Integrated identification-quantification (ID-Quant) workflow utilizing UPLC-QTOF-MS for the therapeutic drug monitoring of multi-component antibiotics without pure standards: Validation using teicoplanin.

The lack of individual pure standard has hampered the application of therapeutic drug monitoring (TDM) for multi-component antibiotics in clinical laboratories. Here, we aimed to develop an integrated identification-quantification (ID-Quant) workflow based on ultra-high-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry (UHPLC-QTOF-MS) to enable the comprehensive determination of all teicoplanin components without needing pure standards. The workflow comprises three steps. First, non-targeted MSE full scanning was used to detect and identify all potential ingredients. Then, characteristic product ions were selected to generate a quantitative time-of-flight multiple reaction monitoring (Tof-MRM) method. Finally, the constituent composition of teicoplanin injection was determined and utilized as an alternative reference standard to monitor the teicoplanin ingredients in human serum samples. As a result, nine teicoplanin analogs were identified from teicoplanin injection (Sanofi-Aventis, France). The overall performance of the Tof-MRM method was satisfactory in terms of linearity, precision, accuracy, and limits of detection. Utilizing the drug as standard, the individual concentrations for each component in patient serum were determined to be 0.120 µg/mL (A3-1), 0.020 µg/mL (N-1), 0.550 µg/mL (N-2), 0.730 µg/mL (A2-1), 4.26 µg/mL (A2-2,3), 4.79 µg/mL (A2-4,5), and 0.290 µg/mL (N-3), respectively. The distribution pattern of teicoplanin components was also discovered to differ from that in the drug injection. Overall, this integrated ID-Quant workflow based on UHPLC-QTOF-MS enables the robust quantitation of all teicoplanin analogs without the need for individual pure standard. This approach could help address the standard unavailability problem in the TDM of multi-component antibiotics.

Construction of an ER stress-related prognostic signature for predicting prognosis and screening the effective anti-tumor drug in osteosarcoma.

BACKGROUND: Osteosarcoma is the most common malignant primary bone tumor in infants and adolescents. The lack of understanding of the molecular mechanisms underlying osteosarcoma progression and metastasis has contributed to a plateau in the development of current therapies. Endoplasmic reticulum (ER) stress has emerged as a significant contributor to the malignant progression of tumors, but its potential regulatory mechanisms in osteosarcoma progression remain unknown. METHODS: In this study, we collected RNA sequencing and clinical data of osteosarcoma from The TCGA, GSE21257, and GSE33382 cohorts. Differentially expressed analysis and the least absolute shrinkage and selection operator regression analysis were conducted to identify prognostic genes and construct an ER stress-related prognostic signature (ERSRPS). Survival analysis and time dependent ROC analysis were performed to evaluate the predictive performance of the constructed prognostic signature. The "ESTIMATE" package and ssGSEA algorithm were utilized to evaluate the differences in immune cells infiltration between the groups. Cell-based assays, including CCK-8, colony formation, and transwell assays and co-culture system were performed to assess the effects of the target gene and small molecular drug in osteosarcoma. Animal models were employed to assess the anti-osteosarcoma effects of small molecular drug. RESULTS: Five genes (BLC2, MAGEA3, MAP3K5, STC2, TXNDC12) were identified to construct an ERSRPS. The ER stress-related gene Stanniocalcin 2 (STC2) was identified as a risk gene in this signature. Additionally, STC2 knockdown significantly inhibited osteosarcoma cell proliferation, migration, and invasion. Furthermore, the ER stress-related gene STC2 was found to downregulate the expression of MHC-I molecules in osteosarcoma cells, and mediate immune responses through influencing the infiltration and modulating the function of CD8+ T cells. Patients categorized by risk scores showed distinct immune status, and immunotherapy response. ISOX was subsequently identified and validated as an effective anti-osteosarcoma drug through a combination of CMap database screening and in vitro and in vivo experiments. CONCLUSION: The ERSRPS may guide personalized treatment decisions for osteosarcoma, and ISOX holds promise for repurposing in osteosarcoma treatment.

Evolution of LC-MS/MS in clinical laboratories.

