AUTHOR]

A mathematical model of cancer chemotherapy is considered as an optimal control problem with the objective of either minimizing a weighted sum of tumor cells and drug dosage or the terminal tumor volume. The control process is subject to three state constraints involving an upper bound on drug toxicity, a lower bound on the white blood cells (WBCs) population, and a constraint to prevent the WBCs count from staying too long below a fixed upper level. The state constraints are imposed for safeguarding the health of patients during treatment. The dynamics of the WBCs population involves delays due to the delay chain of granulocyte development. The control problem is based on a similar model presented in Iliadis and Barbolosi (Comput. Biomed. Res. 33(3):211–226, 2000). However, the authors do not treat necessary conditions which only recently have been presented in the literature. We introduce two variants of the control problem imposing different state constraints. For a basic control problem, we give a thorough discussion of the necessary optimality conditions. Discretization and nonlinear programming methods are employed to determine extremal solutions that precisely satisfy the necessary conditions. It is surprising that in both control problems the time-delayed solution agrees with the non-delayed solution except for the WBCs which are obtained as backward time shifts of the non-delayed WBCs. Since the control variable appears linearly in the Hamiltonian, we find that the control is a combination of bang-bang arcs and boundary arcs of the state constraints. The direct optimization of the switching times and junction times with the boundary defines a finite-dimensional optimization problem for which we can verify second-order sufficient conditions (SSC). To obtain a more practical protocol, we construct an approximative control with fewer control sub-arcs resulting in only a marginal increase in the cost function. [ABSTRACT FROM AUTHOR]

Medicinal effects on gastrointestinal-tract (GIT) organs under normal and pathological conditions are reviewed and analyzed. It is shown that rhythmic processes of digestive organs interact closely with the hierarchical structure of partial in vivo rhythms. This creates the prerequisites for prescribing medicines for GIT disorders considering individual in vivo chronorhythms and drug pharmacokinetic profiles. [ABSTRACT FROM AUTHOR]

Purpose: A medication error (ME) is an error that causes damage or poses a threat of harm to a patient. Several studies have shown that only a minority of MEs actually causes harm, and this might explain why medication reviews at hospital admission reduce the number of MEs without showing an effect on length of hospital stay, readmissions, or death. The purpose of this study was to define drugs that actually cause serious MEs. We conducted a literature search of medication reviews and other preventive efforts. Methods: A systematic search in PubMed, Embase, Cochrane Reviews, Psycinfo, and SweMed+ was performed. Danish databases containing published patient complaints, patient compensation, and reported medication errors were also searched. Articles and case reports were included if they contained information of an ME causing a serious adverse reaction (AR) in a patient. Information concerning AR seriousness, causality, and preventability was required for inclusion. Results: This systematic literature review revealed that 47 % of all serious MEs were caused by seven drugs or drug classes: methotrexate, warfarin, nonsteroidal anti-inflammatory drugs (NSAIDS), digoxin, opioids, acetylic salicylic acid, and beta-blockers; 30 drugs or drug classes caused 82 % of all serious MEs. The top ten drugs involved in fatal events accounted for 73 % of all drugs identified. Conclusion: Increasing focus on seven drugs/drug classes can potentially reduce hospitalizations, extended hospitalizations, disability, life-threatening conditions, and death by almost 50 %. [ABSTRACT FROM AUTHOR]

A new active pharmaceutical ingredient (API) with TRPA1-antagonist activity (phenyltetrahydroquinolinedione derivative) was a white or almost white finely crystalline non-hygroscopic powder consisting of spherical particles with a large surface area: D90 and span were 22.2 μm and 1.9 units, respectively. The substance was sparingly soluble in EtOH (96%) and almost insoluble in H2O and n-hexane, melted at 203.5 – 208.3°C with decomposition, lost 0.11% of its mass upon drying, and contained 0.096% H2O and 99.3% API. The obtained data imposed certain restrictions on development of a dosage form of the substance under consideration, established requirements for production strategies of the corresponding dosage forms, and could also be used for justification of the draft specification of the API. [ABSTRACT FROM AUTHOR]

Background: Therapeutic drug monitoring (TDM) aims at individualising a dosage regimen and is increasingly being performed by estimating individual pharmacokinetic parameters via empirical Bayes estimates (EBEs). However, EBEs suffer from shrinkage that makes them biased. This bias is a weakness for TDM and probably a barrier to the acceptance of drug dosage adjustments by prescribers.Objective: The aim of this article is to propose a methodology that allows a correction of EBE shrinkage and an improvement in their precision.Methods: As EBEs are defined, they can be seen as a special case of ridge estimators depending on a parameter usually denoted λ. After a bias correction depending on λ, we chose λ so that the individual pharmacokinetic estimations have minimal imprecision. Our estimate is by construction always better than EBE with respect to bias (i.e. shrinkage) and precision.Results: We illustrate the performance of this approach with two different drugs: iohexol and isavuconazole. Depending on the patient's actual pharmacokinetic parameter values, the improvement given by our approach ranged from 0 to 100%.Conclusion: This innovative methodology is promising since, to the best of our knowledge, no other individual shrinkage correction has been proposed. [ABSTRACT FROM AUTHOR]

Purpose: Anti-neutrophilic cytoplasmic antibody (ANCA)–associated vasculitis is a rare autoimmune disease. Mycophenolic acid (MPA) is widely used for ANCA-associated nephritis (AAN) but with large pharmacokinetic variability. This study aims to investigate clinical factors impacting MPA disposition in pediatric AAN. Methods: We retrospectively collected 391 MPA concentrations from 25 children diagnosed with AAN. A population pharmacokinetic model was developed to explore the potential effects of demographics and biochemical covariates on MPA. Monte Carlo simulations were performed to optimize dosage regimen. Results: MPA pharmacokinetics best fitted a two-compartment model with first-order absorption and linear elimination. The pharmacokinetic parameters for Ka, CL/F, Vc/F, Vp/F, and Q/F were 0.45 h−1, 9.86 L/h, 19.69 L, 408.32 L, and 23.01 L/h. Dosage form significantly affected drug absorption. CL/F significantly decreased with increasing cystatin C, while decreasing with myeloperoxidase. Cystatin C was superior to serum creatinine in predicting apparent clearance of MPA. A dose regimen of 650 mg/m2 twice daily was required to achieve target exposure in children with normal renal function and no inflammation. The combined effects of myeloperoxidase concentration and renal function resulted in a sixfold range of MPA dose. Conclusion: This was the first study of MPA population pharmacokinetic model in children with AAN. Myeloperoxidase was not only a biomarker of AAN, but also an inflammatory factor to impact drug CL. The influence of renal function and underlying diseases on drug metabolism should be fully considered in personalized medication for AAN. [ABSTRACT FROM AUTHOR]

