This study explores the difficulties in distinguishing different lexical tone contrasts at both sub-lexical and lexical levels for beginning and advanced Dutch learners of Mandarin, using a... Show moreThis study explores the difficulties in distinguishing different lexical tone contrasts at both sub-lexical and lexical levels for beginning and advanced Dutch learners of Mandarin, using a sequence-recall task and an auditory lexical decision task. In both tasks, the Tone 2-Tone 3 contrast is most prone to errors for both groups of learners. A significant improvement in the advanced group was found for this tone contrast in the sub-lexical sequence recall task, but not in the lexical decision task. This is taken as evidence that utilizing tones in on-line spoken word recognition is more complex and demanding for L2 learners than in a memory-based task. The results of the lexical decision task also revealed that advanced learners have developed a stronger sensitivity to Tone 1 compared to the other three tones, with Tone 4 showing the least sensitivity. These findings suggest different levels of robustness and distinctiveness for the representation of different lexical tones in L2 learners’ lexicon and consequently different levels of proficiency in integrating tones for lexical processing. The observed patterns of difficulty are potentially related to the acoustic characteristics of different lexical tone contrasts as well as to the interference of the suprasegmental features of learner’s native language (i.e., the tonal contrasts of Dutch intonation) on the acquisition of the Mandarin lexical tone contrasts. Show less
OBJECTIVEType 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D... Show moreOBJECTIVEType 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed beta-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODSHere we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTSDespite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONSOur findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes. Show less
The ongoing coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is associated with substantial morbidity and mortality.... Show moreThe ongoing coronavirus (CoV) disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome CoV 2 (SARS-CoV-2) is associated with substantial morbidity and mortality. Understanding the immunological and patho-logical processes of coronavirus diseases is crucial for the rational design of effective vaccines and therapies for COVID-19. Previous studies showed that 2'-O-methylation of the viral RNA cap structure is required to prevent the recognition of viral RNAs by intra-cellular innate sensors. Here, we demonstrate that the guanine N7-methylation of the 5' cap mediated by coronavirus nonstructural protein 14 (nsp14) contributes to viral evasion of the type I interferon (IFN-I)-mediated immune response and pathogenesis in mice. A Y414A substitution in nsp14 of the coronavirus mouse hepatitis virus (MHV) significantly decreased N7-methyltransferase activity and reduced guanine N7-methyla-tion of the 5' cap in vitro. Infection of myeloid cells with recombinant MHV harboring the nsp14-Y414A mutation (rMHV(nsp14-Y414A)) resulted in upregulated expression of IFN-I and ISG15 mainly via MDA5 signaling and in reduced viral replication compared to that of wild-type rMHV. rMHV(nsp14-Y414A) replicated to lower titers in livers and brains and exhibited an attenuated phenotype in mice. This attenuated phenotype was IFN-I de-pendent because the virulence of the rMHV(nsp14-Y414A) mutant was restored in Ifnar(-/-) mice. We further found that the comparable mutation (Y420A) in SARS-CoV-2 nsp14 (rSARS-CoV-2(nsp14-Y420A)) also significantly decreased N7-methyltransferase activity in vitro, and the mutant virus was attenuated in K18-human ACE2 transgenic mice. Moreover, infection with rSARS-CoV-2(nsp14-Y420A) conferred complete protection against subsequent and otherwise lethal SARS-CoV-2 infection in mice, indicating the vaccine potential of this mutant.IMPORTANCE Coronaviruses (CoVs), including SARS-CoV-2, the cause of COVID-19, use several strategies to evade the host innate immune responses. While the cap struc-ture of RNA, including CoV RNA, is important for translation, previous studies indi-cate that the cap also contributes to viral evasion from the host immune response. In this study, we demonstrate that the N7-methylated cap structure of CoV RNA is pivotal for virus immunoevasion. Using recombinant MHV and SARS-CoV-2 encoding an inactive N7-methyltransferase, we demonstrate that these mutant viruses are highly attenuated in vivo and that attenuation is apparent at very early times after infection. Virulence is restored in mice lacking interferon signaling. Further, we show that infection with virus defective in N7-methylation protects mice from lethal SARSCoV-2, suggesting that the N7-methylase might be a useful target in drug and vaccine development. Show less
Khoramnia, R.; Figueroa, M.S.; Hattenbach, L.O.; Pavesio, C.E.; Anderesi, M.; Schmouder, R.; ... ; Smet, M.D. de 2021
Purpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO)... Show morePurpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO).Methods This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on MI following anti-VEGF therapy was also conducted.Results Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received >= 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event.Conclusions IOI may precede RV or RO in some patients treated with brolucizumab. Show less
