Engagement Markers Research Articles

Safety, Pharmacokinetics and Pharmacodynamics of TNHH, a Novel Targeted Neutrophil-Inhibitory Hirulog Hybrid Glycoprotein, in Healthy Volunteers.

Targeted neutrophil inhibitory-hirulog (TNHH) is a novel hybrid glycoprotein that may be a potential drug candidate for acute ischaemic stroke. The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of TNHH in healthy volunteers and thereby determine the dose range for future clinical studies. This randomized, placebo-controlled study was a single ascending dose design with dose levels of 0.05-1.8mg/kg (n = 4-6 active, 2 placebos per cohort) in 68 participants. In the TNHH 0.2-1.8mg/kg and control cohorts, pharmacokinetic and pharmacodynamic blood samples were collected over 168h after intravenous (IV) administration. TNHH occupancy in peripheral blood neutrophils and blood coagulation were evaluated as the markers of target engagement. Two subjects withdrew from the trial before administration of the study treatment, 66 subjects are included in the data analysis. TNHH was well tolerated in all dose regimens. In total, five mild, self-limiting adverse events (AEs) were observed in 4 of the 66 study subjects. Dose-proportional increases in maximum plasma concentration (Cmax) and area under the curve (AUC0-t) of TNHH were observed. Traces of TNHH were excreted in urine. The elimination half-life (t½) ranged from 0.6 to 1.3h in the eight groups with ascending dose levels. TNHH combined with CD11b/CD18 quickly achieved > 90% receptor occupancy in groups with doses above 0.2mg/kg. The Cmax and AUC of binding TNHH with CD11b/CD18 increased with the dose. A significant prolongation with dose was observed on thrombin time (TT), and weak influences were observed on prothrombin time (PT) and activated partial thromboplastin time (APTT). TNHH was well-tolerated following IV infusion. The pharmacokinetic and pharmacodynamic characteristics of TNHH indicate that it merits clinical trials. It is recommended that the single dose of TNHH should be 1.0mg/kg in future studies, and the expected effect may be achieved after 5-7days of continuous administration. The study is registered at http://www.chictr.org.cn as ChiCTR-TQR-14004752.

Novel Inhaled Pan-JAK Inhibitor, LAS194046, Reduces Allergen-Induced Airway Inflammation, Late Asthmatic Response, and pSTAT Activation in Brown Norway Rats.

The Janus-activated kinase (JAK) family together with signal transducer and activator of transcription (STAT) signaling pathway has a key role in regulating the expression and function of many inflammatory cytokines. This has led to the discovery of JAK inhibitors for the treatment of inflammatory diseases, some of them already in the market. Considering the adverse effects associated with JAK inhibition by oral route, we wanted to explore whether JAK inhibition by inhaled route is enough to inhibit airway inflammation. The aim of this study was to characterize the enzymatic and cellular potency and the selectivity of LAS194046, a novel JAK inhibitor, compared with the reference compounds ruxolitinib and tofacitinib. The efficacy of this new JAK inhibitor is described in a model of ovalbumin (OVA)-induced airway inflammation in Brown Norway rats by inhaled administration. As potential markers of target engagement, we assessed the effect of LAS194046 on the STAT activation state. LAS194046 is a selective inhaled pan-JAK inhibitor that reduces allergen-induced airway inflammation, late asthmatic response, and phosphor-STAT activation in the rat OVA model. Our results show that topical inhibition of JAK in the lung, without relevant systemic exposure, is sufficient to reduce lung inflammation and improve lung function in a rat asthma model. In summary, JAK-STAT pathway inhibition by inhaled route constitutes a promising therapeutic option for lung inflammatory diseases.

Predicting Outcomes from Engagement With Specific Components of an Internet-Based Physical Activity Intervention With Financial Incentives: Process Analysis of a Cluster Randomized Controlled Trial.

