Differences in Topography of Individual Amyloid Brain Networks by Amyloid PET Images in Healthy Control, Mild Cognitive Impairment, and Alzheimer's Disease.

Amyloid plaques, implicated in Alzheimer's disease, exhibit a spatial propagation pattern through interconnected brain regions, suggesting network-driven dissemination. This study utilizes PET imaging to investigate these brain connections and introduces an innovative method for analyzing the amyloid network. A modified version of a previously established method is applied to explore distinctive patterns of connectivity alterations across cognitive performance domains. PET images illustrate differences in amyloid accumulation, complemented by quantitative network indices. The normal control group shows minimal amyloid accumulation and preserved network connectivity. The MCI group displays intermediate amyloid deposits and partial similarity to normal controls and AD patients, reflecting the evolving nature of cognitive decline. Alzheimer's disease patients exhibit high amyloid levels and pronounced disruptions in network connectivity, which are reflected in low levels of global efficiency (Eg) and local efficiency (Eloc). It is mostly in the temporal lobe where connectivity alterations are found, particularly in regions related to memory and cognition. Network connectivity alterations, combined with amyloid PET imaging, show potential as discriminative markers for different cognitive states. Dataset-specific variations must be considered when interpreting connectivity patterns. The variability in MCI and AD overlap emphasizes the heterogeneity in cognitive decline progression, suggesting personalized approaches for neurodegenerative disorders. This study contributes to understanding the evolving network characteristics associated with normal cognition, MCI, and AD, offering valuable insights for developing diagnostic and prognostic markers.

Impact of aging on long-term cardiac outcomes of true-lumen recanalized chronic total occlusions in patients with overweight/obesity.

BACKGROUND: Obesity paradox addressing all-cause mortality has been described in several chronic total occlusion (CTO) studies. However, the impact of aging on long-term cardiac events in patients with overweight and obesity with CTO recanalization were less studied. METHODS: A total of 458 patients (64.4 ± 11.3 years, 403 male) with CTO interventions were enrolled. The overweight/obesity group included 311 patients with body mass index (BMI) ≧24 kg/m2 and the non-obesity group included 147. With a median follow-up of 40.0 (17.9-61.4) months, 422 patients with successful true-lumen recanalization were further assessed for target lesion failure [TLF: cardiac death, target vessel myocardial infarction (TVMI), target lesion revascularization (TLR)]. RESULTS: At follow-up, the rates of cardiac death, TVMI, TLR, TLF, and stent thrombosis were 1.9%, 1.9%, 9.2%, 10.7%, and 0.5%, respectively. The TVMI-free survival was borderline better (p = 0.067 by log-rank test) in overweight/obesity than non-obesity group. Among patients <65 years of age, the TVMI-free survival was significantly better in the overweight/obesity group (p = 0.013 compared to non-obesity group by log-rank test). In multivariate Cox regression model, the non-obesity patients younger than 65 years were at a higher risk of TVMI, not only among those <65 years of age (hazard ratio = 11.0, 95% CI = 1.1-106.0) but also among the whole patients (hazard ratio=6.9, 95% CI = 1.4-35.1) with successful CTO recanalization. CONCLUSIONS: For those with true-lumen recanalized CTO, the higher risk of TVMI after successful recanalization was rather evident in patients <65 years of age and without overweight/obesity, suggesting that aging might attenuate prognostic significance of "obesity paradox" for CTO interventions.

Magnesium-enriched deep-sea water inhibits NLRP3 inflammasome activation and dampens inflammation.

