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Objective: We examined the influence of 4 different risk information formats on inpatient nurses' preferences and decisions with an acute clinical deterioration decision-support system., Materials and Methods: We conducted a comparative usability evaluation in which participants provided responses to multiple user interface options in a simulated setting. We collected qualitative data using think aloud methods. We collected quantitative data by asking participants which action they would perform after each time point in 3 different patient scenarios., Results: More participants (n = 6) preferred the probability format over relative risk ratios (n = 2), absolute differences (n = 2), and number of persons out of 100 (n = 0). Participants liked average lines, having a trend graph to supplement the risk estimate, and consistent colors between trend graphs and possible actions. Participants did not like too much text information or the presence of confidence intervals. From a decision-making perspective, use of the probability format was associated with greater concordance in actions taken by participants compared to the other 3 risk information formats., Discussion: By focusing on nurses' preferences and decisions with several risk information display formats and collecting both qualitative and quantitative data, we have provided meaningful insights for the design of clinical decision-support systems containing complex quantitative information., Conclusion: This study adds to our knowledge of presenting risk information to nurses within clinical decision-support systems. We encourage those developing risk-based systems for inpatient nurses to consider expressing risk in a probability format and include a graph (with average line) to display the patient's recent trends., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2023.)

Successfully changing prescribing behavior to reduce inappropriate antibiotic and nonsteroidal anti-inflammatory drug (NSAID) prescriptions often requires combining components into a multicomponent intervention. However, multicomponent interventions often fail because of development and implementation complexity. To increase the likelihood of successfully changing prescribing behavior, we applied a systematic process to design and implement a multicomponent intervention. We used Intervention Mapping to create a roadmap for a multicomponent intervention in unscheduled outpatient care settings in the Veterans Health Administration. Intervention Mapping is a systematic process consisting of six steps that we grouped into three phases: (i) understand behavioral determinants and barriers to implementation, (ii) develop the intervention, and (iii) define evaluation plan and implementation strategies. A targeted literature review, combined with 25 prescriber and 25 stakeholder interviews, helped identify key behavioral determinants to inappropriate prescribing (e.g. perceived social pressure from patients to prescribe). We targeted three desired prescriber behaviors: (i) review guideline-concordant prescribing and patient outcomes, (ii) manage diagnostic and treatment uncertainty, and (iii) educate patients and caregivers. The intervention consisted of components for academic detailing, prescribing feedback, and alternative prescription order sets. Implementation strategies consisted of preparing clinical champions, conducting readiness assessments, and incentivizing use of the intervention. We chose a mixed-method study design with a commonly used evaluation framework to assess effectiveness and implementation outcomes in a subsequent trial. This study furthers knowledge about causes of inappropriate antibiotic and NSAID prescribing and demonstrates how theoretical, empirical, and practical information can be systematically applied to develop a multicomponent intervention to help address these causes., (Published by Oxford University Press on behalf of the Society of Behavioral Medicine 2023.)

