Inverted Internal Limiting Membrane Flap VS. ILM Peeling for＜400µm Macular Hole: a meta-analysis and systematic review.

PURPOSE: The inverted internal limiting membrane (ILM) flap technique was initially developed for the closure of large macular holes (MH). However, its efficacy in treating small holes has been a matter of debate. This study aimed to compare the anatomical and visual outcomes of vitrectomy (PPV) combined with the inverted ILM flap and ILM peeling in cases of small and medium-sized MHs. METHODS: A meta-analysis was conducted by searching the relevant literature in databases, including PubMed, Web of Science, Embase, and Cochrane Library. The search included articles published from the inception of the databases up until January 2023. The inclusion criteria limited the studies to only experimental based research. The heterogeneity, publication bias, and sensitivity analysis were performed to ensure the statistical power and reliability of the analysis. RESULTS: Five studies, including two RCTs and three non-randomized concurrent control trials (n-RCTs), comprising a total of 269 eyes, were analyzed. The results showed no significant difference in the MH closure rate between the two group (odds ratio (OR) = 0.29, 95% confidence interval (CI): 0.04-1.96, P = 0.33). Furthermore, there were no significant differences observed in visual acuity, external limiting membrane (ELM) and ellipsoid zone (EZ) integrity at 3 months (ELM OR = 0.88, EZ OR = 0.85) or 12 months (ELM OR = 0.96, EZ OR = 1.39) post-operation between the two groups. CONCLUSION: The surgical repair of MHs smaller than 400µm with ILM flap seem to be similar in VA improvement and anatomical recovery compared to the traditional technique.

PLU-Net: Extraction of multiscale feature fusion.

In recent years, deep learning algorithms have achieved remarkable results in medical image segmentation. These networks with an enormous number of parameters often encounter challenges in handling image boundaries and details, which may result in suboptimal segmentation results. To solve the problem, we develop atrous spatial pyramid pooling (ASPP) and combine it with the squeeze-and-excitation block (SE block), as well as present the PS module, which employs a broader and multiscale receptive field at the network's bottom to obtain more detailed semantic information. We also propose the local guided block (LG block) and also its combination with the SE block to form the LS block, which can obtain more abundant local features in the feature map, so that more edge information can be retained in each down sampling process, thereby improving the performance of boundary segmentation. We propose PLU-Net and integrate our PS module and LS block into U-Net. We put our PLU-Net to the test on three benchmark datasets, and the results show that by fewer parameters and FLOPs, it outperforms on medical semantic segmentation tasks.

Case report: Ultrasound-guided needle knife technique for carpal ligament release in carpal tunnel syndrome treatment.

Carpal tunnel syndrome (CTS) is a common peripheral neuropathy of the hand, mainly manifesting as sensory disturbances, motor dysfunctions, and pain in the fingers and hand. The pathogenesis of the disease is associated with fibrosis of the transverse carpal ligament in the carpal tunnel, which compresses median nerve. In our case, we demonstrate an ultrasound-guided needle knife technique to treat CTS. We guided the patient to a supine position on the examination table. The skin of the wrist area was sterilized for the procedure. After the skin was dry, we positioned sterile drapes, located the median nerve and compression, and marked the compression point. Local anesthesia was administered. An ultrasound-guided needle knife was inserted. The needle knife was advanced under ultrasound guidance. The carpal ligament was incised. A gradual release of pressure on the median nerve was observed on the ultrasound monitor. After treatment, the patient's finger sensation and motor function can significantly improve, and pain symptoms are markedly reduced, this case demonstrates that small needle-knife treatment can serve as a safe and effective minimally invasive therapeutic method.

Co-expression pattern of SLC transporter genes associated with the immune landscape and clinical outcomes in gastric cancer.

