A Multi-task Neural Network for Image Recognition in Magnetically Controlled Capsule Endoscopy.

BACKGROUND AND AIMS: Physicians are required to spend a significant amount of reading time of magnetically controlled capsule endoscopy. However, current deep learning models are limited to completing a single recognition task and cannot replicate the diagnostic process of a physician. This study aims to construct a multi-task model that can simultaneously recognize gastric anatomical sites and gastric lesions. METHODS: A multi-task recognition model named Mul-Recog-Model was established. The capsule endoscopy image data from 886 patients were selected to construct a training set and a test set for training and testing the model. Based on the same test set, the model in this study was compared with the current single-task recognition model with good performance. RESULTS: The sensitivity and specificity of the model for recognizing gastric anatomical sites were 99.8% (95% confidence intervals: 99.7-99.8) and 98.5% (95% confidence intervals: 98.3-98.7), and for gastric lesions were 98.8% (95% confidence intervals: 98.3-99.2) and 99.4% (95% confidence intervals: 99.1-99.7). Moreover, the positive predictive value, negative predictive value, and accuracy of the model were more than 95% in recognizing gastric anatomical sites and gastric lesions. Compared with the current single-task recognition model, our model showed comparable sensitivity, specificity, positive predictive value, negative predictive value, and accuracy (p < 0.01, except for the negative predictive value of ResNet, p > 0.05). The Areas Under Curve of our model were 0.985 and 0.989 in recognizing gastric anatomical sites and gastric lesions. Furthermore, the model had 49.1 M parameters and 38.1G Float calculations. The model took 15.5 ms to recognize an image, which was less than the superposition of multiple single models (p < 0.01). CONCLUSIONS: The Mul-Recog-Model exhibited high sensitivity, specificity, PPV, NPV, and accuracy. The model demonstrated excellent performance in terms of parameters quantity, Float computation, and computing time. The utilization of the model for recognizing gastric images can improve the efficiency of physicians' reports and meet complex diagnostic requirements.

Spartalizumab in combination with platinum-doublet chemotherapy with or without canakinumab in patients with PD-L1-unselected, metastatic NSCLC.

BACKGROUND: Despite promising outcomes of treatment with anti-programmed cell death (PD)-1/PD-ligand (L)1 agents in combination with platinum-doublet chemotherapy (PDC) in the first-line setting, a significant unmet medical need remains in patients with PD-L1-unselected non-small cell lung cancer (NSCLC). METHODS: This multicenter, open-label, phase 1b study comprising dose-confirmation and dose-expansion parts investigated the combination of spartalizumab and various PDC regimens, with or without canakinumab, in treatment-naïve patients with PD-L1-unselected, metastatic NSCLC. The primary objectives were to determine maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of spartalizumab, with or without canakinumab, in combination with PDC in the dose-confirmation part and antitumor activity of spartalizumab in the dose-expansion part. RESULTS: The MTD/RDE of spartalizumab was 300 mg every 3 weeks (Q3W) when administered with either gemcitabine (1250 mg/m2)/cisplatin (75 mg/m2) (group A; no dose-limiting toxicities [DLTs]), pemetrexed (500 mg/m2)/cisplatin (group B; 2 DLTs: grade 2 posterior reversible encephalopathy syndrome and grade 4 hyponatremia), or paclitaxel (200 mg/m2)/carboplatin area under the curve 6 min*mg/mL (group C; 1 DLT: grade 4 neutropenic colitis). The RDE of canakinumab combined with spartalizumab and pemetrexed/cisplatin (group E; no DLTs) was 200 mg Q3W (no dose-expansion part was initiated). No new safety signals were identified. In groups A, B, C, and E, the overall response rates were 57.6%, 55.3%, 51.5%, and 57.1%, respectively. Group B compared with other groups had the longest median progression-free survival (10.4 months vs. 6.2-7.5 months), overall survival (29.7 months vs. 16.1-21.0 months), and duration of response (30.1 months vs. 6.0-8.2 months). CONCLUSIONS: The combination of spartalizumab and PDC, with or without canakinumab, was well tolerated across treatment groups. The antitumor activity across treatment groups was comparable with that of pembrolizumab and pemetrexed combination. Canakinumab did not appear to improve the antitumor activity when combined with spartalizumab, pemetrexed and cisplatin. TRIAL REGISTRATION: The trial was registered in Clinicaltrials.gov with identifier no. NCT03064854. Date of Registration: 06 February 2017.

A 10-year retrospective study of antibacterial-induced thrombocytopenia in a women and children hospital using China Hospital Pharmacovigilance System and Visual Basic for Applications.