Macrolides are widely used at low dosage for long-term therapy of chronic sinusitis. Twenty clinical macrolide-resistant Staphylococcus aureus strains were morphologically compared with 10 clinical macrolide-sensitive strains. PCR amplification was performed to determine the presence of four known macrolide resistance genes. Transmission electron microscopy revealed significantly thicker cell walls in clinical macrolide-resistant strains. Even though the ultrastructural characteristics were shared by all macrolide-resistant strains, they were not associated with the presence or absence of the known macrolide-resistance genes. We also demonstrated that macrolide-resistant mutant strains derived in vitro from a macrolide-sensitive parent strain had thickened cell walls and did not harbor the known macrolide-resistance genes. These results, therefore, revealed that macrolide-resistant S. aureus strains have thickened cell walls as a common ultrastructural characteristic and that cell wall thickening is likely mediated by an unknown gene which is unrelated to any known macrolide resistance gene. [ABSTRACT FROM AUTHOR]

Purpose: Objective of this work was to extend pharmacokinetic scaling theory of the writer for bolus dosing to include the case of constant-rate i.v. dosing over fixed interval so as to allow projection of adult dose and schedule of typically administered anticancer agents to children. Methods: The basis for the scaling is the requirement of time-scaled likeness of the plasma concentrations of an agent for adult and child. Algebraic expressions are established for describing the time history of the concentrations, and formulas for dose and dosing interval are determined so as to ensure the requirement on concentrations. Results: Scaling results for simple drug behavior are illustrated using clinical data for the anticancer agent carboplatin. Basic aspects of the theory are confirmed for dose and dosing interval of adult and 4-year-old child. The theory is also shown to describe tolerable doses for children when scaled from adult dosing requirements and to have application in determining dosing conditions for children requiring individualized dosing because of renal impairment. Scaling with more complex drug behavior is illustrated using preclinical and clinical data for the anticancer agent docetaxel. Adult-to-child scaling is demonstrated and shown to be consistent with previously reported clinical data. Additional consideration is given to the anticancer agents etoposide and melphalan, as widely used in pediatric chemotherapy, and also to the modern practice of combination chemotherapy. Conclusions: Basic theory for scaling adult dose and schedule of anticancer agents to children is presented and demonstrated to be plausible in providing insight into existing and proposed pediatric treatment protocols. [ABSTRACT FROM AUTHOR]

The determination of xenobiotics in keratinized matrices, such as nails and hair, has received considerable attention because of the relatively long detection window for compounds. The distribution of xenobiotics in fingernails, unlike hair, was equivocal. The main aim of this study was to use follow-up surveys to measure zolpidem profiles in nails after subjects consumed a single dose of the drug. In addition, the zolpidem concentrations in nails were compared with data for different biosamples, such as hair and blood from previous work. With these preconditions, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of zolpidem in nails. Nails underwent alkaline hydrolysis and were extracted with diethyl ether. A Capcell Pak C18 MGII column was used to separate the target compound, and an API 4000 Qtrap mass spectrometer was used as a detector. The results for nail samples from seven subjects who had taken a single 10 mg zolpidem dose were significant: two relatively high zolpidem concentrations were observed in the long-term follow-up analysis of nails. The zolpidem concentration was less than 1.74 pg/mg and less than 3.29 pg/mg in fingernails and toenails, respectively. The subsequent peak concentration of zolpidem was observed between 10 and 15 weeks after each subject took a single dose of the drug. This result suggested that the germinal matrix area was a primary in vivo pathway for zolpidem secretion into the nail. The analysis of biosamples, such as nails, may be a useful adjunct to conventional methods of drug testing and hair analysis. Further research is needed concerning the contamination risk in analysis of nail biosamples. [ABSTRACT FROM AUTHOR]

The relationship between target volume and adverse radiation effects (AREs) at low prescription doses requires elucidation. The development of AREs in three series of patients treated in the Gamma Knife is analysed in relation to prescription dose and target volume. There were three groups. In group 1, there were of 275 patients with meningiomas; in group 2, 132 patients with vestibular schwannomas; and in group 3, 107 patients with arteriovenous malformations (AVMs). The minimum follow-up for each group was more than 24 months. All patients were followed up at six monthly intervals. The patients with tumours received a prescription dose of 12 Gy, which was varied to protect normal structures but not in relation to tumour volume per se. The desired AVM prescription dose was 25 Gy, but this was also reduced to protect normal structures and to keep the total dose within certain pre-defined limits. All AREs refer to intra-parenchymal increased perilesional T2 signal on MR irrespective of clinical correlation. There was no relationship between tumour volume and the development of ARE in the tumour groups. There was a highly significant relationship between target volume and the development of ARE for the AVMs with their much higher dose. Radiation-induced clinical trigeminal and facial nerve deficits with both vestibular schwannomas and meningiomas were always associated with an increased T2 signal in the neighbouring brainstem parenchyma. The relationship between target volume and the risk of adverse radiation effects may not apply with lower prescription doses. Individual radiosensitivity may explain why a minority suffer AREs unrelated to target volume. It is possible that radiation-induced brainstem parenchymal damage with concomitant cranial nerve deficits may be commoner after radiosurgery than is usually thought. If tumour control with lower doses is adequate, radiosurgery could be safely considered for larger targets associated with a high risk from microsurgery [ABSTRACT FROM AUTHOR]

