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Xingtong Chen,1,&ast; Qian Chen,1– 3,&ast; Zhigang Qin,1,&ast; Azeem Alam,3 Hailin Zhao,3 Raha West,3 Xianzhe Liu,1 Jieyu Li,1 Xin Li,1 Bin Yi,1 Daqing Ma,2,3 Jianteng Gu1 1Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, People’s Republic of China; 2Perioperative and Systems Medicine Laboratory, National Clinical Research Center for Child Health, Children’s Hospital, Zhejiang University School of Medicine, Zhejiang, People’s Republic of China; 3Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK&ast;These authors contributed equally to this workCorrespondence: Jianteng Gu, Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), 30 Gaotanyan Road, Chongqing, 400038, People’s Republic of China, Tel +86 23 68766122, Fax +86 23 65463270, Email jiantenggu@hotmail.com Daqing Ma, Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK, Email d.ma@imperial.ac.ukBackground: Dexmedetomidine (Dex) may have anti-inflammatory properties and potentially reduce the incidence of postoperative organ injury.Objective: To investigate whether Dex protects pulmonary and renal function via its anti-inflammatory effects in elderly patients undergoing prolonged major hepatobiliary and pancreatic surgery.Design and Setting: Between October 2019 and December 2020, this randomized controlled trial was carried out at a tertiary hospital in Chongqing, China.Patients: 86 patients aged 60– 75 who underwent long-duration (> 4 hrs) hepatobiliary and pancreatic surgery without significant comorbidities were enrolled and randomly assigned into two groups at a 1:1 ratio.Interventions: Patients were given either Dex or an equivalent volume of 0.9% saline (Placebo) with a loading dose of 1 μg kg− 1 for 10 min, followed by 0.5 μg kg− 1 hr− 1 for maintenance until the end of surgery.Main Outcome Measures: The changes in serum concentrations of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α) were primary outcomes.Results: At one hour postoperatively, serum IL-6 displayed a nine-fold increase (P< 0.05) in the Placebo group. Administration of Dex decreased IL-6 to 278.09 ± 45.43 pg/mL (95% CI: 187.75 to 368.43) compared to the Placebo group (P=0.019; 432.16 ± 45.43 pg/mL, 95% CI: 341.82 to 522.50). However, no significant differences in TNF-α were observed between the two groups. The incidence of postoperative acute kidney injury was twice as high in the Placebo group (9.30%) compared to the Dex group (4.65%), and the incidence of postoperative acute lung injury was 23.26% in the Dex group, lower than that in the Placebo group (30.23%), although there was no statistical significance between the two groups.Conclusion: Dex administration in elderly patients undergoing major hepatobiliary and pancreatic surgery reduces inflammation and potentially protects kidneys and lungs.Registration: Chinese Clinical Trials Registry, identifier: ChiCTR1900024162, on 28 June 2019.Keywords: dexmedetomidine, elderly patients, long-duration hepatobiliary and pancreatic laparotomy, perioperative renal function, perioperative pulmonary function

Kun Wang,1 Wei Zhu,2 Wei Huang,3 Kangkang Huang,1 Huidan Luo,1 Lu Long,1 Bin Yi1 1Department of Clinical Laboratory, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 2Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of China; 3Research Center of Carcinogenesis and Targeted Therapy, Xiangya Hospital, Central South University, Changsha, Hunan Province, People’s Republic of ChinaCorrespondence: Bin Yi, Tel +86-13707495781, Email xyyibin@163.comObjective: Ubiquitination is an important post-translational modification. However, the significance of the TRIM family of E3 ubiquitin ligases in head and neck squamous cell carcinoma (HNSCC) has not been determined. In this study, the roles of TRIM E3 ubiquitin ligases in lymphovascular invasion in head and neck squamous cell carcinoma (HNSCC) were evaluated.Materials and Methods: TRIM expression and related parameters were obtained from UbiBrowser2.0, UALCAN, TIMER, TISIDB, LinkedOmics, STRING, and GeneMANIA databases. Immunohistochemistry was used to confirm their expression.Results: TRIM2, TRIM11, TRIM28, and TRIM56 were upregulated in HNSCC with lymphovascular invasion. TRIM expression was strongly associated with immune infiltration, including key treatment targets, like PD-1 and CTL4. Co-expressed genes and possible ubiquitination substrates included tumor-related factors. The TRIMs had predicted roles in ubiquitination-related pathways and vital signaling pathways, eg, MAPK, PI3K-Akt, and JAK-STAT signaling pathways.Conclusion: Ubiquitination mediated by four TRIMs might be involved in the regulation of tumor immunity, laying the foundation for future studies of the roles of the TRIM family on the prediction and personalized medicine in HNSCC. The four TRIMs might exert oncogenic effects by promoting lymphovascular invasion in HNSCC.Keywords: ubiquitination, TRIM, head and neck squamous cell carcinoma, bioinformatic analysis, lymphovascular invasion

Runting Ma, Lianhong Zhou, Wenping Li, Yuanjin Li, Diewenjie Hu, Yi Lu, Cancan Zhang, Beixi Yi Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of ChinaCorrespondence: Lianhong Zhou, Department of Ophthalmology, Renmin Hospital of Wuhan University, No. 238 Jiefang Road, Wuhan, 430060, People’s Republic of China, Tel +86 027-88041911-81219, Email zlh681102@aliyun.comPurpose: This study aimed to analyze myopia distribution in Hubei and the impact of regional Sunshine Duration on myopia in children and adolescents.Patients and Methods: The Cross-sectional study included students (kindergarten to grade 12) through multistage cluster stratified sampling in 17 cities (103 areas) of Hubei, China, who underwent ophthalmic examinations from September 2021 to November 2021. The association of sunshine duration with the prevalence and distribution of myopia was analyzed. Using Moran’s index to quantify the distribution relationship, a spatial analysis was constructed.Results: A total of 435,996 students (53.33% male; mean age, 12.16± 3.74 years) were included in the study. A negative association was identified between myopia prevalence and sunshine duration in the region, especially in population of primary students (r=− 0.316, p< 0.001). Each 1-unit increment in the sunshine duration was associated with a decreased risk of myopia prevalence (OR=0.996; 95% CI, 0.995– 0.998; P < 0.001). Regression showed a linear relationship between sunshine duration and myopia rates of primary school students [Prevalence%= (− 0.1331&ast;sunshine duration+47.73)%, p = 0.02]. Sunshine duration influenced the distribution of myopia rates among primary (Moran’s I=− 0.206, p< 0.001) and junior high school (Moran’s I=− 0.183, p=0.002). Local spatial analysis showed that areas with low sunshine duration had high myopia prevalence concentration.Conclusion: This study revealed sunshine duration associations with myopia prevalence at the regional and population levels. The results may emphasize the significance of promptly implementing myopia control in regions with poor sunshine. The effect of sunshine on myopia is pronounced in the early years of education, especially in primary students.Keywords: myopia, sunshine duration, children, Spatial Analysis, Moran’s Index, epidemiology

Jingyun Shi,1,&ast; Fangping Zhao,1,&ast; Wanyin Yang,2 Yuru Zhu,1 Min Wang,1 Bin Yi1 1Department of NICU, Gansu Provincial Maternal and Child Care Hospital (Gansu Provincial Central Hospital), Lanzhou City, Gansu, 730050, People’s Republic of China; 2Department of NICU, Gansu University of Chinese Medicine, Lanzhou City, Gansu, 730050, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Min Wang; Bin Yi, Department of NICU, Gansu Provincial Maternal and Child care Hospital (Gansu Provincial Central Hospital), No. 143 of Qilihe North Street, Qilihe District, Lanzhou, 730050, People’s Republic of China, Tel +86 13919819662, Email wangmin_wm23@126.com; yibin_bin001@tom.comObjective: To explore the status and influencing factors of COVID-19 vaccination for 3– 7-year-old children born prematurely.Methods: A questionnaire was administered to parents of preterm infants born between 1 January 2016 and 31 December 2019 in Gansu Maternal and Child Health Hospital using convenience sampling.Results: It was found that 96.81% of 282 parents had known about COVID-19 vaccines and acquired COVID-19- and vaccine-related knowledge primarily through WeChat (104/282, 36.88%) and TikTok (91/282, 32.27%). Most parents of the group whose children were vaccinated with a COVID-19 vaccine believed that this approach was effective in preventing COVID-19 (49.75%), whereas most parents of the group whose children were not vaccinated were worried about the adverse reaction and safety of the vaccine (45.88%). According to the regression analysis, the risk factors of children born prematurely receiving a COVID-19 vaccine were no vaccination against COVID-19 in the mothers (odds ratio [OR]=48.489, 95% CI: 6.524– 360.406) and in younger children (OR=12.157, 95% CI: 6.388– 23.139). Previous history of referral (OR=0.229, 95% CI: 0.057– 0.920), history of diseases (OR=0.130, 95% CI: 0.034– 0.503) and high educational level of guardians (OR=0.142, 95% CI: 0.112– 0.557) were protective factors for children born prematurely to receive COVID-19 vaccination.Conclusion: There is a relatively high proportion of children born prematurely receiving COVID-19 vaccination, but some people still have concerns. Publicity in the later stage can be conducted through WeChat, TikTok and other social media platforms, with special attention paid to the populations with lower education levels.Keywords: COVID-19 vaccine, vaccination willingness, children born prematurely, influencing factors

