143174 research outputs found
Sort by
Computational analysis of intracardiac collision risk and optimal site for right ventricular leadless left bundle branch area pacing: a simulation study
No full textBackground: Conduction system pacing (CSP) with leadless left bundle branch area pacing (LBBAP) is a promising application of leadless pacemakers (L-PMs). However, mechanical impact of the L-PM against intracardiac structures may worsen tricuspid regurgitation and induce ventricular arrhythmia. The optimal site of leadless CSP also remains unclear.
Objectives: To quantify device-specific and site-specific collision risks and identify the optimal site for leadless LBBAP using computational modeling.
Methods: We conducted a modeling study assessing collision risks of contemporary (Micra TPS, Aveir AR and Aveir VR) and future L-PM devices and exploring the optimal site for leadless LBBAP using cardiac CT models from 10 heart failure patients. Virtual L-PM implantation on the right ventricular (RV) septal wall was performed and models of the RV free wall, papillary muscles, moderator band, and tricuspid valve (TV) structures enabled assessment of device–structure interactions. Computer simulations examined collision risk across devices of varying dimensions throughout the cardiac cycle.
Results: Collision risk increased with device length and volume, primarily driven by RV wall interactions. Apical pacing sites carried a 73.6–75.2% collision risk, and overall wall collisions increased by 3–8% per 5 mm device length. TV and papillary muscle collisions depended on implant region, with highest risks of collision in basal (>70%) and mid (>40%) inferoseptal regions, respectively. Leadless LBBAP via the left anterior fascicle had the lowest collisions rates.
Conclusion: These findings support patient-specific device selection and careful septal targeting of leadless LBBAP to minimize complications, optimize physiological activation, and guide future L-PM designs
Surface modification of biomolecules for catalysis and delivery applications
No full textThe research is motivated by the urgent need to overcome the logistical and stability limitations of biomolecular therapeutics which often require cold chain storage due to the inherent instability of proteins and nucleic acids at room temperatures. This dissertation explores the surface modification of biomacromolecules, including proteins and DNAs, to enhance their thermal stability, solubility, and functional utility for applications in biocatalysis and therapeutic delivery.
Surface engineering was performed via cationization to increase the thermal stability of β-glucosidase. A comparative analysis between a commercial glucosidase and a thermostable variant (A5IL97) revealed superior activity of the latter in ionic liquids (ILs), achieving high glucose yields in ionic liquids at elevated temperatures. However, attempts to further stabilise the enzyme via carbodiimide-mediated cationisation and surfactant conjugation led to significant loss in activity, attributed to structural disruption during the modification process.
A novel strategy was subsequently developed for the direct conjugation of myoglobin with amine-functionalised ionic liquids, forming protein–ionic liquid complexes (PILs). MALDI-TOF confirmed the attachment of 3-14 IL molecules per protein, drastically altering its solubility profile: while native myoglobin was soluble only in water and DMSO, PILs demonstrated remarkable solubility in a range of organic solvents. Circular dichroism confirmed the retention of modified myoglobin secondary structure up to 95°C, underscoring the potential of PILs to enable biocatalysis in non-aqueous environments.
The research then extended to nucleic acid stabilisation through the development of DNA polyplex–surfactant biofluids (DNA-P-S). These were formed by complexing plasmid DNA with a cationic polymer and an oxidised surfactant. Characterisation via dynamic light scattering and circular dichroism confirmed successful assembly and structural preservation. The DNA-P-S biofluids exhibited a significant increase in thermal stability. These formulations retained transfection efficacy after 9 months at room temperature and heat shock at 70°C for 4 days, while unmodified counterparts lost all activity.Open Acces
Structural biology of T. gondii glideosome-associated Connector (TgGAC)
No full textApicomplexa are an essential phylum of parasites that are closely related to human infectious diseases, especially Toxoplasma gondii (T. gondii). These diseases cannot be fully treated as no targeted drugs are available. Therefore, it is necessary to develop novel drugs to prevent host cells from being infected by Apicomplexa. Apicomplexa possess a unique capability termed gliding motility, which helps with migration, invasion, and egress from host cells. Gliding motility is powered by a highly conserved acto-myosin complex termed the glideosome and is facilitated by a protein termed glideosome-associated connector (GAC), which working as the connection between the glideosome and transmembrane micronemal adhesins (MICs). GAC in T. gondii (TgGAC) is an armadillo repeats-containing (ARM) protein, and its C-terminal can interact with the parasite plasma membrane (PPM) and a MIC2 tail. The high-resolution structure of TgGAC, detailed interaction mechanisms and the specific binding sites between TgGAC and TgMIC2 remain to be determined. This project aims to elucidate the high-resolution 3D structure of TgGAC by X-ray crystallography and study the interactions of the TgGAC and TgMIC2 to further locate the binding sites between them by NMR, MST and MD. Various TgGAC and TgMIC2 mutants have been designed for structural characterization and binding assays.Open Acces
Continuation versus switching direct oral anticoagulant after breakthrough stroke
No full textImportance. Management after an ischemic stroke occurring despite direct oral anticoagulant (DOAC) therapy for atrial fibrillation (AF) varies widely. Switching anticoagulation is common in clinical practice, although evidence supporting this strategy is limited.
