Exploratory Analysis Research Articles

Determinants of serious health outcome-free status in middle-aged and older people with dysglycaemia: Exploratory analysis of the ORIGIN trial.

To assess clinical and biochemical measurements that can identify people with dysglycaemia (i.e. diabetes or pre-diabetes) who remain free of serious outcomes during follow-up. We conducted exploratory analyses using data from the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) study to identify independent determinants of outcome-free status in 12 537 middle-aged and older adults with prediabetes and early type 2 diabetes from 40 countries. Serious outcome-free status was defined as the absence of major cardiovascular outcomes, kidney or retinal outcomes, peripheral artery disease, dementia, cancer, any hospitalization, or death during follow-up. In total, 3328 (26.6%) participants remained free of serious outcomes during a median follow-up of 6.2 years (IQR 5.8, 6.7). Independent clinical determinants of outcome-free status included younger age, female sex, non-White ethnicity, shorter diabetes duration, absence of previous cardiovascular disease, current or former smokers, higher grip strength, Mini-Mental State Examination score, and ankle-brachial index, lower body mass index and kidney disease index, and non-use of renin-angiotensin system drugs and beta-blockers. In a subset of 8401 people with baseline measurements of 238 biomarkers, growth differentiation factor 15, kidney injury molecule-1, N-terminal pro-brain natriuretic peptide, uromodulin, C-reactive protein, factor VII and ferritin were independent determinants. The combination of clinical determinants and biomarkers best identified participants who remained outcome-free (C-statistics 0.71, 95% confidence interval 0.70-0.73; net reclassification improvement 0.55, 95% confidence interval 0.48-0.58). A set of routinely measured clinical characteristics and seven protein biomarkers identify middle-aged and older people with prediabetes or early type 2 diabetes as least likely to experience serious outcomes during follow-up.

Nasal inhalation does not improve memory of visual repetitions.

Several studies suggest that breathing entrains neural oscillations and thereby improves visual detection and memory performance during nasal inhalation. However, the evidence for this association is mixed, with some studies finding no, minor, or opposite effects. Here, we tested whether nasal breathing phase influences memory of repeated images presented in a rapid serial visual presentation (RSVP) task. The RSVP task is ideal for studying the effects of respiratory-entrained oscillations on visual memory because it engages critical aspects of sensory encoding that depend on oscillatory activity, such as fast processing of natural images, repetition detection, memory encoding, and retrieval. It also enables the presentation of a large number of stimuli during each phase of the breathing cycle. In two separate experiments (n = 72 and n = 142, respectively) where participants were explicitly asked to breathe through their nose, we found that nasal breathing phase at target presentation did not significantly affect memory performance. An exploratory analysis in the first experiment suggested a potential benefit for targets appearing approximately 1 s after inhalation. However, this finding was not replicated in the pre-registered second experiment with a larger sample. Thus, in two large sample experiments, we found no measurable impact of breathing phase on memory performance in the RSVP task. These results suggest that the natural breathing cycle does not have a significant impact on memory for repeated images and raise doubts about the idea that visual memory is broadly affected by the breathing phase.

Validation of the Mexican version of the EORTC QLQ-CR29 in patients with colorectal cancer.

The evaluation of the quality of life (QoL) of patients with colorectal cancer (CRC) is an essential measure to measure the impact of the disease and treatments on the lives of patients. However, in Latin America there is no validated and reliable instrument to assess this construct. This study aims to validate the EORTC QLQ-CR29 instrument in the Mexican population with CRC. This study aims to validate the EORTC QLQ-CR29 instrument in the Mexican population with CRC. The study used an instrumental design and a nonprobabilistic sample due to availability, made up of 251 patients with CRC, with an average age of 54.7 ± 12.28 years. Exploratory and confirmatory factor analyses were performed, as well as concurrent validity tests. The exploratory factorial analysis yielded 4 factors that explained 51.64% of the variance, with a Cronbach reliability coefficient of .766 and an Omega index of .725. The confirmatory factor analysis indicated that the proposed theoretical model fits the data almost perfectly, with an error close to 0, which shows that it is a balanced and parsimonious instrument to measure the QoL of the patients with CRC. The EORTC QLQ-CR29 instrument proved to be a valid and reliable instrument for use in clinical care and research directed at patients with CRC in Mexico. Its use is recommended by multidisciplinary health teams in oncology in Mexico, since it allows knowing the patient's perspective on the impact of CRC on their life, guiding therapeutic decision-making and being a primary outcome measure.