Solute carrier (SLC) transporters play a dual role in the occurrence and progression of tumours by acting as both suppressors and promoters. However, the overall impact of SLC transcriptome signatures on the tumour microenvironment, biological behaviour and clinical stratification of gastric cancer has not been thoroughly investigated. Therefore, we comprehensively analysed the expression profiles of the SLC transporter family members to identify novel molecular subtypes in gastric cancer. We identified two distinct SLC subtypes, SLC-S1 and SLC-S2, using non-negative matrix factorization. These subtypes were markedly linked with the tumour microenvironment landscape, biological pathway activation and distinct clinical features of gastric cancer. Furthermore, a new scoring model, the SLC score, was developed to quantify the SLC subtypes. High SLC scores indicated a pattern of 'SLC-S2', characterized by stromal infiltration and activation, poor prognosis and insensitivity to chemotherapy and immunotherapy, but high sensitivity to imatinib. The SLC score could serve as a supplement to the Tumour Node Metastasis (TNM) staging system to guide personalized treatment strategies and predict prognosis for patients with gastric cancer.

Inequalities in care delivery and outcomes for myocardial infarction, heart failure, atrial fibrillation, and aortic stenosis in the United Kingdom.

Cardiovascular diseases are a leading cause of death and disability globally, with inequalities in burden and care delivery evident in Europe. To address this challenge, The Lancet Regional Health-Europe convened experts from a range of countries to summarise the current state of knowledge on cardiovascular disease inequalities across Europe. This Series paper presents evidence from nationwide secondary care registries and primary care healthcare records regarding inequalities in care delivery and outcomes for myocardial infarction, heart failure, atrial fibrillation, and aortic stenosis in the National Health Service (NHS) across the United Kingdom (UK) by age, sex, ethnicity and geographical location. Data suggest that women and older people less frequently receive guideline-recommended treatment than men and younger people. There are limited publications about ethnicity in the UK for the studied disease areas. Finally, there is inter-healthcare provider variation in cardiovascular care provision, especially for transcatheter aortic valve implantation, which is associated with differing outcomes for patients with the same disease. Providing equitable care is a founding principle of the UK NHS, which is well positioned to deliver innovative policy responses to reverse observed inequalities. Understanding differences in care may enable the implementation of appropriate strategies to mitigate differences in outcomes.

Microstructure evolution under thermo-mechanical operating of rocksalt-structure TiN via neural network potential.

In the process of high temperature service, the mechanical properties of cutting tools decrease sharply due to the peeling of the protective coating. However, the mechanism of such coating failure remains obscure due to the complicated interaction between atomic structure, temperature, and stress. This dynamic evolution nature demands both large system sizes and accurate description on the atomic scale, raising challenges for existing atomic scale calculation methods. Here, we developed a deep neural network (DNN) potential for Ti-N binary systems based on first-principles study datasets to achieve quantum-accurate large-scale atomic simulation. Compared with empirical interatomic potential based on the embedded-atom-method, the developed DNN-potential can accurately predict lattice constants, phonon properties, and mechanical properties under various thermodynamic conditions. Moreover, for the first time, we present the atomic evolution of the fracture behavior of large-scale rocksalt-structure (B1) TiN systems coupled with temperature and stress conditions. Our study validates that interatomic brittle fractures occur when TiN stretches beyond its tensile yield point. Such simulation of coating fracture and cutting behavior based on large-scale atoms can shed new light on understanding the microstructure and mechanical properties of coating tools under extreme operating conditions.

Risk factors associated with postoperative delirium in elderly patients undergoing hip surgery.

