Reduction of N-nitrosamine in cured ham using atmospheric cold plasma-treated cauliflower powder.

The effects of cauliflower treated with atmospheric cold plasma (ACP), as a natural nitrite source, on the curing of ground ham and nitrosamine formation were investigated. Ground ham was prepared using sodium nitrite and ACP-treated cauliflower powder (PTCP) to achieve initial nitrite concentrations of 60 and 100 mg/kg, respectively. ACP treatment generated nitrite in cauliflower but significantly reduced the antioxidant activity (P < 0.05). As a nitrite source, PTCP had similar effects as sodium nitrite in the development of cured color in ground ham, with a comparable residual nitrite content (P ≥ 0.05). Three nitrosamines, N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), and N-nitrosopyrrolidine (NPYR), were detected in ground ham. NPYR formation was significantly lower in ground ham treated with PTCP at an initial nitrite concentration of 100 mg/kg (P < 0.05). Therefore, the use of a natural nitrite source manufactured through ACP treatment can prospectively achieve suitable curing efficiency while simultaneously suppressing nitrosamine formation.

Clinicopathologic and molecular characterization of stages II-IV gastric cancer with Claudin 18.2 expression.

BACKGROUND: Claudin 18.2 (CLDN18.2) is a promising target for targeted therapies in gastric cancer (GC). This study investigated the prevalence of CLDN18.2 expression in patients with stages II-IV GC or gastroesophageal junction (GEJ) adenocarcinoma and its correlation with clinicopathologic features and other crucial GC biomarkers. METHODS: We enrolled 1000 patients diagnosed with stages II-IV GC after surgical treatment. Immunohistochemistry for CLDN18 (43-14A clone), PD-L1 (22C3 pharmDx), HER2, and FGFR2 was performed. CLDN18.2 positivity was defined as moderate-to-strong (2+/3+) membranous staining in ≥75% of tumor cells. CLDN18.2 expression was compared with biomarker expression, Epstein-Barr virus (EBV) association and microsatellite instability status, and clinicopathologic features. RESULT: CLDN18.2 was positive in 34.4% of the patients. CLDN18.2 positivity was significantly higher in the middle and upper thirds than in the lower third gastric location (P < .001), but there was no correlation with age, sex, or stage (P > .05). CLDN18.2 positivity was rare (2.8%) in mucinous adenocarcinoma but frequent (90.9%) in a majority of gastric carcinomas with lymphoid stroma. CLDN18.2 positivity was higher in EBV-associated (P < .001) and PD-L1-positive (PD-L1 CPS ≥ 5) GC (P = .014) but lower in HER2 positive GC (P = .005). CLDN18.2 positivity was not significantly associated with overall survival and disease-free survival. CONCLUSION: This study provides a comprehensive evaluation of CLDN18.2 status and its correlation with the clinicopathologic characteristics of patients with stages II-IV GC in Korea and with crucial biomarkers. It may be valuable for guiding future drug development, expanding treatment options, and ultimately improving patient outcomes in GC.

Causal associations between gut microbiota, circulating inflammatory proteins, and epilepsy: a multivariable Mendelian randomization study.

Background: Previous studies have suggested that gut microbiota (GM) may be involved in the pathogenesis of epilepsy through the microbiota-gut-brain axis (MGBA). However, the causal relationship between GM and different epilepsy subtypes and whether circulating inflammatory proteins act as mediators to participate in epileptogenesis through the MGBA remain unclear. Therefore, it is necessary to identify specific GM associated with epilepsy and its subtypes and explore their underlying inflammatory mechanisms for risk prediction, personalized treatment, and prognostic monitoring of epilepsy. Methods: We hypothesized the existence of a pathway GM-inflammatory proteins-epilepsy. We found genetic variants strongly associated with GM, circulating inflammatory proteins, epilepsy and its subtypes, including generalized and partial seizures, from large-scale genome-wide association studies (GWAS) summary data and used Multivariate Mendelian Randomization to explore the causal relationship between the three and whether circulating inflammatory proteins play a mediating role in the pathway from GM to epilepsy, with inverse variance weighted (IVW) method as the primary statistical method, supplemented by four methods: MR-Egger, weighted median estimator (WME), Weighted mode and Simple mode. Results: 16 positive and three negative causal associations were found between the genetic liability of GM and epilepsy and its subtypes. There were nine positive and nine negative causal associations between inflammatory proteins and epilepsy and its subtypes. Furthermore, we found that C-X-C motif chemokine 11 (CXCL11) levels mediated the causal association between Genus Family XIII AD3011 group and epilepsy. Conclusion: Our study highlights the possible causal role of specific GM and specific inflammatory proteins in the development of epilepsy and suggests that circulating inflammatory proteins may mediate epileptogenesis through the MGBA.