BackgroundInvestigating participant engagement and nonusage attrition can help identify the likely active ingredients of electronic health interventions. Research on engagement can identify which intervention components predict health outcomes. Research on nonusage attrition is important to make recommendations for retaining participants in future studies.ObjectiveThis study aimed to investigate engagement and nonusage attrition in the Physical Activity Loyalty (PAL) scheme, a 6-month complex physical activity intervention in workplaces in Northern Ireland. The intervention included financial incentives with reward redemption and self-regulation techniques. Specific objectives were (1) to determine whether engagement in specific intervention components predicted physical activity at 6 months, (2) to determine whether engagement in specific intervention components predicted targeted mediators at 6 months, and (3) to investigate predictors of nonusage attrition for participants recording daily activity via the PAL scheme physical activity monitoring system and logging onto the website.MethodsPhysical activity was assessed at baseline and 6 months using pedometers (Yamax Digiwalker CW-701, Japan). Markers of engagement and website use, monitoring system use, and reward redemption were collected throughout the scheme. Random-effects generalized least-squares regressions determined whether engagement with specific intervention components predicted 6-month physical activity and mediators. Cox proportional hazards regressions were used to investigate predictors of nonusage attrition (days until first 2-week lapse).ResultsA multivariable generalized least-squares regression model (n=230) showed that the frequency of hits on the website’s monitoring and feedback component (regression coefficient [b]=50.2; SE=24.5; P=.04) and the percentage of earned points redeemed for financial incentives (b=9.1; SE=3.3; P=.005) were positively related to 6-month pedometer steps per day. The frequency of hits on the discussion forum (b=−69.3; SE=26.6; P=.009) was negatively related to 6-month pedometer steps per day. Reward redemption was not related to levels of more internal forms of motivation. Multivariable Cox proportional hazards regression models identified several baseline predictors associated with nonusage attrition. These included identified regulation (hazard ratio [HR] 0.88, 95% CI 0.81-0.97), recovery self-efficacy (HR 0.88, 95% CI 0.80-0.98), and perceived workplace environment safety (HR 1.07, 95% CI 1.02-1.11) for using the physical activity monitoring system. The EuroQoL health index (HR 0.33, 95% CI 0.12-0.91), financial motivation (HR 0.93, 95% CI 0.87-0.99), and perceived availability of physical activity opportunities in the workplace environment (HR 0.96, 95% CI 0.93-0.99) were associated with website nonusage attrition.ConclusionsOur results provide evidence opposing one of the main hypotheses of self-determination theory by showing that financial rewards are not necessarily associated with decreases in more internal forms of motivation when offered as part of a complex multicomponent intervention. Identifying baseline predictors of nonusage attrition can help researchers to develop strategies to ensure maximum intervention adherence.Trial RegistrationISRCTN Registry ISRCTN17975376; http://www.isrctn.com/ISRCTN17975376 (Archived by WebCite at http://www.webcitation.org/76VGZsZug)

SAT-LB073 SJX-653, a Novel Selective NK3 Antagonist, Demonstrates Activity on Pharmacodynamic Markers of NK3 Target Engagement