AIMS: We aimed to investigate antibacterial-induced thrombocytopenia using the China Hospital Pharmacovigilance System (CHPS) in conjunction with Visual Basic for Applications (VBA). METHODS: Between September 2011 and December 2022, a 2-phase workflow was employed to identify antibacterial-induced thrombocytopenia, including preliminary screening in phase (I) conducted by CHPS algorithms and causality assessment by trained pharmacists in phase (II) using VBA. The incidence of thrombocytopenia in each antibacterial was calculated, and comparisons were performed between paediatric and adult patients. RESULTS: CHPS algorithms identified 4080 cases from 485 238 admissions (including 223 735 admissions receiving at least 1 antibacterial treatment). After ruling out cases with chemotherapy and abnormal platelet count at admission, 3832 cases were available. Using VBA, pharmacists identified 1039 cases (1246 antibacterial treatments, 28 agents) as potential thrombocytopenia instances (κ = 0.89), with an incidence of 0.46%. All antibacterial treatments correlated temporally with thrombocytopenia. Carbapenems (meropenem 1.77%), glycopeptides (vancomycin 1.55%) and lincosamides (clindamycin 0.44%) were prominent causal groups. The highest incidences of thrombocytopenia in the cephalosporins and penicillins groups were ceftazidime (2.04%) and piperacillin/tazobactam (1.24%), respectively. Among all antibacterial treatments, clindamycin showed the shortest time to onset (TTO), and erythromycin showed the longest TTO. Paediatric patients exhibited a longer TTO (61 vs. 29 h), extended time to nadir (83 vs. 37 h), lower platelet nadir count values (110 vs. 92 × 109/L), and a higher severe case proportion (12.37 vs. 3.86%) when compared with adults. CONCLUSION: Different antibacterial agents exhibit varying incidences of thrombocytopenia, with notable disparities between adults and children in the characteristics of thrombocytopenia.

Association between hemoglobin A1c and abdominal aortic calcification: results from the National Health and Nutrition Examination Survey 2013-2014.

BACKGROUND: Hemoglobin A1c (HbA1c), a "gold standard" for the assessment of glycemic control, was associated with an increased risk of cardiovascular disease and coronary artery calcification. However, its effects on abdominal aortic calcification (AAC) are uncertain. The present study comprehensively investigated the association between HbA1c and AAC in the 2013-2014 National Health and Nutrition Examinations Surveys. METHODS: Among 1,799 participants ≥ 40 years, dual-energy X-ray absorptiometry-derived AAC was quantified using the Kauppila score (AAC-24). Severe AAC was defined as a total AAC-24 > 6. Weighted linear regression models and logistic regression models were used to determine the effects of HbA1c on AAC. The restricted cubic spline model was used for the dose-response analysis. RESULTS: The mean AAC-24 of participants was 1.3, and 6.7% of them suffered from severe AAC. Both AAC-24 and the prevalence of severe AAC increased with the higher tertile of HbA1c (P < 0.001). Elevated HbA1c levels would increase the AAC-24 (ß = 0.73, 95% CI: 0.30-1.16) and the risk of severe AAC (OR = 1.63, 95% CI: 1.29-2.06), resulting in nearly linear dose-response relationships in all participants. However, this positive correlation were not statistically significant when participants with diabetes were excluded. Furthermore, subgroup analysis showed significant interactions effect between HbA1c and hypertension on severe AAC with the OR (95% CI) of 2.35 (1.62-3.40) for normotensives and 1.39 (1.09-1.79) for hypertensives (P for interaction = 0.022). CONCLUSION: Controlling HbA1c could reduce AAC scores and the risk of severe AAC. Glycemic management might be a component of strategies for preventing AAC among all participants, especially normotensives.

Mice expressing nonpolymerizable fibrinogen have reduced arterial and venous thrombosis with preserved hemostasis.

