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There is limited evidence for the acceptability of various drug formulations holding the potential to improve medicines administration to children. Suitable formulations need to meet the requirements of pediatric patients. Previous studies have demonstrated the acceptance of mini-tablets. Oblong tablets may carry more active ingredient content per unit than mini-tablets and could be an important alternative when the drug substance requires administration of higher doses. The primary objective was to demonstrate non-inferiority of acceptability of oblong tablets in comparison to 3 ml glucose syrup in children aged 1 to 5 years. Secondary objectives were investigation of acceptability, swallowability and palatability of mini-tablets, oblong tablets and glucose syrup in children between 1 and 5 years.An open, randomized, single dose two-way cross-over design in two parallel study arms was applied. 280 children were stratified to one of five age groups and randomized to receiving one oblong tablet (2.5 × 6 mm) in comparison either to 3 ml glucose syrup or to three mini-tablets (2 × 2 mm). Acceptability and swallowability were assessed according to pre-defined evaluation criteria. The application of the formulations was video documented to evaluate the palatability.As primary objective, non-inferiority was observed regarding acceptability of the oblong tablet compared to syrup in all age groups (84.4% vs 80.1%, difference 4,29% points with 95% CI of -3.00%,11.57%). For swallowability, superiority of the oblong tablet compared to syrup could be shown (74.5% vs. 53.2%, difference 21.26% points, 95% CI of 11.29%, 31.23%). Regarding palatability,10% of children demonstrated unpleasant reaction after intake of the oblong tablet or mini-tablets as graded by both raters, however, in contrast up to 40% of children after intake of syrup.Oblong tablets are a promising, safe alternative to liquid drug formulations and administration of multiple mini-tablets in children.

Introduction A medicine’s acceptability is likely to have significant impact on pediatric adherence. The importance is underlined in EMA and FDA guidance on this topic where investigation of acceptability is stated as a regulatory expectation. Demonstrating acceptability can be challenging given there is no globally recognized definition and no standardized testing methodology or assessment criteria. Palatability and swallowability are generally recognized as important elements of acceptability, and this work proposes a definition of acceptability using these elements to give a composite endpoint for acceptability for pediatric subjects across all age ranges. Methods This composite acceptability endpoint is based on validated assessment methods for swallowability and palatability in children of different age groups using different galenic placebo formulations, in line with criteria proposed by EMA for assessing acceptability in children from newborn to 18 years of age. Data from two studies investigating mini-tablets, oblong tablets, orodispersible films, and syrup were analyzed to establish the validity, expediency, and applicability of the suggested composite acceptability assessment tool. Results The new composite endpoint is an efficient and suitable way to distinguish preferences of oral formulations: Mini-tablets and oblong tablets had significantly better acceptability than syrups and orodispersible films. Conclusion Since the suggested acceptability criteria takes both swallowability and palatability into account as composite endpoint, it is highly sensitive to detect acceptability differences between oral formulations. It is a well-defined valid approach, which meets regulatory requirements in an appropriate and comprehensive manner and may in future serve as a pragmatic, standardized method to assess and compare acceptability of pediatric formulations with active substances.

Aim To describe the methods and feasibility of the nutritional intervention carried out within the SPRINTT Randomized cotrolled trial. We also illustrate how nutrition interventionists identified participants at risk of malnutrition and the lessons learnt from the nutrition intervention. Findings SPRINTT nutrition intervention was well-received by the majority of the participants. It was mainly carried out using tailored nutrition counselling, but also other means of delivering the intervention were successfully used. Compared with a standard nutrition prescription, an individualized protocol to diagnose malnutrition and follow-up by tailored nutrition counselling helped achieve nutritional targets more effectively in spite of diversity of population in nutritional habits and in some cases reluctance to accept changes. Message The SPRINTT nutrition intervention was feasible and allowed flexibility to the varying needs and cultural differences of this heterogeneous population of frail, older Europeans. It may serve as a model to educate and improve nutrition among community-dwelling older people at risk of mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4., Background The “Sarcopenia and Physical Frailty in Older People: Multicomponent Treatment Strategies” (SPRINTT) project sponsored a multi-center randomized controlled trial (RCT) with the objective to determine the effect of physical activity and nutrition intervention for prevention of mobility disability in community-dwelling frail older Europeans. We describe here the design and feasibility of the SPRINTT nutrition intervention, including techniques used by nutrition interventionists to identify those at risk of malnutrition and to carry out the nutrition intervention. Methods SPRINTT RCT recruited older adults (≥ 70 years) from 11 European countries. Eligible participants (n = 1517) had functional limitations measured with Short Physical Performance Battery (SPPB score 3–9) and low muscle mass as determined by DXA scans, but were able to walk 400 m without assistance within 15 min. Participants were followed up for up to 3 years. The nutrition intervention was carried out mainly by individual nutrition counseling. Nutrition goals included achieving a daily protein intake of 1.0–1.2 g/kg body weight, energy intake of 25–30 kcal/kg of body weight/day, and serum vitamin D concentration ≥ 75 mmol/L. Survey on the method strategies and feasibility of the nutrition intervention was sent to all nutrition interventionists of the 16 SPRINTT study sites. Results Nutrition interventionists from all study sites responded to the survey. All responders found that the SPRINTT nutrition intervention was feasible for the target population, and it was well received by the majority. The identification of participants at nutritional risk was accomplished by combining information from interviews, questionnaires, clinical and laboratory data. Although the nutrition intervention was mainly carried out using individual nutritional counselling, other assisting methods were used as appropriate. Conclusion The SPRINTT nutrition intervention was feasible and able to adapt flexibly to varying needs of this heterogeneous population. The procedures adopted to identify older adults at risk of malnutrition and to design the appropriate intervention may serve as a model to deliver nutrition intervention for community-dwelling older people with mobility limitations. Supplementary Information The online version contains supplementary material available at 10.1007/s41999-020-00438-4.

Antibiotics are among the most commonly prescribed drugs in children. Adherence to the treatment with these drugs is of the utmost importance to prevent the emergence of resistant bacteria, a global health threat. In children, medicine acceptability is likely to have a significant impact on compliance. Herein we used a multivariate approach, considering simultaneously the many aspects of acceptability to explore the drivers of oral antibiotic acceptability in children under twelve, especially in toddlers and in preschoolers. Based on 628 real-life observer reports of the intake of 133 distinct medicines, the acceptability reference framework highlighted the influence of many factors such as age and sex of patients, previous exposure to treatment, place of administration, administration device, flavor agent in excipients and active pharmaceutical ingredient. These findings from an international observational study emphasize the multidimensional nature of acceptability. Therefore, it is crucial to consider all these different aspects for assessing this multi-faceted concept and designing or prescribing a medicine in order to reach adequate acceptability in the target population.

In order to propose a more precise definition and explore how to reduce ethical losses in randomized controlled clinical trials (RCTs), we set out to identify trial participants who do not contribute to demonstrating that the treatment in the experimental arm is superior to that in the control arm. RCTs emerged mid-last century as the gold standard for assessing efficacy, becoming the cornerstone of the value of new therapies, yet their ethical grounds are a matter of debate. We introduce the concept of unnecessary participants in RCTs, the sum of non-informative participants and non-responders. The non-informative participants are considered not informative with respect to the efficacy measured in the trial in contrast to responders who carry all the information required to conclude on the treatment’s efficacy. The non-responders present the event whether or not they are treated with the experimental treatment. The unnecessary participants carry the burden of having to participate in a clinical trial without benefiting from it, which might include experiencing side effects. Thus, these unnecessary participants carry the ethical loss that is inherent to the RCT methodology. On the contrary, responders to the experimental treatment bear its entire efficacy in the RCT. Starting from the proportions observed in a real placebo-controlled trial from the literature, we carried out simulations of RCTs progressively increasing the proportion of responders up to 100%. We show that the number of unnecessary participants decreases steadily until the RCT’s ethical loss reaches a minimum. In parallel, the trial sample size decreases (presumably its cost as well), although the trial’s statistical power increases as shown by the increase of the chi-square comparing the event rates between the two arms. Thus, we expect that increasing the proportion of responders in RCTs would contribute to making them more ethically acceptable, with less false negative outcomes.

Background: Pediatric trials to add missing data for evidence-based pharmacotherapy are still scarce. A tailored training concept appears to be a promising tool to cope with critical and complex situations before enrolling the very first patient and subsequently to ensure high-quality study conduct. The aim was to facilitate study success by optimizing the preparedness of the study staff shift.Method: An interdisciplinary faculty developed a simulation training focusing on the communication within the informed consent procedure and the conduct of the complex pharmacokinetic/pharmacodynamic (PK/PD) sampling within a simulation facility. Scenarios were video-debriefed by an audio-video system and manikins with artificial blood simulating patients were used. The training was evaluated by participants' self-assessment before and during trial recruitment.Results: The simulation training identified different optimization potentials for improved informed consent process and study conduct. It facilitated the reduction of avoidable errors, especially in the early phase of a clinical study. The knowledge gained through the intervention was used to train the study teams, improve the team composition and optimize the on-ward setting for the FP-7 funded “LENA” project (grant agreement no. 602295). Self-perceived ability to communicate core elements of the trial as well as its correct performance of sample preparation increased significantly (mean, 95% CI, p ≤ 0.0001) from 3 (2.5–3.5) to four points (4.0–4.5), and from 2 (1.5–2.5) to five points (4.0–5.0).Conclusion: An innovative training concept to optimize the informed consent process and study conduct was successfully developed and enabled high-quality conduct of the pediatric trials as of the very first patient visit.