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has attracted significant attention in clinical practice owing to its numerous advantages. However, the widespread adoption of this technique is hindered by certain limitations, such as inappropriate analyte selection, low levels of automation, and a lack of specific reference intervals and quality control programs. This review comprehensively summarizes the current challenges associated with LC-MS/MS and proposes potential resolutions. The principle of utility should guide the selection of biomarkers, prioritizing their practical value over sheer quantity. To achieve full-process automation, methodological innovation is crucial for developing high-throughput equipment. Establishing reference intervals for mass spectrometry-based assays across multiple centers and diverse populations is essential for accurate result interpretation. Additionally, the development of commercial quality control materials assumes pivotal importance in ensuring assay reliability and reproducibility. Harmonization and standardization efforts should focus on the development of reference methods and materials for the clinical use of LC-MS/MS. In the future, commercial assay kits and laboratory-developed tests (LDTs) are expected to coexist in clinical laboratories, each offering distinct advantages. The collaborative efforts of diverse professionals is vital for addressing the challenges associated with the clinical application of LC-MS/MS. The anticipated advancements include simplification, increased automation, intelligence, and the standardization of LC-MS/MS, ultimately facilitating its seamless integration into clinical routines for both technicians and clinicians.

Automated magnetic-bead-assisted sequential extraction technology for simultaneous detection of Aß1-42 and Aß1-40 in cerebrospinal fluid: An advance toward fully automated liquid chromatography-tandem mass spectrometry method.

Traditional solid-phase extraction (SPE) LC-MS/MS is limited by high costs, turnaround times, and procedural complexity, which limited the usage in clinical practice. This study aimed to establish a robust UPLC-MS/MS method with automated magnetic-bead-assisted sequential extraction (MBASE) technology to simultaneously measure Aß1-42 and Aß1-40 in cerebrospinal fluid (CSF). A Waters TQ-XS triple quadrupole mass spectrometer and Acquity UPLC Protein BEH C4 column were used. The targeted analytes were extracted and concentrated using the automated MBASE technology with chemically modified magnetic MCX beads. Analytical performance was verified referring to the CLSI C62-A and EP-15-A3 guidelines. A total of 68 CSF samples were collected and analyzed using the MBASE UPLC-MS/MS method, traditional SPE UPLC-MS/MS method, and Lumipulse G fully automated chemiluminescence detection system, and method comparison analysis is conducted. The MBASE UHPLC-MS/MS method showed an analytical performance equivalent to that of traditional SPE technology, with a higher sample throughput and smaller amount of materials ($34.98 vs. $493.96) and labor cost (101 min vs. 140 min) for 96 samples. The limit of quantification (LOQ) of Aß1-42 and Aß1-40 was 0.10 ng/mL and 0.05 ng/mL; recovery was 88.35-107.07 % and 95.72-96.60 %; and total imprecision was 3.69-6.83 % and 3.02-3.61 %, respectively. The measurements were faithfully reproduced within the allowable levels of uncertainty using certified reference materials. The correlations between this MBASE UPLC-MS/MS method, the SPE UPLC-MS/MS method, and Lumipulse G fully automated biochemical analysis method are all deemed good (r = 0.869-0.936), and the MBASE- and SPE-UPLC-MS/MS methods showed comparable measurements. To our knowledge, our study firstly verified the robust performance of the MBASE UPLC-MS/MS method to simultaneously determine Aß1-42 and Aß1-40 in CSF. With further introduce of automation, the assay with high accuracy and low material and labor costs will become a promising clinical technology.

Variations in Blood Copper and Possible Mechanisms During Pregnancy.

Copper (Cu), an essential trace element, is crucial for both the mother and fetus. Currently, an increasing number of studies have focused on blood copper levels during pregnancy. Studies have found that blood copper levels in pregnant women are higher than those in reproductive-age women, but the trend, mainly in the 2nd and 3rd trimester, is still controversial. Most studies showed that blood copper levels gradually increased during pregnancy, while some studies found that blood copper levels remained stable or even decreased in the 3rd trimester. The possible mechanisms of variations in blood copper during pregnancy include the influence of estrogen (hepatic uptake and excretion, ceruloplasmin synthesis, maternal-fetal transport, etc.), the interaction of other trace elements (Fe, Zn, etc.) and other factors. Among them, maternal-fetal copper transport caused by elevated estrogen may be the main reason for the inconsistencies observed in the 2nd and 3rd trimester during pregnancy. However, there are some mechanisms require further investigation. In the future, the trend and mechanisms of blood copper during pregnancy should be explored more deeply to help doctors better monitor copper status and detect copper abnormalities in time.

