Dietary Factors and the Risk of Colorectal Cancer: A Mendelian Randomization Study.

OBJECTIVE: To examine the causal association between 15 dietary factors and the incidence of colorectal cancer through the application of Mendelian randomization methodology. METHODS: The data associated with 15 dietary factors were derived from the IEU OPEN GWAS database, and the colorectal cancer data were sourced from the FinnGen database. The Inverse Variance Weighting method was the principal research method. Sensitivity analyses were implemented to affirm the robustness of the findings. Additionally, we conducted multivariable Mendelian randomization analyses to adjust for the intake of ω-3 and ω-6 polyunsaturated fatty acids. RESULTS: In our research, we observed suggestive causal relationships between genetically predicted water intake and the reduced risk of colorectal cancer (OR = 0.54; 95% CI= 0.31 ∼ 0.93; p = 0.028); genetically predicted ω-3 PUFA intake (OR = 1.17; 95% CI= 1.05 ∼ 1.30; p = 0.005) were suggestively associated with the increased risk of colorectal cancer. In the multivariable Mendelian randomization analysis, the effect of ω-3 PUFA intake remains significant after adjusting for the influence of ω-6 PUFA intake. Horizontal pleiotropy was not present in this study. CONCLUSIONS: There exists a suggestive causal association between increased water intake and decreased risk of colorectal cancer, while ω-3 PUFA intake are suggestive linked to the increased risk of colorectal cancer.

Unhealthy lifestyle factors and the risk of colorectal cancer: a Mendelian randomization study.

The purpose of this study was to investigate the causal association between unhealthy lifestyle style factors and the risk of colorectal cancer, with the aim of preventing the occurrence of colorectal cancer by modifying unhealthy lifestyles. A two-sample Mendelian randomization (MR) approach was employed in this study, utilizing the inverse-variance weighted method as the primary research method. This MR analysis analyzed data of 3022 colorectal cancer cases and 174,006 controls from the FinnGen database. Single nucleotide polymorphisms (SNPs) associated with unhealthy lifestyle factors were selected as instrumental variables (IVs), including two obesity-related indicators, BMI (body mass index) and WHR (waist-to-hip ratio). Four phenotypes of smoking (smoking initiation, ever smoked, smoking per day, smoking cessation) and one phenotype of alcohol consumption (drinks per week). Four phenotypes of physical activity (accelerometer-based physical activity, moderate-to-vigorous physical activity, vigorous physical activity, strenuous sports or other exercises). All SNPs were obtained from published genome-wide association studies. The study found that the obesity-related indicator, higher WHR (OR = 1.38, 95% CI 1.12-1.70; P = 0.002) were associated with an increased risk of colorectal cancer, and two smoking phenotypes, cigarettes per day(OR = 1.30, 95% CI 1.01-1.68; P = 0.042)and smoking initiation (OR = 3.48, 95% CI 1.15-10.55; P = 0.028), were potentially associated with an increased risk of colorectal cancer. However, there was no evidence to suggest that physical activities and alcohol consumption were associated with colorectal cancer (all p > 0.05). In addition, the study detected no pleiotropy (all p > 0.05). This MR analysis indicates a causal association between a higher waist-to-hip ratio and the risk of colorectal cancer and a suggestive association between smoking and the risk of colorectal cancer among Europeans. These findings contribute to the understanding of the etiology of colorectal cancer and have potential implications for its prevention.

Effects of dietary intervention on diabetic nephropathy: an umbrella review of systematic reviews and meta-analyses of randomized controlled trials.

