Hypophosphorylated pRb knock-in mice exhibit hallmarks of aging and vitamin C-preventable diabetes.

Despite extensive analysis of pRB phosphorylation in vitro, how this modification influences development and homeostasis in vivo is unclear. Here, we show that homozygous Rb∆K4 and Rb∆K7 knock-in mice, in which either four or all seven phosphorylation sites in the C-terminal region of pRb, respectively, have been abolished by Ser/Thr-to-Ala substitutions, undergo normal embryogenesis and early development, notwithstanding suppressed phosphorylation of additional upstream sites. Whereas Rb∆K4 mice exhibit telomere attrition but no other abnormalities, Rb∆K7 mice are smaller and display additional hallmarks of premature aging including infertility, kyphosis, and diabetes, indicating an accumulative effect of blocking pRb phosphorylation. Diabetes in Rb∆K7 mice is insulin-sensitive and associated with failure of quiescent pancreatic ß-cells to re-enter the cell cycle in response to mitogens, resulting in induction of DNA damage response (DDR), senescence-associated secretory phenotype (SASP), and reduced pancreatic islet mass and circulating insulin level. Pre-treatment with the epigenetic regulator vitamin C reduces DDR, increases cell cycle re-entry, improves islet morphology, and attenuates diabetes. These results have direct implications for cell cycle regulation, CDK-inhibitor therapeutics, diabetes, and longevity.

SUMMER: a Mendelian randomization interactive server to systematically evaluate the causal effects of risk factors and circulating biomarkers on pan-cancer survival.

Genome-wide association studies (GWASs) underlying case-control design have uncovered hundreds of genetic loci involved in tumorigenesis and provided rich resources for identifying risk factors and biomarkers associated with cancer susceptibility. However, the application of GWAS in determining the genetic architecture of cancer survival remains unestablished. Here, we systematically evaluated genetic effects at the genome-wide level on cancer survival that included overall survival (OS) and cancer-specific survival (CSS), leveraging data deposited in the UK Biobank cohort of a total of 19 628 incident patients across 17 cancer types. Furthermore, we assessed the causal effects of risk factors and circulating biomarkers on cancer prognosis via a Mendelian randomization (MR) analytic framework, which integrated cancer survival GWAS dataset, along with phenome-wide association study (PheWAS) and blood genome-wide gene expression/DNA methylation quantitative trait loci (eQTL/meQTL) datasets. On average, more than 10 traits, 700 genes, and 4,500 CpG sites were prone to cancer prognosis. Finally, we developed a user-friendly online database, SUrvival related cancer Multi-omics database via MEndelian Randomization (SUMMER; http://njmu-edu.cn:3838/SUMMER/), to help users query, browse, and download cancer survival results. In conclusion, SUMMER provides an important resource to assist the research community in understanding the genetic mechanisms of cancer survival.

RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications.

RNA modification is a dynamic and reversible process regulated by a series of writers, erasers and readers (WERs). Abnormal changes of WERs will disrupt the RNA modification homeostasis of their target genes, leading to the dysregulation of RNA metabolisms such as RNA stability and translation, and consequently to diseases such as cancer. A public repository hosting the regulatory relationships between WERs and their target genes will help in understanding the roles of RNA modifications in various physiological and pathological conditions. Previously, we developed a database named 'm6A2Target' to host targets of WERs in m6A, one of the most prevalent RNA modifications in eukaryotic cells. To host all RNA modification (RM)-related WER-target associations, we hereby present an updated database, named 'RM2Target' (http://rm2target.canceromics.org/). In this update, RM2Target encompasses 1 619 653 WER-target associations for nine RNA modifications in human and mouse, including m6A, m6Am, m5C, m5U, m1A, m7G, pseudouridine, 2'-O-Me and A-to-I. Extensive annotations of target genes are available in RM2Target, including but not limited to basic gene information, RNA modifications, RNA-RNA/RNA-protein interactions and related diseases. Altogether, we expect that RM2Target will facilitate further downstream functional and mechanistic studies in the field of RNA modification research.

