Transarterial chemoembolization combined with molecular targeted agents plus immune checkpoint inhibitors for unresectable hepatocellular carcinoma beyond the up-to-seven criteria: a propensity score-matching analysis.

PURPOSE: Not all patients benefit from transarterial chemoembolization (TACE) due to the heterogeneity of the tumour burden in intermediate-stage hepatocellular carcinoma (HCC). To compare the outcomes of transarterial chemoembolization (TACE) combined with molecular-targeted agents plus immune checkpoint inhibitors (TACE-MTAs-ICIs) with those of TACE for patients with unresectable hepatocellular carcinoma (uHCC) that were beyond the up-to-seven criteria. PATIENTS AND METHODS: Between January 2019 and July 2022, 130 patients diagnosed with uHCC beyond the up-to-seven criteria were retrospectively identified, including 47 patients who received TACE-MTAs-ICIs and 83 patients who received TACE alone. The primary endpoints were overall survival (OS) and progression-free survival (PFS); the secondary endpoints included tumour response and adverse events (AEs). RESULTS: There were 43 matched patients. The median OS and PFS times in the TACE-MTAs-ICIs group were significantly longer than those in the TACE group (OS: 27.2 vs. 15.9 months, p = 0.007; PFS: 15.4 months vs. 4.8 months, p < 0.001). The objective response rate (ORR) in the TACE-MTAs-ICIs group was higher than that in the TACE group (65.1% vs. 37.2%, p = 0.010). Reversible AEs (grade 3 or 4) occurred differently in TACE-MTAs-ICIs and TACE groups (83.7% vs. 51.2%, p = 0.001). Univariate and multivariate analyses revealed that TACE-MTAs-ICIs treatment was an independent favourable prognostic factor for both PFS and OS (p < 0.001). CONCLUSION: For uHCC patients beyond the up-to-seven criteria, TACE-MTAs-ICIs provided superior ORR and OS. Early combined TACE and systemic treatment should shift for patients who are beyond these criteria.

The ORR and median OS reached 65.1% and 27.2 months, respectively, in the treatment model of TACE-MTAs-ICIs for patients with unresectable HCC that were beyond the up-to-seven criteria.TACE-TKI-ICI yielded a synergistic effect on these patients and was an independent favourable prognostic factor for PFS and OS.

Serum 25-hydroxyvitamin D, genetic susceptibility and abdominal aortic aneurysm risk.

CONTEXT: The association of serum 25-hydroxyvitamin D [25(OH)D] and genetic polymorphisms of the vitamin D receptor (VDR), and the vitamin D binding protein (VDBP) with incident abdominal aortic aneurysm (AAA) remains uncertain. OBJECTIVE: To investigate whether serum 25(OH)D, genetic polymorphisms of VDR and VDBP, genetic susceptibility to AAA, and the interactions among these factors influence the risk of incident AAA. DESIGN: Retrospective cohort study. SETTING: UK Biobank. PARTICIPANTS: 447,529 participants without a diagnosis of prevalent aortic aneurysm or aortic dissection at baseline. EXPOSURE: Serum 25(OH)D concentration. MAIN OUTCOME MEASURE: Incident AAA. RESULTS: During a median follow-up of 12.5 years, 2,042 participants developed incident AAA. A significant inverse association between serum 25(OH)D and incident AAA was observed (per SD increment, HR, 0.92; 95%CI, 0.88-0.96), which was particularly pronounced in older individuals and those without diabetes (both P for interaction <0.05). Compared to participants with serum 25(OH)D ≥ 50 nmol/L, those with serum 25(OH)D between 25 and <50 nmol/L and <25 nmol/L exhibited a significant higher risk of incident AAA. In the 371,621 participants with genetics assessment, individuals carrying AA alleles of ApaI SNP had a significant increased risk of incident AAA compared to those carrying CC alleles (HR, 1.16; 95%CI, 1.02-1.32). The inverse association between serum 25(OH)D and incident AAA was stronger in individuals with intermediate or high genetic risk for AAA (P for interaction = 0.048). CONCLUSIONS: There was a significant inverse association between serum 25(OH)D and AAA incidence, particularly among individuals with higher genetic risk for AAA, older age, and without diabetics.

Association of dietary manganese intake with new-onset chronic kidney disease in participants with diabetes.