Objective: We retrospectively analyzed the occurrence of postoperative delirium following hip surgery and the associated risk factors. The aim was to establish a clinical foundation for preventing postoperative delirium after hip surgery. Methods: We retrospectively selected elderly patients who had hip surgery at our hospital between January 2022 and August 2022. We included patients who experienced delirium in the observation group and those who did not encounter delirium in the control group. We then proceeded to compare various indicators among these two groups of patients. Results: We analyzed a total of 97 cases of hip surgery, and among them, 32 cases experienced postoperative delirium, resulting in an incidence rate of 32.9%. Various factors were found to be linked to the development of postoperative delirium, including age, height, gender (male), preoperative erythrocyte sedimentation rate (ESR), postoperative ESR, preoperative lactate levels, pain scores on the first day after surgery, type of surgical procedure, and the occurrence of delirium in the post-anesthesia care unit (PACU delirium). Additionally, it was observed that 75% of patients who had PACU delirium also experienced postoperative delirium. Conclusion: Postoperative delirium in patients who have hip surgery had an incidence rate of 32.9%. This phenomenon is linked to various factors that pose a risk, such as the patient age, height, gender, preoperative ESR levels, postoperative ESR levels, preoperative lactate levels, pain scores on the day following surgery, and the specific surgical procedure performed. The likelihood of experiencing delirium increases by 12% for every additional 10 years in patient age. Additionally, the occurrence of delirium in the PACU is a strong indicator of the likelihood of experiencing postoperative delirium.

Traditional Chinese Medicine Compound (Tongxinluo) and Clinical Outcomes of Patients With Acute Myocardial Infarction: The CTS-AMI Randomized Clinical Trial.

Importance: Tongxinluo, a traditional Chinese medicine compound, has shown promise in in vitro, animal, and small human studies for myocardial infarction, but has not been rigorously evaluated in large randomized clinical trials. Objective: To investigate whether Tongxinluo could improve clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI). Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial was conducted among patients with STEMI within 24 hours of symptom onset from 124 hospitals in China. Patients were enrolled from May 2019 to December 2020; the last date of follow-up was December 15, 2021. Interventions: Patients were randomized 1:1 to receive either Tongxinluo or placebo orally for 12 months (a loading dose of 2.08 g after randomization, followed by the maintenance dose of 1.04 g, 3 times a day), in addition to STEMI guideline-directed treatments. Main Outcomes and Measures: The primary end point was 30-day major adverse cardiac and cerebrovascular events (MACCEs), a composite of cardiac death, myocardial reinfarction, emergent coronary revascularization, and stroke. Follow-up for MACCEs occurred every 3 months to 1 year. Results: Among 3797 patients who were randomized, 3777 (Tongxinluo: 1889 and placebo: 1888; mean age, 61 years; 76.9% male) were included in the primary analysis. Thirty-day MACCEs occurred in 64 patients (3.4%) in the Tongxinluo group vs 99 patients (5.2%) in the control group (relative risk [RR], 0.64 [95% CI, 0.47 to 0.88]; risk difference [RD], -1.8% [95% CI, -3.2% to -0.6%]). Individual components of 30-day MACCEs, including cardiac death (56 [3.0%] vs 80 [4.2%]; RR, 0.70 [95% CI, 0.50 to 0.99]; RD, -1.2% [95% CI, -2.5% to -0.1%]), were also significantly lower in the Tongxinluo group than the placebo group. By 1 year, the Tongxinluo group continued to have lower rates of MACCEs (100 [5.3%] vs 157 [8.3%]; HR, 0.64 [95% CI, 0.49 to 0.82]; RD, -3.0% [95% CI, -4.6% to -1.4%]) and cardiac death (85 [4.5%] vs 116 [6.1%]; HR, 0.73 [95% CI, 0.55 to 0.97]; RD, -1.6% [95% CI, -3.1% to -0.2%]). There were no significant differences in other secondary end points including 30-day stroke; major bleeding at 30 days and 1 year; 1-year all-cause mortality; and in-stent thrombosis (<24 hours; 1-30 days; 1-12 months). More adverse drug reactions occurred in the Tongxinluo group than the placebo group (40 [2.1%] vs 21 [1.1%]; P = .02), mainly driven by gastrointestinal symptoms. Conclusions and Relevance: In patients with STEMI, the Chinese patent medicine Tongxinluo, as an adjunctive therapy in addition to STEMI guideline-directed treatments, significantly improved both 30-day and 1-year clinical outcomes. Further research is needed to determine the mechanism of action of Tongxinluo in STEMI. Trial Registration: ClinicalTrials.gov Identifier: NCT03792035.

