Development and external validation of a risk prediction model for depression in patients with coronary heart disease.

BACKGROUND: Depression is an independent risk factor for adverse outcomes of coronary heart disease (CHD). This study aimed to develop a depression risk prediction model for CHD patients. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES). In the training set, reference literature, logistic regression, LASSO regression, optimal subset algorithm, and machine learning random forest algorithm were employed to screen prediction variables, respectively. The optimal prediction model was selected based on the C-index, Net Reclassification Improvement (NRI), and Integrated Discrimination Improvement (IDI). A nomogram for the optimal prediction model was constructed. 3 external validations were performed. RESULTS: The training set comprised 1375 participants, with a depressive symptoms prevalence of 15.2 %. The optimal prediction model was constructed using predictors obtained from optimal subsets algorithm (C-index = 0.774, sensitivity = 0.751, specificity = 0.685). The model includes age, gender, education, marriage, diabetes, tobacco use, antihypertensive drugs, high-density lipoprotein cholesterol (HDLC), and aspartate aminotransferase (AST). The model demonstrated consistent discrimination ability, accuracy, and clinical utility across the 3 external validations. LIMITATIONS: The applicable population of the model is CHD patients. And the clinical benefits of interventions based on the prediction results are still unknown. CONCLUSION: We developed a depression risk prediction model for CHD patients, which was presented in the form of a nomogram for clinical application.

Outcomes of extracorporeal membrane oxygenation cannulation strategy in lung transplantation: A retrospective cohort study.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) with different cannulation strategies is determined according to surgical position and patient condition. However, no cannulation guidelines have been proposed. This retrospective study assessed the outcomes of diverse ECMO cannulation strategies in patients undergoing lung transplantation (LTx). METHODS: Data of patients undergoing intraoperative veno-arterial ECMO-assisted LTx were retrospectively collected from December 1st, 2015 to October 31st, 2021. Patients were classified into three groups based on the different cannulation strategies: femoral artery-femoral vein (F-F)-ECMO, axillary artery-femoral vein (A-F)-ECMO, and ascending aorta-femoral vein (AAO-F)-ECMO. The F-F-ECMO, A-F-ECMO, and AAO-F-ECMO groups comprised 34, 44, and 30 patients, respectively. MAIN RESULTS: The AAO-F-ECMO group exhibited a significantly shorter duration of postoperative ECMO therapy (3 vs. 2 vs. 0 days, P < 0.01).the level of postoperative proBNP was lower on the third and seventh days (P < 0.001). AAO-F-ECMO patients had a significantly lower incidence of postoperative infections, heart failure, and bleeding (P < 0.05). Similar outcomes were observed in postoperative survival rates among the three groups (P > 0.05). CONCLUSIONS: Ascending aorta-femoral vein ECMO can provide sufficient and effective aerobic blood to perfuse organs with fewer side effects than cannulation in the femoral artery-femoral vein or axillary artery-femoral vein.

Characterization and application of Bacillus velezensis D6 co-producing α-amylase and protease.

BACKGROUND: Research on the co-production of multiple enzymes by Bacillus velezensis as a novel species is still a topic that needs to be studied. This study aimed to investigate the fermentation characteristics of B. velezensis D6 co-producing α-amylase and protease and to explore their enzymatic properties and applications in fermentation. RESULTS: The maximum co-production of α-amylase and protease reached 13.13 ± 0.72 and 2106.63 ± 64.42 U mL-1, respectively, under the optimal fermented conditions (nutrients: 20.0 g L-1 urea, 20.0 g L-1 glucose, 0.7 g L-1 MnCl2; incubation conditions: initial pH 7.0, temperature 41 °C, 8% inoculation size and 30% working volume). Moreover, the genetic co-expression of α-amylase and protease increased from 0 to 24 h and then decreased after 36 h at the transcriptional level, which coincided with the growth trend of B. velezensis D6. The optimal reaction temperature of α-amylase was 55-60 °C, while that of protease was 35-40 °C. The activities of α-amylase and protease were retained by over 80% after thermal treatment (90 °C, 1 h), which indicated that two enzymes co-produced by B. velezensis D6 demonstrated excellent thermal stability. Moreover, the two enzymes were stable over a wide pH range (pH 4.0-8.0 for α-amylase; pH 4.0-9.0 for protease). Finally, the degrees of hydrolysis of corn, rice, sorghum and soybeans by α-amylase from B. velezensis D6 reached 44.95 ± 2.95%, 57.16 ± 2.75%, 52.53 ± 4.01% and 20.53 ± 2.42%, respectively, suggesting an excellent hydrolysis effect on starchy raw materials. The hydrolysis degrees of mackerel heads and soybeans by protease were 43.93 ± 2.19% and 26.38 ± 1.72%, respectively, which suggested that the protease from B. velezensis D6 preferentially hydrolyzed animal-based protein. CONCLUSION: This is a systematic study on the co-production of α-amylase and protease by B. velezensis D6, which is crucial in widening the understanding of this species co-producing multi-enzymes and in exploring its potential application. © 2024 Society of Chemical Industry.