Screening for treatment-required sleep apnoea in patients with spinal cord injury within one year after injury in a rehabilitation setting.

The current study aims to assess the efficacy of the Stop-Bang Questionnaire (SBQ) in screening treatment-required sleep apnoea following Spinal Cord Injury (SCI). Additionally, we explore the performance of combined questionnaires and pulse oximetry to determine the most cost-effective method. The study employs a cross-sectional observational design. All patients admitted to in-hospital rehabilitation at the Spinal Cord Injury Centre of Western Denmark from September 2022 to February 2023 were continuously enrolled. Participating patients underwent SBQ screening, a standard sleep questionnaire, and cardiorespiratory monitoring, followed by an individual consultation with a physician. During the study period, 35 SCI patients were admitted, with 24 providing informed consent. Among the 24 included patients, there was a 75% prevalence of mild to severe sleep apnoea, and 46% had treatment-required sleep apnoea. The SBQ missed only one patient with treatment-required sleep apnoea but misclassified eight patients. Combining SBQ with the pulse oximetry demonstrated the best performance in identifying patients with sleep apnoea. The study indicates that SBQ alone is insufficient for screening treatment-required sleep apnoea. Exploratory analysis suggests that combining SBQ with a simple pulse oximetry measurement might enhance accuracy.

Radiomic features of the medial meniscus predicts incident destabilizing meniscal tears: Data from the osteoarthritis initiative.

The objective of this study was to determine the optimal meniscal radiomic features to classify people who will develop an incident destabilizing medial meniscal tear. We used magnetic resonance (MR) images from an existing case-control study that includes images from the first 4 years of the Osteoarthritis Initiative (OAI). For this exploratory analysis (n = 215), we limited our study sample to people with (1) intact menisci at the OAI baseline visit, (2) 4-year meniscal status data, and (3) complete meniscal data from each region of interest. Incident destabilizing meniscal tear was defined as progressing from an intact meniscus to a destabilizing tear by the 48-month visit using intermediate-weighted fat-suppressed MR images. One reader manually segmented each participant's anterior and posterior horn of the medial menisci at the OAI baseline visit. Next, 61 different radiomic features were extracted from each medial meniscus horn. We performed a classification and regression tree (CART) analysis to determine the classification rules and important variables that predict incident destabilizing meniscal tear. The CART correctly classified 24 of the 34 cases and 172 out of 181 controls with a sensitivity of 70.6% and a specificity of 95.0%. The CART identified large zone high gray level emphasis (i.e., more coarse texture) from the posterior horn as the most important variable to classify who would develop an incident destabilizing medial meniscal tear. The use of radiomic features provides sensitive and quantitative measures of meniscal alterations, allowing us to intervene and prevent destabilizing meniscal tears.

Does pain self-efficacy predict, moderate or mediate outcomes in people with chronic headache; an exploratory analysis of the CHESS trial

BackgroundChronic headache disorders are disabling. The CHESS trial studied the effects of a short non-pharmacological intervention of education with self-management support for people affected by migraine and/or tension type headache for at least 15 days per month for at least three months. There were no statistically significant effects on the Headache Impact Test-6 (HIT-6) at 12-months. However, we observed improvement in pain self-efficacy questionnaire (PSEQ) and short-term HIT-6. We explored the impact of the CHESS intervention on PSEQ, and subsequently, on the HIT-6 and chronic headache quality of life questionnaire (CH-QLQ) at four, eighth and 12 months.MethodsWe included all 736 participants from the CHESS trial. We used simple linear regression models to explore the change of HIT-6 and CH-QLQ with treatment and PSEQ at baseline (predictor analysis), and the interaction between treatment and baseline PSEQ (moderator analysis). We considered the change of PSEQ from baseline to four months as a mediator in the mediation analysis.ResultsBaseline PSEQ neither predicted nor moderated outcomes. The prediction effect on change of HIT-6 from baseline to 12 months was 0.01 (95% CI, -0.03 to 0.04) and the interaction (moderation) effect was −0.07 (95% CI, -0.15 to 0.002). However, the change of PSEQ from baseline to 4-month mediated the HIT-6 (baseline to 8-, and 12-month) and all components of CH-QLQ (baseline to 8-, and 12-month). The CHESS intervention improved the mediated variable, PSEQ, by 2.34 (95% CI, 0.484 to 4.187) units and this corresponds to an increase of 0.21 (95% CI, 0.03 to 0.45) units in HIT-6 at 12-months. The largest mediated effect was observed on the CH-QLQ Emotional Function, an increase of 1.12 (95% CI, 0.22 to 2.20).ConclusionsPSEQ was not an effective predictor of outcome. However, change of short-term PSEQ mediated all outcomes, albeit minimally. Future behavioural therapy for chronic headache may need to consider how to achieve larger, and more sustained increases level of self-efficacy than that achieved within the CHESS trial.Trial registrationISRCTN79708100.

Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.

Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2+) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2+ gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.

Assessing climate risk quantification tools – mere fulfilment of duty or actually beneficial?

PurposeThe study aims to assess the effectiveness of prevailing methods for quantifying physical climate risks. Its goal is to evaluate their utility in guiding financial decision-making within the real estate industry. Whilst climate risk has become a pivotal consideration in transaction and regulatory compliance, the existing tools for risk quantification frequently encounter criticism for their perceived lack of transparency and comparability.Design/methodology/approachWe utilise a sequential exploratory mixed-methods analysis to integrate qualitative aspects of underlying tool characteristics with quantitative result divergence. In our qualitative analysis, we conduct interviews with companies providing risk quantification tools. We task these providers with quantifying the physical risk of a fictive pan-European real estate portfolio. Our approach involves an in-depth comparative analysis, hypothesis tests and regression to discern patterns in the variability of the results.FindingsWe observe significant variations in the quantification of physical risk for the pan-European portfolio, indicating limited utility for decision-making. The results highlight that variability is influenced by both the location of assets and the hazard. Identified reasons for discrepancies include differences in regional databases and models, variations in downscaling and corresponding scope, disparities in the definition of scores and systematic uncertainties.Practical implicationsThe study assists market participants in comprehending both the quantification process and the implications associated with using tools for financial decision-making.Originality/valueTo our knowledge, this study presents the initial robust empirical evidence of variability in quantification outputs for physical risk within the real estate industry, coupled with an exploration of their underlying reasons.

Association between pretreatment emotional distress and immune checkpoint inhibitor response in non-small-cell lung cancer.

Emotional distress (ED), commonly characterized by symptoms of depression and/or anxiety, is prevalent in patients with cancer. Preclinical studies suggest that ED can impair antitumor immune responses, but few clinical studies have explored its relationship with response to immune checkpoint inhibitors (ICIs). Here we report results from cohort 1 of the prospective observational STRESS-LUNG study, which investigated the association between ED and clinical efficacy of first-line treatment of ICIs in patients with advanced non-small-cell lung cancer. ED was assessed by Patient Health Questionnaire-9 and Generalized Anxiety Disorder 7-item scale. The study included 227 patients with 111 (48.9%) exhibiting ED who presented depression (Patient Health Questionnaire-9 score ≥5) and/or anxiety (Generalized Anxiety Disorder 7-item score ≥5) symptoms at baseline. On the primary endpoint analysis, patients with baseline ED exhibited a significantly shorter median progression-free survival compared with those without ED (7.9 months versus 15.5 months, hazard ratio 1.73, 95% confidence interval 1.23 to 2.43, P = 0.002). On the secondary endpoint analysis, ED was associated with lower objective response rate (46.8% versus 62.1%, odds ratio 0.54, P = 0.022), reduced 2-year overall survival rate of 46.5% versus 64.9% (hazard ratio for death 1.82, 95% confidence interval 1.12 to 2.97, P = 0.016) and detriments in quality of life. The exploratory analysis indicated that the ED group showed elevated blood cortisol levels, which was associated with adverse survival outcomes. This study suggests that there is an association between ED and worse clinical outcomes in patients with advanced non-small-cell lung cancer treated with ICIs, highlighting the potential significance of addressing ED in cancer management. ClinicalTrials.gov registration: NCT05477979 .