An early-onset specific polygenic risk score optimizes age-based risk estimate and stratification of prostate cancer: population-based cohort study.

BACKGROUND: Early-onset prostate cancer (EOPC, ≤ 55 years) has a unique clinical entity harboring high genetic risk, but the majority of EOPC patients still substantial opportunity to be early-detected thus suffering an unfavorable prognosis. A refined understanding of age-based polygenic risk score (PRS) for prostate cancer (PCa) would be essential for personalized risk stratification. METHODS: We included 167,517 male participants [4882 cases including 205 EOPC and 4677 late-onset PCa (LOPC)] from UK Biobank. A General-, an EOPC- and an LOPC-PRS were derived from age-specific genome-wide association studies. Weighted Cox proportional hazard models were applied to estimate the risk of PCa associated with PRSs. The discriminatory capability of PRSs were validated using time-dependent receiver operating characteristic (ROC) curves with additional 4238 males from PLCO and TCGA. Phenome-wide association studies underlying Mendelian Randomization were conducted to discover EOPC linking phenotypes. RESULTS: The 269-PRS calculated via well-established risk variants was more strongly associated with risk of EOPC [hazard ratio (HR) = 2.35, 95% confidence interval (CI) 1.99-2.78] than LOPC (HR = 1.95, 95% CI 1.89-2.01; I2 = 79%). EOPC-PRS was dramatically related to EOPC risk (HR = 4.70, 95% CI 3.98-5.54) but not to LOPC (HR = 0.98, 95% CI 0.96-1.01), while LOPC-PRS had similar risk estimates for EOPC and LOPC (I2 = 0%). Particularly, EOPC-PRS performed optimal discriminatory capability for EOPC (area under the ROC = 0.613). Among the phenomic factors to PCa deposited in the platform of ProAP (Prostate cancer Age-based PheWAS; https://mulongdu.shinyapps.io/proap ), EOPC was preferentially associated with PCa family history while LOPC was prone to environmental and lifestyles exposures. CONCLUSIONS: This study comprehensively profiled the distinct genetic and phenotypic architecture of EOPC. The EOPC-PRS may optimize risk estimate of PCa in young males, particularly those without family history, thus providing guidance for precision population stratification.

Knowledge mapping of surgical smoke from 2003 to 2022: a bibliometric analysis.

PURPOSE: The purpose of this study is to identify and characterize the literature on surgical smoke, visualize the data and sketch a certain trending outline. METHODS: In the Web of Science Core Collection (WoSCC), all the data were acquired from January 1st 2003 to December 31st 2022. VOSviewer and CiteSpace were employed to visualize data, based on publications, bibliographic coupling, co-citation, or co-authorship relations. Microsoft Excel 2019 was used to comb and categorize all the statistics. RESULT: A total 363 of journal papers were retrieved. The publication number was in a slow but steady growth between 2003 and 2019, followed by a sharp surge in 2020, and then the publication kept in a productive way. Surgical endoscopy and other interventional techniques was the most active journal on surgical smoke. USA played an important role among all the countries/regions. There were 1847 authors for these 363 papers, among whom 44 authors published more than three articles on surgical smoke. "Surgical smoke", "covid-19" and "surgery" were the top 3 appeared keywords, while the latest hot-spot keywords were "COVID-19", "virus", "transmission", "exposure" and "risk". There were 1105 co-cited references and 3786 links appeared in all 363 articles. Among them, 38 references are cited more than 10 times. The most co-cited article was "Detecting hepatitis B virus in surgical smoke emitted during laparoscopic surgery." Based on the titles of references and calculated by CiteSpace, the top 3 cluster trend network are "laparoscopic surgery", "COVID-19 pandemic" and "surgical smoke". CONCLUSION: According to bibliometric analysis, the research on surgical smoke has been drawing attention of more scholars in the world. Increasing number of countries or regions added in this field, and among them, USA, Italy, and China has been playing important roles, however, more wide and intense cooperation is still in expectation.