Obinutuzumab in Refractory Membranous Nephropathy: A Case Series.

Rationale & Objective: Membranous nephropathy (MN), recognized as an autoimmune kidney disease, responds well to anti-CD20 monoclonal antibodies. Obinutuzumab, a type Ⅱ humanized anti-CD20 and immunoglobulin G1 Fc-optimized monoclonal antibody, when compared with rituximab, has demonstrated superior efficacy in B-cell leukemia and lymphoma, especially in rituximab-resistant cases. However, the efficacy and safety of obinutuzumab in MN remain unclear. Study Design: A case series study. Setting & Participants: A total of 18 patients were diagnosed with MN and had received obinutuzumab at our center without secondary MN, undergoing dialysis, having a history of kidney transplantation, or infections requiring treatment. Exposure: Obinutuzumab treatment. Outcomes: Primary outcomes included remission rate, time to first remission, and first relapse-free survival time during the follow-up period. Analytical Approach: Survival analysis was performed with Cox proportional hazards models, log-rank test, and Kaplan-Meier survival analysis. Results: Patients with MN (median age of 52.5 years, 83.3% males) received an average dose of 2.1 ± 0.8 g of obinutuzumab during a median follow-up period of 13.6 months. During the follow-up, 17 patients (94.4%) achieved remission, with 12 patients (66.7%) achieving partial remission, and 5 patients (27.8%) achieving complete remission. The median time to first remission and first relapse-free survival time was 2.7 (1.0-6.1) months and 9.8 (2.6-11.2) months, respectively. Of 12 patients with previous rituximab treatment, all achieved remission successfully, with 8 (66.7%) achieving partial remission and 4 (33.3%) achieving complete remission. Adverse events were mostly mild, and no severe treatment-related adverse events were observed. Limitations: Limited or missing data; risks of selection bias; or recall bias; underestimated first relapse-free survival time because of a limited follow-up period; unmonitored counts of CD19+ B-cells and other lymphocyte subsets. Conclusions: Obinutuzumab demonstrated promising efficacy and safety in inducing remission in MN, particularly in patients with an unsatisfactory response to rituximab.

Membranous nephropathy (MN), an autoimmune kidney disease, usually responds favorably to rituximab, a chimeric anti-CD20 monoclonal antibody. Nevertheless, certain patients exhibit inadequate responses to rituximab. Obinutuzumab, a novel humanized anti-CD20 monoclonal antibody, has shown enhanced efficacy in cases where rituximab fails to address B-cell leukemias and lymphomas. However, its efficacy and safety in MN treatment remain uncertain. A case series involving 18 patients treated with obinutuzumab at our center demonstrated promising results, suggesting favorable efficacy and safety in inducing and maintaining remission, particularly among patients who did not respond well to rituximab previously. These findings signify a potential alternative for MN treatment, though further research is needed to confirm them.

PKCα Induced the Generation of Extracellular Vesicles in Activated Platelets to Promote Breast Cancer Metastasis.