Purpose: To analyze the clinical completeness, correctness, usefulness, and safety of chatbot and medication database responses to everyday inpatient medication-use questions., Methods: We evaluated the responses from an artificial intelligence chatbot, a medication database, and clinical pharmacists to 200 real-world medication-use questions. Answer quality was rated by a blinded group of pharmacists, providers, and nurses. Chatbot and medication database responses were deemed "acceptable" if the mean reviewer rating was within 3 points of the mean rating for pharmacists' answers. We used descriptive statistics for reviewer ratings and Kendall's coefficient to evaluate interrater agreement., Results: The medication database generated responses to 194 (97%) questions, with 88% considered acceptable for clinical correctness, 76% considered acceptable for completeness, 83% considered acceptable for safety, and 81% considered acceptable for usefulness compared to pharmacists' answers. The chatbot responded to only 160 (80%) questions, with 85% considered acceptable for clinical correctness, 65% considered acceptable for completeness, 71% considered acceptable for safety, and 68% considered acceptable for usefulness., Conclusion: Traditional search methods using a drug database provide more clinically correct, complete, safe, and useful answers than a chatbot. When the chatbot generated a response, the clinical correctness was similar to that of a drug database; however, it was not rated as favorably for clinical completeness, safety, or usefulness. Our results highlight the need for ongoing training and continued improvements to artificial intelligence chatbots for them to be incorporated reliably into the clinical workflow. With continued improvement in chatbot functionality, chatbots could be a useful pharmacist adjunct, providing healthcare providers with quick and reliable answers to medication-use questions., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Fast synaptic communication uses diffusible transmitters whose spread is limited by uptake mechanisms. However, on the submicron-scale, the distance between two synapses, the extent of glutamate spread has so far remained difficult to measure. Here, we show that quantal glutamate release from individual hippocampal synapses activates extracellular iGluSnFr molecules at a distance of >1.5 μm. 2P-glutamate uncaging near spines further showed that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-Rs and N-methyl-D-aspartate (NMDA)-Rs respond to distant uncaging spots at approximately 800 and 2000 nm, respectively, when releasing the amount of glutamate contained in approximately five synaptic vesicles. The uncaging-induced remote activation of AMPA-Rs was facilitated by blocking glutamate transporters but only modestly decreased by elevating the recording temperature. When mimicking release from neighboring synapses by three simultaneous uncaging spots in the microenvironment of a spine, AMPA-R-mediated responses increased supra-additively. Interfering with extracellular glutamate diffusion through a glutamate scavenger system weakly reduced field synaptic responses but not the quantal amplitude. Together, our data suggest that the neuropil is more permissive to short-range spread of transmitter than suggested by theory, that multivesicular release could regularly coactivate nearest neighbor synapses and that on this scale glutamate buffering by transporters primarily limits the spread of transmitter and allows for cooperative glutamate signaling in extracellular microdomains., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Summary: HTSeq 2.0 provides a more extensive application programming interface including a new representation for sparse genomic data, enhancements for htseq-count to suit single-cell omics, a new script for data using cell and molecular barcodes, improved documentation, testing and deployment, bug fixes and Python 3 support., Availability and Implementation: HTSeq 2.0 is released as an open-source software under the GNU General Public License and is available from the Python Package Index at https://pypi.python.org/pypi/HTSeq. The source code is available on Github at https://github.com/htseq/htseq., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2022. Published by Oxford University Press.)

Background: Advances in next-generation DNA sequencing technologies are now enabling detailed characterization of sequence variations in cancer genomes. With whole-genome sequencing, variations in coding and non-coding sequences can be discovered. But the cost associated with it is currently limiting its general use in research. Whole-exome sequencing is used to characterize sequence variations in coding regions, but the cost associated with capture reagents and biases in capture rate limit its full use in research. Additional limitations include uncertainty in assigning the functional significance of the mutations when these mutations are observed in the non-coding region or in genes that are not expressed in cancer tissue., Results: We investigated the feasibility of uncovering mutations from expressed genes using RNA sequencing datasets with a method called Variant Detection in RNA(VaDiR) that integrates 3 variant callers, namely: SNPiR, RVBoost, and MuTect2. The combination of all 3 methods, which we called Tier 1 variants, produced the highest precision with true positive mutations from RNA-seq that could be validated at the DNA level. We also found that the integration of Tier 1 variants with those called by MuTect2 and SNPiR produced the highest recall with acceptable precision. Finally, we observed a higher rate of mutation discovery in genes that are expressed at higher levels., Conclusions: Our method, VaDiR, provides a possibility of uncovering mutations from RNA sequencing datasets that could be useful in further functional analysis. In addition, our approach allows orthogonal validation of DNA-based mutation discovery by providing complementary sequence variation analysis from paired RNA/DNA sequencing datasets.

