Cell-Free DNA Maps Tissue Injury and Correlates with Disease Severity in Lung Transplant Candidates.

Rationale: Plasma cell-free DNA levels correlate with disease severity in many conditions. Pretransplant cell-free DNA may risk stratify lung transplant candidates for post-transplant complications. Objectives: To evaluate if pretransplant cell-free DNA levels and tissue sources identify patients at high risk of primary graft dysfunction and other pre- and post-transplant outcomes. Methods: This multicenter, prospective cohort study recruited 186 lung transplant candidates. Pretransplant plasma samples were collected to measure cell-free DNA. Bisulfite sequencing was performed to identify the tissue sources of cell-free DNA. Multivariable regression models determined the association between cell-free DNA levels and the primary outcome of primary graft dysfunction and other transplant outcomes, including Lung Allocation Score, chronic lung allograft dysfunction, and death. Measurements and Main Results: Transplant candidates had twofold greater cell-free DNA levels than healthy control patients (median [interquartile range], 23.7 ng/ml [15.1-35.6] vs. 12.9 ng/ml [9.9-18.4]; P < 0.0001), primarily originating from inflammatory innate immune cells. Cell-free DNA levels and tissue sources differed by native lung disease category and correlated with the Lung Allocation Score (P < 0.001). High pretransplant cell-free DNA increased the risk of primary graft dysfunction (odds ratio, 1.60; 95% confidence interval [CI], 1.09-2.46; P = 0.0220), and death (hazard ratio, 1.43; 95% CI, 1.07-1.92; P = 0.0171) but not chronic lung allograft dysfunction (hazard ratio, 1.37; 95% CI, 0.97-1.94; P = 0.0767). Conclusions: Lung transplant candidates demonstrate a heightened degree of tissue injury with elevated cell-free DNA, primarily originating from innate immune cells. Pretransplant plasma cell-free DNA levels predict post-transplant complications.

Effects of In-Vehicle Touchscreen Location on Driver Task Performance, Eye Gaze Behavior, and Workload During Conditionally Automated Driving: Nondriving-Related Task and Take-Over.

OBJECTIVE: This study investigated the effects of nondriving-related task (NDRT) touchscreen location and NDRT difficulty level on the driver task performance, eye gaze behavior, and workload during SAE Level 3 conditionally automated driving. Two driver tasks were considered: a visuomanual NDRT and a take-over task. BACKGROUND: Touchscreens are expected to play important roles inside automated vehicles. However, few studies have investigated the driver-touchscreen interaction during automated driving. METHOD: A driving simulator experiment was conducted. The experimental task consisted of two successive subtasks: an NDRT followed by a take-over task. NDRT touchscreen location (Upper Left, Upper Right, and Lower Right) and NDRT difficulty level (Easy and Hard) were the independent variables. A set of driver task performance, eye gaze behavior, and perceived workload measures were employed for each subtask as the dependent variables. RESULTS: NDRT touchscreen location significantly affected both the NDRT and the take-over task performance. Lower Right was superior to Upper Right in the NDRT performance but was inferior in the take-over task performance. NDRT touchscreen location affected the perceived physical workload of the NDRT. NDRT difficulty level affected the perceived workload of the take-over task. CONCLUSION: The research findings enhance our understanding of how NDRT touchscreen location and NDRT difficulty level impact the driver task performance during conditionally automated driving, and, further provide useful design implications and knowledge. APPLICATION: The study results would inform the NDRT touchscreen interface design and the NDRT design for conditionally automated vehicles.

Individual-specific postural discomfort prediction using decision tree models.

The objective of the current study was to explore the utilization of the decision tree (DT) algorithm to model posture-discomfort relationships at the individual level. The DT algorithm has the advantage that it makes no assumptions about the distribution of data, is robust in representing non-linear data with noise, and produces white-box models that are interpretable. Individual-level modelling is essential for examining individual-specific postural discomfort perception processes and understanding the inter-individual variability. It also has practical applications, including the development of individual-specific digital human models and more precise and informative population accommodation analysis. Individual-specific DT models were generated using postural discomfort rating data for various seated upper body postures to predict discomfort based on postural and task variables. The individual-specific DT models accurately predicted postural discomfort and revealed large inter-individual variability in the modelling results. DT modelling is expected to greatly facilitate investigating the human discomfort perception process.

Evaluating the delivery of physical activity for people with developmental disabilities using an online knowledge translation approach: part 1 - web accessibility.

Background: Knowledge-to-action gap exists in delivering physical activity (PA) to people with developmental disabilities via online platforms. Although web-based platforms have great potential in facilitating the delivery of PA for this target group, the lack of knowledge regarding web accessibility poses a challenge in accessing PA-related information online.Objective: This study evaluates the delivery of PA in terms of web accessibility. It also aims to identify barriers and facilitators in delivering PA knowledge to people with developmental disabilities online to improve web accessibility for the target user group.Methods: The study employs a concurrent nested design incorporating both quantitative (web usability questionnaire) and qualitative data (in-depth interviews). Fifteen pairs of individuals consisting of a person with developmental disabilities and a primary caregiver participated in the study, and three web-based platforms were selected for web accessibility tests and in-depth interviews.Results: The nested analysis provides a quantitative comparison of web accessibility and identifies barriers and facilitators of delivering PA for the target user group from the web accessibility perspective. Conclusion: The study findings could inform the development of accessible online platforms that distribute health-related knowledge to populations with developmental disabilities. Additionally, they could help enhance the design of other platforms intended for these populations.

