143174 research outputs found
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Successful stimulation of myocardial ganglionic plexuses by TAU 20 in the absence of cardiac damage
No full textAtrial fibrillation (AF) is a major healthcare burden worldwide. The standard invasive treatment for AF that is resistant to pharmacological intervention is a pulmonary vein isolation (PVI) procedure. Ganglionated plexus (GP) ablation can be used as an adjunctive therapy to PVIs, which together reduce the likelihood of AF recurrence. High-frequency stimulation (HFS) is a technique used to identify ectopy-triggering GP sites. However, to locate GP sites, sequential HFS must be delivered over the whole atria. Therefore, ensuring the safety of HFS delivery is integral to avoid irreversible damage from excessive pacing. We tested the Tau-20 version 2 neural simulator, a prototype of a custom-built novel electrophysiological pacing and recording system (patent reference: ASW100372P.EPP) that has the potential to guide intracardiac AF treatments. Using an ex vivo porcine Langendorff model that closely resembles the anatomy and physiology of a human heart, we confirmed that HFS can successfully trigger AF, suggesting that HFS-positive locations contain GP sites. Additionally, we found that HFS delivered via Tau-20 version 2 did not cause any damage to the heart. These findings are evidence that once fully optimized, the Tau-20 system could be suitable for use in clinical settings
Roux-en-Y gastric bypass-associated fecal tyramine promotes colon cancer risk via increased DNA damage, cell proliferation and inflammation
No full textBackground
Fecal abundances of Enterobacteriaceae and Enterococcaceae are elevated in patients following Roux-en-Y gastric bypass (RYGB) surgery. Concurrently, fecal concentrations of tyramine, derived from gut bacterial metabolism of tyrosine and/or food, increased post-RYGB. Furthermore, emerging evidence suggests that RYGB is associated with increased colorectal cancer (CRC) risk. However, the causal link between RYGB-associated microbial metabolites and CRC risk remains unclear. Hence, this study investigated the tyrosine metabolism of Enterobacteriaceae and Enterococcaceae strains isolated from patients post-RYGB and explored the causal effects of tyramine on the CRC risk and tumorigenesis using both human colonic cancer cell line (HCT 116) and wild-type and ApcMin/+ mice.
Results
We isolated 31 bacterial isolates belonging to Enterobacteriaceae and Enterococcaceae families from the feces of patients with RYGB surgery. By culturing the isolates in tyrosine-supplemented medium, we found that Citrobacter produced phenol as a main product of tyrosine, whereas Enterobacter and Klebsiella produced 4-hydroxyphenylacetate, Escherichia produced 4-hydroxyphenyllactate and 4-hydroxyphenylpyruvate, and Enterococcus and two Klebsiella isolates produced tyramine. These observations suggested the gut bacterial contribution to increased fecal concentrations of tyramine post-RYGB. We subsequently evaluated the impact of tyramine on CRC risk and development. Tyramine induced necrosis and promoted cell proliferation and DNA damage of HCT 116 cells. Daily oral administration of tyramine for 49 days to wild-type mice resulted in visible adenomas in 5 out of 12 mice, accompanied by significantly enhanced DNA damage (γH2AX +) and an increased trend of cell proliferation (Ki67 +) in the ileum, along with an upregulated expression of the cell division cycle gene (Cdc34b) in the colon. To evaluate the impact of tyramine on intestinal tumor growth, we treated ApcMin/+ mice with the same doses of tyramine and duration. These mice showed larger colonic tumor size and increased intestinal cell proliferation and inflammation (e.g., increased mRNA expression of IL-17A and higher number of Ly6G + neutrophils) compared to water-treated ApcMin/+ control mice.
