A wearable sweat electrochemical aptasensor based on the Ni-Co MOF nanosheet-decorated CNTs/PU film for monitoring of stress biomarker.

Monitoring cortisol, a hormone released by the adrenal cortex in response to stress, is essential to evaluate the endocrine response to stress stimuli. While the current cortisol sensing methods require large laboratory settings, complex assay, and professional personnel. Herein, a novel flexible and wearable electrochemical aptasensor based on a Ni-Co metal-organic frameworks (MOF) nanosheet-decorated carbon nanotubes (CNTs)/polyurethane (PU) film is developed for rapid and reliable detection of cortisol in sweat. First, the CNTs/PU (CP) film was prepared by a modified wet spinning technology, and the CNTs/polyvinyl alcohol (PVA) solution was thermally deposited on the surface of CP film to form the highly flexible CNTs/PVA/CP (CCP) film with excellent conductivity. Then aminated Ni-Co MOF nanosheet prepared by a facile solvothermal method was conjugated with streptavidin and modified on the CCP film. Biofunctional MOF can effectively capture cortisol aptamer due to its excellent specific surface area. In addition, the MOF with peroxidase activity can catalytic oxidization of hydroquinone (HQ) by hydrogen peroxide (H2O2), which could amplify the peak current signal. The catalytic activity of Ni-Co MOF was substantially suppressed in the HQ/H2O2 system due to the formation of the aptamer-cortisol complex, which reduced the current signal, thereby realizing highly sensitive and selective detection of cortisol. The sensor has a linear range of 0.1-100 ng/mL and a detection limit of 0.032 ng/mL. Meanwhile, the sensor showed high accuracy for cortisol detection under mechanical deformation conditions. More importantly, the prepared MOF/CCP film based three-electrode was assembled with the polydimethylsiloxane (PDMS) substrate, and the sweat-cloth was used as the sweat collection channel to fabricate a wearable sensor patch for monitoring of cortisol in volunteers' sweat in the morning and evening. This flexible and non-invasive sweat cortisol aptasensor shows great potential for quantitative stress monitoring and management.

Detailed phenotype of RNF213 p.R4810K variant identified by the Chinese patients with acute ischaemic stroke or transient ischaemic attack.

BACKGROUND AND PURPOSE: The ring finger protein 213 gene (RNF213) p.R4810K variant increased the risk of acute ischaemic stroke (AIS) attributable to intracranial arterial stenosis (ICAS) in the Japanese and Korean populations. In this study, we aimed to examine the prevalence of the RNF213 p.R4810K variant in Chinese patients with AIS or transient ischaemic attack and identify the phenotype of the carriers. METHODS: We analysed data from the Third China National Stroke Registry. All included participants were divided into two groups by carrier status of the p.R4810K variant. The aetiological classification was conducted according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. The presence of ICAS and extracranial arterial stenosis (ECAS) was defined as 50%-99% stenosis or occlusion of any intracranial and extracranial artery. Logistic regression models and Cox regression models were used to evaluate the association of the p.R4810K variant with TOAST classification, stenosis phenotypes and clinical outcomes. RESULTS: A total of 10 381 patients were enrolled, among which 56 (0.5%) had the heterozygote GA genotype for p.R4810K. The variant carriers were younger (p=0.01), and more likely to suffer from peripheral vascular disease (p=0.04). The p.R4810K variant was associated with large-artery atherosclerosis (LAA) (adjusted OR=1.94, 95% CI 1.13 to 3.33), anterior circulation stenosis (adjusted OR=2.12, 95% CI 1.23 to 3.65) and ECAS (adjusted OR=2.29, 95% CI 1.16 to 4.51). Nevertheless, the p.R4810K variant was not associated with recurrence, poor functional outcome and mortality at 3 months and 1 year. CONCLUSIONS: The RNF213 p.R4810K variant was associated with LAA, anterior circulation stenosis and ECAS in Chinese patients. Given the low carrying rate and only 1-year follow-up information, caution should be taken to interpret our findings in no statistically significant association between the p.R4810K variant and stroke prognosis in Chinese patients.

Mechanism for effect of tanshinone IIA on alleviating cardiomyocyte injury induced by oxygen glucose deprivation. / ä¸¹å‚é ®IIA减轻氧糖剥夺诱导心肌细胞损伤的机制.