Objectives: To analyze the current situation of cross-border access to clinical trials in the EU with an overview of stakeholders' real-life experience, and to identify the needs, challenges, and potential for facilitation of cross-border access. Methods: We employed a mixed methods design. Semi-structured interviews and an online survey were conducted with a wide range of stakeholders: patient representatives, investigators/physicians, policy and regulatory experts, academic and commercial sponsor representatives, ethics committee members. Interviews underwent a framework analysis. The survey was analyzed descriptively. Results: Three hundred ninety six individuals responded to the survey. The majority were investigators/physicians (46%) and patient representatives (33%). Thirty eight individuals were interviewed. The majority were investigators/physicians (29%) and patient representatives (29%). All European regions were represented in the study. The highest response rate was received from residents of Western European countries (38% of survey respondents, 45% of interviewees), the lowest from Eastern Europe (9% of survey respondents, 5% of interviewees). The study suggested that cross-border participation in clinical trials occurs in practice, however very rarely. Ninety two percentage of survey respondents and the majority of interviewees perceived as needed the possibility to access clinical trials abroad. However, most interviewees also opined that patients ideally should not have to travel in order to access experimental treatment. The lack of access to treatment in the home country of the patient was described as the main motivation to participate in a clinical trial in another country. The logistical and financial burden for patients was perceived as the biggest challenge. Different stakeholders expressed diverging opinions regarding the allocation of financial and organizational responsibility for enabling cross-border access to clinical trials. Participants provided a number of proposals for improving the current system, which were carefully evaluated by the research team and informed future recommendations. Conclusions: Participation in clinical trials abroad is happening rarely but should be facilitated. There was a consensus on the need for reliable and accessible information regarding practical aspects, as well as multi-stakeholder, multi-national recommendations on existing options and best practice on cross-border access to clinical trials. Broader interdisciplinary research is recommended before discussing options in the EU legislative framework to enable clearly defined conditions for cross-border access to clinical trials. ispartof: Frontiers In Medicine vol:7 ispartof: location:Switzerland status: published

The evolution of postgraduate vocational education and training in pharmaceutical medicine is described alongside the growth of this scientific-medical discipline and profession for the development of new medicines. Over the past 50 years, whilst the training of competent professionals for their work has been paramount, this has paralleled the need to engage with the rapid and complex changes in R&D technologies, patient and healthcare system needs, and the ethical and regulatory obligations applied to the development of medicines throughout their lifecycle. The move from unstructured training to formal programs with syllabus, curricula and assessments for certification, has been accompanied by educational changes to outcomes-based, learner-centered, competency-based programs. The evolution of education and training along with the development of the set of 57 core competencies for professional practitioners in pharmaceutical medicine are described within the competence framework of seven domains: discovery of medicines and early development; clinical development and clinical trials; medicines regulation; drug safety and surveillance; ethics and subject protection; healthcare marketplace; communication and management. The application of the core competencies in a harmonized, international platform of education and training in medicines development at the undergraduate, postgraduate and continuing professional development levels would invigorate the potential for having a competent workforce with the intent to provide faster access to better and appropriate medicines for patients worldwide.

STUDY QUESTION Are progesterone vaginal pessaries 400 mg twice a day (bid) non-inferior to progesterone vaginal gel (90 mg) once a day (od) in the primary endpoint of clinical pregnancy rate after 38 days of luteal phase support in women undergoing in vitro fertilisation (IVF)? SUMMARY ANSWER Non-inferiority of progesterone vaginal pessaries 400 mg bid to progesterone 8% vaginal gel (90 mg od) was shown for clinical pregnancy rate after 38 days of luteal phase support. WHAT IS KNOWN ALREADY To maximise successful embryo transfer after IVF, additionally administered progesterone is used for proper endometrium transformation in the luteal phase. Vaginally administered progesterone results in adequate secretory transformation of the endometrium. STUDY DESIGN, SIZE, DURATION This multicentre, multinational, open, randomised, two-parallel group, non-inferiority Phase 3 clinical trial was carried out at 17 study sites in five European countries (Belgium, Bulgaria, Czech Republic, Hungary and Serbia) between October 2013 and August 2014. An interactive web response system (IWRS) was implemented for treatment allocation at the sites. Power analysis, based on the assumptions of a non-inferiority margin of −9%, a significance level of α 2.5% (one-sided), power 90%, at a reference pregnancy rate for the progesterone vaginal gel group of 30%, as well as applying a dropout rate of 10%, yielded a total number of 766 patients to be randomised. PARTICIPANTS/MATERIALS, SETTING, METHODS Women aged between 18 and 40 years with a clinical indication for IVF/intracytoplasmic sperm injection (ICSI) and embryo transfer were eligible to participate. The clinical pregnancy rate was assessed by fetal heart movement measured by transvaginal ultrasound at day 38 (D38) (primary endpoint) and D70. Also assessed were biochemical pregnancy rate (assessed by serum β-hCG ≥25 IU/L), clinical implantation rates at D38, patient evaluation of vaginal bleeding and discharge (assessed by diary) and adverse event (AE) incidence, severity and relationship to study medication. MAIN RESULTS AND THE ROLE OF CHANCE A total of 769 female patients were randomised to progesterone 400 mg vaginal pessaries bid (n = 385, 50.1%) or progesterone 90 mg vaginal gel od (n = 384, 49.9%). Patients receiving progesterone vaginal pessaries and progesterone vaginal gel were comparable in demographics, baseline characteristics and number of retrieved oocytes. In the full analysis set (FAS; n = 369 progesterone vaginal pessaries and n = 368 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.3% for progesterone vaginal pessaries and 39.9% for progesterone vaginal gel. In the per protocol analysis set (PP; n = 357 progesterone vaginal pessaries and n = 356 progesterone vaginal gel), clinical pregnancy rates on D38 were 38.1% for progesterone vaginal pessaries and 40.4% for progesterone vaginal gel. For the differences in pregnancy rates between the progesterone vaginal pessaries group and the progesterone vaginal gel, the lower limit of the 97.5% CI was −8.6 and −9.5% for the FAS and PP datasets, respectively. The original prespecified non-inferiority margin of −9% was thus met in the FAS dataset but was marginally below this in the PP dataset. However, the pregnancy rate of the comparator was higher than the anticipated rate of 30%, and a predetermined logistic regression model including treatment group, country and age group effects without interaction terms showed non-inferiority of progesterone vaginal pessaries to progesterone vaginal gel for both the FAS and PP populations, in that the lower limits of the 95% CIs were above 0.7 for both analyses. As a result of this, the relevant authorities accepted to widen the acceptable non-inferiority margin to −10%, and as such both the FAS and PP populations succeeded in showing non-inferiority. Biochemical pregnancy and clinical implantation rates were comparable for both treatments. Both treatment groups showed similar high compliance throughout the study, and the safety profiles were also comparable between the groups. Drug-related AEs occurred with frequencies of 15.1% with progesterone vaginal pessaries and 14.4% with progesterone vaginal gel. LIMITATIONS, REASONS FOR CAUTION Clinical pregnancy rate is a surrogate for the outcome of live birth rate. WIDER IMPLICATIONS OF THE FINDINGS Progesterone 400 mg pessaries bid for luteal phase support is an effective, safe and tolerable treatment option for women undergoing IVF during ART. STUDY FUNDING/COMPETING INTEREST(S) This work was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and by L.D. Collins & Co. Ltd. Gedeon Richter plc has recently entered into a license and distribution agreement to commercialise the vaginal pessaries in the European Union (except Ireland/UK). The progesterone vaginal pessaries studied are now marketed as Cyclogest®, Amelgen®, Cyclovita®, Luteum and Cygest® throughout the EU, Asia and Middle East & North Africa. The competing interests are as follows. H.S.: employee of Gedeon Richter plc/PregLem S.A. C.K.: consultant to L.D. Collins & Co. Ltd and received consulting fees for work performed. T.D.H.: at the initiation and completion of this study, full professor at KU Leuven and Head of Leuven University Fertility Center at the University Hospital Gasthuisberg, Leuven, Belgium. In October 2015, T.D.H. became vice president of Global Medical Affairs Fertility at the pharmaceutical company Merck—marketing authorisation holder of the Progesterone vaginal gel (Crinone®)—and has remained a part-time professor at KU Leuven (Belgium) and adjunct professor at Yale University (New Haven, CT, USA). T.B.M.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. I.K.: consultant to Actavis, later TEVA and received consulting fees for work performed. S.H.: at the initiation and completion of this study, employee of Actavis Group PTC ehf. Trial registration number EudraCT number 2013-001105-81 Trial registration date 2 July 2013 Date of first patient’s enrolment 9 October 2013