Objective: To evaluate the quality of evidence, potential biases, and validity of all available studies on dietary intervention and diabetic nephropathy (DN). Methods: We conducted an umbrella review of existing meta-analyses of randomized controlled trials (RCTs) that focused on the effects of dietary intervention on DN incidence. The literature was searched via PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. According to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE), evidence of each outcome was evaluated and graded as "high", "moderate", "low" or "very low" quality to draw conclusions. Additionally, we classified evidence of outcomes into 4 categories. Results: We identified 36 meta-analyses of RCTs and 55 clinical outcomes of DN from 395 unique articles. Moderate-quality evidence suggested that probiotic supplementation could significantly improve blood urea nitrogen (BUN), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in DN patients. Low-quality evidence indicated that probiotic supplementation significantly improved the serum creatinine concentration, urinary albumin-creatinine ratio (UACR), fasting blood glucose (FBG), HbA1c and high-density lipoprotein cholesterol (HDL-C) in DN patients. In addition, low-quality evidence suggested that a salt restriction diet could significantly improve the creatinine clearance rate (CrCl) in patients with DN. Low-quality evidence suggested that vitamin D supplementation could significantly improve the UACR in patients with DN. In addition, low-quality evidence has indicated that soy isoflavone supplementation could significantly improve BUN, FBG, total cholesterol (TC), triglyceride (TG) and LDL-C levels in patients with DN. Furthermore, low-quality evidence suggested that coenzyme Q10 supplementation could significantly improve HbA1c, TC and HDL-C in patients with DN, and dietary polyphenols also significantly improved HbA1c in patients with DN. Finally, low-quality evidence suggested that supplementation with antioxidant vitamins could significantly improve the serum creatinine concentration, systolic blood pressure, and HbA1c level in patients with DN. Given the small sample size, all significantly associated outcomes were evaluated as class IV evidence. Conclusion: Moderate to low amounts of evidence suggest that supplementation with probiotics, vitamin D, soy isoflavones, coenzyme Q10, dietary polyphenols, antioxidant vitamins, or salt-restricted diets may significantly improve clinical outcomes in patients with DN. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024512670.

Efficacy and safety of mirikizumab as induction and maintenance therapy for Japanese patients with moderately to severely active ulcerative colitis: a subgroup analysis of the global phase 3 LUCENT-1 and LUCENT-2 studies.

BACKGROUND/AIMS: Mirikizumab is a p19-directed anti-interleukin-23 antibody with potential efficacy against ulcerative colitis (UC). We evaluated the efficacy and safety of mirikizumab in a Japanese subpopulation with moderately to severely active UC from the LUCENT-1 and LUCENT-2 studies. METHODS: LUCENT-1 and LUCENT-2 were phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab therapy in adults with moderately to severely active UC. LUCENT-1 was a 12-week induction trial where patients were randomized 3:1 to receive intravenous mirikizumab 300 mg or placebo every 4 weeks (Q4W). Patients achieving a clinical response with mirikizumab following the induction study were re-randomized 2:1 to double-blind treatment with either mirikizumab 200 mg or placebo subcutaneously Q4W during the 40-week maintenance study. The primary outcomes were clinical remission at week 12 of LUCENT-1 and week 40 of LUCENT-2. RESULTS: A total of 137 patients enrolled in Japan were randomized to mirikizumab (n = 102) or placebo (n = 35). Compared with placebo, patients who received mirikizumab showed numerically higher clinical remission at week 12 of induction (32.4% [n = 33] vs. 2.9% [n = 1]) and at week 40 of maintenance (48.9% [n = 23] vs. 28.0% [n = 7]). A greater number of patients achieved key secondary endpoints in the mirikizumab group compared with placebo. The frequency of treatment-emergent adverse events was similar across mirikizumab and placebo groups. Efficacy and safety results observed in the Japanese subpopulation were generally consistent with those in the overall population. CONCLUSIONS: Mirikizumab induction and maintenance treatments were effective in Japanese patients with moderately to severely active UC. No new safety concerns were identified.

Evaluation of the prediction effectiveness for geochemical mapping using machine learning methods: A case study from northern Guangdong Province in China.

