Deciphering Müller cell heterogeneity signatures in diabetic retinopathy across species: an integrative single-cell analysis.

Diabetic retinopathy (DR), a leading cause of visual impairment, demands a profound comprehension of its cellular mechanisms to formulate effective therapeutic strategies. Our study presentes a comprehensive single-cell analysis elucidating the intricate landscape of Müller cells within DR, emphasizing their nuanced involvement. Utilizing scRNA-seq data from both Sprague-Dawley rat models and human patients, we delineated distinct Müller cell clusters and their corresponding gene expression profiles. These findings were further validated through differential gene expression analysis utilizing human transcriptomic data. Notably, certain Müller cell clusters displayed upregulation of the Rho gene, implying a phagocytic response to damaged photoreceptors within the DR microenvironment. This phenomenon was consistently observed across species. Additionally, the co-expression patterns of RHO and PDE6G within Müller cell clusters provided compelling evidence supporting their potential role in maintaining retinal integrity during DR. Our results offer novel insights into the cellular dynamics of DR and underscore Müller cells as promising therapeutic targets for preserving vision in retinal disorders induced by diabetes.

Association of previous stillbirth with subsequent perinatal outcomes: a systematic review and meta-analysis of cohort studies.

OBJECTIVE: We conducted a systematic review and meta-analysis to examine the relationship between stillbirth and various perinatal outcomes in subsequent pregnancy. DATA SOURCES: PubMed, the Cochrane Library, Embase, Web of Science, and CNKI databases were searched up to July 2023. STUDY ELIGIBILITY CRITERIA: Cohort studies that reported the association between stillbirth and perinatal outcomes in subsequent pregnancies were included. METHODS: We conducted this systematic review and meta-analysis in accordance with the PRISMA guidelines. Statistical analysis was performed using R and Stata software. We used random-effects models to pool each outcome of interest. We performed a meta-regression analysis to explore the potential heterogeneity. The certainty (quality) of evidence assessment was performed using the GRADE approach. RESULTS: Nineteen cohort studies were included, involving 4,855,153 participants. From these studies, we identified 28,322 individuals with previous stillbirths who met the eligibility criteria. After adjusting for confounders, evidence of low to moderate certainty indicated that compared with women with previous live births, women with previous stillbirths had higher risks of recurrent stillbirth (odds ratio, 2.68; 95% confidence interval, 2.01-3.56), preterm birth (odds ratio, 3.15; 95% confidence interval, 2.07-4.80), neonatal death (odds ratio, 4.24; 95% confidence interval, 2.65-6.79), small for gestational age/intrauterine growth restriction (odds ratio, 1.3; 95% confidence interval, 1.0-1.8), low birthweight (odds ratio, 3.32; 95% confidence interval, 1.46-7.52), placental abruption (odds ratio, 3.01; 95% confidence interval, 1.01-8.98), instrumental delivery (odds ratio, 2.29; 95% confidence interval, 1.68-3.11), labor induction (odds ratio, 4.09; 95% confidence interval, 1.88-8.88), cesarean delivery (odds ratio, 2.38; 95% confidence interval, 1.20-4.73), elective cesarean delivery (odds ratio, 2.42; 95% confidence interval, 1.82-3.23), and emergency cesarean delivery (odds ratio, 2.35; 95% confidence interval, 1.81-3.06) in subsequent pregnancies, but had a lower rate of spontaneous labor (odds ratio, 0.22; 95% confidence interval, 0.13-0.36). However, there was no association between previous stillbirth and preeclampsia (odds ratio, 1.72; 95% confidence interval, 0.63-4.70) in subsequent pregnancies. CONCLUSION: Our systematic review and meta-analysis provide a more comprehensive understanding of adverse pregnancy outcomes associated with previous stillbirth. These findings could be used to inform counseling for couples who are considering pregnancy after a previous stillbirth.

Risk of kidney and liver diseases after COVID-19 infection: A systematic review and meta-analysis.

