Analysis of risk factors, pathogenic bacteria characteristics, and drug resistance of postoperative surgical site infection in adults with limb fractures.

PURPOSE: We carried out the study aiming to explore and analyze the risk factors, the distribution of pathogenic bacteria, and their antibiotic-resistance characteristics influencing the occurrence of surgical site infection (SSI), to provide valuable assistance for reducing the incidence of SSI after traumatic fracture surgery. METHODS: A retrospective case-control study enrolling 3978 participants from January 2015 to December 2019 receiving surgical treatment for traumatic fractures was conducted at Tangdu Hospital of Air Force Medical University. Baseline data, demographic characteristics, lifestyles, variables related to surgical treatment, and pathogen culture were harvested and analyzed. Univariate analyses and multivariate logistic regression analyses were used to reveal the independent risk factors of SSI. A bacterial distribution histogram and drug-sensitive heat map were drawn to describe the pathogenic characteristics. RESULTS: Included 3978 patients 138 of them developed SSI with an incidence rate of 3.47% postoperatively. By logistic regression analysis, we found that variables such as gender (males) (odds ratio (OR) = 2.012, 95% confidence interval (CI): 1.235 - 3.278, p = 0.005), diabetes mellitus (OR = 5.848, 95% CI: 3.513 - 9.736, p < 0.001), hypoproteinemia (OR = 3.400, 95% CI: 1.280 - 9.031, p = 0.014), underlying disease (OR = 5.398, 95% CI: 2.343 - 12.438, p < 0.001), hormonotherapy (OR = 11.718, 95% CI: 6.269 - 21.903, p < 0.001), open fracture (OR = 29.377, 95% CI: 9.944 - 86.784, p < 0.001), and intraoperative transfusion (OR = 2.664, 95% CI: 1.572 - 4.515, p < 0.001) were independent risk factors for SSI, while, aged over 59 years (OR = 0.132, 95% CI: 0.059 - 0.296, p < 0.001), prophylactic antibiotics use (OR = 0.082, 95% CI: 0.042 - 0.164, p < 0.001) and vacuum sealing drainage use (OR = 0.036, 95% CI: 0.010 - 0.129, p < 0.001) were protective factors. Pathogens results showed that 301 strains of 38 species of bacteria were harvested, among which 178 (59.1%) strains were Gram-positive bacteria, and 123 (40.9%) strains were Gram-negative bacteria. Staphylococcus aureus (108, 60.7%) and Enterobacter cloacae (38, 30.9%) accounted for the largest proportion. The susceptibility of Gram-positive bacteria to Vancomycin and Linezolid was almost 100%. The susceptibility of Gram-negative bacteria to Imipenem, Amikacin, and Meropenem exceeded 73%. CONCLUSION: Orthopedic surgeons need to develop appropriate surgical plans based on the risk factors and protective factors associated with postoperative SSI to reduce its occurrence. Meanwhile, it is recommended to strengthen blood glucose control in the early stage of admission and for surgeons to be cautious and scientific when choosing antibiotic therapy in clinical practice.

MCT1-mediated transport of valeric acid promotes porcine preimplantation embryo development by improving mitochondrial function and inhibiting the autophagic AMPK-ULK1 pathway.

Oocytes and embryos are highly sensitive to environmental stress in vivo and in vitro. During in vitro culture, many stressful conditions can affect embryo quality and viability, leading to adverse clinical outcomes such as abortion and congenital abnormalities. In this study, we found that valeric acid (VA) increased the mitochondrial membrane potential and ATP content, decreased the level of reactive oxygen species that the mitochondria generate, and thus improved mitochondrial function during early embryonic development in pigs. VA decreased expression of the autophagy-related factors LC3B and BECLIN1. Interestingly, VA inhibited expression of autophagy-associated phosphorylation-adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylation-UNC-51-like autophagy-activated kinase 1 (p-ULK1, Ser555), and ATG13, which reduced apoptosis. Short-chain fatty acids (SCFAs) can signal through G-protein-coupled receptors on the cell membrane or enter the cell directly through transporters. We further show that the monocarboxylate transporter 1 (MCT1) was necessary for the effects of VA on embryo quality, which provides a new molecular perspective of the pathway by which SCFAs affect embryos. Importantly, VA significantly inhibited the AMPK-ULK1 autophagic signaling pathway through MCT1, decreased apoptosis, increased expression of embryonic pluripotency genes, and improved embryo quality.