Objective: The Vanderbilt Children's Hospital launched an innovative Technology-Based Patient and Family Engagement Consult Service in 2014. This paper describes our initial experience with this service, characterizes health-related needs of families of hospitalized children, and details the technologies recommended to promote engagement and meet needs., Materials and Methods: We retrospectively reviewed consult service documentation for patient characteristics, health-related needs, and consultation team recommendations. Needs were categorized using a consumer health needs taxonomy. Recommendations were classified by technology type., Results: Twenty-two consultations were conducted with families of patients ranging in age from newborn to 15 years, most with new diagnoses or chronic illnesses. The consultation team identified 99 health-related needs (4.5 per consultation) and made 166 recommendations (7.5 per consultation, 1.7 per need). Need categories included 38 informational needs, 26 medical needs, 23 logistical needs, and 12 social needs. The most common recommendations were websites (50, 30%) and mobile applications (30, 18%). The most frequent recommendations by need category were websites for informational needs (39, 50%), mobile applications for medical needs (15, 40%), patient portals for logistical needs (12, 44%), and disease-specific support groups for social needs (19, 56%)., Discussion: Families of hospitalized pediatric patients have a variety of health-related needs, many of which could be addressed by technology recommendations from an engagement consult service., Conclusion: This service is the first of its kind, offering a potentially generalizable and scalable approach to assessing health-related needs, meeting them with technologies, and promoting patient and family engagement in the inpatient setting., (© The Author 2017. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Objectives: Endotracheal intubation (ETI) is an important skill for all emergency providers; our ability to train and assess our learners is integral to providing optimal patient care. The primary aim of this study was to assess the inter-rater reliability (IRR) and discriminant validity of a novel field ETI assessment tool using a checklist-derived performance score (PS) and critical failure (CF) rate., Methods: Forty-three participants (18 paramedic students, 11 paramedics, and 14 emergency physicians [EPs]) performed ETI during a simulated trauma scenario on a pseudo-ventilated cadaver. Each participant was assessed by two experienced raters. IRR was calculated using the intraclass correlation coefficient. Regarding discriminant validity, a Kruskal-Wallis test was used to analyze PSs and a χ 2 test was used for CFs. Mean global rating scale (GRS) scores were compared using an analysis of variance., Results: The ETI assessment tool had excellent IRR, with an intraclass correlation coefficient of 0.94. There was a significant difference in PSs, CFs, and GRSs (p < 0.05) between cohorts., Conclusion: The novel field ETI assessment tool has excellent reliability among trained raters and discriminates between experienced ETI providers (EPs) and less experienced ETI performers using PSs, CFs, and GRSs on a fresh cadaveric model., (Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.)

Background: Burn Intensive Care Unit (BICU) work is necessarily complex and depends on clinician actions, resources, and variable patient responses to interventions. Clinicians use large volumes of data that are condensed in time, but separated across resources, to care for patients. Correctly designed health information technology (IT) systems may help clinicians to treat these patients more efficiently, accurately, and reliably. We report on a 3-year project to design and develop an ecologically valid IT system for use in a military BICU., Methods: We use a mixed methods Cognitive Systems Engineering approach for research and development. Observations, interviews, artifact analysis, survey, and thematic analysis methods were used to reveal underlying factors that mold the work environment and affect clinician decisions that may affect patient outcomes. Participatory design and prototyping methods have been used to develop solutions., Results: We developed 39 requirements for the IT system and used them to create three use cases to help developers better understand how the system might support clinician work to develop interface prototypes. We also incorporated data mining functions that offer the potential to aid clinicians by recognizing patterns recognition of clinically significant events, such as incipient sepsis. The gaps between information sources and accurate, reliable, and efficient clinical decision that we have identified will enable us to create scenarios to evaluate prototype systems with BICU clinicians, to develop increasingly improved designs, and to measure outcomes., Conclusion: The link from data to analyses, requirements, prototypes, and their evaluation ensures that the solution will reflect and support work in the BICU as it actually occurs, improving staff efficiency and patient care quality., (Reprint & Copyright © 2016 Association of Military Surgeons of the U.S.)

Motivation: Circularized Chromosome Conformation Capture (4C) is a powerful technique for studying the spatial interactions of a specific genomic region called the 'viewpoint' with the rest of the genome, both in a single condition or comparing different experimental conditions or cell types. Observed ligation frequencies typically show a strong, regular dependence on genomic distance from the viewpoint, on top of which specific interaction peaks are superimposed. Here, we address the computational task to find these specific peaks and to detect changes between different biological conditions., Results: We model the overall trend of decreasing interaction frequency with genomic distance by fitting a smooth monotonically decreasing function to suitably transformed count data. Based on the fit, z-scores are calculated from the residuals, and high z-scores are interpreted as peaks providing evidence for specific interactions. To compare different conditions, we normalize fragment counts between samples, and call for differential contact frequencies using the statistical method DESEQ2: adapted from RNA-Seq analysis., Availability and Implementation: A full end-to-end analysis pipeline is implemented in the R package FourCSeq available at www.bioconductor.org., Contact: felix.klein@embl.de or whuber@embl.de, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2015. Published by Oxford University Press.)

