pneumophila, as well as Alisertib MLN8237 the mechanisms and functions of bifunctional DGC/PDE enzymes from other bacteria, has yet to be investigated. Active versus degenerate domains. The availability of high-resolution crystal structures of GGDEF, EAL, and HD-GYP domains combined with site-directed mutagenesis studies allowed the formulation of general rules for distinguishing domains that are likely to be enzymatically active versus degenerate, inactive domains (Fig. 3 and and4).4). In the GGDEF domain, the active site includes the catalytic Asp/Glu residue surroundeA systematic review may evaluate different aspects of a health care intervention such efficacy, effectiveness, and adverse events [1].

To accommodate the evaluation of various research questions such as efficacy or effectiveness and outcomes such as survival or severe adverse events, the inclusion of more than one study design appears to be necessary. If multiple study designs are included in a systematic review they should be well selected and customized to answer to the questions of interest. Efficacy addresses the question whether the intervention of interest can work in the ideal study setting (randomized controlled trial) and typically provides a conclusion for an average patient only [2]. In some situations RCTs are not feasible due to ethical concerns or due to strong patients’ preferences and the results may not be applicable to everyday practice [3]. Some nonrandomized studies are designed to evaluate effectiveness and may show that interventions will work under every day circumstances, for example in a general practice [4].

Effectiveness typically provides a conclusion for a subgroup of patients that can be applied to individual patients. Adverse events can be crucial for approval, the restriction of application to particular indications, or the discontinuation of drugs or other interventions. The comprehensive detection of adverse events may need a long-term observation of a large number of participants and an experimental research design could become a costly and unsuccessful enterprise. It appears that many public commissioners provide predominantly funding for efficacy research [4]. A considerable proportion of researchers appears dichotomized to either require the randomized design for scientific evidence on health care interventions or to also accept designs without randomization as sufficient [5].

A ‘hierarchy of evidence’ was established that clearly downgrades designs other than randomized studies regardless of the type of outcome evaluated [6]. Cilengitide Some authors questioned this hierarchy [7,8]. Advantages and disadvantages of various designs have been reported repeatedly and some authors support the integration of multiple study designs with respect to the outcome of interest [5]. We did not find a report that systematically summarized methods papers about usefulness and complexity of integrating various designs in one systematic review.