Background: NK3 antagonism is a clinically validated mechanism of action for treating menopausal vasomotor symptoms (“hot flashes”). In men, reductions of LH and T are sensitive pharmacodynamic markers of central NK3 antagonism, due to the known inhibitory effect of NK3 antagonists on GnRH pulsatility. Here we present results of a first-in-human study with SJX-653, a novel and selective NK3 antagonist, in healthy adult men. Objective: To characterize the safety, tolerability, pharmacokinetics, and pharmacodynamic activity (as measured by LH and T reductions) of single ascending oral doses of SJX-653 in healthy adult men. Methods: The study was a randomized, placebo-controlled, double-blind, single ascending dose study of orally administered SJX-653 in healthy adult men. Seven cohorts of 6 men were enrolled (4 SJX-653: 2 placebo). Subjects were confined to a Phase 1 unit from Day -1 to Day 3 with a follow-up visit on Day 8. Safety assessments (labs, ECG, vitals) and serial PK/PD samples were collected pre- and post-dose at multiple timepoints. Results: 42 male subjects were randomized and completed the study. Dose levels of 0.5 to 90 mg SJX-653 were evaluated. The median ages of subjects in the SJX-653 and placebo groups were 32.0 and 27.0 years, respectively. Subjects receiving SJX-653 and placebo had comparable mean height, weight, and BMI measurements. There were no serious adverse events (SAEs) or clinically meaningful changes in clinical laboratory values, vital sign measurements, or ECG parameters. AEs were mostly mild and the incidence of adverse events (AEs) was similar between subjects treated with SJX-653 and placebo. Across the 180-fold dose range (0.5 to 90 mg) mean Cmax and AUC0-24 values increased in a dose‑proportional manner with 175-fold and 143-fold increases, respectively. The mean terminal elimination half-life for SJX-653 was 10 to 13 hours. Reductions in LH and T levels were reversible and dose-dependent. LH reductions preceded T reductions by 2-3 hours, as expected. Statistically significant reductions in LH and T from baseline were observed at doses ≥15 mg SJX-653. The maximum mean LH reduction of 70% at 6 hours was in subjects treated with 30 mg SJX-653, versus 10% in placebo-treated subjects at the corresponding timepoint (p = 0.0006). The maximum mean T reduction of 68% at 8 hours was in subjects treated with 60 mg SJX-653, versus 18% in placebo-treated subjects at the corresponding timepoint (p < 0.0001). Conclusions: Single ascending doses of SJX-653 were well tolerated in healthy adult men. There were no SAEs and the incidence of AEs was similar between subjects treated with SJX-653 and placebo. The plasma half-life for SJX-653 was 10-13 hours, consistent with once-daily (QD) dosing. SJX-653 demonstrated clinical proof-of-mechanism as a central NK3 antagonist by causing statistically significant, dose-dependent, and reversible reductions in LH and T. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Behavioural and neural signatures of perceptual decision-making are modulated by pupil-linked arousal.

The timing and accuracy of perceptual decision-making is exquisitely sensitive to fluctuations in arousal. Although extensive research has highlighted the role of various neural processing stages in forming decisions, our understanding of how arousal impacts these processes remains limited. Here we isolated electrophysiological signatures of decision-making alongside signals reflecting target selection, attentional engagement and motor output and examined their modulation as a function of tonic and phasic arousal, indexed by baseline and task-evoked pupil diameter, respectively. Reaction times were shorter on trials with lower tonic, and higher phasic arousal. Additionally, these two pupil measures were predictive of a unique set of EEG signatures that together represent multiple information processing steps of decision-making. Finally, behavioural variability associated with fluctuations in tonic and phasic arousal, indicative of neuromodulators acting on multiple timescales, was mediated by its effects on the EEG markers of attentional engagement, sensory processing and the variability in decision processing.

Epic Apostrophe from Homer to Nonnus

This contribution explores the use of apostrophe (address by the narrator to the heroic figures) in Nonnus’ Dionysiaca. Nonnus inherits the use of this device from his epic predecessors: the emotional force of apostrophe is present in Homer; apostrophe as a marker of intertextual engagement with other genres (such as hymns or bucolic poetry) can be found in Hellenistic poetry. Most of the apostrophes in Nonnus are found in book 25 of the Dionysiaca, a passage rife with explicit poetological discussion of the relation between the Nonnian narrator and Homer. Apostrophe can here be read as a dramatization of this intertextual dialog with his “father” Homer.

An Analysis of Interactional Metadiscourse in Public Speaking: A Case Study in English Speeches of the Prime Minister of Bhutan

Public speaking is an act of presenting a speech to an audience with the goal of altering attitudes, actions, and sentiments, and to leave them inspired by words and impressed by meanings[1]. In general, speakers add metadiscourse markers into their speech to make it comprehensible to the audience rather than a mere exchange of information. This study principally investigated interactional metadiscourse markers used in the English speeches of Mr. Tshering Tobgay, the Honourable Prime Minister of Bhutan, delivered to international audiences on a variety of different topics. The present qualitative descriptive research focused on textual analysis using the metadiscourse model of Hyland[2] and the Appraisal theory of Martin and White[3]. The results of the study showed attitude markers ranked the highest followed by engagement markers, self-mentions, boosters, and hedges. Moreover, the study also revealed that the topics of his speeches influenced the use of the interactional metadiscourse markers of the speaker. In general, this study highlighted elements of metadiscourse markers used by the leader of the country in delivering public speeches. The present study contributed to the existing body of literature related to metadiscourse analysis, especially of spoken texts. The information from this research can be of benefit to language learners, teachers and speakers in general, who are passionate about developing speaking skills.

