IntroductionPragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as “pragmatic” or “naturalistic”. We focused on 89 of these trials that assessed medicines (drugs or biologics).Discussion36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term ‘pragmatic’ to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as ‘pragmatic’ and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic).ConclusionsTo allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real-world practice.

IntroductionThe preclinical phase of Alzheimer's disease (AD) is optimal for identifying early pathophysiological events and developing prevention programs, which are shared aims of the ALFA project, including the ALFA registry and parent cohort and the nested ALFA+ cohort study.MethodsThe ALFA parent cohort baseline visit included full cognitive evaluation, lifestyle habits questionnaires, DNA extraction, and MRI. The nested ALFA+ study adds wet and imaging biomarkers for deeper phenotyping.ResultsA total of 2743 participants aged 45 to 74 years were included in the ALFA parent cohort. We show that this cohort, mostly composed of cognitively normal offspring of AD patients, is enriched for AD genetic risk factors.DiscussionThe ALFA project represents a valuable infrastructure that will leverage with different studies and trials to prevent AD. The longitudinal ALFA+ cohort will serve to untangle the natural history of the disease and to model the preclinical stages to develop successful trials.

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A geographical analysis of how commonly prescribed oral antibiotics are quantitatively and qualitatively responsible for the different local rates of erythromycin and penicillin resistance in Streptococcus pneumoniae in Spain is presented. From 1998 to 1999 a multicenter surveillance study yielded 1,684 consecutive S. pneumoniae isolates from community-acquired respiratory infections. Data on antibiotic sales in the retail market for the same period were gathered, and the corresponding defined doses per 1,000 inhabitants per day were calculated. Macrolides and ␤-lactams were considered separately. Macrolides were subdivided into thrice-, twice-, and once-a-day macrolides, and ␤-lactams were split into aminopenicillins and cephalosporins. Univariate Spearman nonparametric coefficients (R) were calculated, and variables proving to be significantly associated (P < 0.1) were entered into several multiple lineal regression models. Ample variation in both resistance rates and antibiotic consumption was seen. Multivariate analyses showed that integrated consumption of both macrolides and ␤-lactams accounted well for erythromycin (R 2 ‫؍‬ 0.722; P ‫؍‬ 0.002) and penicillin (R 2 ‫؍‬ 0.706; P ‫؍‬ 0.002) resistance. Macrolides were more important drivers for local differences in both erythromycin and penicillin resistance than ␤-lactams were. Consumption of once-a-day macrolides was key for local erythromycin resistance variations. Cephalosporins were slightly more important penicillin resistance drivers than aminopenicillins were.The increasing development of resistance in Streptococcus pneumoniae not only to a single antibiotic but to many antibiotics at the same time (5) (multiresistant S. pneumoniae) is a striking example of the evolutionary adaptability of bacterial populations to antibiotic action. Antibiotics seem to have selected specific subpopulations resistant to the antibiotics frequently prescribed for common infections.The development and subsequent spread of resistant pneumococci do not follow the same pace in different regions of the world. While in Northern European countries, rates of resistance to erythromycin and penicillin remain low, in Spain, France, Hong Kong and certain U.S. states, these rates may be above 50% (5). However, even in low-risk countries, a steady progression of resistance over recent years is being observed (1, 2, 12).Antibiotics are increasingly recognized as the leading force in this growth of resistance (8,9,11,20). Nevertheless, studies performed so far to confirm this issue can only indirectly support the hypothesis of antibiotic consumption as the main driver for resistance differences. Even studies exploring the temporal coincidence between increased antibiotic consumption and resistance do not provide straightforward causal evidence. If the hypothesis is correct, then a positive correlation between antibiotic use in a given location and the corresponding prevalence of resistance should be expected. The aim of this study was to explore this hypothesis as well as to try to asce...

The development of new massive sequencing techniques has now made it possible to significantly reduce the time and costs of whole-genome sequencing (WGS). Although WGS will soon become a routine testing tool, new ethical issues have surfaced. In light of these concerns, a systematic review of papers published by expert authors on IC or specific ethical issues related to IC for WGS analysis in the clinical setting has been conducted using the Pubmed, Embase and Cochrane Library databases. Additionally, a search was conducted for international ethical guidelines for genetic studies published by scientific societies and ethical boards. Based on these documents, a minimum set of information to be provided to patients in the IC form was determined. Fourteen and seven documents from the database search and from scientific societies, respectively, were selected. A very high level of consistency between them was found regarding the recommended IC form content. Pre-test counselling and general information common to all genetic tests should be included in the IC form for WGS for diagnostic purposes, but additional information addressing specific issues on WGS are proposed, such as a plan for the ethical, clinically oriented return of incidental findings. Moreover, storage of additional information for future use should also be agreed upon with the patient in advance. Recommendations for WGS studies in the clinical setting concerning both the elements of information and the process of obtaining the IC as well as how to handle the results obtained are proposed.

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A multicenter susceptibility surveillance (the S.A.U.C.E. project) including 2,721 Streptococcus pneumoniae, 3,174 Streptococcus pyogenes, and 2,645 Haemophilus influenzae consecutive isolates was carried out in 25 hospitals all over Spain from November 2001 to October 2002 to evaluate the current epidemiology of resistance of the main bacteria involved in community-acquired respiratory tract infections. Susceptibility testing was performed in a single centralized laboratory by a broth microdilution method. The prevalence of resistant S. pneumoniae strains was 0.4% for cefotaxime, 4.4% for amoxicillin and amoxicillin-clavulanic acid, 25.6% for cefuroxime-axetil, 34.5% for erythromycin, clarithromycin, and azithromycin, and 36.0% for cefaclor. Phenotypes of resistance to erythromycin were MLS B (macrolide-lincosamide-streptogramin B) in 89.9% (gene ermB) and M (macrolide) in 9.7% of cases (gene mefA). No strain harbored both genes simultaneously. Serotypes 19, 6, 23, 14, and 3 were the most prevalent, accounting for 54.6% of the total isolates. Resistance to macrolides seems to be the most alarming point, since among penicillin-susceptible isolates it reached 15.1% compared to 55.8% among penicillin-resistant strains. Geographically, a number of regions had rates of erythromycin resistance above 40% (even higher in children). Resistance to erythromycin was also high in S. pyogenes isolates: mean regional 33.2%, beta-lactamase-producing H. influenzae were 20%, whereas 4.4% had a beta-lactamase-negative, ampicillin-resistant phenotype. We highlight the importance of different geographical frequencies of coresistance (associations of resistance to different drugs within the same species) and coupled resistance (association of resistance between different species) probably resulting from different local coselective events.Surveillance of antimicrobial resistance should be considered an important tool helping clinicians tailor empirical prescriptions for common infectious diseases. Surveillance data also serve as sentinel checkpoints for emerging phenotypes of resistance and enable performance of studies aiming at characterizing molecular resistance determinants alongside the possibility of tracking the genotypic or clonal relatedness of the isolates harboring the resistance traits detected (4). Besides, when coupled with appropriate data of antimicrobial consumption, they contribute to the understanding of the complex dynamics of the pharmacoepidemiology of resistance. Ideally, they should also serve to assess the impact of measures implemented in response to resistance warnings.The most prevalent bacteria causing community-acquired respiratory tract infections are Streptococcus pneumoniae, Streptococcus pyogenes, and Haemophilus influenzae. In all of

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