Online platforms have significant potential to improve the delivery of physical activity information to individuals with developmental disabilities.Barriers to accessing online platforms due to poor web usability impede the process of online knowledge translation to end-users.Web usability can be enhanced by implementing appropriate interventions, such as restructuring navigation and redesigning the user interface.Improving web usability will enhance the accessibility of physical activity knowledge for individuals with developmental disabilities, which consequently will positively impact their health.

A systematic review of camera monitor system display layout designs: Integration of existing knowledge.

Despite the growing interest in mirrorless vehicles equipped with a camera monitor system (CMS), the human factors research findings on CMS display layout design have not been synthesized yet, hindering the application of the knowledge and the identification of future research directions. In an effort to address the 'lack of integration of the existing knowledge', this literature review addresses the following research questions: 1) what CMS display layout designs have been considered/developed by academic researchers and by automakers, respectively?; 2) among possible CMS display layout design alternatives, which ones have not yet been examined through human factors evaluation studies?; and 3) how do the existing human factors studies on the evaluation of different CMS display layout designs vary in the specifics of research? This review provides significant implications for the ergonomic design of CMS display layouts, including some potential design opportunities and future research directions.

Evaluating the delivery of physical activity for people with developmental disabilities using an online knowledge translation approach: part 2 - content quality.

OBJECTIVE: Web-based platforms for delivering physical activity (PA) to people with developmental disabilities have a great potential to improve the lives of many. However, their design, including the content design, lacks sufficient investigation. This study aims to evaluate three online platforms for delivering PA to people with developmental disabilities in terms of content quality and identify relevant barriers and facilitators of PA delivery. METHODS: The study used a methodological triangulation approach which involved quantitative evaluations by experts using an evaluation rubric, on-site observations and in-depth interviews with recruited participants. The participants consisted of 15 pairs of individuals, each consisting of a person with developmental disabilities and their primary caregiver. They were instructed to watch and follow five PA video content from each of the three platforms. The on-site observations and interviews were conducted in a large computer-equipped meeting room setting. RESULTS: The quantitative and qualitative analysis identified a set of barriers and facilitators of PA delivery related to content quality. Key barriers identified include a lack of content diversity, insufficient understanding of developmental disabilities among content creators, inappropriate language usage, and resistance to engaging in physical activities in home settings. Significant facilitators were pinpointed, such as incorporating engaging elements for individuals with developmental disabilities, utilising easy-read language, and ensuring sufficient repetition for effective learning. The results from the triangulation showed that the multiple methods were complementary and converged on the same outcome. DISCUSSION: The study findings could contribute to the development of adequately adapted PA content to distribute knowledge to populations with developmental disabilities.

Content delivered via online platforms has the potential to convey knowledge about physical activity to a significant number of individuals with developmental disabilities without the limitations of time and space.The absence of prescribed content guidelines to effectively impart physical activity to individuals with developmental disabilities impedes the process of online knowledge translation.There is a requirement for varied physical activity content encompassing various individuals with developmental disabilities, considering their diverse learning contexts.It is essential that content development is evaluated with input from experts in developmental disabilities in order to provide quality physical activity information for people with developmental disabilities.

Long-Term Antioxidant Metal-Organic Frameworks.

Free radicals produced during metabolism induce effects, such as cell damage and cancer, because of their high reactivity. Although antioxidants in food products can eliminate free radicals, they are expelled within a relatively short period of time after serving their function. In this study, we investigated the possibility of using metal-organic frameworks (MOFs) with antioxidants as their ligands. Metal-organic frameworks are crystalline polymers with repetitively coordinated ligands and metal centers. We assume that once antioxidant-based MOFs are ingested, ligands are released on a long-term basis during the process of chemical and physical disintegration. To evaluate their eligibility, we established criteria for biocompatibility, particle size, and long-term antioxidant effects. For biocompatibility, we treated cells with various concentrations of MOFs and their precursors followed by a water-soluble tetrazolium 8 (WST-8) assay. The particle size distribution was analyzed using TEM and ImageJ software, and the antioxidant release was quantified using UV-vis spectroscopy. We concluded that Fe-based FeTHQ with the antioxidant tetrahydroxy-1,4-benzoquinone (THQ) as its ligand is the most effective long-term antioxidant with its effect lasting up to 7 days. Furthermore, microwave synthesis of FeTHQ was conducted to produce more suitable particles for in vivo antioxidant applications.

Toward Consistent Predictions of Core/Valence Ionization Potentials and Valence Excitation Energies by MRSF-TDDFT.