The empirical analysis method of researching the influencing factors of road traffic accidents has significant importance in deepening the understanding of accident mechanisms, guiding traffic management, and improving traffic safety. In order to solve the problem of low accuracy in traditional methods of analysis, a new empirical analysis method of factors influencing road traffic accidents based on structural equation modeling is proposed. Road traffic accident data is collected, and an improved KNN algorithm is used to repair the collected data. Based on principles such as comprehensiveness, relevance, and representativeness, a preliminary index system for road traffic accident influencing factors is constructed, and grey relational degree is used to select the influencing factor indicators. Based on this, research hypotheses are proposed, and a structural equation model is constructed combining measurement models and structural models. The model is then subjected to procedures such as least squares estimation and correction, with the road traffic accident influencing factor indicators as variables of the structural equation model, to achieve empirical analysis of the structural equation model. The empirical analysis results show that factors such as personnel, vehicles, roads, environment, and management have a direct impact on the probability of road traffic accidents. The average accuracy of the analysis is 98.27%, indicating that it can be widely applied in the field of empirical analysis of road traffic accident influencing factors. [ABSTRACT FROM AUTHOR]

The [Fe]/H 2 O 2 oxidation system has found wide applications in chemistry and biology. Halogenation with this [Fe]/H 2 O 2 oxidation protocol and halide (X - ) in the biological system is well established with the identification of heme-iron-dependent haloperoxidases. However, mimicking such halogenation process is rarely explored for practical use in organic synthesis. Here, we report the development of a nonheme iron catalyst that mimics the heme-iron-dependent haloperoxidases to catalyze the generation of HOBr from H 2 O 2 /Br - with high efficiency. We discovered that a tridentate terpyridine (TPY) ligand designed for Fenton chemistry was optimal for FeBr 3 to form a stable nonheme iron catalyst [Fe(TPY)Br 3 ], which catalyzed arene bromination, Hunsdiecker-type decarboxylative bromination, bromolactonization, and oxidation of sulfides and thiols. Mechanistic studies revealed that Fenton chemistry ([Fe]/H 2 O 2 ) might operate to generate hydroxyl radical (HO • ), which oxidize bromide ion [Br - ] into reactive HOBr. This nonheme iron catalyst represents a biomimetic model for heme-iron-dependent haloperoxidases with potential applications in organic synthesis, drug discovery, and biology.

China's electric power industry has made significant efforts to reduce environmental externality in the past two decades. However, the extent of the reduction, the driving factors behind it, and the regional performance are not well clarified. This study constructs a comprehensive framework that integrates the impact pathway approach with index decomposition analysis to explore the driving factors behind the reduction of environmental externality from a spatial-temporal perspective. First, the Greenhouse Gas-Air Pollution Interactions and Synergies (GAINS) model is adopted in the impact pathway approach to assess the environmental losses in China's electric power industry. Second, the temporal index decomposition analysis is used to explore the driving factors behind the reduction in environmental losses during 2005-2020. Third, the spatial index decomposition analysis is employed to investigate the differences in environmental performance across regions and the driving forces behind these differences. The results show that the environmental losses caused by China's electric power industry have been significantly reduced from 3082.1 thousand years of life lost (YLL) in 2005 to 892.3 thousand YLL in 2020, mainly due to the reduction in air pollutant emissions, followed by the cleaner power structure and the adjustment of the spatial layout of electricity. While, increases in power generation scale, population size, and aging have played a negative role in reducing environmental losses. The gaps in environmental losses per unit of electricity between different provinces can be tens or even hundreds of times. The primary drivers of these gaps, apart from the power structure, are atmospheric dispersion conditions and population density. While, the differences in emission intensity effects among provinces are relatively small. Thus, the orientation of policy design needs to shift from setting stricter emission concentration limits to adjusting energy structure and enhancing the construction of electricity transfer channels. Government departments should consider the implicit environmental externality from a more macro perspective when conducting power planning and management., Competing Interests: Declaration of competing interest No conflict of interest exits in the submission of this manuscript, and manuscript is approved by all authors for publication. I would like to declare on behalf of my co-authors that the work described was original research that has not been published previously, and not under consideration for publication elsewhere, in whole or in part. All the authors listed have approved the manuscript that is enclosed., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This study aimed to explore the potential of ANXA6 as a biomarker and its possible mechanisms, like its expression patterns and clinical significance, as well as exploring its underlying biological functions and regulatory networks in nasopharyngeal carcinoma (NPC). Differentially expressed proteins were identified by proteomics technology. PCR, western blotting, immunohistochemistry, and ELISA analysis of serum were used to analyze ANXA6's clinical role. GEO databases investigated its prognosis relationship. Seven databases predicted transcription factors, and GO, KEGG analyzed ANXA6's mechanism. Immune infiltration and immunotherapy datasets were also examined. ANXA6 was significantly downregulated in NPC, linked to poor survival advantage. Its expression level was closely correlated with primary lesion size, lymph node metastasis, distant metastasis and clinical stage. Low serum ANXA6 was associated with lymph node and distant metastasis. MYC may regulate ANXA6 in NPC. Functional analysis revealed co-expressed genes related to immune cells. ANXA6 was linked to immune infiltration and response. High ANXA6 expression predicted better immunotherapy and influenced drug sensitivity. ANXA6, negatively correlated with NPC development and metastasis, is a potential prognostic biomarker with tumor-suppressing effects. Multi-omics analysis highlights its clinical and immune regulatory roles, offering insights for future biomarker and molecular mechanism studies in NPC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Bacterial contamination is an intractable challenge in food safety, environments and biomedicine fields, and places a heavy burden on society. Polydopamine (PDA), a high molecular biopolymer, is considered as a promising candidate to participate in the design of novel antibacterial agents with unique contributions in biocompatibility, adherence, photothermal and metal coordination ability. In this study, coral-like ZIFL-PDA@AgNPs with excellent antibacterial properties and biocompatibility were prepared by embedding AgNPs into the biopolymer PDA-modulated ZIFL-PDA nanostructures by green reduction method to solve the problem with poor stability of AgNPs. Based on the plasma resonance effect of AgNPs, coral-like ZIFL-PDA@AgNPs had enhanced photothermal properties compared with ZIFL-PDA. Due to the synergistic effect between antibacterial metal ions mainly Ag + and the photothermal effect, coral-like ZIFL-PDA@AgNPs showed enhanced anti-mature biofilm and antibacterial properties, which was dependent on its concentration and sterilization time. In addition, regulated by the ZIFL-PDA nanostructure, coral-like ZIFL-PDA@AgNPs demonstrated a unique Ag + long-time sustained release behavior, giving it an extended antibacterial validity period and good biocompatibility. Antibacterial mechanism experiments indicated that coral-like ZIFL-PDA@AgNPs can significantly damage the integrity of bacterial cell membrane, reduce the content of ATP in bacterial by affecting the activity of succinate dehydrogenase, and induce the accumulation of reactive oxygen species, ultimately leading to bacterial death., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The structure-activity relationship (SAR) between toxicity and the types of linking ketones of C7 bridged monocarbonyl curcumin analogs (MCAs) was not clear yet. In the pursuit of effective and less cytotoxic chemotherapeutics, we conducted a SAR analysis using various diketene skeletons of C7-bridged MCAs, synthesized cyclic C7-bridged MCAs containing the identified low-toxicity cyclopentanone scaffold and an o -methoxy phenyl group, and assessed their anti-gastric cancer activity and safety profile. Most compounds exhibited potent cytotoxic activities against gastric cancer cells. We developed a quantitative structure-activity relationship model ( R 2 > 0.82) by random Forest method, providing important information for optimizing structure. An optimized compound 2 exhibited in vitro and in vivo anti-gastric cancer activity partly through inhibiting the AKT and STAT3 pathways, and displayed a favorable in vivo safety profile. In summary, this paper provided a promising class of MCAs and a potential compound for the development of chemotherapeutic drugs.