DNA methylation variations of DNA damage response correlate survival and local immune status in melanomas.

AIM: We aimed to explore the impact of DNA methylation alterations on the DNA damage response (DDR) in melanoma prognosis and immunity. MATERIAL & METHODS: Different melanoma cohorts with molecular and clinical data were included. RESULTS: Hierarchical clustering utilizing different combinations of DDR-relevant CpGs yielded distinct melanoma subtypes, which were characteristic of different prognoses, transcriptional function profiles of DDR, and immunity and immunotherapy responses but were associated with similar tumor mutation burdens. We then constructed and validated a clinically applicable 4-CpG risk-score signature for predicting survival and immunotherapy response. CONCLUSION: Our study describes the close interrelationship among DNA methylation, DDR machinery, local tumor immune status, melanoma prognosis, and immunotherapy response.

Establishment and validation of circulating cell-free DNA signatures for nasopharyngeal carcinoma detection.

BACKGROUND: Early detection of nasopharyngeal carcinoma (NPC) poses a significant challenge. The absence of highly sensitive and specific diagnostic biomarkers for nasopharyngeal carcinoma contributes to the unfavourable prognosis of NPC patients. Here, we aimed to establish a non-invasive approach for detecting NPC using circulating cell-free DNA (cfDNA). METHODS: We investigated the potential of next-generation sequencing (NGS) of peripheral blood cells as a diagnostic tool for NPC. We collected data on genome-wide nucleosome footprint (NF), 5'-end motifs, fragmentation patterns, CNV information, and EBV content from 553 Chinese subjects, including 234 NPC patients and 319 healthy individuals. Through case-control analysis, we developed a diagnostic model for NPC, and validated its detection capability. FINDINGS: Our findings revealed that the frequencies of NF, fragmentation, and motifs were significantly higher in NPC patients compared to healthy controls. We developed an NPC score based on these parameters that accurately distinguished NPC from non-NPC cases according to the American Joint Committee on Cancer staging system from non-NPC (validation set: area under curve (AUC) = 99.9% (95% CI: 99.8%-100%), se: 98.15%, sp: 100%). This model showed superior performance over plasma EBV DNA. Additionally, the NPC score effectively differentiated between NPC patients and healthy controls, even after clinical treatment. Furthermore, the NPC score was found to be independent of potential confounders such as age, sex, or TNM stage. INTERPRETATION: We have developed and verified a non-invasive approach with substantial potential for clinical application in detecting NPC. FUNDING: A full list of funding bodies that contributed to this study can be found in Funding section.

Adaptative responses of Neurospora crassa by histidine kinases upon the attack of the arthropod Sinella curviseta.

Histidine kinases (HKs) are important sensor proteins in fungi and play an essential role in environmental adaptation. However, the mechanisms by which fungi sense and respond to fungivores attack via HKs are not fully understood. In this study, we utilized Neurospora crassa to investigate the involvement of HKs in responding to fungivores attack. We found that the 11 HKs in N. crassa not only affected the growth and development, but also led to fluctuations in antioxidant production. Ten mutants in the genes encoding HKs (except ∆phy1) showed increased production of reactive oxygen species (ROS), especially upon Sinella curviseta attack. The ROS burst triggered changes in conidia and perithecial beaks formation, as well as accumulation of ß-glucan, ergothioneine, ergosterol, and carotenoids. ß-glucan was increased in ∆hk9, ∆os1, ∆hcp1, ∆nik2, ∆sln1, ∆phy1 and ∆phy2 mutants compared to the wild-type strain. In parallel, ergothioneine accumulation was improved in ∆phy1 and ∆hk16 mutants and further increased upon attack, except in ∆os1 and ∆hk16 mutants. Additionally, fungivores attack stimulated ergosterol and dehydroergosterol production in ∆hk9 and ∆os1 mutants. Furthermore, deletion of these genes altered carotenoid accumulation, with wild-type strain, ∆hk9, ∆os1, ∆hcp1, ∆sln1, ∆phy2, and ∆dcc1mutants showing an increase in carotenoids upon attack. Taken together, HKs are involved in regulating the production of conidia and antioxidants. Thus, HKs may act as sensors of fungivores attack and effectively improve the adaptive capacity of fungi to environmental stimuli.