Background: Shock in drug poisoning is a life-threatening condition and current management involves fluid resuscitation and vasopressor therapy. Management is limited by the toxicity of high-dose vasopressors such as catecholamines. Clinical trials have shown the efficacy of angiotensin II as an adjunct vasopressor in septic shock. The aim of this review is to assess the use of angiotensin II in patients with shock secondary to drug overdose. Methods: Medline (from 1946), Embase (from 1947) and PubMed (from 1946) databases were searched until July 2021 via OVID. Included studies were those with shock due to drug poisoning and received angiotensin II as part of their treatment regimen. Of the 481 articles identified, 13 studies (case reports and scientific abstracts) were included in the final analysis with a total of 14 patients. Extracted data included demographics, overdose drug and dosage, angiotensin II dosage, time of angiotensin II administration, haemodynamic changes, length of hospital stay, mortality, complications, cardiac function and other treatment agents used. Results: Thirteen studies were included consisting of 6 case reports, 6 scientific abstracts and 1 case series. Overdose drugs included antihypertensives (n = 8), psychotropics (n = 4), isopropanol (n = 1) and tamsulosin (n = 1). Out of a total of 14 patients, 3 patients died. Ten patients had their haemodynamic changes reported. In terms of MAP or SBP changes, three patients (30%) had an immediate response to angiotensin II, four patients (40%) had responses within 30 min, one patient (10%) within two hours and two patients (20%) did not have their time reported. Two patients were shown to have direct chronotropic effects within 30 min of angiotensin II administration. The median hospital stay for patients was 5 days (IQR = 4). The time from overdose until angiotensin II administration ranged from 5 to 56 h. Other vasopressors used included phenylephrine, noradrenaline, adrenaline, vasopressin, dobutamine, dopamine, methylene blue and ephedrine. A median of 3 vasopressors were used before initiation of angiotensin II. Twelve patients received angiotensin II as their final treatment. Conclusions: Angiotensin II may be useful as an adjunct vasopressor in treating shock secondary to drug poisoning. However, the current literature consisted of only very low-quality studies. To truly assess the utility of angiotensin II use in drug-induced poisoned patients, further well-designed prospective studies are required. [ABSTRACT FROM AUTHOR]

The technology of vibratory mixing has been applied to improve the compressive strength of cement-stabilized macadam (CSM). The aim of this study is to investigate the effect of vibration acceleration and cement dosage on the unconfined compressive strength and density of CSM. The mixtures with four cement dosages (2%, 3%, 4%, and 5%) were prepared by conventional mixing (0 g) and vibratory mixing (1 g, 2 g, and 3.5 g). The unconfined compressive strength was tested under different mixing methods. And the microstructure of CSM was analyzed by scanning electron microscope. The results indicate that samples using vibratory mixing have higher strengths, lower coefficient of variation, and denser microstructures, compared with the conventional compulsory mixing. Compared with 15% in conventional mixing, the strength variable coefficient of CSM is less than 10% in the vibratory mixing method. As the cement dosage and the vibration acceleration increase, the unconfined compressive strength increases. However, cement dosage has a more significant influence on improving the unconfined compressive strength than the mixing method. With the increase of every 1% in cement dosage, the 7-day strength of conventional mixing and in vibratory mixing average increased by 59% and 38%, respectively. However, the maximum improvement rate of the UCS value is 20–56.7% when vibration acceleration increased from 0 to 1 g. Especially when cement dosage is high, the effect of vibratory mixing on improving strength is limited. Besides, vibratory mixing reduces the original cement dosage by over 1.6% with the qualified unconfined compressive strength at vibration acceleration of 2 g, which is recommended in construction practice. [ABSTRACT FROM AUTHOR]

The objective was to study ceftazidime-avibactam resistant and susceptible Klebsiella pneumoniae isolated from a patient admitted to the Policlinico Umberto I of Rome for SARS-CoV2. Data on the evolution of patient's conditions, antimicrobial therapies, and microbiological data were collected. Whole-genome sequencing performed by Illumina and Nanopore sequencing methods were used to type the strains. During the hospitalization, a SARS-CoV2-infected patient was colonized by a KPC-producing K. pneumoniae strain and empirically treated with ceftazidime-avibactam (CZA) when presenting spiking fever symptoms. Successively, ST2502 CZA-resistant strain producing the KPC-31 variant gave a pulmonary infection to the patient. The infection was treated with high doses of meropenem. The KPC-31-producing strain disappeared but the patient remained colonized by a KPC-3-producing K. pneumoniae strain. An interplay between highly conserved KPC-31- and KPC-3-producing ST2502 strains occurred in the SARS-CoV2 patient during the hospitalization, selected by CZA and carbapenem treatments, respectively. [ABSTRACT FROM AUTHOR]

Purpose : We recently introduced voxel-level images of drug occupancy from PET via our "Lassen plot filter." Occupancy images revealed clear dependence of 11C-flumazenil displacement on dose of GABAa inhibitor, CVL-865, but with different scales in different brain regions. We hypothesized that regions requiring higher drug concentrations to achieve desired occupancy would have higher EC50 values. We introduce an "EC50 image" from human data to evaluate this hypothesis. Methods: Five healthy subjects were scanned with the nonselective GABAa tracer, 11C-flumazenil, before and (twice) after administration of CVL-865. We created ten occupancy images and applied an Emax model locally to create one EC50 image. We also performed simulations to confirm our observations of regional variation in EC50 and to identify the main source of variability in EC50. Results: As expected, the EC50 image revealed spatial variation in apparent drug affinity. High EC50 was found in areas of low occupancy for a given drug dose. Simulations demonstrated that sampling from an inadequate range of plasma drug concentrations could impair precision. Conclusion: Our results argue for (a) confidence in the ability of the EC50 images to identify regional differences and (b) a need to tailor the range of drug doses in an occupancy study to regularize the precision of the EC50 throughout the brain. The EC50 image could add value to early-phase drug development by identifying regional variation in affinity that might impact therapy or safety and by guiding dose selection for later-phase trials. [ABSTRACT FROM AUTHOR]