OBJECTIVES: Tanshinone IIA has a wide range of myocardial protective effects. AK003290 is a long noncoding RNA (lncRNA) that is highly expressed in myocardial tissue, and its expression is down-regulated when myocardial injury occurs. This study aims to explore the mechanism for tanshinone IIA in alleviating myocardial cell damage induced by oxygen glucose deprivation (OGD). METHODS: OGD model was established in rat H9C2 cardiomyocytes. siRNA was transfected to reduce AK003290 expression. H9C2 cells were divided into 6 groups: A control group, a tanshinone IIA (TAN) group, an OGD group, a tanshinone IIA+OGD (TAN+OGD) group, a scrambled siRNA transfection+tanshinone IIA+OGD (scrambled siRNA+TAN+OGD) group, and a AK003290 siRNA transfection+tanshinone IIA+OGD (AK003290 siRNA+TAN+OGD) group. H9C2 cells in the TAN group were treated with 40 µmol/L tanshinone IIA for 12 h. The TAN+OGD group was treated with 40 µmol/L tanshinone IIA for 12 h, followed by OGD treatment for 12 h. The scrambled siRNA+TAN+OGD group and AK003290 siRNA+TAN+OGD group were transfected with the scrambled siRNA or AK003290 siRNA. Twenty-four hours later, the cells were treated with tanshinone IIA and OGD. Real-time RT-PCR was used to detect the expression of AK003290. Spectrophotometry was used to detect the content of lactate dehydrogenase (LDH) in cell culture medium to reflect LDH leakage rate, and enzyme-linked immunosorbent assay (ELISA) was used to detect the content of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18). Western blotting was used to detect the protein expression of phospho-nuclear factor- κB (p-NF-κB). RESULTS: Compared with the control group, the leakage rate of LDH, the content of IL-1ß and IL-18 in culture medium, and the protein expression level of p-NF-κB were increased in the OGD group (P<0.01 or P<0.001). Compared with the OGD group, the leakage rate of LDH, the content of IL-1ß and IL-18 in culture medium, and the protein expression level of p-NF-κB were decreased in the TAN+OGD group (P<0.05 or P<0.01). Compared with the control group, the AK003290 expression was increased in the TAN group (P<0.01) and it was decreased in the OGD group (P<0.05). Compared with the OGD group, the AK003290 expression was increased in the TAN+OGD group (P<0.05). Compared with the scrambled siRNA+TAN+OGD group, the leakage rate of LDH, the content of IL-1ß and IL-18 in culture medium, and the protein expression level of p-NF-κB were increased in the AK003290 siRNA+TAN+OGD group (P<0.05 or P<0.01). CONCLUSIONS: Tanshinone IIA inhibits NF-κB activity and attenuates OGD-induced inflammatory injury of cardiomyocytes through up-regulating AK003290.

Irreversible fluorine covalent organic framework based probe nanoelectrospray ionization mass spectrometry for direct and rapid determination of perfluoroalkyl carboxylic acids.

Probe nanoelectrospray ionization mass spectrometry (PESI-MS) is practically desirable for rapid and ultra-sensitive analysis of trace contaminants in environment, but limited with the stable and selective probe coating. Herein, we show the design and preparation of irreversible fluorine-based covalent organic framework (TFPPA-F4) covalently bonded probe to couple with ESI-MS (TFPPA-F4-PESI-MS) for direct and rapid determination of perfluoroalkyl carboxylic acids (PFCAs) in environmental water. Chemical bonding coating of irreversible crystalline TFPPA-F4 not only improved stability of the probe, but also offered accessible multiple interactions including hydrophobic, hydrogen bonding and F-F interactions to promote the kinetics and selectivity for PFCAs. The proposed TFPPA-F4-PESI-MS realized rapid determination of PFCAs (about 4 min) with low limits of detection of 0.06-0.88 ng L-1 and wide linear range of 1-5000 ng L-1 (R2 of 0.9982-0.9998). Recoveries for the spiked lake and pond water were 85.9-111.1 %. TFPPA-F4 based probe can maintain the extraction performance after 100 times of extraction. This work shows the great potential of the irreversible covalent organic framework based PESI-MS in rapid and ultra-sensitive determination of contaminants in environmental samples.

Regulating lactate-related immunometabolism and EMT reversal for colorectal cancer liver metastases using shikonin targeted delivery.