Ceramide metabolism-related prognostic signature and immunosuppressive function of ST3GAL1 in osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor with elevated disability and mortality rates in children and adolescents and the therapeutic effect for osteosarcoma has remained stagnant in the past 30 years. Emerging evidence has shown ceramide metabolism plays a vital role in tumor progression, but its mechanisms in osteosarcoma progression remain unknown. Through consensus clustering and LASSO regression analysis based on the osteosarcoma cohorts from TARGET database, we constructed a ceramide metabolism-related prognostic signature including ten genes for osteosarcoma, with ST3GAL1 exhibiting the highest hazard ratio. Biological signatures analysis demonstrated that ceramide metabolism was associated with immune-related pathways, immune cell infiltration and the expression of immune checkpoint genes. Single-cell profiling revealed that ceramide metabolism was enriched in myeloid, osteoblast and mesenchymal cells. The interaction between TAMs and CD8+ T cells played an essential role in osteosarcoma. ST3GAL1 regulated the SPP1-CD44 interaction between TAMs and CD8+ T cells and IL-10 secretion in TAMs through α2,3 sialic acid receptors, which inhibited CD8+ T cell function. IHC analysis showed that ST3GAL1 expression correlated with the prognosis of osteosarcoma patients. Co-culture assay revealed that upregulation of ST3GAL1 in tumor cells regulated the differentiation of TAMs and cytokine secretion. Collectively, our findings demonstrated that ceramide metabolism was associated with clinical outcome in osteosarcoma. ST3GAL1 facilitated tumor progression through regulating tumor immune microenvironment, providing a feasible therapeutic approach for patients with osteosarcoma.

A comprehensive LC-MS/MS method for the simultaneous measurement of 24 adrenal steroids: From research to clinical practice.

Steroids are essential in the differential diagnosis of congenital adrenal hyperplasia (CAH) subtypes; however, they may confuse physicians with multifarious results. In this study, we established a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous measurement of 24 steroids and developed a steroid metabolite pathway-based report to aid physicians in understanding these results. Solid-phase extraction was used to concentrate and purify target plasma steroids. The linearity, precision, recovery, and matrix effects were thoroughly evaluated. PowerBuilder was used to transfer the results from LC-MS/MS to the graphic report in a laboratory information management system (LIS) and was applied to different subtypes of CAH. Twenty-four steroids were separated and analyzed in one sample preparation and two injections using LC-MS/MS. The linearity of the steroids was excellent, with coefficients of linear regression greater than 0.99. The relative recovery ranged from 90.0 to 107.1 %, whereas the intra- and total coefficient variations were 1.6 âˆ¼ 8.7 % and 2.0 âˆ¼ 9.9 %, respectively. Matrix effects were compensated after internal standard correction. A graphic combination report mode was established and used to effectively identify CAH subtypes. In conclusion, a useful LC-MS/MS method and graphic combination report of 24 steroids based on their metabolite pathways were established.

Expanding flavone and flavonol production capabilities in Escherichia coli.