Motivation: A large choice of tools exists for many standard tasks in the analysis of high-throughput sequencing (HTS) data. However, once a project deviates from standard workflows, custom scripts are needed., Results: We present HTSeq, a Python library to facilitate the rapid development of such scripts. HTSeq offers parsers for many common data formats in HTS projects, as well as classes to represent data, such as genomic coordinates, sequences, sequencing reads, alignments, gene model information and variant calls, and provides data structures that allow for querying via genomic coordinates. We also present htseq-count, a tool developed with HTSeq that preprocesses RNA-Seq data for differential expression analysis by counting the overlap of reads with genes., Availability and Implementation: HTSeq is released as an open-source software under the GNU General Public Licence and available from http://www-huber.embl.de/HTSeq or from the Python Package Index at https://pypi.python.org/pypi/HTSeq., (© The Author 2014. Published by Oxford University Press.)

Dissecting the molecular basis of quantitative traits is a significant challenge and is essential for understanding complex diseases. Even in model organisms, precisely determining causative genes and their interactions has remained elusive, due in part to difficulty in narrowing intervals to single genes and in detecting epistasis or linked quantitative trait loci. These difficulties are exacerbated by limitations in experimental design, such as low numbers of analyzed individuals or of polymorphisms between parental genomes. We address these challenges by applying three independent high-throughput approaches for QTL mapping to map the genetic variants underlying 11 phenotypes in two genetically distant Saccharomyces cerevisiae strains, namely (1) individual analysis of >700 meiotic segregants, (2) bulk segregant analysis, and (3) reciprocal hemizygosity scanning, a new genome-wide method that we developed. We reveal differences in the performance of each approach and, by combining them, identify eight polymorphic genes that affect eight different phenotypes: colony shape, flocculation, growth on two nonfermentable carbon sources, and resistance to two drugs, salt, and high temperature. Our results demonstrate the power of individual segregant analysis to dissect QTL and address the underestimated contribution of interactions between variants. We also reveal confounding factors like mutations and aneuploidy in pooled approaches, providing valuable lessons for future designs of complex trait mapping studies.

Introduction: In many countries, smoking cessation interventions are not routinely delivered as recommended in national and international guidelines. This may be because of incorrect beliefs about their effectiveness. This study assessed which cessation methods are believed to be effective by medical students in different years of undergraduate education as well as predictors of correct beliefs about effectiveness., Methods: In this cross-sectional study, undergraduate students from 27 German medical schools were invited to complete a survey addressing demographic characteristics, smoking status, self-rated knowledge of health consequences, and treatment options for smoking and beliefs about the effectiveness of 8 different methods to achieve long-term smoking cessation. Predictors of beliefs were identified by means of multilevel modeling., Results: A total of 19,526 students completed the survey. Students greatly overestimated the effectiveness of unaided quitting, and differences between years of undergraduate education were small. In the final year, 51% of students wrongly believed that willpower alone was more effective than a comprehensive group cessation program, including nicotine replacement therapy. Multilevel modeling revealed that having never smoked, supporting public smoking bans, and recalling theoretical training in smoking cessation were associated with correct beliefs., Conclusions: A considerable proportion of German medical students believe that willpower alone is more effective than comprehensive treatment programs to support a quit attempt.

The use of alternative poly(A) sites is common and affects the post-transcriptional fate of mRNA, including its stability, subcellular localization and translation. Here, we present a method to identify poly(A) sites in a genome-wide and strand-specific manner. This method, termed 3'T-fill, initially fills in the poly(A) stretch with unlabeled dTTPs, allowing sequencing to start directly after the poly(A) tail into the 3'-untranslated regions (UTR). Our comparative analysis demonstrates that it outperforms existing protocols in quality and throughput and accurately quantifies RNA levels as only one read is produced from each transcript. We use this method to characterize the diversity of polyadenylation in Saccharomyces cerevisiae, showing that alternative RNA molecules are present even in a genetically identical cell population. Finally, we observe that overlap of convergent 3'-UTRs is frequent but sharply limited by coding regions, suggesting factors that restrict compression of the yeast genome.