BACKGROUND: There are few effective medications for treating colorectal cancer and liver metastases (CRLM). The interactions among glycolysis, epithelial-mesenchymal transition (EMT), and immune microenvironment contribute to the progression of CRLM. A main glycolytic enzyme pyruvate Kinase M2 (PKM2) is highly expressed in colorectal cancer and CRLM, and thus can be a potential therapeutic target. METHODS: A therapeutic strategy was proposed and the shikonin-loaded and hyaluronic acid-modified MPDA nanoparticles (SHK@HA-MPDA) were designed for CRLM therapy via PKM2 inhibition for immunometabolic reprogramming. The treatment efficacy was evaluated in various murine models with liver metastasis of colorectal tumor. RESULTS: SHK@HA-MPDA achieved tumor-targeted delivery via hyaluronic acid-mediated binding with the tumor-associated CD44, and efficiently arrested colorectal tumor growth. The inhibition of PKM2 by SHK@HA-MPDA led to the remodeling of the tumor immune microenvironment and reversing EMT by lactate abatement and the suppression of TGFß signaling; the amount of cytotoxic effector CD8+ T cells was increased while the immunosuppressive MDSCs decreased. CONCLUSION: The work provided a promising targeted delivery strategy for CRLM treatment by regulating glycolysis, EMT, and anticancer immunity. An immunometabolic strategy for treating colorectal cancer liver metastases using the shikonin-loaded, hyaluronic acid-modified mesoporous polydopamine nanoparticles (SHK@HA-MPDA) via glycolysis inhibition, anticancer immunity activation, and EMT reversal. SHK@HA-MPDA can inhibit cytoplasmic PKM2 and glycolysis of the tumor and reduce lactate flux, and then activate the DCs and remodel the tumor immune microenvironment. The reduced lactate flux can reduce MDSC migration and suppress EMT.

Structural and functional exploration of three newly identified coagulation factor IX mutations in Chinese hemophilia B patients.

AIM: To structurally and functionally characterize three newly identified F9 missense mutations, C268Y, I316F, and G413V, in Chinese hemophilia B patients. METHODS: FIX mutants were expressed in vitro by transient transfection of Chinese hamster ovary (CHO) cells. One-stage activated partial thromboplastin time (APTT) based assay and enzyme-linked immunosorbent assay (ELISA) were used to measure the coagulation activity and antigen level of FIX in conditioned medium. Western blot analysis was also used to evaluate interference of the mutations with synthesis and secretion of FIX. A structural model of the FIX G413V mutant was constructed and structural disturbance caused by the mutation was determined by molecular dynamics simulations. RESULTS: Both C268Y and I316F impaired expression of FIX. However, the I316F mutant degraded quickly, whereas the C268Y mutant mostly accumulated intracellularly. The G413V mutant could be synthesized and secreted normally, but procoagulant activity was almost completely lost. This loss is likely mostly due to the impact on the catalytic residue cS195. CONCLUSION: The three FIX mutations identified in Chinese hemophilia B patients either impaired the expression of FIX, as was seen with the I316F and C268Y mutants, or impaired the function of FIX, as was seen with the G413V mutant.

Efficacy and underlying mechanisms of acupuncture therapy for PTSD: evidence from animal and clinical studies.

As a major public health problem, posttraumatic stress disorder (PTSD) has a substantial impact on individuals and society. The total excess economic burden of PTSD in the US is estimated to be more than $232.2 billion a year. Acupuncture is widely used in patients with PTSD, and an increasing number of studies have been undertaken to assess the efficacy and underlying mechanisms of acupuncture for the treatment of individuals with PTSD. However, there has not yet been a review that simultaneously elucidates the therapeutic efficacy and biological mechanisms of acupuncture. We wished to examine the efficacy and underlying mechanisms of acupuncture for the treatment of individuals with PTSD. We conducted this review in three sections as follows: a meta-analysis, an acupoint analysis, and mechanism research. PubMed, Web of Science, Embase, Cochrane Library, China National Knowledge Infrastructure Database (CNKI), WanFang Database, China Biology Medicine Database (CBM), Chinese Science and Technology Journals Database (VIP), and other databases were searched from 1 January 2012 to 27 November 2022. Based on the included studies, we first determined whether acupuncture is more effective than psychological treatment or pharmacological treatment for treating and improving the quality of life of individuals with PTSD by meta-analysis. Second, the most commonly used acupoints and parameters of acupuncture were summarized based on animal and clinical studies. Third, we attempt to summarize the current mechanisms of acupuncture in the treatment of PTSD. Finally, 56 acupoint analyses, eight meta-analyses, and 33 mechanistic studies were included. Acupuncture outperformed pharmacotherapy treatment in improving symptom scores by CAPS, HAMA, HAMD, PCL-C, and SCL-90 somatization for PTSD and outperformed psychotherapy treatment in improving symptom scores by CAPS PCL-C and HAMD, according to the meta-analysis. GV20 was the most frequently used acupuncture point in clinical studies and animal studies, with a 78.6% application rate. Acupuncture may be effective in treating PTSD by regulating the structure and components of several brain areas, regulating the neuroendocrine system, and involving signaling pathways. In conclusion, this finding indicates that acupuncture has promising potential for treating PTSD.