SPENCER: a comprehensive database for small peptides encoded by noncoding RNAs in cancer patients.

As an increasing number of noncoding RNAs (ncRNAs) have been suggested to encode short bioactive peptides in cancer, the exploration of ncRNA-encoded small peptides (ncPEPs) is emerging as a fascinating field in cancer research. To assist in studies on the regulatory mechanisms of ncPEPs, we describe here a database called SPENCER (http://spencer.renlab.org). Currently, SPENCER has collected a total of 2806 mass spectrometry (MS) data points from 55 studies, covering 1007 tumor samples and 719 normal samples. Using an MS-based proteomics analysis pipeline, SPENCER identified 29 526 ncPEPs across 15 different cancer types. Specifically, 22 060 of these ncPEPs were experimentally validated in other studies. By comparing tumor and normal samples, the identified ncPEPs were divided into four expression groups: tumor-specific, upregulated in cancer, downregulated in cancer, and others. Additionally, since ncPEPs are potential targets for neoantigen-based cancer immunotherapy, SPENCER also predicted the immunogenicity of all the identified ncPEPs by assessing their MHC-I binding affinity, stability, and TCR recognition probability. As a result, 4497 ncPEPs curated in SPENCER were predicted to be immunogenic. Overall, SPENCER will be a useful resource for investigating cancer-associated ncPEPs and may boost further research in cancer.

RPS: a comprehensive database of RNAs involved in liquid-liquid phase separation.

Liquid-liquid phase separation (LLPS) is critical for assembling membraneless organelles (MLOs) such as nucleoli, P-bodies, and stress granules, which are involved in various physiological processes and pathological conditions. While the critical role of RNA in the formation and the maintenance of MLOs is increasingly appreciated, there is still a lack of specific resources for LLPS-related RNAs. Here, we presented RPS (http://rps.renlab.org), a comprehensive database of LLPS-related RNAs in 20 distinct biomolecular condensates from eukaryotes and viruses. Currently, RPS contains 21,613 LLPS-related RNAs with three different evidence types, including 'Reviewed', 'High-throughput' and 'Predicted'. RPS provides extensive annotations of LLPS-associated RNA properties, including sequence features, RNA structures, RNA-protein/RNA-RNA interactions, and RNA modifications. Moreover, RPS also provides comprehensive disease annotations to help users to explore the relationship between LLPS and disease. The user-friendly web interface of RPS allows users to access the data efficiently. In summary, we believe that RPS will serve as a valuable platform to study the role of RNA in LLPS and further improve our understanding of the biological functions of LLPS.

IBS 2.0: an upgraded illustrator for the visualization of biological sequences.

The visualization of biological sequences with various functional elements is fundamental for the publication of scientific achievements in the field of molecular and cellular biology. However, due to the limitations of the currently used applications, there are still considerable challenges in the preparation of biological schematic diagrams. Here, we present a professional tool called IBS 2.0 for illustrating the organization of both protein and nucleotide sequences. With the abundant graphical elements provided in IBS 2.0, biological sequences can be easily represented in a concise and clear way. Moreover, we implemented a database visualization module in IBS 2.0, enabling batch visualization of biological sequences from the UniProt and the NCBI RefSeq databases. Furthermore, to increase the design efficiency, a resource platform that allows uploading, retrieval, and browsing of existing biological sequence diagrams has been integrated into IBS 2.0. In addition, a lightweight JS library was developed in IBS 2.0 to assist the visualization of biological sequences in customized web services. To obtain the latest version of IBS 2.0, please visit https://ibs.renlab.org.

Association between Liver MRI Proton Density Fat Fraction and Liver Disease Risk.

