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Hairy cellulose nanocrystalloids (HNC) are a brand new family of nanocellulose characterized by having functionalized amorphous poles joined by a crystalline shaft. In this paper we hypothesize that cationic HNC (CNCC) could be used as an effective retention agent in papermaking. To investigate this, we first flocculated a suspension of only fillers, namely kaolinite and CaCO3, and second, a suspension of recycled fibers, with CNCC. It was monitored by photometric dispersion analysis and laser focused beam reflectance. The flocculation mechanism was assessed by means of zeta potential, reflocculation efficiency, flocculation stability and optical microscopy. Finally, the effect of CNCC on drainage, retention and paper mechanical properties was studied. CNCC were found to heteroflocculate fillers at a wide range of dosages, finding a maximum floc size at a dosage of 30 mg/g. On the other hand, the maximum floc size when flocculating the pulp suspension, was found at a lower CNCC dosage (20 mg/g). In this case, fillers were being attached to the exterior surface of the fibers. In both systems, the maximum size increment was observed at the isoelectric point, so a charge neutralization mechanism was proposed. The addition of CNCC not only improved filler retention, but also pulp drainage by reducing these times. Moreover, although mechanical properties of the handsheets were affected by the presence of CNCC, this effect was much lighter than that caused by traditionally used retention systems. Hence, CNCC could replace many additives used in the wet-end of a paper machine, thus simplifying its operation. [ABSTRACT FROM AUTHOR]

Resin acids are mixtures of high molecular weight carboxylic acids found in tree resins. Due to higher hydrophobicity and low solubility, they tend to adsorb on the suspended solids in pulp and paper (P&P) mill wastewater and accumulate in primary sludge through settling. Anaerobic digestion (AD) is a common practice stabilizing sludge; however, high concentration of resin acids affects the AD process. The aim of this research was mainly to determine the impact of ferrate (Fe (VI)) oxidation on selected resin acids and anaerobic digestibility of ferrate-treated primary sludge (PS) spiked with the resin acids. First, batch control oxidation of model resin acids with Fe (VI) was conducted to identify an optimum dosage, pH and contact time using a Box–Behnken design approach. Thereafter, anaerobic treatability studies of primary sludge spiked with resin acids both under control condition and optimum ferrate pretreatment were conducted. Up to 97% oxidation of resin acids occurred in pure water, while only 44%—62% oxidation of resin acids occurred in PS with an increasing Fe (VI) dosage from 0.034 to 0.137 mg Fe (VI)/mg tCODfed. The pretreatment did not affect the anaerobic biodegradability of resin acids; however, it lowered their negative influences on the PS digestibility. About 0.076 mg Fe (VI) dosage/mg tCODfed solubilized the sludge increasing the methane production by 40% compared to the untreated digester. The potential benefits of ferrate pretreatment of P&P primary sludge include resin acids oxidation and subsequent toxicity reduction, higher sludge solubilization enhancing methane production and enabling anaerobic digestion at higher COD loading. [ABSTRACT FROM AUTHOR]

Emulsified asphalt is the primary material for preventive maintenance and cold-mix paving, but its low cohesive strength and poor mechanical properties limit its wide application, even with polymer modification. In this study, Styrene-Butadiene Rubber (SBR) emulsified asphalt was modified with nano-cellulose materials, namely nano paper-cellulose (NPC) and wood-derived nano-cellulose (WDC), to improve its properties. A novel preparation method of nano-cellulose solution was developed, including blending, ultrasonic stirring, and centrifugal treatment. Four types of nano-cellulose solution (0.5% NPC, 0.5%, 1.0%, and 1.5% WDC by weight of water) were selected. The microscopy analysis indicated that 0.5% WDC emulsion had a smaller particle size than 1.5% WDC emulsion. The rheology test indicated that WDC modified residue improved rutting resistance with the increased solution dosage due to the cross-linking effect, but its creep-and-recovery performance was worse than that of SBR emulsion residue. The NPC modified binder had a higher rutting factor than WDC modified binder at the same dosage after short-term aging. In addition, 1.0% WDC could be regarded as the optimal dosage in terms of fatigue and low-temperature performance. Furthermore, Fourier Transform Infrared Spectroscopy (FTIR) results showed that 0.5% NPC modified residue performed better in long-term aging resistance compared with 0.5%WDC modified asphalt. [ABSTRACT FROM AUTHOR]

Introduction: The risk of dose errors is high in paediatric inpatient settings. Computerized provider order entry (CPOE) systems with clinical decision support (CDS) may assist in reducing the risk of dosing errors. Although a frequent type of medication error, the prevalence of dose errors is not well described. Dosing error rates in hospitals with or without CPOE have not been compared.Objective: Our aim was to conduct a systematic review assessing the prevalence and impact of dose errors in paediatric wards with and without CPOE and/or CDS.Methods: We systematically searched five databases to identify studies published between January 2000 and December 2017 that assessed dose error rates by medication chart audit or direct observation.Results: We identified 39 studies, nine of which involved paediatric wards using CPOE with or without CDS. Studies of paediatric wards using paper medication charts reported approximately 8-25% of patients experiencing a dose error, and approximately 2-6% of medication orders and approximately 3-8% of dose administrations contained a dose error, with estimates varying by ward type. The nine studies of paediatric wards using CPOE reported approximately 22% of patients experiencing a dose error, and approximately 1-6% of medication orders and approximately 3-8% of dose administrations contained a dose error. Few studies provided data for individual wards. The severity and prevalence of harm associated with dose errors was rarely assessed and showed inconsistent results.Conclusions: Dose errors occur in approximately 1 in 20 medication orders. Hospitals using CPOE with or without CDS had a lower rate of dose errors compared with those using paper charts. However, few pre/post studies have been conducted and none reported a significant reduction in dose error rates associated with the introduction of CPOE. Future research employing controlled designs is needed to determine the true impact of CPOE on dosing errors among children, and any associated patient harm. [ABSTRACT FROM AUTHOR]

In medical treatments, a fundamental dilemma often arises: on the one hand, an increase in a drug’s dose could lead to a stronger, therapeutic treatment response, but on the other hand this could also lead to increased toxicity risks. In this paper, we propose to solve this dilemma using a Nash bargaining approach. To do so, we reformulate the tradeoff problem in an equivalent form as a dilemma between a drug’s beneficial response and the drug’s safety, where the dilemma then becomes a two-objective problem with safety and response as the objectives. Using a general receptor response model, we show that the set of all feasible outcomes associated with a drug’s treatment is characterized as a convex set, which allows the dilemma to be solved as a bargaining problem between the two objectives. The Nash bargaining solution (NBS) is found in closed form, and interesting properties associated with the solution are presented. In particular, it is shown that one can interpret the NBS as corresponding to a treatment giving the maximal expected safe treatment response associated with the drug. Moreover, the condition when the NBS coincides with the maxmin solution for the two objectives is derived. Two approaches to control the NBS solution are then presented: first, by means of assigning bargaining powers to objectives; second, by means of assigning an upper-bound on the drug’s dosage. The obtained NBS are compared with the dosage returning maximal drug response efficiency. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the use of thermal ink-jetting as a method for dosing drugs onto oral films. Methods: A Hewlett-Packard printer cartridge was modified so that aqueous drug solutions replaced the ink. The performance of the printer as a function of print solution viscosity and surface tension was determined; viscosities between 1.1 and 1.5 mm s were found to be optimal, while surface tension did not affect deposition. A calibration curve for salbutamol sulphate was prepared, which demonstrated drug deposition onto an acetate film varied linearly with concentration (r = 0.9992). The printer was then used to deposit salbutamol sulphate onto an oral film made of potato starch. Results: It was found that when doses were deposited in a single pass under the print head, then the measured dose was in good agreement with the theoretical dose. With multiple passes the measured dose was always significantly less than the theoretical dose. It is proposed that the losses arise from erosion of the printed layer by shearing forces during paper handling. The losses were predictable, and the variance in dose deposited was always less than the BP limits for tablet and oral syrup salbutamol sulphate preparations. Conclusions: TIJ printing offers a rapid method for extemporaneous preparation of personalized-dose medicines. [ABSTRACT FROM AUTHOR]

