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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.

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

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.

Contains fulltext : 220641.pdf (Publisher’s version ) (Closed access) While the role of plasma renin activity (PRA) in heart failure has been widely studied in adults, comprehensive data on pediatric heart failure remain lacking. This drawback is increasingly being addressed by academic research. Nevertheless, such pediatric investigations are commonly conducted only once due to ethical constraints. Therefore, the quality of bioanalytical data must be ensured to acquire meaningful insights into maturing humoral parameters. However, appropriate post-validation assessment of bioanalytical runs is currently underrepresented by regulatory guidance. Thus, for applications in an academic environment, an easy-to-handle six-step bioanalytical quality control system was designed based on regulatory guidelines (e.g. U.S. Food and Drug Administration) combined with international recommendations (e.g. Clinical and Laboratory Standards Institute) and current scientific discussion. Its applicability to an enzyme-linked immunosorbent assay for determination of PRA was investigated within three pediatric trials of the EU-funded "Labeling of Enalapril in Neonates up to Adolescents" project. This quality control system identified 15 % bioanalytical runs as non-compliant to the predefined specifications and ensured the reliable quantification of 940 pharmacodynamic samples. The inter-run assessment of quality controls was able to demonstrate the comparability of the study results. Furthermore, 86 % of incurred sample reanalysis pairs complied with regulatory requirements (>67 %), thus underlining the long-term reproducibility of the utilized ligand-binding assay. Successful participation in interlaboratory testing confirmed the accuracy of the applied method throughout the entire study period. Further investigations showed no notable differences between the five applied lots of the PRA assay. The applicability of this quality control system was proven in an academic environment and ensured reliable results for PRA over the entire 24-month study period.

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 …

Chronic subjective tinnitus is an auditory phantom phenomenon characterized by abnormal neuronal synchrony in the central auditory system. As shown computationally, acoustic coordinated reset (CR) neuromodulation causes a long-lasting desynchronization of pathological synchrony by downregulating abnormal synaptic connectivity. In a previous proof of concept study acoustic CR neuromodulation, employing stimulation tone patterns tailored to the dominant tinnitus frequency, was compared to noisy CR-like stimulation, a CR version significantly detuned by sparing the tinnitus-related pitch range and including substantial random variability of the tone spacing on the frequency axis. Both stimulation protocols caused an acute relief as measured with visual analogue scale scores for tinnitus loudness (VAS-L) and annoyance (VAS-A) in the stimulation-ON condition (i.e. 15 min after stimulation onset), but only acoustic CR neuromodulation had sustained long-lasting therapeutic effects after 12 weeks of treatment as assessed with VAS-L, VAS-A scores and a tinnitus questionnaire (TQ) in the stimulation-OFF condition (i.e. with patients being off stimulation for at least 2.5 h). To understand the source of the long-lasting therapeutic effects, we here study whether acoustic CR neuromodulation has different electrophysiological effects on oscillatory brain activity as compared to noisy CR-like stimulation under stimulation-ON conditions and immediately after cessation of stimulation. To this end, we used a single-blind, single application, cross over design in 18 patients with chronic tonal subjective tinnitus and administered three different 16-minute stimulation protocols: acoustic CR neuromodulation, noisy CR-like stimulation and low frequency range (LFR) stimulation, a CR type stimulation with deliberately detuned pitch and repetition rate of stimulation tones, as control stimulation. We measured VAS-L and VAS-A scores together with spontaneous EEG activity pre-, during- and post-stimulation. Under stimulation-ON conditions acoustic CR neuromodulation and noisy CR-like stimulation had similar effects: a reduction of VAS-L and VAS-A scores together with a decrease of auditory delta power and an increase of auditory alpha and gamma power, without significant differences. In contrast, LFR stimulation had significantly weaker EEG effects and no significant clinical effects under stimulation-ON conditions. The distinguishing feature between acoustic CR neuromodulation and noisy CR-like stimulation were the electrophysiological after-effects. Acoustic CR neuromodulation caused the longest significant reduction of delta and gamma and increase of alpha power in the auditory cortex region. Noisy CR-like stimulation had weaker and LFR stimulation hardly any electrophysiological after-effects. This qualitative difference further supports the assertion that long-term effects of acoustic CR neuromodulation on tinnitus are mediated by a specific disruption of synchronous neural activity. Furthermore, our results indicate that acute electrophysiological after-effects might serve as a marker to further improve desynchronizing sound stimulation., Highlights • Acute effects and acute after-effects of dedicated tinnitus sound therapy are studied with EEG. • Sound therapy causing long-lasting, sustained effects causes pronounced acute after-effects. • Acute EEG after-effects might serve as marker to develop desynchronizing sound therapy.