Clopidogrel Versus Aspirin as Chronic Maintenance Antiplatelet Monotherapy in Patients After Percutaneous Coronary Intervention With Chronic Kidney Disease: A Post Hoc Analysis of the HOST-EXAM Trial.

BACKGROUND: Clopidogrel monotherapy improved clinical outcomes compared with aspirin monotherapy during a chronic maintenance period in patients who underwent coronary stenting in the HOST-EXAM (Harmonizing Optimal Strategy for Treatment of Coronary Artery Stenosis-Extended Antiplatelet Monotherapy) trial. However, it is uncertain whether the beneficial effect of clopidogrel over aspirin is different according to the renal function. METHODS AND RESULTS: We conducted a post hoc analysis of the HOST-EXAM trial. Chronic kidney disease (CKD) was defined as baseline estimated glomerular filtration rate <60 mL/min per 1.73 m2. The primary end point was a composite of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium bleeding type ≥3, during the 2-year follow up. Among the 5438 patients enrolled in the HOST-EXAM trial, 4844 patients (mean age, 63.3±10.6 years; 74.9% men) with a baseline creatinine value were analyzed in this study. A total of 508 (10.5%) patients had CKD, who were at higher risk of the primary end point compared with those without CKD (hazard ratio [HR], 2.01 [95% CI, 1.51-2.67]). Clopidogrel monotherapy was associated with a lower rate of the primary end point in both patients with CKD (HR, 0.74 [95% CI, 0.44-1.25]) and patients without CKD (HR, 0.71 [95% CI, 0.56-0.91]). No significant interaction was observed between the treatment effect and CKD status (P for interaction=0.889). CONCLUSIONS: During the chronic maintenance period after coronary stenting, the risk of thrombotic and bleeding events was significantly higher in patients with CKD compared with those without CKD. There was no statistical difference in the treatment effect of clopidogrel monotherapy in those with versus without CKD.

Exploring public opinion on health effects of prepared dishes in China through social media comments.

Introduction: In the 2020s, particularly following 2022, the Chinese government introduced a series of initiatives to foster the development of the prepared dishes sector, accompanied by substantial investments from industrial capital. Consequently, China's prepared dishes industry has experienced rapid growth. Nevertheless, this swift expansion has elicited varied public opinions, particularly concerning the potential health effects of prepared dishes. Therefore, this study aims to gather and analyze comments from social media on prepared dishes using machine learning techniques. The objective is to ascertain the perspectives of the Chinese populace on the health implications of consuming prepared dishes. Methods: Social media comments, characterized by their broad distribution, objectivity, and timeliness, served as the primary data source for this study. Initially, the data underwent preprocessing to ensure its suitability for analysis. Subsequent steps in this study involved conducting sentiment analysis and employing the BERTopic model for topic clustering. These methods aimed to identify the principal concerns of the public regarding the impact of prepared dishes on health. The final phase of the study involved a comparative analysis of changes in public sentiment and thematic focus across different time frames. This approach provides a dynamic view of evolving public perceptions related to the health implications of prepared dishes. Results: This study analyzed over 600,000 comments gathered from various social media platforms from mid-July 2022 to the end of March 2024. Following data preprocessing, 200,993 comments were assessed for sentiment, revealing that more than 64% exhibited negative emotions. Subsequent topic clustering using the BERTopic model identified that 11 of the top 50 topics were related to public health concerns. These topics primarily scrutinized the safety of prepared dish production processes, raw materials, packaging materials, and additives. Moreover, significant public's interest was in the right to informed consumption across different contexts. Notably, the most pronounced public opposition emerged regarding introducing prepared dishes into primary and secondary school canteens, with criticisms directed at the negligence of educational authorities and the ethics of manufacturers. Additionally, there were strong recommendations for media organizations to play a more active role in monitoring public opinion and for government agencies to enhance regulatory oversight. Conclusion: The findings of this study indicate that more than half of the Chinese public maintain a negative perception towards prepared dishes, particularly concerning about health implications. Chinese individuals display considerable sensitivity and intense reactions to news and events related to prepared dishes. Consequently, the study recommends that manufacturers directly address public psychological perceptions, proactively enhance production processes and service quality, and increase transparency in public communications to improve corporate image and people acceptance of prepared dishes. Additionally, supervisory and regulatory efforts must be intensified by media organizations and governmental bodies, fostering the healthy development of the prepared food industry in China.

