Adverse drug reactions associated with amitriptyline - protocol for a systematic multiple-indication review and meta-analysis

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-thecounter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including <100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using metaregression (for indication, outcome, and time points) and I2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. Discussion: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations

The neural basis of sign language processing in deaf signers: An activation likelihood estimation meta-analysis

The neurophysiological response during processing of sign language (SL) has been studied since the advent of Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI). Nevertheless, the neural substrates of SL remain subject to debate, especially with regard to involvement and relative lateralization of SL processing without production in (left) inferior frontal gyrus (IFG; e.g., Campbell, MacSweeney, & Waters, 2007; Emmorey, 2006, 2015). Our present contribution is the first to address these questions meta-analytically, by exploring functional convergence on the whole-brain level using previous fMRI and PET studies of SL processing in deaf signers. We screened 163 records in PubMed and Web of Science to identify studies of SL processing in deaf signers conducted with fMRI or PET that reported foci data for one of the two whole-brain contrasts: (1) “SL processing vs. control” or (2) “SL processing vs. low-level baseline”. This resulted in a total of 21 studies reporting 23 experiments matching our selection criteria. We manually extracted foci data and performed a coordinate-based Activation Likelihood Estimation (ALE) analysis using GingerALE (Eickhoff et al., 2009). Our selection criteria and the ALE method allow us to identify regions that are consistently involved in processing SL across studies and tasks. Our analysis reveals that processing of SL stimuli of varying linguistic complexity engages widely distributed bilateral fronto-occipito-temporal networks in deaf signers. We find significant clusters in both hemispheres, with the largest cluster (5240 mm3) being located in left IFG, spanning Broca’s region (posterior BA 45 and the dorsal portion of BA 44). Other clusters are located in right middle and inferior temporal gyrus (BA 37), right IFG (BA 45), left middle occipital gyrus (BA 19), right superior temporal gyrus (BA 22), left precentral and middle frontal gyrus (BA 6 and 8), as well as left insula (BA 13). On these clusters, we calculated lateralization indices using hemispheric and anatomical masks: SL comprehension is slightly left-lateralized globally, and strongly left-lateralized in Broca’s region. Sub-regionally, left-lateralization is strongest in BA 44 (Table 1). Next, we performed a contrast analysis between SL and an independent dataset of action observation in hearing non-signers (Papitto, Friederici, & Zaccarella, 2019) to determine which regions are associated with processing of human actions and movements irrespective of the presence of linguistic information. Only studies of observation of non-linguistic manual actions were included in the final set (n = 26), for example, excluding the handling of objects. Significant clusters involved in the linguistic aspects of SL comprehension were found in left Broca’s region (centered in dorsal BA 44), right superior temporal gyrus (BA 22), and left middle frontal and precentral gyrus (BA 6 and 8; Figure 1A, B, D and E). Meta-analytic connectivity modelling for the surviving cluster in Broca’s region using the BrainMap database then revealed that it is co-activated with the classical language network and functionally primarily associated with cognition and language processing (Figure 1C and D). In line with studies of spoken and written language processing (Zaccarella, Schell, & Friederici, 2017; Friederici, Chomsky, Berwick, Moro, & Bolhuis, 2017), our meta-analysis points to Broca’s region and especially left BA 44 as a hub in the language network that is involved in language processing independent of modality. Right IFG activity is not language-specific but may be specific to the visuo-gestural modality (Campbell et al., 2007). References Amunts, K., Schleicher, A., Bürgel, U., Mohlberg, H., Uylings, H. B., & Zilles, K. (1999). Broca’s region revisited: Cytoarchitecture and intersubject variability. The Journal of Comparative Neurology, 412(2), 319-341. Campbell, R., MacSweeney, M., & Waters, D. (2007). Sign language and the brain: A review. Journal of Deaf Studies and Deaf Education, 13(1), 3-20. doi: 10.1093/deafed/enm035 Eickhoff, S. B., Laird, A. R., Grefkes, C., Wang, L. E., Zilles, K., & Fox, P. T. (2009). Coordinate-based activation likelihood estimation meta-analysis of neuroimaging data: A random-effects approach based on empirical estimates of spatial uncertainty. Human Brain Mapping, 30(9), 2907-2926. doi: 10.1002/hbm.20718 Emmorey, K. (2006). The role of Broca’s area in sign language. In Y. Grodzinsky & K. Amunts (Eds.), Broca’s region (p. 169-184). Oxford, England: Oxford UP. Emmorey, K. (2015). The neurobiology of sign language. In A. W. Toga, P. Bandettini, P. Thompson, & K. Friston (Eds.), Brain mapping: An encyclopedic reference (Vol. 3, p. 475-479). London, England: Academic Press. doi: 10.1016/B978-0-12-397025-1.00272-4 Friederici, A. D., Chomsky, N., Berwick, R. C., Moro, A., & Bolhuis, J. J. (2017). Language, mind and brain. Nature Human Behaviour. doi: 10.1038/s41562-017-0184-4 Matsuo, K., Chen, S.-H. A., & Tseng, W.-Y. I. (2012). AveLI: A robust lateralization index in functional magnetic resonance imaging using unbiased threshold-free computation. Journal of Neuroscience Methods, 205(1), 119-129. doi: 10.1016/j.jneumeth.2011.12.020 Papitto, G., Friederici, A. D., & Zaccarella, E. (2019). A neuroanatomical comparison of action domains using Activation Likelihood Estimation meta-analysis [Unpublished Manuscript, Max Planck Institute for Human Cognitive & Brain Sciences]. Leipzig, Germany. Zaccarella, E., Schell, M., & Friederici, A. D. (2017). Reviewing the functional basis of the syntactic Merge mechanism for language: A coordinate-based activation likelihood estimation meta-analysis. Neuroscience & Biobehavioral Reviews, 80, 646-656. doi: 10.1016/j.neubiorev.2017.06.01

