Development and evaluation of a spiral model of assessing EBM competency using OSCEs in undergraduate medical education.

BACKGROUND: Medical students often struggle to understand the relevance of Evidence Based Medicine (EBM) to their clinical practice, yet it is a competence that all students must develop prior to graduation. Objective structured clinical examinations (OSCEs) are a valued assessment tool to assess critical components of EBM competency, particularly different levels of mastery as they progress through the course. This study developed and evaluated EBM based OSCE stations with an aim to establish a spiral approach for EBM OSCE stations for undergraduate medical students. METHODS: OSCE stations were developed with increasingly complex EBM tasks. OSCE stations were classified according to the classification rubric for EBP assessment tools (CREATE) framework and mapped against the recently published core competencies for evidence-based practice (EBP). Performance data evaluation was undertaken using Classical Test Theory analysing mean scores, pass rates, and station item total correlation (ITC) using SPSS. RESULTS: Six EBM based OSCE stations assessing various stages of EBM were created for use in high stakes summative OSCEs for different year groups across the undergraduate medical degree. All OSCE stations, except for one, had excellent correlation coefficients and hence a high reliability, ranging from 0.21-0.49. The domain mean score ranged from 13.33 to 16.83 out of 20. High reliability was demonstrated for the each of the summative OSCE circuits (Cronbach's alpha = 0.67-0.85). In the CREATE framework these stations assessed knowledge, skills, and behaviour of medical students in asking, searching, appraising, and integrating evidence in practice. The OSCE stations were useful in assessing six core evidence-based practice competencies, which are meant to be practiced with exercises. A spiral model of OSCEs of increasing complexity was proposed to assess EBM competency as students progressed through the MBChB course. CONCLUSIONS: The use of the OSCEs is a feasible method of authentically assessing leaner EBM performance and behaviour in a high stakes assessment setting. Use of valid and reliable EBM-based OSCE stations provide evidence for continued development of a hierarchy of assessing scaffolded learning and mastery of EBM competency. Further work is needed to assess their predictive validity.

"You can't always get what you want ": economic thinking, constrained optimization and health professions education.

Every choice we make in health professions education has a cost, whether it be financial or otherwise; by choosing one action (e.g., integrating more simulation, studying more for a summative examination) we lose the opportunity to take an alternative action (e.g., freeing up time for other teaching, leisure time). Economics significantly shapes the way we behave and think as educators and learners and so there is increasing interest in using economic ways of thinking and approaches to examine and understand how choices are made, the influence of constraints and boundaries in educational decision making, and how costs are felt. Thus, in this article, we provide a brief historical overview of modern economics, to illustrate how the core concepts of economics-scarcity (and desirability), rationality, and optimization-developed over time. We explain the important concept of bounded rationality, which explains how individual, meso-factors and contextual factors influence decision making. We then consider the opportunities that these concepts afford for health professions education and research. We conclude by proposing that embracing economic thinking opens up new questions and new ways of approaching old questions which can add knowledge about how choice is enacted in contemporary health professions education.

Acceptability of delivery modes for lifestyle advice in a large scale randomised controlled obesity prevention trial.