Development and validation of an infectious disease control competency scale for public health professionals.

BACKGROUND: Infectious diseases persistently pose global threats, and it is imperative to accelerate the professionalization of public health workforce. This study aimed to develop and validate the infectious disease control competency scale (IDCCS) for public health professionals to fill a theoretical gap and elevate practical capabilities by informing public health professionals' development goals. METHODS: The initial item pool was generated through a literature review, and categorized into three dimensions (knowledge, practical skills, and leadership) based on the competency iceberg model and public health leadership framework. A two-round Delphi process was conducted to determine indicators within the scale. A pilot survey was utilized for item analysis and exploratory factor analysis (EFA). A formal survey was employed for confirmatory factor analysis (CFA). The weight value of each indicator was calculated using the analytic hierarchy process. RESULTS: An initial scale with three primary items, 14 secondary items, and 81 tertiary items was generated. Twenty experts participated in the two rounds of the Delphi process. Authority coefficients exceeded 0.9 in both rounds. Kendall's W was 0.29 and 0.19, respectively (both P < 0.001). Item analysis presented a Cronbach's Alpha of 0.98, with corrected item-total correlation coefficients ranging from 0.33 to 0.78. EFA demonstrated that cumulative variance explanations for the four primary dimensions (knowledge, practical skills, leadership, and personal quality) were 77.463%, 73.976%, 81.174%, and 68.654%, respectively. CFA indicated that all composite reliability values and average variance extracted surpassed 0.8 and 0.5, respectively. The standardized factor loadings of the items ranged from 0.630 to 0.977. Among the seven model fit indices, each of the four dimensions satisfied at least five criteria. A final three-level scale comprising four primary items, 14 secondary items, and 64 tertiary items was constructed. The weight values for the four primary items were 0.4064, 0.2878, 0.2082, and 0.0981, respectively. CONCLUSIONS: The IDCCS was established to evaluate the competencies of knowledge, practical skills, leadership, and personal quality for public health professionals in infectious disease control. This scale demonstrates good reliability and validity, and can be used for performance evaluation, recruitment processes, curriculum development, and individual self-assessment.

Intelligent response micelles with high andrographolide loading for the effective treatment of atherosclerosis.

Atherosclerosis (AS) is a chronic inflammatory disease which associated with a maladaptive immune response driven by macrophages. In the development of AS, macrophages have gradually become new therapeutic targets due to their involvement in numerous inflammatory-related pathological processes in AS. However, despite significant breakthroughs in the development of macrophages targeting nanocarriers, unsatisfactory drug loading, and inexact drug release limited the development of nano-therapy. Therefore, developing a high drug-loading nanocarrier that can accurately release drugs at AS lesions is quite essential. Herein, we optimized double moieties coupled mPEG-PLA copolymer micelles via phenylboronic acid (PBA)-terminated on the hydrophobic chain and cRGD coupled in hydrophilic chain to enhance AS therapy. The micelles loaded with andrographolide (AND) exhibited advanced drug loading capacity, as PBA could form a reversible boronic ester with AND at physiological pH. The cRGD-modified AND-loaded micelles (RPPPA) could be efficaciously internalized by macrophages and efficiently prevent macrophages from differentiating to foam cells. After intravenous administration, RPPPA could accumulate in plaques and exert therapeutic effects. The optimistic therapeutic results of atherosclerosis were shown in RPPPA, included the fewer plaques, a smaller necrotic core, a more stabilized fibrous cap, and lower macrophages and MMP-9, compared with the control group. To sum up, the proposed encouraging therapy can contribute to high drug loading, exact target, and precise drug release as well as reduce inflammation for AS treatment.