Objectives: This study aimed to translate the Vocal Fatigue Index (VFI) into Simplified Chinese and test its reliability and validity in mainland China., Methods: The original English version of the VFI was translated and adapted to a Simplified Chinese version (VFI -SC). Fifty-four participants with voice disorders and 21 healthy controls completed the VFI-SC. Sixteen participants with voice disorders completed it again two weeks later. Reliability, validity, and receiver operating characteristic (ROC) of the VFI-SC were analyzed., Results: The Cronbach's alpha values for the VFI factor scores were found to be 0.930 for tiredness and avoidance of voice use (factor 1), 0.878 for physical discomfort with voice use (factor 2), and 0.915 for improvement of symptoms with voice rest (factor 3). The test-retest reliability was 0.967 for all three factors. There was a significant difference between the total scores of the patient group and the control group ( p  < 0.01). Factor 1 and factor 2 were positively correlated with the Voice Handicap Index (VHI-30). The ROC curves showed acceptable intrinsic accuracies for factor 1 (AUC = 0.883), factor 2 (AUC = 0.901), and factor 3 (AUC = 0.800), with cutoff scores of 22, 7, and 9, respectively., Conclusions: This study provides preliminary evidence that the VFI-SC has good reliability and validity. It can be used to screen for clinical symptoms of voice fatigue in mainland China.

Background: The evaluation of HPV vaccine effectiveness is essential for informing public health strategies, yet there remains a gap in understanding humoral immune responses generated by different HPV vaccine formulations in regional populations. This study addresses this gap by evaluating the immunogenicity of the newly developed HPV vaccine Cecolin (Wantai), alongside various imported vaccines, including bivalent, quadrivalent, and nonavalent options available in China., Methods: From March 2023 to June 2024, a total of 352 participants were enrolled, including 87 females aged 9-14 years who received two doses of the bivalent HPV vaccine (Cecolin), 215 females aged 15-45 years who were fully vaccinated with various HPV vaccines, and 50 non-recipients. Follow-up assessments were conducted at six timepoints during the administration of Cecolin. Serum was collected at enrollment and at each follow-up visit for antibody assessments using a pseudovirion-based neutralization assay (PBNA)., Findings: The longitudinal follow-up of females aged 9-14 years revealed a 100% conversion rate for neutralizing antibodies against HPV types 16 and 18 after the second dose, compared to 94.3% and 97.1% conversion rates six months after the first dose. Compared to participants who received full doses of quadrivalent and nonavalent vaccines, females who received two or three doses of Cecolin exhibited higher neutralizing antibody geometric mean titers (GMTs) and non-vaccine-type (HPV31 and HPV33) antibody seroconversion rates., Interpretation: The domestically produced HPV vaccine Cecolin in China demonstrates strong immunogenicity and holds promise for the large-scale vaccination of females in developing countries to prevent cervical cancer.

Purpose: Pencil-beam scanning proton therapy has been considered a potential modality for the 3D form of spatially fractionated radiation therapy called lattice therapy. However, few practical solutions have been introduced in the clinic. Existing limitations include degradation in plan quality and robustness when using single-field versus multifield lattice plans, respectively. We propose a practical and robust proton lattice (RPL) planning method using multifield and evaluate its dosimetric characteristics compared to clinically acceptable photon lattice plans., Methods and Materials: Seven cases previously treated with photon lattice therapy were used to evaluate a novel RPL planning technique using 2-orthogonal beams: a primary beam (PB) and a robust complementary beam (RCB) that deliver 67% and 33%, respectively, of the prescribed dose to vertices inside the gross target volume (GTV). Only RCB is robustly optimized for setup and range uncertainties. The number and volume of vertices, peak-to-valley dose ratios (PVDRs), and volume of low dose to GTV of proton and photon plans were compared. The RPL technique was then used in the treatment of 2 patients and their dosimetric parameters were reported., Results: The RPL strategy was able to achieve the clinical planning goals. Compared to previously treated photon plans, the average number of vertices increased by 30%, the average vertex volume by 49% (18.2 ± 25.9 cc vs 12.2 ± 14.5 cc, P = .21), and higher PVDR (10.5 ± 4.8 vs 2.5 ± 0.9, P < .005) was achieved. In addition, RPL plans show more conformal dose with less low dose to GTV (V30%, 60.9% ± 7.2% vs 81.6% ± 13.9% and V10%, 88.3% ± 4.5% vs 98.6% ± 3.6% [P < .01]). The RPL plan for 2 treated patients showed PVDRs of 4.61 and 14.85 with vertices-to-GTV ratios of 1.52% and 1.30%, respectively., Conclusions: A novel RPL planning strategy using a pair of orthogonal beams was developed and successfully translated to the clinic. The proposed method can generate better quality plans, a higher number of vertices, and higher PVDRs than currently used photon lattice plans., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The gut microbiome-metabolites-kidney axis is a potential target for treating diabetic kidney disease (DKD). Our previous study found that Liraglutide attenuated DKD in rats by decreasing renal tubular ectopic lipid deposition (ELD) and serum metabolites levels, including L-5-Oxoproline (5-OP). However, the response of gut microbiome-metabolites-kidney axis to Liraglutide in DKD rats and the effect of 5-OP on ELD remain unknown. In this study, Sprague-Dawley rats were used as an animal model of DKD. They were subjected to a high fat diet, streptozotocin and uninephrectomy, followed by Liraglutide treatment (0.4 mg/kg d). Additionally, HK-2 cells were incubated with 30 mM glucose and 200 μM palmitate for 24h, and exposed to different concentrations of 5-OP. In DKD rats, Liraglutide dramatically improved the renal tubule structure. It increased the Simpson index (F = 4.487, p = 0.035) and reduced the Actinobacteria-to-Bacteroidetes ratio (F = 6.189, p = 0.014). At the genus level, Liraglutide increased the relative abundance of Clostridium, Oscillospira, Sarcina, SMB53, and 02d06 while decreasing that of Allobaculum. Meanwhile, 13 metabolites were significantly altered after Liraglutide treatment. Multi-omics analysis found that 5-OP levels were positively correlated with Clostridium abundance but negatively correlated with renal injury related indicators. In HK-2 cells, 5-OP significantly reduced the ELD in a dose-dependent manner through inhibiting the expression of SREBP1 and FAS. Overall, the renoprotective effect of Liraglutide in DKD rats is linked to the improvement of the gut microbiota composition and increased serum 5-OP levels, which may reduce ELD in renal tubular cells by lowering lipid synthesis., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: To evaluate the diagnostic accuracy of machine learning models incorporating multimodal features for predicting radiation pneumonitis in lung cancer through a systematic review and meta-analysis., Methods: Relevant studies were identified through a systematic search of PubMed, Web of Science, Embase, and the Cochrane Library from October 2003 to December 2023. Additional studies were located by reviewing bibliographies and relevant websites. Two independent researchers screened titles, abstracts, and full-text articles according to predefined inclusion and exclusion criteria. Data extraction was performed using standardized forms, and study quality was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 tool. The primary outcomes, including combined sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC), were calculated using STATA MP-64 software(Stata Corporation LLC, College Station, USA) with a random-effects model. Meta-analysis was conducted to synthesize diagnostic accuracy measures, and analyses of heterogeneity and publication bias were performed., Results: A total of 1,406 patients with primary lung cancer were included in this systematic review, drawing data from 9 studies. The pooled analysis revealed a sensitivity of 0.74 [0.58-0.85] and a specificity of 0.91 [0.87-0.95] for machine learning models in diagnosing radiation pneumonitis. The positive likelihood ratio (PLR) was 8.69 [5.21-14.50], the negative likelihood ratio (NLR) was 0.28 [0.16-0.49], and the diagnostic odds ratio (DOR) was 30.73 [11.96-78.97]. The area under the curve (AUC) was 0.93 [0.90-0.95], indicating excellent diagnostic performance. Meta-regression analysis identified that the number of machine learning models, year of publication, and study design contributed to heterogeneity among studies. No evidence of publication bias was found. Overall, machine learning models incorporating multimodal characteristics demonstrated 75% accuracy in predicting moderate to severe radiation pneumonitis., Conclusion: In conclusion, by integrating the current machine learning (ML) algorithm's ability in big data mining, a predictive model can be constructed by combining multi-modal features such as genetics, imaging, and cell factors. By selecting multiple machine learning algorithm frameworks and competing for the best combination model based on research goals, the reliability and accuracy of the radiation pneumonitis prediction model can be greatly improved., Trial Registration: PROSPERO (CRD42024497599)., (© 2024. The Author(s).)