BACKGROUND: We explored the association of dietary manganese (Mn) with new-onset chronic kidney disease (CKD) in participants with diabetes on different glycemia control status and potential mechanisms. METHODS: The study included 7248 adults with diabetes from the UK Biobank who had complete dietary data and were free of CKD at baseline. Dietary information was collected by the online 24-h diet recall questionnaires. The primary outcome was new-onset CKD. RESULTS: 565 (7.8 %) participants developed new-onset CKD during a median follow-up of 11.96 years. Overall, there was a significantly inverse relationship of dietary Mn intake with new-onset CKD in individuals with diabetes at glycated hemoglobin (HbA1c) ≥6.5 % (per SD increment, HR [95%CI]: 0.79 [0.68-0.91]), but not in people with diabetes at HbA1c <6.5 % (per SD increment, HR [95%CI]: 1.07 [0.90-1.29]; P for interaction = 0.004). In individuals with diabetes at HbA1c ≥6.5 %, body mass index and waist circumference significantly mediated the association between dietary Mn intake and new-onset CKD, with mediated proportions of 17.5 % and 17.4 %, respectively. CONCLUSIONS: Higher dietary Mn intake was significantly associated with a lower new-onset CKD risk in participants with diabetes at poor glycemic control status. The inverse association was mainly mediated by obesity. If further confirmed, our findings underscore the importance of maintaining adequate dietary Mn intake for the primary prevention of new-onset CKD in patients with diabetes, especially those with poor glycemic control.

Three-layer circulation in the world deepest hadal trench.

The Challenger Deep (CD) is the deepest known hadal trench in the world. Due to challenges in data sampling at extreme ocean depths, the Lower Circumpolar Deep Water (LCDW) transport and ocean circulation structure in the CD remain unclear. By analyzing data from an extra-deep current meter mooring array, here we find a three-layer circulation in the CD, transitioning downward from westward LCDW flow (about -1.866 ± 2.953 Sv, 1 Sv = 106 m3/s) to cyclonic circulation, and then to anticyclonic circulation. The westward flow reverses its direction during summer, giving evidence for bidirectional connectivity of deep-sea basins, while the cyclonic-anticyclonic circulation is relatively steady. The LCDW intrusion, local topography and turbulent mixing are crucial for modulating the three-layer circulation. Turbulent mixing plays a key role in driving the anticyclonic circulation. Our findings provide insights for understanding the hydrodynamic environment in the ocean's deepest areas.

Evaluation of the Association Between Coffee Consumption, Including Type (Instant, Ground), and Addition of Milk or Sweeteners and New-Onset Hypertension and Potential Modifiers.

BACKGROUND: The association between coffee consumption and incident hypertension remained inconsistent. OBJECTIVE: This study aimed to examine the association of consumption of coffee, including different types (instant and ground) and with different additives, with new-onset hypertension, and evaluate whether genetic variation in caffeine metabolism and inflammation may modify the association. DESIGN: This study utilized a prospective cohort design. PARTICIPANTS/SETTING: A total of 98 765 participants free of hypertension enrolled in the UK Biobank between 2006 and 2010 were included. Dietary coffee consumption was collected using 24-hour dietary recall questionnaires. MAIN OUTCOME MEASURES: The study outcome was new-onset hypertension, ascertained by self-reported medical conditions, hospital inpatient records, death registers, and primary care records. STATISTICAL ANALYSES PERFORMED: Cox proportional hazards models were used to estimate hazard ratio and 95% CI. Potential modifying effects were assessed by likelihood ratio testing. RESULTS: During a median follow-up of 12.1 years, 7090 (7.2%) new-onset cases of hypertension were documented. Overall, regardless of coffee type (instant or ground) and whether adding milk to coffee, there was a U-shaped association between unsweetened coffee consumption and new-onset hypertension, with a 14% to 18% reduction of hypertension risk at >1 to ≤4 drinks per day, whereas a null association was observed between sweetened coffee consumption and the risk of new-onset hypertension. Relative to coffee nonconsumers, the adjusted hazard ratio (95% CI) of new-onset hypertension for participants who drinking unsweetened coffee 1 or fewer, >1 to 2, >2 to 3, >3 to 4, and >4 drinks/day were 0.92 (95% CI 0.85 to 1.00), 0.82 (95% CI 0.76 to 0.89), 0.86 (95% CI 0.79 to 0.96), 0.86 (95% CI 0.77 to 0.96), and 0.88 (95% CI 0.78 to 0.99), respectively. Moreover, a stronger inverse association between moderate consumption of unsweetened coffee and new-onset hypertension was found in participants with higher C-reactive protein levels (P for interaction =.012), whereas an individual's genetic variation in caffeine metabolism did not significantly modify the association (P for interaction = .453). CONCLUSIONS: Regardless of the type of coffee (instant or ground) or the addition of milk to coffee, moderate consumption of unsweetened coffee (>1 to ≤4 drinks/day), but not sweetened coffee, was associated with a lower risk of new-onset hypertension.