The impact of the world’s first regulatory, multi-setting intervention on sedentary behaviour among children and adolescents (ENERGISE): a natural experiment evaluation

BackgroundRegulatory actions are increasingly used to tackle issues such as excessive alcohol or sugar intake, but such actions to reduce sedentary behaviour remain scarce. World Health Organization (WHO) guidelines on sedentary behaviour call for system-wide policies. The Chinese government introduced the world’s first nation-wide multi-setting regulation on multiple types of sedentary behaviour in children and adolescents in July 2021. This regulation restricts when (and for how long) online gaming businesses can provide access to pupils; the amount of homework teachers can assign to pupils according to their year groups; and when tutoring businesses can provide lessons to pupils. We evaluated the effect of this regulation on sedentary behaviour safeguarding pupils.MethodsWith a natural experiment evaluation design, we used representative surveillance data from 9- to 18-year-old pupils before and after the introduction of the regulation, for longitudinal (n = 7,054, matched individuals, primary analysis) and repeated cross-sectional (n = 99,947, exploratory analysis) analyses. We analysed pre-post differences for self-reported sedentary behaviour outcomes (total sedentary behaviour time, screen viewing time, electronic device use time, homework time, and out-of-campus learning time) using multilevel models, and explored differences by sex, education stage, residency, and baseline weight status.ResultsLongitudinal analyses indicated that pupils had reduced their mean total daily sedentary behaviour time by 13.8% (95% confidence interval [CI]: -15.9 to -11.7%, approximately 46 min) and were 1.20 times as likely to meet international daily screen time recommendations (95% CI: 1.01 to 1.32) one month after the introduction of the regulation compared to the reference group (before its introduction). They were on average 2.79 times as likely to meet the regulatory requirement on homework time (95% CI: 2.47 to 3.14) than the reference group and reduced their daily total screen-viewing time by 6.4% (95% CI: -9.6 to -3.3%, approximately 10 min). The positive effects were more pronounced among high-risk groups (secondary school and urban pupils who generally spend more time in sedentary behaviour) than in low-risk groups (primary school and rural pupils who generally spend less time in sedentary behaviour). The exploratory analyses showed comparable findings.ConclusionsThis regulatory intervention has been effective in reducing total and specific types of sedentary behaviour among Chinese children and adolescents, with the potential to reduce health inequalities. International researchers and policy makers may explore the feasibility and acceptability of implementing regulatory interventions on sedentary behaviour elsewhere.

Cardiovascular Structural and Functional Parameters in Idiopathic Pulmonary Fibrosis at Disease Diagnosis.

Prevalence of cardiac and vascular fibrosis in patients with Idiopathic Pulmonary Fibrosis (IPF) has not been extensively evaluated. In this study, we aimed to evaluate the heart and vessels functional and structural properties in patients with IPF compared to healthy controls. An exploratory analysis regarding disease severity in IPF patients has been done. We enrolled 50 patients with IPF (at disease diagnosis before antifibrotic therapy initiation) and 50 controls matched for age and gender. Heart was evaluated through echocardiography and plasmatic NT-pro-brain natriuretic peptide that, together with patients' symptoms, allow to define the presence of Heart Failure (HF) and diastolic dysfunction. Vessels were evaluated through Flow Mediated Dilation (FMD - endothelial function) and Pulse Wave Velocity (PWV-arterial stiffness) RESULTS: Patients with IPF had a prevalence of diastolic disfunction of 83.8%, HF of 37.8% and vascular fibrosis of 76.6%. No statistically significant difference was observed in comparison to the control group who showed prevalence of diastolic disfunction, HF and vascular fibrosis of 67.3%, 24.5% and 84.8%, respectively. Disease severity seems not to affect PWV, FMD, diastolic dysfunction and HF. Patients with IPF early in the disease course do not present a significant CV fibrotic involvement when compared with age- and sex-matched controls. Bigger and adequately powered studies are needed to confirm our preliminary data and longitudinal studies are required in order to understand the time of appearance and progression rate of heart and vascular involvement in IPF subjects.