COVID-19 is not only associated with substantial acute liver and kidney injuries, but also with an elevated risk of post-acute sequelae involving the kidney and liver system. We aimed to investigate whether COVID-19 exposure increases the long-term risk of kidney and liver disease, and what are the magnitudes of these associations. We searched PubMed, Embase, Web of Science, ClinicalTrials.gov, and the Living Overview of the Evidence COVID-19 Repository for cohort studies estimating the association between COVID-19 and kidney and liver outcomes. Random-effects meta-analyses were performed to combine the results of the included studies. We assessed the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. Fifteen cohort studies with more than 32 million participants were included in the systematic review COVID-19 was associated with a 35% greater risk of kidney diseases (10 more per 1000 persons; low certainty evidence) and 54% greater risk of liver disease (3 more per 1000 persons; low certainty evidence). The absolute increases due to COVID-19 for acute kidney injury, chronic kidney disease, and liver test abnormality were 3, 8, and 3 per 1000 persons, respectively. Subgroup analyses found no differences between different type of kidney and liver diseases. The findings provide further evidence for the association between COVID-19 and incident kidney and liver conditions. The absolute magnitude of the effect of COVID-19 on kidney and liver outcomes was, however, relatively small.

The effectiveness and safety of Chinese patent medicines plus calcium dobesilate for the treatment of diabetic retinopathy: A network meta-analysis.

Chinese patent medicines (CPMs) are commonly prescribed by clinicians in China as adjuvant therapy for diabetic retinopathy (DR). The study of network meta-analysis (NMA) aims to compare the effectiveness and safety of three CPMs plus calcium dobesilate (CD) for DR, and to explore optimal CPM for treatment of DR. Methods. Bayesian network meta-analyses were designed to evaluate the safety and effectiveness of different CPMs for the treatment of DR. Systematic Review Registration CRD42022323996. Results. A total of 23 eligible RCTs involving 1824 patients were enrolled. Compared with CD alone, Cmpound Danshen Dripping Pills (DS) + CD or Qiming Granule (QM) + CD considerably enhanced best corrected visual acuity (BCVA); DS + CD or Compound Xueshuantong Capsule (XST) + CD significantly reduced macular thickness; CPMs + CD significantly reduced the level of VEGF. In addition, DS + CD or XST + CD over QM + CD in reducing macular thickness. As for the adverse events, the differences across different CPMs were not statistically significant, and no statistically significant difference between the CPMs and CD. Conclusion. DS plus CD or QM plus CD may be better effective in improving BCVA; DS plus CD or XST plus CD may be better effective in reducing macular thickness; The combination therapy all may be better effective in reducing the level of VEGF. As for safety profile that CPMs plus CD did not increase the incidence of adverse events. The results of this study might support DS as a relatively prior adjuvant therapy option for patients with DR.

Efficacy and safety of Tanreqing injection for cough caused by acute trachea-bronchitis disease: A systematic review and meta-analysis of randomized controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Tanreqing injection (TRQI) is an intravenous herbal preparation derived from 5 types of traditional Chinese medicines including Scutellariae Radix, Lonicerae Japonicae Flos, Forsythiae Fructus, bear bile powder and goral horn, incorporating baicalin, chlorogenic acid, ursodeoxycholic acid, and goose deoxycholic acid and other compounds known for anti-inflammatory properties, is widely used in China to treat cough caused by acute trachea-bronchitis disease (ATB). AIM OF THE STUDY: To investigate the clinical efficacy and safety of Tanreqing injection (TRQI) with and without Western medicine (WM) for cough caused by acute trachea-bronchitis (ATB). MATERIALS AND METHODS: We systematically searched eight databases, including CENTRAL, Embase, PubMed, Science Direct, Wiley, China National Knowledge Infrastructure, Chinese Biomedical Literature Database and WanFang, from inception to August 2023 for randomized clinical trials (RCTs) on TRQI for cough caused by ATB. The critical outcomes of interest were time to symptom disappearance, including time for cough symptom to disappear and time to improve cough and sputum production. Important outcomes included symptom disappearance rate, adverse events (AEs) and lung function. We carried out random-effects meta-analysis using Review Manager 5.4 and assessed the certainty of evidence utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: A total of 2872 citations were identified by our search, of which 26 eligible RCTs enrolled 2731 participants. Low to moderate certainty evidence showed that when compared with WM, TRQI plus WM treatment was associated with a favorable effect on the time for cough symptom to disappear (MD -2.21 d, 95% CI -2.64 to -1.78), time to improve cough and sputum production (MD -0.68 d, 95% CI -0.83 to -0.53), symptom disappearance rate (RR 1.37, 95% CI 1.20 to 1.55), forced vital capacity, and forced expiratory volume in 1 s (MD 0.38 L, 95% CI 0.26 to 0.50; MD 2.92%, 95% CI 1.29 to 4.56, respectively). In terms of AEs, there was no association between TRQI plus WM and WM (RR 0.55, 95% CI 0.14 to 2.21; low-certainty evidence). Very low certainty evidence showed that TRQI alone was associated with reduced time to improve cough and sputum (MD -0.14 d, 95% CI -0.26 to -0.02) and increased symptom disappearance rate (RR 1.89, 95% CI 1.24 to 2.88; low certainty evidence) compared to WM. CONCLUSIONS: The overall efficacy of TRQI or WM for ATB cough is better than that of WM, and TRQI also effectively improve symptoms in patients with similar adverse events. However, due to the lack of methodological rigor of included studies, the present findings should be interpreted with caution. We advocate better high-quality and convincing clinical studies to be performed to prove the effectiveness and safety of TRQIs.