Item does not contain fulltext Aim: Clinical research in pediatrics is progressively initiated by academia. As the reliability of pharmacodynamic measures is closely linked to the quality of bioanalytical data, bioanalytical quality assurance is crucial. However, clear guidance on comprehensive bioanalytical quality monitoring in the academic environment is lacking. Methods & results: By applying regulatory guidelines, international recommendations and scientific discussions, a five-step quality control system for monitoring the bioanalysis of aldosterone by immunoassay was developed. It comprised performance qualification, calibration curve evaluation, analysis of the intra- and inter-run performance via quality control samples, incurred sample reanalysis and external quality assessment by interlaboratory testing. A total of 55 out of 70 runs were qualified for the quantification of aldosterone in the study sample enabling the evaluation of 954 pediatric samples and demonstrating reliability over the 29-month bioanalysis period. Conclusion: The bioanalytical quality control system successfully monitored the aldosterone assay performance and proved its applicability in the academic environment.

Study question Which progesterone vaginal pessary dose regimen induces adequate secretory transformation of the endometrium, in comparison with progesterone vaginal gel and placebo? Summary answer The best secretory transformation of the endometrium was observed during treatment with 400 mg progesterone vaginal pessaries, administered twice daily. What is known already Vaginally administered progesterone is widely used for luteal phase support (LPS) in assisted reproductive techniques (ART). Although several vaginal formulations using various doses are available, little is known on the impact of formulation and doses at the endometrial level. Study design, size, duration The study had a randomised, observer-blind design and comprised two parts. The participants used study medication during two or three treatment periods, separated by washout periods. Subjects in Part 1 (n = 61 treated) received 200 mg progesterone vaginal pessaries twice daily (bid), 400 mg pessaries bid and the comparator 90 mg progesterone vaginal gel once daily (od) in a 3-way crossover design. Subjects in Part 2 (n = 64 treated) received 100 mg pessaries bid in one period and 400 mg pessaries od in the other period in a 2-way crossover design. A subgroup of these subjects (n = 22 treated) received placebo vaginal pessaries bid in a third period in a non-randomised manner. The study was performed from May 2012 until April 2013. Participants/materials, setting, methods The study was performed at a clinical research centre in healthy female volunteers of reproductive age. The subjects used 2 mg estradiol bid for 24 days in each treatment cycle. Progesterone or placebo was administered vaginally from Day 15 onwards during 10 days. In each treatment period, an endometrial biopsy for histological evaluation was performed on Day 23 and pharmacokinetic parameters were determined after the first progesterone dose on Day 15 and after the last dose on Day 24. Main results and the role of chance Frequencies of (early and late) secretory transformation of the endometrium, i.e. adequate responses, during treatment with 200 mg and 400 mg vaginal pessaries bid were comparable with those during 90 mg vaginal gel treatment (90-94%), whereas lower secretory transformation rates were observed during treatment with 100 mg bid and 400 mg od (64-75%). At the time of the endometrial biopsy in the cycle the late secretory state of the endometrium, which is characteristic of adequate luteal support, was observed more often with 400 mg pessaries bid (90%) than with vaginal gel (82%) and with lower pessary doses (64-78%). Pharmacokinetic parameters after repeated dosing of vaginal pessaries showed a dose-dependent, but not dose-proportional, increase of plasma progesterone levels. The lowest incidence of bleeding and spotting was reported during treatment with 400 mg pessaries bid. Limitations reasons for caution The primary outcome parameter, rate of secretory transformation of the endometrium, is a surrogate for endometrial receptivity and for the actual clinical efficacy. Wider implications of the findings Delivery of progestesterone through 400 mg pessaries bid is an effective alternative method for luteal support in ART. Study funding/competing interest(s) The study was funded by Actavis Group PTC ehf., Iceland, part of Teva Pharmaceuticals, and L.D. Collins. I.D. and C.K. are directors of Dinox, a contract research organisation. I.K. is Managing Director of Pharmaplex and M.W. is Managing Director of M.A.R.C.O., service organisations involved in organisation/supervision and evaluation/reporting of clinical trials. All received funding for the conduct of the study from Actavis. S.H. and Th.M. are employees of Actavis. Trial registration number EudraCT number 2012-001726-95.

Child-appropriate drug formulations are a prerequisite of successful drug therapy in children. Efficacy and safety must be given for the active pharmaceutical ingredient, but safety also for the used excipients, components of primary packaging materials, and devices. We are presently experiencing exciting times for pediatric drug development, stimulated by previous governmental incentives in both the European Union and the United States. The most important advances in pediatric drug formulation development are reviewed and evaluated in this article. Scientific publications and recent industry strategies indicate a clear shift from liquid dosage forms to novel solid dosage forms. Solid formulations are usually composed from excipients generally regarded as safe, whereas many liquid formulations contain excipients such as preservatives, antioxidants, or taste-masking agents that raise concerns. Further, some recent clinical studies on swallowability, acceptability, and preference indicate superiority for small-sized tablets, so-called mini-tablets, over conventional liquids. In general, multiparticulate solid dosage forms could partly replace the liquids and provide more stable and cheaper alternatives to existing drug products or new developments. Dispersible solid drug dosage forms like orodispersible tablets, mini-tablets and films are even better opportunities for efficient and safe use in pediatrics. Novel measuring and administration devices may facilitate the handling and drug administration of these modern drug dosage forms. Combination products (drug-device combinations) can easily be linked with new e-health technologies in near future to further improve pediatric drug therapy.

A boy aged 1 year, recently diagnosed with dilated cardiomyopathy, has to be treated with enalapril according to the heart failure protocol. The physician wants to know which adverse events she can expect. What are the potential adverse events related to administration of an ACE inhibitor to children with heart failure? What is the prevalence and what are the possible risk factors? Secondary sources—nil Electronic databases (PubMed/Medline and Embase) and reference lists of relevant articles were searched with the following strategy: ‘angiotensin-converting enzyme inhibitors’ and ‘heart failure’ and ‘children’. The search yielded 415 individual articles, of which 14 were identified as relevant. Heart failure is an important cause of morbidity and mortality in children.1 It is commonly treated with ACE inhibitors (ACE-i) despite the lack of evidence on its efficacy.2 This treatment is based on the assumption that blocking of the renin-angiotensin-aldosterone system has a positive effect on morbidity and mortality, as it does in adults with heart failure.3–6 In adults, the most prevalent adverse events (AEs) related to the use of ACER-i are renal failure,7 8 hypotension,9 10 hyperkalemia,9 11 cough12 and angioedema.13 It is assumed that the safety profile of ACE-i differs for children and differs from that for adults, and for children of different ages, as growth and development contribute to variation in the disposition and effect of most drugs administered …

Reliable pediatric pharmacotherapy in all age groups requires the availability of age-appropriate drug administration. Orodispersible films (ODF) are a promising pediatric oral dosage form. ODFs would meet relevant targets: one dosage form matching the full range of pediatric patients, a minimum of non-toxic excipients, a stable drug formulation easily to be produced. However, there is a lack of reliable data on ODFs' acceptability, swallowability and palatability, especially in young children. The primary objective was to demonstrate non-inferiority in acceptability of a drug-free ODF in comparison to glucose syrup in children aged below one year. Secondary objectives were swallowability and palatability of the two formulations.The study was performed in an open, randomized, two-way cross-over design with three age groups: 2-28 days, 29 days-5 months, 6-12 months. 150 children (N = 50 per age group) were randomized to the order of receiving the ODF (2 × 3 cm) and age-adapted amounts of glucose syrup (0.5-3 mL). Deglutition and swallowing were assessed according to predefined evaluation criteria. The application of the formulations was documented by video to evaluate the palatability.The primary objective was confirmed: Non-inferiority of the acceptability of an ODF compared to syrup was demonstrated, even superiority of the ODF was shown (p 0.0001). The secondary endpoints demonstrated positive results including the superior swallowability of the ODF in comparison to syrup (p 0.0001). The palatability assessments were in favor of the ODF.ODFs are a promising and safe alternative to liquid formulations, even for children of very young ages.

In this research, the authors analyze the protection behavior during power system restoration. The bottom-up network restoration is done with the help of a black-start unit and concludes with a biogas plant taking over the island. The focus of this paper is to evaluate the behavior of protection devices, and to check their selectivity, sensitivity and speed during different network restoration stages. The research is done in two parts: In study case I, a protection investigation is performed based on a short-circuit analysis of the complete microgrid. In study case II, the dynamic behavior of the power plant along with the voltage and frequency protection of distributed energy resources is considered. At the end of the investigation, recommendations for the restoration process in islanding grids are given with regards to the protection concept considering system stability to support automated bottom-up restoration. The results are useful for distribution system operators to design their protection concepts for their grid operation in more flexible ways especially considering islanded operations.