Purpose: To explore the feasibility of a novel intensity-modulated proton arc technique that uses a single-energy beam from the cyclotron. The beam energy is externally modulated at each gantry angle by a tertiary energy modulator (EM). We hypothesize that irradiating in an arc without requiring an energy change from the cyclotron will achieve a faster delivery (main advantage of our technique) while keeping clinically desirable dosimetric results., Methods: In a retrospective cohort of four patients with female pelvis, prostate, lung, and brain cancers, we investigated our volumetric-modulated proton arc therapy (VPAT) technique. Arcs were simulated by sectors of 1°-spaced static beams. Keeping the energy requested from the cyclotron the same for each entire arc was supported by a predesigned EM placed in front of the nozzle. As a feasibility measure, EM thicknesses were calculated. Delivery times and doses to targets and organs at risk (OARs) were compared to those of the clinical plans., Results: VPAT plans were comparable to their clinical counterparts in achieving target dose conformity, being robust to uncertainties, and meeting clinical dose-volume constraints. Cyclotron energies for the four cases were within 159-220 MeV, and energy modulation range was 69-100 MeV, equivalent to 13-19 cm of water-equivalent thickness (WET). Plan delivery times were reduced from > 5 min in our clinical practice to < 3.5 min in VPAT., Conclusion: For the evaluated plans, the novel VPAT approach achieved shorter delivery times without sacrificing robustness, OAR sparing or target coverage. VPAT's EMs had WETs implementable in a clinical setup., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

The harmful effects of PM 2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM 2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM 2.5 ) for 8 weeks. PM 2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM 2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM 2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM 2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM 2.5 -increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM 2.5 -induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM 2.5 -induced kidney injury and the protective effect of metformin on PM 2.5 -induced cellular damage, offering new insights for air pollution-related renal diseases.

Effective treatment of myocardial ischemia-reperfusion (MIR) injury remains an unmet clinical need. Cardiomyocyte apoptosis is common at this stage and poses a significant risk. Corylin, a flavonoid compound extracted from Psoralea corylifolia L., has been shown to have anti-inflammatory, anticancer, and antiatherosclerotic properties. However, whether and how corylin affects MIR injury remain unclear. In this study, we explored the mechanism of corylin as a potent therapeutic agent for MI/R injury, using a left anterior descending (LAD) coronary artery ligation and oxygen-glucose deprivation and reperfusion (OGD/R) model in vivo and in vitro. TUNEL, Annexin-V/PI double staining,Ki67 immunohistochemistry, western blot analysis, and immunofluorescence were used to validate cell apoptosis level and Raf-1/ASK1 complex activity. The interaction between corylin and Raf-1/ASK1 complex was detected using molecular docking, corylin-Raf-1 binding assays, and coimmunoprecipitation (Co-IP). Moreover, TTC staining, echocardiography, HE staining, Masson trichrome staining and serological testing were performed to assess the cardioprotective effects of corylin in vivo. These findings showed that corylin reduces MIR injury-induced cardiomyocyte apoptosis and improves cardiac function. Mechanistically, corylin can interact with Raf-1 and promote the formation of the Raf-1/ASK1 complex, thus inhibiting cardiomyocyte apoptosis. In conclusion, our results demonstrate that corylin ameliorated cardiac dysfunction after MIR injury by reducing myocardial apoptosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Erythropalum scandens Bl. is a medicinal woody vegetable found in southern China and parts of Southeast Asia. Studies have shown improper substrate hindered E. scandens seedling growth, causing water accumulation and nutrient deficiency. In pursuit of an ideal growth medium for E. scandens seedlings during the early stages, this study conducted a pot experiment to identify a mixed substrate with optimal water permeability and fertility. In this study, pure Alfisols soil treatment as the control (CK), and two soilless substrates (peat soil and perlite) were combined with Alfisols soil into different volume ratios, in order to better use soil resources from understory space and balance the texture of mixed substrates. The growth, physiological characteristics and nutrient status of 24-month-old E. scandens seedlings were determined after planting in different mixed ratios. The results showed that as the proportion of peat soil increased in the mix, most indexes exhibited an initial increase followed by a decline, while soluble protein content decreased consistently. Conversely, an increasing perlite ratio resulted in a general decline in most growth and physiological indexes. Root growth, biomass accumulation and chlorophyll content, peaked in the 66.67% Alfisols soil + 33.33% perlite (T4) treatment. Notably, T3 (66.67% Alfisols soil + 33.33% peat soil) showcased the best above-ground growth, while T1 (50.00% Alfisols soil + 50.00% peat soil) excelled in element content accumulation. In conclusion, the cultivation substrate should primarily consist of Alfisols soil, constituting at least 50%. The addition of peat soil enhances above-ground growth and nutrients accumulation, while perlite contributes to robust root development. One third of peat soil and a small amount of perlite can be added to the substrate during E. scandens seedling cultivation, and proper fertilization should also be used in order to increase nutrient accumulation in aboveground and underground parts. This research provides valuable insights into maximizing the potential of E. scandens seedlings through precise cultivation methods., (© 2024. The Author(s).)

Background: Slow transit constipation (STC) is highly prevalent and has rising incidence. Shouhui Tongbian capsule (SHTB) is a traditional Chinese Medicine formula with extensive and highly efficacious usage in STC treatment, however, its mechanism of action, especially the regulation of microbiome and lipid metabolites, remains unclear., Methods: After quality control of SHTB using LC‒MS to obtain its material basis, we tried to elucidate the cohesive modulatory network of SHTB against STC using hyphenated methods from microbiomics, lipidomics, mass spectrometry imaging (MSI) and molecular methods., Results: SHTB could repair intestinal barrier damage, reduce systemic inflammation and increase intestinal motility in a diphenoxylate-induced STC rat model. Based on 16S rDNA sequencing results, SHTB rehabilitated the abnormal changes in Alloprevotella, Coprococcus, Marvinbryantia, etc., which were associated with STC symptoms. Meanwhile, microbial functional prediction showed that lipid metabolism was improved with SHTB administration. The differential lipids, including fatty acids, lysophosphatidylcholine, phosphatidylcholine, sphingomyelin triglyceride and ceramide, that are closely related to STC disease and SHTB efficacy. Furthermore, SHTB significantly reversed the abnormal expression of these key target enzymes in colon samples, including CTP-phosphocholine cytidylyltransferase, CTP-phosphoethanolamine cytidylyltransferase, phosphatidic acid phosphatase, acid sphingomyelinase etc. CONCLUSIONS: Combined analysis demonstrated that SHTB reducing lipid accumulation and recovery of intestinal microbial homeostasis was the critical mechanism by which SHTB treats STC., (© 2024. The Author(s).)

The permeability glycoprotein, encoded by the ABCB1 gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate that the P-gp-mediated efflux ratio can be minimized by computationally driven optimization of the molecular dipole and/or cp K a without recourse to intramolecular hydrogen bonds.