Radiological features on high-resolution MR imaging predicts successful recanalization in patients with symptomatic chronic intracranial large artery occlusion.

RATIONALE AND OBJECTIVES: Endovascular recanalization has been attempted in patients with symptomatic chronic intracranial large artery occlusion (CILAO), however, the heterogeneity of recanalization outcomes present challenges for the clinical application. OBJECTIVE: To determine the radiological features on high-resolution MR imaging (HR-MRI) for predicting successful recanalization of symptomatic CILAO. METHODS: Seventy-three patients with symptomatic CILAO who underwent endovascular recanalization at our center were retrospectively analyzed. Patients' clinical information, HR-MRI characteristics, procedural results, and outcomes were recorded. Factors related to successful recanalization were analyzed by univariate and multivariate analyses. RESULTS: Technical success was achieved in 61 (83.6%) patients, with a complication rate of 13.7% (10/73). Based on multivariate analysis, responsible occluded artery (middle cerebral artery (MCA) trunk versus intracranial internal carotid artery (ICA), P = 0.004; MCA trunk versus intracranial vertebrobasilar artery (VBA), P = 0.010), occlusion with residual lumen (P = 0.036), occlusion with marked plaque enhancement (P = 0.011), and shorter occlusion length (≤10.2 mm versus >10.2 mm, P = 0.008) were identified as independent positive predictors of successful recanalization. Patients were assigned score points according to the coefficients of the prediction model, and the technical success rates were 50.0%, 83.3%, 95.5%, and 100% in patients with score ≤ 2, 3, 4, and ≥ 5 points, respectively. CONCLUSIONS: The HR-MRI modality may be valuable in identifying candidates for endovascular recanalization of symptomatic CILAO. MCA trunk occlusion, occlusion with residual lumen, occlusion with marked plaque enhancement and shorter occlusion length on HR-MRI appear to be significantly associated with the success of recanalization.

Immune cell dynamics and the impact on the efficiency of transvascular antitumor interventional therapies in hepatocellular carcinoma patients.

Objective: This study investigates the impact of transvascular antitumor interventional therapies on immune cell dynamics and its correlation with disease control and progression-free survival (PFS) in hepatocellular carcinoma (HCC) patients. Methods: A single-center observational case-control study was conducted with 119 HCC patients. Transvascular antitumor interventional therapy were administered based on patient-specific evaluations. Peripheral blood samples were collected before and within 28 days after the first treatment to analyze lymphocyte subsets and other immune cells. Results: Higher counts of total white blood cells (WBCs), lymphocytes, monocytes, and basophils were significantly associated with disease control rate. Subgroup analysis revealed that abnormal BMI, diabetes, infection, and multiple lesions were significantly associated with T cell abnormalities. Age, abnormal BMI, hypertension, and abnormal AFP were linked to total T cell abnormalities. NK cells, B cells, Th cells, Tc/Ts cells, and CD4/CD8 ratios did not show significant differences in PFS probabilities. Conclusion: Higher counts of WBCs, lymphocytes, monocytes, and basophils, play a crucial role in the effectiveness of HCC interventional therapy.

A new angiographic scoring for grading the difficulty of recanalization for symptomatic non-acute middle cerebral artery occlusions.