Background A better understanding of the association between liver MRI proton density fat fraction (PDFF) and liver diseases might support the clinical implementation of MRI PDFF. Purpose To quantify the genetically predicted causal effect of liver MRI PDFF on liver disease risk. Materials and Methods This population-based prospective observational study used summary-level data mainly from the UK Biobank and FinnGen. Mendelian randomization analysis was conducted using the inverse variance-weighted method to explore the causal association between genetically predicted liver MRI PDFF and liver disease risk with Bonferroni correction. The individual-level data were downloaded between August and December 2020 from the UK Biobank. Logistic regression analysis was performed to validate the association between liver MRI PDFF polygenic risk score and liver disease risk. Mediation analyses were performed using multivariable mendelian randomization. Results Summary-level and individual-level data were obtained from 32 858 participants and 378 436 participants (mean age, 57 years ± 8 [SD]; 203 108 female participants), respectively. Genetically predicted high liver MRI PDFF was associated with increased risks of malignant liver neoplasm (odds ratio [OR], 4.5; P < .001), alcoholic liver disease (OR, 1.9; P < .001), fibrosis and cirrhosis of the liver (OR, 3.0; P < .004), fibrosis of the liver (OR, 3.6; P = .002), cirrhosis of the liver (OR, 3.8; P < .001), nonalcoholic steatohepatitis (OR, 7.7; P < .001), and nonalcoholic fatty liver disease (NAFLD) (OR, 4.4; P < .001). Individual-level evidence supported these associations after grouping participants based on liver MRI PDFF polygenic risk score (all P < .004). The mediation analysis indicated that genetically predicted high-density lipoprotein cholesterol, type 2 diabetes mellitus, and waist-to-hip ratio (mediation effects, 25.1%-46.3%) were related to the occurrence of fibrosis and cirrhosis of the liver, cirrhosis of the liver, and NAFLD at liver MRI PDFF (all P < .05). Conclusion This study provided evidence of the association between genetically predicted liver MRI PDFF and liver health. © RSNA, 2023 Supplemental material is available for this article. See also the editorials by Reeder and Starekova and Monsell in this issue.

Infiltrating myeloid cell-derived properdin markedly promotes microglia-mediated neuroinflammation after ischemic stroke.

BACKGROUND: Emerging evidence has shown that myeloid cells that infiltrate into the peri-infarct region may influence the progression of ischemic stroke by interacting with microglia. Properdin, which is typically secreted by immune cells such as neutrophils, monocytes, and T cells, has been found to possess damage-associated molecular patterns (DAMPs) properties and can perform functions unrelated to the complement pathway. However, the role of properdin in modulating microglia-mediated post-stroke neuroinflammation remains unclear. METHODS: Global and conditional (myeloid-specific) properdin-knockout mice were subjected to transient middle cerebral artery occlusion (tMCAO). Histopathological and behavioral tests were performed to assess ischemic brain injury in mice. Single-cell RNA sequencing and immunofluorescence staining were applied to explore the source and the expression level of properdin. The transcriptomic profile of properdin-activated primary microglia was depicted by transcriptome sequencing. Lentivirus was used for macrophage-inducible C-type lectin (Mincle) silencing in microglia. Conditioned medium from primary microglia was administered to primary cortex neurons to determine the neurotoxicity of microglia. A series of cellular and molecular biological techniques were used to evaluate the proinflammatory response, neuronal death, protein-protein interactions, and related signaling pathways, etc. RESULTS: The level of properdin was significantly increased, and brain-infiltrating neutrophils and macrophages were the main sources of properdin in the ischemic brain. Global and conditional myeloid knockout of properdin attenuated microglial overactivation and inflammatory responses at the acute stage of tMCAO in mice. Accordingly, treatment with recombinant properdin enhanced the production of proinflammatory cytokines and augmented microglia-potentiated neuronal death in primary culture. Mechanistically, recombinant properdin served as a novel ligand that activated Mincle receptors on microglia and downstream pathways to drive primary microglia-induced inflammatory responses. Intriguingly, properdin can directly bind to the microglial Mincle receptor to exert the above effects, while Mincle knockdown limits properdin-mediated microglial inflammation. CONCLUSION: Properdin is a new medium by which infiltrating peripheral myeloid cells communicate with microglia, further activate microglia, and exacerbate brain injury in the ischemic brain, suggesting that targeted disruption of the interaction between properdin and Mincle on microglia or inhibition of their downstream signaling may improve the prognosis of ischemic stroke.