Pituitary MRI Radiomics Improves Diagnostic Performance of Growth Hormone Deficiency in Children Short Stature: A Multicenter Radiomics Study.

RATIONALE AND OBJECTIVES: To develop an efficient machine-learning model using pituitary MRI radiomics and clinical data to differentiate growth hormone deficiency (GHD) from idiopathic short stature (ISS), making the diagnostic process more acceptable to patients and their families. MATERIALS AND METHODS: A retrospective cohort of 297 GHD and 300 ISS children (4-12 years) were enrolled as training and validation cohorts (8:2 ratio). An external cohort from another institution (49 GHD and 51 ISS) was employed as the testing cohort. Radiomics features extracted from the anterior pituitary gland on sagittal T1-weighted image (1.5 T or 3.0 T) were used to develop a radiomics model after feature selection. Hematological biomarkers were selected to create a clinical model and combine with the optimal radiomics features to create a clinical-radiomics model. The area under the receive operating characteristic curve (AUC) and Delong test compared the diagnostic performance of the previously mentioned three models across different validation and testing cohorts. RESULTS: 17 radiomics features were selected for the radiomics model, and total protein, total cholesterol, free triiodothyronine, and triglyceride were utilized for the clinical model. In the training and validation cohorts, the diagnostic performance of the clinical-radiomics model (AUC=0.820 and 0.801) was comparable to the radiomics model (AUC=0.812 and 0.779, both P >0.05), both outperforming the clinical model (AUC=0.575 and 0.593, P <0.001). In the testing cohort, the clinical-radiomics model exhibited the highest AUC of 0.762 than the clinical and radiomics model (AUC=0.604 and 0.741, respectively, P <0.05). In addition, the clinical and radiomics models demonstrated similar diagnostic performance in the testing cohort (P >0.05). CONCLUSION: Integrating radiomics features from conventional pituitary MRI with clinical indicators offers a minimally invasive approach for identifying GHD and shows robustness in a multicenter setting.

Effect of zwitterionic sulfobetaine incorporation on blood behaviours, phagocytosis, and in vivo biodistribution of pH-responsive micelles with positive charges.

pH-responsive micelles with positive charges are challenged by their significant effect on the cells/proteins and compromise their final fate due to electrostatic interactions. As one of the promising strategies, zwitterion incorporation in micelles has attracted considerable attention and displayed improved protein adsorption and blood circulation performances. However, previous reports in this field have been mostly limited in hemolysis for studying blood behaviour and lack a comprehensive understanding of their interactions with blood components. Herein, we present a prelimilary study on the effect of zwitterionic sulfobetaine incorporation on blood behaviour, phagocytosis, and in vivo biodistribution of pH-responsive micelles with positive charges. Amphiphilic triblock copolymers, namely poly(ε-caprolactone)-b-poly(N,N-diethylaminoethyl methacrylate)-(N-(3-sulfopropyl-N-methacryloxyethy-N,N-diethylammonium betaine)) (PCL-PDEAPSx, x = 2, 6, 10), containing different numbers of sulfobetaine groups were synthesized through four steps to prepare the pH-responsive micelles with positive charges. The effect of the sulfobetaine incorporation displayed different profiles, e.g., the micelles had no effect on RBC aggregation, thrombin time (TT), and platelet aggregation, while the cytotoxicity, hemolysis, RBC deformability, activated partial thromboplastin time (APTT), prothrombin time (PT), platelet activation, protein (albumin, fibrinogen, plasma) adsorption, phagocytosis, and in vivo biodistribution decreased with the increase in the sulfobetaine number, in which the transition mainly occurred at a sulfobetaine/tertiary amine group ratio of 3/7-1/1 compared to that of the mPEG control. In addition, the micelles displayed a strong inhibitory effect on the intrinsic coagulation pathway, which was associated with a significant decrease in the coagulation factor activity. Based on these findings, the related mechanism is discussed and proposed, which can aid the rational design of pH-responsive micelles for improved therapeutics.