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.

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.

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.

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.

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.

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.

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.

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.

Women are four to eight times more likely to be affected by fibromyalgia syndrome (FMS). A lack of cortisol, potentially due to an adrenocortical deficit is postulated in FMS. The cause of such adrenal insufficiency is unknown. It could be assumed that stress exposure during critical periods contributes to vulnerability for FMS. These critical periods might include prenatal periods in which adversities may lead to an impaired development of the adrenal cortex, especially in females. More than 50% of FMS patients report major life events before the onset of the disease. Possibly due to adrenal insufficiency they may not be able to dampen their stress response by secreting sufficient glucocorticoids. Thus, stress mediators, such as catecholamines and pro-inflammatory cytokines, may be disinhibited and affect brain function. This might result in an enhanced responsiveness to external and internal pain- and fatigue-eliciting stimuli. In a study with female FMS patients (N = 93) those patients with a shorter gestational length ( 38 weeks (F (3,31) = 2.94, P = 0.038). Additionally, more than 70% reported severe psychological stress alone or in combination with other factors at disease onset.

Das sinubronchiale Syndrom bezeichnet eine Ausweitung sowohl der klinischen Symptomatik als auch der immunologischen und histologischen Schleimhautveranderungen von den oberen (Rhinitis) auf die unteren Atemwege (Asthma bronchiale). Ein solcher Etagenwechsel tritt nach derzeitiger Auffassung bei 20–50% aller unbehandelten Patienten mit allergischer Rhinitis (Pravalenz ca. 20%) innerhalb von 5–15 Jahren auf [1].

In line with the rising number of recreational divers, the otorhinolaryngologist has to deal with growing numbers of diving-associated disorders of the ear, nose and throat (ENT). Nevertheless, the majority of divers present to their ENT doctor for assessment of their fitness to dive. On the basis of long-term follow-up examinations and increasing experience in diving medicine, even divers with a history of ENT problems can be considered fit to dive. Therefore, diving is possible after tympanoplasty, surgery to improve hearing including stapesplasty, after implantation of middle ear amplifiers or cochlear implants, after sinus or scull base surgery and even after canal wall down mastoidectomy, provided that certain requirements are fulfilled. Assessing fitness to dive after inner ear barotrauma as well as after inner ear decompression illness requires meticulous consideration of residual damage and possible underlying conditions like vascular right-to-left shunts. This article is based on the new recommendations of the German Undersea and Hyperbaric Medical Society for the assessment of fitness to dive in the otorhinolaryngological field.