Photo-Activated Direct Catalytic Oxidation of Gaseous Benzene with a Cu-Connected Serial Heterojunction Array of Co3 O4 /Cux O/Foam Cu Assembled via Layer upon Layer Oxidation.

The foam copper (FCu) has been first used as a promising supporting material to prepare a photo-activated catalyst of Co3 O4 /Cux O/FCu, in which the fine Co3 O4 particles are inlayed on the Cux O nanowires to form a Z-type heterojunction array connected by substrate Cu. The prepared samples have been used as a photo-activated catalyst to directly decompose gaseous benzene and the optimized Co3 O4 /Cux O/FCu demonstrates a 99.5% removal efficiency and 100% mineralizing rate within 15 min in benzene concentration range from 350 to 4000 ppm under simulate solar light irradiation. To track the reactive mechanism, a series of MOx /Cux O/FCu (M = Mn, Fe, Co, Ni, Cu, Zn) is prepared and a novel photo-activated direct catalytic oxidation route is proposed based on the comparative investigation of material properties. Moreover, the approach grew in situ via layer upon layer oxidation on FCu dedicates to the extra lasting reusability and the easy accessibility in the diverse situations. This work provides a novel strategy for the preparation of Cu connected series multidimensional heterojunction array and a promising application for the quick abatement of the high-leveled concentration gaseous benzene and its derivatives from the industrial discharged flow or the accident scene's leakage.

In Situ Growth of Cs3Bi2Br9 Quantum Dots on Bi-MOF Nanosheets via Cosharing Bismuth Atoms for CO2 Capture and Photocatalytic Reduction.

Given the global warming caused by excess CO2 accumulation in the atmosphere, it is essential to reduce CO2 by capturing and converting it to chemical feedstock using solar energy. Herein, a novel Cs3Bi2Br9/bismuth-based metal-organic framework (Bi-MOF) composite was prepared via an in situ growth strategy of Cs3Bi2Br9 quantum dots (QDs) on the surface of Bi-MOF nanosheets through coshared bismuth atoms. The prepared Cs3Bi2Br9/Bi-MOF exhibits bifunctional merits for both the high capture and effective conversion of CO2, among which the optimized 3Cs3Bi2Br9/Bi-MOF sample shows a CO2-CO conversion yield as high as 572.24 µmol g-1 h-1 under the irradiation of a 300 W Xe lamp. In addition, the composite shows good stability after five recycles in humid air, and the CO2 photoreduction efficiency does not decrease significantly. The mechanistic investigation uncovers that the intimate atomic-level contact between Cs3Bi2Br9 and Bi-MOF via the coshared atoms not only improves the dispersion of Cs3Bi2Br9 QDs over Bi-MOF nanosheets but also accelerates interfacial charge transfer by forming a strong bonding linkage, which endows it with the best performance of CO2 photoreduction. Our new finding of bismuth-based metal-organic framework/lead-free halide perovskite by cosharing atoms opens a new avenue for a novel preparation strategy of the heterojunction with atomic-level contact and potential applications in capture and photocatalytic conversion of CO2.

Sb-doped FeOCl nanozyme-based biosensor for highly sensitive colorimetric detection of glutathione.