Several studies have examined the effect of different types of exercise on people with fibromyalgia. The aim of this study was to identify which dosage of resistance training is effective to reduce pain in women with fibromyalgia. Two authors independently selected studies included in a Cochrane Systematic Review and from an updated search up to May 2021 using the following databases: Embase, Central, Lilacs, PEDro, Current Controlled Trials, and WHO International Clinical Trials Registry Platform, Scopus and ISI Web of Science. Inclusion criteria were randomized clinical trials (RCTs) with female patients (18 years of age or older) diagnosed with fibromyalgia according to the American College of Rheumatology (ACR) criteria and the intervention, resistance exercises for pain reduction. The pain outcome value was extracted from studies for meta-analysis. Nine RCTs were included. Compared to the control groups, resistance exercise groups demonstrated a clinically and statistically significant effect on pain reduction when each exercise was performed in 1–2 sets or 3–5 sets of 4–12 or 5–20 repetitions twice a week, for 8–12 weeks, at intensities of 40–80% with one repetition maximum or perceived exertion. Resistance training exercises are effective to reduce pain in women with fibromyalgia when performed at moderate-to-high intensity in 1–2 sets of 4–20 repetitions twice a week, for 8–12 weeks. The protocol was registered on the International Prospective Register of Systematic Reviews (PROSPERO) platform, CRD42018095205. [ABSTRACT FROM AUTHOR]

Predicting the flocculant dosage in the drinking water treatment process is essential for public health. However, due to the complexity of water quality and flocculation, many difficulties remain. The present study aimed to report on using artificial intelligence, namely, the Elman neural network (ENN), to predict the flocculant dosage and explore the applications of the proposed model in waterworks. The flocculation process of drinking water was introduced in this study, and four typical models were developed based on multiple linear regression (MLR), the radial basis function neural network (RBFNN), the least squares support vector machine (LSSVM), and the ENN. To improve the prediction accuracy, a mixed term including long-term data and short-term data was proposed to capture the periodic and time-varying characteristics of water quality data. The weights of each part are updated adaptively according to the comparison of effluent turbidity and set values. The results demonstrate that the proposed ENN model performed better than the other three models in terms of the prediction performance. With the ENN model of flocculant dosage, the root mean square error (RMSE), mean absolute percentage error (MAPE), and coefficient of determination (R2) of the test data were 1.8917, 5.0067, and 0.8999, which were improved by 36.9%, 41.5%, and 14.0% in comparison with the best one (RBFNN) of the other three models, respectively. The effluent turbidity of sedimentation tank was more stable under the control of proposed ENN model of flocculant dosage than the other three models. Considering its performance, the ENN model can be taken as a preferred data intelligence tool for predicting the drinking water flocculant dosage. [ABSTRACT FROM AUTHOR]

Methadone treatment for heroin addiction has been available for 40 years, but there is relatively little research on the effectiveness of Canadian programs. This paper describes one-year retention among the client cohorts entering the British Columbia Methadone Program during expansion between 1996 and 1999, and examines some factors previously shown to influence retention. Fifty-two percent of program entrants were still receiving methadone one year after entry; 24% had left the program at one year but later returned. Age at program entry and average daily dose of methadone were important predictors of continuation. In the logistic regression, only the 1999 year-of-entry cohort appeared to have a different retention trajectory. Year of entry is not a significant predictor of time in the program for those receiving daily or short carry doses only, and other results are consistent between models. Retention rates in the BC Methadone Program are favourable and consistent with published rates. Program expansion does not reduce retention, once the effects of client age and dose are accounted for. Adequate daily dosing appears crucial to both initial retention and return to treatment. [ABSTRACT FROM AUTHOR]

Prospects for the development of a transdermal dosage form (DF) based on microneedles were considered. Methods for obtaining such systems, the application areas, and data from the pharmaceutical market were examined. A wide sample of INNs that are used to reduce pain in osteoarthritis patients was formed based on clinical guidelines. The market capacity, sales by Anatomical Therapeutic Chemical (ATC-2) groups, and sales depending on the DF were discussed. Criteria for the choice of active ingredients with market potential were defined. An analysis of a short list revealed that meloxicam has sufficient market potential to create a microneedle DF. A forecast of meloxicam consumption based on time series models indicated stable sales-growth dynamics and a potential market size of 4.6 billion Russian rubles by 2030. Results of the study indicated good market prospects and justification of pharmaceutical development of a new transdermal DF including meloxicam microneedles as the active ingredient. [ABSTRACT FROM AUTHOR]

Purpose: This online survey looked at the experiences and general perceptions of midwives concerning induction of labour and the specific use of misoprostol. Methods: We published an online questionnaire with 24 questions in German on midwives' experiences and perceptions of different methods of induction of labour. Results: The online survey was answered by 412 midwives between February 2016 and February 2017. At least 20% of the 24 questions were answered in 333 questionnaires, which were included in this analysis. Oral misoprostol was the most common induction method for primipara and for women with a previous vaginal birth and an unfavourable cervix. Apart from alternative methods for induction of labour like castor oil and complementary/alternative methods, oral misoprostol was the preferred method of induction of labour by midwives. Midwives described a wide range of dosage schedules concerning application intervals, starting doses, and the maximum daily dose of misoprostol. Approximately 50% of the participants of this study described prescriptions of more than 200 µg misoprostol daily for induction of labour. Conclusion: Misoprostol is widely used in Germany and was one of the three preferred methods of induction of labour among midwives in our study next to castor oil and complementary/alternative methods. The preparation and dosage of misoprostol vary significantly among hospitals and do not adhere to international guidelines. Midwives voiced their concerns about inconsistent indications and heterogenous use of different methods and dosages of induction. They wished for more patience with late-term pregnancies and individualized shared decision-making between pregnant women and obstetricians. [ABSTRACT FROM AUTHOR]

