Requirements for generic anti-epileptic medicines: a regulatory perspective

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Workplace-based assessment: effects of rater expertise

Traditional psychometric approaches towards assessment tend to focus exclusively on quantitative properties of assessment outcomes. This may limit more meaningful educational approaches towards workplace-based assessment (WBA). Cognition-based models of WBA argue that assessment outcomes are determined by cognitive processes by raters which are very similar to reasoning, judgment and decision making in professional domains such as medicine. The present study explores cognitive processes that underlie judgment and decision making by raters when observing performance in the clinical workplace. It specifically focuses on how differences in rating experience influence information processing by raters. Verbal protocol analysis was used to investigate how experienced and non-experienced raters select and use observational data to arrive at judgments and decisions about trainees’ performance in the clinical workplace. Differences between experienced and non-experienced raters were assessed with respect to time spent on information analysis and representation of trainee performance; performance scores; and information processing––using qualitative-based quantitative analysis of verbal data. Results showed expert-novice differences in time needed for representation of trainee performance, depending on complexity of the rating task. Experts paid more attention to situation-specific cues in the assessment context and they generated (significantly) more interpretations and fewer literal descriptions of observed behaviors. There were no significant differences in rating scores. Overall, our findings seemed to be consistent with other findings on expertise research, supporting theories underlying cognition-based models of assessment in the clinical workplace. Implications for WBA are discussed

The phenotypic presentation of adult individuals with SLC6A1-related neurodevelopmental disorders

IntroductionSLC6A1 is one of the most common monogenic causes of epilepsy and is a well-established cause of neurodevelopmental disorders. SLC6A1-neurodevelopmental disorders have a consistent phenotype of mild to severe intellectual disability (ID), epilepsy, language delay and behavioral disorders. This phenotypic description is mainly based on knowledge from the pediatric population.MethodHere, we sought to describe patients with SLC6A1 variants and age above 18 years through the ascertainment of published and unpublished patients. Unpublished patients were ascertained through international collaborations, while previously published patients were collected through a literature search.ResultsA total of 15 adult patients with SLC6A1 variants were included. 9/13 patients had moderate to severe ID (data not available in two). Epilepsy was prevalent (11/15) with seizure types such as absence, myoclonic, atonic, and tonic–clonic seizures. Epilepsy was refractory in 7/11, while four patients were seizure free with lamotrigine, valproate, or lamotrigine in combination with valproate. Language development was severely impaired in five patients. Behavioral disorders were reported in and mainly consisted of autism spectrum disorders and aggressive behavior. Schizophrenia was not reported in any of the patients.DiscussionThe phenotype displayed in the adult patients presented here resembled that of the pediatric cohort with ID, epilepsy, and behavioral disturbances, indicating that the phenotype of SLC6A1-NDD is consistent over time. Seizures were refractory in >60% of the patients with epilepsy, indicating the lack of targeted treatment in SLC6A1-NDDs. With increased focus on repurposing drugs and on the development of new treatments, hope is that the outlook reflected here will change over time. ID appeared to be more severe in the adult patients, albeit this might reflect a recruitment bias, where only patients seen in specialized centers were included or it might be a feature of the natural history of SLC6A1-NDDs. This issue warrants to be explored in further studies in larger cohorts

Type I insulin-like growth factor receptor over-expression induces proliferation and anti-apoptotic signaling in a three-dimensional culture model of breast epithelial cells