Efficacy and safety of Shenqi Dihuang decoction for lupus nephritis: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Lupus Nephritis (LN) is a serious complication of systemic lupus erythematosus (SLE). However, the treatment of lupus nephritis using traditional Chinese medicine remains controversial. AIM OF THE STUDY: To assess the efficacy and safety of Shenqi Dihuang decoction in the treatment of LN and review the clinical guidelines. MATERIALS AND METHODS: Six databases (China National Knowledge Infrastructure, Wanfang, PubMed, China Biology Medicine, the Cochrane Library, and Embase) were searched from their inception to September 10, 2022, for randomized controlled trials on the treatment of lupus nephritis using Shenqi Dihuang decoction. We conducted a meta-analysis of random effects using Review Manager 5.4 and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach. RESULTS: A total of 15,790 citations were identified, from which 14 eligible randomized controlled trials that enrolled 1002 participants were selected for this systematic review. Low-to-moderate certainty of evidence indicated that when compared with Western medicine, Shenqi Dihuang decoction combined with Western medicine was associated with favorable effects on clinical efficacy (risk ratio (RR) = 1.25, 95% confidence interval (CI): 1.15-1.37), vascular endothelial growth factor (mean difference (MD) = -30.90, 95% CI: -40.18 to -21.63), serum level (MD = -4.81 µmol L-1, 95% CI: -17.14 to 7.53), complement C3 (MD = -0.14 g L-1, 95% CI: -0.23 to -0.04), erythrocyte sedimentation rate (MD = -11.87 mm h-1, 95% CI: -22.01 to -1.73), and SLE disease activity score (MD = -3.38, 95% CI: -4.15 to -2.61), and exhibited a lower risk of infection (RR = 0.2, 95% CI: 0.05-0.90), gastrointestinal reaction (RR = 0.47, 95% CI: 0.17-1.28), and insomnia (RR = 0.29, 95% CI: 0.09-0.92). CONCLUSIONS: This systematic review provides a potential reference for understanding the efficacy and safety of Shenqi Dihuang decoction combined with Western medicine for treating patients with lupus nephritis. However, owing to the limited quality of the studies included in this review, lack of mycophenolate mofetil control, and high heterogeneity among the included studies, the current findings should be interpreted with caution. Therefore, the efficacy and safety of Shenqi Dihuang decoction in patients with PN still require further verification through future high-quality clinical studies.

Establishment of a prediction model for the impact of endometrial thickness on the day of embryo transfer on ectopic pregnancy in frozen-thawed embryo transfer cycle.