Expediting structure–property analyses using variational autoencoders with regression

We present a machine learning approach that expedites structure–property analysis in materials, bypassing traditional feature extraction and exploratory data analysis techniques. This objective is accomplished by employing a variational autoencoder (VAE) structure that is modified to include a regressor network for property prediction (VAE-Regression). This modification allows for direct linkage of imaged features and quantitative part properties within the VAE latent space. We first demonstrate our approach using 2D optical micrographs and corresponding four-point bend fatigue life data from laser beam powder bed fusion additively manufactured Ti-6Al-4V coupons. The VAE-Regression model extracts spatial features, predicts fatigue life, and identifies features of porosity defect governing fatigue behavior such as pore clusters, pores near sample edges, and jagged pore morphologies. These features corroborate fatigue literature on physics-based modeling and experimentation. We then demonstrate the versatility of our methodology using binder jet additively manufactured WC-Co coupons, where porosity and microstructural discontinuities are known to lower the three-point bend transverse rupture strength, but the interaction between the WC and Co are yet to be completely understood. We attempted to understand these interactions using our VAE-Regression architecture. Within our dataset, we show that coarser WC grains surrounded by larger Co pools indicate lower strength, while finer WC grains with smaller Co pools indicate higher strength. This machine learning approach using image-based data will likely prove to be critical in understanding and identifying structure–property relationships in new materials and manufacturing processes.

Randomised, controlled, feasibility trial comparing vasopressor infusion administered via peripheral cannula versus central venous catheter for critically ill adults: A study protocol.

When clinicians need to administer a vasopressor infusion, they are faced with the choice of administration via either peripheral intravenous catheter (PIVC) or central venous catheter (CVC). Vasopressor infusions have traditionally been administered via central venous catheters (CVC) rather than Peripheral Intra Venous Catheters (PIVC), primarily due to concerns of extravasation and resultant tissue injury. This practice is not guided by contemporary randomised controlled trial (RCT) evidence. Observational data suggests safety of vasopressor infusion via PIVC. To address this evidence gap, we have designed the "Vasopressors Infused via Peripheral or Central Access" (VIPCA) RCT. The VIPCA trial is a single-centre, feasibility, parallel-group RCT. Eligible critically ill patients requiring a vasopressor infusion will be identified by emergency department (ED) or intensive care unit (ICU) staff and randomised to receive vasopressor infusion via either PIVC or CVC. Primary outcome is feasibility, a composite of recruitment rate, proportion of eligible patients randomised, protocol fidelity, retention and missing data. Primary clinical outcome is days alive and out of hospital up to day-30. Secondary outcomes will include safety and other clinical outcomes, and process and cost measures. Specific aspects of safety related to vasopressor infusions such as extravasation, leakage, device failure, tissue injury and infection will be assessed. VIPCA is a feasibility RCT whose outcomes will inform the feasibility and design of a multicentre Phase-3 trial comparing routes of vasopressor delivery. The exploratory economic analysis will provide input data for the full health economic analysis which will accompany any future Phase-3 RCT.

Social Perceptions of Masculinity and Sexual Esteem Are Impacted by Viagra Use, Testosterone, and Sexual Performance.

Sexual behaviors play a role in the social construction of masculinity. Moreover, this stereotype has been capitalized upon by pharmaceutical companies, as well as those that sell products not approved by the U.S. Food and Drug Administration, for purposes of marketing sexual medicines. Stereotypical notions of masculinity, however, also emphasize the importance of self-reliance, which may cause some to look unfavorably upon the use of sexual medicine. Consistent with this notion, a male target was viewed as more masculine when his female partner consistently reached orgasm, unless he had no history of erectile dysfunction (ED), but was taking Viagra anyway (Experiment 1; N = 522). In addition, when his partner consistently reached orgasm, ratings of his sexual esteem were also lower if he used Viagra than if he did not, but only if he had no history of ED. In Experiment 2 (N = 711), although there was no effect of a male target's use of testosterone, social perception of his masculinity and sexual esteem increased as his "natural" levels of testosterone increased. In addition, exploratory analysis revealed that if the male target had low (but not normal or high) "natural" levels of testosterone, ratings of his masculinity were higher if his female partner consistently had an orgasm, which suggests that female orgasm served to "rescue" masculinity. Because expectations about drugs drive their use, it is important to address preconceived notions about the use of sexual medicines for purposes of enhancing masculinity and sexual esteem, as the social perception of their use is much more complex.

Excimer laser coronary angioplasty combined with drug-coated balloon in the treatment of in-stent restenosis.