Ginsenoside F2-Mediated Intestinal Microbiota and Its Metabolite Propionic Acid Positively Impact the Gut-Skin Axis in Atopic Dermatitis Mice.

Atopic dermatitis (AD) is a complex inflammatory skin disease induced by multiple factors. AD can also cause intestinal inflammation and disorders of the gut microbiota. Ginseng is a kind of edible and medicinal plant; its main active components are ginsenosides. Ginsenosides have a variety of anti-inflammatory effects and regulate the gut microbiota; however, their role in AD and the underlying mechanisms are unclear. In this study, we found that intragastric administration of ginsenoside F2 improved AD-like skin symptoms and reduced inflammatory cell infiltration, serum immunoglobulin E levels, and mRNA expression of inflammatory cytokines in AD mice. 16s rRNA sequencing analysis showed that ginsenoside F2 altered the intestinal microbiota structure and enriched the short-chain fatty acid-producing microbiota in AD mice. Metabolomic analysis revealed that ginsenoside F2 significantly increased the propionic acid (Pa) content of feces and serum in AD mice, which was positively correlated with significant enrichment of Parabacteroides goldsteinii and Lactobacillus plantarum in the intestines. Pa inhibits inflammatory responses in the gut and skin of AD mice through the G-protein-coupled receptor43/NF-κB pathway, thereby improving skin AD symptoms. These results revealed, for the first time, the mechanism by which ginsenoside F2 improves AD through the Pa (a metabolite of intestinal microbiota)-gut-skin axis.

[Effects of metal materials for oral fixation and restoration on magnetic resonance imaging artifacts and the health of tissues around dental implants].

PURPOSE: To investigate the effects of metal materials for oral fixation and restoration on magnetic resonance imaging artifacts and the health of tissues around dental implants. METHODS: A total of 153 patients undergoing fixed oral restoration were selected from May 2018 to June 2020. They were divided according to the random number table method into group A (cobalt-chromium alloy, n=31), group B (nickel-chromium alloy, n=32), group C (titanium alloy, n=28), group D (pure titanium, n=29) and group E (gold alloy, n=33). The largest area of metal crown artifacts and the number of layers of the 5 groups were compared. The probing depth(PD), modified plaque index(mPLI), modified sulcus bleeding index(mSBI) and papilla index(PI) 6 months after restoration were evaluated.The data were statistically analyzed with SPSS 22.0 software package. RESULTS: One-way ANOVA showed that the largest area of metal crown artifacts and the number of layers involved in the 5 groups had significant differences(P＜0.05). Pairwise comparison showed that the largest area of metal crown artifacts, and the number of involved layers in group E were significantly lower than those in groups A, B, C, and D(P＜0.05). One-way ANOVA showed that there was no significant difference in PD, mPLI, mSBI and PI among 5 groups (P＞0.05). Pairwise comparison showed that there was no significant difference in PD, mPLI, mSBI and PI between group A and group B,C,D and E (P＞0.05). CONCLUSIONS: The artifacts produced by metal materials for oral fixation and restoration are closely related to the types of metal materials. Among them, cobalt-chromium alloys produce the largest artifacts, and gold alloys produce the smallest artifacts. The use of metal materials for oral fixation and restoration will not affect the health of tissues around dental implants.

Ligand Promoted Pd-Catalyzed High para-Selective C-H Olefination.

Achieving high para-selective C-H functionalized products of benzoic acid derivatives using a designed template is still a daunting challenge because the carbonyl group also could coordinate with metal to activate the ortho-C-H bond. Herein, we report the ligand promoted high para-selective C-H olefination of benzoic acid derivatives; we screened a series of ligands increasing the ratio of p:others from 62:38 to 96:4. This work may find application in the construction of para-substituted benzoic acid derivatives.

[Hydrochemical Characteristics and Control Factors of Surface Water in Kuaize River Basin at the Upper Pearl River].