ABSTRACT: Elevated circulating fibrinogen levels correlate with increased risk for both cardiovascular and venous thromboembolic diseases. In vitro studies show that formation of a highly dense fibrin matrix is a major determinant of clot structure and stability. Here, we analyzed the impact of nonpolymerizable fibrinogen on arterial and venous thrombosis as well as hemostasis in vivo using FgaEK mice that express normal levels of a fibrinogen that cannot be cleaved by thrombin. In a model of carotid artery thrombosis, FgaWT/EK and FgaEK/EK mice were protected from occlusion with 4% ferric chloride (FeCl3) challenges compared with wild-type (FgaWT/WT) mice, but this protection was lost, with injuries driven by higher concentrations of FeCl3. In contrast, fibrinogen-deficient (Fga-/-) mice showed no evidence of occlusion, even with high-concentration FeCl3 challenge. Fibrinogen-dependent platelet aggregation and intraplatelet fibrinogen content were similar in FgaWT/WT, FgaWT/EK, and FgaEK/EK mice, consistent with preserved fibrinogen-platelet interactions that support arterial thrombosis with severe challenge. In an inferior vena cava stasis model of venous thrombosis, FgaEK/EK mice had near complete protection from thrombus formation. FgaWT/EK mice also displayed reduced thrombus incidence and a significant reduction in thrombus mass relative to FgaWT/WT mice after inferior vena cava stasis, suggesting that partial expression of nonpolymerizable fibrinogen was sufficient for conferring protection. Notably, FgaWT/EK and FgaEK/EK mice had preserved hemostasis in multiple models as well as normal wound healing times after skin incision, unlike Fga-/- mice that displayed significant bleeding and delayed healing. These findings indicate that a nonpolymerizable fibrinogen variant can significantly suppress occlusive thrombosis while preserving hemostatic potential in vivo.

Genetic Predisposition, Sedentary Behavior, and Incident Coronary Artery Disease: A Prospective Chinese Cohort Study.

PURPOSE: Whether the association of sedentary behaviors with coronary artery disease (CAD) can be influenced by genetic susceptibility remains unclear. We aimed to investigate the joint and interplay effects between genetic risk and sedentary time (ST) and to further explore the extent to which the risk for CAD can be counteracted by reducing ST in different genetic groups. METHODS: This prospective cohort study included 39,164 Chinese adults without CAD history. Genetic susceptibility was quantified by a predefined polygenic risk score (PRS) with 540 genetic variants, and daily ST was assessed by questionnaire. We analyzed the modification effect of genetic risk on the association of ST with CAD using the Cox proportional hazards models. RESULTS: During a median follow-up of 11.60 yr, 1156 CAD events were documented. Higher ST and PRS were separately related to elevated CAD risk. Significant additive interaction was also observed (relative excess risk due to interaction: 0.77; 95% confidence interval [CI] = 0.27-1.28). Compared with participants with low genetic risk and low ST (<6 h·d -1 ), those with high genetic risk and high ST (≥10 h·d -1 ) had the highest CAD risk, with the hazard ratio (HR) and 95% CI of 4.22 (2.65-6.71). When stratified by genetic risks, participants with high ST had gradient increment of CAD risks across low, intermediate, and high genetic risk groups, with HR (95% CI) values of 1.21 (0.61-2.40), 1.57 (1.14-2.16), and 2.15 (1.40-3.31), respectively. For the absolute risk reduction, individuals with high genetic risk achieved the greatest benefit from low ST ( Ptrend = 0.024). CONCLUSIONS: Genetic susceptibility may synergistically interact with ST to increase CAD risk. Reducing ST could attenuate the CAD risk, especially among individuals with high genetic risk.

Safety profile of methotrexate used off-label in ectopic pregnancy: an active monitoring study based on a Chinese hospital pharmacovigilance system.

OBJECTIVE: Methotrexate (MTX) is characterized as first-line therapy although its indication of ectopic pregnancy is off-label use. We aimed to conduct a retrospective cohort study to investigate the incidence, characteristics of adverse drug reactions (ADRs) of MTX, provide valuable insights for medical workers. METHODS: Basing on China Hospital Pharmacovigilance System (CHPS), a retrospective analysis was performed to evaluate the safety of MTX (n = 672). An active monitoring model was set to detect ADR signals from the hospital information system. Frequency, Common Terminology Criteria for Adverse Events (CTCAE) grade proportion and association of dose exposure with ADRs were presented as outcomes. RESULTS: The total incidence of ADRs was 54.0%. Anaemia (37.6%) was the most frequent ADR, followed by hepatic function abnormal (11.3%), hyperuricemia (6.1%), neutropenia (4.6%), leukopenia (4.0%), and dyslipidaemia (2.5%). For the composition of all ADRs, CTCAE grade one, two and three dominated for 86.3%, 12.1% and 1.6%, respectively. The severity of hepatic function abnormal was more serious in the two-dose exposed group (p = .021), while other types of ADRs had no statistical or clinical differences. Logistic regression analysis showed the incidence of any ADRs (OR 1.87 [1.31-2.64]; p = .001), hepatic function abnormal (OR 2.75 [1.69-4.48]; p < .001), dyslipidaemia (OR 5.15 [1.87-14.13]; p = .001) were significantly higher in the two-dose exposed group. After adjusted, the positive associations were still maintained. CONCLUSIONS: MTX is quite safe in ectopic pregnancy, despite its mild to moderate hematotoxicity, hepatotoxicity and nephrotoxicity. Taking CHPS can present the accurate denominator of the incidence of adverse drug reactions into account, our study advocates that it may have great potential to be used as an active monitoring tool for off-label drug use risk management.