The NLRP3 inflammasome is an essential component of the innate immune system, but excessive activation can lead to inflammatory diseases. Ion fluxes across the plasma membrane or from intracellular stores are known to regulate NLRP3 inflammasome activation. Deep-sea water (DSW) contains high concentrations of many mineral ions, which could potentially influence NLRP3 inflammasome activation. However, the impact of DSW on NLRP3 inflammasome activation has not been investigated. Here, we demonstrated that DSW with water hardness levels up to 500 mg/L did not affect cell viability or the expression of NLRP3 inflammasome components in macrophages derived from THP-1 cells. However, the DSW significantly inhibited IL-1ß secretion and caspase-1 activation in response to NLRP3 activators such as nigericin, ATP, or monosodium urate (MSU) crystals. Mechanically, it was discovered that the presence of 5 mM magnesium ions (Mg2+), equivalent to the Mg2+ concentration found in the DSW with a water hardness of 500 mg/L, inhibits NLRP3 inflammasome activation. This indicates that Mg2+ contributes to the mechanism by which DSW mitigates NLRP3 inflammasome activation. Moreover, DSW administration effectively lessens MSU-triggered peritonitis in mice, a commonly used model for examining the impacts of NLRP3 inflammasome activation. These results show that DSW enriched with Mg2+ could potentially be beneficial in modulating NLRP3 inflammasome-associated diseases.

Research on the Collision Risk of Fusion Operation of Manned Aircraft and Unmanned Aircraft at Zigong Airport.

Low-altitude airspace is developing rapidly, but the utilization rate of airspace resources is low. Therefore, in order to solve the problem of the safe operation of the fusion of large UAVs and manned aircraft in the same airspace, this paper analyzes the theoretical calculation of the collision risk of the fusion operation of manned aircraft and UAVs at Feng Ming Airport in Zigong, verifying that while assessing the safety spacing of 10 km in the lateral direction, it further simulates the possibility of calculating the theoretical smaller safety spacing. The study will propose a new theory of error spacing safety margin and improve it according to the traditional Event collision risk model, combining the error spacing safety margin to establish an improved collision model more suitable for the fusion operation of manned and unmanned aircraft and reduce the redundancy of calculation. The error factors affecting manned and unmanned aircraft at Zigong Airport are analyzed, and theoretical calculations are analyzed by combining the actual data of Zigong Airport. Finally, the Monte Carlo simulation method is used to solve the error, substitute the calculation results, and simulate a section of the trajectory of the fusion operation for the reverse argument. The theoretical calculation results show that the collision risk from 10 km to 8 km satisfies the lateral target safety level (TSL) specified by ICAO under both traditional and improved models. The collision risk calculated by the improved model incorporating the error spacing safety margin is smaller, which enhances the safety of the model calculations. The results of the study can provide theoretical references for the fusion operation of manned and unmanned aircraft.

Validation and Measurement Invariance of the Tendency to Avoid Physical Activity and Sport Scale (TAPAS) Among Thai Young Adults.

Examining ways of reducing physical inactivity has been at the forefront of public health research. Moreover, valid and reliable scales are needed to objectively assess physical activity (PA) avoidance. Previous research has shown that experiencing weight stigma and physical appearance-related concerns are associated with physical inactivity. However, there is currently no Thai instrument that assesses physical inactivity in relation to weight stigma. Therefore, the present study examined the psychometric properties of the Thai version of the Tendency to Avoid Physical Activity and Sport Scale (TAPAS). Thai university students (N = 612) recruited via convenience sampling completed an online survey using SurveyMonkey between September 2022 and January 2023. Confirmatory factor analysis (CFA), multigroup CFA, and Pearson correlations (between TAPAS scores, age, body mass index, and time spent exercising) were used to analyze the data. The CFA showed robust psychometric properties for the Thai version of TAPAS regarding its unidimensional structure. The TAPAS was measurement invariant across sex, weight status, and daily hours of exercise. However, no significant Pearson correlations were found. In general, the results showed that the TAPAS is a good scale for assessing PA avoidance among Thai young adults across different sexes, weight status, and daily hours of exercise.

Premium intraocular lens adoption: Insights from a national health insurance analysis.