Objective: This study aims to investigate the factors affecting the ectopic pregnancy (EP) rate in the frozen-thawed embryo transfer (FET) cycle. Methods: This study retrospectively analyzed 5606 FET cycles, including 5496 cycles resulting in intrauterine pregnancy and 110 cycles resulting in EP. Smooth curve fitting and piece-wise linear regression were utilized to evaluate a non-linear association between endometrial thickness (EMT) and EP. Multiple logistic regression analysis was used to study the effect of EMT on the embryo transfer (ET) day and other indexes on EP rate after adjusting for confounding factors. A nomographic prediction model was employed to predict EP occurrence. The predictive efficacy of the model was assessed using the area under the receiver operating characteristic (ROC) curve (AUC), utilizing the bootstrap sampling method for internal validation. Results: After accounting for the confounding factors, the segmented linear regression analysis indicated that the EMT inflection point was 9 mm; the EP rate significantly decreased by 28% with each additional millimeter of EMT up to 9 mm (odds ratio (OR) = 0.72; 95% confidence interval (CI), 0.53-0.99; P = 0.0412) while insignificantly decreased when the EMT was greater than 9 mm (OR = 0.91; 95% CI, 0.76-1.08; P = 0.2487). Multivariate logistic regression analysis revealed that after adjusting for confounders, EP risk significantly increased in the number of previous EPs ≥ 1 (OR = 2.29; 95% CI, 1.26-4.16; P = 0.0064) and tubal factor infertility (OR = 3.86; 95% CI, 2.06-7.24; P < 0.0001). Conversely, EP risk was significantly reduced by the increased EMT (OR = 0.84; 95% CI, 0.74-0.96; P = 0.0078) and the blastocyst transfer (OR = 0.45; 95% CI, 0.27-0.76; P = 0.0027). These variables were used as independent variables in a nomogram prediction model, resulting in an AUC of 0.685. The nomination models were internally verified using self-sampling (bootstrap sampling resampling times = 500). This validation yielded an AUC of 0.689, with a sensitivity of 0.6915 and a specificity of 0.5790. The internal validation indicated minimal fluctuations in the AUC, signifying a relatively stable model. Conclusion: Undergoing EMT on the day of ET poses a separate EP risk in the FET cycle; to mitigate the EP incidence, the EMT should exceed 9 mm before ET. Furthermore, previous EPs and tubal factor infertility were additional factors independently increasing EP risk. Furthermore, implementing blastocyst transfer demonstrated that EP incidence was significantly reduced. Utilizing a nomogram predicting system enables EP risk evaluation before ET for individual patients, establishing a basis for devising clinical strategies for ET.

Association of soft drinks and 100% fruit juice consumption with risk of cancer: a systematic review and dose-response meta-analysis of prospective cohort studies.

BACKGROUND: Studies of the associations between soft drinks and the risk of cancer showed inconsistent results. No previous published systematic reviews and meta-analysis has investigated a dose-response association between exposure dose and cancer risk or assessed the certainty of currently available evidence. Therefore, we aim to demonstrate the associations and assessed the certainty of the evidence to show our confidence in the associations. METHODS: We searched Embase, PubMed, Web of Science, and the Cochrane Library from inception to Jun 2022, to include relevant prospective cohort studies. We used a restricted cubic spline model to conduct a dose-response meta-analysis and calculated the absolute effect estimates to present the results. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence. RESULTS: Forty-two articles including on 37 cohorts enrolled 4,518,547 participants were included. With low certainty evidence, increased consumption of sugar-sweetened beverages (SSBs) per 250 mL/day was significantly associated with a 17% greater risk of breast cancer, a 10% greater risk of colorectal cancer, a 30% greater risk of biliary tract cancer, and a 10% greater risk of prostate cancer; increased consumption of artificially sweetened beverages (ASBs)re per 250 mL/day was significantly associated with a 16% greater risk of leukemia; increased consumption of 100% fruit juice per 250 mL/day was significantly associated with a 31% greater risk of overall cancer, 22% greater risk of melanoma, 2% greater risk of squamous cell carcinoma, and 29% greater risk of thyroid cancer. The associations with other specific cancer were no significant. We found linear dose-response associations between consumption of SSBs and the risk of breast and kidney cancer, and between consumption of ASBs and 100% fruit juices and the risk of pancreatic cancer. CONCLUSIONS: An increment in consumption of SSBs of 250 mL/day was positively associated with increased risk of breast, colorectal, and biliary tract cancer. Fruit juices consumption was also positively associated with the risk of overall cancer, thyroid cancer, and melanoma. The magnitude of absolute effects, however, was small and mainly based on low or very low certainty of evidence. The association of ASBs consumption with specific cancer risk was uncertain. TRIAL REGISTRATION: PROSPERO: CRD42020152223.

Preoperative cerebrospinal fluid biomarkers may be associated with postoperative delirium in patients undergoing knee/hip arthroplasty: the PNDABLE study.