Association between gut microbiota and NAFLD/NASH: a bidirectional two-sample Mendelian randomization study.

Background: Recent studies have suggested a relationship between gut microbiota and non-alcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). However, the nature and direction of this potential causal relationship are still unclear. This study used two-sample Mendelian randomization (MR) to clarify the potential causal links. Methods: Summary-level Genome-Wide Association Studies (GWAS) statistical data for gut microbiota and NAFLD/NASH were obtained from MiBioGen and FinnGen respectively. The MR analyses were performed mainly using the inverse-variance weighted (IVW) method, with sensitivity analyses conducted to verify the robustness. Additionally, reverse MR analyses were performed to examine any potential reverse causal associations. Results: Our analysis, primarily based on the IVW method, strongly supports the existence of causal relationships between four microbial taxa and NAFLD, and four taxa with NASH. Specifically, associations were observed between Enterobacteriales (P =0.04), Enterobacteriaceae (P =0.04), Lachnospiraceae UCG-004 (P =0.02), and Prevotella9 (P =0.04) and increased risk of NAFLD. Dorea (P =0.03) and Veillonella (P =0.04) could increase the risks of NASH while Oscillospira (P =0.04) and Ruminococcaceae UCG-013 (P=0.005) could decrease them. We also identified that NAFLD was found to potentially cause an increased abundance in Holdemania (P =0.007) and Ruminococcus2 (P =0.002). However, we found no evidence of reverse causation in the microbial taxa associations with NASH. Conclusion: This study identified several specific gut microbiota that are causally related to NAFLD and NASH. Observations herein may provide promising theoretical groundwork for potential prevention and treatment strategies for NAFLD and its progression to NASH in future.

Effect of OPRM1/COMT gene polymorphisms on sufentanil labor analgesia: a cohort study based on propensity score matching.

Background: This study investigated the use of COMT G1947A and OPRM1 A118G polymorphisms as predictive markers for sufentanil epidural analgesia. Methods: The visual analogue scale (VAS) score, and sufentanil consumption of 136 pairs of parturients using sufentanil with lidocaine and ropivacaine for epidural analgesia were used for analysis. Results: OPRM1 AG/GG had lower VAS score difference between fifth and 0 min (1.55 vs 1.87; p = 0.012) and higher consumption (19.65 µg vs 17.11 µg; p = 0.049) than AA carriers. COMT GA/AA had higher VAS score difference than GG carriers (1.86 vs 1.55; p = 0.021). Conclusion: Sufentanil may provide better epidural labor analgesia in OPRM1 AA and COMT GA/AA carriers compared with OPRM1 AG/GG and COMT GG carriers. Clinical Trial Registration: ChiCTR1900026897 (Chinese Clinical Trial Center Registry).

Spatial and temporal distribution characteristics of typical pollution loads based on SWAT model across Tuojiang River watershed located in Sichuan Province, Southwest of China.

Tuojiang River watershed is an economically developed and densely populated area in Sichuan Province (southwest of China), which is also an important tributary of the Yangtze River. Nitrogen (N) and phosphorus (P) are the main pollutants affecting water quality, but there is still lack of study on the spatial and temporal distribution characteristics of these two pollutants. In this study, the typical non-point source pollution loads in the Tuojiang River watershed are simulated by Soil and Water Assessment Tool (SWAT) model, and the spatial autocorrelation method is used to reveal the spatial and temporal distribution characteristics of the pollution loads from the annual average and water periods. Combined with redundancy analysis (RDA) and geographically weighted regression (GWR) analysis, the main driving factors affecting the typical non-point source pollution loads in the Tuojiang River watershed are discussed from the global and local perspectives. The results show that (1) from different water periods, the pollution loads of total nitrogen (TN) and total phosphorus (TP) in three water periods show obviously different, is the highest in the abundant water period, with 323.4 kg/ha and 47.9 kg/ha, followed by the normal water period, with 95.7 kg/ha and 14.1 kg/ha, and the lowest in the dry water period, with 28.4 kg/ha and 4.2 kg/ha. The annual average value of TN pollution load is higher than that of TP, with 447.5 kg/ha and 66.1 kg/ha, respectively; (2) the TN and TP pollution loads are stable on the whole, and the overall level in the middle reaches is higher. The pollution loads of Shifang City and Mianzhu City are higher in all three water periods. (3) Elevation and slope are two main driving factors affecting the TN and TP pollution loads in the Tuojiang River watershed. Therefore, the visualization and quantification of temporal and spatial distribution characteristics of typical non-point source pollution loads in the Tuojiang River watershed are helpful to provide the basis for scientific prevention and control of pollution in the Tuojiang River watershed and are of great significance to promote the sustainable, coordinated, and healthy development of water environment and economy in the watershed.