Enhancing the Ag-loading capacity on Ti3C2Tx sheets as hybrid fillers to form composite coatings with excellent antibacterial properties.

The settlement of microorganisms is an unwanted process in various practical fields, where also the first attaching microorganisms could promote other bacterial adhesion, causing an acceleration of bioaccumulation on the solid surface and damage to the surface functions. Developing an advanced composite coating with anti-microorganism attachment features is still a big challenge, and the critical element in any such method is to find an efficient functional agent for use in the coating system that could extend the service period. MXenes have received increasing attentions owing to their unique layer structure and large specific surface area. Increasing studies have been devoted to the development of MXene/polymer composites with creatively designed structures to realize various specific functions. Herein, two-dimensional (2D) transition metal carbide material MXene as a carrier was etched and decorated with cellulose to enhance the anchor points to grasp functional Ag nanoparticles via a simple method. The MXene nanosheets (Ti3C2Tx) were modified by cellulose to graft hydroxy groups on their surface, and then they were incorporated into silver nanoparticles (Ag NPs). The results showed that the cellulose could increase the loading content of the Ag NPs on the MXene surface, and also could act as a stabilized material to form the composite filler MXene@cellulose@Ag NPs (MAC), which could serve as a functional agent. Furthermore, the obtained product MAC filler exhibited excellent dispersibility and stability among all the tested fillers (MXene and MA), and it could help avoid aggregation and promote homogenous dispersal in the coating network. Besides, MAC displayed outstanding antibacterial activities against E. coli and S. aureus at the same concentration among all the fillers. When the filler was embedded into the coating system, the composite coating PCB-MAC possessed abundant active Ag+ ions released by the Ag NPs, which could work against bacterial growth and achieve a favorable antibacterial inhibition effect. Therefore, we believe that the active MAC filler maintained high antibacterial efficiency, evincing its potential as a desirable agent for obtaining an excellent anti-adhesive behavior in numerous broad applications, such as the environment field or medical area.

[Molecular dynamics simulation of force-regulated interaction between glycoprotein Ib α and filamin].

In resting platelets, the 17 th domain of filamin a (FLNa17) constitutively binds to the platelet membrane glycoprotein Ibα (GPIbα) at its cytoplasmic tail (GPIbα-CT) and inhibits the downstream signal activation, while the binding of ligand and blood shear force can activate platelets. To imitate the pull force transmitted from the extracellular ligand of GPIbα and the lateral tension from platelet cytoskeleton deformation, two pulling modes were applied on the GPIbα-CT/FLNa17 complex, and the molecular dynamics simulation method was used to explore the mechanical regulation on the affinity and mechanical stability of the complex. In this study, at first, nine pairs of key hydrogen bonds on the interface between GPIbα-CT and FLNa17 were identified, which was the basis for maintaining the complex structural stability. Secondly, it was found that these hydrogen bonding networks would be broken down and lead to the dissociation of FLNa17 from GPIbα-CT only under the axial pull force; but, under the lateral tension, the secondary structures at both terminals of FLNa17 would unfold to protect the interface of the GPIbα-CT/FLNa17 complex from mechanical damage. In the range of 0~40 pN, the increase of pull force promoted outward-rotation of the nitrogen atom of the 563 rd phenylalanine (PHE 563-N) at GPIbα-CT and the dissociation of the complex. This study for the first time revealed that the extracellular ligand-transmitted axial force could more effectively relieve the inhibition of FLNa17 on the downstream signal of GPIbα than pure mechanical tension at the atomic level, and would be useful for further understanding the platelet intracellular force-regulated signal pathway.

Oral diseases are associated with cognitive function in adults over 60 years old.