Cellular systems depend on multiprotein complexes whose functionalities require defined stoichiometries of subunit proteins. Proper stoichiometry is achieved by controlling the amount of protein synthesis and degradation even in the presence of genetic perturbations caused by changes in gene dosage. As a consequence of increased gene copy number, excess subunits unassembled into the complex are synthesized and rapidly degraded by the ubiquitin–proteasome system. This mechanism, called protein-level dosage compensation, is widely observed not only under such perturbed conditions but also in unperturbed physiological cells. Recent studies have shown that recognition of unassembled subunits and their selective degradation are intricately regulated. This review summarizes the nature, strategies, and increasing complexity of protein-level dosage compensation and discusses possible mechanisms for controlling proteome stoichiometry in multiple layers of biological processes. [ABSTRACT FROM AUTHOR]

Introduction: Ischemic stroke treatment has advanced in the last two decades and intravenous thrombolysis is now considered the standard of care for selected patients. Recanalization can also be achieved by mechanical endovascular treatment for patients with large vessel occlusions. Complicating treatment-related symptomatic intracerebral hemorrhage and prolonged needle-to-recanalization times have been identified as major determinants of poor three-month functional outcomes. A hybrid mechanical-thrombolytic system with a patch imbued with an ultra-low dose of thrombolytic agents loaded onto a stent-retriever has been developed. Methods: In this study, the in situ dose–response relationship of the thrombolytic patch imbued with up to 1000 IU of urokinase plasminogen activator (uPA) was quantified using Raman spectroscopy. Results: Thrombi of up to 400 μm thickness dissolved within 15 min when patches imbued with < 1% of the conventional thrombolysis therapy dosage were applied. The results demonstrated that low-dose thrombolytic patches can dissolve normal clots compressed in the blood vessel in a short time. 500 IU is the threshold uPA dosage in the thrombolytic patch that most effectively dissolves the clots. Conclusion: This study suggests that a novel endovascular stent-retriever loaded with an ultra-low drug dose fibrinolytic patch may be a suitable treatment for patients who are ineligible for conventional thrombolytic therapy. [ABSTRACT FROM AUTHOR]

In the present study, activity concentrations of 226Ra, 232Th and 40K in soil and uranium concentration in groundwater samples collected from Sikar, Rajasthan were estimated for dosimetric purposes. Uranium content in 48 groundwater samples measured using LED fluorimeter, ranged from 0.50 µg L−1 to 93.41 µg L−1. Uranium concentration in 27% groundwater samples exceeded the safe limit (30 µg L−1) advocated by WHO and USEPA. Radio- toxicity quantified as 'Excess Cancer Risk' and chemo-toxicity as 'Lifetime Annual Daily Dose' and 'Hazard Quotient' exhibited minor concerns. The mean activity concentration of 226Ra, 232Th and 40K content in soil samples determined using NaI(Tl) gamma spectrometer were 50.28 Bq kg−1, 34.16 Bq kg−1 and 587.45 Bq kg−1, respectively. Health risk assessment due to radiation exposure form soil was carried out considering indoor/outdoor environmental conditions and age groups. [ABSTRACT FROM AUTHOR]

Background: Methadone is a low-cost, strong opioid that is increasingly used as a first-line treatment for pain in palliative care (PC). Its long and unpredictable half-life and slow elimination phase can make titration challenging. Evidence for titration modalities is scarce. Objective: To describe the titration phase of the treatment with low-dose first-line methadone and the use of methadone for breakthrough pain. Methods: Prospective study with strong opioid–naïve patients with moderate to severe cancer pain followed at a tertiary PC unit in Argentina. Starting methadone dose was 2.5–5 mg/day every 8, 12, or 24 h. Titration allowed daily dose increases from day 1, and prescription of oral methadone 2.5 mg every 2 h with a maximum of 3 rescue doses/day for breakthrough pain. Pain control, methadone stabilization dose, and adverse effects, among other variables, were daily assessed over the first 7 days (T0–T7). Results: Sixty-two patients were included. Initial median (IQR) methadone dose was 5 (2.5) mg/day. Pain intensity decreased from a median (IQR) of 8 (2.3) at T0 to 4 (2.3) at T1 and remained ≤ 4 until T7 (all p < 0.0001 compared to T0). Similar results were obtained through the categorical and tolerability scales for pain. Fifty patients (81%) reached pain control, 66% in the first 48 h. Methadone daily doses at T2 and T7 were higher than that at T0: 7.5 (3) and 6.7 (5.5) versus 5 (2.5), respectively (all p < 0.05). The opioid escalation index at T7 was 1.7%. The median (IQR) number of rescues, stabilization dose, and time for stabilization was 0 (1), 5(4.5) mg, and 3(2) days, respectively. Two patients were discontinued due to delirium. All other side effects were mild. Conclusions: First-line, low-dose methadone using rescue methadone resulted in a pronounced and rapid decrease in pain, with minimal need for titration and for breakthrough doses, and no evidence of accumulation or sedation by the end of the week. [ABSTRACT FROM AUTHOR]

Percutaneous needle electrolysis (PNE) is a physiotherapy technique that has been shown to be effective in different pathologies such as tendinopathies or mammary fistula. For many years, theoretical bactericidal and germicidal effects have been attributed to this type of galvanic currents, partly explained by the changes in pH that it generates. However, these effects have not yet been demonstrated. The aim of this study was to evaluate the bactericidal effect and the changes in pH caused by PNE. S. aureus were prepared in two different solutions (TSB and saline solution) and in different concentrations (from 9 to 6 Log10 CFU/mL). Bacteria were treated with three experimental PNE doses to assess bacterial death levels and the changes caused to the pH of the medium. The viable cell count showed that all experimental PNE doses had a bactericidal effect against a high concentration (9 Log10 CFU/mL) of S. aureus in saline solution (p < 0.001). Furthermore, we found that when the concentration of bacteria decreased, a lower dose of galvanic current generated the same effect as a higher dose. Changes in pH were registered only in experiments performed with saline solution. PNE had a bactericidal effect against S. aureus and the level of this effect was mainly modulated by the solution, the bacterial concentration and the dose. Changes affecting pH were modulated by the type of solution and there was no relationship between this and bacterial death. [ABSTRACT FROM AUTHOR]