Flavones and flavonols are important classes of flavonoids with nutraceutical and pharmacological value, and their production by fermentation with recombinant microorganisms promises to be a scalable and economically favorable alternative to extraction from plant sources. Flavones and flavonols have been produced recombinantly in a number of microorganisms, with Saccharomyces cerevisiae typically being a preferred production host for these compounds due to higher yields and titers of precursor compounds, as well as generally improved ability to functionally express cytochrome P450 enzymes without requiring modification to improve their solubility. Recently, a rapid prototyping platform has been developed for high-value compounds in E. coli, and a number of gatekeeper (2S)-flavanones, from which flavones and flavonols can be derived, have been produced to high titers in E. coli using this platform. In this study, we extended these metabolic pathways using the previously reported platform to produce apigenin, chrysin, luteolin and kaempferol from the gatekeeper flavonoids naringenin, pinocembrin and eriodictyol by the expression of either type-I flavone synthases (FNS-I) or type-II flavone synthases (FNS-II) for flavone biosynthesis, and by the expression of flavanone 3-dioxygenases (F3H) and flavonol synthases (FLS) for the production of the flavonol kaempferol. In our best-performing strains, titers of apigenin and kaempferol reached 128 mg L-1 and 151 mg L-1 in 96-DeepWell plates in cultures supplemented with an additional 3 mM tyrosine, though titers for chrysin (6.8 mg L-1) from phenylalanine, and luteolin (5.0 mg L-1) from caffeic acid were considerably lower. In strains with upregulated tyrosine production, apigenin and kaempferol titers reached 80.2 mg L-1 and 42.4 mg L-1 respectively, without the further supplementation of tyrosine beyond the amount present in the rich medium. Notably, the highest apigenin, chrysin and luteolin titers were achieved with FNS-II enzymes, suggesting that cytochrome P450s can show competitive performance compared with non-cytochrome P450 enzymes in prokaryotes for the production of flavones.

Corrigendum: Research trends and hotspots of glial fibrillary acidic protein within the area of Alzheimer's disease: a bibliometric analysis.

[This corrects the article DOI: 10.3389/fnagi.2023.1196272.].

Association between FIB-4, all-cause mortality, cardiovascular mortality, and cardiovascular disease risk among diabetic individuals: NHANES 1999-2008.

Background: Diabetes is prevalent worldwide and is associated with cardiovascular disease (CVD). Furthermore, due to the insulin resistance, diabetic populations are vulnerable to liver fibrosis, which increases the risk of CVD. Fibrosis-4 index (FIB-4)-a non-invasive biomarker for liver fibrosis-is crucial in predicting CVD among patients with liver diseases. However, the association between FIB-4, death, and CVD in the US diabetic population has not yet been investigated. Method: We conducted a cross-sectional study using the data from the National Health and Nutrition Examination Survey (NHANES) 1999-2008. The mortality status was obtained from the National Death Index through December 31, 2015. Participants were divided into survivor and mortality group to compare the basic characteristics. The association between FIB-4, death, and CVD was analyzed using the restricted cubic spline method and Cox proportional hazards models. In stratified analysis, Participants were stratified based on age, sex, BMI, hypertension, or eGFR respectively. Results: The participants (N = 3,471) were divided into survivor (N = 1,785) and mortality groups (N = 1,632), with the mortality group exhibiting significantly higher FIB-4 values. Moreover, the risk of all-cause mortality (HR 1.24; 95% CI, 1.17-1.32) and CVD mortality (HR 1.17; 95% CI, 1.04-1.31) increased with each FIB-4 SD increase after adjusting for all covariates. However, except for myocardial infarction, FIB-4 had no significant effect on the incidence of the other three CVD subtypes (congestive heart failure, coronary heart disease, and angina pectoris). In stratified analysis, we found that the effect of FIB-4 on CVD mortality was influenced by age, and FIB-4 is a risk factor for people older than 60 years (HR 1.14; 95% CI, 1.01-1.29). Conclusion: Using data from NHANES 1999-2008, FIB-4 was found to be associated with all-cause and CVD mortality in the diabetic population, and this association was significantly affected by age. However, FIB-4 only affected the incidence of myocardial infarction. Future work should investigate the association between FIB-4 and CVD in the diabetic population.

Research trends and hotspots of glial fibrillary acidic protein within the area of Alzheimer's disease: a bibliometric analysis.