BACKGROUND: Preventing obesity is an international health priority and women living in rural communities are at an increased risk of weight gain. Lifestyle programs are needed as part of a comprehensive approach to prevent obesity. Evaluation provides a unique opportunity to investigate and inform improvements in lifestyle program implementation strategies. The Healthy Lifestyle Program for rural women (HeLP-her Rural) is a large scale, cluster randomized control trial, targeting the prevention of weight gain. This program utilises multiple delivery modes for simple lifestyle advice (group sessions, phone coaching, text messages, and an interactive program manual). Here, we describe the acceptability of these various delivery modes. METHODS: A mixed-method process evaluation was undertaken measuring program fidelity, recruitment strategies, dose delivered, program acceptability and contextual factors influencing program implementation. Data collection methodologies included qualitative semi-structured interviews for a sub-group of intervention participants [n = 28] via thematic analysis and quantitative methods (program checklists and questionnaires [n = 190]) analysed via chi square and t-tests. RESULTS: We recruited 649 women from 41 rural townships into the HeLP-her Rural program with high levels of program fidelity, dose delivered and acceptability. Participants were from low socioeconomic townships and no differences were detected between socioeconomic characteristics and the number of participants recruited across the towns (p = 0.15). A face-to-face group session was the most commonly reported preferred delivery mode for receiving lifestyle advice, followed by text messages and phone coaching. Multiple sub-themes emerged to support the value of group sessions which included: promoting of a sense of belonging, mutual support and a forum to share ideas. The value of various delivery modes was influenced by participant's various needs and learning styles. CONCLUSION: This comprehensive evaluation reveals strong implementation fidelity and high levels of dose delivery. We demonstrate reach to women from relatively low income rural townships and highlight the acceptability of low intensity healthy lifestyle programs with mixed face-to-face and remote delivery modes in this population. Group education sessions were the most highly valued component of the intervention, with at least one face-to-face session critical to successful program implementation. However, lifestyle advice via multiple delivery modes is recommended to optimise program acceptability and ultimately effectiveness. TRIAL REGISTRY: Australia & New Zealand Clinical Trial Registry. Trial number ACTRN12612000115831, date of registration 24/01/2012.

Hypothyroidism in Bangladesh: Is Autoimmunity the Next Big Threat?

In many low and middle-income countries, iodine-deficient hypothyroidism leads to complex public health consequences. However, increasing evidence from population-based studies has linked thyroid autoimmunity with excess iodine intake. The iodine supplementation program in Bangladesh was a success story. This cross-sectional study aims to assess the pattern and predictors of autoimmunity among Bangladeshi hypothyroid patients. In this study, 154 consecutive, newly detected, biochemically-confirmed patients with primary hypothyroidism were recruited from the Endocrinology outpatient department of Bangabandhu Sheikh Mujib Medical University and tested for anti-thyroid peroxidase and anti-thyroglobulin antibody levels from October 2015 and November 2016. Patterns of thyroid autoimmunity were assessed via descriptive statistics. Predictors of autoimmunity were assessed with multivariable mixed-effect logistic regression. The mean age of participants was 36.1±11.0 years, and 70.1% were female. The frequency of thyroid autoimmunity in the study subjects was very high, 89.0% were positive for either anti-TPO or anti-Tg antibodies and 48.7% were positive for both. More participants were positive for anti-TPO antibodies (82.5%) than anti-Tg antibodies (55.2%). The risk of autoimmunity was associated with the thyroid's structural abnormalities but not with functional status. Weight gain and hypertension were associated with autoimmunity, whereas diabetes was protective against autoimmunity.

FAK integrates growth-factor and integrin signals to promote cell migration.

Here we show that cells lacking focal adhesion kinase (FAK) are refractory to motility signals from platelet-derived and epidermal growth factors (PDGF and EGF respectively), and that stable re-expression of FAK rescues these defects. FAK associates with activated PDGF- and EGF-receptor (PDGFR and EGFR) signalling complexes, and expression of the band-4.1-like domain at the FAK amino terminus is sufficient to mediate an interaction with activated EGFR. However, efficient EGF-stimulated cell migration also requires FAK to be targeted, by its carboxy-terminal domain, to sites of integrin-receptor clustering. Although the kinase activity of FAK is not needed to promote PDGF- or EGF-stimulated cell motility, kinase-inactive FAK is transphosphorylated at the indispensable Src-kinase-binding site, FAK Y397, after EGF stimulation of cells. Our results establish that FAK is an important receptor-proximal link between growth-factor-receptor and integrin signalling pathways.

Stem cell therapies for recessive dystrophic epidermolysis bullosa.