Nanozymes have been emerging as substitutes for natural enzymes to construct biosensors towards biomolecular detection. However, the detection of glutathione (GSH) by nanozyme-based biosensors still remains a great challenge for research on catalytic activity enhancement and the detection mechanism. In this work, Sb-doped iron oxychloride (Sb-FeOCl) with a well-defined nanorod-like structure is prepared by high-temperature calcination. Sb-FeOCl nanorods have high peroxidase-like activity, which can catalyze the decomposition of H2O2 into ·OH and then oxidize 3,3',5,5'-tetramethylbenzidine (TMB). In view of these intriguing observations, a reliable colorimetric method with a simple mixing and detection strategy is developed for the detection of GSH. The linear range of GSH detection is 1-36 µM. The detection limit of GSH reaches a low level of 0.495 µM (3σ/slope). The GSH sensing system also exhibits excellent specificity and anti-interference. Taking advantage of the advantages of the Sb-FeOCl nanorod-based biosensor, it can be used to quantitatively detect GSH levels in human serum. It can be anticipated that the Sb-FeOCl nanorods have broad prospects in the field of enzymatic biochemical reactions.

An integrative approach for identification of smoking-related genes involving bladder cancer.

Tobacco smoking is one of the most important environmental risk factors involving bladder tumorigenesis. However, smoking-related genes in bladder carcinogenesis and corresponding genetic effects on bladder cancer risk remain unclear. Weighted correlation network analysis (WGCNA) underlying transcriptome of bladder cancer tissues was applied to identify smoking-related genes. The logistic regression model was utilized to estimate genetic effects of single nucleotide polymorphisms (SNPs) in smoking-related genes on bladder cancer risk in the Chinese and European populations with a total of 6510 cases and 6569 controls, as well as the interaction with smoking status. Transcriptome of cells and tissues was used to profile the expression pattern of candidate genes and their genetic variants. Our results demonstrated that a total of 24 SNPs in 14 smoking-related genes were associated with the risk of bladder cancer, of which rs9348451 in CDKAL1 exhibited an interaction with smoking status (ORinteraction = 1.38, Pinteraction = 1.08 × 10-2) and tobacco smoking might combine with CDKAL1 rs9348451 to increase the risk of bladder cancer (Ptrend = 4.27 × 10-4). Moreover, rs9348451 was associated with CDKAL1 expression in bladder cancer, especially in smokers (P < 0.001). Besides, CDKAL1 was upregulated in bladder cancer compared to normal adjacent tissues, as well as upregulated via treatment of cigarette smoke extracts. This study highlights the important role of nurture and nature, as well as their interaction on tumorigenesis, which provides a new way to decipher the etiology of bladder cancer with smoking status.

RMVar: an updated database of functional variants involved in RNA modifications.

Distinguishing the few disease-related variants from a massive number of passenger variants is a major challenge. Variants affecting RNA modifications that play critical roles in many aspects of RNA metabolism have recently been linked to many human diseases, such as cancers. Evaluating the effect of genetic variants on RNA modifications will provide a new perspective for understanding the pathogenic mechanism of human diseases. Previously, we developed a database called 'm6AVar' to host variants associated with m6A, one of the most prevalent RNA modifications in eukaryotes. To host all RNA modification (RM)-associated variants, here we present an updated version of m6AVar renamed RMVar (http://rmvar.renlab.org). In this update, RMVar contains 1 678 126 RM-associated variants for 9 kinds of RNA modifications, namely m6A, m6Am, m1A, pseudouridine, m5C, m5U, 2'-O-Me, A-to-I and m7G, at three confidence levels. Moreover, RBP binding regions, miRNA targets, splicing events and circRNAs were integrated to assist investigations of the effects of RM-associated variants on posttranscriptional regulation. In addition, disease-related information was integrated from ClinVar and other genome-wide association studies (GWAS) to investigate the relationship between RM-associated variants and diseases. We expect that RMVar may boost further functional studies on genetic variants affecting RNA modifications.

Effect of polycyclic aromatic hydrocarbons on cancer risk causally mediated via vitamin D levels.