Patient-reported outcomes in capmatinib-treated patients with METex14-mutated advanced NSCLC: Results from the GEOMETRY mono-1 study.

INTRODUCTION: Capmatinib, a MET inhibitor, showed substantial antitumour activity with manageable side effects in patients with MET exon 14 (METex14)-mutated advanced non-small cell lung cancer (aNSCLC) in the GEOMETRY mono-1 study. We report patient-reported outcomes (PROs) from this study. METHODS: Enrolled treatment-naïve (1L) or pre-treated (2L+) patients with aNSCLC with a METex14-skipping mutation received 400 mg capmatinib twice daily during 21-day treatment cycles. PROs were collected at baseline and every six weeks thereafter using EORTC QLQ-C30 global health status/quality of life (GHS/QoL), QLQ-LC13 symptoms, and EQ-5D-5L visual analogue scale (VAS) questionnaires. RESULTS: As of 6 January 2020, 27/28 1L and 65/69 2L+ patients had completed PROs at baseline; compliance rates remained >70%. Cough improved early, with meaningful improvements (≥10-point change from baseline) observed throughout cycles (mean change from baseline [SD] by week 7: 1L -13.0 [39.9], 2L+ -8.2 [28.4]; week 43: 1L -28.2 [26.7], 2L+ -10.5 [27.3]). QoL, assessed by GHS/QoL and VAS, improved by week 7 in 1L and 2L+ patients, with improvements generally sustained over time. Median time to definitive deterioration (TTDD) in GHS/QoL was 16.6 months (95% CI: 9.7, not estimable [NE]) in 1L and 12.4 months (95% CI: 4.2, 19.4) in 2L+ patients. Median TTDD for dyspnoea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE) for 1L and 2L+ patients, respectively, and NE for cough and chest pain. CONCLUSIONS: Capmatinib was associated with clinically meaningful improvements in cough and preserved QoL, further supporting its use in patients with METex14-mutated aNSCLC. TRIAL REGISTRATION: ClinicalTrials.gov registry number: NCT02414139.

Spatial-temporal characteristics of corrected total phosphorus pollution loads from agricultural non-point sources in Tuojiang River watershed, Sichuan Province of southwestern China.

Traditional method of estimating pollution loads may neglect the internal spatial heterogeneity of socio-economic driving factors, which can result in overestimate and underestimate of pollution loads. In this study, the corrected approach to estimating total phosphorus (TP) pollution load was proposed to explore its future variation to develop effective phosphorus pollution control strategies for water environment management. As the first-class tributary of the Yangtze River, the TP out of limits in the Tuojiang River is serious. Thus, based on the presently related basic datasets related to TP pollution load estimation, we firstly adopted the GM (1,1) model to predict their varied trends from 2021 to 2025. We then used the pollution emission coefficient method to calculate the TP pollution load. Moreover, considering the temporal and spatial heterogeneity of the pollutant generation coefficient, we further introduced population and GDP factors to further modify the pollutant generation coefficient to correct TP pollution load. Finally, we employed the exploratory spatial data analysis (ESDA) method to explore spatial distribution characteristics and spatial autocorrelation of TP pollution load from diverse pollution sources in 2025. The results showed that the total TP pollution load from diverse pollution sources will increase from 12,194.92 t in 2021 to 12,461.26 t in 2025, an increase of 2.18%. More concretely, the TP pollution load from rural domestic sewage, rural domestic waste and livestock, and poultry pollution sources will separately decrease by 94.24 t, 77.9 t, and 86.52 t. However, the TP pollution load from agricultural runoff and agricultural solid wastes pollution sources will increase by 74.52 t and 451.49 t, respectively. The contribution of TP pollution load from diverse pollution sources to total TP pollution load will be as follows: livestock and poultry (63.49%) > agricultural solid wastes (16.72%) > agricultural runoff (12.26%) > rural domestic sewage (4.12%) > rural domestic waste (3.41%). The difference in the spatial distribution of TP pollution load from diverse pollution sources in 2025 will be prominent. TP pollution from rural domestic sewage and rural domestic waste pollution sources is more serious in the Xindu and Longquanyi districts, and that from agricultural runoff and agricultural solid wastes pollution sources is more prominent in the midstream and downstream. TP pollution load from livestock and poultry pollution source is higher in the Renshou, Anyue, Rongxian, Luxian counties, and Jiangyang district. Additionally, TP pollution load from rural domestic sewage, rural domestic waste, agricultural runoff, and agricultural solid wastes pollution sources in 2025 will show a clear spatial correlation, but the spatial correlation of TP pollution load from livestock and poultry pollution source will be weak. The study is effective to eliminate the influence of temporal and spatial variation of pollutants generates coefficients on TP pollution load estimation. The method can reflect the actual condition of pollution loads in watersheds more objectively, which can be applied to estimate other pollution loads of similar watersheds with intensive socio-economic activities. The findings in this study can provide a critical reference for the stakeholders to balance water environment conservation and socio-economic development.