Objective. To evaluate whether continuation of the same DOAC was non-inferior to switching oral anticoagulant therapy with respect to 90-day clinical outcomes.
Design, setting and participants. Multicentre registry-based emulated target trial including consecutive adult patients with AF who experienced a breakthrough ischemic stroke while receiving uninterrupted DOAC therapy and resumed anticoagulation thereafter. Patients were enrolled between 2020 and 2025 across 35 stroke centres in 9 countries in Europe and North Africa, with standardized 90-day follow-up. A non-inferiority comparison of switching versus continuation strategies was performed. Baseline confounding was addressed using inverse probability of treatment weighting (IPTW). The primary non-inferiority margin was +3.0% absolute risk difference in 90-day net clinical benefit.
Exposure. Switching to a different DOAC or vitamin K antagonist was the intervention group and continuation of the pre-stroke DOAC was the comparator group. Main Outcomes and Measures. The primary outcome was 90-day net clinical benefit, defined as recurrent ischemic stroke and moderate-to-severe bleeding. Secondary outcomes included recurrent ischemic events, symptomatic intracranial haemorrhage, moderate-to-severe extracranial bleeding, all-cause mortality, and vascular death.
Results. Among 1006 patients (median age 80.4 years [IQR, 73.4–85.4]; 503 women [50.0%]), 463 (46.0%) continued the same DOAC and 543 (54.0%) switched therapy. After IPTW adjustment, the 90-day net clinical benefit was 4.9% with switching and 5.1% with continuation, corresponding to a risk difference of −0.3% (90% CI, −2.7% to 2.1%), meeting the prespecified noninferiority criterion. For recurrent ischemic events and bleeding outcomes the absolute differences were within the predefined non-inferiority margins. Noninferiority was
not demonstrated for all-cause or vascular mortality.
Conclusions and Relevance. In patients with breakthrough ischemic stroke during DOAC therapy, switching anticoagulation was not associated with clinically meaningful short-term benefit compared with continuation. According to our findings switching did not provide additional benefit compared to continuing the same DOAC. Randomized controlled trials are needed to identify strategies to improve secondary prevention after a breakthrough ischemic stroke
Implementation of evidence-based practice among respiratory therapists in Saudi Arabia: a cross-sectional study
No full textBackground: Evidence-based practice (EBP) has become a foundational component of modern healthcare globally. In Saudi Arabia, the understanding and application of EBP by respiratory therapists (RTs) remains underexplored. This study aimed to assess RTs’ behaviors, attitudes, awareness, knowledge, and barriers related to EBP. Methods: A previously validated online questionnaire was distributed to RTs across Saudi Arabia between February and July 2025. The survey collected sociodemographic data and included 14 items assessing behaviors, attitudes, awareness, knowledge, prior formal EBP training, and perceived barriers to EBP implementation. Results: A total of 301 RTs participated, with 290 completing the survey. Most participants (75.2%) held a bachelor’s degree. Overall, respondents demonstrated positive attitudes toward EBP, with more than 60% agreeing that understanding research methods is essential to respiratory therapy practice. The most frequently used resources for clinical decision-making were personal experience (67.3%), expert opinion (65.5%), and national or international guidelines (65.5%). Awareness of core EBP concepts was moderate; approximately 30% of participants reported a good understanding of terms such as “systematic review,” “quality of evidence,” and “risk of bias.” Several barriers to EBP implementation were identified, most commonly limited access to resources (25.2%), insufficient research knowledge and skills (23.8%), and lack of interest (21.0%). Conclusions: RTs in Saudi Arabia generally support EBP principles and use evidence-based resources in clinical decision-making. However, gaps in training, access to resources, and research competency limit full EBP implementation. Targeted strategies, including integrating mandatory EBP education, expanding professional development, and enhancing access to research resources, are recommended