Objective: Our aim was to analyze the trends and hotspots on glial fibrillary acidic protein (GFAP) within the area of Alzheimer's disease (AD) by using a bibliometric method, which is currently missing. Methods: All articles and reviews on GFAP within the area of AD from inception to December 31, 2022, were searched from the Web of Science Core Collection. Full records were derived, imported into Microsoft Excel, and analyzed by BIBLIOMETRC, VOSviewer, and CiteSpace. Results: In total, 2,269 publications, including 2,166 articles, were ultimately included. The number of publications from 81 countries/regions and 527 academic journals increased annually. The top three prolific countries and institutions were the USA, China, and England, the University of Gothenburg (Sweden), Universidade Federal Rio Grande do Sul (Brasilia), and UCL Queen Square Institute of Neurology (England). Henrik Zetterberg from the University of Gothenburg, Kaj Blennow from the University of Gothenburg, and Alexei Verkhratsky from the University of Manchester were the top three prolific and cited authors; Journal of Alzheimer's Disease, Brain Research, and Neuroscience contributed the most publications. The top key areas of research included "molecular, biology, and genetics" and "molecular, biology, and immunology," and the top published and linked meaningful keywords included oxidative stress, inflammation/neuroinflammation, microglia, hippocampus, amyloid, cognitive impairment, tau, and dysfunction. Conclusion: Based on the bibliometric analysis, the number of publications on GFAP within the area of AD has been rapidly increasing, especially in the past several years. Oxidative stress and inflammation are research hotspots, and GFAP in body fluids, especially blood, could be used for large-scale screening for AD.

Ground testing of release impulse for the aluminum cubic test mass with a compound pendulum for the TianQin project.

In the space-borne gravitational wave detection TianQin project, the locking and releasing of test mass is one of the key technologies. The test mass will be locked during the spacecraft launch and then released to free fall for the science phase. The residual release impulse is required to be on the order of magnitude of 10-5 kg m/s, which allows us to capture the test mass by the force authority of the capacity control. In this paper, the release impulse of the aluminum test mass is measured with a compound pendulum for the TianQin project. The test mass is locked by two tips from opposite positions, and the release impulse is obtained from the oscillation of the pendulum. When the aluminum test mass is locked and released by the stainless steel and aluminum tips, the release impulses and their uncertainties are on the order of magnitude of 10-5and 10-7 kg m/s, respectively. This provides a feasible measurement scheme for the impulse testing in the TianQin project.

Effect of Probiotic Supplementation on the Gut Microbiota Composition of Infants Delivered by Cesarean Section: An Exploratory, Randomized, Open-label, Parallel-controlled Trial.

BACKGROUND: Infants born via cesarean section (CS) are at an increased risk of immune-related diseases later in life, potentially due to altered gut microbiota. Recent research has focused on the administration of probiotics in the prevention of gut microbiota dysbiosis in neonates delivered by CS. This study was performed to investigate the effects of probiotic supplementation on the gut microbiota of CS-delivered infants. METHODS: Thirty full-term neonates delivered by CS were randomized into the intervention (supplemented orally with a probiotic containing Bifidobacterium longum, Lactobacillus acidophilus, and Enterococcus faecalis for 2 weeks) and control groups. Stool samples were collected at birth and 2 weeks and 42 days after birth. The composition of the gut microbiota was analyzed using 16S rRNA sequencing technology. RESULTS: The applied bacterial strains were abundant in the CS-delivered infants supplemented with probiotics. Probiotics increased the abundance of some beneficial bacteria, such as Bacteroides, Acinetobacter, Veillonella, and Faecalibacterium. Low colonization of Klebsiella, a potentially pathogenic bacterium, was observed in the intervention group. CONCLUSIONS: Our results showed that probiotics supplemented immediately after CS enriched the gut microbiota composition and altered the pattern of early gut colonization. TRIAL REGISTRATION: registration number NCT05086458.

Prediction of potential hard sodium carbaboride compounds assuming sp3-bonded covalent clathrates.

Boron-carbon clathrates have attracted great attention due to their unique sp3-bonded structure and excellent electronic properties. Here, by performing first-principles calculations, we predicted six stoichiometric Na-B-C clathrates (NaBC11, Na2B2C10, NaB2C10, Na2B4C8, NaB4C8, and Na2B6C6) based on Na-doped boron-carbon clathrates. As a result, NaBC11, Na2B2C10, and NaB2C10 were found to become energetically favorable. Under ambient conditions, the electronic structure calculations show that NaBC11 and Na2B2C10 are indirect band gap semiconductors, and NaB2C10, Na2B4C8, and NaB4C8 exhibit metallic features. Na2B2C10 and Na2B4C8 are found to be synthesized at 22.7 and 14.2 GPa, respectively. Interestingly, the formation enthalpies of NaxB2C10 and NaxB4C8 (x = 0, 1, and 2) clathrates decrease in turn with the increased number of Na atoms in the same synthetic paths. Moreover, the ideal indentation strengths of NaBC11, Na2B2C10, and NaB2C10 approach 40 GPa, indicating that they are hard materials with superior hardness. These findings offer valuable insights for advancing the synthesis of boron-carbon clathrates.