In this paper, the effect of washing parameters on the quantity of dye discharge from fabric dyed in highly saturated color (FSC) was discussed. Firstly, the FSC was prepared with reactive red 195 to represent the dark clothes. Secondly, the effect of the washing parameters, including washing time, washing temperature, washing water volume, the weight of FSC, and the dosage of detergent, on dye discharge was analyzed through the single factor test. Thirdly, the mathematical relationship between the quantity of dye discharge (DDQ) and the four washing parameters was discussed through the center combination experiment and response surface method. And a quadratic model was built to predict the quantity of dye discharge when the FSC were washed with different washing parameters. The experimental results indicated that the quantity of dye discharge was affected by the four selected washing parameters and the optimal washing parameters to reduce the quantity of dye discharge can be deduced from the quadratic model. The optimized parameters effectively reduced 0.99 mg dye discharge per liter, and the DDQ reduction rate was up to 53.5%. [ABSTRACT FROM AUTHOR]

Mathematical model-based analysis and control of human immunodeficiency virus (HIV) infection have recently provided important advantages in medicine. In this paper, firstly the literature on mathematical models and applied control methods will be surveyed to evaluate the HIV models and therapy. Secondly, a cubature Kalman filter-based nonlinear model predictive control is proposed for the multi-input multi-output control of HIV infection for decreasing the cost of sensory devices and increasing the efficiency of therapy. By doing so both unmeasurable states and personalized parameters of the HIV infection are jointly estimated in a control process to generate suitable drug dosages. In the literature, the applied drug dosages are in continuous or on/off levels. For a practical application of continuous drug dosage-level, it has been discretized into 10 levels of full dosage level. Therefore, the applied drug dosages are in piecewise-continuous levels instead of continuous values or on/off levels. The proposed observer–controller configuration has been applied to the strong and moderate therapy levels of long-term non-progressive as well as fast-progressive patients with personalized parameters, where the application results are discussed for 1-, 5-, 10- and 20-year periods. The computational results show that satisfactory performances are obtained for future applications in terms of the root-mean-squared error of the estimation and control, and in terms of the integral sum of the control input. [ABSTRACT FROM AUTHOR]

Uniform dosimetry is a prerequisite for reproducible laser applications in research and practice. The light–tissue interaction is dependent on the absorbed energy (J) per unit of time (τ) in the case of pulsed lasers, and on the absorbed power (W) per unit of volume (e.g. mm3) in the case of continuous-wave (cw) lasers, and thus directly dependent on the energy distribution within the laser beam. Consequently, precise knowledge of the spatial beam profile, and of the pulse duration and treatment time, is indispensable. The objective of this paper was a theoretical study of the impact of different mode profiles on energy distribution in the beam. Also examined was the question of the influence of changes in the laser parameters on the mode structure. Three erbium:YAG lasers (λ=2.94 μm) were used for this purpose. The transversal mode structure of the lasers was observed by irradiating thermal paper and verified by means of calculations. The effect induced in the mode profile by changing the pulse energy and pulse repetition rate was investigated. The results of the tests show that changes in the laser parameters result in jumps in the transversal modes and associated energy distributions in the beam. The experiments confirm that simply changing the transversal modes has a substantial effect on the threshold energy required for the ablation of dental enamel (50 mJ with TEM00, 22.6 mJ with TEM31). In practice, inhomogeneity makes it impossible to determine the irradiated area in order to calculate the energy or power density. In addition, the energy distribution in the beam changes as a result of variation of the laser output energy and the pulse repetition rate. Consequently, simply measuring the beam diameter yields a totally incorrect result for the applied flux density when using a beam profile with a relatively high mode. [ABSTRACT FROM AUTHOR]

In this study, a portable air floating-electrode dielectric-barrier-discharge (FE-DBD) plasma generator has been developed with a weight of less than 200 g and a volume of less than 480 cm3. Considering the equivalent impedance of human body (EIHB), an equivalent circuit model is developed that couples the FE-DBD generator and the EIHB module to determine the thickness of the dielectric barrier layers of the plasma generator, taking into account the electrical safety for human body during air discharges. The thermal and optical characteristics of the air discharges are also studied showing stable and thermal safety and abundant reactive oxygen and nitrogen species. Furthermore, with a view to biomedical applications of the air FE-DBD plasmas, a dosimetric experimental model using human embryonic kidney 293 (HEK293) cells is proposed to simulate the interactions between the air FE-DBD plasmas and the human body. In this model, the cell culture medium works as the floating electrode and is connected to the EIHB module. The LD50 value, which is the medium lethal dose based on the concept of drug dosage in pharmacy using the FE-DBD plasma source, is measured for a quantitative evaluation of the cytotoxicity after plasma treatment. This study provides a device physical safety and dosage evaluation method for the portable air FE-DBD plasma generator which is helpful for promoting the clinical applications of this type, and even other types of CAP sources. [ABSTRACT FROM AUTHOR]

Intelligent separation is a core technology in the transformation, upgradation, and high-quality development of coal. Realising the intelligent recognition and accurate classification of coal flotation froth is a key technology of intelligent separation. At present, the coal flotation process relies on artificial recognition of froth features for adjusting the reagent dosage. However, owing to the low accuracy and subjectivity of artificial recognition, some problems arise, such as reagent wastage and unqualified product quality. Thus, this paper proposes a new froth image classification method based on the maximal-relevance-minimal-redundancy (MR MR)-semi-supervised Gaussian mixture model (SSGMM) hybrid model for recognition of reagent dosage condition in the coal flotation process. First, the features of morphology, colour, and texture are extracted, and the optimal froth image features are screened out using the maximal-relevance-minimal-redundancy (MRMR) feature selection algorithm based on class information. Second, the traditional GMM clusterer is improved, called SSGMM, by introducing a small number of marked samples, the traditional GMM' problems of unclear training goals, invisible clustering results, and artificially judged clustering results are solved. Then a new hybrid classification model is proposed by combining the MRMR with the modified GMM (SSGMM) which can be named as (MRMR - SSGMM). The optimal froth image features are screened by MRMR to provide the SSGMM classifier. In the process of training and learning the feature samples, using the marked feature samples of froth images to guide the unmarked feature samples. The information of marked feature samples of froth images is mapped to the unmarked feature samples, the classification of the froth images were realised. Finally, the accuracy of the SSGMM classifier is used as the evaluation criterion for the screened features by MRMR. By automatically executing the entire learning process to find the best number of froth image features and the optimal image features, so that the classifier achieves the maximum classification accuracy. Experimental results show that the proposed classification method achieves the best results in accuracy and time, compared with other benchmark classification methods. Application results show that the method can provide reliable guidance for the adjustment of the reagent dosage, realize the accurate and timely control of the reagent dosage, reduce the consumption of the reagent and the incidence of production accidents, and stabilize the product quality in the coal flotation production process. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this review is to assess the extent of the use of off-label and/or unlicenced drugs among hospitalised children. Methods: A systematic search was made in MEDLINE-PubMED for papers published from 1994 to 2012, addressing the prescription of off-label and/or unlicenced drugs for the paediatric population in hospital care. Results: Of the 829 studies retrieved, 34 met the inclusion criteria. Prescriptions ranged from 12.2 to 70.6 % for off-label and from 0.2 to 47.9 % for unlicensed drugs. The percentage of children who received at least one off-label and/or unlicensed drug ranged from 42.0 to 100 %, with newborns being the population that received most of such drugs. Off-label prescriptions were essential for dose modification (7.1-73.1 %) and unlicensed prescriptions for formulation modification purposes (3.6-100 %). Conclusions: These findings show that: (i) off-label and/or an unlicensed prescribing is widespread among the hospitalised paediatric population worldwide, (ii) there is no consensus on a definition of off-label and/or unlicensed drugs and (iii) preterm newborns receive most off-label and/or unlicensed drugs. By shedding new light on off-label and/or unlicensed drug prescribing, these findings will hopefully contribute to generating new, more effective knowledge about the paediatric population's need for quality drugs that are both safe and efficacious. [ABSTRACT FROM AUTHOR]