HIF-1 activation is protective in acute kidney injury (AKI), but its underlying mechanism is not fully understood. Stress-induced tRNA derived small RNAs play an emerging role in cellular processes. This study investigated the role of HIF-1 associated tiRNA-Lys-CTT-003 (tiR-Lys) in an AKI mouse model. Our sequencing results showed that ischemia can promote the production of renal tiR-Lys by activating HIF-1α. FG-4592, a HIF-1 inducer, can also upregulate the expression of tiR-Lys in renal tubular cells. Both overexpression of tiR-Lys and FG-4592 pre-treatment could improve mitochondrial damage and lipid peroxidation with alleviated renal function and morphological damage in cisplatin-induced AKI mice. While the anti-ferroptosis effect of FG-4592 were largely eliminated by tiR-Lys inhibitor. Notably, tiR-Lys directly alleviated cell death and MDA accumulation induced by the ferroptosis inducer Erastin, accompanied with restored expression of GPX4. RNA-Pulldown and RIP-qPCR results revealed that tiR-Lys can interact with the RNA-binding protein GRSF1.tiR-lys overexpression can preserve protein expression of GRSF1 decreased by cisplatin. Inhibiting Grsf1 via shRNA eliminated the upregulation of GPX4 by tiR-Lys. In conclusion, our study demonstrates that HIF-1α-induced tiR-Lys is protective in cisplatin-induced AKI, primarily by upregulating the level of GPX4 through interaction with GRSF1, thereby inhibiting ferroptosis in renal tubular epithelial cells., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Traditional tendon engineering using cell-loaded scaffold has limited application potential due to the need of autologous cells. We hypothesize that potent mechanical loading can efficiently induce in situ Achilles tendon regeneration in a rabbit model by using a cell-free porous composite scaffold. In this study, melt-spinning was used to fabricate PGA (polyglycolic acid) and PLA (polylactic acid) filament fibers as well as non-woven PGA fibers. The PLA/PGA (4:2) filament fibers were further braided into a hybrid yarn，which was knitted into a PLA/PGA tubular mesh with potent mechanical property for sustaining natural tendon strain. The results showed that a complete cross-section of Achilles tendon created a model of full mechanical loading on the bridging scaffold, which could efficiently induce in situ tendon regeneration by promoting host cell infiltration, matrix production and tissue remodeling. Histologically, mechanical loading assisted in forming parallel aligned collagen fibers and tenocytes in a fashion similar to those of native tendon. Transmission electron microscope further demonstrated that mechanical strain induced collagen fibril development by increasing fibril diameter and forming bipolar structure, which resulted in enhanced mechanical properties. Interestingly, the synergistic effect between mechanical loading and hyaluronic acid modification was also observed on the induced tenogenic differentiation of infiltrated host fibroblasts. In conclusion, potent mechanical loading is the key inductive microenvironment for in situ tendon regeneration for this polymer-based composite scaffold with proper matrix modification, which may serve as a universal scaffold product for tendon regeneration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The membrane lipid damage caused by reactive oxygen species(ROS) and various peroxides, namely lipid peroxidation, plays an important role in the progression of diabetic nephropathy (DN).We previously reported that vitamin D receptor(VDR) plays an active role in DN mice by modulating autophagy disorders. However, it is unclear whether the ATP-citrate lyase (ACLY)/NF-E2-related factor-2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) pathway is associated with the reduction of lipid peroxidation by VDR in the DN model. We found that in the DN mouse model, VDR knockout significantly aggravated mitochondrial morphological damage caused by DN, increased the expression of ACLY, promoted the accumulation of ROS, lipid peroxidation products Malondialdehyde(MDA) and 4-hydroxy-2-nonenal (4-HNE),consumed the Nrf2/Keap1 system, thus increasing lipid peroxidation. However, the overexpression of VDR and intervention with the VDR agonist paricalcitol (Pari) can reduce the above damage. On the other hand, cellular experiments have shown that Pari can significantly reduce the elevated expression of ACLY and ROS induced by advanced glycation end products (AGE). However, ACLY overexpression partially eliminated the positive effects of the VDR agonist. Next, we verified the transcriptional regulation of ACLY by VDR through chromatin immunoprecipitation (ChIP)-qPCR and dual luciferase experiments. Moreover, in AGE models, knockdown of ACLY decreased lipid peroxidation and ROS production, while intervention with Nrf2 inhibitor ML385 partially weakened the protective effect of ACLY downregulation. In summary, VDR negatively regulates the expression of ACLY through transcription, thereby affecting the state of Nrf2/Keap1 system and regulating lipid peroxidation, thereby inhibiting kidney injury induced by DN., (© 2024 Federation of American Societies for Experimental Biology.)

Background: Evidence suggests that insulin resistance (IR) is an autonomous risk factor for cardiovascular disease (CVD). Nevertheless, the association between estimated glucose disposal rate (eGDR), a novel indicator of IR, and incident CVD and mortality in chronic kidney disease (CKD) patients without diabetes remains uncertain., Methods: The study included 19,906 participants from the UK Biobank who had an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m 2 or a urinary albumin-to-creatinine ratio (UACR) ≥ 30 mg/g and no history of CVD and diabetes. Individuals were divided into three categories based on tertiles of eGDR. The outcome was a composite CVD (coronary heart disease (CHD) and stroke) and mortality (all-cause, non-accidental, and cardiovascular mortality). Furthermore, a cohort of 1,600 individuals from the US National Health and Nutrition Examination Survey (NHANES) was applied to validate the association between eGDR and mortality. The Cox proportional hazards regression models were used to examine the association between eGDR and event outcomes., Results: During a follow-up of around 12 years, 2,860 CVD, 2,249 CHD, 783 stroke, 2,431 all-cause, 2,326 non-accidental and 492 cardiovascular deaths were recorded from UK Biobank. Higher eGDR level was not only associated with lower risk of CVD (hazard ratio [HR] 0.641, 95% confidence interval [CI] 0.559-0.734), CHD (HR 0.607, 95% CI 0.520-0.709), stroke (HR 0.748, 95% CI 0.579-0.966), but also related to reduced risk of all-cause (HR 0.803, 95% CI 0.698-0.923), non-accidental (HR 0.787, 95% CI 0.682-0.908), and cardiovascular mortality (HR 0.592, 95% CI 0.423-0.829). Validation analyses from NHANES yielded consistent relationship on mortality., Conclusions: In these two large cohorts of CKD patients without DM, a higher eGDR level was associated with a decreased risk of CVD and mortality., (© 2024. The Author(s).)

Rapeseed (Brassica napus) is an important oilseed crop worldwide. Plant vascular tissues are responsible for long-distance transport of water and nutrients and for providing mechanical support. The lateral roots absorb water and nutrients. The genetic basis of vascular tissue and lateral root development in rapeseed remains unknown. This study characterized an ethyl methanesulfonate-mutagenized rapeseed mutant, T16, which showed dwarf stature, reduced lateral roots, and leaf wilting. SEM observations showed that the internode cells were shortened. Observations of tissue sections revealed defects in vascular bundle development in the stems and petioles. Genetic analysis revealed that the phenotypes of T16 were controlled by a single semi-dominant nuclear gene. Map-based cloning and genetic complementarity identified BnaA03.IAA13 as the functional gene; a G-to-A mutation in the second exon changed glycine at position 79 to glutamic acid, disrupting the conserved degron motif VGWPP. Transcriptome analysis in roots and stems showed that auxin and cytokinin signaling pathways were disordered in T16. Evolutionary analysis showed that AUXIN/INDOLE-3-ACETIC ACID is conserved during plant evolution. The heterozygote of T16 showed significantly reduced plant height while maintaining other agronomic traits. Our findings provide novel insights into the regulatory mechanisms of vascular tissue and lateral root development, and offer a new germplasm resource for rapeseed breeding., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Experimental Biology.)

Objectives: This study aims to investigate the speech characteristics and assess the potential risk of voice fatigue and voice disorders in Chinese transgender women (TW)., Methods: A case-control study was conducted involving TW recruited in Shanghai, China. The participants included 15 TW, 20 cisgender men (CISM), and 20 cisgender women (CISW). Acoustic parameters including formants (F 1 , F 2 , F 3 , F 4 ), cepstral peak prominence (CPP), jitter, shimmer, harmonic-to-noise ratio (HNR), noise-to-harmonics (NHR), fundamental frequency (f 0 ), and intensity, across vowels, passages, and free talking. Additionally, the Voice Handicap Index-10 (VHI-10) and the Voice Fatigue Index were administered to evaluate voice-related concerns., Results: (1) The F 1 of TW was significantly higher than that of CISW for the vowels /i/ and /u/, and significantly higher than that of CISM for the vowels /a/, /i/, and /u/. The F 2 of TW was significantly lower than CISW for the vowels /i/, significantly higher than CISW for the vowels /u/, and significantly higher than CISM for the vowels /a/ and /u/. F 3 was significantly lower in TW than in CISW for the vowels /a/ and /i/. The F4 formant was significantly lower in TW than in CISW for the vowels /a/ and /i/, but significantly higher than in CISM for the vowel /u/. (2) The f 0 of TW was significantly lower than that of CISW for the vowels /a/, /i/, /u/, during passage reading, and in free speech, but was significantly higher than CISM during passage reading and free talking. Additionally, TW exhibited significantly higher intensity compared with CISW for the vowel /a/ and during passage reading. (3) Jitter in TW was significantly higher than in CISW for the vowels /i/ and /u/, and significantly lower than in CISM during passage reading and free talking. Shimmer was significantly higher in TW compared with both CISW and CISM across the vowels /a/, /i/, during passage reading, and in free talking. The HNR in TW was significantly lower than in both CISW and CISM across all vowels, during passage reading, and in free talking. The NHR was significantly higher in TW than in CISW across all vowels, during passage reading, and in free talking, and significantly higher than in CISM for the vowels /a/, /i/, during passage reading, and in free talking. The CPP in TW was significantly lower than in CISW during passage reading and free talking, and significantly lower than in CISM across all vowels, during passage reading, and in free speech. (4) The VHI-10 scores were significantly higher in TW compared with both CISM and CISW., Conclusions: TW exhibit certain acoustic parameters, such as f 0 and some of the formants, that fall between those of CISW and CISM without undergoing phonosurgery or voice training. The findings suggest a potential risk for voice fatigue and the development of voice disorders as TW try to modify their vocal characteristics to align with their gender identity., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest. The authors are responsible for the authenticity and originality of the research and paper., (Copyright © 2024 The Voice Foundation. Published by Elsevier Inc. All rights reserved.)