BACKGROUND: This study explores the utilization patterns of premium and nonpremium intraocular lenses (IOLs) under Taiwan's National Health Insurance, given the potential out-of-pocket expenses incurred by cataract surgery patients. METHODS: A cross-sectional, population-based analysis was performed on patients who underwent IOL implantation between 2016 and 2020. IOLs were categorized into nonpremium and premium, with the latter further divided based on function. Logistic and multinomial logistic regression analyses were employed to identify factors influencing IOL implantation, with data stratified by medical institute type, ownership, and patient demographics. RESULTS: In total, 1,194,805 IOLs were implanted during the study period. The rate of premium IOL implantation was lower compared to non-premium IOL implantation. However, the adoption rate of premium IOLs increased more rapidly than that of non-premium IOLs. Specifically, the adoption rate for premium IOLs was 35.2% in 2016, rising to 42.6% in 2020. Patients receiving treatment in clinics were considerably more likely to use nonpremium IOLs than were those receiving treatment in medical centers (12.7% higher probability for clinics; P < 0.001). The implantation of higher-end premium IOLs was more prevalent in clinics than in other medical institutes. The prevalence of premium IOL implantation was higher in private hospitals than in public hospitals (odds ratio: 1.403; P < 0.001). Premium IOLs were more commonly implanted in younger patients with higher income levels and without relative contraindications. CONCLUSIONS: IOL selection is associated with both personal and institutional characteristics. These factors should be considered in public policy development aimed at regulating the IOL market within a universal health insurance framework.

Real-world experience of angiotensin receptor-neprilysin inhibitors in patients with heart failure and dialysis.

Introduction: Although angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation. Methods: This multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness. Results: Out of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28-3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings. Conclusion: ARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.

Airway Anomalies in Pediatric Patients After Surgery for Congenital Heart Disease: Single-Center Retrospective Cohort Study, Taiwan 2017-2020.

OBJECTIVES: Airway anomalies increase risk of morbidity and mortality in postoperative pediatric patients with congenital heart disease (CHD). We aimed to identify airway anomalies and the association with intermediate outcomes in patients undergoing surgery for CHD. DESIGN: Single-center, hospital-based retrospective study in Taiwan, 2017-2020. SETTING: A tertiary referral hospital in Taiwan. PATIENTS: All pediatric patients who underwent surgery for CHD and were admitted to the PICU and had data about airway evaluation by cardiopulmonary CT scan or bronchoscopy. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 820 CHD patients identified as having undergone airway evaluation in the PICU, 185 (22.6%) were diagnosed with airway anomalies, including structural lesions in 146 of 185 (78.9%), and dynamic problems were seen in 87 of 185 (47.0%). In this population, the explanatory factors associated with greater odds (odds ratio [OR]) of airway anomaly were premature birth (OR, 1.90; p = 0.002), genetic syndromes (OR, 2.60; p < 0.001), and in those with preoperative ventilator use (OR, 4.28; p < 0.001). In comparison to those without airway anomalies, the presence of airway anomalies was associated with higher hospital mortality (11.4% vs. 2.7%; p < 0.001), prolonged intubation days (8 d [1-27 d] vs. 1 d [1-5 d]; p < 0.001), longer PICU length of stay (23 d [8-81 d] vs. 7 d [4-18 d]; p < 0.001), and greater hazard of intermediate mortality (adjusted hazard ratio, 2.60; p = 0.001). CONCLUSIONS: In our single-center retrospective study, 2017-2020, between one-in-five and one-in-four of our postoperative CHD patients undergoing an airway evaluation had airway anomalies. Factors associated with greater odds of airway anomaly included, those with premature birth, or genetic syndromes, and preoperative ventilator use. Overall, in patients undergoing airway evaluation, the finding of an airway anomalies was associated with longer postoperative intubation duration and greater hazard of intermediate mortality.

Ginger essential oil prevents NASH progression by blocking the NLRP3 inflammasome and remodeling the gut microbiota-LPS-TLR4 pathway in mice.