FuseLinker: Leveraging LLM's pre-trained text embeddings and domain knowledge to enhance GNN-based link prediction on biomedical knowledge graphs.

OBJECTIVE: To develop the FuseLinker, a novel link prediction framework for biomedical knowledge graphs (BKGs), which fully exploits the graph's structural, textual and domain knowledge information. We evaluated the utility of FuseLinker in the graph-based drug repurposing task through detailed case studies. METHODS: FuseLinker leverages fused pre-trained text embedding and domain knowledge embedding to enhance the graph neural network (GNN)-based link prediction model tailored for BKGs. This framework includes three parts: a) obtain text embeddings for BKGs using embedding-visible large language models (LLMs), b) learn the representations of medical ontology as domain knowledge information by employing the Poincaré graph embedding method, and c) fuse these embeddings and further learn the graph structure representations of BKGs by applying a GNN-based link prediction model. We evaluated FuseLinker against traditional knowledge graph embedding models and a conventional GNN-based link prediction model across four public BKG datasets. Additionally, we examined the impact of using different embedding-visible LLMs on FuseLinker's performance. Finally, we investigated FuseLinker's ability to generate medical hypotheses through two drug repurposing case studies for Sorafenib and Parkinson's disease. RESULTS: By comparing FuseLinker with baseline models on four BKGs, our method demonstrates superior performance. The Mean Reciprocal Rank (MRR) and Area Under receiver operating characteristic Curve (AUROC) for KEGG50k, Hetionet, SuppKG and ADInt are 0.969 and 0.987, 0.548 and 0.903, 0.739 and 0.928, and 0.831 and 0.890, respectively. CONCLUSION: Our study demonstrates that FuseLinker is an effective novel link prediction framework that integrates multiple graph information and shows significant potential for practical applications in biomedical and clinical tasks. Source code and data are available at https://github.com/YKXia0/FuseLinker.

Unusual Geometric and Electronic Structures at Domain Boundaries in a Heterochiral Charge Density Wave Superlattice.

Domain boundaries (DBs) in charge density wave (CDW) systems not only are important for understanding the mechanism of how CDW interplays with other quantum phases but also have potential for future CDW-based nanodevices. However, current research on DBs in CDW materials has been mainly limited to those between homochiral CDW domains, whereas DBs between heterochiral CDW domains, especially in the atomic layers, remain largely unexplored. Here, we have studied the geometric and electronic states of heterochiral DBs in single-layer and bilayer 1T-NbSe2 using scanning tunneling microscopy/spectroscopy. We observe the existence of diverse CDW configurations in a single heterochiral CDW DB with atomic resolution and reveal the corresponding electronic states. In addition, interlayer stacking further enriches the electronic properties of the DB. Our results offer deep insights into the relationship between the detailed CDW nanostructures and electronic behaviors, which has significant implications for DB engineering in strongly correlated CDW systems and related nanodevices.

Outdoor light at night is a modifiable environmental factor for metabolic syndrome: The 33 Communities Chinese Health Study (33CCHS).