Recent advance of small-molecule drugs for clinical treatment of multiple myeloma.

Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.

Association of Normal Serum Uric Acid Level and Cardiovascular Disease in People Without Risk Factors for Cardiac Diseases in China.

Background Healthy individuals with normal level of serum uric acid (SUA) may not be truly at the lowest risk of cardiovascular disease (CVD). This study aimed to assess the association of SUA levels with CVD and its subtypes in people without CVD risk factors and determine a suitable target of SUA to prevent CVD. Methods and Results We enrolled 25 284 participants who were free of CVD, absent of CVD risk factors, and with an SUA level between 180 and 359 µmol/L (3-6 mg/dL) at baseline from the Kailuan study. Cox proportional hazards models were applied to calculated adjusted hazard ratio (HR) and 95% CI for the risk of CVD and its subtypes. During a median follow-up of 12.97 years (interquartile range, 12.68-13.16 years), we identified 1007 cases of CVD. There was an increase in the risk of incident CVD with increasing SUA levels (Ptrend=0.0011). Compared with participants with SUA levels of 180 to 239 µmol/L (3-4 mg/dL), the HR of CVD was 1.12 (95% CI, 0.96-1.31) and 1.28 (95% CI, 1.08-1.52) for SUA levels of 240 to 299 µmol/L (4-5 mg/dL) and 300 to 359 µmol/L (5-6 mg/dL), respectively. A multivariable-adjusted spline regression model showed a J-shaped association between SUA and the risk of CVD. Similar results were observed for stroke and myocardial infarction. Conclusions The risk of incident CVD increased with elevating SUA levels among individuals without hyperuricemia or other traditional CVD risk factors. These findings highlighted the importance of primordial prevention for SUA level increase along with other traditional CVD risk factors.

Association of body mass index and waist-to-height ratio with outcomes in ischemic stroke: results from the Third China National Stroke Registry.

BACKGROUND AND PURPOSE: Conflicting reports of obesity paradox have led to confusion about weight management strategies for post-stroke patients. The main purpose of this study is to determine whether the obesity paradox measured by body mass index (BMI) or by waist-to-height ratio (WHtR) is real. METHODS: We evaluated the association of general obesity measured by BMI, and abdominal obesity measured by WHtR with 1-year all-cause mortality, recurrence of stroke and combined vascular events of acute ischemic stroke (AIS) patients in a cohort -- the Third China National Stroke Registry (CNSR-III). Cox proportional hazards models and restricted cubic splines were performed to investigate the association between obesity and clinical outcomes. RESULTS: A total of 14,146 patients with ischemic stroke were included. When BMI was used as a measure of obesity, compared to the normal weight patients, mortality decreased in overweight patients (hazard ratio [HR] 0.74 [95% confidence interval (CI) 0.61-0.91], P = 0.0035) and obese patients (HR 0.54 [0.40-0.73], P < 0.0001); and increased in underweight patients (HR 2.55 [1.75-3.73], P < 0.0001). After adjustment for confounding factors, the protective effect of obesity and overweight disappeared. BMI had no association with recurrence of stroke or combined vascular events. When WHtR was used as a measure of obesity, obese patients had lower 1-year all-cause mortality (HR 0.64 [0.43-0.97], P = 0.0357). After adjustment for confounding factors, this difference disappeared; overweight patients still had lower all-cause mortality (adjusted hazard ratio [aHR] 0.42 [0.26-0.67], P = 0.0003), recurrence of stroke (aHR 0.77 [0.60-0.99], P = 0.0440) and combined vascular events (aHR 0.75 [0.58-0.95], P = 0.0198). CONCLUSIONS: Among Chinese patients with AIS, our study does not support the BMI paradox; overweight patients measured by WHtR had a more favorable prognosis. TOAST subtypes did not modify the association.

A co-delivery system based on chlorin e6-loaded ROS-sensitive polymeric prodrug with self-amplified drug release to enhance the efficacy of combination therapy for breast tumor cells.