BACKGROUND: Diet and gut microbiota contribute to non-alcoholic steatohepatitis (NASH) progression. High-fat diets (HFDs) change gut microbiota compositions, induce gut dysbiosis, and intestinal barrier leakage, which facilitates portal influx of pathogen-associated molecular patterns including lipopolysaccharides (LPS) to the liver and triggers inflammation in NASH. Current therapeutic drugs for NASH have adverse side effects; however, several foods and herbs that exhibit hepatoprotection could be an alternative method to prevent NASH. METHODS: We investigated ginger essential oil (GEO) against palm oil-containing HFDs in LPS-injected murine NASH model. RESULTS: GEO reduced plasma alanine aminotransferase levels and hepatic pro-inflammatory cytokine levels; and increased antioxidant catalase, glutathione reductase, and glutathione levels to prevent NASH. GEO alleviated hepatic inflammation through mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome and LPS/Toll-like receptor four (TLR4) signaling pathways. GEO further increased beneficial bacterial abundance and reduced NASH-associated bacterial abundance. CONCLUSION: This study demonstrated that GEO prevents NASH progression which is probably associated with the alterations of gut microbiota and inhibition of the LPS/TLR4/NF-κB pathway. Hence, GEO may offer a promising application as a dietary supplement for the prevention of NASH.

Real-world experience with CDK4/6 inhibitors in hormone receptor-positive metastatic and recurrent breast cancer: findings from an Asian population.

PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy have demonstrated significant clinical benefits in progression-free and overall survival. This study investigates the outcomes associated with two kinds of CDK4/6i in patients with hormone receptor (HR)-positive metastatic and relapsed breast cancer to inform real-world evidence of treatment strategies. METHODS: This retrospective study included 340 Taiwanese patients with HR-positive advanced breast cancer from the Taipei Veterans General Hospital, between 2018 and 2023. We analyzed patient characteristics, treatment strategies and outcomes associated with two CDK4/6i. The efficacy of patients who experienced economic burden and interrupted CDK4/6i treatment after 2 years of National Health Insurance (NHI) reimbursement was also investigated. RESULTS: Patients receiving ribociclib and palbociclib showed no significant differences in age, histology, body mass index(BMI), or pathologic status. The distribution of disease status and endocrine therapy partners was comparable between the two groups. Dose reduction was similar, while patients with palbociclib tended to discontinue CDK4/6i usage, and those with ribociclib tended to switch to the other CDK4/6i or endocrine partners. There was no significant difference in progression-free survival (PFS) between the two CDK4/6i in the first-line setting. Adverse prognostic factors were increasing HER2 IHC score, higher Ki-67 levels, visceral and liver metastasis, prior chemotherapy, and endocrine therapy resistance, while higher BMI, bone-only metastasis, and letrozole treatment were associated with a lower risk of progression. The limited follow-up time in our study was insufficient to assess the outcomes of patients treated with interrupted CDK4/6i for up to two years under the NHI reimbursement policy. CONCLUSION: Treatment outcomes between the two types of CDK4/6i did not differ significantly, indicating the safety and efficacy of CDK4/6i for the Asian population. Ribociclib and palbociclib showed similar efficacy in PFS in the real-world setting.

Sciatic nerve stimulation alleviates neuropathic pain and associated neuroinflammation in the dorsal root ganglia in a rodent model.