Direct evaluation of the electrocardiographic spatial QRS-T angle without the need for orthogonal transformation
No full textIncreased electrocardiogram (ECG) spatial QRS-T wave angle is a recognised risk factor. Standard evaluation of the angle requires deriving orthogonal ECG leads, either by general transformation matrices into XYZ leads or by singular value decomposition (SVD). This study shows that the transformation is not needed, and that the spatial QRS-T angle can be calculated directly from the original ECG leads. The direct computation was tested using long-term 12-lead ECGs of 523 healthy volunteers (259 females). A total of 659,313 individual 10-second ECG samples were obtained providing 7,350,733 individual beats which were analysed both by the direct method using 8 algebraically independent leads and by the conventional XYZ and SVD transformations. On average, the results of the direct non-transformation method were closer to the SVD-based results (averaged differences below 1 degree) than to the XYZ-based results (averaged differences below 2 degrees). The subject-specific regressions to the underlying heart rate showed that the proposed direct method was significantly more reproducible (p < 0.0001) and that it showed more compact variability within individual ECG samples (p < 0.0001). Thus, the study shows not only that the QRS-T angle can be computed without any orthogonal transformation but that the results of the direct computation are also more precise
Plasma proteomic biomarkers as mediators for the associations between frailty phenotypes and chronic respiratory diseases
No full textFrailty, a hallmark of systemic vulnerability in aging populations, is increasingly recognized in the clinical management of chronic respiratory diseases (CRDs). Molecular mechanism underpinning the relationships remain insufficiently elucidated. This study hence aimed to investigate whether proteomic biomarkers—circulating plasma proteins reflecting systemic inflammation, metabolism, and tissue remodeling—are associated with CRDs and may serve as potential mediators of the observed links. We analyzed data from a population-based cohort of 22,802 adults with proteomic measurements. Frailty was assessed by three phenotypes, including frailty index, physical frailty, and psychological frailty. Related-proteomic signatures were estimated by both linear and elastic regression models. Cox regression models were applied to explore the associations of frailty phenotypes and their proteomic signatures with incident CRDs, including asthma, chronic obstructive pulmonary disease (COPD), and idiopathic pulmonary fibrosis (IPF), as well as lung function outcomes, with full adjustments for potential confounders. Furthermore, mediation analyses were conducted to explore underlying mechanisms, complemented by pathway enrichment analyses to reveal relevant biological functions. Over a median follow-up of 13.2 years, 617 participants developed asthma, 701 developed COPD, and 228 developed IPF. Higher frailty index was associated with elevated risks of asthma (HR 1.95, 95% CI 1.64 to 2.31) and COPD (2.02, 1.71 to 2.38). Corresponding proteomic signature also related to increased risks of asthma (HR 1.22, 1.11 to 1.34) and COPD (1.65, 1.53 to 1.78). Mediation analysis suggested that the frailty index partially mediated the association with COPD, accounting for 26.0% (95% CI: 18.7 to 37.5%) of the total effect, respectively, particularly for GDF15, WFDC2, and PLAUR. Pathway enrichment analysis showed that these mediating proteins were predominantly involved in immune activation, inflammatory signaling, and metabolic stress responses. Frailty phenotypes contribute to elevated CRDs risks, partly through proteomic dysregulation in inflammatory and metabolic pathways
What’s the point? How users functionalise points in gamified systems
No full textPoints are widely used design elements in gamified systems. Yet how they motivate is still unclear: what motivational meaning or functional significance do users ascribe to points and when? To answer this question, we conducted a semi-structured interview study with 27 users of two popular gamified platforms, Duolingo and Habitica. Through reflexive thematic analysis, we constructed six different types of functionalisation variously proposed in prior gamification and personal informatics work but often not empirically supported. We highlight the importance of functional design detail (such as points should proportionally reward effort) and derive design guidelines