OBJECTIVE: To investigate the bidirectional association between oral diseases and cognitive function comprehensively. SUBJECTS AND METHODS: This cross sectional study utilized data from the National Health and Nutrition Examination Survey. Oral diseases include periodontitis, dental caries, and tooth loss (end point of oral disease resulting in tooth extraction). Cognitive function included three domains: memory, processing speed, and executive function. A global cognitive score was then derived from sum of the three cognitive domains. Oral cognition associations were examined using various statistical models: (1) Regress oral disease on cognitive function; (2) Regress cognitive function on oral disease; and (3) Structural equation modelling treating cognition and oral disease as latent variables. RESULTS: There were 2508 participants aged 60+ who had both oral and cognitive information. Associations between various oral disease and global cognitive score were observed (Odds ratio ORcog->periodontitis 0.95, 95% Confidence Interval [0.92, 0.99]; ßcog->caries -0.13, [-0.23, -0.04]; ßcog->tooth loss -0.03 [-0.04, -0.01]; ßtooth loss->cog -0.04 [-0.06, -0.02]; ßcaries->cog -0.03 [-0.06, -0.01]; ßperiodontitis->cog -0.39 [-0.69, -0.10]). Significant correlation was also found between these oral disease and cognitive function using structural equation model (r -0.22, [-0.34, -0.10]). CONCLUSIONS: This study found robust bidirectional associations between oral disease and cognitive function using various modelling approaches among the aging population.

Prognosis, characteristics, and provision of care for patients with the unspecified heart failure electronic health record phenotype: a population-based linked cohort study of 95262 individuals.

Background: Whether the accuracy of the phenotype ascribed to patients in electronic health records (EHRs) is associated with variation in prognosis and care provision is unknown. We investigated this for heart failure (HF, characterised as HF with preserved ejection fraction [HFpEF], HF with reduced ejection fraction [HFrEF] and unspecified HF). Methods: We included individuals aged 16 years and older with a new diagnosis of HF between January 2, 1998 and February 28, 2022 from linked primary and secondary care records in the Clinical Practice Research Datalink in England. We investigated the provision of guideline-recommended diagnostic investigations and pharmacological treatments. The primary outcome was a composite of HF hospitalisation or all-cause death, and secondary outcomes were time to HF hospitalisation, all-cause death and death from cardiovascular causes. We used Kaplan-Meier curves and log rank tests to compare survival across HF phenotypes and adjusted for potential confounders in Cox proportional hazards regression analyses. Findings: Of a cohort of 95,262 individuals, 1271 (1.3%) were recorded as having HFpEF, 10,793 (11.3%) as HFrEF and 83,198 (87.3%) as unspecified HF. Individuals recorded as unspecified HF were older with a higher prevalence of dementia. Unspecified HF, compared to patients with a recorded HF phenotype, were less likely to receive specialist assessment, echocardiography or natriuretic peptide testing in the peri-diagnostic period, or receive angiotensin-converting enzyme inhibitors, beta blockers or mineralocorticoid receptor antagonists up to 12 months after diagnosis (risk ratios compared to HFrEF, 0.64, 95% CI 0.63-0.64; 0.59, 0.58-0.60; 0.57, 0.55-0.59; respectively) and had significantly worse outcomes (adjusted hazard ratios compared to HFrEF, HF hospitalisation and death 1.66, 95% CI 1.59-1.74; all-cause mortality 2.00, 1.90-2.10; cardiovascular death 1.77, 1.65-1.90). Interpretation: Our findings suggested that absence of specification of HF phenotype in routine EHRs is inversely associated with clinical investigations, treatments and survival, representing an actionable target to mitigate prognostic and health resource burden. Funding: Japan Research Foundation for Healthy Aging and British Heart Foundation.

Synthesis and Characterization of Photo-Cross-Linkable Silk Fibroin Methacryloyl Hydrogel for Biomedical Applications.