BACKGROUND: Satellite glial cells (SGCs) in the dorsal root ganglia (DRG) play a pivotal role in the formation of neuropathic pain (NP). Sciatic nerve stimulation (SNS) neuromodulation was reported to alleviate NP and reduce neuroinflammation. However, the mechanisms underlying SNS in the DRG remain unclear. This study aimed to elucidate the mechanism of electric stimulation in reducing NP, focusing on the DRG. METHODS: L5 nerve root ligation (NRL) NP rat model was studied. Ipsilateral SNS performed 1 day after NRL. Behavioral tests were performed to assess pain phenotypes. NanoString Ncounter technology was used to explore the differentially expressed genes and cellular pathways. Activated SGCs were characterized in vivo and in vitro. The histochemical alterations of SGCs, macrophages, and neurons in DRG were examined in vivo on post-injury day 8. RESULTS: NRL induced NP behaviors including decreased pain threshold and latency on von Frey and Hargreaves tests. We found that following nerve injury, SGCs were hyperactivated, neurotoxic and had increased expression of NP-related ion channels including TRPA1, Cx43, and SGC-neuron gap junctions. Mechanistically, nerve injury induced reciprocal activation of SGCs and M1 macrophages via cytokines including IL-6, CCL3, and TNF-α mediated by the HIF-1α-NF-κB pathways. SNS suppressed SGC hyperactivation, reduced the expression of NP-related ion channels, and induced M2 macrophage polarization, thereby alleviating NP and associated neuroinflammation in the DRG. CONCLUSIONS: NRL induced hyperactivation of SGCs, which had increased expression of NP-related ion channels. Reciprocal activation of SGCs and M1 macrophages surrounding the primary sensory neurons was mediated by the HIF-1α and NF-κB pathways. SNS suppressed SGC hyperactivation and skewed M1 macrophage towards M2. Our findings establish SGC activation as a crucial pathomechanism in the gliopathic alterations in NP, which can be modulated by SNS neuromodulation.

Dendritic cell vaccine for glioblastoma: an updated meta-analysis and trial sequential analysis.

BACKGROUND: Dendritic cell (DC) vaccine is an emerging immunotherapy that could potentially improve glioblastoma survival. The first phase III clinical trial of DC vaccine was recently published. This meta-analysis aims to update and reappraise existing evidence on the efficacy of DC vaccine in patients with glioblastoma. METHODS: We searched PubMed, Embase, and Cochrane Library for clinical trials of DC vaccine for glioblastoma. The quality of the studies was assessed using the RoB 2.0 and ROBINS-I tools. The results of overall survival (OS) and progression-free survival (PFS) were pooled using hazard ratios (HRs) with corresponding 95% confidence intervals (CI). Summary effects were evaluated using random effects models. Trial sequential analysis (TSA) was performed. RESULTS: Seven clinical trials involving 3,619 patients were included. DC vaccine plus standard care was associated with significantly improved OS (HR = 0.71; 95% CI, 0.57 - 0.88) and PFS (HR = 0.65; 95% CI, 0.43 - 0.98). In the subgroup of newly diagnosed glioblastoma, DC vaccine was associated with improved PFS (HR = 0.59; 95% CI, 0.39 - 0.90). TSA of OS showed that the cumulative z-score line for the DC vaccine crossed the benefit boundary and reached the required sample size. TSA of PFS and subgroup analysis of newly diagnosed glioblastoma showed that the required sample size was not reached. CONCLUSIONS: This updated meta-analysis, which included the first phase III trial of a DC vaccine for glioblastoma, demonstrated that the DC vaccine was associated with improved OS. Moreover, TSA showed that the required sample size was reached, indicating a true-positive result. Future studies are required for patient subgroups with newly diagnosed and recurrent glioblastoma.

Estimating the risk of major adverse cardiac events following radiotherapy for left breast cancer using a modified generalized Lyman normal-tissue complication probability model.