The aim of this study is to investigate the safety and efficacy of excimer laser coronary angioplasty (ELCA) combined with drug-coated balloons(DCBs) in the treatment of in-stent restenosis (ISR), and to explore whether the contrast injection technique would improve the neointimal tissue ablation of ELCA. We studied patients diagnosed with ISR between January 2019 and October 2022 at two medical centers. These patients underwent DCB angioplasty guided by optical coherence tomography (OCT). Based on whether ELCA was performed before DCB treatment, patients were categorized into two groups: the ELCA + DCB group and the DCB group. All patients underwent clinical follow-up 1 year after the procedure. The primary endpoint was the 1-year rate of target lesion revascularization (TLR), which was defined as any repeat percutaneous intervention or bypass surgery on the target vessel conducted to address restenosis or other complications related to the target lesion. The secondary endpoints including immediate luminal gain (ΔMLA, defined as the difference in minimum lumen area before and after the intervention). A total of 85 lesions in 75 patients were included. The mean age of the study population was 64.2 ± 12.0 years, with 81.3% male. Baseline clinical characteristics were well-balanced, and procedural success was 100% in both groups. The ELCA + DCB group (n = 24) exhibited a greater ΔMLA compared to the DCB group (n = 61) (3.57 ± 0.79 mm² vs. 2.50 ± 1.06 mm², [95% confidence interval,CI: 0.57-1.69], p < 0.001), The reduction in 1-year TLR was more frequently observed in patients from the ELCA + DCB group compared to the DCB group (hazard ratio 0.33 [95% CI: 0.11-0.99]; log-rank p = 0.048). The exploratory analysis showed that ELCA with contrast infusion is associated with greater acute lumen gain compared to ELCA with saline infusion (p < 0.001). The combination of ELCA and DCB is a safe and effective treatment strategy for in-stent stenosis. Additionally, compared with saline injection, ELCA with contrast injection is associated with greater acute lumen gain. However, the optimal contrast agent concentration and long-term outcome of the contrast injection technique need confirmation through larger sample sizes and prospective studies.

A registered report of a two-site study of variations of the flanker task: ERN experimental effects and data quality.

Error-related negativity is a widely used measure of error monitoring, and many projects are independently moving ERN recorded during a flanker task toward standardization, optimization, and eventual clinical application. However, each project uses a different version of the flanker task and tacitly assumes ERN is functionally equivalent across each version. The routine neglect of a rigorous test of this assumption undermines efforts to integrate ERN findings across tasks, optimize and standardize ERN assessment, and widely apply ERN in clinical trials. The purpose of this registered report was to determine whether ERN shows similar experimental effects (correct vs. error trials) and data quality (intraindividual variability) during three commonly used versions of a flanker task. ERN was recorded from 172 participants during three versions of a flanker task across two study sites. ERN scores showed numerical differences between tasks, raising questions about the comparability of ERN findings across studies and tasks. Although ERN scores from all three versions of the flanker task yielded high data quality and internal consistency, one version did outperform the other two in terms of the size of experimental effects and the data quality. Exploratory analyses of the error positivity (Pe) provided tentative support for the other two versions of the task over the paradigm that appeared optimal for ERN. The present study provides a roadmap for how to statistically compare psychometric characteristics of ERP scores across paradigms and gives preliminary recommendations for flanker tasks to use for ERN- and Pe-focused studies.

Multimodal practices of unpacking and repacking subject-specific knowledge in CLIL physics and chemistry lessons

BackgroundDifferent school subjects have their specific meaning-making practices for building and conveying knowledge. Research drawing on the Semantics dimension of the Legitimation Code Theory has noted the importance of shifting between levels of abstraction and context-dependency in knowledge-building. There is a need to better understand how such shifting between different levels of abstraction is accomplished with multimodal resources in classroom interaction. AimsThis study aims at exploring subject-specific knowledge construction as a form of translanguaging, i.e., as movement between different registers and multimodal resources of meaning-making. DataThe data comes from a Finnish teacher development project aimed at supporting CLIL teachers' professional development. This exploratory study analyses teachers’ knowledge-building practices in two STEM lessons video-recorded in the project, Physics and Chemistry. MethodsThe data is analysed using multimodal conversation analysis and analysis of semantic waves. Analysis focuses on how the teachers engage in unpacking and repacking subject-specific knowledge by talking, gesturing, as well as displaying, handling, and modifying various kinds of multimodal materials and artefacts. ResultsThe teachers were found to use a versatile set of multimodal translanguaging practices for unpacking and repacking. The findings also indicate complexity in semantic waves due to multimodal resources accomplishing simultaneous shifts in semantic gravity and density, with either aligning or diverging functions. ConclusionsThe simultaneous use of different multimodal resources and their potential to serve different functions point to the need to acknowledge the multidimensionality of semantic waves. The multimodal translanguaging approach also has implications for conceptualising subject-specific knowledge-building as inherently multimodal.