As immunization campaigns are accelerating, understanding how to distribute the scarce doses of vaccines is of paramount importance and a quantitative analysis of the trade-offs involved in domestic-only versus cooperative distribution is still missing. In this study we use a network Susceptible-Infected-Removed (SIR) model to show circumstances under which it is in a country's self-interest to ensure other countries can obtain COVID-19 vaccines rather than focusing only on vaccination of their own residents. In particular, we focus our analysis on the United States and estimate the internal burden of COVID-19 disease under different scenarios about vaccine cooperation. We show that in scenarios in which the US has reached the threshold for domestic herd immunity, the US may find it optimal to donate doses to other countries with lower vaccination coverage, as this would allow for a sharp reduction in the inflow of infected individuals from abroad. [ABSTRACT FROM AUTHOR]

Purpose: This observational study aimed to evaluate the safety and efficacy of pegteograstim prophylaxis in patients with lymphoma and solid malignancies. Methods: This study was conducted at 18 sites in Korea between November 2015 and August 2018. Results: In total, 611 patients (female, 61.2%) with a median age of 58 (range, 18–88) years were included. Most patients had lymphomas (n = 371, 60.7%) and breast cancer (n = 230, 37.6%) and were administered R-CHOP21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone per 21 days) (n = 284, 46.5%) and AC (doxorubicin and cyclophosphamide) (n = 177, 29.0%). The total pegteograstim dose in the 611 patients was 14,970 mg (2495 doses), with each patient receiving an average daily dose of 6.0 mg. Neutropenia grade 4 occurred in 97 patients (15.9%), and febrile neutropenia (FN) occurred in 31 patients (5.1%). Among the 611 patients, 267 patients (43.7%) developed 882 adverse events (AEs), and 11 patients (1.8%) experienced 18 adverse drug reactions (ADRs). There were 62 patients (10.2%) who experienced 81 cases of serious adverse events (SAEs), with FN and pneumonia being the most frequent at 14 and 13 episodes, respectively, in 13 patients (2.1%). Meanwhile, 1 patient (0.2%) developed 2 episodes of serious ADRs (grade 1 and grade 2 hypotension). No safety concerns in the elderly and patients with liver and/or renal disease were identified. Conclusion: The prophylactic use of pegteograstim might have good overall safety and efficacy in patients with lymphomas and solid malignancies in routine clinical practice, even in those who are elderly and have liver and renal diseases. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) can affect bone metabolism and homeostasis of serum electrolytes that are associated with abnormal levels of vitamin D. Mycophenolate mofetil (MMF) is a commonly used immunosuppressant with the active metabolite mycophenolic acid (MPA). The area under the plasma concentration–time curve (AUC) of MPA is often monitored during the treatment to assess the exposure levels. This study aims to explore the association between exposure levels of MPA and 25-hydroxyvitamin D [25(OH)D] levels in children with SLE. Methods: Repeated measured data of children with SLE who were treated with MMF and under therapeutic drug monitoring (TDM) were retrospectively collected from the electronic medical records. MPA exposure levels were reflected by the area under the concentration–time curve over 24 h (AUC0–24h). Univariate and multivariate linear regression models were employed to analyze factors associated with 25(OH)D levels. Hierarchical linear models were developed to analyze the intra- and inter-individual effects of AUC0–24h on the variance of 25(OH)D levels. Results: Data from 184 children with SLE (142 female and 42 male) with 518 follow-ups were collected. The median age was 14 years (range 3–18 years) at TDM. Children with normal 25(OH)D levels had significantly higher AUC0–24h than children with low 25(OH)D levels (98.71 vs. 84.05 mg·h/L, P = 0.004). Intra- and inter-individual effects of AUC0–24h on 25(OH)D levels were similar ( γ 10 = 0.034 vs. γ 01 = 0.037) but only the intra-individual effect was significant (P = 0.001) in hierarchical models. Other associated factors include age, sex, season at measurement, glucocorticoid daily dose, and external vitamin D3 supplements. Conclusion: 25(OH)D levels are associated with MPA exposure levels, and may serve as a potential indicator to optimize the exposure level of MPA during treatment. AUC0–24h of 98.71 mg·h/L or AUC0–12h of 49.36 mg·h/L could be the targeted exposure level for children with SLE. [ABSTRACT FROM AUTHOR]

This study aimed to determine whether self-report cognitive function is a predictor of symptomatic remission in amisulpride-treated schizophrenia. Patients with DSM-IV schizophrenia diagnoses who received amisulpride treatment, were recruited. Each patient received amisulpride with a flexible-dose strategy of 400-800 mg daily for eight weeks. Remission was defined by a shorter version of the Positive and Negative Symptom Scale(PANSS)criteria, which includes six items (PANSS-6) with scores of less than three in each item(criteria A) or total six scores of less than fourteen(criteria B). Three hundred and three patients completed the study in 15 hospitals in China. By criteria A, 244 (80.5%) achieved symptomatic remission at endpoint, and 258 (85.1%) by criteria B. Duration of illness (DOI) (criteria A: t = 2.31, P = 0.025,criteria B:t = 2.24,p = 0.026) and perceived deficits questionnaire at baseline (PDQ20 Day0) (criteria A: t = 3.32, P = 0.001,criteria B:t = 2.76,p = 0.006) in remission groups were less than that in non-remission groups. Logistic regression analysis took into account sex, age, age-onset, DOI, and PDQ20(Day0), and showed that PDQ20(Day0) was a predictor for symptomatic remission in criteria A (B = − 0.02, P = 0.014) and criteria B (B = − 0.03, P = 0.005). The odds ratio (OR) of achieving remission will be reduced by 2% in criteria A and 3% in criteria B. There were no significant differences in gender composition, age, BMI, education level, age-onset, a daily dose of amisulpride and the percentage of PDQ20 Improvement between remission and nonremission in criteria A or criteria B. Receiver operating characteristic(ROC) curves were found for PDQ20(Day0) to define the precise scores to predict remission of schizophrenia (criteria A:AUC = 0.614, S.E. = 0.041, 95% CI = 0.535–0.694, p = 0.007; criteria B:AUC = 0.633, S.E. = 0.045, 95% CI = 0.545–0.721, p = 0.005). Our data suggest that an early self-report cognitive function in amisulpride-treated schizophrenia is important in predicting for symptomatic remission, the fewer scores of PDQ20 at baseline mean the patients have less daily cognitive difficulty, the more likely the patient is to achieve symptomatic remission. [ABSTRACT FROM AUTHOR]