Diving is a very popular leisure activity with an increasing number of participants. As more than 80% of the diving related problems involve the head and neck region, every otorhinolaryngologist should be familiar with diving medical standards. We here present an analysis of more than 300 patients we have treated in the past four years. Between January 2002 and October 2005, 306 patients presented in our department with otorhinological disorders after diving, or after diving accidents. We collected the following data: name, sex, age, date of treatment, date of accident, diagnosis, special aspects of the diagnosis, number of dives, diving certification, whether and which surgery had been performed, history of acute diving accidents or follow up treatment, assessment of fitness to dive and special remarks. The study setting was a retrospective cohort study. The distribution of the disorders was as follows: 24 divers (8%) with external ear disorders, 140 divers (46%) with middle ear disorders, 56 divers (18%) with inner ear disorders, 53 divers (17%) with disorders of the nose and sinuses, 24 divers (8%) with decompression illness (DCI) and 9 divers (3%) who complained of various symptoms. Only 18% of the divers presented with acute disorders. The most common disorder (24%) was Eustachian tube dysfunction. Female divers were significantly more often affected. Chronic sinusitis was found to be associated with a significantly higher number of performed dives. Conservative treatment failed in 30% of the patients but sinus surgery relieved symptoms in all patients of this group. The middle ear is the main problem area for divers. Middle ear ventilation problems due to Eustachian tube dysfunction can be treated conservatively with excellent results whereas pathology of the tympanic membrane and ossicular chain often require surgery. More than four out of five patients visited our department to re-establish their fitness to dive. Although the treatment of acute diving-related disorders is an important field for the treatment of divers, the main need of divers seems to be assessment and recovery of their fitness to dive.

Background. Against the background of constantly intensifying economic pressure in the healthcare sector, in the future confirmation of subjective and economic benefit of different forms of therapy will be the criterion applied by the health insurance companies to decide whether to reimburse the costs they involve. The aim of this study was to provide confirmation that patients with chronic rhinosinusitis (CRS) do benefit from functional endonasal sinus surgery (FESS). Patients and methods. One year after undergoing FESS for the treatment of CRS, 82 patients completed various questionnaires. The Glasgow Benefit Inventory (GBI) was used, as it is a validated instrument for the assessment of benefit. In addition, the patients were asked to complete questionnaires relating to pre- and postoperative use of resources (use of antibiotics, visits to their doctors and time unfit for work) and also to give an overall rating of their satisfaction with the outcome, the difference in their symptoms after FESS and the likelihood that they would recommend this treatment to friends or relatives. Results. Three out of four GBI scales [total score (+22.6), general benefit (+26.8), physical functioning (+23.7)]indicated that patients experienced significant benefit. The frequency of visiting their doctors, their intake of antibiotics and the amount of time off work were all significantly reduced. The vast majority of patients were satisfied with the overall result and the level of symptom relief achieved and would recommend FESS to friends and relatives. Conclusion. The vast majority of these patients with CRS experienced FESS as highly beneficial. A significant reduction of resource usage was reported after the operation.

The total number of competencies mentioned in the Abstract and pages 4 and 5 of the paper are erroneously reported as 60. The actual number is 57. Apologies for the involuntary mistake and confusion created.

To determine the prevalence of alternobaric vertigo (AV) in sport divers and to find out whether AV led to dangerous situations underwater. Furthermore, to examine whether objective neurootologic tests are associated with the manifestation of AV.Retrospective cohort study.Sixty-three sport divers with an average diving experience of 10 years and 650 dives were questioned regarding their medical and diving history and the manifestation of vertigo during diving.Microscopic otoscopy, tympanometry, stapedius reflexes, hearing threshold for air and bone conduction, caloric video-oculography including analysis of the slow-phase velocity of the nystagmus, acoustic brain stem responses, and magnetic resonance imaging were performed to find possible differences between divers with and without AV.We found 17 divers with AV (27%). There was no significant difference in all measured parameters apart from sex and history of middle ear equalization difficulty in divers with AV. Ten (59%) of 17 female divers and 7 (15%) of 46 male divers experienced AV, representing a significant sex difference (p0.001). Correlation with our divers' outpatient clinic revealed that female divers had a significantly higher incidence of middle ear equalization disorders which could be an explanation for the predominance of female divers with symptoms of AV. None of the divers reported any dangerous or life-threatening situations following AV. Whether AV leads to dangerous situations underwater remains unclear, but this hypothesis is not supported by our data.Alternobaric vertigo is a common finding in divers. In our study group, female divers had a four-time higher risk to suffer AV. Our data do not support the thesis that AV is a life-threatening condition.