Metabolic syndrome (MetS) is a significant public health problem and presents an escalating clinical challenge globally. To combat this problem effectively, urgent measures including identify some modifiable environmental factors are necessary. Outdoor artificial light at night (LAN) exposure garnered much attention due to its impact on circadian rhythms and metabolic process. However, epidemiological evidence on the association between outdoor LAN exposure and MetS remains limited. To determine the relationship between outdoor LAN exposure and MetS, 15,477 adults participated the 33 Communities Chinese Health Study (33CCHS) in 2009 were evaluated. Annual levels of outdoor LAN exposure at participants' residential addresses were assessed using satellite data from the Defense Meteorological Satellite Program (DMSP) Operational Linescan System (OLS). Generalized linear mixed effect models were utilized to assess the association of LAN exposure with MetS and its components, including elevated waist circumference (WC), triglycerides (TG), blood pressure (BP), fasting blood glucose (FBG), and reduced high-density lipoprotein cholesterol (HDL-C). Effect modification by various social demographic and behavior factors was also examined. Overall, 4701 (30.37 %) participants were defined as MetS. The LAN exposure ranged from 6.03 to 175.00 nW/cm2/sr. The adjusted odds ratio (OR) of MetS each quartile increment of LAN exposure were 1.43 (95 % CI: 1.21-1.69), 1.44 (95 % CI: 1.19-1.74) and 1.52 (95 % CI: 1.11-2.08), respectively from Q2-Q4. Similar adverse associations were also found for the components of MetS, especially for elevated BP, TG and FBG. Interaction analyses indicated that the above associations were stronger in participants without habitual exercise compared with those with habitual exercise (e.g. OR were 1.52 [95 % CI: 1.28-1.82] vs. 1.27 [95 % CI, 1.04-1.55], P-interaction = 0.042 for MetS). These findings suggest that long-term exposure to LAN can have a significant deleterious effect on MetS, potentially making LAN an important modifiable environmental factor to target in future preventive strategies.

A disproportionality analysis of sunitinib in the FDA adverse event reporting system (FAERS).

Objective: This study aimed to analyze the FAERS database to identify adverse event associated with sunitinib to offer valuable insights for the judicious utilization of medication in clinical settings. Methods: Various disproportionality analysis techniques, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPN), and multi-gamma Poisson shrinkage (MGPS), were employed to analyze adverse drug reaction (ADR) reports pertaining to sunitinib in the FAERS database from its market introduction up to the first quarter of 2023. Subsequently, a secondary screening process was conducted to identify reliable positive signals. Results: The analysis of sunitinib adverse event signals at the system-organ classification level encompassed 27 organ systems, with gastrointestinal and endocrine disorders emerging as the predominant SOCs. A total of 237 significant adverse events meeting all four algorithms were detected. Notably, this study revealed previously unreported adverse events, including pleural effusion and ascites, while potential adrenal toxicity-related adverse events, highlighted in the drug's specification, were not identified in this analysis. The study examined the relationship between the duration of sunitinib dosing and the onset of adverse events, revealing a median onset of 48 days (IQR, 15-160 days). The findings indicated that a majority of adverse events manifested early in the dosing period, with tumor progression, disease progression, and mortality becoming more prevalent after one year of treatment. Conclusion: In the clinical utilization of sunitinib, vigilant monitoring of potential adverse reactions is imperative during the initial phase of drug administration. In addition to the documented adverse reactions outlined in the drug specification, healthcare providers should remain attentive to potential adverse reactions such as pleural effusion, ascites, and tumor development.

Laparoscopic Pylorus Preserving Gastrectomy vs Distal Gastrectomy for Early Gastric Cancer; A Multicenter Randomized Controlled Trial (KLASS-04).

OBJECTIVE: To evaluate the long-term outcomes of laparoscopic pylorus preserving gastrectomy (LPPG) with laparoscopic distal gastrectomy (LDG) for early gastric cancer (EGC). SUMMARY BACKGROUND DATA: PPG is considered as a function preserving surgery for EGC. However, there has been no multicenter randomized controlled trial comparing PPG with DG until now. METHODS: A multicenter randomized controlled trial (KLASS-04) with 256 patients with cT1N0M0 gastric cancer located in the mid portion of the stomach was conducted. The primary endpoint was the incidence of dumping syndrome at postoperative 1 year. Secondary endpoints included survival and recurrence, gallstone formation, nutritional parameters, gastroscopic findings, and quality of life (QOL) for 3 years. RESULTS: In the intention-to-treat analyses, there was no difference in the incidence of dumping syndrome at one year postoperatively (13.2% in LPPG vs. 15.8% in LDG, P=0.622). Gallstone formation after surgery was significantly lower in LPPG than in LDG (2.33% vs. 8.66%, P=0.026). Hemoglobin (+0.01 vs. -0.76 gm/dL, P<0.001) and serum protein (-0.15 vs. -0.35 gm/dL, P=0.002) were significantly preserved after LPPG. However, reflux esophagitis (17.8% vs. 6.3%, P=0.005) and grade IV delayed gastric emptying (16.3% vs. 3.9%, P=0.001) were more common in LPPG. Changes in body weight and postoperative QOL were not significantly different between groups. Three-year overall survival and disease-free survival were not different (1 case of recurrence of in each group, P=0.98). CONCLUSIONS: LPPG can be used as an alternative surgical option for cT1N0M0 gastric cancer in the mid portion of the stomach.