The Kuaize River is a small typical karst watershed in the source area of the Pearl River as well as an important coal mining area in Eastern Yunnan with a fragile ecological environment. Strengthening the research on the water environment in the region plays an important role in supporting the comprehensive management of the ecological environment and water resources in the source region of the Pearl River. Through the systematic collection of surface water, karst groundwater, and mine water samples, mathematical statistics analysis, correlation analysis, ion ratio analysis, absolute principal component scores multiple linear regression(APCS-MLR), and other methods were used to study the characteristics of hydrochemical evolution and control factors in Kuaize River Basin. The results showed that the average pH value of surface water in Kuaize River Basin was 7.8, which was weakly alkaline. The main cations were Ca2+ and Na+, showing the characteristics of Ca2+>Na+>Mg2+>K+. The main anions were HCO3- and SO42-, showing the characteristics of HCO3->SO42->NO3->Cl-. The variation coefficients of Na+, SO42-, and NO3- in surface water were high, showing strong spatial variability. The water chemical type of the trunk stream was mainly HCO3-Ca, whereas the water chemical type of the tributary was relatively complex, mainly HCO3-Ca, HCO3-Ca·Na, and HCO3·SO4-Ca·Na. The chemical composition of surface water was mainly affected by rock weathering, cation exchange, and human activities. Ca2+, Mg2+, Na+, and HCO3- in surface water mainly came from the weathering of carbonate rock and silicate rock; SO42- mainly came from the oxidation of sulfide, such as pyrite in coal seams; K+, Cl-, and NO3- mainly came from domestic sewage and agricultural activities. The APCS-MLR receptor model analysis results showed that the surface water in the Kuaize River Basin was mainly affected by sulfide oxidation, carbonate weathering, weathering of silicate rock in mine water, domestic sewage, agricultural activities, and unknown sources. In general, the contribution rate of human activities such as mining, domestic sewage, and agricultural activities to the surface water reached 47.17%, indicating that human activities were the key driving factor of surface water chemistry in the Kuaize River Basin.

Mannose-Binding Lectin Reduces Oxidized Low-Density Lipoprotein Induced Vascular Endothelial Cells Injury by Inhibiting LOX1-ox-LDL Binding and Modulating Autophagy.

Objective: To investigate the role of mannose-binding lectin (MBL) in modulating autophagy and protecting endothelial cells (ECs) from oxidized low-density lipoprotein (ox-LDL)-induced injury. Methods: Serum MBL concentration and carotid intima-media thickness (cIMT) were measured in 94 obese and 105 healthy children. ECs were transfected with MBL over-expression plasmid, LOX1 was knocked-down to explore the protective role of MBL in ox-LDL induced ECs injury. Dendritic cells (DCs) were co-cultured with ECs, and inflammatory factors, DC maturation, and autophagy was assessed. WT and ApoE-/- mice were fed with a high fat diet (HFD) with or without MBL-adenovirus injection for 16 weeks and aortic vascular endothelial tissue was isolated, then atherosclerotic plaque, cell injury and autophagy were analyzed. Results: Serum MBL concentration in obese children was lower than healthy controls and was negatively correlated with cIMT. The uptake of ox-LDL was decreased in LOX1 knock-down ECs. MBL over-expression in vitro inhibited LOX1-ox-LDL binding. Both LOX1 knock-down and MBL over-expression can ameliorate EC autophagy and cell injury. MBL over-expression in vivo alleviated atherosclerotic plaque formation, influenced DC maturation and down-regulated IL-6, IL-12, and TNF-a levels. Conclusions: MBL exerts a protective role in ox-LDL-induced EC injury by modulating DC maturation and EC autophagy via inhibiting LOX1-ox-LDL binding.

Ginsenoside Rg1 activates brown adipose tissue to counteract obesity in high-fat diet-fed mice by regulating gut microbes and bile acid composition.