To determine the prevalence of temporomandibular disorders (TMD) in scuba divers and to identify the risk factors for the development of pain in the stomatognathic system before and after diving by the use of a questionnaire.: Retrospective cohort study based on questionnaires.A total of 296 active divers, aged 18 to 65 years, participating in scuba diving meetings in Heidelberg, Germany.Each diver answered a questionnaire containing 29 questions, predominantly on symptoms of TMD.The data collected from the divers were calculated by the use of logistic regression tests. Risk factors for the development of TMD were evaluated.Clenching seemed to be the greatest risk factor for pain while holding the mouthpiece and for pain in the masticatory muscle system after diving. Limited mouth opening and clenching were responsible for the development of pain in the temporomandibular joint after the dive. The prevalence of TMD-related symptoms was higher in women before, during, and after the dive.Individuals exhibiting TMD-related symptoms seem to be at the greatest risk of developing pain in the masticatory muscle system and/or the temporomandibular joint during or after the dive.

Hintergrund In den letzten Jahren nahm die Zahl der Sporttaucher und in der Folge die Anzahl von Tauchunfallen stetig zu. Die meisten tauchmedizinischen Erkrankungen betreffen das Hals-Nasen-Ohren-arztliche Gebiet. Insbesondere kochleovestibulare Storungen nach dem Tauchen konnen zu persistierenden Schadigungen des Innenohrs fuhren.

Objectives/Hypothesis: Inner ear decompression illness is thought to be a rare phenomenon in recreational divers, isolated signs and symptoms of inner ear dysfunction usually being attributed to inner ear barotrauma. Study Design: We present 11 cases of inner ear dysfunction in nine divers with inner ear decompression illness. Results: All nine divers had significant right-to-left shunt as diagnosed by transcranimal Doppler sonography. Conclusions: The authors thought that mechanism of causation in these cases may have been intravascular bubble emboli and that inner ear decompression illness may be more common among recreational divers than currently recognized. Failure to treat inner ear decompression illness with recompression therapy can result in permanent disability. Because the differential diagnosis between inner ear barotrauma and inner ear decompression illness can be impossible, the authors suggested that divers who present with inner ear symptoms following a dive should have recompression immediately after having undergone bilateral paracentesis.

Background Poorly conceived study designs are still a main reason for clinical trials to fail in paediatric patients. Especially, recruitment of a representative population re-mains hard to be achieved. Low recruitment rates prolong study conduct and reduce data acquisition and quality. Pharmacokinetic and pharmacodynamic investigations are mandatory in the paediatric study designs for submission to competent authorities. Therefore, non-professional tech-niques in blood sampling and patient/parent communica-tion can be main drivers for low recruitment rates. To meet these particular challenges, a novel approach for the train-ing of study teams in the EU-funded LENA project was cho-sen that goes beyond current standards. Aim of LENA (La-belling Enalapril from Newborns up to Adolescents) is to investigate pharmacokinetic (PK) and pharmacodynamics (PD) data of enalapril in children suffering from heart failure. Methods A three-parted modular training was designed by addressing the most critical hurdles of the paediatric LENA trials by focusing on communication of study related information and blood sampling of time-critical and sensi-tive parameters. As first step, the entire team (principle inves-tigator, physicians, nurses) of every clinical centre involved in the project attended a hands-on simulation training at the specialised Medical Simulation Centre in Salzburg. During this training, LENA specific situations were exercised using manikins and original medical devices. Video-based de-briefing of the scenarios enriched the learning experience. In the second training step, the complex PK/PD sampling procedure was refreshed during an on-site training. Scope of this individualised training element was to evaluate the trial centres’ capability for obtaining samples for all pharma-cokinetic and pharmacodynamic investigations as required in the most realistic scenario possible. This phase was de-signed to resemble a regular LENA study-visit and included performance of study related procedures from sampling to bioanalysis at the central laboratory utilising healthy volun-teers. Third, -if requested-the clinical teams were accompa-nied during the first paediatric patient visits by experts to ensure the maximum support during recruitment and study conduct in the beginning. Additionally, participants’ perfor-mance and preparedness for the study as well as the useful-ness of the training were assessed using surveys based on five-point Likert scales. Results 23 participants from five different European coun-tries were trained at the simulation centre. The performance in sampling of time-critical humoral parameters was op-timised to meet the predefined time limits, and to enable maximum reliable data extraction by reducing invalid sam-ples. Participant’s abilities to communicate core elements of the studies and to successfully perform PK/PD sampling increased significantly (p=0.0003). The on-site training re-vealed results out of specification at one site. After repeating the on-site training, PD samples collected at all sites allowed for detection of sensitive parameters in low sample volumes. PK data were within the expected specifications. Conclusion Simulation training and on-site training sub-stantially improved the participants’ performance. This tai-lored training was assessed as a helpful teaching tool in trial preparation and lead to good recruitment rates within the LENA project so far. Further follow-up surveys will evaluate the actual impact of this training on the study success. The research leading to these results has received funding from the EU’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n°6 02 295 (LENA).

