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Clinicians and patients often try a treatment for an initial period to inform longer-term therapeutic decisions. A more rigorous approach involves N-of-1 trials. In these single-patient crossover trials, typically conducted in patients with chronic conditions, individual patients are given candidate treatments in a double-blinded, random sequence of alternating periods to determine the most effective treatment for that patient. However, to date, these trials are rarely done outside of research settings and have not been integrated into general care where they could offer substantial benefit. Designating this classical, N-of-1 trial design as type 1, there also are new and evolving uses of N-of-1 trials that we designate as type 2. In these, rather than focusing on optimizing treatment for chronic diseases when multiple approved choices are available, as is typical of type 1, a type 2 N-of-1 trial tests treatments designed specifically for a patient with a rare disease, to facilitate personalized medicine. While the aims differ, both types face the challenge of collecting individual-patient evidence using standard, trusted, widely accepted methods. To fulfill their potential for producing both clinical and research benefits, and to be available for wide use, N-of-1 trials will have to fit into the current healthcare ecosystem. This will require generalizable and accepted processes, platforms, methods, and standards. This also will require sustainable value-based arrangements among key stakeholders. In this article, we review opportunities, stakeholders, issues, and possible approaches that could support general use of N-of-1 trials and deliver benefit to patients and the healthcare enterprise. To assess and expand the benefits of N-of-1 trials, we propose multistakeholder meetings, workshops, and the generation of methods, standards, and platforms that would support wider availability and the value of N-of-1 trials.

Abstract Emil Kraepelin's nosology has been reinvented, for better or worse. In the United States, the rise of the neo-Kraepelinian nosology of DSM-III resuscitated Kraepelin's work but also differed from many of his ideas, especially his overtly biological ontology. This neo-Kraepelinian system has led to concerns regarding overdiagnosis of psychiatric syndromes ("nosologomania") and perhaps scientifically ill-founded psychopharmacological treatment for presumed neo-Kraepelinian syndromes. In the early 20th century, Karl Jaspers provided unique insights into Kraepelin's work, and Jaspers even proposed an alternate nosology which, though influenced by Kraepelin, also introduced the concept of ideal types. Jaspers' critique of Kraepelin may help us reformulate our current neo-Kraepelinian nosology for the better.

Abstract Objective To assess the scientific and ethical basis for clinical innovation in psychopharmacology. Methods We conducted a literature review, utilizing MEDLINE search and bibliographic cross-referencing, and historical evidence regarding the discovery and development of new medications in psychiatry. Clinical innovation was defined as use of treatments in a clinical setting which have not been well-proven in a research setting. Results Empirical data regarding the impact of clinical innovation in psychopharmacology are lacking. A conceptual and historical assessment of this topic highlights the ethical and scientific importance of clinical innovation. Ethically, it touches a borderline that, in our judgment, is not adequately framed in contemporary mainstream bioethics. Currently, research is viewed as not at all benefiting the patients who participate in it, while clinical care is viewed as being solely for the benefit of patients. Clinical innovation straddles these two worlds, uncomfortably at times. While many argue that clinical innovation should either be avoided or folded into research projects, we argue that clinical innovation is necessary for progress in psychopharmacology research, and that it can prosper best when guided by the following ethical principles: 1.) The treatment should be based on a viable hypothesis. 2.) Whenever possible, one's clinical observations should be reported so they can be evaluated by the scientific community. 3.) One should be willing to report unexpected observations of drug effects. 4.) A high standard of informed consent should be maintained. Again, this proposal goes against the standard view among bioethicists that research and clinical care are categorically opposed activities, as made clear by the either-or dichotomy of the Belmont Report on bioethics. This approach has so polarized our profession into clinicians versus researchers, that many clinicians will not apply new knowledge produced by clinical research until it eventually gets incorporated into formal treatment guidelines, while researchers have little to guide them as to what kind of new knowledge it is most important to provide. Summary Clinical innovation brings out the ambiguities in our current ethical conceptions of research versus clinical care. Yet, historically, clinical innovation has been an important contributor to progress in psychopharmacology. We argue that clinical innovation should not be discouraged, but rather it should occur under certain ethical conditions. "Almost everyone can and should do research...because almost everyone has a unique observational opportunity at some time in his life which he has an obligation to record....If one considers the fundamental operations or methods of research, one immediately realizes that most people do research at some time or another, except that they do not call their activity by that name. There are seven operations....In simple language they are counting, sorting, measuring, comparing, nature-study, guess testing, and reappraisal....Guess testing is of course what most people think of when the word research is mentioned; except that it is bad manners to call a guess a guess. It should be called an hypothesis. Let us make one plea. Guessing becomes merely a game unless it is done in the context of a plan for action. It is a waste of time elaborating untestable hypotheses 1." John Cade

Excipients, considered "inactive ingredients," are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant K d values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.

This study investigated the turbulent wake flow behind a flat-back Ahmed body using a combination of time-resolved tomographic particle image velocimetry measurements and spectral proper orthogonal decomposition (SPOD). The experiments were conducted at a Reynolds number of ReH = 10 000, which is defined as U∞H / ν , where U∞ represents the free-stream velocity, H is the height of the body and ν represents the viscosity. The SPOD analysis revealed four distinct flow motions present in the wake of the Ahmed body, each occupying a specific range of Strouhal number, StH. Here, StH is defined as f × H / U∞ , where f is the frequency of the motion. At the lowest resolved StH of 0.007, the system exhibited a bi-stability mode, in which the wake switched between asymmetric states consisting of a tilted toroidal vortex and a streamwise vortex. In the next StH range of 0.014 to 0.123, the flow demonstrated swinging/flapping motions, characterized by small spanwise and vertical movements of the wake barycentre. These movements were attributed to the tilting of the toroidal vortex. The third category included the vortex-shedding motions and consisted of quasi-streamwise vortices. These vortices advected in the downstream direction, causing oblique displacements of the barycentre in the streamwise-vertical plane. The peak energy of the vortex shedding was observed at StH = 0.164. Finally, shear layer instabilities induced small vertical and spanwise velocity fluctuations along the shear layers at a high StH of 1.147. [ABSTRACT FROM AUTHOR]