Sacubitril/valsartan and cardiovascular biomarkers among patients with recent COVID-19 infection: The PARACOR-19 randomized clinical trial.

The PARACOR-19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID-19) infection. PARACOR-19 was a single-centre, double-blind RCT of patients with cardiovascular risk factors and a history of COVID-19 infection 4-16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co-primary endpoints were change from baseline to 12 weeks in high-sensitivity cardiac troponin T (hs-cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th-75th) time from COVID-19 diagnosis to enrolment was 67 (48-80) days. Median age was 67 (62-71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co-primary endpoints of change from baseline in hs-TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and 51% greater reduction in C-terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group. In this pilot RCT of patients who recovered from acute COVID-19, sacubitril/valsartan did not lower hs-cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT-proBNP and CITP. Sacubitril/valsartan was well tolerated. ClinicalTrials.gov NCT04883528.

Cost-effectiveness of sutimlimab in cold agglutinin disease.

Primary cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia caused by cold-reactive antibodies that bind to red blood cells and lead to complement-mediated hemolysis. Patients with primary CAD experience the burden of increased health resource utilization and reduced quality of life. The standard-of-care (SOC) in patients with primary CAD has included cold avoidance, transfusion support, and chemoimmunotherapy. The use of sutimlimab, a humanized monoclonal antibody that selectively inhibits C1-mediated hemolysis, was shown to reduce transfusion-dependence and improve quality of life across two pivotal phase 3 studies, further supported by 2-year extension data. Using data from the transfusion-dependent patient population that led to sutimlimab's initial FDA approval, we performed the first-ever cost-effectiveness analysis in primary CAD. The projected incremental cost-effectiveness ratio (ICER) in our Markov model was $2 340 000/QALY, significantly above an upper-end conventional US willingness-to-pay threshold of $150 000/QALY. These results are consistent across scenarios of higher body weight and a pan-refractory SOC patient phenotype (i.e., treated sequentially with bendamustine-rituximab, bortezomib, ibrutinib, and eculizumab). No parameter variations in deterministic sensitivity analyses changed our conclusion. In probabilistic sensitivity analysis, SOC was favored over sutimlimab in 100% of 10 000 iterations. Exploratory threshold analyses showed that significant price reduction (>80%) or time-limited treatment (<18 months) followed by lifelong clinical remission off sutimlimab would allow sutimlimab to become cost-effective. The impact of sutimlimab on health system costs with longer term follow-up data merits future study and consideration through a distributional cost-effectiveness framework.

Politicians' high-status signals make less-educated citizens more supportive of aggression against government: A video-vignette survey experiment.

Various branches of the literature suggest that exposure to the high-status appearances and lifestyles of politicians in contemporary "diploma democracies" affects the attitudes and behavior of less-educated citizens because it confronts them with their lower status in the political domain. Informed by this, we theorize that such exposure inspires docility (a lower subjective social status, weaker feelings of political entitlement) and revolt (anger, more support for aggression against government). To investigate this, we conducted an original, pre-registered, video-vignette survey experiment among a representative sample of the Dutch population. While our findings likely generalize to other liberal democracies, the Dutch context is suitable to test our theorizing because low-status and high-status appearances and lifestyles are found across the political arena, irrespective of politicians' substantive positions or use of populist rhetoric. Each less-educated respondent (n=1390) was presented with a professionally produced video of an actor playing the part of a fictitious politician. This politician signaled either a low or a high status via his appearance and lifestyle. The potentially confounding factors of his substantive positions and populist rhetoric were randomized and controlled for. We find that exposure to the high-status politician increased less-educated citizens' support for aggression against the government. Through exploratory analyses, we assess how the responses of docility and revolt are interrelated, and how they are shaped by less-educated citizens' economic status.