BACKGROUND: We introduced an adapted Lyman normal-tissue complication probability (NTCP) model, incorporating clinical risk factors and censored time-to-event data, to estimate the risk of major adverse cardiac events (MACE) following left breast cancer radiotherapy (RT). MATERIALS AND METHODS: Clinical characteristics and MACE data of 1100 women with left-side breast cancer receiving postoperative RT from 2005 to 2017 were retrospectively collected. A modified generalized Lyman NTCP model based on the individual left ventricle (LV) equivalent uniform dose (EUD), accounting for clinical risk factors and censored data, was developed using maximum likelihood estimation. Subgroup analysis was performed for low-comorbidity and high-comorbidity groups. RESULTS: Over a median follow-up 7.8 years, 64 patients experienced MACE, with higher mean LV dose in affected individuals (4.1 Gy vs. 2.9 Gy). The full model accounting for clinical factors identified D50 = 43.3 Gy, m = 0.59, and n = 0.78 as the best-fit parameters. The threshold dose causing a 50 % probability of MACE was lower in the high-comorbidity group (D50 = 30 Gy) compared to the low-comorbidity group (D50 = 45 Gy). Predictions indicated that restricting LV EUD below 5 Gy yielded a 10-year relative MACE risk less than 1.3 and 1.5 for high-comorbidity and low-comorbidity groups, respectively. CONCLUSION: Patients with comorbidities are more susceptible to cardiac events following breast RT. The proposed modified generalized Lyman model considers nondosimetric risk factors and addresses incomplete follow-up for late complications, offering comprehensive and individualized MACE risk estimates post-RT.

Role of calcification in J-CTO score: a viewpoint of intraplaque guidewire tracking techniques.

BACKGROUND: As the burden and distribution of calcification within chronic total occlusion (CTO) lesions can be diverse, its effect on CTO recanalization using multiple devices and techniques is debatable. This study investigated the role of calcification in wiring-based intraplaque tracking techniques for CTO recanalization. METHODS: A modified J-CTO score without counting calcification was used to analyze the procedures of 458 consecutive patients who underwent CTO interventions. Failed guidewire crossing and intraplaque tracking were considered procedural failures. Recanalization time details were analyzed for successful procedures. RESULTS: In patients with calcified CTO, the rate of procedural success only significantly declined to be lower than that of noncalcified CTO when the modified J-CTO score was ≥3 (77% vs. 94%, p = 0.008). In 422 patients with successful procedures, the presence of calcification was irrelevant to guidewire crossing time, but was accompanied with longer time from guidewire cross to final angiogram when the modified J-CTO score was 1-2 (53 ± 35 vs. 35 ± 17 [noncalcified] min, p < 0.001). Multivariate analyses showed that calcification was independently associated with procedural failure (odds ratio [OR] = 5.1, 95% confidence interval [CI] = 1.4-18.3) in lesions with modified J-CTO ≥3, and prolonged angioplasty/stenting procedures >60 min (OR = 4.8, 95% CI = 2.2-10.2) in successfully recanalized lesions with modified J-CTO score 1-2. CONCLUSIONS: Using intraplaque guidewire tracking, calcification was unfavorable for very difficult CTO lesions, and caused prolongation of angioplasty time for lesions with moderate complexity. This suggested that the role of calcification in the J-CTO score could be altered when different recanalization techniques were applied for CTO interventions.

Since several commonly used scoring systems for grading the difficulty of CTO-PCI are derived from multiple recanalization techniques and devices, their application should be fundamental. However, most CTO interventionists usually have their own favored recanalization techniques in the real-world. As one of the parameters of J-CTO score, the findings of the study suggest that the interpretation of calcification during CTO-PCI could be altered and should be cautious if different recanalization technique was used.

Evaluation of glucose-lowering medications in older people: a comprehensive systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is increasingly being diagnosed in older adults. Our objective is to assess the advantages and potential drawbacks of different glucose-lowering medications in this specific population. METHODS: A network meta-analysis was conducted to identify randomized controlled trials that examined patient-centered outcomes in adults aged ≥65 years with T2DM. We searched PubMed, Cochrane CENTRAL, and Embase up to September 23, 2023. Quality of eligible studies were assessed using the Cochrane RoB 2.0 tool. RESULTS: A total of 22 trials that involved 41 654 participants were included, incorporating sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, sulfonylureas (SU) and acarbose. Our findings reveal that GLP-1RAs reduce the risk of major adverse cardiovascular events (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.97) and body weight (mean difference [MD], -3.87 kg; 95% CI, -5.54 to -2.21). SGLT2 inhibitors prevent hospitalization for heart failure (RR, 0.66; 95% CI, 0.57 to 0.77), renal composite outcome (RR, 0.69; 95% CI, 0.53 to 0.89), and reduce body weights (MD, -1.85 kg; 95% CI, -2.42 to -1.27). SU treatment increases the risk of any hypoglycaemia (RR, 4.19; 95% CI, 3.52 to 4.99) and severe hypoglycaemia (RR, 7.06; 95% CI, 3.03 to 16.43). GLP-1RAs, SGLT2 inhibitors, metformin, SU and DPP-4 inhibitors are effective in reducing glycaemic parameters. Notably, the number of treatments needed decreases in most cases as age increases. CONCLUSIONS: Novel glucose-lowering medications with benefits that outweigh risks should be prioritized for older patients with diabetes.