Background: Endovascular recanalization is a feasible option for treating symptomatic non-acute middle cerebral artery occlusion (MCAO) patients. Hence, we aimed to establish a new angiographic scoring to grade the recanalization difficulty of MCAO to determine the suitable patients for endovascular treatment. Methods: We retrospectively analyzed a total of 113 consecutive recurrent symptomatic non-acute MCAO patients who underwent endovascular recanalization from July 2015 to August 2021 in four Chinese comprehensive stroke centers. All patients were reappraised using a new angiographic scoring based on the stump morphology, the MCA occlusion length, MCA bend, and the distal vascular bed of MCAO. We used the final results to establish the patients' outcomes. Results: The total successful recanalization and perioperative complication rates were 83.2% (94/113) and 15.9% (18/113), respectively. No deaths occurred within 30 days. Moreover, 96.9, 90, 87.5, 52.6, and 50% of the patients achieved recanalization with scores of 0, 1, 2, 3, and 4 (p < 0.001), respectively. However, the perioperative complication rate showed the opposite trend. (3.1% vs. 7.5% vs. 6.3% vs. 52.6% vs. 50%; p < 0.001). The median time of successful microwire crossing of the occlusion lesion (TMO) in the score 0 group was shorter than the other groups (2 min, 9 min, 8.5 min, 14 min, and 20 min; p < 0.001). When a score of 2 was used as the optimal cut-off point, the sensitivity and specificity were 86.2 and 63.2%, respectively. Conclusion: The new angiographic scoring can effectively predict the successful recanalization rate, perioperative complication rate, and TMO of endovascular recanalization for non-acute MCAO. It can also be used as an effective clinical evaluation tool to determine the suitable non-acute MCAO patients for recanalization, especially with a score ≤ 2.

Chongrenside D from Smilax china L protects against inflammation-induced joint destruction via inhibiting osteoclastogenesis.

Background: Bone-destructive diseases including rheumatoid arthritis (RA), osteoporosis, and bone metastases, are increasingly prevalent and worrisome due to the over-activated of osteoclasts. Chongrenside D (CGD) is a furostanol saponin extracted from Smilax china L, which has been demonstrated to have anti-inflammatory properties in our previous research. However, its effect on rheumatoid arthritis, especially on osteoclast differentiation and bone destruction has not yet been investigated. Methods: We evaluated the toxicity of CGD on the cell we used, RANKL-induced osteoclast formation, bone resorption activity, and osteoclast-specific genes or protein expression using bone marrow-derived monocytes (BMMs) -derived osteoclasts. Furthermore, the protective function of CGD on the paws of osteolytic mice was carried out using micro-CT, H&E, TRAP staining, as well as real-time PCR, and western blotting. Inflammatory cytokine levels were conducted through ELISA assay. The relative signaling pathways were investigated using western blotting, immunofluorescence microscopy and real-time PCR. Results: CGD notably inhibited RANKL-induced osteoclast formation, and suppressed the expression of osteoclast markers and actin ring formation, thus attenuating its bone resorption activity. For in vivo work, CGD protected against joint bone destruction induced by LPS, increased trabecular number and thickness, and reduced trabecular separation. CGD also inhibited the levels of inflammatory cytokines IL-6and TNF-α, improved the integrity of joint bones and decreased TRAP-positive staining area. The mechanistic study indicated that CGD down-regulated MMP9 and FAK-Src signaling, which were crucial for the resorption function of osteoclasts. CGD also inhibited MAPK pathway-mediated cell differentiation and survival, finally resulting in weak osteoclastogenesis. Conclusion: CGD exerts a significant anti-osteolytic activity both in vitro and in vivo by inhibiting RANKL-induced osteoclastogenesis and function. Consequently, our study indicated that CGD may have a potential therapeutic role in the precaution of osteolytic bone disease.

Longitudinal Patterns of Ankle-Brachial Index and Their Association With Progression of CKD in Patients With Type 2 Diabetes and Elevated Body Mass Index.

RATIONALE & OBJECTIVE: Ankle-brachial index (ABI) is used to screen for vascular complications in the setting of diabetes. This study sought to examine the relationship of longitudinal ABI data and chronic kidney disease (CKD) progression in patients with type 2 diabetes (T2D) and elevated body mass index (BMI). STUDY DESIGN: A post-hoc analysis of the Look AHEAD trial. SETTING & PARTICIPANTS: This study included 3,631 participants in the Look AHEAD trial with a baseline glomerular filtration rate (eGFR) >60 ml/min/1.73 m2. EXPOSURES: Average ABI and average annual change in ABI were calculated based on annual ABI measurements during the first 4 years of the study. OUTCOME: CKD progression, defined as kidney failure requiring maintenance dialysis or the occurrence of eGFR<60 ml/min/1.73 m2 with a drop of ≥30% at a follow-up visit relative to the first eGFR measurement. ANALYTICAL APPROACH: Restricted cubic spline and Cox proportional hazards models were fit to estimate associations and to explore non-linearity. RESULTS: Over a median follow-up of 10.1 years, 1,051 participants developed CKD progression. There was a reversed J-shaped relationship of CKD progression with average ABI (when ABI <1.17: HR (per SD decrement), 1.23; 95%CI, 1.06-1.42; when ABI ≥ 1.17: HR (per SD increment), 1.10; 95%CI, 1.00-1.22) and average annual change in ABI (when change in ABI <-0.007: HR (per SD decrement), 1.37; 95%CI, 1.12-1.66; when change in ABI ≥-0.007: HR (per SD increment), 1.13; 95%CI, 1.03-1.24). LIMITATIONS: Observational study, potential unmeasured confounding. CONCLUSIONS: Low and high average ABI, even at clinically normal values, as well as decreasing and increasing average annual ABI, were associated a higher risk of CKD progression in patients with T2D and elevated BMI. Monitoring ABI and its changes over time may facilitate CKD risk stratification in patients with T2D.