Background: Recently, various combination therapies for tumors have garnered popularity because of their synergistic effects in improving therapeutic efficacy and reducing side effects. However, incomplete intracellular drug release and a single method of combining drugs are inadequate to achieve the desired therapeutic effect. Methods: A reactive oxygen species (ROS)-sensitive co-delivery micelle (Ce6@PTP/DP). It was a photosensitizer and a ROS-sensitive paclitaxel (PTX) prodrug for synergistic chemo-photodynamic therapy. Micelles size and surface potential were measured. In vitro drug release, cytotoxicity and apoptosis were investigated. Results: Ce6@PTP/DP prodrug micelles exhibited good colloidal stability and biocompatibility, high PTX and Ce6 loading contents of 21.7% and 7.38%, respectively. Upon light irradiation, Ce6@PTP/DP micelles endocytosed by tumor cells can generate sufficient ROS, not only leading to photodynamic therapy and the inhibition of tumor cell proliferation, but also triggering locoregional PTX release by cleaving the thioketal (TK) bridged bond between PTX and methoxyl poly (ethylene glycol). Furthermore, compared with single drug-loaded micelles, the light-triggered Ce6@PTP/DP micelles exhibited self-amplified drug release and significantly greater inhibition of HeLa cell growth. Conclusion: The results support that PTX and Ce6 in Ce6@PTP/DP micelles exhibited synergistic effects on cell-growth inhibition. Thus, Ce6@PTP/DP micelles represent an alternative for realizing synergistic chemo-photodynamic therapy.

Preparation of Antibacterial, Arginine-Modified Ag Nanoclusters in the Hydrogel Used for Promoting Diabetic, Infected Wound Healing.

Diabetic foot ulcers with complex healing wounds accompanied by bacterial infection are considered a significant clinical problem which are made worse by the lack of effective treatments. Traditional antibiotics and dressings have failed to address wound infection and healing, and multifunctional combination therapies are attractive for treating chronic wounds. In this study, arginine (Arg) was loaded onto the surface of silver nanoclusters and encapsulated in a hydrogel to achieve antibacterial, anti-inflammatory, angiogenic, and collagen deposition functions through the slow release of Arg combined with silver nanoclusters. In vitro studies indicated that Arg-Ag@H composites inhibited methicillin-resistant Staphylococcus aureus and Escherichia coli by 94 and 97%, respectively. The inhibition of bacterial biofilms reached 85%, and the migration ability of human venous endothelial cells (HUVECs) increased by 50%. In vitro studies showed that Arg-Ag@H composites increased the healing area of wounds by 26% and resulted in a 98% skin wound-healing rate. Safety studies confirmed the excellent biocompatibility of Arg-Ag@H. The results suggest that Arg-Ag@H offers new possibilities for treating chronic diabetic wounds.

Identification of distinct tumor cell patterns with single-cell RNA sequencing integrating primary lung adenocarcinoma and brain metastasis tumor.

Background: Lung adenocarcinoma (LUAD) is the most common form of lung cancer and is often accompanied by brain metastasis (BM). The heterogeneity of the tumor renders all current conventional treatments less effective. This study aims to dissect tumor cell heterogeneity and identify potential therapeutic targets. Methods: We conducted single-cell RNA-sequencing (scRNA-seq) in 8 patients with treatment-naïve LUAD BM and included scRNA-seq data of 10 primary LUAD samples and their matched adjacent normal tissue from GSE131907 to determine the tumor cell heterogeneity. Results: Our analyses revealed tumor cells derived from brain metastases were more heterogeneous. Tumor cells from BM harbored significantly more copy number variants (CNVs), and cells of magnoid subtype were the critical source of malignant cells both in BM and the primary lung tumor. Pseudo-time trajectory analysis revealed that malignant cells had upregulated genes enriched for cell cycle and cell division. Integrated analysis of tumor cells revealed 2 distinct malignant cell clusters (cluster 4 and cluster 6) and their marker genes. The signatures identified in the single-cell profile had prognostic value in the bulk tumor profiles. Moreover, the signature of cluster 4 had significant prognostic value in predicting patients surviving longer than 3.5 years, while the signature of cluster 6 showed better predictive ability within 1 year. Magnoid-type cells are most likely to develop into the riskiest cell type and potentially promote tumor progression. Conclusions: scRNA profiling that integrates LUAD BM and primary LUAD can provide information on those malignant cells with BM potential, offering additional prognostic information at cellular level, and may serve as a foundational resource for further tumor cell dissection and therapeutic target exploration.

Specific changes and clinical significance of plasma D-dimer during pregnancy and puerperium: a prospective study.