This study compares seven machine learning models to investigate whether they improve the accuracy of geochemical mapping compared to ordinary kriging (OK). Arsenic is widely present in soil due to human activities and soil parent material, posing significant toxicity. Predicting the spatial distribution of elements in soil has become a current research hotspot. Lianzhou City in northern Guangdong Province, China, was chosen as the study area, collecting a total of 2908 surface soil samples from 0 to 20 cm depth. Seven machine learning models were chosen: Random Forest (RF), Support Vector Machine (SVM), Ridge Regression (Ridge), Gradient Boosting Decision Tree (GBDT), Artificial Neural Network (ANN), K-Nearest Neighbors (KNN), and Gaussian Process Regression (GPR). Exploring the advantages and disadvantages of machine learning and traditional geological statistical models in predicting the spatial distribution of heavy metal elements, this study also analyzes factors affecting the accuracy of element prediction. The two best-performing models in the original model, RF (R2 = 0.445) and GBDT (R2 = 0.414), did not outperform OK (R2 = 0.459) in terms of prediction accuracy. Ridge and GPR, the worst-performing methods, have R2 values of only 0.201 and 0.248, respectively. To improve the models' prediction accuracy, a spatial regionalized (SR) covariate index was added. Improvements varied among different methods, with RF and GBDT increasing their R2 values from 0.4 to 0.78 after enhancement. In contrast, the GPR model showed the least significant improvement, with its R2 value only reaching 0.25 in the improved method. This study concluded that choosing the right machine learning model and considering factors that influence prediction accuracy, such as regional variations, the number of sampling points, and their distribution, are crucial for ensuring the accuracy of predictions. This provides valuable insights for future research in this area.

VNS improves VSMC metabolism and arteriogenesis in infarcted hearts through m/n-AChR-Akt-SDF-1α in adult male rats.

Vagal nerve stimulation (VNS) provides a novel therapeutic strategy for injured hearts by activating cholinergic anti-inflammatory pathways. However, little information is available on the metabolic pattern and arteriogenesis of VSMCs after MI. VNS has been shown to stimulate the expression of CPT1α, CPT1ß, Glut1, Glut4 and SDF-1α in coronary VSMCs, decreasing the number of CD68-positive macrophages while increasing CD206-positive macrophages in the infarcted hearts, leading to a decrease in TNF-α and IL-1ß accompanied by a reduced ratio of CD68- and CD206-positive cells, which were dramatically abolished by atropine and mecamylamine in vivo. Knockdown of SDF-1α substantially abrogated the effect of VNS on macrophagecell alteration and inflammatory factors in infarcted hearts. Mechanistically, ACh induced SDF-1α expression in VSMCs in a dose-dependent manner. Conversely, atropine, mecamylamine, and a PI3K/Akt inhibitor completely eliminated the effect of ACh on SDF-1α expression. Functionally, VNS promoted arteriogenesis and improved left ventricular performance, which could be abolished by Ad-shSDF-1α. Thus, VNS altered the VSMC metabolism pattern and arteriogenesis to repair the infarcted heart by inducing SDF-1α expression, which was associated with the m/nAChR-Akt signaling pathway.

Geochemical characteristics and health risks of heavy metals in agricultural soils and crops from a coal mining area in Anhui province, China.

Soil contamination by heavy metals (HMs) in mining areas is a major issue because of its significant impact on the environmental quality and physical health of residents. Mining of minerals used in energy production, particularly coal, has led to HMs entering the surrounding soil through geochemical pathways. In this study, a total of 166 surface soil and 100 wheat grain samples around the Guobei coal mine in southeast China were collected, and trace metal levels were determined via inductively coupled plasma mass spectrometry (ICP-MS). The average HMs (Ni, As, Cr, Cu, Pb, Cd, and Zn) concentrations were lower than the screening values in China (GB 15618-2018) but higher than the soil background values in the Huaibei Bozhou area of Anhui Province (except Zn), indicating HMs enrichment. Based on the geoaccumulation index (Igeo) and ecological risk index (IER), Cd pollution levels were low, while for the other metals the samples were pollution-free, and therefore no ecological risk warning was issued for the mining area. Both Cr and Pb had a higher noncarcinogenic health risks for adults and children. The lifetime carcinogenic risks (LCR) of Cr, Pb, and Cd were within acceptable levels. A positive matrix factorization (PMF) model identified two factors that could explain the HMs sources: factor 1 for Zn, Cd, and Pb, factor 2 for Ni, As, Cr, and Cu. Furthermore, HMs enrichment was observed in surface soil and the Carboniferous-Permian coal seams in the Guobei coal mine, which may suggest that coal mining is an important source for HMs enrichment in surface soil. Overall, this study provides a theoretical basis for undertaking the management and assessment of soil HMs pollution around a coal mine.

Structural and dynamical properties of concentrated alkali- and alkaline-earth metal chloride aqueous solutions.