Photo-cross-linkable hydrogels have recently gained increased interest in the field of biomedical applications. In this study, silk fibroin was derivatized with methacrylic anhydride (MA) to obtain silk fibroin methacryloyl (SFMA), forming hydrogel under UV light exposure in 1 min. The SFMA sol-gel transition did not involve significant structural change at the early stage. Then, the formation of the irreversible ß-sheet was confirmed after 24 h. The resulting SFMA hydrogel showed a homogeneous porous structure with pore sizes ranging from 400 to 700 µm, depending on the content. In addition, these hydrogels demonstrated a lower swelling capacity, higher rheological properties and compressive modulus, and slow degradation behavior at higher content, likely due to the higher degree of cross-linking. An experiment with cells indicated the good cell compatibility of these hydrogels, as revealed by Cell Counting Kit-8 (CCK-8) assays. As a tissue-engineered material, this photo-cross-linkable SFMA is expected to have a wide range of applications in the biomedical field.

The molecular mechanism of non-covalent inhibitor WU-04 targeting SARS-CoV-2 3CLpro and computational evaluation of its effectiveness against mainstream coronaviruses.

There is an urgent need for highly effective therapeutic agents to interrupt the continued spread of SARS-CoV-2. As a pivotal protease in the replication process of coronaviruses, the 3CLpro protein is considered as a potential target of drug development to stop the spread and infection of the virus. In this work, molecular dynamics (MD) simulations were used to elucidate the molecular mechanism of a novel and highly effective non-covalent inhibitor, WU-04, targeting the SARS-CoV-2 3CLpro protein. The difference in dynamic behavior between the apo-3CLpro and the holo-3CLpro systems suggests that the presence of WU-04 inhibits the motion amplitude of the 3CLpro protein relative to the apo-3CLpro system, thus maintaining a stable conformational binding state. The energy calculations and interaction analysis show that the hot-spot residues Q189, M165, M49, E166, and H41 and the warm-spot residues H163 and C145 have a strong binding capacity to WU-04 by forming multiple hydrogen bonds and hydrophobic interactions, which stabilizes the binding of the inhibitor. After that, the resistance of WU-04 to the six SARS-CoV-2 variants (Alpha, Beta, Gamma, Delta, Lambda, and Omicron) and two other mainstream coronavirus (SARS-CoV and MERS-CoV) 3CLpro proteins was further investigated. Excitingly, the slight difference in energy values relative to the SARS-CoV-2 system indicates that WU-04 is still highly effective against the coronaviruses, which becomes crucial evidence that WU-04 is a pan-inhibitor of the 3CLpro protein in various SARS-CoV-2 variants and other mainstream coronaviruses. The study will hopefully provide theoretical insights for the future rational design and improvement of novel non-covalent inhibitors targeting the 3CLpro protein.

Study on the Fluorination Process of Sc2O3 by NH4HF2.

Research on rare-earth fluorides is of urgent and critical importance for the preparation and emerging applications of high-purity alloys. The fluorination of Sc2O3 by NH4HF2 to fabricate ScF3 is investigated. The effects of the fluorination temperature, time and mass ratio of reactant on the fluorination rate and fluoride are discussed in this work. The fluorination reaction was first confirmed using thermodynamic calculation. The thermal and mass stability of the fluorination process were analyzed by thermogravimetric and differential scanning calorimetric (TG-DSC). The as-obtained products at different fluorination temperatures were characterized by Powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and high-resolution transmission electron microscopy (HRTEM). The results indicated that the fluorination began at room temperature (RT) with the formation of (NH4)3ScF6. With the increase of temperature, the reaction proceeded sequentially through the formation of NH4ScF4, (NH4)2Sc3F11, and finally ScF3. The fluorination rate increased with the increase of fluorination temperature and holding time. ScF3 with a purity of 99.997 wt.% could be obtained by fluorination at 400 °C for 2 h.

Subsite-specific metastatic organotropism and risk in gastric cancer: A population-based cohort study of the US SEER database and a Chinese single-institutional registry.