BACKGROUND: Pregnant and puerperal women are high-risk populations for developing venous thromboembolism (VTE). Plasma D-dimer (D-D) is of good value in the diagnosis of exclusion of VTE in the nonpregnant population. Since there is no consensus reference range of plasma D-D applicable to pregnant and puerperal women, the application of plasma D-D is limited. To investigate the change characteristics and the reference range of plasma D-D levels during pregnancy and puerperium and to explore the pregnancy- and childbirth-related factors affecting plasma D-D levels and the diagnostic efficacy of plasma D-D for excluding VTE during early puerperium after caesarean section. METHODS: A prospective cohort study was conducted with 514 pregnant and puerperal women (cohort 1), and 29 puerperal women developed VTE 24-48 h after caesarean section (cohort 2). In cohort 1, the effects of the pregnancy- and childbirth-related factors on the plasma D-D levels were analyzed by comparing the differences in plasma D-D levels between different groups and between different subgroups. The 95th percentiles were calculated to establish the unilateral upper limits of the plasma D-D levels. The plasma D-D levels at 24-48 h postpartum were compared between normal singleton pregnant and puerperal women in cohort 2 and women from the cesarean section subgroup in cohort 1, binary logistic analysis was used to analyze the relevance between plasma D-D level and the risk of VTE developing 24-48 h after caesarean section, and a receiver operating characteristic (ROC) curve was used to assess the diagnostic efficacy of plasma D-D for excluding VTE during early puerperium after caesarean section. RESULTS: The 95% reference ranges of plasma D-D levels in the normal singleton pregnancy group were ≤ 1.01 mg/L in the first trimester, ≤ 3.17 mg/L in the second trimester, ≤ 5.35 mg/L in the third trimester, ≤ 5.47 mg/L at 24-48 h postpartum, and ≤ 0.66 mg/L at 42 days postpartum. The plasma D-D levels of the normal twin pregnancy group were significantly higher than those of the normal singleton pregnancy group during pregnancy (P < 0.05), the plasma D-D levels of the GDM group in the third trimester were significantly higher than those of the normal singleton pregnancy group (P < 0.05). The plasma D-D levels of the advanced age subgroup at 24-48 h postpartum were significantly higher than those of the nonadvanced age subgroup (P < 0.05), and the plasma D-D levels of the caesarean section subgroup at 24-48 h postpartum were significantly higher than those of the vaginal delivery subgroup (P < 0.05). The plasma D-D level was significantly correlated with the risk of VTE developing at 24-48 h after caesarean section (OR = 2.252, 95% CI: 1.611-3.149). The optimal cut-off value of plasma D-D for the diagnosis of exclusion of VTE during early puerperium after caesarean section was 3.24 mg/L. The negative predictive value for the diagnosis of exclusion of VTE was 96.1%, and the area under the curve (AUC) was 0.816, P < 0.001. CONCLUSIONS: The thresholds of plasma D-D levels in normal singleton pregnancy and parturient women were higher than those of nonpregnant women. Plasma D-D had good value in the diagnosis of exclusion of VTE occurring during early puerperium after caesarean section. Further studies are needed to validate these reference ranges and assess the effects of pregnancy- and childbirth-related factors on plasma D-D levels and the diagnostic efficacy of plasma D-D for excluding VTE during pregnancy and puerperium.

Study on the correlation between mineral bone metabolism and CRP in patients with SHPT during perioperative period.

OBJECTIVE: This study mainly observes changes in perioperative mineral bone metabolism-related indicators and inflammatory factors in patients with secondary hyperparathyroidism (SHPT), and analyzed the correlation between mineral bone metabolism-related indicators and inflammatory factors. METHODS: Clinical data were collected. The study detects mineral bone metabolism-related indicators and inflammatory factor of perioperative patients with SHPT before and 4 days after operation. The production of high-sensitivity c-reactive protein (hs-CRP) in human hepatocytes cells (LO2 cells) stimulated by different concentrations of parathyroid hormone-associated protein was detected by enzyme-linked immunosorbent assay, reverse-transcription polymerase chain reaction (RT-PCR), and western blot. RESULTS: The levels of mineral bone metabolism-related indicators and hs-CRP in SHPT group were significantly higher than those of control group. After operation, serum calcium, serum phosphorus, iPTH, FGF-23 decreased, and the level of osteoblast active biomarkers increased, while the level of osteoclast active biomarkers decreased. The levels of hs-CRP decreased significantly after operation. With the increase of PTHrP concentration, hs-CRP level in supernatant of LO2 cells decreased first and then increased. RT-PCR and western blot shows the same trend. CONCLUSION: Parathyroidectomy can significantly improve bone resorption and inflammation in SHPT patients. We speculate that there may be an optimal range of PTH concentrations to minimize inflammation in the body.