Concentrated ionic aqueous electrolytes possess a diverse array of applications across various fields, particularly in the field of energy storage. Despite extensive examination, the intricate relationships and numerous physical mechanisms underpinning diverse phenomena remain incompletely understood. Molecular dynamics simulations are employed to probe the attributes of aqueous solutions containing LiCl, NaCl, KCl, MgCl2, and CaCl2, spanning various solute fractions. The primary emphasis of the simulations is on unraveling the intricate interplay between these attributes and the underlying physical mechanisms. The configurations of cation-Cl- and Cl--Cl- pairs within these solutions are disclosed. As the solute fraction increases, consistent trends manifest regardless of solute type: (i) the number of hydrogen bonds formed by the hydration water surrounding ions decreases, primarily attributed to the growing presence of counter ions in proximity to the hydration water; (ii) the hydration number of ions exhibits varying trends influenced by multiple factor; and (iii) the diffusion of ions slows down, attributed to the enhanced confinement and rebound of cations and Cl- ions from the surrounding atoms, concurrently coupled with the changes in ion vibration modes. In our analysis, we have, for the first time, clarified the reasons behind the slowing down of the diffusion of the ions with increasing solute fraction. Our research contributes to a better understanding and manipulation of the attributes of ionic aqueous solutions and may help designing high-performance electrolytes.

Efficacy of Chinese traditional patent medicines for heart failure with preserved ejection fraction: a Bayesian network meta-analysis of 64 randomized controlled trials.

Background: Heart failure with preserved ejection fraction (HFpEF) is associated with substantial morbidity and mortality, and modern medicine offers less effective treatment for HFpEF. Much evidence shows that Chinese traditional patent medicines (CTPMs) have good efficacy for HFpEF, but the advantages and disadvantages of different CTPMs for HFpEF are still unclear. This study used network meta-analysis (NMA) to compare clinical efficacies of different CTPMs for HFpEF. Methods: Randomized controlled trials (RCTs) of CTPMs for treating HFpEF were searched in seven Chinese and English databases from inception to September 2023: China National Knowledge Infrastructure (CNKI), Wanfang, VIP, China Biology Medicine, PubMed, Cochrane Library, and Embase. Two researchers independently screened the literature, extracted data, and evaluated the quality of the included studies. The GeMTC package in R (version 4.1.2) was used to perform Bayesian NMA. Results: A total of 64 RCTs were included, involving six CTPMs and 6,238 patients. The six CTPMs were Qili Qiangxin capsule (QLQXC), Qishen Yiqi dropping pill (QSYQDP), Yixinshu capsule (YXSC), Yangxinshi tablet (YXST), Shexiang Baoxin Pill (SXBXP), and Tongxinluo capsule (TXLC). Conventional Western medicine (CWM) treatment was given to the control group, and CWM treatment combined with CTPM treatment was given to the experimental group. The results indicated that CPTMs + CWM were all superior to CWM alone; SXBXP + CWM had the best efficacies in improving the New York Heart Association cardiac functional classification efficiency; TXLC + CWM was best at improving the ratio of early diastolic mitral inflow velocity to late diastolic mitral inflow velocity (E/A); QSYQDP + CWM was best at reducing N-terminal pro-B type natriuretic peptide (NT-proBNP); and QSYQDP + CWM was best at improving the 6-min walking test. In terms of safety, there was no significant difference between CTPMs + CWM and CWM. Conclusion: Compared with CWM alone, CTPMs + CWM combinations have certain advantages and good safety in the treatment of HFpEF. QSYQDP + CWM and SXBXP + CWM may be the potential optimal integrative medicine-based treatments for HFpEF. Given the limitations of this study, further high-quality, multicenter, large sample, randomized, and double-blind studies are needed to confirm the current results. Systematic Review Registration: identifier, CRD42022303938.

[Regularity of prescriptions for sick sinus syndrome based on latent structure combined with association rules].