Platelet extracellular vesicles (PEVs) play an important role in tumor development. However, the mechanisms underlying their biogenesis have not been fully elucidated. Protein kinase Cα (PKCα) is an important regulator of platelet activation, but the effect of PKCα on EV generation is unclear. We used small-particle flow cytometry and found that the number of PEVs was increased in patients with breast cancer compared to those with benign breast disease. This was accompanied by increased levels of activated PKCα in breast cancer platelets. Treating platelets with the PKCα agonist phorbol 12-myristate 13-acetate (PMA) increased the phosphorylation PKCα and induced PEV production, while the PKCα inhibitor GÖ6976 showed the opposite effects. Notably, incubating platelets from patients with benign tumors with the culture supernatant of MDA-MB-231 cells induced PKCα phosphorylation in the platelets. Mass spectrometry and coimmunoprecipitation assays showed that Dynamin 2 (DNM2), a member of the guanosine-triphosphate-binding protein family, might cooperate with activated PKCα to regulate PEV production by breast cancer platelets. Similar results were observed in a mouse model of lung metastasis. In addition, PEVs were engulfed by breast cancer cells and promoted cancer cell migration and invasion via miR-1297 delivery. These findings suggested that PKCα cooperates with DNM2 to induce PEV generation, and PEV release might triggered by factors in the breast cancer environment.

Key genes and regulatory networks for diabetic retinopathy based on hypoxia-related genes: a bioinformatics analysis.

AIM: To prevent neovascularization in diabetic retinopathy (DR) patients and partially control disease progression. METHODS: Hypoxia-related differentially expressed genes (DEGs) were identified from the GSE60436 and GSE102485 datasets, followed by gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Potential candidate drugs were screened using the CMap database. Subsequently, a protein-protein interaction (PPI) network was constructed to identify hypoxia-related hub genes. A nomogram was generated using the rms R package, and the correlation of hub genes was analyzed using the Hmisc R package. The clinical significance of hub genes was validated by comparing their expression levels between disease and normal groups and constructing receiver operating characteristic curve (ROC) curves. Finally, a hypoxia-related miRNA-transcription factor (TF)-Hub gene network was constructed using the NetworkAnalyst online tool. RESULTS: Totally 48 hypoxia-related DEGs and screened 10 potential candidate drugs with interaction relationships to upregulated hypoxia-related genes were identified, such as ruxolitinib, meprylcaine, and deferiprone. In addition, 8 hub genes were also identified: glycogen phosphorylase muscle associated (PYGM), glyceraldehyde-3-phosphate dehydrogenase spermatogenic (GAPDHS), enolase 3 (ENO3), aldolase fructose-bisphosphate C (ALDOC), phosphoglucomutase 2 (PGM2), enolase 2 (ENO2), phosphoglycerate mutase 2 (PGAM2), and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). Based on hub gene predictions, the miRNA-TF-Hub gene network revealed complex interactions between 163 miRNAs, 77 TFs, and hub genes. The results of ROC showed that the except for GAPDHS, the area under curve (AUC) values of the other 7 hub genes were greater than 0.758, indicating their favorable diagnostic performance. CONCLUSION: PYGM, GAPDHS, ENO3, ALDOC, PGM2, ENO2, PGAM2, and PFKFB3 are hub genes in DR, and hypoxia-related hub genes exhibited favorable diagnostic performance.

Zonotopic Distributed Fusion Over Binary Sensor Networks With Bit Rate Allocation: A Coding-Decoding Approach.

In this article, the zonotopic distributed fusion estimation problem is investigated for a class of general nonlinear systems over binary sensor networks subject to unknown-but-bounded (UBB) noises. The network communication from nodes to the fusion center is confined to the limited bit rate. To alleviate the impact from less measurement information of the binary sensor, a modified innovation is constructed to improve the estimation accuracy. Then, a novel coding-decoding approach is proposed to ensure that the decoder has the ability to decode information from each node. Based on the matrix weighting fusion method, a distributed fusion algorithm is put forward under the zonotopic set-membership filtering framework, and the F -radius of the local zonotopic sets are derived and minimized by selecting the filtering gain parameters. Moreover, the bit rate allocation scheme and the weighting coefficients are determined by resolving two optimization problems. In addition, a sufficient condition is established to guarantee the uniform boundedness of the F -radius of the fused zonopotic. Finally, the ballistic object tracking systems is utilized to illustrate the availability of the presented algorithm.

Rnai-based functional analysis of bursicon genes related to cuticle pigmentation in a ladybird beetle.