This paper identifies the origin of the linearity at low-dose concept [i.e., linear no threshold (LNT)] for ionizing radiation-induced mutation. After the discovery of X-ray-induced mutations, Olson and Lewis (Nature 121(3052):673-674, ) proposed that cosmic/terrestrial radiation-induced mutations provide the principal mechanism for the induction of heritable traits, providing the driving force for evolution. For this concept to be general, a LNT dose relationship was assumed, with genetic damage proportional to the energy absorbed. Subsequent studies suggested a linear dose response for ionizing radiation-induced mutations (Hanson and Heys in Am Nat 63(686):201-213, ; Oliver in Science 71:44-46, ), supporting the evolutionary hypothesis. Based on an evaluation of spontaneous and ionizing radiation-induced mutation with Drosophila, Muller argued that background radiation had a negligible impact on spontaneous mutation, discrediting the ionizing radiation-based evolutionary hypothesis. Nonetheless, an expanded set of mutation dose-response observations provided a basis for collaboration between theoretical physicists (Max Delbruck and Gunter Zimmer) and the radiation geneticist Nicolai Timoféeff-Ressovsky. They developed interrelated physical science-based genetics perspectives including a biophysical model of the gene, a radiation-induced gene mutation target theory and the single-hit hypothesis of radiation-induced mutation, which, when integrated, provided the theoretical mechanism and mathematical basis for the LNT model. The LNT concept became accepted by radiation geneticists and recommended by national/international advisory committees for risk assessment of ionizing radiation-induced mutational damage/cancer from the mid-1950s to the present. The LNT concept was later generalized to chemical carcinogen risk assessment and used by public health and regulatory agencies worldwide. [ABSTRACT FROM AUTHOR]

It has become quite common in recent early oncology trials to include both the dose-finding and the dose-expansion parts within the same study. This shift can be viewed as a seamless way of conducting the trials to obtain information on safety and efficacy hence identifying an optimal dose (OD) rather than just the maximum tolerated dose (MTD). One approach is to conduct a dose-finding part based solely on toxicity outcomes, followed by a dose expansion part to evaluate efficacy outcomes. Another approach employs only the dose-finding part, where the dose-finding decisions are made utilizing both the efficacy and toxicity outcomes of those enrolled patients. In this paper, we compared the two approaches through simulation studies under various realistic settings. The percentage of correct ODs selection, the average number of patients allocated to the ODs, and the average trial duration are reported in choosing the appropriate designs for their early-stage dose-finding trials, including expansion cohorts. [ABSTRACT FROM AUTHOR]

Abstract. The abstracts of the joint congress of EANM/ WCNMB in Berlin 1998 and of the 45th Annual Meeting of the Society of Nuclear Medicine in Toronto 1998 have been analysed and compared in terms of comprehensibility, composition, questions at issue, methods, patient/subject number, type of conclusion and duplication of information between the meetings. All 1362 and 1096 abstracts, respectively, were analysed from the abstract books with regard to ten "hard" and four "soft" variables. The dominant topics were new radiopharmaceuticals, methods of synthesis, examination methods, evaluation of examinations, investigation algorithms, technical devices and novel use of radiopharmaceuticals. In addition to these topics, there were numerous reports about established radiopharmaceuticals and techniques, often without a specific merit mentioned. There were also many abstracts with questions outside nuclear medicine, but using such techniques. Few papers reported negative findings or dealt with quality assurance, dosimetry, and cost-effectiveness. Many of the conclusions contained hyperbole. Some abstracts were very extensive and detailed. Sixty-seven contributions conveyed identical information at both meetings. Structured and/or paragraphed abstracts promote clarity and reduce the number of lines that need to be read in order to comprehend the background and aim of the abstract. Such contributions were more frequent at the EANM/WCNMB congress while the SNM meeting covered a wider field with a greater representation of radiophysics, instrumentation, and computer evaluations. [ABSTRACT FROM AUTHOR]

The administration of the adrenal hormone corticosterone by injection or subcutaneous implantation of its modified-release dosage forms is often used to model situations associated with the effects of various stressors on the brain. The present methodological study investigated the possibility of using Alzet osmotic pumps (OPs) with a capacity of 200 µL and a release rate of 1 µL/h, loaded with corticosterone solutions of 25, 50 and 100 mg/mL or a vehicle (dimethyl sulfoxide/polyethylene glycol-400). The objective was to determine the optimal concentration of corticosterone solution loaded into osmotic pumps to create an increased level of the hormone in the rat blood and brain regions. An increase in blood corticosterone levels was only observed on mg/mL (OP-100). Corticosterone accumulation in the frontal cortex, neocortex and hippocampus increased significantly by day 3 after implantation in the OP-100 group. Thus, OPs with a corticosterone solution in DMSO/PEG-400, at a hormone concentration of 100 mg/mL and release rate of 1 µL/h, can be used to create elevated corticosterone levels in the blood and brain regions of rats. [ABSTRACT FROM AUTHOR]

Introduction: Neurodegeneration is the term describing the death of neurons both in the central nervous system and periphery. When affecting the central nervous system, it is responsible for diseases like Alzheimer's disease, Parkinson's disease, Huntington's disorders, amyotrophic lateral sclerosis, and other less frequent pathologies. There are several common pathophysiological elements that are shared in the neurodegenerative diseases. The common denominators are oxidative stress (OS) and inflammatory responses. Unluckily, these conditions are difficult to treat. Because of the burden caused by the progression of these diseases and the simultaneous lack of efficacious treatment, therapeutic approaches that could target the interception of development of the neurodegeneration are being widely investigated. This review aims to highlight the most recent proposed novelties, as most of the previous approaches have failed. Therefore, older approaches may currently be used by healthcare professionals and are not being presented.Methods: This review was based on an electronic search of existing literature, using PubMed as primary source for important review articles, and important randomized clinical trials, published in the last 5 years. Reference lists from the most recent reviews, as well as additional sources of primary literature and references cited by relevant articles, were used.Results: Eighteen natural pharmaceutical substances and 24 extracted or recombinant products, and artificial agents that can be used against OS, inflammation, and neurodegeneration were identified. After presenting the most common neurodegenerative diseases and mentioning some of the basic mechanisms that lead to neuronal loss, this paper presents up to date information that could encourage the development of better therapeutic strategies.Conclusions: This review shares the new potential pharmaceutical and not pharmaceutical options that have been recently introduced regarding OS and inflammatory responses in neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Although educators frequently act as if curricula are as standardized as drug doses (300 mg of PBL t.i.d.), such is not the case. As a case in point, at its inception, Problem Based Learning was hailed as a major curriculum innovation, with the promise of enormous gains in learning outcomes. Very quickly, ecclesiastical debates arose as what was true PBL and what was "modified PBL". Ironically, systematic reviews conducted fairly early in its evolution showed that the gains in learning outcome from PBL were neither large nor uniform (Vernon and Blake in Acad Med 68:550-563, 1993), and the most consistent finding was greater student satisfaction. In this paper, we review five decades of experience with the first PBL curriculum at McMaster. We point out how the curriculum has evolved, both theoretically and practically, in response to external influences, based both on empirical evidence and practical demands. We describe these changes in four broad domains-theoretical rationale, the curriculum, assessment and admissions. [ABSTRACT FROM AUTHOR]

