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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.
This systematic review investigated how successful children/adolescents with poor literacy skills learn a foreign language compared with their peers with typical literacy skills. Moreover, we explored whether specific characteristics related to participants, foreign language instruction, and assessment moderated scores on foreign language tests in this population. Overall, 16 studies with a total of 968 participants (poor reader/spellers: n = 404; control participants: n = 564) met eligibility criteria. Only studies focusing on English as a foreign language were available. Available data allowed for meta-analyses on 10 different measures of foreign language attainment. In addition to standard mean differences (SMDs), we computed natural logarithms of the ratio of coefficients of variation (CVRs) to capture individual variability between participant groups. Significant between-study heterogeneity, which could not be explained by moderator analyses, limited the interpretation of results. Although children/adolescents with poor literacy skills on average showed lower scores on foreign language phonological awareness, letter knowledge, and reading comprehension measures, their performance varied significantly more than that of control participants. Thus, it remains unclear to what extent group differences between the foreign language scores of children/adolescents with poor and typical literacy skills are representative of individual poor readers/spellers. Taken together, our results indicate that foreign language skills in children/adolescents with poor literacy skills are highly variable. We discuss the limitations of past research that can guide future steps toward a better understanding of individual differences in foreign language attainment of children/adolescents with poor literacy skills.