Hydrogen has been proposed as an energy carrier in storage systems, fueled by excess electricity from volatile power production and re-electrified in times of electricity shortage. Unfortunately, these storage systems suffer from fairly poor return efficiencies. There is however a multitude of other production methods and usages that not seldom are intermixed with storage, creating possibilities for hydrogen as an attractive energy carrier. In many cases, hydrogen is mixed with other species. A brief introduction of possible hydrogen production methods and ways to convert hydrogen into electricity are presented. Emphases are put on comparing electrochemical methods (fuel cells and electrolyzers) to more traditional methods, mainly turbine-based power production.

Enalapril is recommended as the first line of therapy and is proven to improve survival rates for treatment of Pediatric Heart Failure; however, an approved drug and child appropriate dosage formulation is still absent. The present analysis was conducted to perform a detailed model informed population pharmacokinetic analysis of prodrug enalapril and its active metabolite enalaprilat in serum and urine. Further, a model informed dosage form population-pharmacokinetic analysis was conducted to evaluate differences in pharmacokinetics of enalapril and its active metabolite enalaprilat when prodrug was administered to 24 healthy adults in a crossover, two periods, two treatments, phase I clinical trial using child-appropriate orodispersible mini-tablets (ODMT) and reference (Renitec®) dosage formulation. A simultaneous semi-mechanistic population-pharmacokinetic model was developed using NONMEM software, which predicted full profile serum and urine concentrations of enalapril and enalaprilat. First-order conditional estimation with interaction was used for parameter estimation. Transit compartments added using Erlang distribution method to predicted enalapril absorption and enalaprilat formation phases. Normalized body weight was identified as covariate related to enalapril volume of distribution. Visual predictive check (VPC) plots and conducted bootstrap analysis validated the model. The data from the two formulations were pooled for population-pharmacokinetic analysis and covariate effect of the formulation was found on mean transit time (MTT1) of enalapril absorption. In addition, data of each formulation were modeled separately and the estimated parameters of each individual administered both formulations were correlated using paired samples Wilcoxon rank test (p < 0.05 = significant) which also showed only a significant difference (p = 0.03) in MTT1 i.e., 5 min early appearance of enalapril from ODMT compared to reference tablets. No difference in the pharmacokinetics of active enalaprilat was found from the ODMT compared to the reference formulation. The population pharmacokinetic analysis provided detailed information about the pharmacokinetics of enalapril and enalaprilat, which showed that the ODMT formulation might have similar pharmacodynamic response compared to the reference formulation. ispartof: FRONTIERS IN PEDIATRICS vol:7 ispartof: location:Switzerland status: published

The angiotensin-converting enzyme inhibitor enalapril is commonly used to treat chronic heart failure in children. Because some children are unable to swallow capsules or tablets, a new, age-appropriate, orodispersible minitablet (ODMT) containing 1 mg of enalapril was developed within the EU-funded LENA (Labeling of Enalapril from Neonates up to Adolescents) consortium. In order to support the clinical evaluation of this new formulation in children, a relative bioavailability study was performed in healthy adults, comparing the bioavailability of enalapril in the ODMT with that of a reference product (RP) Renitec, a registered standard enalapril tablet formulation. In this open-label, randomized 3-way crossover study, 24 healthy subjects received a 10-mg enalapril dose administered as (1) 2 × 5-mg tablets of the RP swallowed with water, (2) 10 × 1-mg ODMT swallowed with water, and (3) 10 × 1 mg ODMT dispersed on the tongue. When the relative bioavailability of the ODMT formulation swallowed with water was compared with that of the RP, the estimated 90%CIs for the ratio of area under the concentration-time curve (AUC0-∞ ) and or peak concentration (Cmax ) of enalapril were 92.34% to 106.49% and 91.28% to 115.72%, respectively, which are within the accepted bioequivalence limits of 80% to 125%. Following dispersion of the ODMT in the mouth, a slightly higher Cmax for enalapril was observed as compared with the RP with an upper 90%CI of 127.57%, slightly exceeding the bioequivalence limit. Taken together, it was demonstrated that the method of administration of the ODMT, swallowed or dispersed, did not significantly affect the bioavailability of enalapril. ispartof: CLINICAL PHARMACOLOGY IN DRUG DEVELOPMENT vol:9 issue:2 pages:203-213 ispartof: location:United States status: published

Introduction: Treatment of paediatric heart failure is based on paradigms extensively tested in the adult population assuming similar underlying pathophysiological mechanisms. Angiotensin converting enzyme inhibitors (ACEI) like enalapril are one of the cornerstones of treatment and commonly used off-label in children. Dose recommendations have been extrapolated from adult experience, but the relationship between dose and pharmacokinetics (PK) in (young) children is insufficiently studied. Furthermore, appropriate paediatric formulations are lacking. Within the European collaborative project LENA, a novel formulation of enalapril orodispersible minitablets (ODMT), suitable for paediatric administration, will be tested in (young) children with heart failure due to either dilated cardiomyopathy or congenital heart disease in two pharmacokinetic bridging studies. Paediatric PK data of enalapril and its active metabolite enalaprilat will be obtained. In a follow-up study, the safety of enalapril ODMTs will be demonstrated in patients on long-term treatment of up to 10 months. Furthermore, additional information about pharmacodynamics (PD) and ODMT acceptability will be collected in all three studies. Methods and Analysis: Phase II/III, open-label, multicentre study. Children with dilated cardiomyopathy (DCM) (n = 25; 1 month to less than 12 years) or congenital heart disease (CHD) (n = 60; 0 to less than 6 years) requiring or already on ACEI will be included. Exclusion criteria include severe heart failure precluding ACEI use, hypotension, renal impairment, hypersensitivity to ACEI. For those naïve to ACEI up-titration to an optimal dose will be performed, those already on ACEI will be switched to an expected equivalent dose of enalapril ODMT and optimised. In the first 8 weeks of treatment, a PK profile will be obtained at the first dose (ACEI naïve patients) or when an optimal dose is reached. Furthermore, population PK will be done with concentrations detected over the whole treatment period. PD and safety data will be obtained at least at 2-weeks intervals. Subsequently, an intended number of 85 patients will be followed-up up to 10 months to demonstrate long-term safety, based on the occurrence of (severe) adverse events and monitoring of vital signs and renal function. Ethics and dissemination: Clinical Trial Authorisation and a favourable ethics committee opinion were obtained in all five participating countries. Results of the studies will be submitted for publication in a peer-reviewed journal. Trial registration numbers: EudraCT 2015-002335-17, EudraCT 2015-002396-18, EudraCT 2015-002397-21. Keywords: Clinical pharmacology, Paediatric cardiology, Heart failure, Dilated cardiomyopathy, Congenital heart disease

Less than 10% of medicines approved by the FDA since 1980 have provided enough information as regards risks for birth defects associated with their use (Adam et al. (2011) [1]). Nevertheless, it is estimated that over 90% of pregnant women take over-the-counter (OTC) or prescription medication (Ke et al., 2014 [2]). Considering the fact that the use of medication in the period before conception and during lactation can also influence the development of the child, information on the impact of their usage during reproductive life is important for everyone. The lack of clear information on this topic results in situations where life-saving medication is discontinued, withheld or used in a reduced dosage by pregnant women, while on the other hand medicines with (potential) toxic effects are taken. This is unacceptable and it is a major public concern that must be addressed. Currently, Europe lacks a robust and comprehensive information system about medication use in reproductive life (from preconception, during pregnancy and during lactation). In order to improve maternal health, and subsequently the health of our next generation, reliable and up to date information should be made available. It should be readily accessible for both health care providers and women who are considering getting pregnant or who are already pregnant. In order to tackle this gap in public health, this paper describes current knowledge of the use of medicines before and during pregnancy. It calls upon all stakeholders involved in medical care, research and medicine regulation, such as policy makers, regulators and governmental agencies, to take action to protect patients and improve public health.

