Teaching clinical informatics to third-year medical students: negative results from two controlled trials

BACKGROUND: Prior educational interventions to increase seeking evidence by medical students have been unsuccessful. METHODS: We report two quasirandomized controlled trials to increase seeking of medical evidence by third-year medical students. In the first trial (1997–1998), we placed computers in clinical locations and taught their use in a 6-hour course. Based on negative results, we created SUMSearch(TM), an Internet site that automates searching for medical evidence by simultaneous meta-searching of MEDLINE and other sites. In the second trial (1999–2000), we taught SUMSearch's use in a 5½-hour course. Both courses were taught during the medicine clerkship. For each trial, we surveyed the entire third-year class at 6 months, after half of the students had taken the course (intervention group). The students who had not received the intervention were the control group. We measured self-report of search frequency and satisfaction with search quality and speed. RESULTS: The proportion of all students who reported searching at least weekly for medical evidence significantly increased from 19% (1997–1998) to 42% (1999–2000). The proportion of all students who were satisfied with their search results increased significantly between study years. However, in neither study year did the interventions increase searching or satisfaction with results. Satisfaction with the speed of searching was 27% in 1999–2000. This did not increase between studies years and was not changed by the interventions. CONCLUSION: None of our interventions affected searching habits. Even with automated searching, students report low satisfaction with search speed. We are concerned that students using current strategies for seeking medical evidence will be less likely to seek and appraise original studies when they enter medical practice and have less time

Modularity and Intrinsic Evolvability of Hsp90-Buffered Change

Hsp90 controls dramatic phenotypic transitions in a wide array of morphological features of many organisms. The genetic-background dependence of specific abnormalities and their response to laboratory selection suggested Hsp90 could be an ‘evolutionary capacitor’, allowing developmental variation to accumulate as neutral alleles under normal conditions and manifest selectable morphological differences during environmental stress. The relevance of Hsp90-buffered variation for evolution has been most often challenged by the idea that large morphological changes controlled by Hsp90 are unconditionally deleterious. To address this issue, we tested an Hsp90-buffered abnormality in Drosophila for unselected pleiotropic effects and correlated fitness costs. Up to 120-fold differences in penetrance among six highly related selection lines, started from an initially small number of flies and rapidly selected for and against a deformed eye trait (dfe), did not translate into measurable differences in any of several tests of viability, lifespan or competitive fitness. Nor were 17 dfe Quantitative Trait Loci (QTL) associated with fitness effects in over 1,400 recombinant lines. Our ability to detect measurable effects of inbreeding, media environment and the white mutation in the selection line backgrounds independent of dfe penetrance suggests that, within the limitations of laboratory tests of fitness, this large morphological change controlled by Hsp90 was selectable independent of strong, correlated and unconditionally deleterious effects—abundant, polygenic variation hidden by Hsp90 allows potentially deleterious alleles to be readily replaced during selection by less deleterious alleles with similar phenotypic effects. Hsp90 links environmental stress with the expression of developmental variation controlling unprecedented morphological plasticity. As outlined here and in the companion paper of this issue, the complex genetic architecture of Hsp90-buffered variation supports a remarkable modularity of Hsp90 effects on quantitative and qualitative phenotypes, consistent with the ‘Hsp90 capacitor hypothesis’ and standard quantitative genetic models of threshold traits

How physicians perceive and utilize information from a teratogen information service: The Motherisk Program

BACKGROUND: Teratogen information services have been developed around the world to disseminate information regarding the safety of maternal exposures during pregnancy. The Motherisk Program in Toronto, Canada, fields thousands of these inquiries per year. Our primary objective was to evaluate the perception and utilization of information received from us by physicians. Our secondary objective was to examine their information seeking behavior, in particular regarding teratogen information. METHODS: A one page survey was sent to physicians who had called Motherisk for information concerning pregnancy exposures in the previous 30 days for three months. Among the questions that were asked were demographics, which included gender, years in practice, specialty, information resources, and how they utilized the information received from Motherisk. RESULTS: We received 118/200 completed questionnaires (59% response rate). The mean age of the respondents was: 42 ± 9 years, mean years of practice was: 14 ± 8 years, males: 46(38%) and females 72(62%) and 95(80%) were family physicians. 56(48%) researched their question prior to calling Motherisk, 106(91%) and passed on the information received to their patient verbatim. The top four resources for information were: 1) The CPS (PDR), 2) textbooks, 3) journals and 4) colleagues. Only 8% used the Medline for gathering information. CONCLUSIONS: Physicians feel that a teratogen information service is an important component in the management of women exposed to drugs, chemicals, radiation and infections diseases etc. during pregnancy. Despite the advent of the electronic age, a minority of the physicians in our survey elected to use electronic means to seek information

The SNAPSHOT study protocol : SNAcking, Physical activity, Self-regulation, and Heart rate Over Time

Peer reviewedPublisher PD

Identification of four families of yCCR4- and Mg(2+)-dependent endonuclease-related proteins in higher eukaryotes, and characterization of orthologs of yCCR4 with a conserved leucine-rich repeat essential for hCAF1/hPOP2 binding