This study aims to mine the regularity of traditional Chinese medicine(TCM) prescriptions for sick sinus syndrome(SSS) and provide a reference for clinical syndrome differentiation and treatment. The relevant papers were retrieved from CNKI, Wanfang, VIP, and SinoMed with the time interval from inception to January 31, 2023. The relevant information from qualified papers was extracted to establish a library. Lantern 5.0 and Rstudio were used to analyze the latent structure and association rules of TCMs with the frequency ≥3%, which combined with frequency descriptions, were used to explore the rules of TCM prescriptions for SSS. A total of 192 TCM prescriptions were included, involving 115 TCMs with the cumulative frequency of 1 816. High-frequency TCMs include Aconiti Lateralis Radix Praeparata, Ginseng Radix et Rhizoma, Glycyrrhizae Radix et Rhizoma, Astragali Radix, and Salviae Miltiorrhizae Radix et Rhizoma. The high-frequency medicines mainly had the effects of tonifying, releasing exterior with pungent-warm, and activating blood and resolving stasis. The analysis of the latent structure model yielded 13 hidden variables, 26 hidden classes, 8 comprehensive cluster models, and 21 core prescriptions. Accordingly, the common syndromes of SSS were inferred as heart-Yang Qi deficiency, heart-spleen Yang deficiency, heart-kidney Yang deficiency, Yang deficiency and blood stasis, both Qi and Yin deficiency and blood stasis, and Yin and Yang deficiency. The analysis of association rules predicted 30 strong association rules, among which Ginseng Radix et Rhizoma-Aconiti Lateralis Radix Praeparata had the highest support. SSS is a syndrome with Yang deficiency and Qi deficiency as the root causes and cold, phlegm, and stasis as the manifestations. The clinical treatment of SSS should focus on warming Yang and replenishing Qi, which should be supplemented with the therapies of activating blood and resolving stasis, warming interior and dissipating cold, or regulating Qi movement for resolving phlegm according to the patients' syndromes.

Immunotherapy strategies for EGFR-mutated advanced NSCLC after EGFR tyrosine-kinase inhibitors failure.

Background: This study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Methods: We retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test. Results: A total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group. Conclusion: NSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

Vagus nerve stimulation-induced stromal cell-derived factor-l alpha participates in angiogenesis and repair of infarcted hearts.

AIMS: We aim to explore the role and mechanism of vagus nerve stimulation (VNS) in coronary endothelial cells and angiogenesis in infarcted hearts. METHODS AND RESULTS: Seven days after rat myocardial infarction (MI) was prepared by ligation of the left anterior descending coronary artery, the left cervical vagus nerve was treated with electrical stimulation 1 h after intraperitoneal administration of the α7-nicotinic acetylcholine inhibitor mecamylamine or the mAChR inhibitor atropine or 3 days after local injection of Ad-shSDF-1α into the infarcted heart. Cardiac tissue acetylcholine (ACh) and serum ACh, tumour necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6) levels were detected by ELISA to determine whether VNS was successful. An inflammatory injury model in human coronary artery endothelial cells (HCAECs) was established by lipopolysaccharide and identified by evaluating TNF-α, IL-1ß and IL-6 levels and tube formation. Immunohistochemistry staining was performed to evaluate CD31-positive vessel density and stromal cell-derived factor-l alpha (SDF-1α) expression in the MI heart in vivo and the expression and distribution of SDF-1α, C-X-C motif chemokine receptor 4 and CXCR7 in HCAECs in vitro. Western blotting was used to detect the levels of SDF-1α, V-akt murine thymoma viral oncogene homolog (AKT), phosphorylated AKT (pAKT), specificity protein 1 (Sp1) and phosphorylation of Sp1 in HCAECs. Left ventricular performance, including left ventricular systolic pressure, left ventricular end-diastolic pressure and rate of the rise and fall of ventricular pressure, should be evaluated 28 days after VNS treatment. VNS was successfully established for MI therapy with decreases in serum TNF-α, IL-1ß and IL-6 levels and increases in cardiac tissue and serum ACh levels, leading to increased SDF-1α expression in coronary endothelial cells of MI hearts, triggering angiogenesis of MI hearts with increased CD31-positive vessel density, which was abolished by the m/nAChR inhibitors mecamylamine and atropine or knockdown of SDF-1α by shRNA. ACh promoted SDF-1α expression and its distribution along with the branch of the formed tube in HCAECs, resulting in an increase in the number of tubes formed in HCAECs. ACh increased the levels of pAKT and phosphorylation of Sp1 in HCAECs, resulting in inducing SDF-1α expression, and the specific effects could be abolished by mecamylamine, atropine, the PI3K/AKT blocker wortmannin or the Sp1 blocker mithramycin. Functionally, VNS improved left ventricular performance, which could be abolished by Ad-shSDF-1α. CONCLUSIONS: VNS promoted angiogenesis to repair the infarcted heart by inducing SDF-1α expression and redistribution along new branches during angiogenesis, which was associated with the m/nAChR-AKT-Sp1 signalling pathway.