Differences between atrial fibrillation diagnosed before and after stroke: A large real-world cohort study.

The clinical characteristics and long-term outcomes of patients with ischemic stroke (IS) and atrial fibrillation detected after stroke (AFDAS) have not been clearly established. Previous studies evaluating patients with AFDAS were limited by the low prescription rates of anticoagulants and short follow-up periods. Consecutive patients hospitalized for IS between 2014 and 2017 were identified from a National Health Insurance Research Database. The included patients were categorized into three groups: (1) known diagnosis of AF (KAF) before the index stroke, (2) AFDAS, and (3) without AF (non-AF). Univariable and multivariable Cox regression analyses were performed to estimate the hazard ratio (HR) for independent variables and recurrent IS, hemorrhagic stroke, or all-cause mortality. We identified 158,909 patients with IS of whom 16,699 (10.5%) had KAF and 7,826 (4.9%) had AFDAS. The patients with AFDAS were younger, more often male, and had lower CHA2DS2-VASc scores (3.8 ± 1.9 versus 4.9 ± 1.8, p < 0.001) than the patients with KAF. Anticoagulant treatment significantly reduced the risks of all outcomes. The standardized mortality rates were 40.4, 28.6, and 18.4 (per 100 person-years) for the patients with KAF, AFDAS, and non-AF, respectively. Compared with AFDAS, KAF was associated with lower risks of recurrent IS [hazard ratio (HR): 0.91, 95% confidence interval (CI): 0.86-0.97, p < 0.01] and hemorrhagic stroke (HR: 0.88, 95% CI: 0.79-0.99, p < 0.01) and a higher risk of all-cause mortality (HR: 1.11, 95% CI: 1.07-1.16, p < 0.001). The risks of recurrent IS and hemorrhagic stroke were higher and of all-cause mortality was lower for patients with AFDAS than with KAF. There is a strong need to refine treatment modalities to reduce the high mortality in patients with KAF and AFDAS.

Hub metastatic gene signature and risk score of breast cancer patients with small tumor sizes using WGCNA.

BACKGROUND: Breast cancer (BC) is the most common cancer in women and accounts for approximately 15% of all cancer deaths among women globally. The underlying mechanism of BC patients with small tumor size and developing distant metastasis (DM) remains elusive in clinical practices. METHODS: We integrated the gene expression of BCs from ten RNAseq datasets from Gene Expression Omnibus (GEO) database to create a genetic prediction model for distant metastasis-free survival (DMFS) in BC patients with small tumor sizes (≤ 2 cm) using weighted gene co-expression network (WGCNA) analysis and LASSO cox regression. RESULTS: ABHD11, DDX39A, G3BP2, GOLM1, IL1R1, MMP11, PIK3R1, SNRPB2, and VAV3 were hub metastatic genes identified by WGCNA and used to create a risk score using multivariable Cox regression. At the cut-point value of the median risk score, the high-risk score (≥ median risk score) group had a higher risk of DM than the low-risk score group in the training cohort [hazard ratio (HR) 4.51, p < 0.0001] and in the validation cohort (HR 5.48, p = 0.003). The nomogram prediction model of 3-, 5-, and 7-year DMFS shows good prediction results with C-indices of 0.72-0.76. The enriched pathways were immune regulation and cell-cell signaling. EGFR serves as the hub gene for the protein-protein interaction network of PIK3R1, IL1R1, MMP11, GOLM1, and VAV3. CONCLUSION: Prognostic gene signature was predictive of DMFS for BCs with small tumor sizes. The protein-protein interaction network of PIK3R1, IL1R1, MMP11, GOLM1, and VAV3 connected by EGFR merits further experiments for elucidating the underlying mechanisms.