BACKGROUND: The yeast yCCR4 factor belongs to the CCR4-NOT transcriptional regulatory complex, in which it interacts, through its leucine-rich repeat (LRR) motif with yPOP2. Recently, yCCR4 was shown to be a component of the major cytoplasmic mRNA deadenylase complex, and to contain a fold related to the Mg(2+)-dependent endonuclease core. RESULTS: Here, we report the identification of nineteen yCCR4-related proteins in eukaryotes (including yeast, plants and animals), which all contain the yCCR4 endonuclease-like fold, with highly conserved CCR4-specific residues. Phylogenetic and genomic analyses show that they form four distinct families, one of which contains the yCCR4 orthologs. The orthologs in animals possess a leucine-rich repeat domain. We show, using two-hybrid and far-Western assays, that the human member binds to the human yPOP2 homologs, i.e. hCAF1 and hPOP2, in a LRR-dependent manner. CONCLUSIONS: We have identified the mammalian orthologs of yCCR4 and have shown that the human member binds to the human yPOP2 homologs, thus strongly suggesting conservation of the CCR4-NOT complex from yeast to human. All members of the four identified yCCR4-related protein families show stricking conservation of the endonuclease-like catalytic motifs of the yCCR4 C-terminal domain and therefore constitute a new family of potential deadenylases in mammals

Stability of Strong Species Interactions Resist the Synergistic Effects of Local and Global Pollution in Kelp Forests

Foundation species, such as kelp, exert disproportionately strong community effects and persist, in part, by dominating taxa that inhibit their regeneration. Human activities which benefit their competitors, however, may reduce stability of communities, increasing the probability of phase-shifts. We tested whether a foundation species (kelp) would continue to inhibit a key competitor (turf-forming algae) under moderately increased local (nutrient) and near-future forecasted global pollution (CO2). Our results reveal that in the absence of kelp, local and global pollutants combined to cause the greatest cover and mass of turfs, a synergistic response whereby turfs increased more than would be predicted by adding the independent effects of treatments (kelp absence, elevated nutrients, forecasted CO2). The positive effects of nutrient and CO2 enrichment on turfs were, however, inhibited by the presence of kelp, indicating the competitive effect of kelp was stronger than synergistic effects of moderate enrichment of local and global pollutants. Quantification of physicochemical parameters within experimental mesocosms suggests turf inhibition was likely due to an effect of kelp on physical (i.e. shading) rather than chemical conditions. Such results indicate that while forecasted climates may increase the probability of phase-shifts, maintenance of intact populations of foundation species could enable the continued strength of interactions and persistence of communities

Worm Grunting, Fiddling, and Charming—Humans Unknowingly Mimic a Predator to Harvest Bait

Background: For generations many families in and around Florida’s Apalachicola National Forest have supported themselves by collecting the large endemic earthworms (Diplocardia mississippiensis). This is accomplished by vibrating a wooden stake driven into the soil, a practice called ‘‘worm grunting’’. In response to the vibrations, worms emerge to the surface where thousands can be gathered in a few hours. Why do these earthworms suddenly exit their burrows in response to vibrations, exposing themselves to predation? Principal Findings: Here it is shown that a population of eastern American moles (Scalopus aquaticus) inhabits the area where worms are collected and that earthworms have a pronounced escape response from moles consisting of rapidly exiting their burrows to flee across the soil surface. Recordings of vibrations generated by bait collectors and moles suggest that ‘‘worm grunters’ ’ unknowingly mimic digging moles. An alternative possibility, that worms interpret vibrations as rain and surface to avoid drowning is not supported. Conclusions: Previous investigations have revealed that both wood turtles and herring gulls vibrate the ground to elicit earthworm escapes, indicating that a range of predators may exploit the predator-prey relationship between earthworms and moles. In addition to revealing a novel escape response that may be widespread among soil fauna, the results sho

Transglutaminase 6: a protein associated with central nervous system development and motor function.

Transglutaminases (TG) form a family of enzymes that catalyse various post-translational modifications of glutamine residues in proteins and peptides including intra- and intermolecular isopeptide bond formation, esterification and deamidation. We have characterized a novel member of the mammalian TG family, TG6, which is expressed in a human carcinoma cell line with neuronal characteristics and in mouse brain. Besides full-length protein, alternative splicing results in a short variant lacking the second β-barrel domain in man and a variant with truncated β-sandwich domain in mouse. Biochemical data show that TG6 is allosterically regulated by Ca(2+) and guanine nucleotides. Molecular modelling indicates that TG6 could have Ca(2+) and GDP-binding sites related to those of TG3 and TG2, respectively. Localization of mRNA and protein in the mouse identified abundant expression of TG6 in the central nervous system. Analysis of its temporal and spatial pattern of induction in mouse development indicates an association with neurogenesis. Neuronal expression of TG6 was confirmed by double-labelling of mouse forebrain cells with cell type-specific markers. Induction of differentiation in mouse Neuro 2a cells with NGF or dibutyryl cAMP is associated with an upregulation of TG6 expression. Familial ataxia has recently been linked to mutations in the TGM6 gene. Autoantibodies to TG6 were identified in immune-mediated ataxia in patients with gluten sensitivity. These findings suggest a critical role for TG6 in cortical and cerebellar neurons

PD-1 Regulates Neural Damage in Oligodendroglia-Induced Inflammation

We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system

EEG Microstate Analysis in Drug-Naive Patients with Panic Disorder

Patients with panic disorder (PD) have a bias to respond to normal stimuli in a fearful way. This may be due to the preactivation of fear-associated networks prior to stimulus perception. Based on EEG, we investigated the difference between patients with PD and normal controls in resting state activity using features of transiently stable brain states (microstates). EEGs from 18 drug-naive patients and 18 healthy controls were analyzed. Microstate analysis showed that one class of microstates (with a right-anterior to left-posterior orientation of the mapped field) displayed longer durations and covered more of the total time in the patients than controls. Another microstate class (with a symmetric, anterior-posterior orientation) was observed less frequently in the patients compared to controls. The observation that selected microstate classes differ between patients with PD and controls suggests that specific brain functions are altered already during resting condition. The altered resting state may be the starting point of the observed dysfunctional processing of phobic stimuli