Obesity is a global health problem strongly linked to gut microbes and their metabolites. In this study, ginsenoside Rg1 (Rg1) reduced lipid droplet size and hepatic lipid accumulation by activating uncoupling protein 1 expression in brown adipose tissue (BAT), which in turn inhibited high-fat diet (HFD)-induced weight gain in mice. Furthermore, the intestinal flora of mice was altered, the abundance of Lachnoclostridium, Streptococcus, Lactococcus, Enterococcus and Erysipelatoclostridium was upregulated, and the concentrations of fecal bile acids were altered, with cholic acid and taurocholic acid concentrations being significantly increased. In addition, the beneficial effects of Rg1 were eliminated in mice treated with a combination of antibiotics. In conclusion, these results suggest that Rg1 activates BAT to counteract obesity by regulating gut microbes and bile acid composition in HFD-fed mice.

Soil microbial residue characteristics in Pinus massoniana lamb. Plantations.

A large amount of stable soil organic matter (SOM) is derived from microbial necromass, which can be assessed by quantifying amino sugar biomarkers. Pinus massoniana Lamb. Plantations are widely distributed in China and play a vital role in forest carbon sequestration. However, the patterns of soil microbial residue remain poorly understood. In this study, amino sugars were used to characterize patterns of soil microbial residues at three soil depths (0-10, 10-20, and 20-30 cm) in P. massoniana plantations of different ages (young, middle-aged, near-mature, mature, and over-mature; denoted as YG, MD, NM, MT, and OM, respectively). In the topsoil (0-10 cm), the total nitrogen (TN) content of the OM forest was the highest, whereas the soil organic carbon (SOC) content of the MT forest was the highest. Consistent with changes in SOC and TN, total microbial residue content decreased with increasing soil depth. However, the total microbial residues C to SOC contribution increased considerably with increasing depth, suggesting that more SOC was derived from microbial residues in the subsoil than that from the topsoil. The fungal residue C to SOC contribution was higher than that of bacterial residue C. Total amino sugar content in the topsoil increased with increasing age, and MT and OM had a significantly higher content than that of other forests. At all soil depths, SOC and TN content predominantly determined microbial necromass, whereas soil microbial biomass content predominantly determined microbial necromass in the topsoil; soil pH predominantly determined microbial necromass in the 10-20 cm soil layer; and soil pH and Ca2+ content were the primary factors in the soil layer below 20 cm. The study provides valuable insights into controls of microbial-derived organic C could be applied in Earth system studies for predicting SOC dynamics in forests.

Fecal transplant from myostatin deletion pigs positively impacts the gut-muscle axis.

The host genome may influence the composition of the intestinal microbiota, and the intestinal microbiota has a significant effect on muscle growth and development. In this study, we found that the deletion of the myostatin (MSTN) gene positively regulates the expression of the intestinal tight junction-related genes TJP1 and OCLN through the myosin light-chain kinase/myosin light chain pathway. The intestinal structure of MSTN-/- pigs differed from wild-type, including by the presence of a thicker muscularis and longer plicae. Together, these changes affect the structure of intestinal microbiota. Mice transplanted with the intestinal microbiota of MSTN-/- pigs had myofibers with larger cross-sectional areas and higher fast-twitch glycolytic muscle mass. Microbes responsible for the production of short-chain fatty acids (SCFAs) were enriched in both the MSTN-/- pigs and recipient mice, and SCFAs levels were elevated in the colon contents. We also demonstrated that valeric acid stimulates type IIb myofiber growth by activating the Akt/mTOR pathway via G protein-coupled receptor 43 and ameliorates dexamethasone-induced muscle atrophy. This is the first study to identify the MSTN gene-gut microbiota-SCFA axis and its regulatory role in fast-twitch glycolytic muscle growth.

Association between antibiotic exposure and adverse outcomes of children and pregnant women: evidence from an umbrella review.