Multicenter registry of multisystem inflammatory syndrome in children (MIS-C) and Paired comparison with Kawasaki disease.

OBJECTIVES: This study aimed to identify clinical characteristics to differentiate multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD) in Taiwan, an island with a delayed cluster of MIS-C and a high incidence of KD. Additionally, we studied risk factors for developing severe complications in patients with MIS-C. METHODS: We conducted a retrospective, multicenter, cohort, and observational study that linked data on patients with MIS-C between May and December 2022 and patients with KD between 2019 and 2021 from 12 medical centers. Hemodynamic compromise, defined as the need for inotropic support or fluid challenge, was recorded in patients with MIS-C. We also evaluated maximal coronary Z-scores before treatment and one month after disease onset. RESULTS: A total of 83 patients with MIS-C and 466 patients with KD were recruited. A 1:1 age and gender-matched comparison of 68 MIS-C and KD pairs showed that MIS-C patients had a lower percentage of positive BCG red halos, lower leukocyte/platelet counts, more gastrointestinal symptoms, and a higher risk of hemodynamic compromise. In Taiwan, 38.6% of MIS-C patients experienced hemodynamic compromise, with presence of conjunctivitis and elevated levels of procalcitonin (>1.62 ng/mL) identified as independent risk factors. CONCLUSIONS: We identified two independent risk factors associated with hemodynamic compromise in MIS-C patients. The comparison between matched MIS-C and KD patients highlighted significant differences in clinical presentations, like BCG red halos, which may aid in the differential diagnosis of the two disease entities, especially in regions with a high incidence rate of KD.

Association of PCSK9 inhibitors with mortality: insights from a retrospective cohort analysis.

BACKGROUND AND AIMS: PCSK9 inhibitors are effective in reducing cardiovascular events, but their impact on all-cause mortality and medical utilization compared to statins is unclear. This study investigated PCSK9 inhibitor use and its impact on mortality and medical utilization versus statins, using TriNetX database data with up to 9 years of follow-up. METHODS AND RESULTS: This retrospective cohort study analyzed TriNetX data spanning July 1, 2015, to December 31, 2023, including 79 194 PCSK9 inhibitor users (alirocumab, evolocumab, inclisiran) and 5 437 513 statin users with hyperlipidemia. The primary outcomes were all-cause mortality and medical utilization, including hospital inpatient services, emergency department visits, critical care, and mechanical ventilation. Propensity score matching showed that PCSK9 inhibitor use was associated with a 28.3% lower risk of all-cause mortality (adjusted hazard ratio [aHR] 0.717, 95% CI: 0.673-0.763) and significant reductions in medical utilization (hospital inpatient services usage: aHR 0.692, 95% CI: 0.664-0.721; emergency department services: aHR 0.756, 95% CI: 0.726-0.788; critical care services: aHR 0.619, 95% CI: 0.578-0.664; and mechanical ventilation: aHR 0.537, 95% CI: 0.484-0.596) compared to statins. These findings were consistent across various demographics and clinical subgroups. The sensitivity analyses supported the robustness of the findings. CONCLUSION: PCSK9 inhibitors significantly reduced all-cause mortality and medical utilization compared to statins, suggesting their important role in dyslipidemia management, particularly for statin-naïve or intolerant patients. Further research, including randomized controlled trials, is needed to confirm these findings and explore the underlying mechanisms.