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BACKGROUND A clinical research application must be submitted for approval by a competent ethics committee (EC) before a study can be executed. There is very limited information on how such submissions could be optimised, especially regarding research in children and adolescents, which requires particular caution and age-adapted patient information. METHODS We assessed all research applications from the University Children’s Hospital Zurich submitted to the EC of the Canton of Zurich in 2014–2015, i.e., in the first two years after Switzerland’s new Human Research Act came into effect. Moreover, we validated our findings by assessing a randomly selected sample of applications from the same hospital in 2018–2019. RESULTS We assessed a total of 86 applications from 2014–2015, originating from 29 departments and sub-specialties. The EC judged that it was not responsible for three applications and declined an assessment for another three because the studies had already been conducted. Thus, we included 80 applications in the present analysis (18 clinical trials, 52 research projects, 10 further use projects). Applicants withdrew four applications before the EC’s final decision and the EC rejected two after assessment. The EC had objections in 46 (62%) of the remaining 74 applications. Formal, including formal legal, objections (n = 503) and legal objections (n = 287) accounted for the vast majority of objections. There were also 71 ethical and 82 scientific objections. The most frequent formal and formal legal objections were incomplete or missing age-adapted patient information (49%) and incorrect templates for informed consent and signature forms (46%). A review of the 20 randomly selected applications from 2018–2019 confirmed that four out of the five most frequent deficiencies relating to informed consent were identical to those observed in the 2014–2015 applications. CONCLUSIONS Careful preparation of submission documents by the investigators and close adherence to formal and legal requirements have the potential to considerably optimise and expedite the EC review process, and thus the commencement of the clinical research. Keywords: age-adapted patient information, formal deficiencies, legal deficiencies, ethical deficiencies, scientific deficiencies

The issue of contraception and pregnancy tests among minor adolescent women participating in clinical trials, whether healthy or suffering from a disease, represents a challenging issue for paediatricians and researchers, given the potential harmful effect of various therapeutic procedures being tested. First, they need to gauge at what age or developmental stage they need to impose pregnancy tests and contraception. Second, if the adolescent denies any sexual activity, it may be ethically questionable to impose such procedures. Third, these professionals must deal with the issue of confidentiality, taking into account the fact that some adolescents engage in penetrative sexual intercourse without their parents or caregivers knowing. Fourth, in such cases, they must assess the extent to which a minor adolescent can be considered as competent (capable of making autonomous decisions) and deserves privacy and confidentiality. There is indeed a legal obligation for the provider to check that sexual experiences and intercourse take place within a safe relationship. Fifth, if the prescription of contraception is warranted, they have to decide who should assist the adolescent in choosing the method. Finally, with the occurrence of a positive pregnancy test, they may face the rare instance of a competent minor adolescent who refuses to inform her parents. This article has been developed by a group of experts under the auspices of swissethics, the Swiss Association of Research Ethics Committees and SwissPedNet, the umbrella organisation that coordinates the paediatric research in Switzerland. The paper reviews how to address practical and ethical questions regarding minor adolescents of childbearing potential enrolled in a clinical trial that may involve teratogenic medication and offers a series of concrete advice and tools for dealing with problematic situations. Most paediatric protocols stipulate that adolescents included in clinical trials involving potentially teratogenic drugs should undergo pregnancy tests and use contraception. The circumstances in which such requirements are undertaken, however, has not been sufficiently addressed. The recommendations presented in this article will assist researchers in assessing which circumstances apply when considering minor adolescents as individuals with childbearing potentials. It also offers concrete suggestions for tackling such situations.

The use of a combined (composite) endpoint as a primary outcome in clinical studies offers many advantages, e.g., increased statistical efficiency, smaller sample sizes, shorter study completion times, and the possibility for a summary measure of different treatment effects. However, basic clinical and statistical requirements need to be respected in order to obtain valid results and to avoid difficulties in their interpretation later. Each component of a combined endpoint must be clinically meaningful. Patients must be followed up until death or to the planned end of the trial; these rules also apply to premature treatment withdrawal or after occurrence of the first pre-defined component event. All components of the composite endpoint need to be analysed separately in order to find out how they contribute to the overall result and to avoid the masking of negative effects on one or more components. Difficulties in interpretation may arise when the results for single components of the combined endpoint head in opposite directions, and when "hard" clinical outcomes are combined with "soft" endpoints, particularly if the latter occur much more frequently but are of minor clinical relevance.

Oxidative stress and endothelial dysfunction have been introduced as a unifying pathological mechanism for early atherosclerotic disease. They are caused by a variety of stimuli including cigarette smoking (environmental) and type 2 diabetes (disease factor). However, the role of hyperinsulinemia, a marker of insulin resistance, as a risk factor for atherosclerosis remains to be clarified.To study the relationship of smoking, hyperinsulinaemia and biochemical markers of oxidative stress and endothelial dysfunction, in patients with coronary artery disease.Case-control study of 5-year survivor status in smokers, former smokers and nonsmokers with angiographically documented stable coronary artery disease classified by self-reporting of smoking status together with plasma cotinine measurements.Cardiology and cardiac surgery unit of a tertiary care referral centre.Plasma levels of vitamins C, E and selenium, and the adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed in 214 patients at baseline together with the glucose and insulin response to an oral glucose challenge. Sixty known or newly diagnosed type 2 diabetic patients (28%) were identified and excluded from further analysis.E-selectin and ICAM-1, serving as markers of endothelial dysfunction, significantly correlated with hyperinsulinaemia (p0.05). Circulating immunoreactive insulin was elevated in active smokers and former smokers as compared to non-smokers after an oral glucose load (p0.05 for the area under the insulin time curve), despite a similar glucose response. Smoking was associated with a decrease in antioxidant vitamins C (p = 0.02) and E (p = 0.03), and an increase of E-selectin (p0.05) and ICAM-1 (p0.001). Low baseline ICAM-1 and high vitamin C levels emerged as the most significant multivariate predictors of 5-year survival (p0.001).Hyperinsulinaemia in smokers is linked with markers of endothelial dysfunction. Impaired vascular reactivity can thus be a new possible mechanism linking insulin resistance and smoking.