The Validation of Speech Corpora

1.2 Intended audience........................

Hypermedia Learning Objects System - On the Way to a Semantic Educational Web

While eLearning systems become more and more popular in daily education, available applications lack opportunities to structure, annotate and manage their contents in a high-level fashion. General efforts to improve these deficits are taken by initiatives to define rich meta data sets and a semanticWeb layer. In the present paper we introduce Hylos, an online learning system. Hylos is based on a cellular eLearning Object (ELO) information model encapsulating meta data conforming to the LOM standard. Content management is provisioned on this semantic meta data level and allows for variable, dynamically adaptable access structures. Context aware multifunctional links permit a systematic navigation depending on the learners and didactic needs, thereby exploring the capabilities of the semantic web. Hylos is built upon the more general Multimedia Information Repository (MIR) and the MIR adaptive context linking environment (MIRaCLE), its linking extension. MIR is an open system supporting the standards XML, Corba and JNDI. Hylos benefits from manageable information structures, sophisticated access logic and high-level authoring tools like the ELO editor responsible for the semi-manual creation of meta data and WYSIWYG like content editing.Comment: 11 pages, 7 figure

A formal verification framework and associated tools for enterprise modeling : application to UEML

The aim of this paper is to propose and apply a verification and validation approach to Enterprise Modeling that enables the user to improve the relevance and correctness, the suitability and coherence of a model by using properties specification and formal proof of properties

Truth-Theoretic Semantics and Its Limits

Donald Davidson was one of the most influential philosophers of the last half of the 20th century, especially in the theory of meaning and in the philosophy of mind and action. In this paper, I concentrate on a field-shaping proposal of Davidson’s in the theory of meaning, arguably his most influential, namely, that insight into meaning may be best pursued by a bit of indirection, by showing how appropriate knowledge of a finitely axiomatized truth theory for a language can put one in a position both to interpret the utterance of any sentence of the language and to see how its semantically primitive constituents together with their mode of combination determines its meaning (Davidson 1965, 1967, 1970, 1973a). This project has come to be known as truth-theoretic semantics. My aim in this paper is to render the best account I can of the goals and methods of truth-theoretic semantics, to defend it against some objections, and to identify its limitations. Although I believe that the project I describe conforms to the main idea that Davidson had, my aim is not primarily Davidson exegesis. I want to get on the table an approach to compositional semantics for natural languages, inspired by Davidson, but extended and developed, which I think does about as much along those lines as any theory could. I believe it is Davidson’s project, and I defend this in detail elsewhere (Ludwig 2015; Lepore and Ludwig 2005, 2007a, 2007b, 2011). But I want to develop and defend the project while also exploring its limitations, without getting entangled in exegetical questions

Genome-wide screening for DNA variants associated with reading and language traits

This research was funded by: Max Planck Society, the University of St Andrews - Grant Number: 018696, US National Institutes of Health - Grant Number: P50 HD027802, Wellcome Trust - Grant Number: 090532/Z/09/Z, and Medical Research Council Hub Grant Grant Number: G0900747 91070Reading and language abilities are heritable traits that are likely to share some genetic influences with each other. To identify pleiotropic genetic variants affecting these traits, we first performed a genome‐wide association scan (GWAS) meta‐analysis using three richly characterized datasets comprising individuals with histories of reading or language problems, and their siblings. GWAS was performed in a total of 1862 participants using the first principal component computed from several quantitative measures of reading‐ and language‐related abilities, both before and after adjustment for performance IQ. We identified novel suggestive associations at the SNPs rs59197085 and rs5995177 (uncorrected P ≈ 10–7 for each SNP), located respectively at the CCDC136/FLNC and RBFOX2 genes. Each of these SNPs then showed evidence for effects across multiple reading and language traits in univariate association testing against the individual traits. FLNC encodes a structural protein involved in cytoskeleton remodelling, while RBFOX2 is an important regulator of alternative splicing in neurons. The CCDC136/FLNC locus showed association with a comparable reading/language measure in an independent sample of 6434 participants from the general population, although involving distinct alleles of the associated SNP. Our datasets will form an important part of on‐going international efforts to identify genes contributing to reading and language skills.Publisher PDFPeer reviewe