In arthropods, the binding of a bursicon (encoded by burs and pburs) heterodimer or homodimer to a leucine-rich repeat-containing G protein coupled receptor LGR2 (encoded by rk) can activate many physiological processes, especially cuticle pigmentation during insect ecdysis. In the current paper, we intended to ascertain whether bursicon signaling mediates body coloration in the 28-spotted larger potato ladybird, Henosepilachna vigintioctomaculata, and if so, by which way bursicon signal governs the pigmentation. The high expression of Hvburs, Hvpburs and Hvrk occurred in the young larvae, pupae and adults, especially in the head and ventral nerve cord. RNA interference (RNAi) aided knockdown of Hvburs, Hvpburs or Hvrk in the prepupae caused similar phenotypic defects. The pigmentation of the resultant adults was affected, with significantly reduced dark areas on the sternums. Moreover, the accumulated mRNA levels of two sclerotin biosynthesis genes, aspartate 1-decarboxylase gene Hvadc and N-ß-alanyldopamine synthase gene Hvebony, were significantly increased in the Hvburs, Hvpburs or Hvrk RNAi beetles. Furthermore, depletion of either Hvadc or Hvebony could completely rescue the impaired coloration on the sternums of Hvpburs RNAi adult. Our results supported that bursicon heterodimer-mediated signal regulate cuticle pigmentation. The bursicon signaling may tune the ratio of melanins (dark/black, brown) to sclerotins (light yellow, colorless) exerting its regulative role in the pigmentation of H. vigintioctomaculata sternums.

Two-dimensional ferromagnetic semiconductor Cr2XP: first-principles calculations and Monte Carlo simulations.

Two-dimensional room-temperature intrinsic ferromagnetic semiconductors have attracted widespread attention due to their applications in spintronic devices. However, it is difficult for the material to have a Curie temperature above room temperature according to the Mermin-Wagner theorem. By using the method of band engineering, we design a new promising two-dimensional room-temperature intrinsic ferromagnetic semiconductor Cr2XP (X = P, As, Sb) with large magnetization. The formation of a semiconducting gap for Cr2XP is discussed in terms of hybridization, occupation and distribution of electronic states and charge transfer. Large magnetic moments of about 6.16-6.37µB originate from the occupation of Cr-d electrons in the crystal field. Competition between Cr-d-Cr-d and Cr-d-X-p-Cr-d exchange interactions leads to the emergence of a ferromagnetic order phase. Furthermore, Curie temperatures, approaching 278 K, 464 K and 1590 K for Cr2P2, Cr2AsP and Cr2SbP, are estimated by employing Monte Carlo simulations based on the Heisenberg model. The magnetic anisotropy energy of Cr2XP is discussed using magnetic second-order perturbation theory. In addition, Cr2XP possesses excellent thermodynamic, dynamical, thermal and mechanical stabilities and can overcome its own gravity to retain its planar structure without the support of the substrate. These above-mentioned advantages will offer some valuable insights into two-dimensional intrinsic ferromagnetic semiconductor Cr2XP in spintronic devices.

Seawater barium and sulfide removal improved marine habitability for the Cambrian Explosion of early animals.

An increase in atmospheric pO2 has been proposed as a trigger for the Cambrian Explosion at ∼539-514 Ma but the mechanistic linkage remains unclear. To gain insights into marine habitability for the Cambrian Explosion, we analysed excess Ba contents (Baexcess) and isotope compositions (δ138Baexcess) of ∼521-Myr-old metalliferous black shales in South China. The δ138Baexcess values vary within a large range and show a negative logarithmic correlation with Baexcess, suggesting a major (>99%) drawdown of oceanic Ba inventory via barite precipitation. Spatial variations in Baexcess and δ138Baexcess indicate that Ba removal was driven by sulfate availability that was ultimately derived from the upwelling of deep seawaters. Global oceanic oxygenation across the Ediacaran-Cambrian transition may have increased the sulfate reservoir via oxidation of sulfide and concurrently decreased the Ba reservoir by barite precipitation. The removal of both H2S and Ba that are deleterious to animals could have improved marine habitability for early animals.

Non-intubated tracheal resection and reconstruction for a tracheal tumor in an 8-year-old child.