Self-expanding metal stent for relieving the stricture after endoscopic injection for esophageal varices.

BACKGROUND: Esophageal stricture is one of the complications after esophageal varices sclerotherapy injection (ESI), and the incidence rate is between 2%-10%. AIM: To explore the efficacy of self-expanding metal stent (SEMS) for the stricture after endoscopic injection with cyanoacrylate (CYA) and sclerotherapy for esophageal varices. METHODS: We retrospectively analyzed the efficacy of SEMS to improve the stricture after endoscopic injection with CYA and sclerotherapy for esophageal varices in 4 patients from February 2023 to June 2023. RESULTS: The strictures were improved in four patients after stenting. The stent was removed after two weeks because of chest pain with embedding into esophageal mucosa in one patient. The stent was removed after one month, however, the stent was reinserted because of the strictures happening again in two patients. The stent was removed after three months, however, the stent was reinserted because of the strictures happening again in one patient. The stent embedded into esophageal mucosa in three patients. There were 3 patients suffered reflux esophagitis, and the acid reflux was relieved by taking hydrotalcite. There was no other complication of esophageal perforation, bleeding from varices or infection. CONCLUSION: SEMS may relieve the stricture which happened after endoscopic injection with CYA and sclerotherapy for esophageal varices. However, when we should remove the stent still needs to be explored.

Altered Liver Enzyme Markers in Patients with Asymptomatic, and Mild Omicron Infection: A Retrospective Study.

Purpose: The emergence of the SARS-CoV-2 Omicron variant has posed a significant global public health challenge. Elucidating the laboratory profiles of individuals infected with this variant is crucial for assessing organ damage. This study aimed to investigate the variations in liver function tests and their correlation with demographic characteristics and inflammatory markers in patients with early Omicron variant infections. Patients and Methods: A retrospective cohort study was conducted on 1133 mild or asymptomatic COVID-19 cases at Tianjin First Central Hospital. Data on age, gender, body mass index (BMI), and serum markers were collected and analyzed. Statistical analyses were performed using SPSS software, version 24.0. Results: Abnormal liver function parameters, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin (TBIL), were observed in 314 (27.71%) patients. "Hepatocellular type" was identified in 56 (4.94%) patients, "cholestatic type" in 185 (16.33%) patients, and "mixed type" in 73 (6.44%) patients. In the mixed group, we observed a pronounced elevation in the levels of ALT, AST, and GGT. Moreover, the hepatocellular group exhibited a statistically significant increase in AST and ALT concentrations relative to both the normal and cholestatic groups. Notably, the cholestatic group demonstrated a substantial increment in ALP levels. Males had a significantly higher prevalence of "abnormal liver enzyme markers" compared to females. Patients with "abnormal liver enzyme markers" exhibited significantly decreased immunoglobulin G (IgG) levels and elevated levels of inflammatory markers, including procalcitonin (PCT), interleukin-6 (IL6), as well as C-reactive protein (CRP) compared to normal group. Logistic regression analysis revealed that male gender and PCT levels were significantly associated with the risk of abnormal liver enzyme markers. Patients in hepatocellular group were likely accompanied with high CRP levels, whereas those in the cholestatic type were associated with high IL6 levels. Conclusion: Early Omicron infection might cause liver stress response. Elevated liver enzyme marker levels were correlated with age, gender, inflammatory factors, and IgG.

[Spatiotemporal Variation Characteristics of Ozone and Identification of Key Influencing Factors Based on Random Forest Model： A Case Study of Chuzhou City].