Conclusions
Our results collectively suggested that RYGB-associated fecal bacteria could contribute to tyramine production and tyramine increased CRC risk by increasing DNA damage, cell proliferation, and pro-inflammatory responses of the gut. Monitoring and modulating tyramine concentrations in high-risk individuals could aid CRC prognosis and management
Higher precipitation in East Asia and western United States expected with future Southern Ocean warming
No full textPrecipitation over East Asia and the western United States is projected to increase as a result of global warming, although substantial uncertainties persist regarding the magnitude. A key factor driving these uncertainties is the tropical surface warming pattern, yet the mechanisms behind both this warming pattern and the resulting regional precipitation changes remain elusive. Here we use a set of climate model experiments to argue that these changes are partly driven by global teleconnection from the Southern Ocean, which rapidly absorbs anthropogenic heat but releases it with a delay of decades to a century. We show that the delayed Southern Ocean warming contributes to broad tropical ocean warming with an El Niño-like pattern, enhancing precipitation during summer in East Asia and winter in the western United States. The atmospheric teleconnections from the tropical ocean link the Southern Ocean warming to the Northern Hemisphere regional wetting. Southern Hemisphere low clouds are a key regulator of this teleconnection, partly explaining the projected uncertainty of regional precipitation. The documented teleconnection has practical implications: even if climate mitigation reduces carbon dioxide levels, the delayed Southern Ocean warming will sustain a wetter East Asia and western United States for decades to centuries
Factors influencing the use of online symptom checkers in the United Kingdom: cross-sectional study
No full textBackground:
The National Health Service (NHS) faces increasing strain. Concurrently, demand for health information, consumer empowerment, and health awareness continues to grow. These trends, coupled with the ubiquity of smartphones and internet access, are positioning online symptom checkers (OSCs) as promising tools for preliminary diagnosis and triage. While there is increasing data on the demographics, motivations, and perspectives of current and potential users of OSCs globally, no study has yet quantified or ranked the various factors associated with the use of OSCs in the United Kingdom.
Objective:
This study aimed to assess key trends and user perceptions on the usability and effectiveness of OSC in the United Kingdom. We also sought to identify concerns related to the privacy, security, and accuracy of OSCs and to quantify the weight of these various factors on the use of OSCs.
Methods:
A cross-sectional survey of UK adults was conducted using an electronic questionnaire. A convenience sample was recruited between February and March 2024 through web-based platforms and personal networks. The survey included questions on awareness, use, perceptions, and concerns regarding OSCs, as well as respondents’ demographics. Responses were pseudo-anonymized and analyzed using univariable and multivariable logistic regression models to assess relationships between demographic factors; perceived usability, reliability, and risks; and OSC use.
Results:
The survey collected responses from 634 participants. The majority (543/634, 85.7%) had used OSCs, primarily the NHS 111 service (498/634, 78.6%). Younger age (<46 years old), being female (adjusted odds ratio [aOR] 1.79, 95% CI 1.05‐3.06), and having children (aOR 3.19, 95% CI 1.56‐6.51) were associated with higher odds of using OSCs. Key motivations for using OSCs included understanding symptoms (501/634, 79.0%) and determining the need for medical care (491/634, 77.4%). Key concerns negatively impacting use related to privacy (aOR 0.58, 95% CI 0.35-0.97) and fear of replacing traditional, face-to-face consultations (aOR 0.47, 95% CI 0.26‐0.87). The most important factor found to affect the decision to use OSCs was the perceived ease of use (aOR 8.17, 95% CI 4.25-15.71), followed by the perceived helpfulness in decision-making (aOR 2.96, 95% CI 1.62‐5.42), and respondents’ trust in their diagnostic accuracy (aOR 2.24, 95% CI 1.32‐3.79).
