FDA’s Position on Off-Label Use and Promotion of Drugs and Devices and Recent Enforcement Efforts by the Department of Justice

Off-label drug or medical device “use” is the practice of prescribing drugs or medical devices to patients for a purpose not included on the federally approved label. Off-label “marketing” is the practice of attempting to influence physicians to prescribe drugs or devices for off-label purposes. The Federal Food and Drug Administration (FDA) maintains regulatory authority over the proper labeling of drugs and medical devices. This paper summarizes the FDA’s position on off-label use, promotion, and marketing and provides a summary of recent enforcement actions by the U.S. Department of Justice regarding off-label marketing

The effect of sequence and environment on the structure and dimerization of amyloid precursor protein

Aggregation of amyloid β (Aβ) protein has been linked to the development of Alzheimer's Disease (AD). The genesis of Aβ involves the cleavage Amyloid Precursor Protein (APP) by β-secretase, producing the 99-residue C99 peptide, and the subsequent cleavage of C99 by γ-secretase to produce Aβ. A detailed understanding of the γ-cleavage process is essential to our undertsanding of the pathological mechanisms linking the aggregation of Aβ to the development of AD. This work seeks to provide insight into critical aspects of the structure and dynamics of C99, and the particular roles played by (1) C99 amino acid sequence and (2) the lipid composition of the membrane environment. Many studies have focused on the importance of the C99 sequence, including known studies of Familial AD (FAD) mutants as well as engineered mutations. Specific mutations have been found to affect the processing of C99, which has been linked to changes in the structure of C99 and the formation of C99 homodimers. Similarly, changes in the membrane environment, through variation in lipid composition and the presence of cholesterol, have been found to affect C99 structure and positioning within the membrane as well as C99 dimerization. The results of this work extend our understanding of the APP-C99 system and its interaction with the environment. Using a multiscale simulation approach, we find key structural effects of engineered mutations that suggest possible mechanistic insight into the γ-cleavage process. Using C99 congener peptides, we examine the effect of local membrane environment on the dimerization of C99, focusing on the roles of both the transmembrane (TM) region as well as the juxtamembrane (JM) domain. Further studies characterize the role of a FAD mutation, and demonstrate the effect of the mutation on the dimerization of C99 in agreement with experimental findings. Overall, this work leads to critical insight into the role of sequence and membrane on the structure of C99 in a membrane environment, and provides support for the conjecture that the structure of C99 monomer and homodimer are critical to our understanding of the processing of C99, a critical step in the genesis of Aβ peptide and the etiology of Alzheimer's Disease

Some Personal Observations on My Drawing

The reasons for my involvement in drawing for the past two years are several. In particular, I rediscovered drawing at a time when a new approach to solving problems of form in painting was a major concern for me. I had not built up&nbsp; past vocabulary of form and technique in using drawing as a creative means, thus I did not have to unlearn old habits in order to solve problems, but could approach these problems with a fresh material. Even the pencil which is a major element of my recent drawings has become a new tool with endless possibilities. It would probably be possible to say that there is a concern for levels of readability in my drawings. In addition, the success of the drawings depends on the tension that exists between forms that are more easily recognized and those that have an ambiguous nature. &nbsp;</p

The Reliability And Validity Of The Thin Slice Technique: Observational Research On Video Recorded Medical Interactions

