GAPPS (Grading and Assessment of Pharmacokinetic-Pharmacodynamic Studies) a critical appraisal system for antimicrobial PKPD studies - development and application in pediatric antibiotic studies

Introduction: There are limited data on optimal dosing of antibiotics in different age groups for neonates and children. Clinicians usually consult pediatric formularies or online databases for dose selection, but these have variable recommendations, are usually based on expert opinion and are not graded based on the existing pharmacokinetic-pharmacodynamic (PKPD) studies. We describe here a potential new tool that could be used to grade the strength of evidence emanating from PKPD studies. Areas covered: A scoring system was developed (GAPPS tool) to quantify the strength of each PK assessment and rate the studies quality in already published articles. GAPPS was evaluated by applying it to pediatric PKPD studies of antibiotics from the 2019 Essential Medicines List for children (EMLC), identified through a search of PubMed. Expert opinion: Evidence for most antibiotic dose selection decisions was generally weak, coming from individual PK studies and lacked PKPD modeling and simulations. However, the quality of evidence appears to have improved over the last two decades. Incorporating a formal grading system, such as GAPPS, into formulary development will provide a transparent tool to support decision-making in clinical practice and guideline development, and guide PKPD authors on study designs most likely to influence guidelines

A framework for Operational Security Metrics Development for industrial control environment

Security metrics are very crucial towards providing insights when measuring security states and susceptibilities in industrial operational environments. Obtaining practical security metrics depend on effective security metrics development approaches. To be effective, a security metrics development framework should be scope-definitive, objective-oriented, reliable, simple, adaptable, and repeatable (SORSAR). A framework for Operational Security Metrics Development (OSMD) for industry control environments is presented, which combines concepts and characteristics from existing approaches. It also adds the new characteristic of adaptability. The OSMD framework is broken down into three phases of: target definition, objective definition, and metrics synthesis. A case study scenario is used to demonstrate an instance of how to implement and apply the proposed framework to demonstrate its usability and workability. Expert elicitation has also be used to consolidate the validity of the proposed framework. Both validation approaches have helped to show that the proposed framework can help create effective and efficient ICS-centric security metrics taxonomy that can be used to evaluate capabilities or vulnerabilities. The understanding from this can help enhance security assurance within industrial operational environments

Trends in drinking habits among adolescents in the Baltic countries over the period of transition: HBSC survey results, 1993–2002

BACKGROUND: The Baltic countries – Estonia, Latvia, and Lithuania – are considered to be an example of regional homogeneity over the period of transition. The World Health Organization cross-national study on Health Behavior in School-aged Children (HBSC) allows a comparison and time trends analysis of behavioral patterns among adolescents in this region. The aim of this study was to estimate the prevalence and trends of alcohol consumption and drunkenness among adolescents of Estonia, Latvia, and Lithuania in 1993/94, 1997/98, and 2001/02. METHODS: Representative samples of 5286 boys and 6485 girls aged 15 from Estonia, Latvia, and Lithuania were surveyed in 1993/94, 1997/98, and 2001/02 school-year within the framework of HBSC study. The standardized survey methods were applied. The research focused on the following outcome variables: i) frequency of drinking beer, wine, and spirits; and ii) frequency of drunkenness. The same wording of questions on the consumption of alcohol was retained in each survey. RESULTS: Beer was the most frequently used alcoholic beverage across the Baltic countries among adolescents. The rate of weekly drinking of any alcoholic beverage increased considerably during the eight years of observation, especially among Estonian and Lithuanian students. In 2001/02, 25% of boys and 12.5% of girls have reported drinking alcohol at least weekly. The rate of regular alcohol drinking was two times higher in boys, while irregular drinking was more prevalent in girls. Two or more episodes of drunkenness in the lifespan were reported by 30% of boys and 15% of girls in 1993/94 and by 52% of boys and 36% of girls in 2001/02. The use of alcoholic beverages was related to the perceived family wealth: the students from the families perceived by them as wealthy were more likely to drink weekly as compared to the students from the families perceived by them as not wealthy. CONCLUSION: Over the period between 1993 and 2002 the prevalence of alcohol consumption among adolescents increased considerably across the Baltic countries. The efforts of dealing with this problem should employ a combination of measures, including the strategies relevant for the period of transition