Summary: Many patients at increased risk of fractures do not take their medication appropriately, resulting in a substantial decrease in the benefits of drug therapy. Improving medication adherence is urgently needed but remains laborious, given the numerous and multidimensional reasons for non-adherence, suggesting the need for measurement-guided, multifactorial and individualized solutions. Introduction: Poor adherence to medications is a major challenge in the treatment of osteoporosis. This paper aimed to provide an overview of the consequences, determinants and potential solutions to poor adherence and persistence to osteoporosis medication. Methods: A working group was organized by the European Society on Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal diseases (ESCEO) to review consequences, determinants and potential solutions to adherence and to make recommendations for practice and further research. A systematic literature review and a face-to-face experts meeting were undertaken. Results: Medication non-adherence is associated with increased risk of fractures, leading to a substantial decrease in the clinical and economic benefits of drug therapy. Reasons for non-adherence are numerous and multidimensional for each patient, depending on the interplay of multiple factors, suggesting the need for multifactorial and individualized solutions. Few interventions have been shown to improve adherence or persistence to osteoporosis treatment. Promising actions include patient education with counselling, adherence monitoring with feedback and dose simplification including flexible dosing regimen. Recommendations for practice and further research were also provided. To adequately manage adherence, it is important to (1) understand the problem (initiation, implementation and/or persistence), (2) to measure adherence and (3) to identify the reason of non-adherence and fix it. Conclusion: These recommendations are intended for clinicians to manage adherence of their patients and to researchers and policy makers to design, facilitate and appropriately use adherence interventions. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of oral Chinese herbal medicine (OCHM) for heart failure with preserved ejection fraction (HFpEF). Methods: PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Chinese Biological Medicine Database (CBM), Wanfang Database, Chongqing VIP Information (VIP) and China National Knowledge Infrastructure (CNKI) were searched for appropriate articles from respective inceptions until June 3, 2018. Randomized controlled trials (RCTs) investigating the effectiveness of OCHM for the patients with HFpEF were eligible. Quality assessment was performed by employing the Cochrane Risk of Bias assessment tool. Papers were independently reviewed by two reviewers and analyzed using Cochrane software Revman 5.3. Dichotomous data were analyzed by relative risk (RR) with a 95% confidence interval (CI), while continuous variables were analyzed by using mean difference (MD) with 95% CI for effect size. Results: A total of 16 RCTs involving 1,320 participants were identified. Fourteen of the trials used conventional Western medicine (CWM) as the control, the control of 1 trial was no treatment, and another was placebo. Three of the trials served Chinese patent medicine (CPM) as interventions, and other OCHM were Chinese medicine decoctions (CMDs). Only limited evidence showed experimental group with OCHM may get better effect on brain natriuretic peptide (BNP: MD -37.29, 95% CI -53.08 to -21.50, P<0.00001) or N terminal pro B type natriuretic peptide (NT-proBNP: MD -236.04, 95% CI -356.83 to -115.25, P=0.0001), Minnesota Living with Heart Failure questionnaire (MLHFQ, MD -9.94, 95% CI -16.77 to -3.11, P=0.004), but the results had high heterogeneities. With concerns on 12 of 16 trials, the meta-analysis found that the adjuvant therapy of OCHM might be more effective in increasing overall response rate (RR 1.17, 95% CI 1.11 to 1.24, P<0.00001), when compared with CWM alone. Subgroup meta-analysis between CPMs and CMDs showed that the two CPMs may have more therapeutic effect on MLHFQ, but not on NT-proBNP, and CMD came to the opposite conclusion. No significant differences were found between experimental groups and control groups on 6-min walk test (6MWT). Adverse events, such as more defecation, weakness, cardiopalmus, edema, cough and hypotension, were mild in all groups and disappeared after the easement of pharmacological intervention. Conclusions: Due to the insufficient quality of trials that were analyzed, it is not appropriate to confirm or deny the potency of OCHMs in treating HFpEF at the present time. More rigorously designed RCTs focusing on primary endpoints with long-term follow-up are warranted to validate the effect of OCHMs for patients with HFpEF. [ABSTRACT FROM AUTHOR]

In France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox®. In March 2017, at the request of French authorities, a new formulation of Levothyrox® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation. [ABSTRACT FROM AUTHOR]

Administration of intravenous contrast media to children is a routine practice at many clinical imaging centers, that can involve special considerations. In this paper, we provide practical information to facilitate optimal performance and oversight of this task. We provide targeted screening questions that can help to identify high-risk pediatric patients for both iodine-based and gadolinium-based intravenous contrast media administration. These include children at risk for allergic-like reactions, thyroid dysfunction, contrast-induced nephropathy, and nephrogenic systemic fibrosis. We make recommendations for addressing "yes" responses to screening questions using risk stratification schema that are specific to children. We also present criteria for selecting children for premedication prior to intravenous contrast administration, and suggest pediatric regimens. Additionally, we discuss practical nuances of intravenous contrast media administration to children and provide a quick-reference table of appropriate treatments with pediatric dosages for adverse contrast reactions. [ABSTRACT FROM AUTHOR]

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.'s work, texts of Internal and Emergency Medicine, and electronic resources were reviewed for atropine dosing recommendations. For comparison, recommendations were assessed using the same mean dose (23.4 mg) and the highest dose (75 mg) of atropine as used in the original paper. Recommendations were also compared with the dosing regimen from the World Health Organization (WHO). Thirteen of the original recommendations were updated and 15 additional references were added giving a convenience sample of 28. Sufficient information to calculate time to targeted dose was provided by 24 of these samples. Compared to 2004, current recommendations have greatly increased the speed of atropinization with 13/24 able to reach the mean and high atropine dose within 30 min compared to 1/36 in 2004. In 2004, there were 13 regimens where the maximum time to reach 75 mg was over 18 h, whereas now, there are 2. While only one recommendation called for doubling the dose for faster escalation in 2004, 15 of the 24 current works include dose doubling. In 2004, Eddleston et al. called for an evidence-based guideline for the treatment of OP poisoning that could be disseminated worldwide. Many current recommendations can adequately treat patients within 1 h. While the WHO recommendations remain slow to treat patients with OP poisoning, other authorities are close to a consensus on rapid atropinization. [ABSTRACT FROM AUTHOR]