Conclusions:
OSCs are widely used in the United Kingdom, particularly the NHS 111 service, driven primarily by ease of use and perceived helpfulness in decision support. However, privacy and security concerns, as well as fears of OSCs replacing traditional consultations, pose significant barriers. Addressing these concerns is crucial for enhancing user trust and maximizing the benefits of OSCs in supporting self-care and improving health care efficiency
Role of layer thickness and grain size contrast in rolling contact fatigue of coarse/fine-grained layered materials: a crystal plasticity study
No full textHeterogeneous layered materials combine high strength and ductility, offering improved damage tolerance under tribological loading. Among the key microstructural factors, layer thickness and grain size contrast have a critical influence on the mechanical behavior during rolling contact fatigue (RCF). A crystal plasticity finite element (CPFE) model was developed to simulate rolling contact responses in coarse-grained (CG)/fine-grained (FG) layered structures. The simulations reveal that layer thickness modulates strain localization, dislocation activity, and damage evolution in a sliding-orientation-dependent manner. FG layers serve as barriers to strain transmission and suppress damage propagation from adjacent CG layers. Furthermore, dislocation partitioning at CG/FG interfaces promotes strain delocalization and enhances RCF resistance. These findings provide mechanistic insights for optimizing layered microstructure design for advanced tribological applications
Trends in facial reanimation surgery - a bibliometric analysis
No full textBackground: Facial paralysis is a debilitating condition with far-reaching physical, psychological, and social effects. Facial reanimation surgery (FRS) employs a range of static and dynamic procedures to restore form and function. This bibliometric analysis aims to evaluate the top 100 most-cited FRS articles to identify trends, gaps, and methodological quality across the highest-impact studies. By doing so, it provides valuable insights into the evolution of the field, highlights areas requiring further research, and informs future clinical practices and decision-making. Understanding the current landscape of FRS research will help guide the development of higher-quality studies, promote evidence-based practices, and ultimately improve patient outcomes. Methods: The top 100 most-cited articles related to FRS were identified through a comprehensive Web of Science search covering publications from 1976 to 2024. Data including citation count, study focus, and Oxford Centre for Evidence-Based Medicine (OCEBM) levels of evidence (LOE) were extracted. Results: The most-cited articles in FRS spanned a total of 6841 citations and involved 5570 patients. Citation per article ranged from 31 to 535. A large proportion of studies were LOE 3 (n = 43), with fewer studies of higher evidence levels (LOE 2 and 1). Surgical technique was the dominant subject area (n = 64), while validated patient-reported outcome measures (PROMs) were utilized in only 8 studies. Conclusions: Our findings underscore the need for improved research methodologies and the broader adoption of validated PROMs in FRS research. Standardized tools and multi-center, high-level studies will help optimize patient care and decision-making in this field. This analysis provides key insights into the evolution of FRS and offers actionable recommendations for future research, particularly in interdisciplinary fields such as craniofacial surgery. Multi-institutional studies and collaborative research will be essential to advancing this field and providing optimal patient care
Fibroblast cyclo-oxygenase-2 associated with the kidney restrains methylarginines and thrombosis: relevance to cardiovascular side effects of non-steroidal anti-inflammatory drugs
No full textUse of non-steroidal anti-inflammatory drugs (NSAIDs), which work by inhibiting cyclo-oxygenase-2, is associated with an increased risk of thrombotic cardiovascular events. There is increasing evidence for a role of renal cyclo-oxygenase-2 in NSAID-induced cardiovascular side effects, including through dysregulation of methylarginines, endogenous inhibitors of nitric oxide synthase. However, delineating the significance of renal pathways has been hampered by a lack of suitable models. Here we have generated mouse models of cyclo-oxygenase-2 deficiency from relevant cell types to test directly their contributions. Deletion of cyclo-oxygenase-2 from fibroblasts reduced total renal expression without altering expression elsewhere. Fibroblast cyclo-oxygenase-2 knockout increased thrombosis after arterial injury, which was associated with the accumulation of plasma methylarginines and consequent systemic endothelial nitric oxide dysfunction. The pro-thrombotic phenotype in these animals was reversed by L-arginine, which competes against the inhibitory effect of methylarginines, in line with a mechanistic contribution. By comparison, pro-thrombotic phenotypes in endothelial cyclo-oxygenase-2 knockout mice, which occur via a vascular mechanism, were not associated with changes in methylarginines and were insensitive to L-arginine. Taken together, these studies provide direct evidence for a role of fibroblast and renal cyclo-oxygenase-2 in anti-thrombotic protection and demonstrate that to understand, predict, treat, and/or prevent NSAID-induced cardiovascular side effects, we must consider these pathways.
Graphical Abstract
Our findings from cell-specific mouse models suggest COX-2 in fibroblasts in the kidney regulate methylarginine pathways. When this is blocked, ADMA accumulates in the circulation to cause systemic nitric oxide synthase inhibition and resulting in increased in thrombotic tone. We propose this mechanism functions alongside vascular COX-2 and other pathways to explain how non-steroidal anti-inflammatory drugs increase risk of thrombotic events in humans
Serovars and antimicrobial resistance profiles of Actinobacillus pleuropneumoniae isolates from clinical-case pigs in Taiwan
No full textBackground
Pleuropneumonia remains an important challenge to swine production worldwide. The causative agent, Actinobacillus pleuropneumoniae serovar prevalence in countries can change over time. Few Taiwanese A. pleuropneumoniae prevalence studies have been published, and recent large-scale investigations remain notably scarce. This study aimed to identify the serovars and antimicrobial sensitivity of 96 current Taiwanese A. pleuropneumoniae clinical isolates.