Association of Multitrajectories of Lipid Indices With Premature Cardiovascular Disease: A Cohort Study.

Background The multitrajectory model can identify joint longitudinal patterns of different lipids simultaneously, which might help better understand the heterogeneous risk of premature cardiovascular disease (CVD) and facilitate targeted prevention programs. This study aimed to investigate the associations between multitrajectories of lipids with premature CVD. Methods and Results The study enrolled 78 526 participants from the Kailuan study, a prospective cohort study in Tangshan, China. Five distinct multitrajectories of triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol over 6-year exposure were identified on the basis of Nagin's criteria, using group-based multitrajectory modeling. During a median follow-up of 6.75 years (507 645.94 person-years), 665 (0.85%) premature CVDs occurred. After adjustment for confounders, the highest risk of premature CVD was observed in group 4 (the highest and increasing triglyceride, optimal and decreasing LDL-C, low and decreasing high-density lipoprotein cholesterol) (hazard ratio [HR], 2.13 [95% CI, 1.36-3.32]), followed by group 5 (high and decreasing triglyceride, optimal and increasing LDL-C, low and decreasing high-density lipoprotein cholesterol) (HR, 2.07 [95% CI, 1.45-2.98]), and group 3 (optimal and increasing triglyceride, borderline high and increasing LDL-C, optimal and decreasing high-density lipoprotein cholesterol) (HR, 1.90 [95% CI, 1.32-2.73]). Conclusions Our results showed that the residual risk of premature CVD caused by increasing triglyceride levels remained high despite the fact that LDL-C levels were optimal or declining over time. These findings emphasized the importance of assessing the joint longitudinal patterns of lipids and undertaking potential interventions on triglyceride lowering to reduce the residual risk of premature CVD, even among individuals with optimal LDL-C levels.

Combined treatment with glucosamine and chondroitin sulfate improves rheumatoid arthritis in rats by regulating the gut microbiota.

BACKGROUND: To investigate the ameliorative effects of glucosamine (GS), chondroitin sulphate (CS) and glucosamine plus chondroitin sulphate (GC) on rheumatoid arthritis (RA) in rats, and to explore the mechanism of GS, CS and GC in improving RA based on the gut microbiota. METHODS: RA rat models were effectively developed 14 days after CFA injection, and then garaged with GS, CS and GC. Body weight and paw volume of rats were monitored at multiple time points at the beginning of CFA injection. Until D36, serum and ankle tissue specimens were used to measure levels of circulating inflammatory factors (TNF-α, IL-1ß, MMP-3, NO and PGE2) and local inflammatory indicators (TLR-4 and NF-κB). On D18, D25, and D36, intergroup gut microbiota was compared using 16S rRNA gene sequencing and bioinformatics analysis. We also performed the correlation analysis of gut bacteria, joint swelling and inflammatory indicators. RESULTS: GC, rather than GS and CS, could reduce right paw volumes, levels of TLR-4 and NF-κB in synovial tissues. In addition, enriched genera in RA model rats screened out by LEfSe analysis could be inhibited by GC intervention, including potential LPS-producing bacteria (Enterobacter, Bacteroides, Erysipelotrichaceae_unclassified and Erysipelotrichaceae_uncultured) and some other opportunistic pathogens (Esherichia_Shigella, Nosocomiicoccus, NK4A214_group, Odoribacter, Corynebacterium and Candidatus_Saccharimonas.etc.) that positively correlated with pro-inflammatory cytokines, right paw volume, and pathology scores. Furthermore, the gut microbiota dysbiosis was observed to recover before alleviating joint swelling after interventions. CONCLUSIONS: GC could inhibit potential LPS-producing bacteria and the activation of TLR-4/NF-κB pathway in RA rats, thus alleviating RA-induced joint injury.

Endoscopic retrograde stent drainage therapies for malignant biliary obstruction: the distal opening of stent location above or across the duodenal papilla? A systematic review and meta-analysis.