The cause of ozone pollution is a complex scientific problem. Studying the spatiotemporal variation characteristics of O3 at different time scales and analyzing the key influencing factors of O3 concentration is of great significance for the precise formulation of urban air pollution control measures and the improvement of urban air quality. Based on the analysis of the spatiotemporal variation characteristics of O3 concentration in Chuzhou City, we studied the 12 ozone-influencing factors of meteorology and pollutants at multiple time scales using Spearman correlation analysis and a random forest model. The results showed that： ① The O3 pollution level of Chuzhou City showed an aggravating trend, and the O3 concentration distribution showed a spatial pattern of "high in the southeast and low in the northwest." ② From February to May, SO2 concentration had a strong impact on the increase in O3 concentration. From June to September, PM2.5 and PM10 were significantly positively correlated with ozone and had a greater impact. ③ Relative humidity, temperature, and wind speed had a significant impact on O3, whereas barometric pressure and hourly rainfall had a weak impact. ④ The O3 pollution mechanism in Chuzhou City changed from "pollutant-controlled" to "meteorology-controlled." ⑤ Among meteorological and pollutant factors, the three influencing factors that had the greatest influence on O3 concentration were temperature, wind speed, and relative humidity, with PM10 concentration, PM2.5 concentration, and SO2 concentration also contributing. All of the above six influencing factors had a significant nonlinear relationship with the O3 concentration.

Plasma proteomics for risk prediction of Alzheimer's disease in the general population.

We aimed to develop and validate a protein risk score for predicting Alzheimer's disease (AD) and compare its performance with a validated clinical risk model (Cognitive Health and Dementia Risk Index for AD [CogDrisk-AD]) and apolipoprotein E (APOE) genotypes. The development cohort, consisting of 35,547 participants from England in the UK Biobank, was randomly divided into a 7:3 training-testing ratio. The validation cohort included 4667 participants from Scotland and Wales in the UK Biobank. In the training set, an AD protein risk score was constructed using 31 proteins out of 2911 proteins. In the testing set, the AD protein risk score had a C-index of 0.867 (95% CI, 0.828, 0.906) for AD prediction, followed by CogDrisk-AD risk factors (C-index, 0.856; 95% CI, 0.823, 0.889), and APOE genotypes (C-index, 0.705; 95% CI, 0.660, 0.750). Adding the AD protein risk score to CogDrisk-AD risk factors (C-index increase, 0.050; 95% CI, 0.008, 0.093) significantly improved the predictive performance for AD. However, adding CogDrisk-AD risk factors (C-index increase, 0.040; 95% CI, -0.007, 0.086) or APOE genotypes (C-index increase, 0.000; 95% CI, -0.054, 0.055) to the AD protein risk score did not significantly improve the predictive performance for AD. The top 10 proteins with the highest coefficients in the AD protein risk score contributed most of the predictive power for AD risk. These results were verified in the external validation cohort. EGFR, GFAP, and CHGA were identified as key proteins within the protein network. Our result suggests that the AD protein risk score demonstrated a good predictive performance for AD risk.

Perfusion deficit and vessel wall characteristics to predict recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion.

BACKGROUND: To investigate the association between perfusion deficit, vessel wall characteristics, and risk of recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. METHODS: We retrospectively reviewed chronic symptomatic patients due to anterior circulation large vessel occlusion in our center. All patients received multiparametric magnetic resonance imaging (including perfusion-weighted imaging and high-resolution vessel wall imaging) within 4 weeks to 3 months after symptom onset. The association between baseline clinical or imaging variables and recurrent ischemic events was assessed in bivariate models and multivariable logistic regression to identify independent predictors of recurrence. RESULTS: Among 71 enrolled patients, 21.1% (15/71) patients had recurrent ischemic events (nine ischemic strokes and six transient ischemic attacks) during a 2-year follow-up. In bivariate models, hypertension, occlusion with hyperintense signals, the presence of intraluminal thrombus, Tmax >4 s volume, Tmax >6 s volume, Tmax >8 s volume, and Tmax >10 s volume were associated with recurrence (all p < 0.05). In multivariate analysis, hypertension (p = 0.039, OR 10.057 (95% CI, 1.123-90.048)), higher deficit volume of Tmax >4 s (p = 0.011, OR 1.012 (95% CI, 1.003-1.021)) and occlusion with hyperintense signal (p = 0.030, OR 6.732 (95% CI, 1.200-37.772)) were still independent predictors of recurrent ischemic events. CONCLUSIONS: Besides hypertension history, higher deficit volume of Tmax >4 s and occlusion with hyperintense signal determined using multiparametric MRI are strongly associated with risk for recurrent ischemic events in medically treated patients with chronic symptomatic anterior circulation large vessel occlusion. Future studies are needed to determine the utility of revascularization strategies in such high-risk patients.