Results
Among the 99 A. pleuropneumoniae determinations, 40 (40.4%) were serovar 15, 29 (29.3%) were serovar 5, 15 (15.2%) were serovar 1, 11 (11.1%) were serovar 7, and 4 (4.0%) were serovar 2. Therefore serovar 15 was the most predominant between 2015 and 2022. Resistance of the isolates was minimal to ceftiofur (3.2%), cephalexin (5.2%), cephalothin (6.3%) and enrofloxacin (9.3%), moderate to gentamicin (28.4%), and high for florfenicol, amoxicillin and ampicillin (45.1–68.4%).
Conclusions
This study updates the serovar and antimicrobial sensitivity patterns of Taiwanese clinical A. pleuropneumoniae isolates, showing that serovars 15, 5, 1, 7, and 2 collectively predominate in clinical outbreaks. Local A. pleuropneumoniae isolates exhibited high resistance to antimicrobials currently used in the Taiwanese pig production, such as amoxicillin, ampicillin, and florfenicol. However, there was low resistance to cephalexin, cephalothin, tilmicosin and lincospectin (injectable only) which can be recommended for current use in Taiwan, considering both efficacy and public health risks. Notably, isolates of the same serovar collected from the same farm on the same day occasionally displayed distinct resistance patterns, emphasizing the complex dynamics of antimicrobial resistance. Our data will help veterinarians and producers refine vaccination and treatment protocols, highlighting the importance of ongoing surveillance to respond effectively to evolving resistance trends
Development of an assessment tool for ultrasound‐guided regional anaesthesia image interpretation
No full textIntroduction
The success of ultrasound-guided regional anaesthesia depends on the acquisition and interpretation of optimal ultrasound images. This study aimed to develop an assessment tool to evaluate proficiency in interpreting ultrasound images for regional anaesthesia.
Methods
This study involved domain and item generation; preliminary testing; and content validity evaluation by an expert panel review. Questions were generated by the study group and pilot testing was conducted with UK-based anaesthesia consultants and resident doctors. Face validity was tested by thematic analysis of participant feedback questionnaires, discriminative ability using Rasch modelling of item response and internal reliability using Cronbach's α method.
Results
A 57-item pilot test was completed by 43 participants across clinical experiences from stage 1 training to consultant. Median (IQR [range]) completion time was 55 (41–64 [29–94]) min and fatigue point was question 49 of 57 (37–57 [15–57]). Rasch analysis led to the exclusion of seven items and content validity evaluation resulted in the removal of a further six items, resulting in a 44-item question set. The test showed good face validity, with a Cronbach's α of 0.92, indicating high internal reliability.
Discussion
This study produced a 44-item assessment tool to assess the proficiency of ultrasound image interpretation in regional anaesthesia for a range of upper limb, lower limb and truncal blocks, with proven face validity, internal reliability and content validity. Further testing with a larger sample is planned to verify reliability and validity, with the hope that this may be an asset for regional anaesthesia training and assessment
SoK: Bitcoin Layer Two (L2)
No full textIn this article, we present the first Systematization of Knowledge (SoK) on constructing Layer Two (L2) solutions for Bitcoin. We carefully examine a representative subset of ongoing Bitcoin L2 solutions (40 out of 335 extensively investigated cases) and provide a concise yet impactful identification of six classic design patterns through two approaches (i.e., modifying transactions and creating proofs). Notably, we are the first to incorporate the inscription technology (emerged in mid-2023), along with a series of related innovations. We further establish a reference framework that serves as a baseline criterion ideally suited for evaluating the security aspects of Bitcoin L2 solutions, and which can also be extended to broader L2 applications. We apply this framework to evaluate each of the projects we investigated. We find that the inscription-based approaches introduce new functionality (i.e., programability) to Bitcoin systems, whereas existing proof-based solutions primarily address scalability challenges. Our security analysis reveals new attack vectors targeting data/state (availability, verification), assets (withdrawal, recovery), and users (disputes, censorship)