Objective: Without careful attention to the work of users, implementation of health IT can produce new risks and inefficiencies in care. This paper uses the technology use mediation framework to examine the work of a group of nurses who serve as mediators of the adoption and use of a barcode medication administration (BCMA) system in an inpatient setting., Materials and Methods: The study uses ethnographic methods to explore the mediators' work. Data included field notes from observations, documents, and email communications. This variety of sources enabled triangulation of findings between activities observed, discussed in meetings, and reported in emails., Results: Mediation work integrated the BCMA tool with nursing practice, anticipating and solving implementation problems. Three themes of mediation work include: resolving challenges related to coordination, integrating the physical aspects of BCMA into everyday practice, and advocacy work., Discussion: Previous work suggests the following factors impact mediation effectiveness: proximity to the context of use, understanding of users' practices and norms, credibility with users, and knowledge of the technology and users' technical abilities. We describe three additional factors observed in this case: 'influence on system developers,' 'influence on institutional authorities,' and 'understanding the network of organizational relationships that shape the users' work.', Conclusion: Institutionally supported clinicians who facilitate adoption and use of health IT systems can improve the safety and effectiveness of implementation through the management of unintended consequences. Additional research on technology use mediation can advance the science of implementation by providing decision-makers with theoretically durable, empirically grounded evidence for designing implementations.

In forensic toxicology, several fatal intoxications with fentanyl have occurred in the recent past, but there are rare discussions in the literature of postmortem fentanyl blood concentrations subsequent to lethal and non lethal applications. To study this problem, we analyzed postmortem blood concentrations (vena femoralis) of 118 cases with therapeutic use of fentanyl and compared them with serum levels of 27 living persons after therapeutic administration of fentanyl patches (Durogesic). Basically, blood concentrations in postmortem specimens cannot be directly compared with in vivo serum levels: in our study, we observed that postmortem fentanyl blood concentrations were on average up to nine times higher than in vivo serum levels at the same dose. These differences could be explained by postmortem redistribution, but they were higher than expected on the basis of the physical and chemical properties of fentanyl alone. The special pharmacokinetics of the drug after long term transdermal application seem to play an important role in this phenomenon. In addition, there was no clear correlation between transdermal fentanyl dose and blood or serum concentrations, either antemortem or postmortem. Our study provides extensive data for postmortem peripheral blood concentrations after therapeutic non-fatal fentanyl patch application and demonstrates once more that in forensic toxicology, blood concentrations must be holistically interpreted with respect to all aspects of a case.

Patients with Parkinson's disease suffer from significant motor impairments and accompanying cognitive and affective dysfunction due to progressive disturbances of basal ganglia-cortical gating loops. Parkinson's disease has a long presymptomatic stage, which indicates a substantial capacity of the human brain to compensate for dopaminergic nerve degeneration before clinical manifestation of the disease. Neuroimaging studies provide evidence that increased motor-related cortical activity can compensate for progressive dopaminergic nerve degeneration in carriers of a single mutant Parkin or PINK1 gene, who show a mild but significant reduction of dopamine metabolism in the basal ganglia in the complete absence of clinical motor signs. However, it is currently unknown whether similar compensatory mechanisms are effective in non-motor basal ganglia-cortical gating loops. Here, we ask whether asymptomatic Parkin mutation carriers show altered patterns of brain activity during processing of facial gestures, and whether this might compensate for latent facial emotion recognition deficits. Current theories in social neuroscience assume that execution and perception of facial gestures are linked by a special class of visuomotor neurons ('mirror neurons') in the ventrolateral premotor cortex/pars opercularis of the inferior frontal gyrus (Brodmann area 44/6). We hypothesized that asymptomatic Parkin mutation carriers would show increased activity in this area during processing of affective facial gestures, replicating the compensatory motor effects that have previously been observed in these individuals. Additionally, Parkin mutation carriers might show altered activity in other basal ganglia-cortical gating loops. Eight asymptomatic heterozygous Parkin mutation carriers and eight matched controls underwent functional magnetic resonance imaging and a subsequent facial emotion recognition task. As predicted, Parkin mutation carriers showed significantly stronger activity in the right ventrolateral premotor cortex during execution and perception of affective facial gestures than healthy controls. Furthermore, Parkin mutation carriers showed a slightly reduced ability to recognize facial emotions that was least severe in individuals who showed the strongest increase of ventrolateral premotor activity. In addition, Parkin mutation carriers showed a significantly weaker than normal increase of activity in the left lateral orbitofrontal cortex (inferior frontal gyrus pars orbitalis, Brodmann area 47), which was unrelated to facial emotion recognition ability. These findings are consistent with the hypothesis that compensatory activity in the ventrolateral premotor cortex during processing of affective facial gestures can reduce impairments in facial emotion recognition in subclinical Parkin mutation carriers. A breakdown of this compensatory mechanism might lead to the impairment of facial expressivity and facial emotion recognition observed in manifest Parkinson's disease.