Authorial Stance-Taking and Engagement by Iranian PhD Candidates of TEFL in Writing Their Dissertations

Writing has a special role in academic society as most of the information is transferred though publications. It has various aspects and among them stance taking and engagement have received less attention. The current study aimed at investigating how Iranian PhD candidates take stance and engagement in their dissertations. The participants of the study included Iranian PhD candidates and corpus for text analysis contained PhD dissertations written by them. Discourse analysis was carried out on the corpus to identify stance taking and engagement based on the framework proposed by Hyland (2008). Overall, it was found that Iranian PhD candidates use all the elements of stance taking although some elements were more present than others. For instance, the use of stance makers of boosters like actually, believe(s), believed, certain, clear, definite, demonstrate(s), demonstrated, and establish were present in the dissertations about 12.38% while the use of self-mention like I, me, my, our, us, we, the researcher, and the researchers were present about 39.04% out of all instances of stance markers used by the PhD candidates. With regard to the engagement, it was found that all the engagement markers were present in the dissertation except engagement markers such as Questions and Directive (imperative). As in stance taking the elements of engagement were present with various degrees. For instance, the use of interjections like the use of word Key was 12.42% while that of modals such as have to, must, need, ought, and should was 59.62%. The results were discussed and their implications were presented.

Metadiscourse: Variation across communicative contexts

Writers interact with readers using explicit signals of textual organization (e.g., firstly; however) and stance (e.g., possibly, surprisingly), known as metadiscourse markers (MDMs). Most metadiscourse studies, however, focus on academic writing exclusively, with minimal efforts comparing MDMs usage across communicative contexts. The present study examines English-as-Foreign-Language (EFL) learners’ use of MDMs in academic and colloquial writing. Each participant produced two texts on the same topic: a personal email to a close friend (colloquial) and an academic report to school principals (academic). The corpus of 704 texts were coded using Hyland’s metadiscourse model (2005). Trained EFL teachers scored texts for overall writing quality. The study first presented a distributional map of MDMs used in the EFL academic and colloquial writing corpora. Then, multi-level models revealed both similarities and differences in the use of MDM subtypes to serve distinct communicative purposes (e.g., more code glosses in academic writing; more boosters and engagement markers in colloquial writing). Finally, the use of MDMs was analyzed in relation to overall writing quality within and across communicative contexts. The results highlighted the strengths and weaknesses in EFL learners’ use of MDMs and informed the design of pedagogical approach attuned to the pragmatic functions of MDMs.

The Prevalence and Frequency of Authorial Identity among Undergraduate Students in Fiji

Expressing an authoritative voice is an essential part of academic writing at university. However, the performance of the authorial self in writing is complex yet fundamental to academic success as a large part of academic assessment involves writing to the academy. More specifically, the performance of the authorial self can be complex for English as a Second Language (ESL) student-writers. This research investigated the extent to which ESL first-year students at the Fiji National University perform their authorial voice using interactional metadiscourse in their academic writing. The study employed a quantitative analysis of corpus produced by 16 Fijian ESL undergraduate students enrolled in an EAP course. The research found that the ESL authorial voice was predominantly expressed through boosters and attitude markers, with relatively little usage of other interactional metadiscoursal elements such as hedges, engagement markers and self-mentions. Further, the research showed that this particular cohort expressed their authorial voice and identity through boosted arguments and avoiding language that directly mentions the authorial self. The study concludes that the ESL authorial self for this cohort manifests itself in a selected range of selected interactional metadiscoursal elements, requiring the need to raise the awareness of self-reflective expressions for ESL students. The study also encourages further exploration of ESL authorial identity construction in academic writing at undergraduate level and beyond.