This study aimed to determine the status of groundwater contamination with faecal coliform and nitrate in the rural areas of Mardan district, Pakistan. Both analytes require regular monitoring according to the National Environmental Quality Standards (NEQS) of Pakistan. Groundwater samples (n = 100) were collected from 25 villages across four zones. Samples were analysed for physicochemical parameters including pH, electrical conductivity (EC), Escherichia coli (E. coli) contamination, nitrite, and nitrate ( NO 2 - and NO 3 - ). Whilst the average concentrations of NO 3 - in the water samples were within the permissible limits of 50 mg L−1 set by the World Health Organisation (WHO) and NEQS two villages exceeded the safety limits. Non-carcinogenic health risks of NO 3 - were estimated in terms of average daily dose (ADD) and hazard quotient (HQ). The HQ values for NO 3 - were > 1 for children signifying potential health risks; however, the adult population had HQ < 1 which indicates no risk. Groundwater samples tested positive for E. coli contamination in 13 villages, suggesting that residents may be living at risk of various microbial diseases due to drinking of contaminated water. The findings of this study provide valuable baseline data for groundwater researchers, policymakers, and the local public health department. [ABSTRACT FROM AUTHOR]

To improve the accuracy of warfarin daily dose prediction, we develop an evolutionary synthetic oversampling technique (ESMOTE) with a cocktail ensemble model (CEM) called ESMOTE-CEM. Different from conventional oversampling methods, ESMOTE finds the near-optimal oversampling parameters by evolving the parameter representation based on the pre-predicted warfarin dose and then synthesizes new samples to balance the data. The CEM, which improves the performance of random forest (RF) and boosted regression tree (BRT) models using a hybrid mechanism in the regression calculation, estimates the daily dose of warfarin. We test the ESMOTE-CEM on a dataset of 733 samples collected from the First Affiliated Hospital of Soochow University and the International Warfarin Pharmacogenetics Consortium (IWPC). The results show that ESMOTE outperformed the other oversampling methods by at least 6.98% for R2 and 5.03% for the mean squared error (MSE). In terms of the percentage of patients whose predicted warfarin dose is within 20% of the actual stable therapeutic dose (20%-p value), the ESMOTE-CEM achieves a 20%-p value of 50%. Moreover, compared to RF, BRT and AdaBoost models, the CEM is the most suitable base predictive model for ESMOTE. [ABSTRACT FROM AUTHOR]

Objective: The aim of this meta-analysis was to evaluate the effectiveness of glutamine for preventing or treating moderate-to-severe oral mucositis induced by chemotherapy or radiation therapy in patients with cancer. Methods: PubMed, Cochrane Library, and Embase were searched for eligible randomized controlled trials (RCTs) up to June 2020. The outcomes analyzed were oral mucositis (at all levels of severity). Data were pooled using the random-effects model and are expressed as risk ratios (RRs) and corresponding 95% confidence intervals (CIs). Heterogeneity was assessed and quantified using I2. Results: Sixteen RCTs were included in this review. In this meta-analysis, compared with placebo, glutamine significantly reduced the incidence of grade 3 and 4 oral mucositis induced by chemotherapy or radiation therapy (RR, 0.53; 95% CI, 0.32–0.88). In subgroup analysis, oral glutamine administration (RR, 0.56; 95% CI, 0.34–0.92) and a medium or low daily dose of glutamine (RR, 0.58; 95% CI, 0.44–0.77; RR, 0.53; 95% CI, 0.28–0.94; respectively) decreased risk. Glutamine caused a borderline significant reduction in the risk of grade 3 and 4 oral mucositis induced by radiotherapy (RR, 0.75; 95% CI, 0.58–0.99) and especially in its prevention (RR, 0.51; 95% CI, 0.28–0.94). Conclusions: Glutamine significantly reduces the risk of oral mucositis during chemotherapy or radiation therapy. Furthermore, large prospective trials are required to support these findings. [ABSTRACT FROM AUTHOR]