BACKGROUND: Studies exploring whether metastatic organotropism and risk in gastric cancer (GC) differ by primary anatomical site are scarce. METHODS: This study included 15,260 and 1623 patients diagnosed with GC from the Surveillance, Epidemiology, and End Results (SEER) registry database and the Nanfang Hospital in China, respectively. Patients were stratified according to primary site of GC, and the incidence of metastasis to different organs was used to determine the metastatic organotropism for each GC subsite. Finally, the metastatic organotropism and risk were compared among the different subsite groups. RESULTS: Liver metastasis was the most common metastasis site in cardia GC, whereas other-site metastases were more common in the body, antrum, overlapping lesions, and unspecified GCs. Liver and other-site metastases were also frequently observed in the fundus, pylorus, lesser curvature, and greater curvature GCs. Patients with GC with definite primary tumor sites in the SEER and validation Nanfang hospital cohorts were compared by grouping as proximal and distal GCs for further analysis. In the SEER cohort, the top three metastatic sites of proximal GC were liver (21.4%), distant lymph node (LN) (14.6%), and other-site (mainly peritoneum, 11.9%), whereas those of distal GC were other-site (mainly peritoneum, 19.5%), liver (11.8%), and distant LN (9.5%). The incidence of metastasis to the liver, distant LN, lung, and brain was significantly higher in patients with proximal GC than in those with distal GC in both the SEER and Nanfang cohorts (p < 0.05). However, metastasis to other-site/peritoneum was significantly lower in patients with proximal GC compared to those with distal GC in the Nanfang Hospital and SEER cohorts, respectively (p < 0.05). CONCLUSION: Liver and distant LN are the preferred metastatic sites for proximal GC, whereas peritoneal metastasis is more common in distal GC. Proximal GC has a higher risk of lymphatic and hematogenous metastases, and a lower risk of transcoelomic metastasis than distal GC. Our findings highlight the need to stratify GC by its primary subsite to aid in planning and decision-making related to metastatic management in clinical practice.

The involvement of transient receptor potential channels in mast cell activation by microbubbles.

This study was to explore the activation of mast cells by microbubbles, with the focus on transient receptor potential (TRP) channels mediated degranulation and calcium influx. Bone marrow-derived mast cells (BMMCs) were primarily obtained from femurs in mice and induced differentiation for 4 weeks. After the purity identification, BMMCs were contacted by homogeneous microbubbles with the diameter of 1 mm for 1 h. ß-hexosaminidase and histamine levels in supernatants were assessed by enzyme-linked immunosorbent assay (ELISA) and the CD63 expression was tested by flow cytometry. The intracellular calcium binding with Fluo-4 AM dyes in BMMCs was observed under the fluorescence microscope and the mean fluorescence intensity was quantitatively measured by flow cytometry. ß-hexosaminidase release, histamine concentration, CD63 expression and calcium influx were significantly increased in BMMCs group upon microbubble stimulation compared to the control groups. After preconditioning with the available inhibitors and microbubble contact, only transient receptor potential vanilloid 1 (TRPV1) and TRPV4 inhibitors robustly suppressed the microbubble-induced degranulation. Likewise, the elevated fluorescence intensity of cytosolic calcium level was also significantly weaken. The results demonstrated microbubble stimulus effectively promoted BMMCs degranulation, which could be substantially restrained by inhibitors targeted for blocking TRPV1 or TRPV4 channel. The alternation of intracellular calcium level in BMMCs was consistent with the changes of degranulation capacity. It's suggested that the activation of BMMCs by microbubbles may involve specific TRP calcium dependent channels.

Distribution characteristics, source identification and health risk assessment of trace metals in the coastal groundwater of Taizhou City, China.