Online conference announcements as spaces for disciplinary communication

Abstract The aim of the study is to explore online conference announcements as sites for disciplinary communication and the way they are realized linguistically. A corpus of 50 conference announcements included in a major listserv in the field of linguistics is analysed, focusing on rhetorical structure and major interpersonal features, namely self mentions, engagement markers, modal verbs and the use of passive voice. Results show that linguistic interpersonal markers are deployed in the text according to the various communicative functions the text has and also the role played by the writer at each stage and, subsequently, the roles ascribed to readers. Moreover, it is claimed that the wide distribution of conference announcements ensured through electronic platforms reinforces the strategic role of these texts as vehicles of communication and interaction among disciplinary members.

A Comparative Study on Engagement Resources in American and Chinese CSR Reports

Based on Martin and White&amp;rsquo;s (2005) heteroglossic engagement system of Appraisal Theory, adopting UAM Corpus Tool and Chi-Square test, this study aims to explore authorial stance and distinctive rhetorical strategies that have been employed to realize interpersonal meaning by the application of engagement resources in American and Chinese CSR reports. It can be concluded that all types of engagement resources are widely employed in both American and Chinese corpus, with contraction resources significantly different in two corpora. It also finds that American CSR reports employ each type of engagement markers equally, while Chinese CSR reports tend to highly use expansion resources to enhance authorial voice. Besides, American CSR reports employ contraction resources in a more diversified and flexible way than Chinese CSR reports writers do. Lastly, they are also different in acknowledging what kinds of external propositions as expansion resources. This study confirms that engagement system is an important tool to help CSR reports writers to align authorial voices with readers, thereby accomplishing promotional and persuasive purposes. It may give some implications to CSR report addressers, addressees, business English teaching and reading.

Time-varying whole-brain functional network connectivity coupled to task engagement.

Brain functional connectivity (FC), as measured by blood oxygenation level-dependent (BOLD) signal, fluctuates at the scale of 10s of seconds. It has recently been found that whole-brain dynamic FC (dFC) patterns contain sufficient information to permit identification of ongoing tasks. Here, we hypothesize that dFC patterns carry fine-grained information that allows for tracking short-term task engagement levels (i.e., 10s of seconds long). To test this hypothesis, 25 subjects were scanned continuously for 25 min while they performed and transitioned between four different tasks: working memory, visual attention, math, and rest. First, we estimated dFC patterns by using a sliding window approach. Next, we extracted two engagement-specific FC patterns representing active engagement and passive engagement by using k-means clustering. Then, we derived three metrics from whole-brain dFC patterns to track engagement level, that is, dissimilarity between dFC patterns and engagement-specific FC patterns, and the level of brainwide integration level. Finally, those engagement markers were evaluated against windowed task performance by using a linear mixed effects model. Significant relationships were observed between abovementioned metrics and windowed task performance for the working memory task only. These findings partially confirm our hypothesis and underscore the potential of whole-brain dFC to track short-term task engagement levels.

The Associations between Substance Use, Sexual Behavior, Deviant Behaviors and Adolescents' Engagement in Sexting: Does Relationship Context Matter?

While prior research has identified multiple associations between engagement in sexting and risky behaviors, most existing studies do not take into account the contexts in which sexting occurs. The present study extends prior research by examining whether the associations between adolescents' sexting behavior and engagement in substance use, sexual behaviors, and deviant behaviors differ depending on the relational context (within or outside of a romantic relationship) in which young people engage in sexting. Results from a survey of 1187 secondary school students (61.3% girls, n = 728) between 16 and 22 years old (M = 17.82 years; SD = 0.88) revealed that sexting with a romantic partner is not a significant marker of engagement in risk behaviors. However, single youth who engage in sexting outside of a romantic relationship are more likely to report substance use, relative to their non-sexting counterparts. These findings underscore the need to use more nuanced measures to investigate sexting and for sexual education initiatives to integrate messages about substance use.