Associations of tea consumption with blood pressure progression and hypertension incidence.

BACKGROUND: Association between tea consumption and incident hypertension remains uncertain. This study conducted to examine the health effects of tea consumption on blood pressure progression and hypertension incidence. METHODS: A population-based cohort of 38,913 Chinese participants without hypertension at baseline were included in the current study. Information on tea consumption was collected through standardized questionnaires. Associations of tea consumption with blood pressure progression and incident hypertension were analyzed using logistic regression models and Cox proportional hazards regression models, respectively. RESULTS: During a median follow-up of 5.9 years, 17,657 individuals had experienced progression to a higher blood pressure stage and 5,935 individuals had developed hypertension. In multivariate analyses, habitual tea drinkers (≥ 3 times/week for at least six months) had a 17% lower risk for blood pressure progression [odds ratio (OR) = 0.83, 95% CI: 0.79-0.88] and a 14% decreased risk for incident hypertension [hazard ratio (HR) = 0.86, 95% CI: 0.80-0.91] compared with non-habitual tea drinkers. Individuals in different baseline blood pressure groups could obtain similar benefit from habitual tea drinking. In terms of tea consumption amount, an inverse, linear dose-response relation between monthly consumption of tea leaves and risk of blood pressure progression was observed, while the risk of incident hypertension did not reduce further after consuming around 100 g of tea leaves per month. CONCLUSIONS: Our study demonstrated that habitual tea consumption could provide preventive effect against blood pressure progression and hypertension incidence.

Effects of the total physical activity and its changes on incidence, progression, and remission of hypertension.

OBJECTIVES: Moderate to vigorous physical activity is recommended to prevent hypertension according to the current guidelines. However, the degree to which the total physical activity (TPA) and its changes benefit normotensives and hypertensives is uncertain. We aimed to examine the effects of TPA and its changes on the incidence, progression, and remission of hypertension in the large-scale prospective cohorts. METHODS: A total of 73,077 participants (55,101 normotensives and 17,976 hypertensives) were eligible for TPA analyses. During a mean follow-up of 7.16 years (394,038 person-years), 12,211 hypertension cases were identified. TPA was estimated as metabolic equivalents and categorized into quartiles. Cox proportional hazards regression and multivariable logistic regression were used to estimate associations of TPA and changes in TPA with incident hypertension and progression/remission of hypertension. RESULTS: Compared with the lowest quartile of TPA, normotensives at the third and the highest quartile had a decreased risk of incident hypertension, with hazard ratios (HRs) of 0.86 [95% confidence interval (CI): 0.81-0.91] and 0.81 (95% CI: 0.77-0.86), respectively. Hypertensives at the highest quartile of TPA demonstrated a decreased risk of progression of hypertension [odds ratio (OR) = 0.87, 95% CI: 0.79-0.95], and an increased probability of hypertension remission (OR = 1.17, 95% CI: 1.05-1.29). Moreover, getting active from a sedentary lifestyle during the follow-up period could reduce 25% (HR = 0.75, 95% CI: 0.58-0.96) risk of incident hypertension, whereas those becoming sedentary did not achieve benefit from initially being active. CONCLUSIONS: Our findings indicated that increasing and maintaining TPA levels could benefit normotensives, whereas higher TPA levels were needed to effectively control progression and improve remission of hypertension. Physical activity played undoubtedly an essential role in both primary and secondary prevention of hypertension.

Inhibition of stearoyl-coenzyme A desaturase 1 ameliorates hepatic steatosis by inducing AMPK-mediated lipophagy.