Clinical outcomes after a first-episode of psychosis (FEP) are heterogeneous. Many patient-related factors such as gender and comorbidity have been studied to predict symptomatic outcomes. However, psychiatrist-related factors such as prescription behaviour and gender have received little attention. We assessed the relationship between patients' psychiatrists, psychosis severity and daily functioning in 201 patients remitted from an FEP for a duration of one year, treated by 18 different psychiatrists. We controlled for baseline severity, dose and type of antipsychotic medication, frequency of visits, and patients' education. Symptom severity, daily functioning, and antipsychotic drug use were assessed at baseline and at 3, 6, and, 12 months follow-up. We found that psychiatrists accounted for 9.1% of the explained variance in patients' symptom severity and 10.1% of the explained variance in daily functioning.These effects persisted even when controlling for factors such as baseline severity and the prescribed dose. The effect of prescribed dose on symptom severity and daily functioning differed between psychiatrists. Treatment centre, session frequency, and medication nonadherence were not related to symptom severity. Our results emphasize the importance of individual psychiatrist factors in symptomatic outcomes after an FEP. Further identification of psychiatrist-related factors such as the quality of therapeutic alliances and shared decision-making, may optimize psychiatrists' training with the goal of improving patient outcomes. [ABSTRACT FROM AUTHOR]

We aimed to investigate the factors associated with vitamin D deficiency and changes in 25 (OH)D levels, as well as the impact of those changes on disease activity and renal function among SLE patients. This retrospective cohort study was based on the medical records of SLE patients hospitalized between 2010 and 2021. We collected relevant information from this patient population. Logistic regression analysis was employed to determine the factors associated with vitamin D deficiency and increased 25 (OH)D levels, and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) accordingly. At baseline, among the 1257 SLE patients, the median and interquartile range of 25 (OH)D levels were 14 (9, 20) ng/ml, with 953 (75.8%) patients exhibiting 25 (OH)D deficiency (< 20 ng/ml). The presence of 25 (OH)D deficiency was found to be associated with renal involvement and a high glucocorticoid (GC) maintenance dose. Among the 383 patients who were followed up for an average of 18 months, an increase of at least 100% in 25 (OH)D levels was positively associated with a decreased GC maintenance dose and vitamin D3 supplementation, with adjusted odds ratios(OR) (95% confidence interval [CI]) of 2.16 (1.02, 4.59) and 1300 (70, 22300), respectively. Furthermore, an increased level of 25 (OH)D was significantly associated with a decrease in the Disease Activity Index 2000 score and the urinary protein/creatinine ratio. Patients with SLE have low vitamin D levels, especially those with impaired kidney function. Increased 25 (OH)D levels can be achieved through supplementation with high doses of vitamin D3 and are associated with improvements in disease activity and the urinary protein/creatinine ratio. [ABSTRACT FROM AUTHOR]

An important aspect of improving care for people with hemophilia B (HB) is developing optimal treatment strategies. Here we aimed to provide in-silico evidence, comparing the estimated optimal posology of factor IX (FIX) products to support the patient-physician decision-making process. A population pharmacokinetic (popPK) model-based assessment comparing the performance of FIX products (rFIX, rIX-FP, rFIXFc, N9-GP) was developed. PopPK analyses were used to determine a product's optimal posology to target predefined steady-state FIX activity trough levels in a hypothetical population of 10,000 people with severe HB. Model-derived optimal posologies were compared across several parameters including trough levels, proportion of patients per regimen and consumption, considering 64 hypothetical patient scenarios of different FIX trough level targets and ages. Results indicated a marked difference between FIX products estimated to achieve target trough levels, consumption and dosing frequencies. rIX-FP was associated with higher trough levels than rFIX and rFIXFc, at a lower weekly dose and administration frequency, across all age groups. N9-GP use in adolescents and adults was associated with lower consumption compared with rIX-FP. Insights from this study may be utilized by clinicians to inform decision-making, by considering the model-generated estimated optimal posologies alongside multiple clinical factors and patient preferences. [ABSTRACT FROM AUTHOR]

Aim of the Review To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. Method We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. Results Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. Conclusion Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use. [ABSTRACT FROM AUTHOR]

im of the Review To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. Method We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. Results Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. Conclusion Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use. [ABSTRACT FROM AUTHOR]

The article discusses the results of trials into potential myasthenia gravis (MG) treatment approaches that may replace or reduce steroids' need and use quantitative MG (QMG) score and prednisone dose requirement as primary or secondary outcomes. Papers discussed include trial of thymectomy in patients with non-thymomatous MG, trial to determine whether methotrexate can be used as steroid-sparing agent in MG, and trial for leflunomide treatment in corticosteroid dependent MG.

This paper presents state-of-the-art statistical methods for dose-finding experiments in first-in-man clinical studies of drugs for the treatment of malignancies. Most early-phase clinical trials are not hypothesis driven, which might be the reason why statistical considerations have been largely ignored in dose-finding studies. The standard experimental design for dose-finding clinical studies employs a rule-based, dose-escalation scheme in which escalation depends on the number of patients at a dose level who experience dose-limiting toxicity. The standard design is widely used because of its algorithm-based simplicity for clinical investigators. In the last two decades, new approaches for dose-finding have been proposed, all aiming to (i) model the toxicity of a new treatment as a percentile of the dose-toxicity relationship; (ii) minimize the number of patients treated at unacceptably high toxic dose levels; and (iii) minimize the number of patients needed to complete the study. In this paper, we describe some of these methodologies in simple terms for nonstatisticians. [ABSTRACT FROM AUTHOR]

To determine the effect of artesunate (AT) on the disposition kinetics of sulfadoxine/pyrimethamine (SP) in humans. In a randomized cross-over study, 16 healthy volunteers were given a dose of three SP tablets containing 500 mg of sulfadoxine (SDX) and 25 mg of pyrimethamine (PYR) (=SP group), while the second arm received three SP tablets + two AT tablets of 200 mg in total followed by 100 mg AT for the next 4 days (SP+AT group). Blood samples (100 μl) were collected by means of a finger prick and dried on filter paper. The blood spots were wrapped in polythene folders and stored at room temperature until analysis. The samples were assayed using high-performance liquid chromatographic methods. The peak concentration Cmax), time required to attain peak concentration (Tmax), half-life ( t ½) and area under the plasma concentration-time curve (AUC) were determined. The Cmax of SDX were 92.9 and 98.9 μg/ml for the SP and SP+AT arms, respectively; for PYR, these were 0.86 and 0.79 μg/ml, respectively. The Tmax of SDX were 10 and 8 h for the SP and SP+AT arms, respectively; for PYR, these were 4.0 and 3.0 h, respectively. The AUC0–288 of SDX were 15,840 and 18,876 μg/ml h for the SP and SP+AT arms, respectively; for PYR, they were 124 and 112 μg/ml h, respectively. The t ½ of values for SDX were 165 and 180 h for the SP and SP+AT arms, respectively; for PYR, these were 158 and 177 h, respectively. There was no statistically significant difference between the Cmax, Tmax, AUC0–288 and t ½ between the two arms ( p > 0.05). Taking AT concomitantly with SP does not have any impact in the disposition of SP. [ABSTRACT FROM AUTHOR]