In tonal languages such as Mandarin, both lexical tone and sentence intonation are primarily signaled by F0. Their F0 encodings are sometimes in conflict and sometimes in congruency. The present... Show moreIn tonal languages such as Mandarin, both lexical tone and sentence intonation are primarily signaled by F0. Their F0 encodings are sometimes in conflict and sometimes in congruency. The present study investigated how tone and intonation, with F0 encodings in conflict or in congruency, are processed and how semantic context may affect their processing. To this end, tone and intonation identification experiments were conducted in both semantically neutral and constraining contexts. Results showed that the overall performance of tone identification was better than that of intonation. Specifically, tone identification was seldom affected by intonation information irrespective of semantic contexts. However, intonation identification, particularly question intonation, was susceptible to the final lexical tone identity and affected by the semantic context. In the semantically neutral context, questions ending with a rising tone and a falling tone were equally difficult to identify. In the semantically constraining context, questions ending with a falling tone were much better identified than those ending with a rising tone. This perceptual asymmetry suggests that top-down information provided by the semantically constraining context can play a facilitating role for listeners to disentangle intonational information from tonal information, but mainly in sentences with the lexical falling tone in the final position. Show less
Ahlgren, P.; Chen, Y.; Colliander, C.; Eck, N.J.P. van 2020
The effects of enhancing direct citations, with respect to publication–publication relatedness measurement, by indirect citation relations (bibliographic coupling, cocitation, and extended direct... Show moreThe effects of enhancing direct citations, with respect to publication–publication relatedness measurement, by indirect citation relations (bibliographic coupling, cocitation, and extended direct citations) and text relations on clustering solution accuracy are analyzed. For comparison, we include each approach that is involved in the enhancement of direct citations. In total, we investigate the relative performance of seven approaches. To evaluate the approaches we use a methodology proposed by earlier research. However, the evaluation criterion used is based on MeSH, one of the most sophisticated publication-level classification schemes available. We also introduce an approach, based on interpolated accuracy values, by which overall relative clustering solution accuracy can be studied. The results show that the cocitation approach has the worst performance, and that the direct citations approach is outperformed by the other five investigated approaches. The extended direct citations approach has the best performance, followed by an approach in which direct citations are enhanced by the BM25 textual relatedness measure. An approach that combines direct citations with bibliographic coupling and cocitation performs slightly better than the bibliographic coupling approach, which in turn has a better performance than the BM25 approach. Show less
Objective To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.Methods We conducted a systematic review of existing guidelines... Show moreObjective To evaluate the development and implementation of clinical practice guidelines for the management of depression globally.Methods We conducted a systematic review of existing guidelines for the management of depression in adults with major depressive or bipolar disorder. For each identified guideline, we assessed compliance with measures of guideline development quality (such as transparency in guideline development processes and funding, multidisciplinary author group composition, systematic review of comparative efficacy research) and implementation (such as quality indicators). We compared guidelines from low- and middle-income countries with those from high-income countries.Findings We identified 82 national and 13 international clinical practice guidelines from 83 countries in 27 languages. Guideline development processes and funding sources were explicitly specified in a smaller proportion of guidelines from low- and middle-income countries (8/29; 28%) relative to high-income countries (35/58; 60%). Fewer guidelines (2/29; 7%) from low- and middle-income countries, relative to high-income countries (22/58; 38%), were authored by a multidisciplinary development group. A systematic review of comparative effectiveness was conducted in 31% (9/29) of low- and middle-income country guidelines versus 71% (41/58) of high-income country guidelines. Only 10% (3/29) of low- and middle-income country and 19% (11/58) of high-income country guidelines described plans to assess quality indicators or recommendation adherence.Conclusion Globally, guideline implementation is inadequately planned, reported and measured. Narrowing disparities in the development and implementation of guidelines in low- and middle-income countries is a priority. Future guidelines should present strategies to implement recommendations and measure feasibility, cost-effectiveness and impact on health outcomes. Show less
Most psycholinguistic models of speech production agree on an earlier semantic processing stage and a later word-form encoding stage. Using a logographic language, Mandarin Chinese, Zhang and... Show moreMost psycholinguistic models of speech production agree on an earlier semantic processing stage and a later word-form encoding stage. Using a logographic language, Mandarin Chinese, Zhang and Weekes [2009. Orthographic facilitation effects on spoken word production: Evidence from Chinese. Language and Cognitive Processes, 24(7–8), 1082–1096. https://doi.org/10.1080/ 01690960802042133] reported an early effect of orthography in a picture-word-interference study and suggested orthography affects speech production via a lexical-semantic pathway at an early stage. This early orthographic effect without co-occurrence of phonological effect, however, was not replicated [Zhao, La Heij, & Schiller, 2012. Orthographic and phonological facilitation in speech production: New evidence from picture naming in Chinese. Acta Psychologica, 139(2), 272–280. https://doi.org/10.1016/j.actpsy.2011.12.001]. The present study aimed to dissociate further the semantic and phonological representations from orthography by using simplex Chinese characters. The results of Experiment 1 and 2 revealed an orthographic effect but only at a similar point in time as the phonological effect, both of which followed the semantic effect. Our results thus raise further doubts about the role of orthography at the conceptual level of speech planning and lend new evidence to a two-step model of speech production. Show less