Malaysian ESL Students’ Perception of Metadiscoure in Essay Writing&amp;nbsp;

This study investigated the use of metadiscourse markers and highlighted the problems that Malaysian ESL students face in writing essays. An action research approach using both quantitative and qualitative analyses were used to explore metadiscoure usage. The subjects of this study were diploma students who had enrolled in an English for Academic Purposes (EAP) course in a private college in Malaysia. A total of 143 scripts of the essays written in the essay writing section of the final examination were assessed and analyzed using Hyland’s (2005a) interpersonal model of metadiscourse. Results revealed that transitions were the most frequently used interactive metadiscourse, making up 54% of the total interactive markers, while evidentials were the least frequently occurring with only 2 occurrences. Under the interactional resources, engagement markers were found to be the most favored, accounting for 40.7% of the interactional markers, while attitude markers appeared the least with only 3 occurrences. The findings of this study suggest that metadiscourse practices play a crucial role in creating a cohesive and a coherent piece of writing. In addition, ESL students need to be explicitly instructed on the communicative function of metadiscourse markers in academic writing.

Discovery and translation of a target engagement marker for AMP-activated protein kinase (AMPK).

BackgroundActivation of the AMP-activated protein kinase (AMPK) is an attractive approach for the treatment of type 2 diabetes. AMPK activation reduces glucose levels in animal models of type 2 diabetes by increasing glucose uptake in skeletal muscles and reducing hepatic glucose production. Furthermore, AMPK activation ameliorates hepatic steatosis in animal models. For the clinical development of AMPK activators it is essential to have a reliable target engagement marker for appropriate dose finding and to support proof of clinical principle. While the activation of AMPK by quantification of the phosphorylation of AMPK at Thr172 in target tissues can be assessed pre-clinically, this is not feasible in clinical studies. Therefore, we attempted to identify and translate a peripheral target engagement biomarker downstream of AMPK activation for clinical use in blood samples.MethodsFor pharmacological activation of AMPK, two AMPK activators were synthesized (compound 1 and 2). A compound with structural similarities but no pharmacological effect on AMPK phosphorylation was synthesized as negative control (compound 3). Whole blood from healthy volunteers was incubated with an AMPK activator for up to 6 hours and mRNA sequencing was performed. Additionally, human PBMCs were isolated to evaluate Thr172-phosphorylation of AMPK in Western blots. In order to enable identification of translatable biomarker candidates, blood samples from HanWistar rats treated for two weeks with an AMPK activator were also subjected to mRNA sequencing. Furthermore, concentration-response curves for four biomarker candidates were recorded in human blood samples using Nanostring nCounter technology. Finally, ZDF rats were treated with increasing doses of compound 2 for five weeks to investigate the glucose-lowering efficacy. To investigate changes of mRNA expression of two selected biomarker candidates in this ZDF rat study, qRT-PCR was performed.ResultsPharmacological activation of AMPK in human PBMCs revealed an increase in Thr172-phosphorylation of AMPK, confirming target engagement in these blood cells. RNA sequencing of human blood samples identified 608 deregulated genes after AMPK activation. Additionally, AMPK activation led to deregulation of 367 genes in whole blood from HanWistar rats which mapped to the respective human genes. 22 genes out of the intersection of genes deregulated in both species are proposed as potential translatable target engagement biomarker candidates. The most prominent genes were transmembrane glycoprotein NMB (GPNMB, osteoactivin), calcium-binding protein A9 (S100A9), peptidoglycan recognition protein (PGLYRP1) and Ras homolog gene family, member B (RHOB). Specificity for AMPK was shown by testing inactive compound 3 in HanWistar rats. The exposure-effect relationship for GPNMB was investigated in a subchronic study in diabetic ZDF rats. GPNMB showed a dose-dependent up-regulation both acutely and after subchronic dosing. GPNMB up-regulation correlated with an increased Thr172-phosphorylation of AMPK in liver and quadriceps muscle in rats.ConclusionGPNMB has been identified as a translatable target engagement biomarker for use in clinical studies.

Differential tissue response to growth hormone in mice.