SCD1 is a key enzyme controlling lipid metabolism and a link between its activity and NAFLD has been proposed. Lipophagy is a novel regulatory approach to lipid metabolism regulation, which is involved in the development of NAFLD. However, the possible functional connection between SCD1 and lipophagy in NAFLD remains unknown. To investigate the molecular mechanisms through which SCD1 regulates lipophagy in hepatic steatosis, the model of hepatic steatosis was established by inducing mouse primary hepatocytes with sodium palmitate and feeding C57BL/6 mice with HFD. Our results indicated that sodium palmitate-treated hepatocytes exhibited increased SCD1 expression, AMPK inactivation and defective lipophagy. Inhibition of SCD1 expression in hepatocytes resulted in enhanced AMPK activity and lipophagy, and reduced lipid deposition. Although SCD1 overexpression led to decreased AMPK activity and lipophagy, lipid deposition was increased in hepatocytes. SCD1 regulated lipophagy through AMPK to affect lipid metabolism in mouse primary hepatocytes. Additionally, compared to HFD-fed mice, CAY10566(an SCD1-specific inhibitor)-treated mice exhibited significantly decreased hepatic steatosis and hepatic lipid droplet accumulation, as well as enhanced AMPK activity and lipophagy. This study elucidated that SCD1 inhibition ameliorates hepatic steatosis by inducing AMPK-mediated lipophagy, suggesting that the SCD1-AMPK-lipophagy pathway is a potential therapeutic target for NAFLD.

Black carp NAP1 positively regulates MDA5-mediated antiviral signaling during the innate immune activation.

NAK-associated protein 1 (NAP1) is involved in NF-κB activation and interferon (IFN) induction in human and mammal; however, the role of teleost NAP1 in innate immunity remains unknown. In this paper, NAP1 homologue of black carp (Mylopharyngodon piceus) has been cloned and characterized. Black carp NAP1 (bcNAP1) migrated around 47 kDa in immunoblot assay and was identified as a cytosolic protein by immunofluorescent staining. bcNAP1 showed little IFN promoter-inducing ability in the reporter assay and bcNAP1 presented no antiviral activity against either grass carp reovirus (GCRV) or spring viremia of carp virus (SVCV) in the plaque assay. However, when co-expressed with black carp MDA5 (bcMDA5), bcNAP1 enhanced bcMDA5-mediated IFN promoter induction in the reporter assay. Accordingly, the plaque assay data demonstrated that the antiviral activity of bcMDA5 against both GCRV and SVCV was upregulated by bcNAP1. Additionally, the association between bcNAP1 and bcMDA5 has been identified through immunofluorescent staining and co-immunoprecipitation (co-IP) assay. Thus, the data generated in this study support the conclusion that bcNAP1 interacts with bcMDA5 and up-regulates bcMDA5-mediated antiviral signaling during host innate immune activation.

Nitroxide-Modified Protein-Incorporated Nanoflowers with Dual Enzyme-Like Activities.

PURPOSE: Combined superoxide dismutase (SOD)/catalase mimetics have attracted much attention because of their efficacy against reactive oxygen species-associated diseases; however, their application is often limited owing to their poor stability and the absence of favorable grafting sites. To address this, we developed a new class of SOD/catalase mimetics based on hybrid nanoflowers, which exhibit superior stability and possess the desired grafting sites for drugs and endogenous molecules. METHODS: In this work, for the first time, we used polynitroxylated human serum albumin (PNA) to mediate the formation of hybrid copper-based nanoflowers. H2O2 depletion and O2 evolution assays were first performed to determine the catalase-like activity of the hybrid nanoflowers. Next, the xanthine oxidase/cytochrome c method was used to assay the SOD-like activity of the nanoflowers. Further characteristics of the nanoflowers were evaluated using scanning electron microscopy (SEM), electron paramagnetic resonance (EPR), and Fourier-transform infrared spectroscopy (FTIR). Operational stability was assessed via the reusability assay. RESULTS: The H2O2 depletion and O2 evolution assays indicated that PNA-incorporated nanoflowers have genuine catalase-like activity. Kinetic analysis revealed that the reactions of the incorporated nanoflowers with H2O2 not only obey Michaelis-Menton kinetics, but that the nanoflowers also possess a higher affinity for H2O2 than that of native catalase. The FTIR spectra corroborated the presence of PNA in the hybrid nanoflowers, while the EPR spectra confirmed the intermolecular interaction of nitroxides bound to the human serum albumin incorporated into the nanoflowers. The remarkable operational reproducibility of the hybrid nanoflowers in catalase-like and SOD-like reactions was verified across successive batches. CONCLUSION: Herein, a comparison of Michaelis constants showed that the hybrid nanoflower, a catalase mimetics, outperforms the native catalase. Acting as a "better-than-nature" enzyme mimetics, the hybrid nanoflower with superior stability and desired ligand grafting sites will find widespread utilization in the medical sciences.