INTRODUCTION: It has been reported that non-intubated anesthesia can be used successfully in adult trachea reconstruction. Herein, our center reported a case of a child undergoing non-intubated trachea reconstruction for benign tracheal tumors. CASE DESCRIPTION: In January 2023, it was decided to attempt tracheal resection and reconstruction (TRR) in an 8-year-old child with an inflammatory myofibroblastic tumor under non-intubated spontaneous breathing. After anesthesia induction, the laryngeal mask airway (LMA) was inserted. Thereafter, a bilateral superficial cervical plexus block was performed with 15 mL of 0.25% ropivacaine injected into each side. The patient was induced to resume spontaneous breathing by artificially assisted ventilation with an oxygen flow of 2 to 5 L/min and FiO2=1. After tracheotomy, the oxygen flow was increased to 15 L/min to improve the local oxygen flow to maintain the pulse oxygen saturation (SpO2) above 90% under spontaneous breathing. The patient had stable spontaneous breathing after tracheal anastomosis. The anastomosis was perfect without leakage. The LMA was removed and oxygen was given by the nasal catheter under light sedation at post anesthesia care unit (PACU). CONCLUSION: Tracheal reconstruction under spontaneous breathing may be an alternative anesthesia method for upper tracheal surgery in children.

Prolonged administration of the granisetron transdermal delivery system reduces capecitabine plus oxaliplatin regimen induced nausea and vomiting.

OBJECTIVE: To evaluate the safety and efficacy of the granisetron transdermal delivery system (GTDS) combined with Dexamethasone for preventing chemotherapy-induced nausea and vomiting (CINV) in patients receiving Capecitabine plus Oxaliplatin (CapeOX) therapy. DESIGN: Open-label, prospective, multi-center phase II trial. SETTING: Three institutions. PARTICIPANTS: Fifty-four patients scheduled to receive CapeOX chemotherapy. INTERVENTIONS: Participants received GTDS (3.1 mg applied to the upper arm 48 h before chemotherapy, replaced on day 5, and discarded on day 12) and Dexamethasone. MAIN OUTCOME MEASURES: The primary endpoint was the complete control rate of CINV. Secondary endpoints included the duration of delayed complete control, complete control rate in the acute phase, safety, and quality of life. RESULTS: The complete control rate for delayed CINV over the entire period (25-480 h) was 72.7% (95% CI 0.57-0.88). The duration of delayed complete control was 17.2 ± 4.5 days, with 51.5% of patients experiencing no nausea during the delayed phase. The complete control rate in the acute phase was 81.8% (95% CI 0.69-0.95). No serious adverse events related to the antiemetic regimen were reported. CONCLUSION: Prolonged administration of GTDS is safe and effective for preventing CINV in patients with gastrointestinal malignancies treated with CapeOX. TRIAL REGISTRATION: ClinicalTrials.gov registry (NCT05325190); registered on October 10, 2021.

Increasing the frequency of plant-based food intake in daily diets reduces the risk of cardiovascular disease among elderly Chinese: a cohort study.

Objective: There is limited research on the relationship between the frequency of plant-based food intake and the risk of cardiovascular disease (CVD) among elderly Chinese. This study aims to evaluate the association between plant-based dietary index (PDI) and CVD risks, providing evidence for elderly Chinese to reduce CVD risks by increasing the frequency of plant-based food consumption. Methods: This study analyzed data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS) 2011-2018, employing a multivariate modified Poisson regression model, trend tests, and restricted cubic spline (RCS) analysis to assess the linear and non-linear relationship between the PDI and CVD risks. Subgroup analyses and interaction tests were conducted to evaluate the robustness and population-specificity of the results. Results: This study included a total of 1,414 elderly Chinese, and at the end of follow-up, 487 participants had developed CVD. The multivariate modified Poisson regression model revealed a negative association between PDI and CVD risks [RR = 0.983, 95%CI = (0.970, 0.997)]. Similarly, the multivariate trend test (p = 0.031) and RCS analysis (P for nonlinear = 0.600) indicated a linear relationship between PDI and CVD risks. Subgroup analyses showed that the relationship between PDI and CVD risk was not influenced by gender, BMI, smoking, alcohol use, or exercise. Conclusion: The PDI was negatively correlated with CVD risks, indicating that increasing the frequency of plant-based food intake in the diet may reduce CVD risks among elderly Chinese.

Sirt7 protects against vascular calcification via modulation of reactive oxygen species and senescence of vascular smooth muscle cells.