A comparison of the biomechanical properties of three different lumbar internal fixation methods in the treatment of lumbosacral spinal tuberculosis: finite element analysis.

There are various internal fixation methods in treating lumbosacral spinal tuberculosis. The study compared the stability and stress distribution in surrounding tissues/implants, such as discs, endplates and screw-rod internal fixation system, etc. when applying three different lumbar internal fixation methods to treat lumbosacral spinal tuberculosis. A finite element model was constructed and validated. The spinal stability was restored using three methods: a titanium cage with lateral double screw-rod fixation (group 1), autologous bone with posterior double screw-rod fixation (group 2), and a titanium cage with posterior double screw-rod fixation (group 3). For comparison, group 4 represented the intact L3-S1 spine. Finally, a load was applied, and the ranges of motion and Von Mises stresses in the cortical endplates, screw-rod internal fixation system and cortical bone around the screws in the different groups were recorded and analyzed. All six ranges of motion (flexion, extension, left/right lateral bending, left/right rotation) of the surgical segment were substantially lower in groups 1 (0.53° ~ 1.41°), 2 (0.68° ~ 1.54°) and 3 (0.55° ~ 0.64°) than in group 4 (4.48° ~ 10.12°). The maximum stress in the screw-rod internal fixation system was clearly higher in group 2 than in groups 1 and 3 under flexion, left/right lateral bending, and left/right rotation. However, in extension, group 1 had the highest maximum stress in the screw-rod internal fixation system. Group 2 had the lowest peak stresses in the cortical endplates in all directions. The peak stresses in the cortical bone around the screws were higher in group 1 and group 2 than in group 3 in all directions. Thus, titanium cage with posterior double screw-rod fixation has more advantages in immediate reconstruction of lumbosacral spinal stability and prevention of screw loosening.

Earliest systematic coal exploitation for fuel extended to ~3600 B.P.

Coal has long fueled human civilizations. The history of systematic coal fuel exploitation has been traced back to the late third millennium before present (post-2500 B.P.). Although sporadic combustion of coal for fuel was reported in some prehistoric archaeological sites, evidence for the systematic exploitation of coal for fuel before 2500 B.P. remains lacking. Here, we report comprehensive understanding for the earliest systematic exploitation of coal for fuel at the Jirentaigoukou site in Xinjiang, northwestern China, at ~3600 B.P. The main body of the site witnessed systematic exploitation of bituminous coals, illustrating a complete chaîne opératoire with selective mining, planned storage, and extensive combustion. Our results transform the knowledge of energy history by extending the upper limit of the systematic exploitation of coal for fuel by approximately a millennium, and provide a precedent of energy transition under intense conflict between social demand and environmental deterioration.

Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Biocompatibility and osseointegration properties of a novel high strength and low modulus ß- Ti10Mo6Zr4Sn3Nb alloy.