BACKGROUND: Antibiotics are widely prescribed among children and pregnant women, but their safety profile is controversial. This study aimed to summarize and appraise current evidence for the potential impact of antibiotic exposure on pregnancy outcomes and children's health. METHODS: PubMed, Embase, Web of Science and the Cochrane Database of Systematic Reviews were searched from inception to June 2022. Meta-analyses of any study design comparing the impact of antibiotic exposure with nonexposure among children, pregnant women and prepregnant women on adverse health outcomes of children and pregnancy were retrieved. The quality of evidence was assessed by a Measurement Tool to Assess Systematic Reviews 2 (AMSTAR2) and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE). Data were reanalyzed, and the credibility of the evidence was determined. RESULTS: Out of 2956 studies identified, 19 articles with 39 associations were included. Totally 19 of the associations (48.72%) were statistically significant with a P value ≤ 0.05, while only six were supported by highly suggestive evidence. Children with postnatal antibiotic exposure had a higher risk of developing asthma odds ratio (OR): 1.95, 95% confidence interval (CI): 1.76-2.17, wheezing (OR: 1.81, 95% CI 1.65-1.97) and allergic rhinoconjunctivitis (OR: 1.66, 95% CI 1.51-1.83), with prediction intervals excluding the nulls. Quality assessed by both AMSTAR2 and GRADE of included meta-analyses were very low in general. CONCLUSIONS: Antibiotic exposure in early life was associated with children's long-term health, especially in cases of allergic diseases. Prenatal exposure might also influence children's health in some aspects but requires more high-quality evidence. Potential adverse effects of antibiotics on pregnancy outcomes were not observed in our study. Studies with higher quality and better quantification of antibiotic exposure are needed in the future.

The ginsenoside Rh2 protects porcine oocytes against aging and oxidative stress by regulating SIRT1 expression and mitochondrial activity.

Post-ovulatory aging, a major problem faced by oocytes cultured in vitro, causes oxidative damage and mitochondrial dysfunction in oocytes. The ginsenoside Rh2 is one of the main monomeric components of ginseng, but its effects on porcine oocytes are unknown. In the present study, in vitro aging (IVA) and accelerated induction of aging using H2O2 resulted in DNA damage and an increased incidence of abnormal spindle formation in porcine oocytes. Rh2 supplementation increased the antioxidant capacity, reduced the occurrence of early apoptosis, and improved the development of in vitro fertilized blastocysts. It also rescued the abnormal aggregation of mitochondria and the decrease of the mitochondrial membrane potential under mitochondrial dysfunction. Meanwhile, Rh2 enhanced mRNA expression of the anti-aging and mitochondrial biogenesis-related genes silent information regulator of transcription 1 (SIRT1) and peroxisome proliferator-activated receptor coactivator 1-α (PGC-1α), and the antioxidant gene superoxide dismutase 1 (SOD1). The protection of porcine oocytes against aging and oxidative stress by Rh2 was confirmed using the SIRT1-specific inhibitor EX-527. Our results reveal that Rh2 upregulates SIRT1/PGC-1α to enhance mitochondrial function in porcine oocytes and improve their quality. Our study indicates that Rh2 can be used to prevent mitochondrial dysfunction in oocytes.

Dynamic changes in intestinal microbiota and metabolite composition of pre-weaned beef calves.

Gut microbes and their metabolites are essential for maintaining host health and production. The intestinal microflora of pre-weaned calves gradually tends to mature with growth and development and has high plasticity, but few studies have explored the dynamic changes of intestinal microbiota and metabolites in pre-weaned beef calves. In this study, we tracked the dynamics of faecal microbiota in 13 new-born calves by 16S rRNA gene sequencing and analysed changes in faecal amino acid levels using metabolomics. Calves were divided into the relatively high average daily gain group (HA) and the relatively low average daily gain group (LA) for comparison. The results demonstrated that the alpha diversity of the faecal microbiota increased with calf growth and development. The abundance of Porphyromonadaceae bacterium DJF B175 increased in the HA group, while that of Lactobacillus reuteri decreased. The results of the LEfSe analysis showed that the microbiota of faeces of HA calves at eight weeks of age was enriched with P. bacterium DJF B175, while Escherichia coli and L. reuteri were enriched in the microbiota of faeces of LA calves. Besides, the total amino acid concentration decreased significantly in the eighth week compared with that in the first week (P < 0.05). Overall, even under the same management conditions, microorganisms and their metabolites interact to play different dynamic regulatory roles. Our results provide new insights into changes in the gut microbiota and metabolites of pre-weaned calves.