The importance and merits of greater patient involvement in medicines research and development (R&D) are commonly acknowledged and are thought to offer benefits for all involved parties. It helps to improve discovery, development, and evaluation of new effective medicines, based on the collaborative identification and understanding of unmet needs, research priorities, optimization of clinical study design, outcome measures, and endpoint development. It can result in increased transparency, trust and mutual respect between patients and other stakeholders. This applies to all stages of medicines R&D, from industry-led research, to regulation and licensing of medicines, to appraisal by health technology assessment (HTA) bodies. Integration of patients into the medicines development process needs to be structured and governed by clear rules and modes of operation to be effective and yield the best results for all stakeholders. Existing codes of practice for patient involvement with various stakeholders do not comprehensively cover the full scope of R&D, with the exception of more general statements applicable to interaction. Overarching guidance on meaningful and ethical interaction is missing. One specific aim of the European Patients' Academy on Therapeutic Innovation (EUPATI) was to close this gap through the development of guidance documents for selected stakeholders. Four separate guidance documents were developed, incorporating the results from comprehensive internal and external consultation. They cover patient involvement in: pharmaceutical industry-led medicines R&D; ethics committees; regulatory authorities; HTA. Each guidance suggests where patient involvement could be adopted or strengthened. The EUPATI guidance document for patient involvement in industry-led medicines research and development covers the interaction between patients and the pharmaceutical industry within all functions throughout the medicines R&D lifecycle in relation to medicines for human use. It relates to activities pre-approval and post approval, involving individuals and groups of patients. The guideline distinguishes between the level of expertise in a disease area that is required and the different areas where patient involvement can take place; however, this is not meant to limit involvement, and these opportunities may change and increase over time. This EUPATI guidance document is aimed at the pharmaceutical industry who want to engage patients in R&D activities, however all stakeholders involving patients in pharmaceutical-led medicines R&D should understand and use this EUPATI guidance document.

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) started in 1990 with the mission to harmonize technical guidelines and obligations for the development and authorization of human pharmaceuticals through the cooperation of drug regulatory authorities and the pharmaceutical industry of the main drug markets in the world. To evaluate the achievements of ICH over the last 23 years, 30 European experts were interviewed. The interviewee panel was selected to encompass representatives of both the pharmaceutical industry (20 interview partners) and the health authorities (10 interview partners). Many of the interview partners have actively contributed to ICH by leading or participating in working groups. Based on the interviews, this article highlights the strengths and weaknesses of ICH with a focus on ideas and visions to improve the status quo.

The main aim of health technology assessment (HTA) is to inform decision making by health care policy makers. It is a systematic process that evaluates the use of health technologies and generally involves a critical review of international evidence related to clinical effectiveness of the health technology vs. the best standard of care. It can also include an evaluation of cost effectiveness, and social and ethical impacts in the local health care system. The HTA process advises whether or not a health technology should be used, and if so, how it is best used and which patients are most likely to benefit from it. The importance of patient involvement in HTA is becoming widely recognized, for scientific and democratic reasons. The extent of patient involvement in HTA varies considerably across Europe. Commonly HTA is still focused on quantitative evidence to determine clinical and/or cost effectiveness, but the interest in understanding patients' experiences and preferences is increasing. Some HTA bodies provide support for participation in their processes, but again this varies widely across Europe. The involvement of patients in HTA is determined at the national and regional level, and is not subject to any European-wide legislation. The guidance text presented in this article was developed as part of the work of the European Patients' Academy on Therapeutic Innovation (EUPATI) and covers the interaction between HTA bodies and patients and their representatives when medicines are being assessed. Other EUPATI guidance documents relate to patient involvement in pharmaceutical industry-led research and development, ethics committees, and regulatory authorities. The guidance provides recommendations for activities to support patient involvement in HTA bodies and specific guidance for individual HTA processes. It seeks to improve patient involvement, using the outcomes of published research and consensus-building exercises. It also draws on good practice examples from individual HTA bodies. The guidance is not intended to be prescriptive and should be used according to specific circumstances, national legislation, or the unique needs of each interaction. This article represents the formal publication of the HTA guidance text with discussion about recent progress in, and continuing barriers to, patient involvement in HTA.

The importance and merits of greater patient involvement in medicines research and development (R&D) are commonly acknowledged and is thought to offer benefits for all involved parties. It improves discovery, development, and evaluation of new effective medicines, based, among others, on the collaborative identification and understanding of unmet needs, research priorities, optimization of clinical study design, as well as incorporating patient views in regulatory activities. It fosters increased transparency, trust and mutual respect between patients and other stakeholders and applies to all stages of medicines R&D, inclusive of regulation and licensing of medicines and appraisal by health technology assessment (HTA) bodies. In order to be effective and beneficial for all stakeholders, patient engagement as an integral part of medicines R&D needs clear and mutually agreed rules. Existing codes of practice for patient involvement do not comprehensively cover the full scope of patient engagement in all processes related to R&D. One specific aim of the European Patients' Academy on Therapeutic Innovation (EUPATI) was to close this gap through the development of guidance documents for pharmaceutical industry-led medicines R&D, ethics committees, regulatory authorities and health technology assessment (HTA). The guidance in this article covers patient involvement in the regulatory field and draws on the mature “Framework for interaction between the European Medicines Agency and patients and consumers and their organizations.” It expands on the EMA framework, specifically including National Competent Authorities (NCAs). It sets out objectives for patient involvement in medicines regulation and recommends concrete suggested working practices. It is primarily aimed at regulatory authorities wishing to interact with patients or their organizations in their activities but should also be considered by patients/patient organizations planning to collaborate with regulatory authorities.

Importance Scuba diving is becoming increasingly popular. However, scuba diving is associated with specific risks; 80% of adults and 85% of juvenile divers (aged 6-17 years) have been reputed to have an ear, nose, or throat complaint related to diving at some point during their diving career. Divers frequently seek advice from primary care physicians, diving physicians, and otorhinolaryngologists, not only in the acute setting, but also related to the long-term effects of diving. Observations The principles underpinning diving-related injuries that may present to the otorhinolaryngologist rely on gas volume and gas saturation laws, and the prevention of these injuries requires both that the diver is skilled and that their anatomy allows for pressure equalization between the various anatomical compartments. The overlapping symptoms of middle ear barotrauma, inner ear barotrauma, and inner ear decompression sickness can cause a diagnostic conundrum, and a thorough history of both the diver’s symptoms and the dive itself are required to elucidate the diagnosis. Correct diagnosis and appropriate treatment result in a more timely return to safe diving. Conclusions and Relevance The aim of this review is to provide a comprehensive overview of otorhinolaryngological complications during diving. With the increasing popularity of diving and the frequency of ear, nose, or throat–related injuries, it could be expected that these injuries will become more common and this review provides a resource for otorhinolaryngologists to diagnose and treat these conditions.

The first formal conference of the EUropean Federation for Exploratory MEdicines Development (EUFEMED) held in London was the result of a collaborative effort of its founding associations: the Association for Applied Human Pharmacology (AGAH; Germany), the Association for Human Pharmacology in the Pharmaceutical Industry (AHPPI; UK), the Belgian Association of Phase-I Units (BAPU; Belgium), and Club Phase-I (France). The conference focused on innovation and risk management in early clinical drug development. Among other innovations, immunotherapy in oncology and inflammatory diseases were discussed as well as the importance of adaptive trial designs in early clinical drug development. Consideration was given to assessing and mitigating risk in early clinical drug development, and included a preconference workshop. Different measures to minimize risks in healthy volunteers and patients in first-in-human trials were discussed in addition to the importance of non-clinical data, the need for reliable biomarkers, improved communication on adverse events (AEs) and well-trained study sites with ready access to intensive care units and clinical specialists. The need for a European-wide system for prevention of over-volunteering was also discussed. The conference provided opportunity to discuss these developments and concerns and the changing regulatory environment with stakeholders from academia, industry, and regulatory agencies including the European Medicines Agency (EMA). Presentations given by invited speakers are published on http://www.eufemed.eu/london-conference-2017/. ispartof: Frontiers in Pharmacology vol:8 issue:JAN ispartof: location:London status: published

One of the most critical risks for modern societies is a largescale power system blackout. Critical infrastructure has emergency power supplies (e.g., nuclear power plants, hospitals, or communication infrastructure) to confront power outage situations. However, after about 8 h of a blackout, fuel supplies and battery capacities normally run out. Thus, it is of utmost importance to restore the power system as robustly and quickly as possible. This responsibility lies with the transmission system operators (TS Os), and it is in their best interest to rapidly accomplish it.

Da sich der Tauchsport zunehmender Beliebtheit erfreut, steigt auch die Zahl der Taucher, die sich mit einer tauchmedizinischen Fragestellung an ihren behandelnden Arzt wenden. Erkrankungen im HNO-Bereich sind die haufigste Ursache fur einen Arztbesuch von Tauchern. Die Otitis externa, das Mittelohrbarotrauma, Schwierigkeiten mit dem Druckausgleich und das Barotrauma der Nasennebenhohlen stellen die Mehrzahl der behandelten Erkrankungen bei Tauchern dar. Erkrankungen des Innenohres sind zwar seltener, ihnen kommt aber eine besondere Bedeutung zu, da sie haufig zu bleibenden Schaden fuhren.