One long-neglected fact in linguistic research on Standard Chinese (SC) is that most speakers of SC also speak a local dialect, which may share phonological features with SC. Tonal information can... Show moreOne long-neglected fact in linguistic research on Standard Chinese (SC) is that most speakers of SC also speak a local dialect, which may share phonological features with SC. Tonal information can be a determinant of the phonological similarities or differences between some Chinese dialects and SC, yet relatively little empirical research has been conducted on the tonal system of other language varieties in Chinese aside from SC. Among these dialects, Xi’an Mandarin (XM) is particularly interesting for the seemingly simple, yet intricate mapping between its lexical tones with those in SC. In this study, the tonal systems of XM and SC were compared empirically. Tones with similar contours from XM and SC were paired, and both tone production and perception experiments were car- ried out on bidialectal speakers of XM and SC. The two experiments together showed that there is indeed systematic mapping of tones between XM and SC. The degree of similarity of the mapped tone pair in tone perception was largely dependent on the acoustic phonetic similarity between the tones in tone production, with a phonological rule playing a role in the tone pair of low contour. Show less
A broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories.Glycosylation is a topic of intense current... Show moreA broad-based interlaboratory study of glycosylation profiles of a reference and modified IgG antibody involving 103 reports from 76 laboratories.Glycosylation is a topic of intense current interest in the development of biopharmaceuticals because it is related to drug safety and efficacy. This work describes results of an interlaboratory study on the glycosylation of the Primary Sample (PS) of NISTmAb, a monoclonal antibody reference material. Seventy-six laboratories from industry, university, research, government, and hospital sectors in Europe, North America, Asia, and Australia submitted a total of 103 reports on glycan distributions. The principal objective of this study was to report and compare results for the full range of analytical methods presently used in the glycosylation analysis of mAbs. Therefore, participation was unrestricted, with laboratories choosing their own measurement techniques. Protein glycosylation was determined in various ways, including at the level of intact mAb, protein fragments, glycopeptides, or released glycans, using a wide variety of methods for derivatization, separation, identification, and quantification. Consequently, the diversity of results was enormous, with the number of glycan compositions identified by each laboratory ranging from 4 to 48. In total, one hundred sixteen glycan compositions were reported, of which 57 compositions could be assigned consensus abundance values. These consensus medians provide community-derived values for NISTmAb PS. Agreement with the consensus medians did not depend on the specific method or laboratory type. The study provides a view of the current state-of-the-art for biologic glycosylation measurement and suggests a clear need for harmonization of glycosylation analysis methods. Show less
Breathy phonation refers to the laryngeal setting where the vocal folds are less tense and make less contact than in “modal” phonation, which consequently leads to continuous leaking of voiceless... Show moreBreathy phonation refers to the laryngeal setting where the vocal folds are less tense and make less contact than in “modal” phonation, which consequently leads to continuous leaking of voiceless airflow, giving rise to the perception of breathiness in a speech sound. In Austronesian languages, contrastive breathy segments are very rare. For the Austronesian languages of Island Southeast Asia, only one language has been reported to have phonemically breathy vowels: Kedang, a language spoken on Lembata island, in eastern Indonesia. In this paper, we revisit the earlier analysis that in Kedang, breathiness distinguishes phonemic “breathy” from “modal” vowels. Presenting evidence of distributional, acoustic, and etymological nature, we argue that the so-called breathy onsetless vowels do not appear to be similar to breathy vowels described in the literature. Their “breathy” nature may have a historical source in initial glottal consonants that were lost, but is currently used as a phonetic strategy that is intended to enhance the perceptual contrast between syllables with a phonemic glottal onset versus onsetless syllables. We also suggest that the glottal stop in Kedang is phonemic in all positions and indicatea possible historical trajectory for its development. Show less
Background: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A... Show moreBackground: Mobile technology may help to better understand the adherence to treatment. MASK-rhinitis (Mobile Airways Sentinel NetworK for allergic rhinitis) is a patient-centred ICT system. A mobile phone app (the Allergy Diary) central to MASK is available in 22 countries.Objectives: To assess the adherence to treatment in allergic rhinitis patients using the Allergy Diary App.Methods: An observational cross-sectional study was carried out on all users who filled in the Allergy Diary from 1 January 2016 to 1 August 2017. Secondary adherence was assessed by using the modified Medication Possession Ratio (MPR) and the Proportion of days covered (PDC) approach.Results: A total of 12143 users were registered. A total of 6949 users reported at least one VAS data recording. Among them, 1887 users reported >= 7 VAS data. About 1195 subjects were included in the analysis of adherence. One hundred and thirty-six (11.28%) users were adherent (MPR >= 70% and PDC <= 1.25), 51 (4.23%) were partly adherent (MPR >= 70% and PDC = 1.50) and 176 (14.60%) were switchers. On the other hand, 832 (69.05%) users were non-adherent to medications (MPR <70%). Of those, the largest group was non-adherent to medications and the time interval was increased in 442 (36.68%) users.Conclusion and clinical relevance: Adherence to treatment is low. The relative efficacy of continuous vs on-demand treatment for allergic rhinitis symptoms is still a matter of debate. This study shows an approach for measuring retrospective adherence based on a mobile app. This also represents a novel approach for analysing medication-taking behaviour in a real-world setting. Show less