The Reliability and Validity of the Thin Slice Technique: Observational Research on Video Recorded Medical Interactions Introduction: Observational research using the thin slice technique has been routinely incorporated in observational research methods, however there is limited evidence supporting use of this technique compared to full interaction coding. The purpose of this study was to determine if this technique could be reliability coded, if ratings are consistent between the first, second and third slice, and if they are indeed representative of full interactions. Methods: Three 30-second thin slices were sampled from the beginning, middle and end of a full-length video-recorded patient/physician interaction collected a part of a larger research study in a low income urban primary care clinic. Thin slice excerpts and full interactions were rated on five dimensions (liking, attention, coordination, trust and rapport) using a nine point Likert scale ranging from `none\u27 to `high\u27 by eight independent coders. Reliability was assessed using the intraclass correlation measure, validity of thin slices was assessed using the Friedman test (non-parametric equivalent of the Repeated measures ANOVA), and the comparison of thin slice coding to full interaction coding was assessed using the Wilcoxon Sign Ranks test (nonparametric version of the Paired t-test). Results: Thin slice reliability on Likert scale items ranged from .762-.910 with an average IRR of .850. Friedman tests conducted on all five variables (liking, attention, coordination, trust and rapport) comparing the rating of the three slices of the interaction were non-significant. Results of the Wilcoxon Signed Ranks test indicated there was a significant difference between the composite thin slice rating (average across three slices) and the full interaction ratings with full interaction variables rated consistently higher than their respective thin slice composite. Conclusion: Results indicate that thin slices can be reliability coded by independent coders with a high degree of agreement across coders. Observational ratings across thin slices sampled at the beginning middle and end of an interaction were not significantly different demonstrating convergent validity. However, there was a significant difference between ratings obtained from thin slices and ratings obtained from the interaction as a whole, indicating care should be taken when thin slices are used to represent the interaction as a whole

Maternal fish oil supplementation in pregnancy: A 12 year follow-up of a randomised controlled test

A number of trials have been undertaken to assess whether the intake of omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) during pregnancy can influence the neurological development of the offspring, yet no consensus from these trials has been reached. We aimed to investigate the long-term effects (12 years) of fish oil supplementation in pregnancy on neurodevelopment, including cognition, language and fine motor skills. In a follow up of a previously published randomised controlled trial of 98 pregnant women, their children were assessed at 12 years of age using a battery of neurodevelopmental assessments. Fifty participants were assessed at 12 years, with 25 participant’s mothers receiving fish oil supplementation, and 25 receiving control capsules. There were no significant differences for any of the assessment measures completed. Our data indicate that fish oil supplementation during pregnancy does not influence the cognition, language or fine motor skills of children in late primary school (12 years of age)

Measuring troublesomeness of chronic pain by location

Background Current measures of pain assess the relative contribution of pain in different body regions to the overall impact of pain. We developed a series of questions to measure the relative 'troublesomeness' of pain in different body regions (the "troublesomeness grid"). The study aimed to determine whether the "troublesomeness grid" is an appropriate measure to assess the severity of pain in different body regions, allowing the comparative severity of pain in different body regions to be assessed. Methods We used data from a pilot for a population survey of pain (N = 205) and from the population survey itself (N = 2504) to assess the 'troublesomeness grid's performance. Specifically, its face and content validity using overall and item non-completion rates; its criterion related validity by exploring the relationship between troublesomeness and standard measures of pain, disability, distress and health utility for the five body regions most commonly affected by chronic pain; and its reliability and reproducibility in a test/re-test study. Results The troublesomeness grid appeared to have good face validity as it had good completion rates. It also appeared to have good content validity as the percentage agreement between the grid and the pain manikin was high (over 90%). In terms of criterion related validity, troublesomeness was most strongly correlated with pain intensity and health related quality of life, but less with disability and distress. The test-retest reliability was between 80% and 90% for the majority of body regions examined. Conclusion The troublesomeness grid is well completed and appears to be an appropriate tool to assess the comparative severity of pain in different body regions

Evaluation of best practices in the design of online evidence-based practice instructional modules