Cis-diaminechloro-[2-(diethylamino) ethyl 4-amino-benzoate, N4]-chloride platinum (II) monohydrochloride monohydrate (DPR) is a monofunctional Pt triamine complex synthesized starting from cisplatin and procaine hydrochloride, characterized by a good antitumor activity coupled with low toxic effects and able to impair prenatal development of mice but at doses outside or just in the upper range of therapeutic doses. In the present paper the transplacental passage of DPR-derived Pt was investigated in CD1 mice on days 9, 13, 16 and 18 of pregnancy, 24 h after ip administration of 21 mg/kg DPR. For comparison, groups of mice were treated with an equivalent Pt-containing dose of cisplatin (10.7 mg/kg). Similarly to cisplatin, small amounts of Pt were detected in fetuses on day 9. From day 13 of gestation the concentration of DPR- and cisplatin-derived Pt increased up to the highest fetal concentrations detected on day 16. On day 18 the concentration of Pt decreased. Most importantly, on days 13-18 of pregnancy cisplatin-derived Pt was always significantly higher than that assayed after DPR administration. In addition, on day 13 of pregnancy Pt exposure of fetuses was significantly higher when dams were treated with cisplatin (AUC0.5-24= 3.40 vs. 4.95 µg·h/g). Finally, it is worth noting that serum decay of Pt after DPR or cisplatin administration in adult female mice was similar with AUC0.13-2hs of 7.5 and 6.6 µg·h/ml, respectively. When we determined the concentration of Pt into the main organs of fetuses from dams treated with either DPR or cisplatin on day 18 of gestation, we observed a different organ distribution. In fact, while the concentration of DPR-derived Pt was greater in the heart (1.08±0.30 vs. 0.78±0.35 µg/g,p<0.10), an opposite situation was found in the kidney (0.51±0.20 vs. 0.69±0.22 µg/g,p<0.05). In conclusion, our data show that DPR may pass through the placenta with an efficiency significantly lower than that of cisplatin. This finding may represent one of the possible causes of the lower embryotoxic/teratogenic effect of DPR as compared to cisplatin. [ABSTRACT FROM AUTHOR]

Background: Selection of the starting dose for the entry into humans (EIH) study is an essential first step in clinical drug development. Objectives: This paper is a review of different approaches that may be used to calculate the starting dose, presents the results of a current practice survey that reflect practice patterns at a large pharmaceutical company, and discusses selected topics related to the calculation of the starting dose. Results: The methods used in the field of oncology for cytotoxic compounds are usually derived from a dose associated with some toxicity in animals multiplied by a safety factor. In therapeutic areas other than oncology, the methods may be classified as four different approaches: (1) dose by factor methods that utilize the no observable adverse effect level (NOAEL) from preclinical toxicology studies multiplied by a safety factor; (2) the similar drug approach that may be used when clinical data are available for another compound of the same chemical class as the investigational drug; (3) the pharmacokinetically guided approach that uses systemic exposure rather than dose for the extrapolation from animal to man; and (4) the comparative approach that consists of utilizing two or more methods to estimate a starting dose and then critically comparing the results to arrive at the optimal starting dose. A "real-life" example illustrates the use of each method. Advantages, limitations, and underlying assumptions of each of the methods are discussed. The results of the survey showed that the pharmacokinetically guided approach is the most commonly used method, followed by dose by factor methods. Conclusion: The task of estimating the starting dose is moving beyond empirical methods to those that are increasingly more systematic and theory based. [ABSTRACT FROM AUTHOR]

Purpose: Wenjing decoction is a well-accepted traditional Chinese medicine for the treatment of primary dysmenorrhea in East Asia, but its clinical effectiveness and risk have not been adequately assessed. In this paper, we conducted a systematic review and meta-analysis to evaluate the efficacy of Wenjing decoction for the treatment of primary dysmenorrhea.Methods: Eight databases were used in our research: the Cochrane Library, the Web of Science, PubMed, EMBASE, the Chinese Biomedical Literature Database (CBM), the Chinese National Knowledge Infrastructure (CNKI), the Chinese Scientific Journal Database, and the Wan-fang Database. The following search terms were used: (Wenjing decoction OR Wenjing formula OR Wenjing tang) AND (primary dysmenorrhea OR dysmenorrhea OR painful menstruation) AND (randomized controlled trial). No language limitation was used.Results: A total of 18 studies, including 1736 patients, were included in the meta-analysis. Wenjing decoction was shown to be significantly better than nonsteroidal anti-inflammatory drugs for the improvement of primary dysmenorrhea according to the clinical effective rate (RR 1.41, 95% CI 1.24-1.61), the visual analogue scale (MD -1.77, 95% CI -2.69 to -0.84), and the pain scale for dysmenorrhea (MD -1.81, 95% CI -2.41 to -1.22).Conclusions: The results supported the clinical use of Wenjing decoction for the treatment of primary dysmenorrhea. However, the quality of the evidence for this finding was low due to a high risk of bias in the included studies. Therefore, well-designed randomized controlled trials are still needed to further evaluate the efficacy of Wenjing decoction for the treatment of primary dysmenorrhea. [ABSTRACT FROM AUTHOR]

Vaccination is a critical component for ensuring the ongoing health HIV-infected adults. Since this group may have reduced immune responses and shorter durations of protection post-vaccination, HIV-specific guidelines have been published. This review article provides a comprehensive discussion of the current guidelines and evidence-based data for vaccinating HIV-infected adults, including data on dosing schedules, immunogenicity studies, and safety. In the current paper, part II of the review, live vaccines, as well as vaccines for travelers and specific occupational groups, will be discussed. [ABSTRACT FROM AUTHOR]

Following the publication of our paper regarding a population-based model of doxorubicin pharmacokinetics in children in Clinical Pharmacokinetics last year (Voller et al. 54:1139-1149, 2015), we have received many inquiries on the practical clinical consequences of this model; however, a population-based model is only one of the aspects to be taken into account when developing dosing algorithms. In addition, any new method of dose calculation would need clinical validation and, subsequently, a new clinical trial. However, such a trial, especially with regard to burden to the children involved, requires optimal preparation and the selection of the best hypotheses. The European Paediatric Oncology Off-Patent Medicines Consortium (EPOC), represented by the authors, would therefore like to initiate an interdisciplinary discussion on the clinical and pharmacological goals for dose calculation. This current opinion summarizes the existing knowledge on the pharmacokinetics and pharmacodynamics of doxorubicin. Our aim was to define the clinical needs as precisely as possible, with the intention of stimulating discussion between the clinical pediatric oncologist and the pediatric pharmacologist. By doing so, we hope to define surrogates for best practice of a common doxorubicin dose in children. The intent is for a trial to validate a rational dose calculation rule, leading to a regulatory process and subsequent labeling. [ABSTRACT FROM AUTHOR]

Chemical reaction networks are powerful tools for modeling cell signaling and its disruptions in diseases like cancer. Realistic chemical reaction networks involve hundreds of proteins and reactions, resulting in a model depending on a consistently large number of kinetic parameters. Since finely calibrating all the parameters would require an unrealistic amount of data, proper sensitivity analysis is required to identify a subset of parameters for which fine tuning is needed and thus provide a fundamental tool for the qualitative analysis of the network. We present a multidisciplinary approach for computing a set of synthetic sensitivity indices. These indices rank the kinetic parameters, based on the impact that errors in their values would have on the protein concentration profile at equilibrium. Our tests on a chemical reaction network devised for colorectal cells demonstrate the effectiveness of the considered sensitivity indices in different scenarios including in-silico drug dosage and novel therapeutic target discovery. The Matlab code for computing the synthetic sensitivity indices and the data concerning the network for colorectal cells are available at https://github.com/theMIDAgroup/CRN_sensitivity. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a common cause of brain metastases, approximately 40% of patients with lung cancer will develop brain metastases at some point during their disease. Hypofractionated stereotactic radiotherapy (HSRT) has been demonstrated to be effective in controlling limited brain metastases. However, there is still no conclusive on the optimal segmentation of HSRT. The aim of our study was to explore the correlation between the HSRT dosage and its treatment effect and toxicity. Methods: A retrospective analysis was conducted on patients with non-small cell lung cancer (NSCLC) brain metastasis at Hangzhou Cancer Hospital from 1 January 2019 to 1 January 2021. The number of brain metastases did not exceed 10 in all patients and the number of fractions of HSRT was 5. The prescription dose ranges from 25 to 40 Gy. The Kaplan–Meier method was used for estimation of the localised intracranial control rate (iLC). Adverse radiation effects (AREs) were evaluated according to CTCAE 5.0. This study was approved by the Institutional Ethics Review Board of the Hangzhou Cancer Hospital (#73/HZCH-2022). Results: Forty eligible patients with a total of 70 brain metastases were included in this study. The 1-year iLC was 76% and 89% in the prescribed dose ≤ 30 Gy and > 30 Gy group, respectively (P < 0.05). For patients treated with HSRT combined with targeted therapy, immunotherapy and chemotherapy, the 1-year iLC was 89%, 100%, and 45%, respectively. No significant associations were observed between the number, maximum diameter, location, and type of pathology of brain metastases. The rate of all-grade AREs was 33%. Two patients who received a total dose of 40 Gy developed grade 3 headache, the rest of the AREs were grade 1–2. Conclusions: Increasing the prescription dose of HSRT improves treatment effect but may also exacerbate the side effects. Systemic therapy might impact the iLC rate, and individualized treatment regimens need to be developed. [ABSTRACT FROM AUTHOR]