Nightshift work can induce oxidative DNA damage: a pilot study.

BACKGROUND: Regular sleep is very important for human health; however, the short-term and long-term effects of nightshift with sleep deprivation and disturbance on human metabolism, such as oxidative stress, have not been effectively evaluated based on a realistic cohort. We conducted the first long-term follow-up cohort study to evaluate the effect of nightshift work on DNA damage. METHODS: We recruited 16 healthy volunteers (aged 33 ± 5 years) working night shifts at the Department of Laboratory Medicine at a local hospital. Their matched serum and urine samples were collected at four time points: before, during (twice), and after the nightshift period. The levels of 8-oxo-7,8-dihydroguanosine (8-oxoG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), two important nucleic-acid damage markers, were accurately determined based on a robust self-established LC‒MS/MS method. The Mann-Whitney U or Kruskal-Wallis test was used for comparisons, and Pearson's or Spearman's correlation analysis was used to calculate the correlation coefficients. RESULTS: The levels of serum 8-oxodG, estimated glomerular filtration rate-corrected serum 8-oxodG, and the serum-to-urine 8-oxodG ratio significantly increased during the nightshift period. These levels were significantly higher than pre-nightshift work level even after 1 month of discontinuation, but no such significant change was found for 8-oxoG. Moreover, 8-oxoG and 8-oxodG levels were significantly positively associated with many routine biomarkers, such as total bilirubin and urea levels, and significantly negatively associated with serum lipids, such as total cholesterol levels. CONCLUSION: The results of our cohort study suggested that working night shifts may increase oxidative DNA damage even after a month of discontinuing nightshift work. Further studies with large-scale cohorts, different nightshift modes, and longer follow-up times are needed to clarify the short- and long-term effects of night shifts on DNA damage and find effective solutions to combat the negative effects.

METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance.

Osteosarcoma is the most common bone tumor that leads to high mortality in adolescents and children. The tRNA N7-methylguanosine methyltransferase METTL1 is located in chromosome 12q14.1, a region that is frequently amplified in osteosarcoma patients, while its functions and underlying mechanisms in regulation of osteosarcoma remain unknown. Herein we show that METTL1 and WDR4 are overexpressed in osteosarcoma and associated with poor patient prognosis. Knockdown of METTL1 or WDR4 causes decreased tRNA m7G modification level and impairs osteosarcoma progression in vitro and in vivo. Conversely, METTL1/WDR4 overexpression promotes osteosarcoma proliferation, migration and invasion capacities. tRNA methylation and mRNA translation profiling indicate that METTL1/WDR4 modified tRNAs enhance translation of mRNAs with more m7G tRNA-decoded codons, including extracellular matrix (ECM) remodeling effectors, which facilitates osteosarcoma progression and chemoresistance to doxorubicin. Our study demonstrates METTL1/WDR4 mediated tRNA m7G modification plays crucial oncogenic functions to enhance osteosarcoma progression and chemoresistance to doxorubicin via alteration of oncogenic mRNA translation, suggesting METTL1 inhibition combined with chemotherapy is a promising strategy for treatment of osteosarcoma patients.

Metabolic phenotypes and risk of end-stage kidney disease in patients with type 2 diabetes.