Polycyclic aromatic hydrocarbons (PAHs) widely exist in environmental substrates and are closely related to individual circulating vitamin D levels and tumorigenesis. Therefore, we proposed to evaluate the relationship between PAH exposure, vitamin D, and the risks for 14 cancer types via a causal inference framework underlying the mediation analysis. We evaluated seven urine monohydroxylated PAH (OH-PAH) and serum vitamin D concentrations of 3306 participants from the National Health and Nutrition Examination Survey between the 2013 and 2016 survey cycles and measured PAH concentrations in 150 subjects from the Nanjing cohort. We observed a significant negative dose-response relationship between increased OH-PAH levels and vitamin D deficiency. Each unit increase in ∑OH-PAHs could lead to a decrease in vitamin D levels (ßadj = -0.98, Padj = 2.05 × 10-4 ). Body mass index could have interaction effects with ∑OH-PAHs and affect vitamin D levels. Coexposure to naphthalene and fluorene metabolites mutually affected vitamin D levels. Notably, vitamin D could causally mediate the relationship between OH-PAHs and nine types of cancer (e.g., colorectal cancer, liver cancers, etc.). This study first emphasizes the causal cascade of individual OH-PAHs, vitamin D, and cancer risk, providing insights into prevention via the environment.

Drug resistance profiles and influencing factors among HIV-infected children and adolescents receiving long-term ART: a multicentre observational study in China.

OBJECTIVES: To analyse the characteristics and determinants of drug resistance mutations (DRMs) in HIV-infected children and adolescents on long-term ART in China. METHODS: An observational cohort study was conducted in five centres. All participants younger than 15 years at ART initiation were screened, and those identified as having virological failure (VF) with viral load (VL) ≥ 400 copies/mL were included for genotypic resistance testing. Logistic regression analysis was performed and the accumulation of major mutations was analysed in a subgroup of resistant individuals with complete VL results since HIV diagnosis. RESULTS: Among 562 eligible participants, protease and RT regions were successfully amplified for 93 who failed treatment with a median of 10.0 years ART. Sixty-eight (73.1%) harboured ≥1 major mutations. NRTI, NNRTI and dual-class resistance accounted for 48.4%, 63.4% and 38.7%, respectively. Only 3.2% were resistant to PIs. Age at ART initiation [adjusted OR (aOR) = 0.813, 95% CI 0.690-0.957], subtype B (aOR = 4.378, 95% CI 1.414-13.560) and an initial NNRTI-based regimen (aOR = 3.331, 95% CI 1.180-9.402) were independently associated with DRMs. Among 40 resistant participants with additional VL data, 55.0% had continued VF on a suboptimal regimen and the estimated duration of VF was positively correlated with the total number of major mutations (r = 0.504, P = 0.001). CONCLUSIONS: The development of DRMs was common in children and adolescents receiving long-term treatment, and continued VF was prevalent in those with resistance. Timely genotypic testing and new child-friendly formulations are therefore urgently required.

Highly Sensitive Colorimetric Detection of Glutathione in Human Serum Based on Iron-Copper Metal-Organic Frameworks.

Emerging metal-organic framework (MOF)-based mimic enzymes have been exploited to design a colorimetric sensor for the detection of biomolecules. However, it is challenging to figure out the glutathione (GSH) detection method and the corresponding sensing mechanism using an MOF-based colorimetric sensor. In this work, a novel iron-copper MOF with high activity is synthesized by a wet-chemical method. A GSH colorimetric sensor based on the peroxidase-like properties of the iron-copper MOF is developed. Hydrogen peroxide is converted to hydroxyl radicals by the peroxidase-like properties of the iron-copper MOF mimic enzyme, which can catalyze the colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxidized TMB (ox-TMB). The kinetic constant of the MOF mimic enzyme (0.02 mM for H2O2) is superior to horseradish peroxidase (HRP). The GSH content can be quantified by proposing a sensor based on the colorimetric method and color turn-off mechanism. The turn-off mechanism of GSH analysis includes two aspects. On the one hand, the blue ox-TMB can be deoxidized to colorless TMB by GSH. On the other hand, hydroxyl radicals (•OH) can be consumed by GSH. The linear range and limit of detection are 2-20 and 0.439 µM, respectively. At the same time, GSH detection also shows good specificity and anti-interference characteristics. Therefore, MOF-based colorimetric sensors have been used to qualitatively and quantitatively measure GSH contents in human serum. The mechanism and application of the iron-copper MOF pave a way for the development of mimic enzymes with polymetallic active sites in the field of colorimetric sensing.