Introduction: Ti6Al4V titanium alloy is widely used in producing orthopedic and maxillofacial implants, but drawbacks include high elastic modulus, poor osseointegration performance, and toxic elements. A new medical titanium alloy material with better comprehensive performance is urgently needed in the clinic. Methods: Ti10Mo6Zr4Sn3Nb titanium alloy (referred to as Ti-B12) is a unique medical ß titanium alloy material developed by us. The mechanical properties of Ti-B12 depict that it has advantages, such as high strength, low elastic modulus, and fatigue resistance. In our study, the biocompatibility and osseointegration properties of Ti-B12 titanium alloy are further studied to provide theoretical guidance for its clinical transformation. Results and Discussion: The titanium alloy Ti-B12 displays no significant effect on MC3T3-E1 cell morphology, proliferation, or apoptosis in vitro. Neither Ti-B12 titanium alloy nor Ti6Al4V titanium alloy depicts a significant difference (p > 0.05); Ti-B12 material extract injected into the abdominal cavity of mice does not cause acute systemic toxicity. The skin irritation test and intradermal irritation test reveal that Ti-B12 does not cause skin allergic reactions in rabbits. Compared to Ti6Al4V, Ti-B12 titanium alloy material has more advantages in promoting osteoblast adhesion and ALP secretion (p < 0.05). Although there is no significant difference in OCN and Runx2 gene expression between the three groups on the 7th and 14th days of differentiation induction (p > 0.05), the expression of Ti-B12 group is higher than that of Ti6Al4V group and blank control group. Furthermore, the rabbit in vivo test present that 3 months after the material is implanted in the lateral epicondyle of the rabbit femur, the Ti-B12 material fuses with the surrounding bone without connective tissue wrapping. This study confirms that the new ß-titanium alloy Ti-B12 not only has low toxicity and does not cause rejection reaction but also has better osseointegration performance than the traditional titanium alloy Ti6Al4V. Therefore, Ti-B12 material is expected to be further promoted in clinical practice.

The spatiotemporal matching pattern of Ezrin/Periaxin involved in myoblast differentiation and fusion and Charcot-Marie-Tooth disease-associated muscle atrophy.

BACKGROUND: Clinically, Charcot-Marie-Tooth disease (CMT)-associated muscle atrophy still lacks effective treatment. Deletion and mutation of L-periaxin can be involved in CMT type 4F (CMT4F) by destroying the myelin sheath form, which may be related to the inhibitory role of Ezrin in the self-association of L-periaxin. However, it is still unknown whether L-periaxin and Ezrin are independently or interactively involved in the process of muscle atrophy by affecting the function of muscle satellite cells. METHOD: A gastrocnemius muscle atrophy model was prepared to mimic CMT4F and its associated muscle atrophy by mechanical clamping of the peroneal nerve. Differentiating C2C12 myoblast cells were treated with adenovirus-mediated overexpression or knockdown of Ezrin. Then, overexpression of L-periaxin and NFATc1/c2 or knockdown of L-periaxin and NFATc3/c4 mediated by adenovirus vectors were used to confirm their role in Ezrin-mediated myoblast differentiation, myotube formation and gastrocnemius muscle repair in a peroneal nerve injury model. RNA-seq, real-time PCR, immunofluorescence staining and Western blot were used in the above observation. RESULTS: For the first time, instantaneous L-periaxin expression was highest on the 6th day, while Ezrin expression peaked on the 4th day during myoblast differentiation/fusion in vitro. In vivo transduction of adenovirus vectors carrying Ezrin, but not Periaxin, into the gastrocnemius muscle in a peroneal nerve injury model increased the numbers of muscle myosin heavy chain (MyHC) I and II type myofibers, reducing muscle atrophy and fibrosis. Local muscle injection of overexpressed Ezrin combined with incubation of knockdown L-periaxin within the injured peroneal nerve or injection of knockdown L-periaxin into peroneal nerve-injured gastrocnemius muscle not only increased the number of muscle fibers but also recovered their size to a relatively normal level in vivo. Overexpression of Ezrin promoted myoblast differentiation/fusion, inducing increased MyHC-I+ and MyHC-II + muscle fiber specialization, and the specific effects could be enhanced by the addition of adenovirus vectors for knockdown of L-periaxin by shRNA. Overexpression of L-periaxin did not alter the inhibitory effects on myoblast differentiation and fusion mediated by knockdown of Ezrin by shRNA in vitro but decreased myotube length and size. Mechanistically, overexpressing Ezrin did not alter protein kinase A gamma catalytic subunit (PKA-γ cat), protein kinase A I alpha regulatory subunit (PKA reg Iα) or PKA reg Iß levels but increased PKA-α cat and PKA reg II α levels, leading to a decreased ratio of PKA reg I/II. The PKA inhibitor H-89 remarkably abolished the effects of overexpressing-Ezrin on increased myoblast differentiation/fusion. In contrast, knockdown of Ezrin by shRNA significantly delayed myoblast differentiation/fusion accompanied by an increased PKA reg I/II ratio, and the inhibitory effects could be eliminated by the PKA reg activator N6-Bz-cAMP. Meanwhile, overexpressing Ezrin enhanced type I muscle fiber specialization, accompanied by an increase in NFATc2/c3 levels and a decrease in NFATc1 levels. Furthermore, overexpressing NFATc2 or knocking down NFATc3 reversed the inhibitory effects of Ezrin knockdown on myoblast differentiation/fusion. CONCLUSIONS: The spatiotemporal pattern of Ezrin/Periaxin expression was involved in the control of myoblast differentiation/fusion, myotube length and size, and myofiber specialization, which was related to the activated PKA-NFAT-MEF2C signaling pathway, providing a novel L-Periaxin/Ezrin joint strategy for the treatment of muscle atrophy induced by nerve injury, especially in CMT4F.