Population Pharmacokinetic Study of Benzylpenicillin in Critically Unwell Adults

Pharmacokinetics are highly variable in critical illness, and suboptimal antibiotic exposure is associated with treatment failure. Benzylpenicillin is a commonly used beta-lactam antibiotic, and pharmacokinetic data of its use in critically ill adults are lacking. We performed a pharmacokinetic study of critically unwell patients receiving benzylpenicillin, using data from the ABDose study. Population pharmacokinetic modelling was undertaken using NONMEM version 7.5, and simulations using the final model were undertaken to optimize the pharmacokinetic profile. We included 77 samples from 12 participants. A two-compartment structural model provided the best fit, with allometric weight scaling for all parameters and a creatinine covariate effect on clearance. Simulations (n = 10,000) demonstrated that 25% of simulated patients receiving 2.4 g 4-hourly failed to achieve a conservative target of 50% of the dosing interval with free drug above the clinical breakpoint MIC (2 mg/L). Simulations demonstrated that target attainment was improved with continuous or extended dosing. To our knowledge, this study represents the first full population PK analysis of benzylpenicillin in critically ill adults

Suicidal tendencies and attitude towards freedom to choose suicide among Lithuanian schoolchildren: results from three cross-sectional studies in 1994, 1998, and 2002

BACKGROUND: Suicidal behaviour is increasingly becoming a phenomenon associated with young people and an important public health issue in Lithuania. However, there are very few studies evaluating impact of young peoples' attitudes towards suicide to their suicidal behaviour. A better understanding of the relations among the variables associated with suicidal ideation and threats in the normal population of adolescents may eventually result in a better understanding of the more serious forms of adolescent suicidal behaviour. The aim of the present study was to evaluate prevalence of suicidal tendencies among Lithuanian schoolchildren and to estimate its association with an attitude towards suicide in 1994 – 2002. METHODS: Three country representative samples of schoolchildren, aged 11, 13 and 15, were surveyed in 1994 (n = 5428), 1998 (n = 4513), and 2002 (n = 5645) anonymously in conformity with the methodology of the World Health Organization Cross – National study on Health Behaviour in School-aged Children (HBSC). RESULTS: About one third of respondents reported about suicidal ideation, plans or attempts to commit suicide. In the study period of eight years, the percentage of adolescents who reported sometime suicidal ideation decreased but the percentage of adolescents who declared serious suicidal behaviour remained on the same high level (8.1%, 9.8% and 8.4% correspondingly in 1994, 1998 and 2002). Moreover, the number of suicidal attempts changed from 1.0% in 1994 to 1.8% in the year 1998 and to 1,7% in the year 2002. The schoolchildren's attitude towards suicide became more agreeable: 36.6%, 41.9% and 62.5% of respondents, correspondingly in 1994, 1998 and 2002, answered that they agree with a person's freedom to make a choice between life and suicide. A multiple logistic regression analysis with low level of suicidality and high level of suicidality versus non suicidal behaviour as dependent variables for gender, age, year of the survey and attitude towards freedom to choose suicide as independent variables approved a significant association between studied covariates over the entire study period. CONCLUSION: Suicidal tendencies are quite frequent among Lithuanian adolescents. An increasing number of schoolchildren are expressing an agreeable attitude towards suicide. The approving attitude towards suicide among adolescents correlates with suicidal ideation and behaviour

Joint UK societies' 2019 consensus statement on renal denervation

Improved and durable control of hypertension is a global priority for healthcare providers and policymakers. There are several lifestyle measures that are proven to result in improved blood pressure (BP) control. Moreover, there is incontrovertible evidence from large scale randomised controlled trials (RCTs) that antihypertensive drugs lower BP safely and effectively in the long-term resulting in substantial reduction in cardiovascular morbidity and mortality. Importantly, however, evidence is accumulating to suggest that patients neither sustain long-term healthy behaviours nor adhere to lifelong drug treatment regimens and thus alternative measures to control hypertension warrant further investigation. Endovascular renal denervation (RDN) appears to hold some promise as a non-pharmacological approach to lowering BP and achieves renal sympathectomy using either radiofrequency energy or ultrasound-based approaches. This treatment modality has been evaluated in clinical trials in humans since 2009 but initial studies were compromised by being non-randomised, without sham control and small in size. Subsequently, clinical trial design and rigour of execution has been greatly improved resulting in recent sham-controlled RCTs that demonstrate short-term reduction in ambulatory BP without any significant safety concerns in both medication-naïve and medication-treated hypertensive patients. Despite this, the joint UK societies still feel that further evaluation of this therapy is warranted and that RDN should not be offered to patients outside of the context of clinical trials. This document reviews the updated evidence since our last consensus statement from 2014 and provides a research agenda for future clinical studies.This article is freely available online via Open Access. Click on the Publisher URL to access the full-text via the publisher's site

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Mobiles Rohrverlegesystem Schlussbericht

Available from TIB Hannover: F04B1601+a / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEBundesministerium fuer Wirtschaft und Arbeit, Bonn (Germany)DEGerman