INTRODUCTION: Activation of the type I insulin-like growth factor receptor (IGFIR) promotes proliferation and inhibits apoptosis in a variety of cell types. Transgenic mice expressing a constitutively active IGFIR or IGF-I develop mammary tumors and increased levels of IGFIR have been detected in primary breast cancers. However, the contribution of IGFIR activation in promoting breast cancer progression remains unknown. Mammary epithelial cell lines grown in three-dimensional cultures form acinar structures that mimic the round, polarized, hollow and growth-arrested features of mammary alveoli. We used this system to determine how proliferation and survival signaling by IGFIR activation affects breast epithelial cell biology and contributes to breast cancer progression. METHODS: Pooled, stable MCF-10A breast epithelial cells expressing wild-type IGFIR or kinase-dead IGFIR (K1003A) were generated using retroviral-mediated gene transfer. The effects of over-expression of wild-type or kinase-dead IGFIR on breast epithelial cell biology were analyzed by confocal microscopy of three-dimensional cultures. The contribution of signaling pathways downstream of IGFIR activation to proliferation and apoptosis were determined by pharmacological inhibition of phosphatidylinositol 3' kinase (PI3K) with LY294002, MAP kinase kinase (MEK) with UO126 and mammalian target of rapamycin (mTOR) with rapamycin. RESULTS: We found that MCF-10A cells over-expressing the IGFIR formed large, misshapen acinar structures with filled lumina and disrupted apico-basal polarization. This phenotype was ligand-dependent, occurring with IGF-I or supraphysiological doses of insulin, and did not occur in cells over-expressing the kinase-dead receptor. We observed increased proliferation, decreased apoptosis and increased phosphorylation of Ser(473 )of Akt and Ser(2448 )of mTOR throughout IGFIR structures. Inhibition of PI3K with LY294002 or MEK with UO126 prevented the development of acinar structures from IGFIR-expressing but not control cells. The mTOR inhibitor rapamycin failed to prevent IGFIR-induced hyperproliferation and survival signaling. CONCLUSION: Increased proliferation and survival signaling as well as loss of apico-basal polarity by IGFIR activation in mammary epithelial cells may promote early lesions of breast cancer. Three-dimensional cultures of MCF-10A cells over-expressing the IGFIR are a useful model with which to study the role of IGFIR signaling in breast cancer progression and for characterizing the effects of chemotherapeutics targeted to IGFIR signaling

Genetic Variability of the mTOR Pathway and Prostate Cancer Risk in the European Prospective Investigation on Cancer (EPIC)

The mTOR (mammalian target of rapamycin) signal transduction pathway integrates various signals, regulating ribosome biogenesis and protein synthesis as a function of available energy and amino acids, and assuring an appropriate coupling of cellular proliferation with increases in cell size. In addition, recent evidence has pointed to an interplay between the mTOR and p53 pathways. We investigated the genetic variability of 67 key genes in the mTOR pathway and in genes of the p53 pathway which interact with mTOR. We tested the association of 1,084 tagging SNPs with prostate cancer risk in a study of 815 prostate cancer cases and 1,266 controls nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). We chose the SNPs (n = 11) with the strongest association with risk (p<0.01) and sought to replicate their association in an additional series of 838 prostate cancer cases and 943 controls from EPIC. In the joint analysis of first and second phase two SNPs of the PRKCI gene showed an association with risk of prostate cancer (ORallele = 0.85, 95% CI 0.78–0.94, p = 1.3×10−3 for rs546950 and ORallele = 0.84, 95% CI 0.76–0.93, p = 5.6×10−4 for rs4955720). We confirmed this in a meta-analysis using as replication set the data from the second phase of our study jointly with the first phase of the Cancer Genetic Markers of Susceptibility (CGEMS) project. In conclusion, we found an association with prostate cancer risk for two SNPs belonging to PRKCI, a gene which is frequently overexpressed in various neoplasms, including prostate cancer

An overview of treatment approaches for chronic pain management

Pain which persists after healing is expected to have taken place, or which exists in the absence of tissue damage, is termed chronic pain. By definition chronic pain cannot be treated and cured in the conventional biomedical sense; rather, the patient who is suffering from the pain must be given the tools with which their long-term pain can be managed to an acceptable level. This article will provide an overview of treatment approaches available for the management of persistent non-malignant pain. As well as attempting to provide relief from the physical aspects of pain through the judicious use of analgesics, interventions, stimulations, and irritations, it is important to pay equal attention to the psychosocial complaints which almost always accompany long-term pain. The pain clinic offers a biopsychosocial approach to treatment with the multidisciplinary pain management programme; encouraging patients to take control of their pain problem and lead a fulfilling life in spite of the pain. © 2016 Springer-Verlag Berlin Heidelber

Improved student learning of infant growth and development.

All physicians who care for children require a knowledge of normal growth and development in order to detect and interpret abnormalities. Yet traditional instruction tends to focus on the ill child and rarely provides students the opportunity to follow up the cases of healthy children over a prolonged period of time. A new course was developed that enabled students to observe the longitudinal developmemt of a normal infant from birth to age 16 months. At the completion of the course, a multiple-choice examination covering developmental concepts from birth to age 6 years was administered to the students who participated in this course (experimental group) and to two comparison groups. The experimental group scored substantially higher than both comparison groups on items covering birth to age 18 months. The program offers an opportunity for medical students to observe the longitudinal development of a normal infant and appears complementary to other instructional methods