Human epidermis is composed of a stratified squamous epithelium that provides a mechanical barrier against the external environment and which is renewed every 3-4 weeks by resident stem cells in the epidermis. However, in the inherited skin fragility disorder, recessive dystrophic epidermolysis bullosa (RDEB), there is recurrent trauma-induced subepidermal blistering that disrupts epidermal homeostasis and is likely to deplete the epidermal stem cell pool. This review article discusses the nature of epidermal stem cells and other stem cell populations in the skin, as well as other possible extracutaneous sources of stem cells, that might have physiological or therapeutic relevance to cell therapy approaches for RDEB. Strategies to identify, create and use cells with multipotent or pluripotent properties are explored and current clinical experience of stem cell therapy in RDEB is reviewed. There is currently no single optimal therapy for patients with RDEB, but cell therapy technologies are evolving and hold great potential for modifying disease severity and improving quality of life for people living with RDEB.

Influence of narrow band imaging (NBI) videobronchoscopy on the assessment of central lung cancer extension and therapeutic decision.

OBJECTIVES: Determination of specificity and sensitivity of narrow band imaging (NBI) in the assessment of tumor extension in centrally located lung cancer, when compared to white light bronchoscopy (WLB) alone, and evaluation of possible influence of NBI on therapeutic decision in patients with lung cancer. PATIENTS AND METHODS: We evaluated 36 patients with suspected lung cancer. All patients underwent WLB followed by NBI bronchoscopy. We were using videobronchoscope BF-1T180 and EVIS LUCERA SPECTRUM processor unit. RESULTS: Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for NBI in the assessment of tumor extension were 97.8, 85, 93.7, and 94.4%, respectively; and for WLB 92.3, 60, 69.6, and 88.9%, respectively. In 14 patients, NBI revealed more extensive tumor than WLB (p =.0057). In eight patients, NBI showed significant influence on therapeutic decision (p =.001). CONCLUSION: NBI videobronchoscopy had better specificity and sensitivity in the assessment of tumor extension in centrally located lung cancer, and it might play a significant role in the therapeutic decision.

Matrix survival signaling: from fibronectin via focal adhesion kinase to c-Jun NH(2)-terminal kinase.

Most transformed cells have lost anchorage and serum dependence for growth and survival. Previously, we established that when serum is absent, fibronectin survival signals transduced by focal adhesion kinase (FAK), suppress p53-regulated apoptosis in primary fibroblasts and endothelial cells (Ilic et al. 1998. J. Cell Biol. 143:547-560). The present goals are to identify survival sequences in FAK and signaling molecules downstream of FAK required for anchorage-dependent survival of primary fibroblasts. We report that binding of the SH3 domain of p130Cas to proline-rich region 1 of FAK is required to support survival of fibroblasts on fibronectin when serum is withdrawn. The FAK-p130Cas complex activates c-Jun NH2-terminal kinase (JNK) via a Ras/Rac1/Pak1/MAPK kinase 4 (MKK4) pathway. Activated (phospho-) JNK colocalizes with FAK in focal adhesions of fibroblasts cultured on fibronectin, which supports their survival, but not in fibroblasts cultured on collagen, which does not. Cells often survive in the absence of extracellular matrix if serum factors are provided. In that case, we confirm work of others that survival signals are transduced by FAK, phosphatidylinositol 3'-kinase (PI3-kinase), and Akt/protein kinase B (PKB). However, when serum is absent, PI3-kinase and Akt/PKB are not involved in the fibronectin-FAK-JNK survival pathway documented herein. Thus, survival signals from extracellular matrix and serum are transduced by FAK via two distinct pathways.

Extracellular matrix survival signals transduced by focal adhesion kinase suppress p53-mediated apoptosis.

In many malignant cells, both the anchorage requirement for survival and the function of the p53 tumor suppressor gene are subverted. These effects are consistent with the hypothesis that survival signals from extracellular matrix (ECM) suppress a p53-regulated cell death pathway. We report that survival signals from fibronectin are transduced by the focal adhesion kinase (FAK). If FAK or the correct ECM is absent, cells enter apoptosis through a p53-dependent pathway activated by protein kinase C lambda/iota and cytosolic phospholipase A2. This pathway is suppressible by dominant-negative p53 and Bcl2 but not CrmA. Upon inactivation of p53, cells survive even if they lack matrix signals or FAK. This is the first report that p53 monitors survival signals from ECM/FAK in anchorage- dependent cells.

A nonlinear model of ionic wave propagation along microtubules.