Preferences of gastric cancer survivors for follow-up care-a multicenter discrete choice experiment study.

PURPOSES: The purposes of this discrete choice experiment are as follows: (1) to investigate the preferences of gastric cancer survivors for follow-up care, and (2) to quantify the importance of follow-up care-related characteristics that may affect the gastric cancer survivors' choices of their follow-up, so as to provide references for the development of the follow-up strategy of gastric cancer survivors. METHODS: Discrete choice experimental design principle was applied to develop the survey instrument. All questionnaires were filled out by the respondents and collected on site. A mixed logit model was used to estimate gastric cancer survivors' preferences. Willingness to pay estimates and simulations of follow-up uptake rates were calculated. RESULTS: All six attributes are significantly important for the follow-up care of gastric cancer survivors (p < 0.05). Achieving very thorough follow-up contents was the most valued attribute level (coefficient = 1.995). Specialist doctors are the most preferred providers followed by specialist nurses, and gastric cancer survivors were willing to pay more for these attribute levels. Changes in attribute levels affected uptake rate of follow-up. When the multiple attribute levels were changed at the same time, a very thorough follow-up content was provided by the same specialist doctor (specialist nurse), and the probability of receiving follow-up increases by 95.82% (94.90%). CONCLUSIONS: The characteristics of follow-up care in our study reflect the health management services' expectations of gastric cancer survivors. A dedicated specialist nurse involved in follow-up care should be developed to contribute to solve the complex and multifaceted personal needs of gastric cancer survivors.

Preferences of first-degree relatives of gastric cancer patients for gastric cancer screening: a discrete choice experiment.

BACKGROUND: It is very necessary to implement gastric cancer screening in China to reduce the mortality of gastric cancer, but there are no national screening guidelines and programs. Understanding of individual preferences is conducive to formulating more acceptable screening strategies, and discrete choice experiments can quantify individual preferences. In addition, the first-degree relatives of gastric cancer patients are at high risk for gastric cancer. Compared with those without a family history of gastric cancer, the risk of gastric cancer in first-degree relatives of gastric cancer patients is increased by 60%. Therefore, a discrete choice experiment was carried out to quantitatively analyse the preferences of first-degree relatives of gastric cancer patients for gastric cancer screening to serve as a reference for the development of gastric cancer screening strategies. METHODS: A questionnaire was designed based on a discrete choice experiment, and 342 first-degree relatives of gastric cancer patients were investigated. In STATA 15.0 software, the data were statistically analysed using a mixed logit model. RESULTS: The five attributes included in our study had a significant influence on the preferences of first-degree relatives of gastric cancer patients for gastric cancer screening (P < 0.05). Participants most preferred the sensitivity of the screening program to be 95% (coefficient = 1.424, P < 0.01) with a willingness to pay 2501.902 Yuan (95% CI, 738.074-4265.729). In addition, the participants' sex and screening experiences affected their preferences. An increase in sensitivity 35 to 95% had the greatest impact on the participants' willingness to choose a gastric cancer screening program. CONCLUSION: The formulation of gastric cancer screening strategies should be rooted in people's preferences. The influence of sex differences and screening experiences on the preferences of people undergoing screening should be considered, and screening strategies should be formulated according to local conditions to help them play a greater role.