Vascular calcification is frequently seen in patients with chronic kidney disease (CKD), and significantly increases cardiovascular mortality and morbidity. Sirt7, a NAD+-dependent histone deacetylases, plays a crucial role in cardiovascular disease. However, the role of Sirt7 in vascular calcification remains largely unknown. Using in vitro and in vivo models of vascular calcification, this study showed that Sirt7 expression was significantly reduced in calcified arteries from mice administered with high dose of vitamin D3 (vD3). We found that knockdown or inhibition of Sirt7 promoted vascular smooth muscle cell (VSMC), aortic ring and vascular calcification in mice, whereas overexpression of Sirt7 had opposite effects. Intriguingly, this protective effect of Sirt7 on vascular calcification is dependent on its deacetylase activity. Unexpectedly, Sirt7 did not alter the osteogenic transition of VSMCs. However, our RNA-seq and subsequent studies demonstrated that knockdown of Sirt7 in VSMCs resulted in increased intracellular reactive oxygen species (ROS) accumulation, and induced an Nrf-2 mediated oxidative stress response. Treatment with the ROS inhibitor N-acetylcysteine (NAC) significantly attenuated the inhibitory effect of Sirt7 on VSMC calcification. Furthermore, we found that knockdown of Sirt7 delayed cell cycle progression and accelerated cellular senescence of VSMCs. Taken together, our results indicate that Sirt7 regulates vascular calcification at least in part through modulation of ROS and cellular senescence of VSMCs. Sirt7 may be a potential therapeutic target for vascular calcification.

Developing and validating a predictive model of delivering large-for-gestational-age infants among women with gestational diabetes mellitus.

BACKGROUND: The birth of large-for-gestational-age (LGA) infants is associated with many short-term adverse pregnancy outcomes. It has been observed that the proportion of LGA infants born to pregnant women with gestational diabetes mellitus (GDM) is significantly higher than that born to healthy pregnant women. However, traditional methods for the diagnosis of LGA have limitations. Therefore, this study aims to establish a predictive model that can effectively identify women with GDM who are at risk of delivering LGA infants. AIM: To develop and validate a nomogram prediction model of delivering LGA infants among pregnant women with GDM, and provide strategies for the effective prevention and timely intervention of LGA. METHODS: The multivariable prediction model was developed by carrying out the following steps. First, the variables that were associated with LGA risk in pregnant women with GDM were screened by univariate analyses, for which the P value was < 0.10. Subsequently, Least Absolute Shrinkage and Selection Operator regression was fit using ten cross-validations, and the optimal combination factors were selected by choosing lambda 1se as the criterion. The final predictors were determined by multiple backward stepwise logistic regression analysis, in which only the independent variables were associated with LGA risk, with a P value < 0.05. Finally, a risk prediction model was established and subsequently evaluated by using area under the receiver operating characteristic curve, calibration curve and decision curve analyses. RESULTS: After using a multistep screening method, we establish a predictive model. Several risk factors for delivering an LGA infant were identified (P < 0.01), including weight gain during pregnancy, parity, triglyceride-glucose index, free tetraiodothyronine level, abdominal circumference, alanine transaminase-aspartate aminotransferase ratio and weight at 24 gestational weeks. The nomogram's prediction ability was supported by the area under the curve (0.703, 0.709, and 0.699 for the training cohort, validation cohort, and test cohort, respectively). The calibration curves of the three cohorts displayed good agreement. The decision curve showed that the use of the 10%-60% threshold for identifying pregnant women with GDM who are at risk of delivering an LGA infant would result in a positive net benefit. CONCLUSION: Our nomogram incorporated easily accessible risk factors, facilitating individualized prediction of pregnant women with GDM who are likely to deliver an LGA infant.