Microtubules (MTs) are important cytoskeletal polymers engaged in a number of specific cellular activities including the traffic of organelles using motor proteins, cellular architecture and motility, cell division and a possible participation in information processing within neuronal functioning. How MTs operate and process electrical information is still largely unknown. In this paper we investigate the conditions enabling MTs to act as electrical transmission lines for ion flows along their lengths. We introduce a model in which each tubulin dimer is viewed as an electric element with a capacitive, inductive and resistive characteristics arising due to polyelectrolyte nature of MTs. Based on Kirchhoff's laws taken in the continuum limit, a nonlinear partial differential equation is derived and analyzed. We demonstrate that it can be used to describe the electrostatic potential coupled to the propagating localized ionic waves.

Hair cycle and wound healing in mice with a keratinocyte-restricted deletion of FAK.

Focal adhesion kinase (FAK) is a critical component in transducing signals downstream of both integrins and growth factor receptors. To determine how the loss of FAK affects the epidermis in vivo, we have generated a mouse model with a keratinocyte-restricted deletion of fak (FAKK5 KO mice). FAK(K5 KO) mice displayed three major phenotypes--irregularities of hair cycle, sebaceous glands hypoplasia, and a thinner epidermis--pointing to defects in the proliferative capacity of multipotent stem cells found in the bulge. FAK-null keratinocytes in conventional primary culture undergo massive apoptosis hindering further analyses, whereas the defects observed in vivo do not shorten the mouse lifespan. These results suggest that the structure and the signaling environment of the native tissue may overcome the lack of signaling through FAK. Our findings point to the importance of in vivo and three-dimensional in vitro models in analyses of cell migration, proliferation, and survival. Surprisingly, the difference between FAKloxP/+ and FAKK5 KO mice in wound closure was not statistically significant, suggesting that in vivo loss of FAK does not affect migration/proliferation of basal keratinocytes in the same way as it affects multipotent stem cells of the skin.

Intrinsic FAK activity and Y925 phosphorylation facilitate an angiogenic switch in tumors.

Elevated focal adhesion kinase (FAK) expression occurs in advanced cancers, yet a signaling role for FAK in tumor progression remains undefined. Here, we suppressed FAK activity in 4T1 breast carcinoma cells resulting in reduced FAK Y925 phosphorylation, Grb2 adaptor protein binding to FAK, and signaling to mitogen-activated protein (MAP) kinase (MAPK). Loss of a FAK-Grb2-MAPK linkage did not affect 4T1 cell proliferation or survival in culture, yet FAK inhibition reduced vascular endothelial growth factor (VEGF) expression and resulted in small avascular tumors in mice. This FAK-Grb2-MAPK linkage was essential in promoting angiogenesis as reconstitution experiments using Src-transformed FAK-null fibroblasts revealed that point mutations affecting FAK catalytic activity (R454) or Y925 phosphorylation (F925) disrupted the ability of FAK to promote MAPK- and VEGF-associated tumor growth. Notably, in both FAK-inhibited 4T1 and Src-transformed FAK-null cells, constitutively activated (CA) mitogen-activated protein kinase kinase 1 (MEK1) restored VEGF production and CA-MEK1 or added VEGF rescued tumor growth and angiogenesis. These studies provide the first biological support for Y925 FAK phosphorylation and define a novel role for FAK activity in promoting a MAPK-associated angiogenic switch during tumor progression.

Focal adhesion kinase and p130Cas mediate both sarcomeric organization and activation of genes associated with cardiac myocyte hypertrophy.