A long-term prescription of tetracyclines in course dosages is widely applicable for treating bacterial infections such as malaria, cholera, and syphilis. This work aims to optimize the sensing method of tetracyclines using modified upconversion nanoparticles conjugated with tetracycline aptamers in a microtiter plate method. A fluorescence-based spectrophotometer is used to optimize the concentration of tetracyclines relative to their fluorescence quenching readings. The decrease in fluorescence intensity of upconversion nanoparticles when exposed to tetracyclines indicates a possible enhancement in detection sensitivity, with an estimated increase of around ~ 0.1 nM concentration. With the help of tetracycline aptamer conjugated upconversion nanoparticles, we developed a low toxic, susceptible, cost-effective, and simple method for tetracyclines detection. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the benefit-risk of 3 commonly used Chinese medicine injections, Aidi Injection (ADI), Cinobufagin Injection (CINI) and Compound Kushen Injection (CKI), in the treatment of primary liver cancer (PLC), so as to provide a reference for clinical decision-making. Methods: Randomized controlled trials (RCTs) of ADI, CINI and CKI in the treatment of PLC published in the databases of China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, SinoMed, PubMed, Cochrane Library, and Web of Science were retrieved from January 2020 to October 2022. The data of benefit and risk indicators were combined to obtain the effect value. The multi-criteria decision analysis (MCDA) model was applied to build the decision tree. The benefit value, risk value and benefit risk value of the 3 injections in PLC treatment were calculated. Monte Carlo simulation was carried out to calculate the 95% confidence interval and probability of differences among the 3 injections, so as to optimize the evaluation results. Results: A total of 71 RCTs were included. The benefit values of ADI, CINI and CKI combined with transcatheter arterial chemoembolization (TACE) were 42, 38 and 36, respectively. The risk values were 42, 25 and 37, respectively. The benefit risk values were 42, 31 and 37, respectively. The benefit risk differences of ADI vs. CINI, ADI vs. CKI, and CKI vs. CINI were 11 (−0.86, 17.75), 5 (−5.01, 11.09), and 6 (−1.87, 12.63), respectively. The probability that ADI superior to CINI, ADI superior to CKI, and CKI superior to CINI was 96.26%, 77.27%, and 92.62%, respectively. Conclusion: Based on the results of MCDA model, CINI combined with TACE has the greatest risk in the treatment of the PLC. Considering the efficacy and safety, the possible priority of the 3 Chinese medicine injections combined with TACE in the treatment of PLC is ADI, CKI and CINI. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to provide clinicians with important considerations and caveats when evaluating published literature on medication dosing in obese subjects, since much of this literature involves short-term pharmacokinetic or pharmacodynamic studies that are not designed to look at clinically important outcomes. A secondary objective is to suggest improvements in the reporting of dosing information derived from clinical studies and incorporated into product information labeling that should help clinicians design medication-specific dosing regimens for patients with obesity. Data sources included published studies, review papers, and clinical practice guidelines concerning drug dosing of subjects with obesity. Medication dosing recommendations in product labeling typically are derived from studies of normal healthy volunteers and patients with single-system disease states or patients in a specialized setting (e.g. operating room, intensive care unit). Even in studies with relatively large sample sizes there are often relatively few subjects with extremes of body composition such as patients with a body mass index (BMI) greater than 40 kg/m, so the appropriateness of labeled dosing information for these subjects is particularly ill-defined. Investigations of medication labeling information have demonstrated the inadequacy of this information for dosing patients of more extreme body size. Clinical investigations of drugs should be designed and the results reported in a manner that allows for meaningful recommendations for drug dosing in patients with varying degrees of obesity. Until and when such studies are routinely performed, there are steps that can be taken by the pharmaceutical industry, clinicians, and governmental agencies to help insure optimal drug dosing in obesity. [ABSTRACT FROM AUTHOR]

This paper is aimed to study the clustering method for Chinese medicine (CM) medical cases. The traditional K-means clustering algorithm had shortcomings such as dependence of results on the selection of initial value, trapping in local optimum when processing prescriptions form CM medical cases. Therefore, a new clustering method based on the collaboration of firefly algorithm and simulated annealing algorithm was proposed. This algorithm dynamically determined the iteration of firefly algorithm and simulates sampling of annealing algorithm by fitness changes, and increased the diversity of swarm through expansion of the scope of the sudden jump, thereby effectively avoiding premature problem. The results from confirmatory experiments for CM medical cases suggested that, comparing with traditional K-means clustering algorithms, this method was greatly improved in the individual diversity and the obtained clustering results, the computing results from this method had a certain reference value for cluster analysis on CM prescriptions. [ABSTRACT FROM AUTHOR]

Over the past two decades, there has been growing concern over the lack of proper medication for children. This review attempts to evaluate the current progress of EU Pediatric Regulation made since 2007. The lack of properly evaluated pediatric medication has for long been a source of concern in the European Union. The drugs that were used in the past were often not properly evaluated, and dosage was arbitrarily calculated. Therefore, it was necessary to establish the Pediatric Regulation (EC no. 1901/2006) in the EU which would mandate research for pediatric drugs. Current legislations in place not only require mandatory research by pharma industry but also have guidelines to direct the quality of pediatric research performed. The main aim of this regulation was to advance high-quality research and development of pediatric drugs, thereby increasing the availability of safe and effective drugs for children. It also aimed to improve the information available on existing pediatric drugs. It has been 9 years since the pediatric regulation was framed. The pharma industry now sees pediatric research as an integral process of development. Drug companies which develop plans for a new drug, new form of drug, new indication, or new route of administration for adults are obliged to integrate in their development plan similar research for pediatric populations as well.Conclusion: It is hoped that the implementation of the current legislation will be reflected better in the future by the marketing of better and safer drugs for the pediatric population. The upcoming assessment to the European Commission in 2017 will further inform us on the impact after 10 years implementation of the legislation. What is Known: • The lack of properly evaluated pediatric medication has for long been a source of concern in the European Union. • Therefore, it was necessary to establish the EU Pediatric Regulation which would mandate research for pediatric drugs. What is New: • It has been 9 years since the pediatric regulation was framed, and the teething problems are slowly being overcome and the regulation is being used with increasing confidence. • As the Regulation is due for revision in 2017, this paper gives a current perspective on the impact of the regulation on availability and access to medicine for children. [ABSTRACT FROM AUTHOR]