Automatic breast cancer diagnosis based on hybrid dimensionality reduction technique and ensemble classification.

INTRODUCTION: Feature selection in the face of high-dimensional data can reduce overfitting and learning time, and at the same time improve the accuracy and efficiency of the system. Since there are many irrelevant and redundant features in breast cancer diagnosis, removing such features leads to more accurate prediction and reduced decision time when dealing with large-scale data. Meanwhile, ensemble classifiers are powerful techniques to improve the prediction performance of classification models, where several individual classifier models are combined to achieve higher accuracy. METHODS: In this paper, an ensemble classifier algorithm based on multilayer perceptron neural network is proposed for the classification task, in which the parameters (e.g., number of hidden layers, number of neurons in each hidden layer, and weights of links) are adjusted based on an evolutionary approach. Meanwhile, this paper uses a hybrid dimensionality reduction technique based on principal component analysis and information gain to address this problem. RESULTS: The effectiveness of the proposed algorithm was evaluated based on the Wisconsin breast cancer database. In particular, the proposed algorithm provides an average of 17% better accuracy compared to the best results obtained from the existing state-of-the-art methods. CONCLUSION: Experimental results show that the proposed algorithm can be used as an intelligent medical assistant system for breast cancer diagnosis.

Clinical Effect of Mirikizumab Treatment on Bowel Urgency in Patients with Moderately to Severely Active Ulcerative Colitis and the Clinical Relevance of Bowel Urgency Improvement for Disease Remission.

Background: Bowel urgency reduces ulcerative colitis patients' quality of life. Mirikizumab, a p19-directed anti-IL-23 antibody, demonstrates ulcerative colitis efficacy. Mirikizumab efficacy to reduce bowel urgency and bowel urgency association with other endpoints were analyzed in 2 Phase 3 trials. Methods: LUCENT-1 (Induction): 1162 patients randomized 3:1 to intravenous 300 mg mirikizumab or placebo every 4 weeks for 12 weeks. LUCENT-2 (Maintenance): 544 mirikizumab responders during induction were re-randomized 2:1 to subcutaneous mirikizumab 200 mg or placebo every 4 weeks for 40 weeks (52 weeks of continuous treatment). Bowel urgency was measured using the Urgency Numeric Rating Scale (0-10); for patients with LUCENT-1 baseline score ≥3, bowel urgency clinically meaningful improvement (≥3-point decrease) and remission (score ≤1) rates in mirikizumab versus placebo groups were compared at Weeks 12 and 52. Associations between bowel urgency and other efficacy endpoints were assessed at Weeks 12 and 52. Results: A significantly higher proportion of mirikizumab patients versus placebo achieved clinically meaningful improvement in bowel urgency and remission at Weeks 12 and 52. Significantly higher percentages of patients achieving bowel urgency clinically meaningful improvement or remission, compared with those who did not, also achieved endpoints for clinical, corticosteroid-free, endoscopic, and symptomatic remission; clinical response; normalized fecal calprotectin and C-reactive protein; and improved quality of life. Conclusions: In patients with ulcerative colitis, bowel urgency improvement was associated with better clinical outcomes than in patients without improvement during induction and maintenance. A greater proportion of mirikizumab patients achieved sustainable bowel urgency improvement and remission compared to placebo patients.