Background: Obesity often initiates or coexists with metabolic abnormalities. This study aimed to investigate the pathological characteristics and the independent or mutual relations of obesity and metabolic abnormalities with end-stage kidney disease (ESKD) in patients with type 2 diabetes (T2D) and associated diabetic kidney disease (DKD). Methods: A total of 495 Chinese patients with T2D and biopsy-confirmed DKD between 2003 and 2020 were enrolled in this retrospective study. The metabolic phenotypes were based on the body weight index (BMI)-based categories (obesity, BMI ≥ 25.0 kg/m2) and metabolic status (metabolically unhealthy status, ≥ 1 criterion National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) excluding waist circumference and hyperglycemia) and were categorized into four types: metabolically healthy non-obesity (MHNO), metabolically healthy obesity (MHO), metabolically unhealthy non-obesity (MUNO), and metabolically unhealthy obesity (MUO). The pathological findings were defined by the Renal Pathology Society classification. Cox proportional hazards models were used to estimate hazard ratios (HRs) for ESKD. Results: There are 56 (11.3%) MHNO patients, 28 (5.7%) MHO patients, 176 (35.6%) MUNO patients, and 235 (47.5%) MUO patients. The high prevalence of the Kimmelstiel-Wilson nodule and severe mesangial expansion were associated with obesity, whereas severe IFTA was related to metabolically unhealthy status. In the multivariate analysis, the adjusted HR (aHR) was 2.09 [95% confidence interval (CI) 0.99-4.88] in the MHO group, 2.16 (95% CI 1.20-3.88) in the MUNO group, and 2.31 (95% CI 1.27-4.20) in the MUO group compared with the MHNO group. Furthermore, the presence of obesity was insignificantly associated with ESKD compared with non-obese patients (aHR 1.22, 95% CI 0.88-1.68), while the metabolically unhealthy status was significantly associated with ESKD compared to the metabolically healthy status in the multivariate analysis (aHR 1.69, 95% CI 1.10-2.60). Conclusion: Obesity itself was insignificantly associated with ESKD; however, adding a metabolically unhealthy status to obesity increased the risk for progression to ESKD in T2D and biopsy-proven DKD.

Research in the genetics of pheochromocytoma and paraganglioma: a bibliometric analysis from 2002 to 2022.

Over the past two decades, there has been a significant growth in articles focusing on the genetics of pheochromocytoma and paraganglioma (PPGL). We used bibliometric methods to investigate the historical changes and trend in PPGL research. There was a total of 1263 articles published in English from 2002 to 2022 included in our study. The number of annual publications and citations in this field has been increasing in the past 20 years. Furthermore, most of the publications originated from the European countries and the United States. The co-occurrence analysis showed close cooperation between different countries, institutions, or authors. The dual-map discipline analysis revealed that majority articles focused on four disciplines: #2 (Medicine, Medical, Clinical), #4 (Molecular, Biology, Immunology), #5 (Health, Nursing, Medicine), and #8 (Molecular, Biology, Genetics). The hotspot analysis revealed the keywords that have been landmark for PPGL genetics research in different time periods, and there was continued interest in gene mutations, especially on SDHX family genes. In conclusion, this study displays the current status of research and future trends in the genetics of PPGL. In future, more in-depth research should concentrate on crucial mutation genes and their specific mechanisms to assist in molecular target therapy. It is hoped that this study may help to provide directions for future research on genes and PPGL.

The association of plasma NT-proBNP level and progression of diabetic kidney disease.

AIMS: Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD). The identification of risk factors involved in the progression of DKD to ESKD is expected to result in early detection and appropriate intervention and improve prognosis. This study aimed to explore whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) and biopsy-proven DKD. METHODS: Patients with biopsy-proven DKD who were followed up at West China Hospital over 12 months were enrolled. The kidney outcome was defined as progression to ESKD. The cutoff value of plasma NT-proBNP concentration was calculated by using receiver operating characteristic (ROC) curve analysis. The influence of NT-proBNP levels on kidney outcome in patients with DKD was assessed using Cox regression analysis. RESULTS: A total of 30 (24.5%) patients reached ESKD during a median follow-up of 24.1 months. The baseline serum NT-proBNP level had a significant correlation with baseline proteinuria, kidney function, glomerular lesions, interstitial fibrosis tubular atrophy (IFTA), and arteriolar hyalinosis. Multivariate Cox regression analysis indicated that increased NT-proBNP level was significantly associated with a higher risk of progression to ESKD (HR 6.43; 95% CI (1.65-25.10, p = 0.007), and each 1 SD increase in LG (NT-proBNP) was also associated with a higher risk (HR 2.43; 95% CI 1.94-5.29, p = 0.047) of an adverse kidney outcome after adjusting for confounding factors. CONCLUSIONS: A higher level of plasma NT-proBNP predicts kidney prognosis in patients with biopsy-proven DKD. This warrants further investigation into the potential mechanisms.