The recent introduction of the first FDA approved 3D-printed drug has fuelled interest in 3D printing technology, which is set to revolutionize healthcare. Since its initial use, this rapid prototyping (RP) technology has evolved to such an extent that it is currently being used in a wide range of applications including in tissue engineering, dentistry, construction, automotive and aerospace. However, in the pharmaceutical industry this technology is still in its infancy and its potential yet to be fully explored. This paper presents various 3D printing technologies such as stereolithographic, powder based, selective laser sintering, fused deposition modelling and semi-solid extrusion 3D printing. It also provides a comprehensive review of previous attempts at using 3D printing technologies on the manufacturing dosage forms with a particular focus on oral tablets. Their advantages particularly with adaptability in the pharmaceutical field have been highlighted, which enables the preparation of dosage forms with complex designs and geometries, multiple actives and tailored release profiles. An insight into the technical challenges facing the different 3D printing technologies such as the formulation and processing parameters is provided. Light is also shed on the different regulatory challenges that need to be overcome for 3D printing to fulfil its real potential in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

The paper presents an analytical method for quantification of low molecular weight (LMW) selenium compounds in human plasma based on liquid chromatography inductively coupled plasma mass spectrometry (LC-ICP-MS) and post column isotope dilution-based quantification. Prior to analysis, samples were ultrafiltrated using a cut-off value of 3000 Da. The method was validated in aqueous solution as well as plasma using standards of selenomethionine (SeMet), Se-methylselenocysteine (MeSeCys), selenite, and the selenosugar Se-methylseleno- N-acetylgalactosamine (SeGal) for linearity, precision, recoveries, and limits of detection and quantitation with satisfactory results. The method was applied for analysis of a set of plasma samples from cancer patients receiving selenite treatment in a clinical trial. Three LMW selenium compounds were observed. The main compounds, SeGal and selenite were tentatively identified by retention time matching with standards in different chromatographic systems, while the third minor compound was not identified. The identity of the selenosugar was verified by ESI-MS-MS product ion scanning, while selenite was identified indirectly as the glutathione (GSH) reaction product, GS-Se-SG. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Fosfomycin (FOS) administered intravenously has been recently rediscovered for the treatment of systemic infections due to multidrug-resistant bacteria. Its pharmacokinetic properties suggest a time-dependent dosing schedule with more clinical benefits from prolonged (PI) or continuous infusion (CI) than from intermittent infusion. We revised literature concerning PI and CI FOS to identify the best dosing regimen based on current evidence. We performed a MEDLINE/PubMed search. Ninety-one studies and their pertinent references were screened. Seventeen studies were included in the present review. The activity of FOS against Gram-negative and Gram-positive bacteria was evaluated in fourteen and five studies, respectively. Six studies evaluated FOS activity in combination with another antibiotic. Daily dosing of 12, 16, 18 or 24 g, administered with different schedules, were investigated. These regimens resulted active against the tested isolates in most cases. Emergence of resistant isolates has been shown to be preventable through the coadministration of another active antibiotic. FOS is a promising option to treat systemic infections caused by multidrug-resistant bacteria. Coadministration with another active molecule is required to prevent the emergence of resistant bacterial strains. The results of our review suggest that a therapeutic regimen including a loading dose of FOS 8 g followed by a daily dose of 16 g or 24 g CI could be the best therapeutic approach for patients with normal renal function. The dosing regimens in patients with renal insufficiency and CI or PI superiority compared with intermittent infusion in clinical settings should be further investigated. [ABSTRACT FROM AUTHOR]

Microdosing studies allow clinical investigation of pharmacokinetics earlier in drug development, before all high-dose safety concerns have been sorted out. Furthermore, microdosing allows inclusion of target groups that are inadmissible in high-dose phase I trials. A potential concern when considering a microdosing study is that a particular drug candidate may display non-linear pharmacokinetics. Saturation of, for example, membrane transport or metabolism at exposure levels between the microdose and therapeutic dose may limit the predictivity of high-dose pharmacokinetics from microdose observations. Guidance on the likelihood of appreciable non-linear pharmacokinetics based on preclinical information can be helpful in staging the clinical phase and the place of microdosing in it. We present a decision tree that evaluates concerns about non-linearities raised in the preclinical phase and their potential impact on the proportionality between microdose and intended therapeutic dose as predicted from preclinical information. The expected maximum concentrations at relevant sites are estimated by non-compartmental methods. These are compared with dissolution, Michaelis constants for active or enzymatic processes, and binding protein concentrations to assess the potential saturation of the processes below therapeutic doses. The decision tree was applied to ten published cases comparing microdose and therapeutic dose pharmacokinetics, for which concerns about non-linear pharmacokinetics were raised a priori. The decision tree was able to discriminate cases showing substantial non-linearities from cases displaying dose-proportional pharmacokinetics. The recommendations described in this paper may be useful in deciding whether a microdosing study is a sensible option to gain early insight in clinical pharmacokinetics of drug candidates. [ABSTRACT FROM AUTHOR]

Purpose: Busulfan (Bu) exposure is critical for efficacy and safety. Body weight (BW), or adjusted ideal body weight (AIBW)-based dosing (WBD) algorithm, has been used in hematopoietic stem cell transplantation (HSCT). A recently completed phase 2 study revealed that 33.6 % of the subjects were under-, or over-exposed, with this WBD algorithm. This paper was to investigate Bu dosing algorithm in an attempt to improve the suboptimal Bu exposure. Methods: Population PK modeling was conducted using the data from 207 patients. Dosing algorithm was developed based on derived covariate model of CL. Model-based simulation was conducted to assist test PK study design. A simplified CL estimation method was proposed based on the PK structure model for Bu. Results: A one-compartment structure model adequately described the PK profile of Bu following an IV infusion. BSA best described the inter-individual variability of CL. The proposed dosing algorithm was dose (mg) = (31.7 × BSA − 11.6) × target AUC [µM min]/1,000. With this dosing algorithm, 14.3 % patients could be under- or over-exposed. A test PK study with reduced study duration and three PK samples can provide as nearly as good an estimate of CL compared to 12 PK samples on two different occasions. Conclusion: The proposed dosing algorithm can significantly improve the sub-exposure of Bu. A shortened test PK study duration with reduced PK samples can provide as near as good estimate for Bu CL. A simplified CL estimation method is valid. [ABSTRACT FROM AUTHOR]

Objective: To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative breast cancer (TNBC). Methods: Murine-derived triple-negative mammary carcinoma cell line, 4T1 cells, was cultured and inoculated into mouse mammary glands. Sixty-six mice were randomly assigned into 6 groups (n=11 in ench): naïve, control, LD 4HF (low dose 4HF), HD 4HF (high dose 4HF), LD 4HF + D (low dose and doxorubicin), and D (doxorubicin). Apart from the naïve group, each mouse received subcutaneous inoculation with 5 × 105 4T1 cells resuspended in 100 µL of normal saline in the mammary fat pads. Starting from the day of tumor cell inoculation, tumors were grown for 6 days. The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF, respectively. The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin (5 mg/kg). The D group received weekly intraperitoneal injections of doxorubicin (5 mg/kg). The treatment naïve mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week. The control group received daily oral gavage of 0.2 mL double-distilled water. The treatment period was 30 days. At the end of treatment, mice organs were harvested to analyze immunological activities via immunophenotyping, gene and multiplex analysis, histological staining, and gut microbiota analysis. Results: Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens (P<0.05), altered the hypoxia and overall immune lymphocyte landscape, and manipulated gut microbiota to favor the anti-tumor immunological activities. Moreover, immunosuppressive genes, cytokines, and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated (P<0.05). 4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response (P<0.05). Conclusion: The above results provide evidence for evaluating the immune regulating mechanisms of 4HF in breast cancer and support its clinical significance in its potential as an adjunctive therapeutic agent or immune supplement. [ABSTRACT FROM AUTHOR]