Patient-specific biases in fat fraction estimates of malignant bone marrow due to relaxation times measured with STEAM at 3T
No full textSemi-quantitative fat fraction estimation using 2-point Dixon sequences is widely used in whole body (WB) MR imaging for malignant bone disease but is biased by relaxation times. Understanding this bias requires water- and fat-specific relaxometry data in normal-appearing marrow and lesions. This study measured bone marrow relaxation times in healthy volunteers and WB-MRI patients using MRS at 3T. Five healthy female volunteers (mean age 38.0 ± 2.5 years) and 24 patients with
malignant bone disease undergoing clinical WB-MRI (13 male; mean age 67.7 ± 9.7 years; primary cancers: breast = 5, melanoma = 1, multiple myeloma = 8, prostate = 10) underwent variable inversion/echo time STEAM and 3D gradient echo fat-water imaging. MRS water and fat peaks were fitted to determine T1, T2, R2* (from linewidths), and proton density fat fraction (PDFF). Scan-rescan repeatability of MRS parameters was assessed in volunteers. Lesions were classified by disease state according to clinical reports and segmented in Dixon
imaging data for comparison of fat fraction estimates with MRS. Repeatability was evaluated using coefficients of variation. Summary statistics (mean, standard deviation and range) were reported; exploratory inferential statistics were also determined with normality (Shapiro-Wilk) and variance (Levene’s) tests before one-way ANOVA and Tukey’s comparisons (p < 0.05). Monte Carlo simulations assessed relaxation bias on PDFF.
All quantitative MRS parameters were repeatable (coefficient of variation < 10%). Water T1 and T2 were most sensitive to disease state in patients, ranging from 1121–2206 ms and 15–71 ms respectively, and were demonstrated to substantially affect 2-point Dixon fat fraction estimates with Monte Carlo simulation. Imaging PDFF achieves closer agreement with MRS PDFF than 2-point Dixon methods. These findings remain preliminary due to the small sample size, but they suggest value in future studies with larger cohorts evaluating water relaxation times or PDFF in malignant bone disease
Maternal diet-induced hypercholanemia alters gut microbiota and metabolome in adult female Western diet-fed offspring
No full textChildren of mothers with intrahepatic cholestasis of pregnancy (ICP) are more likely to develop metabolic disease later in life. Using a mouse model of gestational cholestasis, we previously found that 18-week-old offspring had metabolic alterations that were exacerbated in female offspring when challenged with a Western diet (WD). Microbiota changes are emerging as a potential mechanism for developmental programming, and the maternal gut microbiota is known to be altered in pregnancy and in ICP. We hypothesized that, in our model, the offspring gut microbiota is altered by maternal gestational disease, potentially impacting future offspring metabolic health. Female mice were fed a cholic acid (CA)-supplemented diet for 1 week preceding and throughout pregnancy to mimic gestational hypercholanemia. Female offspring were challenged with a WD from 12 to 18 weeks of age and cecal contents were collected for metataxonomics and metabolomic profiling. Maternal CA dietary supplementation was associated with markedly increased cecal sulfated bile acid species (up to 387-fold increase). Whilst WD-feeding of offspring was associated with a greater proportion of primary to secondary bile acids, and more tauro-conjugated bile acids than for offspring fed a normal diet, this adaptation to WD-feeding was not evident for those whose mothers were fed a CA-supplemented diet. Indeed, WD-fed offspring of CA-supplemented mothers had a >2-fold reduction in CA and dehydrocholic acid levels compared to those from NC-fed mothers. This corresponded with an altered profile of cecal microbiota, with clear separation of microbiotal profiles according to maternal diet in the WD-fed, but not NC-fed, offspring. This observational mouse study has shown that exposure to maternal hypercholanemia can significantly impact the effects of an obesogenic diet on offspring intestinal bile acid metabolism and gut microbiota, likely increasing their vulnerability to metabolic dysfunction when exposed to the “second hit” of an unhealthy postnatal environment