Explicit guidelines are needed to develop safe and effective patient portals. This paper proposes general principles, policies, and procedures for patient portal functionality based on MyHealthAtVanderbilt (MHAV), a robust portal for Vanderbilt University Medical Center. We describe policies and procedures designed to govern popular portal functions, address common user concerns, and support adoption. We present the results of our approach as overall and function-specific usage data. Five years after implementation, MHAV has over 129,800 users; 45% have used bi-directional messaging; 52% have viewed test results and 45% have viewed other medical record data; 30% have accessed health education materials; 39% have scheduled appointments; and 29% have managed a medical bill. Our policies and procedures have supported widespread adoption and use of MHAV. We believe other healthcare organizations could employ our general guidelines and lessons learned to facilitate portal implementation and usage.

Objective: Repair of focal articular cartilage lesions is usually performed by employing cell-based therapeutic strategies such as autologous chondrocyte implantation (ACI). The aim of this study was to determine whether periosteum exerts pro-chondrogenic effects on the transplanted cells beyond its biomechanical role in ACI., Methods: Micromass pellets of human articular chondrocytes were cocultured for up to 28 days with human periosteal explants either with physical contact or separated by a membrane allowing paracrine interactions only. Quantitative reverse transcription (RT)-PCR, ELISA, immunohistochemistry and collagen isolation were used to analyse the expression and secretion of TGF-beta1, collagens I and II and chondrogenic differentiation markers such as MIA (CD-RAP) and aggrecan., Results: TGF-beta1 gene expression was induced significantly in paracrine cocultures in periosteum, whereas it was repressed in physical contact cocultures. However, a higher TGF-beta1 secretion rate was observed in physical contact cocultures compared with periosteal monocultures. The expression of COL2A1, melanoma inhibitory activity (cartilage-derived retinoic acid-sensitive protein) [MIA (CD-RAP)] and aggrecan was mainly unaffected by culture conditions, whereas COL1A1 gene expression was increased in periosteal paracrine cocultures. Collagen I staining was induced in micromass pellets from paracrine cocultures, whereas it was repressed in chondrocytes from physical contact cocultures., Conclusions: We found evidence for a bidirectional regulating system with paracrine signalling pathways between periosteum and articular chondrocytes. Stimulation of TGF-beta1 and COL1A1 gene expression in periosteal paracrine cocultures and the increased release of TGF-beta1 protein in physical contact conditions indicate an anabolic, and not merely chondrogenic micro-environment in this in vitro model for periosteal-based ACI.

Affective neuroscience has been strongly influenced by the view that a 'feeling' is the perception of somatic changes and has consequently often neglected the neural mechanisms that underlie the integration of somatic and other information in affective experience. Here, we investigate affective processing by means of functional magnetic resonance imaging in nine cortically blind patients. In these patients, unilateral postgeniculate lesions prevent primary cortical visual processing in part of the visual field which, as a result, becomes subjectively blind. Residual subcortical processing of visual information, however, is assumed to occur in the entire visual field. As we have reported earlier, these patients show significant startle reflex potentiation when a threat-related visual stimulus is shown in their blind visual field. Critically, this was associated with an increase of brain activity in somatosensory-related areas, and an increase in experienced negative affect. Here, we investigated the patients' response when the visual stimulus was shown in the sighted visual field, that is, when it was visible and cortically processed. Despite the fact that startle reflex potentiation was similar in the blind and sighted visual field, patients reported significantly less negative affect during stimulation of the sighted visual field. In other words, when the visual stimulus was visible and received full cortical processing, the patients' phenomenal experience of affect did not closely reflect somatic changes. This decoupling of phenomenal affective experience and somatic changes was associated with an increase of activity in the left ventrolateral prefrontal cortex and a decrease of affect-related somatosensory activity. Moreover, patients who showed stronger left ventrolateral prefrontal cortex activity tended to show a stronger decrease of affect-related somatosensory activity. Our findings show that similar affective somatic changes can be associated with different phenomenal experiences of affect, depending on the depth of cortical processing. They are in line with a model in which the left ventrolateral prefrontal cortex is a relay station that integrates information about subcortically triggered somatic responses and information resulting from in-depth cortical stimulus processing. Tentatively, we suggest that the observed decoupling of somatic responses and experienced affect, and the reduction of negative phenomenal experience, can be explained by a left ventrolateral prefrontal cortex-mediated inhibition of affect-related somatosensory activity.