The challenges faced by the biopharmaceutical industry in its key role to overcome the bottlenecks in innovative medicines development are related to addressing the technical knowledge gaps, the limitations to clinical trial testing, and the lack of clarity in the global pathways and processes to efficient outcomes. It is postulated that the lack of an adequately sized and appropriately trained multi-professional workforce, both in the industry and in the clinical research field, to enable fulfillment of the demanding aims for medicines development is a significant part of the problem. The current global status of pharmaceutical medicine’s efforts to conduct education and training is seen as patchy, inadequate, and without recognition, direction or leadership. It is therefore proposed that the movement towards competency-based education (CBE) should be harnessed, and core competency job and role profiles and competency curricula should be developed. CBE presents a means of addressing the educational and training needs within medicines development, harmonizing the workforce and the requirement for increased inter-professional teamwork. An educational environment in which aspiring and established biomedical professionals could readily learn about the competencies they need to pursue a particular career path is envisioned. Utilizing competencies provides the building blocks to align and harmonize the desired learning outcomes for effective performance amongst a multi-professional workforce. The effective implementation of training programs as described here has the potential to transform drug development procedures into an efficient and integrated process; medical product life-cycle management would result in the availability of better and safer medicines more rapidly, for the benefit of patients and society.

To assess the acceptability and swallowability of several minitablets when administered as a unit dose compared with an equivalent dose of syrup in children aged 6 months to 5 years.The acceptability and swallowability of multiple drug-free minitablets in comparison with glucose syrup was assessed in 372 children of 2 age groups (186 in age group 1 [6-23 months of age] and 186 in age group 2 [2-5 years of age]) in a randomized, 3-way, single administration cross-over study. Age group 1 received 25 minitablets, 100 minitablets, and 5 mL syrup. Age group 2 received 100 minitablets, 400 minitablets, and 10 mL syrup.Superiority was demonstrated in age group 1 for acceptability (25 minitablets, P .017; 100 minitablets, P .0001) and swallowability (25 minitablets and 100 minitablets, both P .0001) compared with syrup. In age group 2, noninferiority of acceptability was found only for 400 minitablets (P .0003), not for 100 minitablets. Subgroup analysis revealed a strong sequential effect. For swallowability, noninferiority could be demonstrated for 100 minitablets (P .01) but not for 400 minitablets.Administration of ≥25 minitablets is well-tolerated, feasible, and safe in children aged from 6 months, and was superior to the equivalent dose of syrup. Children aged1 year accept ≤400 minitablets even better than the equivalent dose of syrup. Minitablets open the perspective for introducing small-sized solid drug formulations for all children, thus, further shifting the paradigm from liquid toward small-sized solid drug formulations.German Clinical Trials Register (DRKS): DRKS00008843.

Cuneiform tablets appertain to the oldest textual artifacts and are in extent comparable to texts written in Latin or ancient Greek. The Cuneiform Commentaries Project (CPP) from Yale University provides tracings of cuneiform tablets with annotated transliterations and translations. As a part of our work analyzing cuneiform script computationally with 3D-acquisition and word-spotting, we present a first approach for automatized learning of transliterations of cuneiform tablets based on a corpus of parallel lines. These consist of manually drawn cuneiform characters and their transliteration into an alphanumeric code. Since the Cuneiform script is only available as raster-data, we segment lines with a projection profile, extract Histogram of oriented Gradients (HoG) features, detect outliers caused by tablet damage, and align those features with the transliteration. We apply methods from part-of-speech tagging to learn a correspondence between features and transliteration tokens. We evaluate point-wise classification with K-Nearest Neighbors (KNN) and a Support Vector Machine (SVM); sequence classification with a Hidden Markov Model (HMM) and a Structured Support Vector Machine (SVM-HMM). Analyzing our findings, we reach the conclusion that the sparsity of data, inconsistent labeling and the variety of tracing styles do currently not allow for fully automatized transliterations with the presented approach. However, the pursuit of automated learning of transliterations is of great relevance as manual annotation in larger quantities is not viable, given the few experts capable of transcribing cuneiform tablets.

Gas turbines are widely used power generation equipment and very important for its efficiency and flexible operability. With the increasing demand of low carbon or less greenhouse gas emission from gas turbine, usage of clean fuel (i.e. hydrogen) is highly recommended. Adaptation with various type of fuels without any operability issues are the primary focus of interest while design and development of a low NOx gas turbine combustion system. Due to chemical and physical property variation of different fuel, a common combustion system design is complex and require extensive testing. The present paper is focused on fuel flexibility of an industrial prototype burner, designed and manufactured by Siemens Industrial Turbomachinery AB, Sweden. In this work, a baseline case (Methane fuel) is compared with different custom fuel blends (mixture of methane with natural gas and hydrogen). The primary and secondary combustion characteristics were modified when hydrogen blended fuels were introduced. The Lean Blowout limit was extended for the primary and secondary flames. The secondary flame macro structure was captured using Planar Laser Induced Fluorescence and natural luminosity imaging; whereas primary flame location was characterized by the thermocouple readings. Operational stability map and emission (NOx and CO) capability of the burner was determined from the experiment. Numerical calculation using ANSYS FLUENT was performed to simulate the combustion process and compare the results with experiment. The experimental and simulation effort provided information about the flame macrostructure and operability (lean operability limit was extended by 100 K) of the new technology burner when the combustion system was exposed to different type of fuels.

BackgroundACE-inhibitors are first choice treatment for adult and paediatric patients with heart failure. Since there are no systematic data on pharmacokinetics and safety in the young heart failure population, the EU funded a drug development program1 to fill those gaps for the ACE-inhibitor enalapril. An age appropriate paediatric formulation was also required.MethodsA paediatric patient cohort with heart failure was recruited to fulfil the paediatric investigation plan (PIP) requirements. The PIP required a total of 85 evaluable patients from birth to less than 12 years of age with a subset cohort of 25 patients with heart failure due to dilated cardiomyopathy and a subset of 60 heart failure patients of congenital heart disease. Out of these, 54% of patients must be aged below 12 months to provide a substantial amount of young patients.ResultsThe LENA consortium recruited 102 children from birth to 12 years. Out of those, 89 patients fulfilled relevant protocol criteria and could be regarded as evaluable. Of these, 26 demonstrated heart failure due to cardiomyopathy and 63 due to congenital heart disease. Sixty five patients (73%) were below 12 months of age. Moreover, 22 patients were below 3 months of age, 26 patients from 3 months to less than 6 months and 17 patients from 6 months up to 12 months of age.ConclusionsThe LENA consortium had recruited the PDCO required number of paediatric patients for the drug development program LENA. As more than 2/3 of patients belong to the most vulnerable patient population below the age of 12 months, relevant data can be generated to fill gaps for the safe and reliable treatment with ACE-inhibitors of children with heart failure.ReferencesThe research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant agreement n°602295 (LENA)Disclosure(s)Nothing to disclose

ObjectiveTo characterise heart failure (HF) maintenance pharmacotherapy for children across Europe and investigate how angiotensin-converting enzyme inhibitors (ACE-I) are used in this setting.MethodsA Europe-wide web-based survey was conducted between January and May 2015 among European paediatricians dedicated to cardiology.ResultsOut of 200-eligible, 100 physicians representing 100 hospitals in 27 European countries participated. All participants reported prescribing ACE-I to treat dilated cardiomyopathy-related HF and 97% in the context of congenital heart defects; 87% for single ventricle physiology. Twenty-six per cent avoid ACE-I in newborns. Captopril was most frequently selected as first-choice for newborns (73%) and infants and toddlers (66%) and enalapril for children (56%) and adolescents (58%). Reported starting and maintenance doses varied widely. Up to 72% of participants follow formal creatinine increase limits for decision-making when up-titrating; however, heterogeneity in the cut-off points selected existed. ACE-I formulations prescribed by 47% of participants are obtained from more than a single source. Regarding symptomatic HF maintenance therapy, 25 different initial drug combinations were reported, although 79% select a regimen that includes ACE-I and diuretic (thiazide and/or loop), 61% ACE-I and aldosterone antagonist; 44% start with beta-blocker, 52% use beta-blockers as an add-on drug. Of the 89 participants that prescribe pharmacotherapy to asymptomatic patients, 40% do not use ACE-I monotherapy or ACE-I-beta-blocker two-drug only combination.ConclusionsDespite some reluctance to use them in newborns, ACE-I seem key in paediatric HF treatment strategies. Use in single ventricle patients seems frequent, in apparent contradiction with current paediatric evidence. Disparate dosage criteria and potential formulation-induced variability suggest significant differences may exist in the risk-benefit profile children are exposed to. No uniformity seems to exist in the drug regimens in use. The information collected provides relevant insight into real-life clinical practice and may facilitate research to identify the best therapeutic options for HF children.

The removal of particulate emissions from gasoline injection engines is a new challenge within the exhaust aftertreatment system that will arise with the introduction of limits for particle number emitted by gasoline engines. Besides a possible adjustment of the engine management to lower the particulate emissions, catalyzed gasoline particulate filters (GPF) are conceivable as efficient pollution control devices. As an advantage, these catalyzed filters in addition could be able to support the conversion of all other regulated pollutants. Therefore, an emission study was carried out with systems consisting of a three-way catalyst and a catalyzed GPF and the impact of a dedicated washcoat on the filtration efficiency of the filter was analyzed. The conversion performance of the gasoline particulate filters was examined with regard to carbon monoxide, hydrocarbons and nitrous oxides emissions. Furthermore, the influence of the additional converter on fuel consumption and CO2 emissions over different driving cycles will be discussed. In a detailed exhaust system study a correlation between the distance of engine-outlet to GPF-inlet and the filtration efficiency of the system was observed.