This study was carried out to evaluate and analyze the fluctuations in groundwater for certain trace metals (Fe, Mn, Cu, Zn, Al, Cd, Cr, Pb, As, and Se) in Taizhou City over three years (2020-2022), evaluate the potential human health risks due to the consumption of groundwater. To quantify the spatiotemporal changes in groundwater trace metals, the heavy metal pollution index (HPI) and heavy metal evaluation index (HEI) were utilized. Furthermore, multivariate statistical methods were utilized to distinguish the sources of trace elements. Deterministic health risk assessment and Monte Carlo health risk simulation methods were employed to evaluate human health risks associated with exposure to trace metals. The results indicate that areas with higher pollution are in the south-central region, with low HPI increasing from 50% to 75% and low HEI from 68.75% to 81.25%, reflecting improved water quality. Correlation matrix analysis and principal component analysis (PCA) pinpointed anthropogenic sources as major trace metal contributors. Cr and As concentrations were associated with farming activities, Cd and Pb concentrations showed links to local industries such as e-waste recycling and shipbuilding. Furthermore, Cu levels in groundwater was influenced by the combined effects of industry, agriculture, and urban sewage discharge. Based on the hazard quotient (HQ) and hazard index (HI) calculations, the majority of groundwater samples did not exceed the reference values, indicating acceptable noncarcinogenic risks for both adults and children. However, the analysis of carcinogenic risk (CR) and uncertainty revealed an overall decreasing trend in carcinogenic risk, with Cr and Cd possessing the highest potential for causing carcinogenic risks. The sensitivities were 46.3%, 53.3%, and 70.3% for Cr, and 18.8%, 27.6%, and 9.3% for Cd.

[Molecular dynamics simulation of force-regulated interaction between talin and Rap1b].

The binding of talin-F0 domain to ras-related protein 1b (Rap1b) plays an important role in the formation of thrombosis. However, since talin is a force-sensitive protein, it remains unclear whether and how force regulates the talin-F0/Rap1b interaction. To explore the effect of force on the binding affinity and the dynamics mechanisms of talin-F0/Rap1b, molecular dynamics simulation was used to observe and compare the changes in functional and conformational information of the complex under different forces. Our results showed that when the complex was subjected to tensile forces, there were at least two dissociation pathways with significantly different mechanical strengths. The key event determining the mechanical strength difference between the two pathways was whether the ß4 sheet of the F0 domain was pulled away from the original ß1-ß4 parallel structure. As the force increased, the talin-F0/Rap1b interaction first strengthened and then weakened, exhibiting the signature of a transition from catch bonds to slip bonds. The mechanical load of 20 pN increased the interaction index of two residue pairs, ASP 54-ARG 41 and GLN 18-THR 65, which resulted in a significant increase in the affinity of the complex. This study predicts the regulatory mechanism of the talin-F0/Rap1b interaction by forces in the intracellular environment and provides novel ideas for the treatment of related diseases and drug development.

Future Innovations in Novel Detection for Atrial Fibrillation (FIND-AF): pilot study of an electronic health record machine learning algorithm-guided intervention to identify undiagnosed atrial fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with a fivefold increased risk of stroke. Oral anticoagulation reduces the risk of stroke, but AF is elusive. A machine learning algorithm (Future Innovations in Novel Detection of Atrial Fibrillation (FIND-AF)) developed to predict incident AF within 6 months using data in primary care electronic health records (EHRs) could be used to guide AF screening. The objectives of the FIND-AF pilot study are to determine yields of AF during ECG monitoring across AF risk estimates and establish rates of recruitment and protocol adherence in a remote AF screening pathway. METHODS AND ANALYSIS: The FIND-AF Pilot is an interventional, non-randomised, single-arm, open-label study that will recruit 1955 participants aged 30 years or older, without a history of AF and eligible for oral anticoagulation, identified as higher risk and lower risk by the FIND-AF risk score from their primary care EHRs, to a period of remote ECG monitoring with a Zenicor-ECG device. The primary outcome is AF diagnosis during ECG monitoring, and secondary outcomes include recruitment rates, withdrawal rates, adherence to ECG monitoring and prescription of oral anticoagulation to participants diagnosed with AF during ECG monitoring. ETHICS AND DISSEMINATION: The study has ethical approval (the North West-Greater Manchester South Research Ethics Committee reference 23/NW/0180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the Funder's open access policy. TRIAL REGISTRATION NUMBER: NCT05898165.