Characterizing Rotational Dynamics and Heterogeneity via Single-Molecule Intensity Measurements.

Dynamic heterogeneity in glassy systems has typically been characterized at the single-molecule level by extracting rotational relaxation time scales from linear dichroism (LD) collected via two orthogonally polarized channels. However, in such measurements, localization precision is diminished due to photons lost relative to collection in a single detection channel. This poses challenges in characterizing rotational and translational dynamics simultaneously, as translational measurements require high localization precision. In this paper, we present a method for extracting rotational dynamics of glassy systems at the single-molecule level from intensity fluctuations of fluorescent probe molecules in a wide-field configuration without the use of a polarizing optical component. Through numerical analysis, we show that LD and intensity measurements probing rotational dynamics report similar, approximately second-order rotational correlation decays even at low signal to noise. Thus, within the assumptions of small, isotropic rotations, LD and intensity autocorrelation analysis should provide identical information on the time scale and heterogeneity of rotational dynamics. We then present experimental results that validate this numerical result, with direct comparison of LD and intensity-based approaches across probe molecules in both polymeric and small-molecule glass formers as well as across optical configurations. Our results demonstrate moderate correlation on a per-probe basis between rotational time scales obtained from both approaches, with deviations consistent with those expected in a dynamically heterogeneous system. We envision that this easily accessible strategy will be of use across disciplines for characterizing single-molecule rotational dynamics in limited signal situations and/or when high-precision localization is required.

Diagnostic accuracy and predictors of alpha-synuclein accumulation in the gastrointestinal tract of Parkinson's disease.

The only characteristic of alpha-synuclein (AS) accumulation in the gastrointestinal (GI) tract of Parkinson's disease (PD) found in pathological studies is the "rostrocaudal gradient," which describes the more frequent presence of AS accumulation in the upper GI tract than in the lower GI tract. This study aimed to determine the diagnostic accuracy and identify predictors of AS accumulation in the GI tract of PD patients. The frequency of AS accumulation in the GI tract was compared between PD patients (N = 97) who underwent radical GI surgery for cancer and individually matched controls (N = 94). We evaluated AS accumulation in the neural structures using phosphorylated AS immunohistochemistry. A multivariable logistic regression analysis was conducted to determine the predictors of AS accumulation in the GI tract of PD patients. The frequency of AS accumulation was significantly higher in PD patients (75.3%) than in controls (8.5%, p-value < 0.001). The sensitivity and specificity of the full-layer evaluation were 75.3% and 91.5%, respectively. When the evaluation was confined to the mucosal/submucosal layer, the sensitivity and specificity were 46.9% and 94.7%, respectively. The rostrocaudal gradient of AS accumulation was found in PD patients. The duration from symptom onset to surgery was significantly longer in PD patients with AS accumulation (4.9 ± 4.9 years) than in PD patients without AS accumulation (1.8 ± 4.1 years, p-value = 0.005). Both disease duration and rostrocaudal gradient independently predicted the presence of AS accumulation in the GI tract of PD patients. Our study suggests PD-related AS accumulation in the GI tract follows a temporally increasing but spatially static progression pattern.

COPD Subtypes Are Differentially Associated With Cardiovascular Events and COPD Exacerbations.