Activation of HIF-1α/ACLY signaling axis promotes progression of clear cell renal cell carcinoma with VHL inactivation mutation / 中华病理学杂志

Objective: To explore the potential pathogenesis of clear cell renal cell carcinoma (ccRCC) based on the HIF-1α/ACLY signaling pathway, as well as to provide new ideas for the treatment of ccRCC. Methods: Seventy-eight ccRCC cases diagnosed at the First Affiliated Hospital of Soochow University, Suzhou, China were collected. The VHL mutation was examined using exon sequencing. The expression of HIF-1α/ACLY in VHL-mutated ccRCC was evaluated using immunohistochemical staining and further validated in VHL-mutated ccRCC cell lines (786-O, A498, UM-RC-2, SNU-333, and Caki-2) using Western blot. The mRNA and protein levels of ACLY were detected using real-time quantitative PCR and Western blot after overexpression or interference with HIF-1α in ccRCC cell lines. HeLa cells were treated with CoCl2 and hypoxia (1%O2) to activate HIF-1α and then subject to the detection of the ACLY mRNA and protein levels. The potential molecular mechanism of HIF-1α-induced ACLY activation was explored through JASPAR database combined with chromatin immunoprecipitation assay (ChIP) and luciferase reporter gene assay. The effect of HIF-1α/ACLY regulation axis on lipid accumulation was detected using BODIPY staining and other cell biological techniques. The expression of ACLY was compared between patients with ccRCC and those with benign lesions, and the feasibility of ACLY as a prognostic indicator for ccRCC was explored through survival analysis. Results: Exon sequencing revealed that 55 (70.5%) of the 78 ccRCC patients harbored a VHL inactivation mutation, and HIF-1α expression was associated with ACLY protein levels. The protein levels of ACLY and HIF-1α in ccRCC cell lines carrying VHL mutation were also correlated to various degrees. Overexpression of HIF-1α in A498 cells increased the mRNA and protein levels of ACLY, and knockdown of HIF-1α in Caki-2 cells inhibited the mRNA and protein levels of ACLY (P<0.001 for all). CoCl2 and hypoxia treatment significantly increased the mRNA and protein levels of ACLY by activating HIF-1α (P<0.001 for all). The quantification of transcriptional activity of luciferase reporter gene and ChIP-qPCR results suggested that HIF-1α could directly bind to ACLY promoter region to transcriptionally activate ACLY expression and increase ACLY protein level (P<0.001 for all). The results of BODIPY staining suggested that the content of free fatty acids in cell lines was associated with the levels of HIF-1α and ACLY. The depletion of HIF-1α could effectively reduce the accumulation of lipid in cells, while the overexpression of ACLY could reverse this process. At the same time, cell function experiments showed that the proliferation rate of ccRCC cells with HIF-1α knockdown was significantly decreased, and overexpression of ACLY could restore proliferation of these tumor cells (P<0.001). Survival analysis further showed that compared with the ccRCC patients with low ACLY expression, the ccRCC patients with high ACLY expression had a poorer prognosis and a shorter median survival (P<0.001). Conclusions: VHL mutation-mediated HIF-1α overexpression in ccRCC promotes lipid synthesis and tumor progression by activating ACLY. Targeting the HIF-1α/ACLY signaling axis may provide a theoretical basis for the clinical diagnosis and treatment of ccRCC.

Integrated care teams in primary care improve clinical outcomes and care processes in patients with non-communicable diseases

INTRODUCTION@#Primary care physicians face the increasing burden of managing multimorbidities in an ageing population. Implementing an integrated care team (ICT) with defined roles and accountability to share consultation tasks is an emerging care model to address this issue. This study compared outcomes with ICT versus usual care for patients with multimorbidities in primary care.@*METHODS@#Data was retrospectively extracted from the electronic medical records (EMRs) of consecutive adult Asian patients empanelled to ICT and those in UC at a typical primary care clinic (polyclinic) in eastern Singapore in 2018. The study population had hypertension, and/or hyperlipidaemia and/or type 2 diabetes mellitus (T2DM). Clinical outcomes included the proportion of patients (ICT vs. UC) who attained their treatment goals after 12 months. Process outcomes included the proportion of patients who completed annual diabetic eye and foot screenings, where applicable.@*RESULTS@#Data from 3,302 EMRs (ICT = 1,723, UC = 1,579) from January 2016 to September 2017 was analysed. The ICT cohort was more likely to achieve treatment goals for systolic blood pressure (SBP) (adjusted odds ratio [AOR] = 1.52, 95% confidence interval [CI] = 1.38-1.68), low-density lipoprotein cholesterol (AOR = 1.72, 95% CI = 1.49-1.99), and glycated haemoglobin (AOR = 1.28, 95% CI = 1.09-1.51). The ICT group had higher uptake of diabetic retinal screening (89.1% vs. 83.0%, P < 0.001) and foot screening (85.2% vs. 77.9%, P < 0.001).@*CONCLUSION@#The ICT model yielded better clinical and process outcomes than UC, with more patients attaining treatment goals.