We report herein a photoinduced radical 1,3-dipolar cycloaddition between the 2-benzothiazolimines and tetrahydroisoquinoline derivatives with an organo-photocatalyst. A variety of benzothiazole-based hexahydroimidazo[2,1- a ]isoquinoline architectures with great synthetic value were conveniently and efficiently constructed in moderate to good yields and excellent diastereoselectivities with highly tolerant functional groups. Moreover, the practicality and utility of this protocol were demonstrated by scale-up synthesis and facile elaboration. Preliminary mechanistic investigations indicated that the reaction proceeded via a visible-light-induced radical 1,3-dipolar cycloaddition pathway. This finding is expected to stimulate a more extensive exploration of the green and concise synthesis of structurally diverse heterocyclic molecules in the synthetic community.

Introduction: This study aimed to examine the susceptibility profile of Escherichia coli in urinary tract infections (UTIs) among elderly diabetic patients to support judicious and evidence-based antibiotic use., Methods: From January 2021 to December 2022, urine culture results were analyzed to determine the distribution of pathogens, especially E. coli, and their drug susceptibility., Results: E. coli infection was the most prevalent infection in elderly diabetic patients with UTIs, accounting for 32.6% of cases. Moreover, this bacterium's multiple resistance rate (38.3%) was significantly higher than other bacteria's multiple resistance rate (χ2 = 81.644, p &lt; 0.05). Compared to older diabetic patients with optimal glucose control (HbA1c ≤7.0%), patients with poor glycemic control (HbA1c &gt;7.0%) had lower resistance rates to lactams, and urine pH values were higher (p &lt; 0.05)., Conclusion: The most common cause of UTIs is E. coli, with advanced age and diabetes being the main risk factors. To optimize UTI treatment safety and efficacy, antibiotics should be administered based on the patient's age and blood glucose control., (© 2024 S. Karger AG, Basel.)

The traditional Mongolian medicine Erdun-Uril is a conventional combination of 29 herbs commonly used for the treatment of cerebrovascular ailments. It has the effects of reducing inflammation, counteracting oxidative stress, and averting strokes caused by persistent cerebral hypoperfusion. Prior research on Erdun-Uril has predominantly concentrated on its pharmacodynamics and mechanism of action; however, there has been a lack of systematic and comprehensive investigation into its chemical constituents. Therefore, it is crucial to establish an efficient and rapid method for evaluating the chemical constituents of Erdun-Uril. In this study, Erdun-Uril was investigated using UHPLC-Q-Exactive Orbitrap MS combined with parallel reaction monitoring for the first time. Eventually, a total of 237 compounds, including 76 flavonoids, 68 phenolic compounds, 19 alkaloids, 7 amino acids, etc., were identified based on the chromatographic retention time, bibliography data, MS/MS 2 information, neutral loss fragments (NLFs), and diagnostic fragment ions (DFIs). And of these, 225 were reported for the first time in this study. This new discovery of these complex components would provide a reliable theoretical basis for the development of pharmacodynamics and quality standards of the Mongolian medicine Erdun-Uril.

Background: Optical flow ratio (OFR) is a novel computational fractional flow reserve derived from optical coherence tomography (OCT). However, the impact of combining post-stenting morphology (OCT) and physiology (OFR) remains largely unknown., Methods: OCT and OFR were analysed at an independent core laboratory. Target lesion failure (TLF) was defined as the composite of cardiac death, target lesion myocardial infarction, and target lesion revascularisation. Suboptimal stent deployment was identified with at least 1 TLF-related OCT or OFR characteristic., Results: A total of 448 patients with acute coronary syndrome (459 vessels) were assessed. Stent expansion < 80%, minimal stent area < 4.5 mm 2 , stent edge lipid-rich plaque and OFR < 0.90 were independent predictors of TLF (all P < 0.001). Patients with OCT-suboptimal (adjusted hazard ratio [aHR] 7.88, 95% CI 2.73-22.72,-P < 0.001) or OFR-suboptimal (aHR 5.78, 95% CI 2.54-13.14; P < 0.001) stent deployment showed significantly higher risk of TLF compared with those with optimal stent deployment, with a significant interaction (P interaction < 0.001). OCT and OFR both-suboptimal stent deployment was confirmed as an independent predictor of TLF (aHR 9.39, 95% CI 4.25-20.76; P < 0.001)., Conclusions: Combined OCT and OFR conferred an optimal reclassification of stent deployment, which may aid in decision making regarding a tailored PCI strategy for optimal stent deployment., (Copyright © 2024. Published by Elsevier Inc.)

Solid-state potassium metal batteries are promising candidates for grid-scale energy storage due to their low cost, high energy density and inherent safety. However, solid state K-ion conductors struggle with poor ionic conductivity due to the large ionic radius of K + -ions. Herein, we report precise regulation of phase heterogeneity and reciprocity of the P2/P3-symbiosis K 0.62 Mg 0.54 Sb 0.46 O 2 solid electrolyte (SE) for boosting a high ionic conductivity of 1.6×10 -4  S cm -1 at 25 °C. The bulk ionic conducting mechanism is explored by elucidating the effect of atomic stacking mode within the layered framework on K + -ion migration barriers. For ion diffusion at grain boundaries, the P2/P3 biphasic symbiosis property assists in tunning the SE microstructure, which crystallizes in rod-like particles with lengths of tens of micrometers facilitating long-distance ion transport and significantly decreasing grain boundary resistance. Potassium metal symmetric cells using the modified SE deliver excellent cycling life over 300 h at 0.1 mA cm -2 and a high critical current density of 0.68 mA cm -2 . The quasi-solid-state potassium metal batteries (QSSKBs) coupled with two kinds of layered oxide cathodes demonstrate remarkable stability over 300 cycles, outperforming the liquid electrolyte counterparts. The QSSKB system provides a promising strategy for high-efficiency, safe, and durable large-scale energy storage., (© 2024 Wiley-VCH GmbH.)

Crossovers create genetic diversity and are required for equal chromosome segregation during meiosis. Crossover number and distribution are highly regulated by different mechanisms that are not yet fully understood, including crossover interference. The chromosome axis is crucial for crossover formation. Here, we explore the function of the axis protein ASYNAPSIS3. To this end, we use the allotetraploid species Brassica napus; due to its polyploid nature, this system allows a fine-grained dissection of the dosage of meiotic regulators. The simultaneous mutation of all 4 ASY3 alleles results in defective synapsis and drastic reduction of crossovers, which is largely rescued by the presence of only one functional ASY3 allele. Crucially, while the number of class I crossovers in mutants with 2 functional ASY3 alleles is comparable to that in wild type, this number is significantly increased in mutants with only one functional ASY3 allele, indicating that reducing ASY3 dosage increases crossover formation. Moreover, the class I crossovers on each bivalent in mutants with 1 functional ASY3 allele follow a random distribution, indicating compromised crossover interference. These results reveal the distinct dosage-dependent effects of ASY3 on crossover formation and provide insights into the role of the chromosome axis in patterning recombination., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Background: Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown., Methods: To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation., Results: EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response., Conclusions: Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.M. Kim reports consulting or advisory roles at Amgen, AstraZeneca/MedImmune, BeiGene, Borung, Daiichi Sankyo, Hanmi, HK inno.N, IMBdx. Inc., Janssen, Novartis, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda. Y.S. Ju is a founder of Inocras Inc. Se. Park, J. Lim, K. Yi, B. Yi, and Y.S. Ju have stock or stock option of Inocras Inc. D.W Kim reports research funding from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Daiichi, -Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, and GSK and travel and accommodation support for advisory board-meeting attendance from Amgen and Daiichi-Sankyo. No disclosures were reported by the other authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: This study aims to analyze the expression of colposcopy combined with PD-L1 (programmed death ligand-1) and miR-124 (microRNA-124) in CC (cervical cancer) and CIN (cervical precancerous lesions), providing insights for clinical screening and diagnosis of these conditions., Method: A total of 60 patients with suspicious cervical lesions were selected from the gynecological clinic at Jinhua People's Hospital between June 2021 and December 2021. The patients were divided into three groups: LSIL (low-grade squamous intraepithelial lesions), HSIL (high-grade squamous intraepithelial lesions), and no SIL group, with 20 cases per group. This sample distribution ensures a comprehensive representation of different lesion severities. Pathological tissues were collected from each group for immunohistochemistry analysis to assess PD-L1 expression. Peripheral blood samples were also obtained from the patients for PCR analysis to evaluate miR-124 expression. These techniques allowed us to examine the expression levels of PD-L1 and miR-124 in the samples accurately., Result: The HSIL group exhibited a higher rate of positive PD-L1 expression compared to the LSIL and no lesion groups. Additionally, the expression level of miR-124 was lower in the HSIL group compared to the LSIL and no lesion groups (P < .05). Statistical measures such as means, standard deviations, and P values were used to quantify these differences, providing a more comprehensive understanding of the results., Conclusions: Combining colposcopy results with the expression of PD-L1 and miR-124 can effectively evaluate precancerous lesions of cervical cancer. This combined approach holds significant clinical implications by potentially enhancing early detection, diagnosis, and treatment strategies for CC and CIN. Further research in this area may lead to improved patient outcomes and contribute to the development of targeted therapies.