Unlabelled: ShortRead is a package for input, quality assessment, manipulation and output of high-throughput sequencing data. ShortRead is provided in the R and Bioconductor environments, allowing ready access to additional facilities for advanced statistical analysis, data transformation, visualization and integration with diverse genomic resources., Availability and Implementation: This package is implemented in R and available at the Bioconductor web site; the package contains a 'vignette' outlining typical work flows.

Unlabelled: In many genomic studies, one works with genome-position-dependent data, e.g. ChIP-chip or ChIP-Seq scores. Using conventional tools, it can be difficult to get a good feel for the data, especially the distribution of features. This article argues that the so-called Hilbert curve visualization can complement genome browsers and help to get further insights into the structure of one's data. This is demonstrated with examples from different use cases. An open-source application, called HilbertVis, is presented that allows the user to produce and interactively explore such plots., Availability: http://www.ebi.ac.uk/huber-srv/hilbert/.

Objectives: Sensory nerve fibres (NFs) contain two major neuropeptides, substance P (SP) and calcitonin gene-related peptide (CGRP). The pro-inflammatory role of SP is known, while CGRP has anti-inflammatory activities by inhibiting T helper type 1 cytokines, TNF secretion and leucocyte proliferation. We demonstrated the increase of SP-positive NFs in RA as compared with OA. This study investigated the density of CGRP-positive NFs relative to SP-positive NFs or sympathetic NFs in synovial tissue of patients with RA and OA., Methods: By immunofluorescent staining of synovial tissue of 25 patients with RA and 35 patients with OA, NFs positive for CGRP, SP and tyrosine hydroxylase (sympathetic NFs) were quantified., Results: Density of CGRP-positive NFs was higher in OA than in RA, and density of SP-positive NFs tended to be higher in RA. In RA patients, comparison of CGRP-positive and SP-positive NFs in the same synovial tissue demonstrated less CGRP-positive than SP-positive NFs. The ratio of CGRP-positive NFs to SP-positive NFs was lower in RA as compared with OA. In OA, but not in RA, density of CGRP-positive NFs positively correlated with density of sympathetic NFs, which is much lower in RA patients., Conclusion: The preponderance of SP-positive NFs over CGRP-positive NFs or sympathetic NFs most probably supports the pro-inflammatory process in patients with RA. The reasons for the loss of CGRP in sensory NFs are not known.

Objective: Computerized clinical reminders (CRs) were designed to reduce clinicians' reliance on their memory and to present evidence-based guidelines at point of care. However, the literature indicates that CR adoption and effectiveness has been variable. We examined the impact of four design modifications to CR software on learnability, efficiency, usability, and workload for intake nursing personnel in an outpatient clinic setting. These modifications were included in a redesign primarily to address barriers to effective CR use identified during a previous field study., Design: In a simulation experiment, 16 nurses used prototypes of the current and redesigned system in a within-subject comparison for five simulated patient encounters. Prior to the experimental session, participants completed an exploration session, where "learnability" of the current and redesigned systems was assessed., Measurements: Time, performance, and survey data were analyzed in conjunction with semi-structured debrief interview data., Results: The redesign was found to significantly increase learnability for first-time users as measured by time to complete the first CR, efficiency as measured by task completion time for two of five patient scenarios, usability as determined by all three groupings of questions taken from a commonly used survey instrument, and two of six workload subscales of the NASA Task Load Index (TLX) survey: mental workload and frustration., Conclusion: Modest design modifications to existing CR software positively impacted variables that likely would increase the willingness for first-time nursing personnel to adopt and consistently use CRs.