A patient in his late 50s who suffered from necrotising fasciitis is described in this case report. The patient first presented at the chest pain unit, where he reported of respiratory distress and showed systemic signs of an infection. Because of progressive skin lesions indicative of necrotising fasciitis on both the lower extremities, the patient was immediately rushed into surgery and was treated at the intensive care unit. Despite receiving immediate treatment, the patient died of this rapidly spreading infectious disease. Because of the fast advance of this disease, we would like to emphasise the importance of early recognition of symptoms.

Background The organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study (‘CLEOPATRA’ study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris. Methods and results A total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo ( n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 weeks of treatment. Treatment with PETN over 12 weeks did not modify the primary endpoint total exercise duration (TED, P = 0.423). In a pre-specified sub-analysis of patients with reduced exercise capacity (TED at baseline ≤9 min, n = 257), PETN appeared more effective than placebo treatment ( P = 0.054). Superiority of PETN over placebo was evident in patients who were symptomatic at low exercise levels ( n = 120; P = 0.017). Pentaerithrityl tetranitrate 80 mg b.i.d. was well tolerated, and the overall safety profile was comparable with placebo. Conclusion Although providing no additional benefit in unselected patients with known coronary artery disease, PETN therapy, administered in addition to modern anti-ischaemic therapy, could increase exercise tolerance in symptomatic patients with reduced exercise capacity.

A better education and training of clinical investigators and their teams is one of the factors that could foster the development of clinical research in Europe, a key objective of the Innovative Medicines Initiative (IMI). PharmaTrain (an IMI programme on training in medicines development), and European Clinical Research Infrastructures Network (ECRIN) have joined forces to address this issue. An advisory group composed of representatives of universities, pharmaceutical companies and other organisations met four times between June 2011 and July 2012. This resulted in a position paper proposing a strategy to improve and harmonize clinical investigator training in Europe, and including a detailed syllabus and list of learning outcomes. Major recommendations are the establishment of minimal and mutually recognized certification requirement for investigators throughout the EU and the creation of a European platform to provide a suitable course and examination infrastructure.

Humans usually show 24-hour sleep-wake cycles, which are geared by an inherent, interindividually varying biological clock. The behavioral daytime preferences differ according to the chronotype, which is in turn basically associated with the timing and controlling of the circadian rhythms of biological and psychological parameters. We were interested in the association between chronotype and the levels of cortisol and the clock gene hPER1 in the evening, and therefore examined 29 healthy men. Our data indicate that morning types show lower levels of cortisol and a lower gene expression of hPER1 in the evening.