Purpose: A higher minimum monitor unit (minMU) for pencil-beam scanning proton beams in intensity-modulated proton therapy is preferred for more efficient delivery. However, plan quality may be compromised when the minMU is too large. This study aimed to identify the optimal minMU (OminMU) to improve plan delivery efficiency while maintaining high plan quality., Methods: We utilized clinical plans including six anatomic sites (brain, head and neck, breast, lung, abdomen, and prostate) from 23 patients previously treated with the Varian ProBeam system. The minMU of each plan was increased from the current clinical minMU of 1.1 to 3-24 MU depending on the daily prescribed dose (DPD). The dosimetric parameters of the plans were evaluated for consistency against a 1.1-minMU plan for target coverage as well as organs-at-risk dose sparing. DPD/minMU was defined as the ratio of DPD to minMU (cGy/MU) to find the OminMU by ensuring that dosimetric parameters did not differ by >1% compared to those of the 1.1-minMU plan., Results: All plans up to 5 minMU showed no significant dose differences compared to the 1.1-minMU plan. Plan qualities remained acceptable when DPD/minMU ≥35 cGy/MU. This suggests that the 35 cGy/MU criterion can be used as the OminMU, which implies that 5 MU is the OminMU for a conventional fraction dose of 180 cGy. Treatment times were decreased by an average of 32% (max 56%, min 7%) and by an average of 1.6 min when the minMU was increased from 1.1 to OminMU., Conclusion: A clinical guideline for OminMU has been established. The minMU can be increased by 1 MU for every 35 cGy of DPD without compromising plan quality for most cases analyzed in this study. Significant treatment time reduction of up to 56% was observed when the suggested OminMU is used., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: The mpox pandemic has caused widespread public concern around the world. The spread of misinformation through the internet and social media could lead to an infodemic that poses challenges to mpox control., Objective: This review aims to summarize mpox-related infodemiology studies to determine the characteristics, influence, prevention, and control measures of the mpox infodemic and propose prospects for future research., Methods: The scoping review was conducted based on a structured 5-step methodological framework. A comprehensive search for mpox-related infodemiology studies was performed using PubMed, Web of Science, Embase, and Scopus, with searches completed by April 30, 2024. After study selection and data extraction, the main topics of the mpox infodemic were categorized and summarized in 4 aspects, including a trend analysis of online information search volume, content topics of mpox-related online posts and comments, emotional and sentiment characteristics of online content, and prevention and control measures for the mpox infodemic., Results: A total of 1607 articles were retrieved from the databases according to the keywords, and 61 studies were included in the final analysis. After the World Health Organization's declaration of an mpox public health emergency of international concern in July 2022, the number of related studies began growing rapidly. Google was the most widely used search engine platform (9/61, 15%), and Twitter was the most used social media app (32/61, 52%) for researchers. Researchers from 33 countries were concerned about mpox infodemic-related topics. Among them, the top 3 countries for article publication were the United States (27 studies), India (9 studies), and the United Kingdom (7 studies). Studies of online information search trends showed that mpox-related online search volume skyrocketed at the beginning of the mpox outbreak, especially when the World Health Organization provided important declarations. There was a large amount of misinformation with negative sentiment and discriminatory and hostile content against gay, bisexual, and other men who have sex with men. Given the characteristics of the mpox infodemic, the studies provided several positive prevention and control measures, including the timely and active publishing of professional, high-quality, and easy-to-understand information online; strengthening surveillance and early warning for the infodemic based on internet data; and taking measures to protect key populations from the harm of the mpox infodemic., Conclusions: This comprehensive summary of evidence from previous mpox infodemiology studies is valuable for understanding the characteristics of the mpox infodemic and for formulating prevention and control measures. It is essential for researchers and policy makers to establish prediction and early warning approaches and targeted intervention methods for dealing with the mpox infodemic in the future., (©XiangYu Yan, Zhuo Li, Chunxia Cao, Longxin Huang, Yongjie Li, Xiangbin Meng, Bo Zhang, Maohe Yu, Tian Huang, Jiancheng Chen, Wei Li, Linhui Hao, Dongsheng Huang, Bin Yi, Ming Zhang, Shun Zha, Haijun Yang, Jian Yao, Pengjiang Qian, Chun Kai Leung, Haojun Fan, Pei Jiang, Tiejun Shui. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 30.08.2024.)

The fiber signal combiner with high output power and high beam quality is an urgent problem to be solved. In this paper, the structure of the double-cone (both the input fibers and the output fiber are tapered) is proposed to improve the beam quality of the fiber signal combiner, and it is verified by simulation and experiment, with the output fiber of 50 µm core tapered to 35 µm as an example. The prepared 3 × 1 double-cone fiber signal combiner reaches the output power of 8.64 kW, and the beam quality is measured as M 2  = 2.91. Compared with the M 2  = 3.41 of the fiber signal combiner with non-tapered output fiber, the M 2 of the double-cone fiber signal combiner is reduced by 14.7%.

As a Brassica crop, Brassica napus typically has single flowers that contain four petals. The double-flower phenotype of rapeseed has been a desirable trait in China because of its potential commercial value in ornamental tourism. However, few double-flowered germplasms have been documented in B. napus, and knowledge of the underlying genes is limited. Here, B. napus D376 was characterized as a double-flowered strain that presented an average of 10.92 ± 1.40 petals and other normal floral organs. F 1 , F 2 and BC 1 populations were constructed by crossing D376 with a single-flowered line reciprocally. Genetic analysis revealed that the double-flower trait was a recessive trait controlled by multiple genes. To identify the key genes controlling the double-flower trait, bulk segregant analysis sequencing (BSA-seq) and RNA-seq analyses were conducted on F 2 individual bulks with opposite extreme phenotypes. Through BSA-seq, one candidate interval was mapped at the region of chromosome C05: 14.56-16.17 Mb. GO and KEGG enrichment analyses revealed that the DEGs were significantly enriched in carbohydrate metabolic processes, notably starch and sucrose metabolism. Interestingly, five and thirty-six DEGs associated with floral development were significantly up- and down-regulated, respectively, in the double-flowered plants. A combined analysis of BSA-seq and RNA-seq data revealed that five genes were candidates associated with the double flower trait, and BnaC05.ERS2 was the most promising gene. These findings provide novel insights into the breeding of double-flowered varieties and lay a theoretical foundation for unveiling the molecular mechanisms of floral development in B. napus., (© 2024. The Author(s).)

Purpose: To compare the effects of 6-week barbell weighted-jump-squat (WJS) training with and without eccentric load reduction on explosive performance., Methods: Twenty well-trained male athletes were randomly assigned to either an experimental group (n = 10) or a control group (n = 10). Participants completed 12 WJS training sessions (6 sets of 5 repetitions of barbell back squat at 30% of 1-repetition maximum [1RM]) twice a week over a 6-week period. While the control group used 0% eccentric loading (ie, traditional WJS), the experimental group utilized a 50% eccentric loading reduction with a mechanical braking unit (ie, eccentric load set at 15% of 1RM). Performance assessments, including countermovement jump, 20-m sprint, standing long jump, and 1RM barbell back squat, were conducted both before (pretests) and after (posttests) the intervention., Results: Both the experimental group and the control group demonstrated a significant increase in countermovement-jump height (+6.4% [4.0%] vs +4.9% [5.7%]; P < .001) and peak power output (+2.3% [2.7%] vs +1.9% [5.1%]; P = .017), faster 20-m sprint times (+9.4% [4.8%] vs +9.2% [5.5%]; P < .001), longer standing long jump (+3.1% [2.5%] vs +3.0% [3.3%]; P < .001), and higher 1RM back squat (+6.4% [4.0%] vs +4.9% [5.7%]; P < .001) from pretests to posttests. However, there was no significant condition × time interaction for any variable (all P ≥ .294)., Conclusions: Both WJS training methods, with and without load reduction in the eccentric phase, effectively enhance explosive performance. Nevertheless, athletes in later stages of injury rehabilitation or intense training may find reducing eccentric load a more tolerable strategy for achieving similar performance gains compared with traditional isoinertial loading.

