Conducting research in individual patients: lessons learnt from two series of N-of-1 trials

BACKGROUND: Double-blind randomised N-of-1 trials (N-of-1 trials) may help with decisions concerning treatment when there is doubt regarding the effectiveness and suitability of medication for individual patients. The patient is his or her own control, and receives the experimental and the control treatment during several periods of time in random order. Reports of N-of-1 trials are still relatively scarce, and the research methodology is not as firmly established as that of RCTs. Recently, we have conducted two series of N-of-1 trials in general practice. Before, during, and after data-collection, difficulties regarding outcome assessment, analysis of the results, the withdrawal of patients, and the follow-up had to be dealt with. These difficulties are described and our solutions are discussed. DISCUSSION: To prevent or anticipate difficulties in N-of-1 trials, we argue that that it is important to individualise the outcome measures, and to carefully consider the objective, type of randomisation and the analysis. It is recommended to use the same dosages and dosage forms that the patient used before the trial, to start the trial with a run-in period, to formulate both general and individualised decision rules regarding the efficacy of treatment, to adjust treatment policies immediately after the trial, and to provide adequate instructions and support if treatment is adjusted. SUMMARY: Because of the specific characteristics of N-of-1 trials it is difficult to formulate general 'how to do it' guidelines for designing N-of-1 trials. However, when the design of each N-of-1 trial is tailored to the specific characteristics of each individual patient and the underlying medical problem, most difficulties in N-of-1 trials can be prevented or overcome. In this way, N-of-1 trials may be of help when deciding on drug treatment for individual patients

Common and Distinct Genetic Properties of ESCRT-II Components in Drosophila

BACKGROUND: Genetic studies in yeast have identified class E vps genes that form the ESCRT complexes required for protein sorting at the early endosome. In Drosophila, mutations of the ESCRT-II component vps25 cause endosomal defects leading to accumulation of Notch protein and increased Notch pathway activity. These endosomal and signaling defects are thought to account for several phenotypes. Depending on the developmental context, two different types of overgrowth can be detected. Tissue predominantly mutant for vps25 displays neoplastic tumor characteristics. In contrast, vps25 mutant clones in a wild-type background trigger hyperplastic overgrowth in a non-autonomous manner. In addition, vps25 mutant clones also promote apoptotic resistance in a non-autonomous manner. PRINCIPAL FINDINGS: Here, we genetically characterize the remaining ESCRT-II components vps22 and vps36. Like vps25, mutants of vps22 and vps36 display endosomal defects, accumulate Notch protein and--when the tissue is predominantly mutant--show neoplastic tumor characteristics. However, despite these common phenotypes, they have distinct non-autonomous phenotypes. While vps22 mutations cause strong non-autonomous overgrowth, they do not affect apoptotic resistance. In contrast, vps36 mutations increase apoptotic resistance, but have little effect on non-autonomous proliferation. Further characterization reveals that although all ESCRT-II mutants accumulate Notch protein, only vps22 and vps25 mutations trigger Notch activity. CONCLUSIONS/SIGNIFICANCE: The ESCRT-II components vps22, vps25 and vps36 display common and distinct genetic properties. Our data redefine the role of Notch for hyperplastic and neoplastic overgrowth in these mutants. While Notch is required for hyperplastic growth, it appears to be dispensable for neoplastic transformation

Team Learning: the Missing Construct from a Cross-Cultural Examination of Higher Education?

Team learning should be an important construct in organizational management research because team learning can enhance organizational learning and overall performance. However, there is limited understanding of how team learning works in different cultural contexts. Using an international comparative research approach, we developed a framework of antecedents and outcomes in the higher education context and tested it with samples from the UK and Vietnam. The results show that a common framework is applicable in the two different contexts, subject to slight modifications. However, this study does not find that team learning (measured via the proxy of “attitude towards team learning”) exhibits any statistically significant relationship as a predictor of the proposed outcomes. Other findings from this study on educational contexts are important not only to scholars in this field, but also for practicing managers, particularly those who study and operate in the extensive global market

Review of methods used by chiropractors to determine the site for applying manipulation

Background: With the development of increasing evidence for the use of manipulation in the management of musculoskeletal conditions, there is growing interest in identifying the appropriate indications for care. Recently, attempts have been made to develop clinical prediction rules, however the validity of these clinical prediction rules remains unclear and their impact on care delivery has yet to be established. The current study was designed to evaluate the literature on the validity and reliability of the more common methods used by doctors of chiropractic to inform the choice of the site at which to apply spinal manipulation. Methods: Structured searches were conducted in Medline, PubMed, CINAHL and ICL, supported by hand searches of archives, to identify studies of the diagnostic reliability and validity of common methods used to identify the site of treatment application. To be included, studies were to present original data from studies of human subjects and be designed to address the region or location of care delivery. Only English language manuscripts from peer-reviewed journals were included. The quality of evidence was ranked using QUADAS for validity and QAREL for reliability, as appropriate. Data were extracted and synthesized, and were evaluated in terms of strength of evidence and the degree to which the evidence was favourable for clinical use of the method under investigation. Results: A total of 2594 titles were screened from which 201 articles met all inclusion criteria. The spectrum of manuscript quality was quite broad, as was the degree to which the evidence favoured clinical application of the diagnostic methods reviewed. The most convincing favourable evidence was for methods which confirmed or provoked pain at a specific spinal segmental level or region. There was also high quality evidence supporting the use, with limitations, of static and motion palpation, and measures of leg length inequality. Evidence of mixed quality supported the use, with limitations, of postural evaluation. The evidence was unclear on the applicability of measures of stiffness and the use of spinal x-rays. The evidence was of mixed quality, but unfavourable for the use of manual muscle testing, skin conductance, surface electromyography and skin temperature measurement. Conclusions: A considerable range of methods is in use for determining where in the spine to administer spinal manipulation. The currently published evidence falls across a spectrum ranging from strongly favourable to strongly unfavourable in regard to using these methods. In general, the stronger and more favourable evidence is for those procedures which take a direct measure of the presumptive site of care– methods involving pain provocation upon palpation or localized tissue examination. Procedures which involve some indirect assessment for identifying the manipulable lesion of the spine–such as skin conductance or thermography–tend not to be supported by the available evidence.https://doi.org/10.1186/2045-709X-21-3