In addition to the propositional content of verbal utterances, significant linguistic and emotional information is conveyed by the tone of speech. To differentiate brain regions subserving processing of linguistic and affective aspects of intonation, discrimination of sentences differing in linguistic accentuation and emotional expressiveness was evaluated by functional magnetic resonance imaging. Both tasks yielded rightward lateralization of hemodynamic responses at the level of the dorsolateral frontal cortex as well as bilateral thalamic and temporal activation. Processing of linguistic and affective intonation, thus, seems to be supported by overlapping neural networks comprising partially right-sided brain regions. Comparison of hemodynamic activation during the two different tasks, however, revealed bilateral orbito-frontal responses restricted to the affective condition as opposed to activation of the left lateral inferior frontal gyrus confined to evaluation of linguistic intonation. These findings indicate that distinct frontal regions contribute to higher level processing of intonational information depending on its communicational function. In line with other components of language processing, discrimination of linguistic accentuation seems to be lateralized to the left inferior-lateral frontal region whereas bilateral orbito-frontal areas subserve evaluation of emotional expressiveness.

Motor training consisting of voluntary movements leads to performance improvements and results in characteristic reorganizational changes in the motor cortex. It has been proposed that repetition of passively elicited movements could also lead to improvements in motor performance. In this study, we compared behavioural gains, changes in functional MRI (fMRI) activation in the contralateral primary motor cortex (cM1) and in motor cortex excitability measured with transcranial magnetic stimulation (TMS) after a 30 min training period of either voluntarily (active) or passively (passive) induced wrist movements, when alertness and kinematic aspects of training were controlled. During active training, subjects were instructed to perform voluntary wrist flexion-extension movements of a specified duration (target window 174-186 ms) in an articulated splint. Passive training consisted of wrist flexion- extension movements elicited by a torque motor, of the same amplitude and duration range as in the active task. fMRI activation and TMS parameters of motor cortex excitability were measured before and after each training type. Motor performance, measured as the number of movements that hit the target window duration, was significantly better after active than after passive training. Both active and passive movements performed during fMRI measurements activated cM1. Active training led to more prominent increases in (i) fMRI activation of cM1; (ii) recruitment curves (TMS); and (iii) intracortical facilitation (TMS) than passive training. Therefore, a short period of active motor training is more effective than passive motor training in eliciting performance improvements and cortical reorganization. This result is consistent with the concept of a pivotal role for voluntary drive in motor learning and neurorehabilitation.

Proteoglycans are macromolecules displaying structural roles as well as regulatory functions in the maintenance of the extracellular matrix. Biglycan/PG-I and decorin/PG-II are two small proteoglycans that are structurally related but differ considerably in their localization in vivo and behaviour in vitro. Decorin and, to a minor extent, biglycan, can be located at the surface of type I collagen fibrils and have been shown to influence collagen fibrillogenesis. However, the physiological role of biglycan in the dermis is not known. Biopsies obtained from keloids were bisected and processed for total RNA extraction and immunohistochemistry. Northern blot analysis of total RNA obtained from keloids with high growth tendency in vivo showed a marked induction of biglycan and collagen alpha 1(I)mRNA expression in comparison with total RNA obtained from normal skin or keloids with little growth tendency. In contrast, decorin mRNA expression remained largely unaltered. Studying these biopsies by immunohistochemistry, decorin expression in the dermis was unaltered comparing normal and keloid tissue, whereas a markedly increased staining for biglycan was observed in the keloid tissue, which was most pronounced in the nodular formations, and was a characteristic feature of keloids. The altered expression of biglycan in keloid tissue might be involved in the abnormal regulation of extracellular matrix deposition either through the binding of growth factors or by influencing the three-dimensional organization of collagen fibres or associated molecules.

The incidental finding of monoclonal immunoglobulin components (MC) in some infections prompted us to study this phenomenon more systematically. Using isoelectric focusing with immunoblotting (detection limit for MC 0.1 mg/ml), the following infections were studied for the presence of MC: visceral leishmaniasis, cytomegalovirus (CMV) infection, echinococcosis and infectious mononucleosis. MC were found in 16 of 20 leishmania patients and in eight of 18 CMV patients, but in only one of 20 echinococcosis patients and in none of 30 infectious mononucleosis patients. The MC were mostly transient, where tested. A minority of the MC found in the leishmaniasis patients was shown to bind to leishmania antigens. The specificity of the majority of the MC remains unknown. Further study is required to explain the high incidence of MC in CMV infection and visceral leishmaniasis.