OBJECTIVES: The research determined to what extent best practices are being followed by freely available online modules aimed at teaching critical thinking and evidence-based practices (EBPs) in health sciences fields. METHODS: In phase I, an evaluation rubric was created after reviewing the literature. Individual rubric questions were assigned point values and grouped into sections, and the sections weighted. Phase II involved searching Internet platforms to locate online EBP modules, which were screened to determine if they met predetermined criteria for inclusion. Phase III comprised a first evaluation, in which two authors assessed each module, followed by a second evaluation of the top-scoring modules by five representatives from different health sciences units. RESULTS: The rubric's 28 questions were categorized into 4 sections: content, design, interactivity, and usability. After retrieving 170 online modules and closely screening 91, 42 were in the first evaluation and 8 modules were in the second evaluation. Modules in the first evaluation earned, on average, 59% of available points; modules in the second earned an average of 68%. Both evaluations had a moderate level of inter-rater reliability. CONCLUSIONS: The rubric was effective and reliable in evaluating the modules. Most modules followed best practices for content and usability but not for design and interactivity. IMPLICATIONS: By systematically collecting and evaluating instructional modules, the authors found many potentially useful elements for module creation. Also, by reviewing the limitations of the evaluated modules, the authors were able to anticipate and plan ways to overcome potential issues in module design

Serine Phosphorylation of HIV-1 Vpu and Its Binding to Tetherin Regulates Interaction with Clathrin Adaptors

HIV-1 Vpu prevents incorporation of tetherin (BST2/ CD317) into budding virions and targets it for ESCRT-dependent endosomal degradation via a clathrin-dependent process. This requires a variant acidic dileucine-sorting motif (ExxxLV) in Vpu. Structural studies demonstrate that recombinant Vpu/tetherin fusions can form a ternary complex with the clathrin adaptor AP-1. However, open questions still exist about Vpu's mechanism of action. Particularly, whether endosomal degradation and the recruitment of the E3 ubiquitin ligase SCFβTRCP1/2 to a conserved phosphorylated binding site, DSGNES, are required for antagonism. Re-evaluation of the phenotype of Vpu phosphorylation mutants and naturally occurring allelic variants reveals that the requirement for the Vpu phosphoserine motif in tetherin antagonism is dissociable from SCFβTRCP1/2 and ESCRT-dependent tetherin degradation. Vpu phospho-mutants phenocopy ExxxLV mutants, and can be rescued by direct clathrin interaction in the absence of SCFβTRCP1/2 recruitment. Moreover, we demonstrate physical interaction between Vpu and AP-1 or AP-2 in cells. This requires Vpu/tetherin transmembrane domain interactions as well as the ExxxLV motif. Importantly, it also requires the Vpu phosphoserine motif and adjacent acidic residues. Taken together these data explain the discordance between the role of SCFβTRCP1/2 and Vpu phosphorylation in tetherin antagonism, and indicate that phosphorylation of Vpu in Vpu/tetherin complexes regulates promiscuous recruitment of adaptors, implicating clathrin-dependent sorting as an essential first step in tetherin antagonism

The regulation of circadian entrainment in mice by the adenosine the A2A/A1 receptor antagonist CT1500

Circadian entrainment in mice relies primarily on photic cues that trigger the transcription of the core clock genes Period1/2 in the suprachiasmatic nucleus (SCN), thus aligning the phase of the clock with the dawn/dusk cycle. It has been shown previously that this pathway is directly regulated by adenosine signalling and that adenosine A2A/A1 receptor antagonists can both enhance photic entrainment and phase shift circadian rhythms of wheel-running behaviour in mice. In this study, we tested the ability of CT1500, a clinically safe adenosine A2A/A1 receptor antagonist to effect circadian entrainment. We show that CT1500 lengthens circadian period in SCN ex vivo preparations. Furthermore, we show in vivo that a single dose of CT1500 enhances re-entrainment to a shifted light dark cycle in a dose-dependent manner in mice and also phase shifts the circadian clock under constant dark with a clear time-of-day related pattern. The phase response curve shows CT1500 causes phase advances during the day and phase delays at dusk. Finally, we show that daily timed administration of CT1500 can entrain the circadian clock to a 24 h rhythm in free-running mice. Collectively, these data support the use of CT1500 in the treatment of disorders of circadian entrainment