Hypertrophic terminally differentiated cardiac myocytes show increased sarcomeric organization and altered gene expression. Previously, we established a role for the nonreceptor tyrosine kinase Src in signaling cardiac myocyte hypertrophy. Here we report evidence that p130Cas (Cas) and focal adhesion kinase (FAK) regulate this process. In neonatal cardiac myocytes, tyrosine phosphorylation of Cas and FAK increased upon endothelin (ET) stimulation. FAK, Cas, and paxillin were localized in sarcomeric Z-lines, suggesting that the Z-line is an important signaling locus in these cells. Cas, alone or in cooperation with Src, modulated basal and ET-stimulated atrial natriuretic peptide (ANP) gene promoter activity, a marker of cardiac hypertrophy. Expression of the C-terminal focal adhesion-targeting domain of FAK interfered with localization of endogenous FAK to Z-lines. Expression of the Cas-binding proline-rich region 1 of FAK hindered association of Cas with FAK and impaired the structural stability of sarcomeres. Collectively, these results suggest that interaction of Cas with FAK, together with their localization to Z-lines, is critical to assembly of sarcomeric units in cardiac myocytes in culture. Moreover, expression of the focal adhesion-targeting and/or the Cas-binding proline-rich regions of FAK inhibited ANP promoter activity and suppressed ET-induced ANP and brain natriuretic peptide gene expression. In summary, assembly of signaling complexes that include the focal adhesion proteins Cas, FAK, and paxillin at Z-lines in the cardiac myocyte may regulate, either directly or indirectly, both cytoskeletal organization and gene expression associated with cardiac myocyte hypertrophy.

Influence of non-dipping pattern of blood pressure in gestational hypertension on maternal cardiac function, hemodynamics and intrauterine growth restriction.

BACKGROUND: An association between gestational hypertension (GH) and changes of maternal cardiac function was previously reported. AIM: The study assessed the effect of non-dipping pattern of blood pressure (BP) in GH on haemodynamic function and intrauterine growth restriction (IUGR). METHODS: This study included 126 women (91 with GH and 35 normotensive controls). Based on the BP values measured by ambulatory blood pressure monitoring (ABPM), all hypertensive women were classified in dipper (46 women) or in non-dipper group (45 women). All participants underwent echocardiography and ABPM during the third trimester. RESULTS: Participants with GH and non-dipping pattern had significantly lower velocity of longitudinal systolic function (s') (p<0.0005), and cardiac output index (COi) compared to dippers (p<0.0005) and controls (p=0.002). Diastolic velocities at the mitral valve annulus were also lower in non-dippers e's (non-dippers vs dippers p=0.023; non-dippers vs controls p<0.0005) and e'l (non-dippers vs dippers p=0.048; non-dippers vs controls p<0.0005). There were significant differences in the index of the left ventricle filling pressure E/e' and myocardial mass index between women with GH and controls, but with no significant difference among dippers and non-dippers. Total vascular resistance was increased in non-dipping group compared to normotensives and dippers (p<0.0005). Multivariate regression analysis revealed that the peak night-time diastolic BP, left ventricular mass index and CO index were identified as independent predictors of IUGR. CONCLUSION: Changes in maternal hemodynamics, as well as IUGR, are strongly related to the non-dipping pattern of BP.

Screening for prostate cancer.

BACKGROUND: Any form of screening aims to reduce mortality and increase a person's quality of life. Screening for prostate cancer has generated considerable debate within the medical community, as demonstrated by the varying recommendations made by medical organizations and governed by national policies. Much of this debate is due to the limited availability of high quality research and the influence of false-positive or false-negative results generated by use of the diagnostic techniques such as the digital rectal examination (DRE) and prostate specific antigen (PSA) blood test. OBJECTIVES: To determine whether screening for prostate cancer reduces prostate cancer mortality and has an impact on quality of life. SEARCH STRATEGY: Electronic databases (PROSTATE register, CENTRAL the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, CANCERLIT and the NHS EED) were searched electronically in addition to hand searching of specific journals and bibliographies in an effort to identify both published and unpublished trials. SELECTION CRITERIA: All randomised controlled trials of screening versus no screening or routine care for prostate cancer were eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: The search identified 99 potentially relevant articles that were selected for full text review. From these 99 citations, two randomised controlled trials were identified as meeting the review's inclusion criteria. Data from the trials were independently extracted by two authors. MAIN RESULTS: Two randomised controlled trials with a total of 55,512 participants were included; however, both trials had methodological weaknesses. Re-analysis using intention-to-screen and meta-analysis of results from the two randomised controlled trials indicated no statistically significant difference in prostate cancer mortality between men randomised for prostate cancer screening and controls (RR 1.01, 95% CI: 0.80-1.29). Neither study assessed the effect of prostate cancer screening on quality of life, all-cause mortality or cost effectiveness. AUTHORS' CONCLUSIONS: Given that only two randomised controlled trials were included, and the high risk of bias of both trials, there is insufficient evidence to either support or refute the routine use of mass, selective or opportunistic screening compared to no screening for reducing prostate cancer mortality. Currently, no robust evidence from randomised controlled trials is available regarding the impact of screening on quality of life, harms of screening, or its economic value. Results from two ongoing large scale multicentre randomised controlled trials that will be available in the next several years are required to make evidence-based decisions regarding prostate cancer screening.