Objective To explore the acceptance of uncoated drug-free mini-tablets 2 mm in diameter in children aged 0.5–6 years and their ability to swallow the mini-tablets. Methods 60 children aged 0.5–6 years (10 subjects per year of life) were enrolled in our prospective, open random, two-way cross-over exploratory pilot study. The children were administered either an uncoated drug-free mini-tablet 2 mm in diameter with a beverage of their choice or 3 ml of glucose syrup 15% followed by the other formulation. Deglutition was visually assessed for the two different dosage forms using a predefined criteria list. Results The study hypothesis was that children would accept the liquid formulation better than the solid mini-tablets. Surprisingly, the authors found that the acceptance of the mini-tablets, defined as immediate swallowing or chewing first with subsequent swallowing, was higher or at least equal to that of the syrup. Very young children (6–12 months) were fully capable of swallowing the mini-tablets and may even accept them better than the sweet liquid formulation. Some children aged between 2 and 4 years chewed the tablets before swallowing, but still accepted them quite well. The acceptance rate of the mini-tablets in the different age groups was much higher than expected. Conclusions Uncoated mini-tablets seem to be a very promising alternative to liquid formulations and could be used at an earlier age in paediatric drug therapy than previously anticipated.

To review recent advances in diagnosis and treatment control of gastroduodenal ulcer bleeding with an endoscopic Doppler device. To investigate the effectiveness of prophylactic injection therapy in peptic ulcers after acute haemorrhage. Open prospective study involving 147 patients with bleeding from gastric and duodenal ulcers. Patients without actively bleeding lesions with and without stigmata of recurrent haemorrhage (Forrest II and III ulcers) were included. Endoscopic detection of ulcer localization. Transendoscopic Doppler ultrasound examination with a pulsed high frequency Doppler device. Prophylactic injection treatment in all cases with Doppler-positive lesions (ulcers with arterial vessels responsible for bleeding). Endoscopic and Doppler control investigation was performed on days 2, 5 and 28. The patients were adjuvantly treated with omeprazole. The ulcers in 86 patients (58.5%) were Doppler-positive. After sclerotherapy, relapse bleeding was observed in five patients (5.8%); haemorrhage was successfully stopped endoscopically in two. Three patients (3.5%) had to undergo surgery because of acute arterial haemorrhage. The remaining 61 patients exhibited Doppler-negative lesions without arterial vessels. Two patients suffered from recurrent bleeding (3.3%), which could be managed by injection treatment. The mortality rate in both the Doppler and the non-Doppler group was 0%. Endoscopic Doppler sonography is of high diagnostic value in the evaluation of ulcer haemorrhage. The value of local sclerotherapy was also supported.

Over the last couple of decades, learning through simulation has become popularised for various reasons and is continuing to expand exponentially despite a lack of robust evidence that it actually improves outcomes for patients and learners. There has been a particular growth in the use of high-fidelity virtual reality simulators for surgical training as the technology has become more affordable. In the field of Otolaryngology, simulation appears to help teach simple procedural skills through to complex surgery of the temporal bone and paranasal sinuses. This is happening in an era when quality of care and patient safety are top of the agenda and cadaveric material is in short supply. In this article, we explore the history behind simulation, review the available evidence and discuss its applications within Otolaryngology.

The new length-adjustable titanium prosthesis can give good results in terms of hearing results in ossiculoplasty. The possibility to readjust the length intraoperatively was seen as a good feature.Hearing results of ossiculoplasty with a newly designed prosthesis in 14 patients were evaluated. The prosthesis is designed to allow adjustment of length in situ.A retrospective pilot study was carried out, comparing the preoperative and postoperative audiological and clinical results with an age- and pathology-matched group. The setting was the Department of Otolaryngology at the University of Heidelberg Medical Center, a tertiary referral center. In all, 14 patients underwent tympano-ossiculoplasty in which autologous reconstruction was not an option. The ossiculoplasty was performed as a therapeutic measure with the new titanium prosthesis. We evaluated the air–bone gap closure as established from preoperative and postoperative audiograms. We also looked at the clinical aspect of the tympanic membrane.The average air–bone gap came to a closure within 15 dB in 43% of the cases (6 of 14 patients). No re-perforations or extrusions of the prostheses were observed.