Identification of amino acids metabolomic profiling in human plasma distinguishes lupus nephritis from systemic lupus erythematosus.

Lupus nephritis (LN) is an immunoinflammatory glomerulonephritis associated with renal involvement in systemic lupus erythematosus (SLE). Given the close relationship between plasma amino acids (AAs) and renal function, this study aimed to elucidate the plasma AA profiles in LN patients and identify key AAs and diagnostic patterns that distinguish LN patients from those with SLE and healthy controls. Participants were categorized into three groups: normal controls (NC), SLE, and LN. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to quantify AA levels in human plasma. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were utilized to identify key AAs. The diagnostic capacity of the models was assessed using receiver operating characteristic (ROC) curve analysis and area under the ROC curve (AUC) values. Significant alterations in plasma AA profiles were observed in LN patients compared to the SLE and NC groups. The OPLS-DA model effectively separated LN patients from the SLE and NC groups. A joint model using histidine (His), lysine (Lys), and tryptophan (Trp) demonstrated exceptional diagnostic performance, achieving an AUC of 1.0 with 100% sensitivity, specificity, and accuracy in predicting LN. Another joint model comprising arginine (Arg), valine (Val), and Trp also exhibited robust predictive performance, with an AUC of 0.998, sensitivity of 93.80%, specificity of 100%, and accuracy of 95.78% in distinguishing between SLE and LN. The joint forecasting models showed excellent predictive capabilities in identifying LN and categorizing lupus disease status. This approach provides a novel perspective for the early identification, prevention, treatment, and management of LN based on variations in plasma AA levels.

Accelerometer-derived moderate-to-vigorous physical activity and incident nonalcoholic fatty liver disease.

BACKGROUND: The liver effects of concentrated vs. more evenly distributed moderate-to-vigorous physical activity (MVPA) patterns remain unclear. We aimed to examine the association of accelerometer-measured MVPA and different MVPA patterns with liver outcomes. METHODS: Eighty-eight thousand six hundred fifty-six participants without prior liver diseases from UK Biobank were included. MVPA was measured by a wrist-worn accelerometer. Based on the guideline-based threshold (≥ 150 min/week), MVPA patterns were defined as inactive (< 150 min/week), active weekend warrior (WW; ≥ 150 min/week with ≥ 50% of total MVPA achieved within 1-2 days), and regularly active (≥ 150 min/week but not active WW) patterns. The primary outcome was incident nonalcoholic fatty liver disease (NAFLD). RESULTS: During a median follow-up of 6.8 years, 562 participants developed NAFLD. Overall, there was a nonlinear inverse association of total MVPA with incident NAFLD (P for nonlinearity = 0.009): the risk of NAFLD rapidly decreased with the increment of MVPA (per 100 min/week increment: HR = 0.68; 95%CI, 0.57-0.81) when MVPA < 208 min/week, while moderately declined (HR = 0.91; 95%CI, 0.84-0.99) when MVPA ≥ 208 min/week. For MVPA patterns, compared with inactive group, both active WW (HR = 0.55, 95%CI, 0.44-0.67) and active regular (HR = 0.49, 95%CI, 0.38-0.63) group were associated with a similar lower risk of NAFLD. Similar results were observed for each secondary outcome, including incident severe liver diseases, incident liver cirrhosis, and liver magnetic resonance imaging-based liver steatosis and fibrosis. CONCLUSIONS: Regardless of whether MVPA was concentrated within 1 to 2 days or spread over most days of the week, more MVPA was associated with a lower risk of incident liver outcomes, including NAFLD, liver cirrhosis, liver steatosis, and fibrosis, to MVPA more evenly distributed.

Enhanced prediction of atrial fibrillation risk using proteomic markers: a comparative analysis with clinical and polygenic risk scores.