Mesodermal defect in late phase of gastrulation by a targeted mutation of focal adhesion kinase, FAK.

FAK is a unique non-receptor protein tyrosine kinase that was found in cellular focal adhesions. An increasing number of in vitro observations has suggested that FAK mediates signaling through integrins brought about by interactions with extracellular matrix (ECM). It is highly tyrosine-phosphorylated in v-src-transformed cells and during embryogenesis. To clarify the function of FAK in cell-ECM interactions, embryonic phenotype of its mutant was analysed. FAK-deficient embryos could implant and initiate gastrulation normally, but showed abnormalities in subsequent development. The abnormalities were characterized as a general deficiency in mesoderm, and the phenotype was quite similar to that caused by fibronectin-deficiency. The results suggest that FAK mediates fibronectin-integrin interactions uniquely at this stage of development, thereby playing an essential role in development of mesodermal cell lineages.

Impaired development of CD4+ CD8+ thymoyctes by csk-'knock-in' into fyn locus.

p59fyn is one of the Src-family kinases thought to play an important role in signaling through T cell receptor. However, Fyn deficiency has caused no overt defects in vivo on T cell development, nor has it caused any changes in the phosphorylation status of molecules such as ZAP-70 which have been proposed as p59fyn substrates. This could be explained as being due to compensation of Fyn deficiency by other Src-family kinases. Here, we have 'knocked-in' the csk gene, a negative regulator of Src-family kinases, into fyn locus to challenge the problem of redundant functions among Src-family kinases. The csk-'knock-in' mice displayed atrophy of the thymic cortex and impaired development of CD4+ CD8+ thymocytes. This was concomitant with decrease in tyrosine phosphorylation of ZAP-70 and p120cbl.

Biological and clinical significance of clonogenic assays in patients with myelodysplastic syndromes.

Biological and clinical significance of growth pattern of hematopoietic progenitors were investigated in 117 patients with primary myelodysplastic syndromes (MDSs) at referral. Abnormal (i.e., "leukemic" or absent) growth of GM colonies (CFU-GM) and GM clusters was found in 47% of patients with "advanced" MDS (RAEB, RAEB-t, and CMML) and in 15% of "low-risk" (RA/RARS) patients. In vitro erythropoiesis was decreased in most of the patients, with significantly lower number of BFU-E in "advanced" MDS than in RA/RARS patients. Megakaryocyte progenitors (CFU-MK) were very low or absent in almost all the patients, regardless of the FAB type. Significant correlation was demonstrated between the number of BFU-E and hemoglobin concentration and between number of CFU-MK and platelet count. Growth capacity of GM progenitors appears to be in proportion to "myeloproliferative" capacity of the malignant clone. T-cell depletion had no influence on growth capacity of hematopoietic progenitors, nor did colony growth respond in a dose-dependent manner to different concentrations of LCM. Growth capacity of MDS hematopoietic progenitors was independent of Bournemouth score, of the presence and type of cytogenetic abnormality, and of the expression of CD95 and caspase-3 antigens on bone marrow cells. However, in patients with "abnormal" growth of GM progenitors, CD34 antigen expression was significantly higher than in patients with "normal" growth. "Abnormal" GM growth was found to be independently predictive regarding the survival and the risk for AML development. In contrast, the prognostic value of erythroid and megakaryocyte cultures was found to be limited.