To ensure optimal, reliable treatment, it is necessary to investigate the efficacy, safety and the optimal dose of drug substances and to develop suitable age-specific pharmaceutical formulations for the different paediatric age groups due to a lack of evidence-based therapeutic options for children. While WHO recommends the use of solid dosage forms in general, European Medicines Agency (EMA) requires evidence for the suitability of these dosage forms in the targeted age group. This review aims to summarize and discuss the data obtained in acceptability studies on the suitability of coated and uncoated mini-tablets in children of different ages in comparison to a sweet syrup considered as gold standard. The predefined outcome parameters 'acceptability' and 'capability to swallow' of the two different mini-tablet formulations (uncoated and film-coated) were statistically significantly higher than that of the syrup.

The current healthcare systems are built around the traditional paradigm of patients suffering from a single acute illness. They are, therefore, largely unprepared to face the increasing demands for health services arising from the expansion of an older population with specific medical needs related to multiple chronic disorders. As a consequence, the medical conditions of a large and growing segment of the older European population are not efficiently managed by the available healthcare services. In the context of an aging population, policy makers such as the European Commission and European Institutions, such as the European Medicines Agency (EMA), devote time and resources to study and accompany the need of the aging population. The EMA recognizes the importance of making sure that the needs of the Elderly are considered during development, approval, and use of new medicines, and, therefore, engages with healthcare professional organisations. The Sarcopenia and Physical Frailty in Older People: Multicomponent Intervention Strategies (SPRINTT) is the obvious result of these strategies. The present article describes the SPRINTT workpackage activities aimed at engaging the scientific discussion on the physical frailty and sarcopenia with the EMA as one of its interlocutor, acknowledging the need to collaborate on this topic to foster a productive dialogue.

In ESS, a 5 MW proton beam will hit a helium cooled tungsten target to generate neutrons by spallation. For the purpose of investigating various aspects of cooling with helium, an experimental system has been constructed at Lund University, Department of Energy Sciences. A helium flow of 3 g/s is circulated in a closed loop with pre-heater, cooler, filters and a test vessel. The vessel has windows for measurements and is designed for 10 bar and above 400 °C. In the test vessel, a tube forms a helium jet of up to 150 m/s onto a coin shaped material sample. One purpose of the system is to investigate erosion of sample surfaces. Drilling and attaching equipment to the surface had to be avoided, so the setup has been benchmarked and the comparison was used to tune a CFD model. Then the model is used to assess the conditions in the experiments. The setup, as well as the tests and calculations, are described and it is concluded that the temperature and velocity estimates are sufficient for the experiments to be performed.

In the present work, a downscaled prototype 4th generation Dry Low Emission gas turbine (SGT-750) burner (designed and manufactured by Siemens Industrial Turbomachinery AB, Sweden) was investigated using an atmospheric experimental facility. The primary purpose of the research is to analyze flame stability and emission capability of the burner. OH Planar Laser-Induced Fluorescence (OH-PLIF), and chemiluminescence imaging were performed to characterize the flame structure and location. From the OH-PLIF images, the reaction zone and post flame region could be identified clearly. The chemiluminescence images provide an estimation of the overall heat release from the secondary combustion zone inside the Quarl. Emission was measured using a water-cooled emission probe, placed at the exit of the combustor to sample NOx and CO concentrations. The global equivalence ratio (Φ) was varied from rich to lean limit (flame temperature change from 1950 K to 1570 K) for understanding the stable and instable reaction zones inside the Quarl. Total thermal power was varied from 70 kW to 140 kW by changing global Φ and burner throat velocity (60 to 80 m/s). Near the lean blowout (LBO) event (at global Φ ∼ 0.4), instability of reaction zone is revealed from the flame images. Incorrect modulation of Pilot and RPL fuel splits show instable flame. Flame instability mitigation was possible using higher amount of RPL and Pilot fuel (trade-off with emission performance). The main flame LBO margin was extended by applying higher Pilot fuel and using higher preheat air temperature. Numerical analysis was carried out using Fluent to understand the scalar and vector fields. A basic chemical reactor network model was developed to predict the NOx and CO emission with experimental results. NOx emission prediction showed good agreement with experiment; whereas the model is failed to capture accurate CO emission in the lean operating points.

Lean premixed dry low emission (DLE) combustion system in a gas turbine engine is a globally accepted concept to reduce pollutant emissions and to improve combustion efficiency. This study is focused on an industrial downscaled prototype burner (4th Generation Dry Low Emission Burner for SGT-750 designed and manufactured by Siemens Industrial Turbo machinery AB), which has been tested extensively at atmospheric conditions. To enhance the operability and alleviate flame dynamics behavior, multiple fuel and air circuits (i.e. Rich-Pilot-Lean (RPL), Pilot and Main) are engaged in the burner. Primarily, present study evaluates the RPL-Pilot interaction effect on the main combustion zone. A highly swirled flow from the burner exit produces a central recirculation zones (CRZ) to recirculate the hot vitiated gas for sustaining the combustion process. The main flame is stabilized in the inner shear layer (ISL), which is found in the diverging section (named as Quarl). The total power of the burner was varied between 70–140 kW and the fuel used for the experiment was 99.5% pure methane. A short length quartz liner was used for the experiment and the residence time of the combustor is 9 ms. At the liner exit, emission sampling (CO, NOx) has been conducted using a water-cooled emission probe. Optical measurements were permitted, as the Quarl and combustor liner were optically accessible. Planar laser-induced fluorescence of OH molecule (OH-PLIF) and natural chemiluminescence measurements were conducted to visualize the flame characteristics and its response by changing the RPL and Pilot fuel splits. A comprehensive study was performed by varying the RPL residence time to investigate the main flame stabilization and pollutant formation of the burner. Higher RPL residence time exhibits NOx benefits but at the same time flame instability was increased. Pilot fuel percentage modification demonstrate negative impact on NOx formation due to the limited mixing of fuel and air. With the increase of Pilot fuel split, CO emission decreases, which is advantageous for increasing the LBO margin. The study has identified a number of critical situations where the flame was stabilized without any RPL and Pilot combustion. Apart from the experimental results, a simple reactor network model has been applied for predicting NOx emission. Different kinetic mechanisms were assessed and the prediction results are compared to experimental results. Heat loss from the combustor wall played a significant role on emission formation and was included in the reactor model. This study provides a good understanding of the new DLE industrial burner concept and the RPL-pilot interaction effect on the emission.

To explore the advantages and challenges of working with the Good Clinical Practice (GCP)-International Conference of Harmonization (ICH) E6 guideline and its interpretation from the perspective of clinical trial teams based in sub-Saharan Africa.; We conducted 60 key informant interviews with clinical trial staff at different levels in clinical research centres in Kenya, Ghana, Burkina Faso and Senegal and thematically analysed the responses.; Clinical trial teams perceived working with ICH-GCP as highly advantageous and regarded ICH-GCP as applicable to their setting and efficiently applied. Only for informed consent did some clinical trial staff (one-third) perceive the guideline as insufficiently applicable. Specific challenges included meeting the requirements for written and individual consent, conditions for impartial witnesses for illiterates or legally acceptable representatives for children, guaranteeing voluntary participation and ensuring full understanding of the consent given. It was deemed important to have ICH-GCP compliance monitored by relevant ethics committees and regulatory authorities, without having guidelines applied overcautiously.; Clinical trial teams in sub-Saharan Africa perceived GCP as a helpful guideline, despite having been developed by northern organisations and despite the high administrative burden of implementing it. To mitigate consent challenges, we suggest adapting GCP and making use of the flexibility it offers.

INTRODUCTION: Decompression sickness (DCS) is caused by formation and growth of bubbles from excess dissolved gas in body tissues following reduction in ambient pressure. Inner ear decompression sickness (IEDCS) is a complex disorder involving the vestibulo-cochlear apparatus whose pathophysiology remains incompletely understood. METHODS: The records of 662 consecutive DCS cases treated over a 7-yr period at 2 UK hyperbaric units were examined for symptoms suggesting IEDCS (nausea, vomiting, dizziness, and hearing loss arising within 2 h of surfacing). For IEDCS cases, demographics, dive, treatment, and outcome data were extracted with particular attention to the outcome of testing for a right-to-left shunt. RESULTS: Included were 31 men and 2 women with a mean age of 46 yr (range 31-61 yr). Of these, 16 patients had isolated IEDCS and 17 patients had associated symptoms ranging from joint pain to tingling and numbness. The depth of the dive leading to the incident ranged from 49-256 ft (15-78 m). As primary treatment, 21 patients received a U.S. Navy Treatment Table 6 (USN TT6) and 11 patients received a Comex 30. No difference in the speed of recovery or number of treatments needed was seen between the two tables. All patients were advised to have a right to left shunt (RLS) check, but only 30 complied with that, with 24 (80%) testing RLS positive. CONCLUSION: Our retrospective study confirms the correlation between IEDCS and the presence of a significant patent foramen ovale (PFO). In our series 48% of patients had an isolated IEDCS. IEDCS responds slowly to treatment irrespective of the initial table used. Recovery is thought to be mainly a central compensation process.