Background: Prostate cancer ranks among the six most lethal malignancies worldwide. Telomerase, a reverse transcriptase enzyme, plays a pivotal role in extending cellular telomeres and is intimately associated with cell proliferation and division. However, the interconnection between prostate cancer and telomerase-related genes (TEASEs) remains unclear., Methods: Somatic mutations and copy number alterations of TEASEs were comprehensively analyzed. Subsequently, the transcripts of prostate cancer patients in TCGA and GEO databases were integrated to delineate new molecular subtypes. Followed by constructing a risk model containing nine characteristic genes through Lasso regression and Cox prognostic analysis among different subtypes. Various aspects including prognosis, tumor microenvironment (TME), landscape of immunity, tumor mutational burden (TMB), stem cell correlation, and median inhibitory concentration amongst different risk groups were compared. Finally, the expression, prognosis, and malignant biological behavior of ZW10 interactor (ZWINT) in vitro was explored., Results: TEASEs exhibited a notably high mutation frequency. Three distinct molecular subtypes and two gene subclusters based on TEASEs were delineated, displaying significant associations with prognosis, immune function regulation, and clinical characteristics. Low-risk patients demonstrated superior prognosis and better response to immunotherapy. Conversely, high-risk patients exhibited higher TMB and stronger stem cell correlations. It was also found that the patients' sensitivity to chemotherapy agents was impacted by the risk score. Finally, ZWINT's potential as a novel diagnostic and prognostic biomarker for prostate cancer was validated., Conclusions: TEASEs play a pivotal role in modulating immune regulation and immunotherapeutic responses, thereby significantly impacting the diagnosis, prognosis, and treatment strategies for affected patients., (© 2024. The Author(s).)

With the aging of the population, the prevalence of osteoporosis (OP) is rising rapidly, making it an important public health concern. Early screening and effective treatment of OP are the primary challenges facing the management of OP today. Quanduzhong capsule (QDZ) is a single preparation composed of Eucommia ulmoides Oliv., which is included in the Pharmacopoeia of the People's Republic of China. It is used to treat OP in clinical practice, but its mechanisms are unclear. This study involved 30 patients with OP, 30 healthy controls (HC), and 28 OP patients treated with QDZ to identify potential biomarkers for the early diagnosis of OP and to investigate the potential mechanism of QDZ in treating OP. The serum samples were analyzed using targeted amino acid metabolomics. Significant differences in amino acid metabolism were identified between the OP cohort and the HC group, as well as between OP patients before and after QDZ treatment. Compared with HC, the serum levels of 14 amino acids in OP patients changed significantly. Kynurenine, arginine, citrulline, methionine, and their combinations are expected to be potential biomarkers for OP diagnosis. Notably, QDZ reversed the changes in levels of 10 amino acids in the serum of OP patients and significantly impacted numerous metabolic pathways during the treatment of OP. This study focuses on screening potential biomarkers for the early detection of OP, which offers a new insight into the mechanism study of QDZ in treating OP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Cancer-associated fibroblasts (CAFs) are the prominent cell type in the tumor microenvironment (TME), and CAF subsets have been identified in various tumors. However, how CAFs spatially coordinate other cell populations within the liver TME to promote cancer progression remains unclear., Methods: We combined multi-region proteomics (6 patients, 24 samples), 10X Genomics Visium spatial transcriptomics (11 patients, 25 samples), and multiplexed imaging (92 patients, 264 samples) technologies to decipher the expression heterogeneity, functional diversity, spatial distribution, colocalization, and interaction of fibroblasts. The newly identified CAF subpopulation was validated by cells isolated from 5 liver cancer patients and in vitro functional assays., Results: We identified a liver CAF subpopulation, marked by the expression of COL1A2, COL4A1, COL4A2, CTGF, and FSTL1, and named F5-CAF. F5-CAF is preferentially located within and around tumor nests and colocalizes with cancer cells with higher stemness in hepatocellular carcinoma (HCC). Multiplexed staining of 92 patients and the bulk transcriptome of 371 patients demonstrated that the abundance of F5-CAFs in HCC was associated with a worse prognosis. Further in vitro experiments showed that F5-CAFs isolated from liver cancer patients can promote the proliferation and stemness of HCC cells., Conclusions: We identified a CAF subpopulation F5-CAF in liver cancer, which is associated with cancer stemness and unfavorable prognosis. Our results provide potential mechanisms by which the CAF subset in the TME promotes the development of liver cancer by supporting the survival of cancer stem cells., (© 2024. The Author(s).)

The present study aims to screen and evaluate the early clinical predictors for type 2 diabetes mellitus (T2DM) patients with mild cognitive impairment (MCI) and dementia in Hunan province. A cross-sectional study was conducted from May 2023 to October 2023 to collect data on long-term T2DM patients who settled in Hunan province and were treated in the Department of Geriatrology at Xiangya Hospital of Central South University. The patients were grouped according to the Montreal Cognitive Assessment (MoCA) scale. Basic patient information and multiple serum markers were collected, and differences between groups were compared using one-way ANOVA or Kruskal-Wallis (KW) tests. The multivariate logistic regression analysis was utilized to assess risk factors and Nomogram models were constructed. The logistic regression analysis showed that years of education and serum levels of 1, 5-AG were related factors for the progression of T2DM to T2DM with MCI, and body weight, years of education and FPN levels affected the progression of T2DM with MCI to T2DM with dementia. Based on this, two Nomogram risk prediction models were established. The area under the curve (AUC) of the Nomogram model predicting T2DM progression to T2DM combined with MCI was 0.741, and the AUC of the Nomogram model predicting T2DM combined with MCI progression to T2DM combined with dementia was 0.734. The calibration curves (DCA) of the two models in the training and validation sets were symmetrically distributed near the diagonal line, indicating that the models in the training and validation sets could match each other. In summary, body weight, years of education, and serum HDL-3, FPN, and 1, 5-AG levels are associated with the development of MCI and dementia in T2DM patients. The Nomogram models constructed based on these factors can predict the risk of MCI and dementia in T2DM patients, providing a basis for clinical decision-making.

Background: Compared with intravascular ultrasound guidance, there is limited evidence for optical coherence tomography (OCT) guidance during primary percutaneous coronary intervention (pPCI) in ST-segment elevation myocardial infarction (STEMI) patients., Aims: We investigated the role of OCT in guiding a reperfusion strategy and improving the long-term prognosis of STEMI patients., Methods: All patients who were diagnosed with STEMI and who underwent pPCI between January 2017 and December 2020 were enrolled and divided into OCT-guided versus angiography-guided cohorts. They had routine follow-up for up to 5 years or until the time of the last known contact. All-cause death and cardiovascular death were designated as the primary and secondary endpoints, respectively., Results: A total of 3,897 patients were enrolled: 2,696 (69.2%) with OCT guidance and 1,201 (30.8%) with angiographic guidance. Patients in the OCT-guided cohort were less often treated with stenting during pPCI (62.6% vs 80.2%; p<0.001). The 5-year cumulative rates of all-cause mortality and cardiovascular mortality in the OCT-guided cohort were 10.4% and 8.0%, respectively, significantly lower than in the angiography-guided cohort (19.0% and 14.1%; both log-rank p<0.001). All 4 multivariate models showed that OCT guidance could significantly reduce 5-year all-cause mortality (hazard ratio [HR] in model 4: 0.689, 95% confidence interval [CI]: 0.551-0.862) and cardiovascular mortality (HR in model 4: 0.692, 95% CI: 0.536-0.895). After propensity score matching, the benefits of OCT guidance were consistent in terms of all-cause mortality (HR: 0.707, 95% CI: 0.548-0.913) and cardiovascular mortality (HR: 0.709, 95% CI: 0.526-0.955)., Conclusions: Compared with angiography alone, OCT guidance may change reperfusion strategies and lead to better long-term survival in STEMI patients undergoing pPCI. Findings in the current observational study should be further corroborated in randomised trials.