Effects of plateau hypoxia on population pharmacokinetics and pharmacodynamics of metformin in patients with Type 2 diabetes / 中南大学学报(医学版)

OBJECTIVES@#Metformin is the basic drug for treating diabetes, and the plateau hypoxic environment is an important factor affecting the pharmacokinetics of metformin, but there have been no reports of metformin pharmacokinetic parameters in patients with diabetes mellitus type 2 (T2DM) in the high-altitude hypoxic environment. This study aims to investigate the effect of the hypoxic environment on the pharmacokinetics and assess the efficacy and safety of metformin administration in patients with Type 2 diabetes mellitus (T2DM).@*METHODS@#A total of 85 patients with T2DM taking metformin tablets in the plateau group (n=32, altitude: 1 500 m) and control group (n=53, altitude: 3 800 m) were enrolled according to the inclusion and exclusion criteria, and 172 blood samples were collected in the plateau group and the control Group. A ultra-performance liquid chromatography/tandem mass spectrometry (UFLC-MS/MS) method was established to determine the blood concentration of metformin, and Phoenix NLME software was used to establish a model of pharmacokinetics of metformin in the Chinese T2DM population. The efficacy and serious adverse effects of metformin were compared between the 2 groups.@*RESULTS@#The population pharmacokinetic modeling results showed that plateau hypoxia and age were the main covariates for model building, and the pharmacokinetic parameters were significantly different between the plateau and control groups (all P<0.05), including distribution volume (V), clearance (CL), elimination rate constant (Ke), half-life(T1/2), area under the curve (AUC), time to reach maximum concentration (Tmax). Compared with the control group, AUC was increased by 23.5%, Tmax and T1/2 were prolonged by 35.8% and 11.7%, respectively, and CL was decreased by 31.9% in the plateau group. The pharmacodynamic results showed that the hypoglycaemic effect of T2DM patients in the plateau group was similar to that in the control group, the concentration of lactic acid was higher in the plateau group than that in the control group, and the risk of lactic acidosis was increased after taking metformin in the plateau population.@*CONCLUSIONS@#Metformin metabolism is slowed down in T2DM patients in the hypoxic environment of the plateau; the glucose-lowering effect of the plateau is similar, and the attainment rate is low, the possibility of having serious adverse effects of lactic acidosis is higher in T2DM patients on the plateau than on the control one. It is probably suggested that patients with T2DM on the plateau can achieve glucose lowering effect by extending the interval between medication doses and enhancing medication education to improve patient compliance.

Research progress on proactive healthy lifestyle and disease immunoprevention / 中华预防医学杂志

The paradox of increasing health needs and limited health resources prompted a change in the traditional concept of disease prevention and control, and the concept of proactive health has emerged. Proactive health aimed to prevent and control disease and improve the body's immunity by using controlled methods and means to activate the body's self-healing ability and to identify foreign harmful substances as well as damage factors and tumor cells that the body itself may produce while giving full play to individual initiative. With the continuous development of science, people could maintain and improve their immune system from many aspects, which could be roughly divided into nonpharmaceutical interventions and pharmaceutical interventions. Nonpharmacological interventions included changing lifestyles and habits, adjusting the nutritional structure and intake of food, regulating mindsets and emotions, and improving the living and working environment, etc. This review systematically elaborated on the functions and molecular mechanisms of nutrition, exercise, sleep, and emotion in regulating immunity, to provide some scientific evidence and theoretical support for proactive health.