Development of a diagnostic nomogram for alpha-fetoprotein-negative hepatocellular carcinoma based on serological biomarkers.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Serum biomarkers play an important role in the early diagnosis and prognosis of HCC. Because a certain percentage of HCC patients are negative for alpha-fetoprotein (AFP), the diagnosis of AFP-negative HCC is essential to improve the detection rate of HCC. AIM: To establish an effective model for diagnosing AFP-negative HCC based on serum tumour biomarkers. METHODS: A total of 180 HCC patients were enrolled in this study. The expression levels of GP73, des-γ-carboxyprothrombin (DCP), CK18-M65, and CK18-M30 were detected by a fully automated chemiluminescence analyser. The variables were selected by logistic regression analysis. Several models were constructed using stepwise backward logistic regression. The performance of the models was compared using the C statistic, integrated discrimination improvement, net reclassification improvement, and calibration curves. The clinical utility of the nomogram was assessed using decision curve analysis (DCA). RESULTS: The results showed that the expression levels of GP73, DCP, CK18-M65, and CK18-M30 were significantly greater in AFP-negative HCC patients than in healthy controls (P < 0.001). Multivariate logistic regression analysis revealed that GP73, DCP, and CK18-M65 were independent factors for diagnosing AFP-negative HCC. By comparing the diagnostic performance of multiple models, we included GP73 and CK18-M65 as the model variables, and the model had good discrimination ability (area under the curve = 0.946) and good goodness of fit. The DCA curves indicated the good clinical utility of the nomogram. CONCLUSION: Our study identified GP73 and CK18-M65 as serum biomarkers with certain application value in the diagnosis of AFP-negative HCC. The diagnostic nomogram based on CK18-M65 combined with GP73 demonstrated good performance and effectively identified high-risk groups of patients with HCC.

Rupture risk of intracranial aneurysms: Comparison between small ruptured intracranial aneurysms and large unruptured intracranial aneurysms.

To compare the differences in clinical and morphological features between small ruptured intracranial aneurysms and large unruptured intracranial aneurysms to evaluate the risk factors for the rupture of IAs. The clinical data of 189 consecutive patients with 193 IAs were reviewed. The patients and IAs were divided into ruptured (<5 mm) and unruptured groups (>10 mm). The characteristics of the patients and the intracranial aneurysms (IAs) were compared between the 2 groups, and the risk factors for rupture of IAs were assessed using multiple logistic regression. Patient age (odds ratio [OR], 0.955), IA located at the internal carotid artery (ICA, OR, 0.202), irregular shape (OR, 0.083) and parent vessel diameter (OR, 0.426) were negatively correlated with the risk of IA rupture. IAs located at bifurcations (OR, 6.766) were positively correlated with the risk of IA rupture. In addition to the size of the IAs, regardless of IAs shape, other factors, such as younger age (<63.5 years), location at a bifurcation, IAs located at the ICA and a small parent vessel diameter (<3.25 mm), can influence the risk of IA rupture.

Genomic characterization revealing the high rate of tet(X4)-positive Escherichia coli in animals associated with successful genetic elements.

Introduction: The rapid spread of plasmid-mediated tet(X4) conferring high tigecycline resistance poses a significant threat to public health. Escherichia coli as the most common pathogen which carries tet(X4) has been widely disseminated in China. Thus, comprehensive investigations are required to understand the mechanism of transmission of tet(X4)-positive E. coli. Methods: In this study, a total of 775 nonduplicate samples were collected in Guangdong, China from 2019 to 2020. We screened for tet(X4)-positive E. coli by PCR amplification and species identification. Furthermore, we analyzed the phylogenetics and genetic context of tet(X4)-positive E. coli through whole-genome sequencing and long-reads sequencing. Results: Overall, 146 (18.84%) tet(X4)-positive E. coli were isolated, comprising 2 isolates from humans and 144 isolates from pigs. The majority of tet(X4)-positive E. coli exhibited resistance to multiple antibiotics but all of them were susceptible to amikacin and colistin. Phylogenetic analysis showed that ST877, ST871, and ST195 emerged as the predominant sequence types in tet(X4)-positive E. coli. Further analysis revealed various genetic environments associated with the horizontal transfer of tet(X4). Notably, a 100-kbp large fragment insertion was discovered downstream of tet(X4), containing a replicon and a 40-kbp gene cluster for the bacterial type IV secretion system. Discussion: The high colonization rate of tet(X4)-positive E. coli in animals suggests that colonization as a key factor in its dissemination to humans. Diverse genetic context may contribute to the transfer of tet(X4). Our findings underline the urgent need for controlling the spread of plasmid-mediated tigecycline resistance.

Assessment of the reversibility of resistance in the absence of antibiotics and its relationship with the resistance gene's fitness cost: a genetic study with mcr-1.