Optimizing exchange-correlation functionals for both core/valence ionization potentials (cIPs/vIPs) and valence excitation energies (VEEs) at the same time in the framework of MRSF-TDDFT is self-contradictory. To overcome the challenge, within the previous "adaptive exact exchange" or double-tuning strategy on Coulomb-attenuating XC functionals (CAM), a new XC functional specifically for cIPs and vIPs was first developed by enhancing exact exchange to both short- and long-range regions. The resulting DTCAM-XI functional achieved remarkably high accuracy in its predictions with errors of less than half eV. An additional concept of "valence attenuation", where the amount of exact exchange for the frontier orbital regions is selectively suppressed, was introduced to consistently predict both VEEs and IPs at the same time. The second functional, DTCAM-XIV, exhibits consistent overall prediction accuracy at ∼0.64 eV. By preferentially optimizing VEEs within the same "valence attenuation" concept, a third functional, DTCAM-VAEE, was obtained, which exhibits improved performance as compared to that of the previous DTCAM-VEE and DTCAM-AEE in the prediction of VEEs, making it an attractive alternative to BH&HLYP. As the combination of "adaptive exchange" and "valence attenuation" is operative, it would be exciting to explore its potential with a more tunable framework in the future.

Extreme elevations of donor-derived cell-free DNA increases the risk of chronic lung allograft dysfunction and death, even without clinical manifestations of disease.

BACKGROUND: Lung transplant recipients are traditionally monitored with pulmonary function testing (PFT) and lung biopsy to detect post-transplant complications and guide treatment. Plasma donor-derived cell free DNA (dd-cfDNA) is a novel molecular approach of assessing allograft injury, including subclinical allograft dysfunction. The aim of this study was to determine if episodes of extreme molecular injury (EMI) in lung transplant recipients increases the risk of chronic lung allograft dysfunction (CLAD) or death. METHODS: This multicenter prospective cohort study included 238 lung transplant recipients. Serial plasma samples were collected for dd-cfDNA measurement by shotgun sequencing. EMI was defined as a dd-cfDNA above the third quartile of levels observed for acute rejection (dd-cfDNA level of ≥5% occurring after 45 days post-transplant). EMI was categorized as Secondary if associated with co-existing acute rejection, infection or PFT decline; or Primary if not associated with these conditions. RESULTS: EMI developed in 16% of patients at a median 343.5 (IQR: 177.3-535.5) days post-transplant. Over 50% of EMI episodes were classified as Primary. EMI was associated with an increased risk of severe CLAD or death (HR: 2.78, 95% CI: 1.26-6.22, p = 0.012). The risk remained consistent for the Primary EMI subgroup (HR: 2.34, 95% CI 1.18-4.85, p = 0.015). Time to first EMI episode was a significant predictor of the likelihood of developing CLAD or death (AUC=0.856, 95% CI=0.805-0.908, p < 0.001). CONCLUSIONS: Episodes of EMI in lung transplant recipients are often isolated and may not be detectable with traditional clinical monitoring approaches. EMI is associated with an increased risk of severe CLAD or death, independent of concomitant transplant complications.

Racial Differences in Donor-Derived Cell-Free DNA and Mitochondrial DNA After Heart Transplantation, on Behalf of the GRAfT Investigators.

BACKGROUND: Black heart transplant patients are at higher risk of acute rejection (AR) and death than White patients. We hypothesized that this risk may be associated with higher levels of donor-derived cell-free DNA (dd-cfDNA) and cell-free mitochondrial DNA. METHODS: The Genomic Research Alliance for Transplantation is a multicenter, prospective, longitudinal cohort study. Sequencing was used to quantitate dd-cfDNA and polymerase chain reaction to quantitate cell-free mitochondrial DNA in plasma. AR was defined as ≥2R cellular rejection or ≥1 antibody-mediated rejection. The primary composite outcome was AR, graft dysfunction (left ventricular ejection fraction <50% and decrease by ≥10%), or death. RESULTS: We included 148 patients (65 Black patients and 83 White patients), median age was 56 years and 30% female sex. The incidence of AR was higher in Black patients compared with White patients (43% versus 19%; P=0.002). Antibody-mediated rejection occurred predominantly in Black patients with a prevalence of 20% versus 2% (P<0.001). After transplant, Black patients had higher levels of dd-cfDNA, 0.09% (interquartile range, 0.001-0.30) compared with White patients, 0.05% (interquartile range, 0.001-0.23; P=0.003). Beyond 6 months, Black patients showed a persistent rise in dd-cfDNA with higher levels compared with White patients. Cell-free mitochondrial DNA was higher in Black patients (185 788 copies/mL; interquartile range, 101 252-422 133) compared with White patients (133 841 copies/mL; interquartile range, 75 346-337 990; P<0.001). The primary composite outcome occurred in 43% and 55% of Black patients at 1 and 2 years, compared with 23% and 27% in White patients, P<0.001. In a multivariable model, Black patient race (hazard ratio, 2.61 [95% CI, 1.35-5.04]; P=0.004) and %dd-cfDNA (hazard ratio, 1.15 [95% CI, 1.03-1.28]; P=0.010) were associated with the primary composite outcome. CONCLUSIONS: Elevated dd-cfDNA and cell-free mitochondrial DNA after heart transplant may mechanistically be implicated in the higher incidence of AR and worse clinical outcomes in Black transplant recipients. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.