LncRNA ENST00000602558.1 regulates ABCG1 expression and cholesterol efflux from vascular smooth muscle cells through a p65-dependent pathway.

BACKGROUND AND AIMS: Long non-coding RNAs (lncRNAs) have proven to be involved in the progression of atherosclerosis and dyslipidemia. In addition, vascular smooth muscle cells (VSMCs) phenotype switching, including VSMCs-derived foam cells formation, plays a key role in the pathogenesis of atherosclerosis. LncRNA ENST00000602558.1, one of the differentially expressed lncRNAs between coronary artery disease (CAD) patients and healthy controls identified by our previous study, was located to TG and HDL susceptibility loci, but its role and underlying mechanism in the pathogenesis of atherosclerosis remain unclear. The present study aims to explore the role and underlying mechanism of ENST00000602558.1 in the regulation of cholesterol efflux from VSMCs. METHODS: ABCG1 mRNA and protein expression in VSMCs was detected using qRT-PCR and Western blot, respectively. ABCG1-mediated cholesterol efflux to HDL from VSMCs was measured by means of NBD-cholesterol fluorescence intensity. The binding of ENST00000602558.1 to p65 and p65 to ABCG1 promoter region was detected by RNA immunoprecipitation (RIP) assay and chromatin immunoprecipitation (ChIP) assay, respectively. RESULTS: Overexpression of ENST00000602558.1 downregulated ABCG1 mRNA and protein expression, while knockdown of ENST00000602558.1 upregulated ABCG1 mRNA and protein expression. Consistently, ENST00000602558.1 overexpression decreased ABCG1-mediated cholesterol efflux to HDL from VSMCs by 30.38% (p < 0.001), and knockdown of ENST00000602558.1 increased ABCG1-mediated cholesterol efflux to HDL from VSMCs by 30.41% (p = 0.001). In addition to cholesterol efflux, overexpression of ENST00000602558.1 increased lipid accumulation and TC/TG levels, while knockdown of ENST00000602558.1 decreased lipid accumulation and TC/TG levels in VSMCs. Furthermore, we confirmed that ENST00000602558.1 regulated ABCG1 expression and ABCG1-mediated cholesterol efflux from VSMCs through binding to p65. CONCLUSIONS: In conclusion, ENST00000602558.1 played an important role in mediating cholesterol efflux to HDL from VSMCs by regulating ABCG1 expression through binding to p65.

Exenatide alleviates adriamycin-induced heart dysfunction in mice: Modulation of oxidative stress, apoptosis and inflammation.

BACKGROUND: Adriamycin (ADR) is an effective antineoplastic drug; the clinical application of ADR is limited due to fatal heart dysfunction. Exenatide has antioxidant, anti-apoptotic and anti-inflammatory properties. It can alleviate heart damage induced by ischaemia-reperfusion injury. Thus, we assumed that exenatide would produce protective effects on ADR-induced heart dysfunction. METHOD: Mice were treated with exenatide 1 h prior to every ADR treatment for 20 days. Left ventricular function and performance were assessed by echocardiography. Additionally, H9c2 cells were pretreated with exenatide followed by ADR, and intracellular reactive oxygen species (ROS) and cell viability, as well as the lactate dehydrogenase (LDH) and the creatine kinase MB (CK-MB), were subsequently measured. Flow cytometry and TUNEL staining were applied to assess the effect of exenatide on cardiac damage caused by ADR. Western blot and RT-PCR were performed to detect the effect of exenatide on apoptosis-related genes (Bcl-2 and Bax) and inflammation-related genes and/or proteins (tumour necrosis factor-α, interleukin-6, nuclear factor-κB, and p53). RESULT: Echocardiography showed that cardiac dysfunction caused by ADR was significantly improved by treatment with exenatide. ADR mice had harmful changes in the levels of ROS and CK-MB/LDH production, as well as the targeted apoptotic and inflammatory molecules, and these effects were also reversed by exenatide. In vitro, exenatide mitigated ADR-induced oxidative stress and CK-MB/LDH production, as well as Annexin V+/PI+ and TUNEL+ apoptosis in H9c2 cells. CONCLUSION: In conclusion, our research demonstrated the potential protective effects of exenatide on ADR-induced heart dysfunction through suppressing oxidative stress, apoptosis and inflammation.