BACKGROUND: The intensive use of antibiotics has resulted in strong natural selection for the evolution of antimicrobial resistance (AMR), but whether, and under what circumstances, the removal of antibiotics would result in a rapid reduction in AMR has been insufficiently explored. We aimed to test the hypothesis that in the simple, yet common, case of AMR conferred by a single gene, removing antibiotics would quickly reduce the prevalence of resistance if the AMR gene imposes a high fitness cost and costless resistance is extremely rare among its proximal mutants. METHODS: In this genetic study, to test our hypothesis, we used the mcr-1 gene in Escherichia coli, which confers resistance to the last-resort antibiotic colistin, as a model. A high-throughput reverse genetics approach was used to evaluate mcr-1 variants for their fitness cost and resistance levels relative to a non-functional construct, by measuring relative growth rates in colistin-free media and at 2 µg/mL and 4 µg/mL colistin. We identified costless resistant mcr-1 mutants, and examined their properties within the context of the sequential organisation of mcr-1's functional domains as well as the evolutionary accessibility of these mutations. Finally, a simple population genetic model incorporating the measured fitness cost was constructed and tested against previously published real-world data of mcr-1 prevalence in colonised inpatients in China since the 2017 colistin ban in fodder additives. FINDINGS: We estimated the relative growth rates of 14 742 mcr-1 E coli variants (including the wild type), 3449 of which were single-nucleotide mutants. E coli showed 73·8% less growth per 24 h when carrying wild-type mcr-1 compared with the non-functional construct. 6252 (42·4%) of 14 741 mcr-1 mutants showed colistin resistance accompanied by significant fitness costs, when grown under 4 µg/mL colistin selection. 43 (0·3%) mcr-1 mutants exhibited costless resistance, most of which contained multiple mutations. Among the 3449 single mutants of mcr-1, 3433 (99·5%) had a fitness cost when grown in colistin-free media, with a mean relative growth of 0·305 (SD 0·193) compared with the non-functional variant. 3059 (88·7%) and 1833 (53·1%) of 3449 single mutants outgrew the non-functional mcr-1 in the presence of 2 µg/mL and 4 µg/mL colistin, respectively. Single mutations that gave rise to costless mutants were rare in all three domains of mcr-1 (transmembrane domain, flexible linker, and catalytic domain), but the linker domain was enriched with cost-reducing and resistance-enhancing mutations and depleted with cost-increasing mutations. The population genetics model based on the experimental data accurately predicts the rapid decline in mcr-1 prevalence in real-world data. INTERPRETATION: Many identified costless resistant variants that consist of multiple mutations are unlikely to evolve easily in nature. These findings for colistin and mcr-1 might be applicable to other cases in which AMR entails a substantial fitness cost that cannot be mitigated in proximal mutants. FUNDING: National Natural Science Foundation of China, and National Key Research and Development Program of China.

Humoral Immunogenicity of mRNA-1345 RSV Vaccine in Older Adults.

BACKGROUND: The mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in adults ≥60 years in the ConquerRSV trial. Here, humoral immunogenicity results from the trial are presented. METHODS: This phase 2/3 trial randomly assigned adults (≥60 years) to mRNA-1345 50-µg encoding prefusion F (preF) glycoprotein (n = 17,793) vaccine or placebo (n = 17,748). RSV-A and RSV-B neutralizing antibody (nAb) and preF binding antibody (bAb) levels at baseline and day 29 post-vaccination were assessed in a per-protocol immunogenicity subset ([PPIS]; mRNA-1345, n = 1515; placebo, n = 333). RESULTS: Day 29 nAb geometric mean titers (GMTs) increased 8.4-fold against RSV-A and 5.1-fold against RSV-B from baseline. Seroresponses (4-fold rise from baseline) in the mRNA-1345 groups were 74.2% and 56.5% for RSV-A and RSV-B, respectively. Baseline GMTs were lower among participants who met the seroresponse criteria than those who did not. mRNA-1345 induced preF bAbs at day 29, with a pattern similar to nAbs. Day 29 antibody responses across demographic and risk subgroups were generally consistent with the overall PPIS. CONCLUSION: mRNA-1345 enhanced RSV-A and RSV-B nAbs and preF bAbs in adults (≥60 years) across various subgroups, including those at risk for severe disease, consistent with its demonstrated efficacy in the prevention of RSV disease.