Growth hormone (GH) has been shown to act directly on multiple tissues throughout the body. Historically, it was believed that GH acted directly in the liver and only indirectly in other tissues via insulin‐like growth hormone 1 (IGF‐1). Despite extensive work to describe GH action in individual tissues, a comparative analysis of acute GH signaling in key metabolic tissues has not been performed. Herein, we address this knowledge gap. Acute tissue response to human recombinant GH was assessed in mice by measuring signaling via phospho‐STAT5 immunoblotting. STAT5 activation is an easily and reliably detected early marker of GH receptor engagement. We found differential tissue sensitivities; liver and kidney were equally GH‐sensitive and more sensitive than white adipose tissue, heart, and muscle (gastrocnemius). Gastrocnemius had the greatest maximal response compared to heart, liver, white adipose tissue, and whole kidney. Differences in maximum responsiveness were positively correlated with tissue STAT5 abundance, while differences in sensitivity were not explained by differences in GH receptor levels. Thus, GH sensitivity and responsiveness of distinct metabolic tissues differ and may impact physiology and disease.

Projecting Gender Identity in Argumentative Written Discourse

Generally speaking, writers use various resources for introducing themselves to their readers. Among these, stance and engagement discourse markers are fundamental properties which manifest the underlying interaction process between writers and readers. The present paper sought to investigate whether male and female Iranian EFL learners performed differently in terms of using stance and engagement features in their writing assignments. To this end, a corpus comprising 80 argumentative essays written by advanced learners (40 males and 40 females) were collected and analyzed respectively. Hyland’s (2008) framework of stance and engagement features including hedges, boosters, attitude markers and self-mention as well as readers’ use of engagement markers such as pronouns, directives, questions, and shared knowledge served as a tertium comprationis for comparing and contrasting the written corpora created by male and female students. For analyzing the data, a software named Hermetic Word Counter was utilized to determine the frequency of the targeted tokens. The findings revealed that male and female writers made a differential use of stance and engagement features in writing argumentative essays. The significance of the differences was further attested by the application of a chi-square statistical technique. Regarding stance-taking, it was found out that both groups followed the same patterns of stance-taking except for the use of hedges and boosters. Moreover, compared to male students, the female writers tried to create reader engagement by asking questions.

Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers.

ObjectiveTo evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72‐associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume.MethodsWe measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel‐wise analyses.ResultsPoly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus.InterpretationThis study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72‐associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.

Curriculum Design and Implementation of the Emergency Medicine Chief Resident Incubator.

BackgroundChief residents receive minimal formal training in preparation for their administrative responsibilities. There is a lack of professional development programs specifically designed for chief residents.ObjectiveIn 2015, Academic Life in Emergency Medicine designed and implemented an annual, year-long, training program and virtual community of practice for chief residents in emergency medicine (EM). This study describes the curriculum design process and reports measures of learner engagement during the first two cycles of the curriculum.MethodsKern’s Six-Step Approach for curriculum development informed key decisions in the design and implementation of the Chief Resident Incubator. The resultant curriculum was created using constructivist social learning theory, with specific objectives that emphasized the needs for a virtual community of practice, longitudinal content delivery, mentorship for participants, and the facilitation of multicenter digital scholarship. The 12-month curriculum included 11 key administrative or professional development domains, delivered using a combination of digital communications platforms. Primary outcomes measures included markers of learner engagement with the online curriculum, recognized as modified Kirkpatrick Level One outcomes for digital learning.ResultsAn average of 206 chief residents annually enrolled in the first two years of the curriculum, with an overall participation by 33% (75/227) of the allopathic EM residency programs in the United States (U.S.). There was a high level of learner engagement, with an average 13,414 messages posted per year. There were also 42 small group teaching sessions held online, which included 39 faculty and 149 chief residents. The monthly e-newsletter had a 50.7% open rate. Digital scholarship totaled 23 online publications in two years, with 67 chief resident co-authors and 21 faculty co-authors.ConclusionsThe Chief Resident Incubator is a virtual community of practice that provides longitudinal training and mentorship for EM chief residents. This incubator conceptual framework may be used to design similar professional development curricula across various health professions using an online digital platform.