Bisher existierte kein validiertes Messinstrument der krankheitsspezifischen gesundheitsbezogenen Lebensqualitat („health-related quality of life“, HR-QOL) bei Erwachsenen mit chronischer Tonsillitis (CTO). Nach einer Itemreduktion der alpha-Version des Tonsillectomy Outcome Inventory (TOI) entstand das TOI-14. Es erfasst neben dem Gesamtscore die Skalen Halsprobleme, allgemeine Gesundheit, Ressourcen und sozialpsychologische Einschrankungen. In Phase 2 wurde das TOI-14 an 108 Erwachsenen mit CTO, bei denen eine Tonsillektomie durchgefuhrt wurde, prospektiv validiert. Das TOI-14 wies im Schnitt eine gute Reliabilitat auf. Es erfasst alle wichtigen Konzepte der HR-QOL. Patienten mit CTO konnen von Gesunden hochsensitiv unterschieden werden. Alle Scores zeigten eine masige bis gute Ubereinstimmung mit der subjektiven Lebensqualitatseinschrankung. Die Sensitivitat des Fragebogens konnte sehr grose Effekte postoperativ demonstrieren. Das TOI-14 stellt das erste weltweit validierte Messinstrument der krankheitsspezifischen HR-QOL bei Erwachsenen mit CTO dar. Durch seine einfache Handhabung kann es sowohl in der Ergebnis(Outcome)-Forschung als auch im klinischen Alltag eingesetzt werden.

Aim of the study is to evaluate the effects of medical and surgical treatment in divers with paranasal sinus barotrauma (PSB) secondary to chronic rhinosinusitis (CRS). In this retrospective, cross-sectional, descriptive study 40 adult divers with CRS were included. Treatment of divers implied a 5-day course of a systemic steroid and a 6-week course of saline nasal irrigations and topical nasal steroid with mometasone in maximal dosage. If symptoms persisted, functional endoscopic sinus surgery (FESS) was performed. Questionnaires included the Sinonasal Outcome Test-20 German Adapted Version (SNOT-20 GAV), dive-related questions (DRQ) and general questions. Questionnaires were completed retrospectively by recalling the symptoms before and after therapy. Forty of 82 divers completed the questionnaires. Mean follow-up was 42 months (range 13-95 months). There was a statistically significant improvement of the Total score (TS) and of every subscore, except the General Quality of Life score, in the SNOT-20 GAV as well as of the TS in the DRQ. Before treatment, divers who required surgery reported significantly more symptoms than divers who were treated conservatively. Post treatment there were no significant differences between the medical and surgical group. Overall, 35 divers could resume diving after therapy even though PSB still occurred but without complications. Divers with sinus problems can successfully be managed medically and if conservative treatment fails, FESS shows a statistically significant improvement of symptoms and no serious long-term hazards for diving.

This article summarizes the conclusions and discussion from a workshop in Brussels, jointly organized by the European Forum for Good Clinical Practice and the European CRO Federation, looking at how pediatric and geriatric clinical research might learn from each other in dealing with the ethical issues particular to each area. Experience with the Paediatric Regulation, which since 2007 has provided the legal framework in Europe for all research involving children, suggests that the incorporation of geriatric expertise at all levels in the drug discovery process, including ethics committees, would yield considerable benefits. This should be combined with an upward revision of the age ranges that define who is elderly and a public debate about the need for research involving elderly people. Further work on practical guidelines on the ethical conduct of clinical trials in elderly people should be a priority. In both pediatric and geriatric research, the concepts of consent, assent, and dissent require furthe...

Importance Self-contained underwater breathing apparatus (scuba) diving has become increasingly popular with millions of people diving each year. Otorhinolaryngologists are often consulted either by patients or diving physicians regarding fitness to dive, and at present, the guidelines do not provide comprehensive information regarding the evaluation of this patient cohort. The aim of this review is to provide a comprehensive overview of existing otorhinolaryngological guidelines for fitness to dive recreationally. Observations There is a paucity of guidelines for assessing otorhinolaryngological fitness to dive in the recreational diver. Comprehensive guidelines exist from US, European, and UK regulatory bodies regarding fitness for commercial diving; however, not all of these can be directly extrapolated to the recreational diver. There are also a variety of conditions that are not covered either by the existing fitness for recreational diving guidelines or the commercial regulatory bodies. Conclusions and Relevance With the paucity of recreational fitness to dive guidelines we must draw on information from the commercial diving regulatory bodies. We have provided our own recommendations on the conditions that are not covered by either of the above, to provide otorhinolaryngologists with the information they require to assess fitness for recreational diving.

The effects on quality of life (QoL) in adult patients with chronic tonsillitis are multidimensional. Tonsillectomy has been and is still the standard for treating these patients, who fulfil certain clinical criteria, and is thus the main determinant in the change of QoL. The reduction in severity and frequency of symptoms, health care utilization, physician visits and days off work are major factors in the improvement of QoL. Other important aspects are the management of the postoperative pain and the avoidance of post tonsillectomy hemorrhage. Economic benefits of tonsillectomy receive increasing attention as there can be direct associations with the patients' QoL. Studies concerning the clinical efficacy of tonsillectomy, various techniques in order to achieve the best outcome, postoperative pain relieving measures, methods to minimize postoperative hemorrhage rates, and studies of cost-effectiveness of this intervention will be reviewed and discussed.

Bisher stand kein validiertes Instrument zur Messung der Lebensqualitat nach Parotidektomie bei benignen Erkrankungen der Parotis zur Verfugung. In diese retrospektive Studie wurden Patienten eingeschlossen, die sich in den Jahren 2003 bis 2006 einer Parotidektomie aufgrund einer benignen Erkrankung unterzogen. Eine Expertengruppe identifizierte Einzelfragen, die potenzielle Beschwerden nach einer Parotidektomie erfassten (alpha-Version). Nach Ausfullen des Fragebogens durch die Patienten erfolgte eine Itemreduktion durch sequenzielle statistische Analyseverfahren. Die daraus resultierende beta-Version wurde validiert durch Bestimmung der Reliabilitat und der Validitat. In die Studie wurden 199 Patienten eingeschlossen, von denen 70 (35%) die Fragebogen ausfullten. Die alpha-Version des Instruments wies 20 Items auf (Parotidectomy Outcome Inventory-20, POI-20), die beta-Version 8 Items (POI-8). Das Cronbach-alpha wies mit einem Wert von 0,84 auf eine gute interne Konsistenz hin. Die Messung der Test-Retest-Reliabilitat des POI-8 bei 49 Patienten zeigte eine hochsignifikante Korrelation (r=0,91). Das Bestehen einer guten Ubereinstimmungsvaliditat mit einer globalen krankheitsspezifischen Frage konnte gezeigt werden (r=0,78). Der POI-8 ist das erste krankheitsspezifische reliable und valide Instrument zur Messung der gesundheitsbezogenen Lebensqualitat nach Parotidektomie bei benignen Erkrankungen der Ohrspeicheldruse.

Background. Diseases of the inner ear such as presbycusis, tinnitus, sudden hearing loss, and vertigo affect many patients, but so far there are no specific therapy options. Gene therapy might become a potential modality of treatment. Viral vectors are standard in animal models to date. Future considerations, however, call for a further evaluation of non-viral transfection methods. Material and methods. The non-viral transfection agents Metafectene™, Superfect™, Effectene™, and Mirus TranslT™ were incubated with a plasmid coding for GFP. In vivo, the plasmid-agent mix was injected via the membrane of the round window, and 48 h later the inner ear was perfused, harvested, decalcified, and histologically evaluated for GFP expression. Results. Cationic lipids (Metafectene™) and dendrimers (Superfect™) were able to transfect cells in the area of the organ of Corti and lead to GFP expression. The polyamine (Mirus TranslT™) did show expression of GFP in the area of Rosenthal's canal and in the area of the inner hair cell. The combination of a non-liposomal lipid with a DNA condensing component (Effectene™) did not show transfection of the organ of Corti. In the area of the spiral ganglia cells, GFP expression was seen with all the transfection agents. Conclusions. Non-viral transfection agents are able to introduce a reporter gene in cells of the inner ear in vitro and in vivo. There are, however, differences in the effciency of the transfection. They might be an alternative in gene therapy of the inner ear. Further investigations to elucidate their potential are needed.