BACKGROUND: Proteomic biomarkers have shown promise in predicting various cardiovascular conditions, but their utility in assessing the risk of atrial fibrillation (AF) remains unclear. This study aimed to develop and validate a protein-based risk score for predicting incident AF and to compare its predictive performance with traditional clinical risk factors and polygenic risk scores in a large cohort from the UK Biobank. METHODS: We analysed data from 36 129 white British individuals without prior AF, assessing 2923 plasma proteins using the Olink Explore 3072 assay. The cohort was divided into a training set (70%) and a test set (30%) to develop and validate a protein risk score for AF. We compared the predictive performance of this score with the HARMS2-AF risk model and a polygenic risk score. RESULTS: Over an average follow-up of 11.8 years, 2450 incident AF cases were identified. A 47-protein risk score was developed, with N-terminal prohormone of brain natriuretic peptide (NT-proBNP) being the most significant predictor. In the test set, the protein risk score (per SD increment, HR 1.94; 95% CI 1.83 to 2.05) and NT-proBNP alone (HR 1.80; 95% CI 1.70 to 1.91) demonstrated superior predictive performance (C-statistic: 0.802 and 0.785, respectively) compared with HARMS2-AF and polygenic risk scores (C-statistic: 0.751 and 0.748, respectively). CONCLUSIONS: A protein-based risk score, particularly incorporating NT-proBNP, offers superior predictive value for AF risk over traditional clinical and polygenic risk scores, highlighting the potential for proteomic data in AF risk stratification.

Enhanced IL-37-IL-1R8 axis is negatively associated with inflammatory and clinical severity of chronic rhinosinusitis with nasal polyps.

Background: The importance of IL-37 and downstream signal in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP) demanding further investigation. Objective: We sought to address the potential importance of the IL-37-IL-1R8 axis in regulating inflammatory response in patients with CRSwNP. Methods: Nasal polyp (NP) tissues and control sinonasal tissues were obtained from adult CRSwNP, chronic rhinosinusitis without nasal polyps patients and healthy control subjects. The mRNA and protein levels of IL-37 and IL-1R8 in nasal tissues were examined by using quantitative PCR, immunohistochemical staining, and immunoblotting. In addition, the regulation of IL-1R8 expression was evaluated in human nasal epithelial cells (HNECs) in the presence of different stimuli. Results: The mRNA and protein levels of IL-37 and IL-1R8 were significantly elevated in nasal polyps compared with that in control tissues. IL-37 and IL-1R8 were mainly distributed in the epithelial layer and lamina propria of tissues. IL-1R8 mRNA level in nasal polys was negatively associated with eosinophil and neutrophil infiltration, as well as endoscopic score and computed tomography score. Moreover, the mRNA expression of IL-1R8 in HNECs was significantly increased by toll-like receptor agonists, but significantly inhibited by proinflammatory cytokines, which can be rescued by using steroid (DEX). Conclusion: Our findings showed that enhanced IL-37-IL-1R8 axis in NP tissues was negatively associated with inflammatory and clinical severity of CRSwNP patients, which could be considered as a future therapeutic target in CRSwNP patients.

Regular Mobile Phone Use and Incident Cardiovascular Diseases: Mediating Effects of Sleep Patterns, Psychological Distress, and Neuroticism.

BACKGROUND: The relationship between mobile phone use and incident cardiovascular disease (CVD) is uncertain. We aimed to examine the association of regular mobile phone use with incident CVD and explore the mediating effects of sleep and mental health. METHODS: A total of 444,027 individuals from the UK Biobank without a history of CVD were included. Regular mobile phone use was defined as at least 1 call per week. Weekly mobile phone usage time was self-reported as the average time of calls per week over the previous 3 months. The primary outcome was incident CVD. The secondary outcomes included each component of CVD and increased carotid intima-media thickness (CIMT). We applied Cox proportional hazard models to assess the association between mobile phone use and incident CVD, and mediation analyses to investigate the role of sleep patterns, psychologic distress, and neuroticism. RESULTS: In a median follow-up period of 12.3 years, 56,181 individuals developed incident CVD. Compared with nonregular mobile phone users, regular mobile phone users had a significantly higher risk of incident CVD (hazard ratio 1.04, 95% confidence interval 1.02-1.06) and increased CIMT (odds ratio 1.11, 95% CI 1.04-1.18). Among regular mobile phone users, weekly mobile phone usage time was positively associated with the risk of incident CVD, especially in current smokers (P for interaction = 0.001) and diabetic individuals (P for interaction = 0.037). Of the relationship between weekly mobile phone usage time and incident CVD, 5.11% was mediated by sleep patterns, 11.5% by psychological distress, and 2.25% by neuroticism. CONCLUSIONS: Weekly mobile phone usage time was positively associated with incident CVD risk, which was partly explained by poor sleep, psychologic distress, and neuroticism.