The purpose of this paper was to compare manganese-DPDP (Mn-DPDP) and gadolinium chelate (Gd-DTPA) contrast agents for enhancement of the normal pancreas. A total of 14 patients with focal liver disease underwent Mn-DPDP- and Gd-DTPA-enhanced 1.5 T MR examinations using spoiled gradient-echo (FLASH) technique at two separate times. Contrast agents were injected according to the currently recommended practices; Gd-DTPA was injected as a rapid bolus injection in a dosage of 0.1 mmol/kg, and Mn-DPDP was injected as a slow IV injection in a dosage of 5 mumol/kg. Quantitative region of interest measurements were made in 11 patients, and percent contrast enhancement of the pancreas and pancreas-fat signal-to-noise ratios (SNR) were determined for each agent. Images were also evaluated qualitatively by consensus reading of two investigators and overall scan quality was rated on a scale from 1 (poor) to 4 (very good). Enhancement of the pancreas immediately post Gd-DTPA was significantly higher than 15 min post Mn-DPDP (73.3 vs 36.3%; p = 0.003). On postcontrast images the pancreas-fat SNR measurements were 7.7 (i.e., pancreas higher in signal than fat) and -6.1 for Gd-DTPA and Mn-DPDP, respectively, which was significantly different (p < 0.001). Image quality was rated as 3.1 and 2.5 for Gd-DTPA- and Mn-DPDP-enhanced images, respectively. The normal pancreas enhances significantly more with Gd-DTPA than with Mn-DPDP administered under the conditions of this study. Overall image quality is also greater on the Gd-DTPA-enhanced images. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate current fluconazole treatment regimens in critically ill adults over the typical treatment course. Methods: Data from critically ill adults treated with fluconazole (n=30) were used to develop a population pharmacokinetic model. Probability of target attainment (PTA) (fAUC24/MIC >100) was determined from simulations for four previously proposed treatment regimens: (i) 400 mg once daily, (ii) an 800 mg loading dose followed by 400 mg once daily, (iii) 400 mg twice daily, and (iv) a 12 mg/kg loading dose followed by 6 mg/kg once daily. The effect of body weight (40, 70, 120 kg) and renal function (continuous renal replacement therapy (CRRT); 20, 60, 120, 180 mL/min creatinine clearance) on PTA was assessed. Results: Early (0–48 h) fluconazole target attainment for infections with a minimum inhibitory concentration (MIC) of 2 mg/L was highly variable. PTA was highest with an 800 mg loading dose for underweight (40 kg) patients and with a 12 mg/kg loading dose for the remainder. End-of-treatment PTA was highest with the 400 mg twice daily maintenance dosing for patients who were under- or normal weight and 6 mg/kg maintenance dosing for overweight (120 kg) patients. None of the fluconazole regimens reliably attained early targets for MICs of ≥4 mg/L. Conclusion: Current fluconazole dosing regimens do not achieve adequate early target attainment in critically ill adults, particularly in those who are overweight, have higher creatinine clearance, or are undergoing CRRT. Current fluconazole dosing strategies are generally inadequate to treat organisms with an MIC of ≥4 mg/L. [ABSTRACT FROM AUTHOR]

Purpose: Desmoid fibromatosis (DF) is a locally aggressive connective-tissue tumor arising in deep soft tissues. Although multiple therapeutic modalities have been demonstrated effective for DF, there is no standard systemic treatment for progressive and recurrent DF. As a part of systemic treatment, tyrosine kinase inhibitors have shown promising activity against DF with tolerable toxicity profiles. Thus, the aim of this study was to investigate the efficacy and safety of apatinib, a novel multi-target angiogenesis inhibitor, in patients with DF. Methods: We retrospectively analyzed the medical records of patients with advanced extremity DF regularly treated with apatinib between October 2017 and January 2020 in our center. Apatinib was initially administered with a dose of 250 mg daily and the dose was adjusted according to the toxicity. Tumor response was assessed by the Response Evaluation Criteria in Solid Tumors 1.1 criteria. The primary endpoint was progression-free survival (PFS); objective response rates and drug-related adverse events were also evaluated. Results: A total of 22 (6 male, 16 female) patients with advanced extremity DF were included. The mean medication time was 17 months. None of the patients reached a complete response, but ten (45.5%) patients achieved partial response, and 11 patients (50%) achieved stable disease. One (4.5%) patient developed progressive disease, and the 1-year PFS rate was 95.2%. The disease control rate was 95.4% (21/22) and the objective response rate was 45.5% (10/22). Meanwhile, 18 (81.8%) patients with a tumor shrinkage were accompanied by a decreased signal intensity of lesions in T2-weighted magnetic resonance imaging. The most frequent adverse events included hand-foot syndrome (n = 7, 31.8%), fatigue (n = 6, 27.2%), local pain (n = 4, 18.1%), diarrhea (n = 4, 18.1%). Conclusion: Apatinib is an effective and well-tolerated option for patients with advanced extremity DF. Indeed, further prospective, randomized studies with larger cases are required to fully explore the clinical utility of apatinib in DF. [ABSTRACT FROM AUTHOR]

The deposited dose in the human respiratory tract and its influencing factors were investigated for 8 urban/suburban locations within Greek cities. A dosimetry model (ExDoM2) was implemented assuming a 24-h exposure scenario to ambient PM10 whereby regional deposition rates were obtained. Simulations were performed considering three cases (Sahara dust, cold, and warm periods) with seasonal and diurnal variations examining the relative sources and other influencing factors in each case. Health risk indexes such as the relative risk and attributable fraction were also estimated. Overall, higher daily deposited dose was obtained for all urban compared with suburban locations (p < 0.05) and for cold compared with the warm periods (252–820 μg for cold period and 300–686 μg for warm period) for all locations. This finding was associated with increased deposition rate on cold period during evening/night hours, as a result of significant heating emissions. Besides that, most of the urban locations showed relative comparable deposition rates during the day, compared with the daily mean, for the two periods (cold and warm), indicating that urban-associated sources such as exhaust emissions and road dust resuspension contribute similarly to the deposited dose irrespectively of the season. Finally, the highest deposited dose was obtained during Sahara dust events ranged from 1881 to 4648 μg. [ABSTRACT FROM AUTHOR]

This study aimed to analyze the influence of renal insufficiency on the anticoagulant effects and safety of warfarin in Chinese patients. Data on the creatinine levels of participants enrolled in a randomized controlled study were screened and divided into the non-renal insufficiency group, mild renal insufficiency group, and moderate renal insufficiency group, according to the creatinine clearance rate. The primary outcome measures were stable dose and average daily dose of warfarin. Secondary outcome measures were percentage of time in the therapeutic international normalized ratio (INR) (%TTR), and the first time to reach the therapeutic INR. Adverse events included bleeding events, thromboembolic events, and mortality. All participants with renal function test results and a baseline INR of less than 1.5 were included in the primary and secondary outcome analysis. The SPSS Statistics 21.0 software was used for statistical analysis. The randomized controlled trial was registered in Clinicaltrials.gov (NCT02211326). A total of 571 patients were included in this analysis. Multiple regression analysis showed that the renal function was correlated with stable dose, average daily dose, and the first time to reach therapeutic INR after adjusting for confounding factors. However, no correlation was noted between kidney function and %TTR. No significant differences were observed across the various safety parameters among the three groups. Renal function is an important consideration in patients using warfarin. [ABSTRACT FROM AUTHOR]