BACKGROUND: The coronary artery calcium score (CACS) and ratio of the pulmonary artery to aorta diameters (PA:A ratio) measured from chest CT scans have been established as predictors of cardiovascular events and COPD exacerbations, respectively. However, little is known about the reciprocal relationship between these predictors and outcomes. Furthermore, the prognostic implications of COPD subtypes on clinical outcomes remain insufficiently characterized. RESEARCH QUESTION: How can these two chest CT scan-derived parameters predict subsequent cardiovascular events and COPD exacerbations in different COPD subtypes? STUDY DESIGN AND METHODS: Using COPDGene study data, we assessed prospective cardiovascular disease (CVD) and COPD exacerbation risk in patients with COPD (Global Initiative for Chronic Obstructive Lung Disease spirometric grades 2-4), focusing on CACS and PA:A ratio at study enrollment, with logistic regression models. These outcomes were analyzed in three COPD subtypes: 1,042 patients with non-emphysema-predominant disease (NEPD) (low attenuation area at -950 Hounsfield units [LAA-950] < 5%), 1,324 patients with emphysema-predominant disease (EPD) (LAA-950 ≥ 10%), and 465 patients with intermediate emphysema disease (5% ≤ LAA-950 < 10%). RESULTS: Our study indicated significantly higher overall risk for cardiovascular events in patients with higher CACS (≥ median; OR, 1.61; 95% CI, 1.30-2.00) and increased COPD exacerbations in those with higher PA:A ratios (≥ 1; OR, 1.80; 95% CI, 1.46-2.23). Notably, patients with NEPD showed a stronger association between these indicators and clinical events than those with EPD (with CACS/CVD, NEPD vs EPD: OR, 2.02 vs 1.41; with PA:A ratio/COPD exacerbation, NEPD vs EPD: OR, 2.50 vs 1.65); the difference in ORs between COPD subtypes was statistically significant for CACS/CVD. INTERPRETATION: Two chest CT scan parameters, CACS and PA:A ratio, hold distinct predictive values for cardiovascular events and COPD exacerbations that are influenced by specific COPD subtypes. TRIAL REGISTRATION: ClinicalTrials.gov; No.: NCT00608764; URL: www. CLINICALTRIALS: gov.

The Impact of Transcatheter Aortic Valve Implantation on Health Care Costs and Clinical Outcomes Based on Frailty Risk: A Nationwide Cohort Analysis.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) is preferred for treating severe aortic stenosis in older, frail populations, yet the impact of frailty on economic and clinical outcomes of TAVI is not well studied. METHODS: This retrospective cohort study included 2175 TAVI patients from 2015 to 2019, using Korea's National Health Insurance Service database, stratifying patients into low, intermediate, and high-frailty groups, using the Hospital Frailty Risk Score (HFRS). Health care costs, admissions, and total length of hospitalization were analyzed using Wilcoxon-rank test 12 months pre- and post-TAVI. Composite endpoint of death, stroke, and major bleeding, with individual outcomes, were compared using χ2 tests and Kaplan-Meier analysis. RESULTS: Mean age was 80.2 years, and 47.3% were male; 747 (34.3%) were low frailty, 1159 (53.3%) were moderate frailty, and 269 (12.4%) were high frailty. After TAVI, medical costs decreased in the intermediate- (pre-TAVI: 2,269,000 KRW [$1668 USD], post-TAVI: 1,607,000 KRW [$1181 USD]; P < 0.001) and high-frailty groups (pre-TAVI: 3,949,000 KRW [$2904 USD], post-TAVI: 2,188,000 KRW [$1609 USD]; P < 0.001). All frailty groups had shorter length of hospital stay post-TAVI (26 to 21 days in the low-frailty, 44 to 31 days in the intermediate-frailty, and 65 to 41 days in the high-frailty group; all P <0.001). The composite outcome was higher in the frailer groups (27.8% in the low-frailty vs 31.5% in the intermediate-frailty vs 37.9% in the high-frailty group; P = 0.008). All groups showed comparable rates of cardiovascular death, stroke, or bleeding. CONCLUSIONS: TAVI is clinically viable and cost-saving treatment option for frail patients with severe aortic stenosis.