OBJECTIVE: To systematically evaluate the efficacy and safety of the method of placing the distal stent opening above the duodenal papilla (hereinafter referred to Above method) for endoscopic retrograde stent internal drainage in MBO patients. METHODS: PubMed, Embase, Web of science and Cochrane databases were searched to identify clinical studies comparing the stent distal opening mounted above the papilla and across the papilla (hereinafter referred to Across method), Comparison indicators included stent patency, stent occlusion rate, clinical success rate, overall complication rate, postoperative cholangitis rate, and overall survival. Revman5.4 software was used for meta-analysis, funnel plot and publication bias and Egger's test were completed by Stata14.0 software. RESULTS: A total of 11 clinical studies (8 case-control studies, 3 RCT studies) were included, with a total of 751 patients (318 cases in the Above group and 433 cases Across group). The overall patency of Above method was longer than that of Across method (HR = 0.60, 95%CI [0.46-0.78], p < 0.001). Subgroup analysis showed statistical difference using plastic stent (HR = 0.49, 95%CI [0.33,0.73], p < 0.001). Inversely, there didn't exist significant difference in which metal stent were adopted (HR= 0.74, 95%CI [0.46,1.18], p = 0.21). Similarly, there also without statistical difference between patients with plastic stent placed above the papilla and metal stent mounted Across the papilla (HR = 0.73, 95%CI [0.15,3.65], p = 0.70). Moreover, the overall complication rate of the Above method was lower than that of the Across method (OR = 0.48,95%CI [0.30,0.75], p = 0.002). On the contrary, the differences of stent occlusion rate (OR = 0.86,95%CI [0.51,1.44], p = 0.56), overall survival (HR = 0.90, 95%CI [0.71,1.13]), p = 0.36), the clinical success rate (OR = 1.30, 95%CI [0.52,3.24], p = 0.57) and postoperative cholangitis rats (OR = 0.73, 95%CI [0.34,1.56], p = 0.41) were not statistically significant. CONCLUSIONS: The distal opening of the stent can be placed above the duodenal main papilla for eligible MBO patients who receiving endoscopic retrograde stent drainage treatment, which can effectively prolong the patency duration when plastic stent is used, and reduce the overall risk of complications.

Ultrasensitive alkaline phosphatase activity assay based on controllable signal probe production coupled with the cathodic photoelectrochemical analysis.

A highly sensitive and selective split-type perovskite-based photoelectrochemical (PEC) platform was developed for measuring alkaline phosphatase (ALP) activity in milk and serum samples. ALP in the test sample hydrolyzed 2-phosphate sesquimagnesium salt hydrate (AAPS) in a 96-microwell plate to produce ascorbic acid (AA), a PEC electron donor. The resulting AA, which could preferentially annihilate the photogenerated holes, indirectly reflects ALP activity. The PEC used a cetyltrimethylammonium bromide (CTAB)-functionalized CH3NH3PbI3 (CTAB@CH3NH3PbI3) film as the cathode to monitor the controlled AA production. Due to the excellent photoelectric characteristics of the CH3NH3PbI3 perovskite and the split-type assay, excellent sensitivity and selectivity for ALP detection were obtained. Under the optimum experimental conditions, ALP activity with a limit of detection (LOD) of 2.6 × 10-4 U/L in a linear dynamic range of 10-3 âˆ¼ 102 U/L was obtained. With its sensitive, rapid, and high-throughput detection capabilities, this split-type and label-free PEC platform has great potential for use in food and biomedical analysis.

Fecal Metabolomics Reveals the Foraging Strategies of Giant Pandas for Different Parts of Bamboo.

Climate change-induced food shortages pose major threats to wildlife conservation, and the exclusive reliance of giant pandas on bamboo makes them particularly vulnerable. The aim of this study was to provide insight into the reasons for the foraging strategies of giant pandas to selectively forage for different bamboo parts (bamboo shoot, culm, and leaf) during different seasons. This study used a metabolomic approach to analyze the fecal metabolites of giant pandas and conducted a correlation analysis with their gut microbiota. The results indicate that the fecal metabolites of giant pandas differ significantly depending on the bamboo parts they forage on, with higher sugar content observed when they consume bamboo culm with high fiber content. By functional annotation, culm group metabolites were enriched in the galactose metabolic pathway, while shoot group metabolites were enriched in the phenylalanine, tyrosine and tryptophan biosynthesis pathways. Moreover, Streptococcus showed a significant positive correlation with glucose and acetic acid content. Therefore, the foraging strategy of giant pandas is based on the ability to utilize the nutrient content of different bamboo parts. Captive feeding and habitat construction should enrich bamboo species to allow them to express their natural foraging strategies and improve their welfare and reproductive status.