BACKGROUND: In the global aging population, the incidence of postoperative delirium (POD) is increasing. Therefore, finding its effective predictive tools becomes crucial. We aimed to identify potential Cerebrospinal fluid (CSF)biomarkers for POD. METHODS: A total of 825 patients undergoing knee/hip arthroplasty under combined spinal-epidural anesthesia were selected. The patients were aged 40 to 90 years with American Society of Anesthesiologists physical status I~II. The Mini-Mental State Examination was completed 1 day before the operation. CSF was extracted after successful spinal-epidural combined puncture, and α-synuclein (α-syn), amyloid beta40 (Aß40), amyloid beta42 (Aß42), t-Tau, phosphorylated Tau (p-Tau), progranulin (PGRN) and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF were measured by enzyme-linked immunosorbent assays (ELISA). The patient's operation time, anesthesia time, intraoperative blood loss and fluid input were also recorded. After the operation, the occurrence rate and severity of POD were determined by the Confusion Assessment Method and the Memorial Delirium Assessment Scale (MDAS), respectively. Patients were categorized into POD group and non-POD group. Logistic regression analysis was performed on the indicators with statistically significant differences, and the area under the ROC curve (AUC) was used to estimate the predictive accuracy of the biomarkers for POD. RESULTS: A total of 92 patients developed POD and the incidence of POD was 11.15%. The results of the multivariable logistic regression showed that CSF t-Tau (P = 0.004, OR = 1.006, 95%CI 1.002~1.009) and α-syn (P = 0.004, OR = 1.001, 95%CI 1.000~1.001) were positively associated with the occurrence rate of POD, while Aß42 (P < 0.001, OR = 0.989, 95%CI 0.986~0.993), CSF PGRN (P = 0.002, OR = 0.999, 95%CI 0.999~1.000), Aß42/ t-Tau (P < 0.001, OR = 0.181, 95%CI 0.102~0.319) and Aß42/p-Tau (P < 0.001, OR = 0.617, 95%CI 0.526~0.725) were inversely proportional to the occurrence of POD. ROC curve analysis indicated that Aß42/t-Tau (AUC = 0.823), CSF Aß42 (AUC = 0.813), Aß42/p-Tau (AUC = 0.810), α-syn (AUC = 0.644) and PGRN (AUC = 0.638) could predict the occurrence rate of POD. The combination of all these biomarkers showed a greater AUC(0.896) than using any of them alone. CONCLUSIONS: CSF Aß42, PGRN, α-syn, Aß42/t-Tau and Aß42/p-Tau might be associated with the occurrence rate of POD in patients undergoing knee/hip arthroplasty. TRIAL REGISTRATION: Clinical Registration No. ChiCTR2000033439.

Subjective cognitive decline may mediate the occurrence of postoperative delirium by P-tau undergoing total hip replacement: The PNDABLE study.

Objective: We again investigated the relationship between subjective cognitive decline (SCD) and postoperative delirium (POD) with a larger sample queue. We also determined whether SCD could cause the occurrence of POD through cerebrospinal fluid (CSF) biomarkers. Methods: A prospective, observational cohort study was implemented in the Qingdao Municipal Hospital Affiliated with Qingdao University. This study recruited 1,471 qualified patients affiliated with the Perioperative Neurocognitive Disorder And Biomarker Lifestyle (PNDABLE) study scheduled for total hip replacement under combined spinal and epidural anesthesia from June 2020 to May 2022. The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) were used to assess the cognitive level of the patients the day before surgery. Pittsburgh sleeps quality index (PSQI) scale was used to assess sleep status. Patients were divided into the SCD group and the non-SCD (NSCD) group based on the Subjective Cognitive Decline Scale (SCDS). CSF was collected after a successful spinal-epidural combined puncture, and amyloid-ß40 (Aß40), amyloid-ß42 (Aß42), total tau (T-tau), and phosphorylated tau (P-Tau) in CSF were analyzed by enzyme-linked immunosorbent assays. After the surgery, the incidence of POD was determined by the Confusion Assessment Scale (CAM), and Memorial Delirium Assessment Scale (MDAS) score was used to determine the severity of POD. Logistic regression and sensitivity analyses were performed to determine the relationship between CSF biomarkers, SCD, and POD. The mediating effect was used to analyze the function of specific CSF biomarkers in the relationship between SCD and POD. The risk factors of SCD were also separately verified by logistic regression and sensitivity analysis models. Results: The total incidence rate of POD was 19.60% (n = 225/1148), which was 29.3% (n = 120/409) in the SCD group and 14.2% (n = 105/739) in the NSCD group. We comprehensively considered the effect of covariates such as age, hypertension, and diabetes. Multivariate logistic regression analysis showed that SCD (OR = 1.467, 95%CI: 1.015-2.120, p = 0.042) and P-tau (OR = 1.046, 95%CI: 1.028-1.063, p < 0.001) were risk factors for POD. The sensitivity analysis results were consistent with the above results. Mediation analysis showed that the relationship between SCD and POD was partially mediated by P-tau, which accounted for 31.25% (P-tau, IE = 4.279 × 10-2, p < 0.001). For SCD, the results of logistic regression analysis models showed that age (OR = 1.035, 95% CI: 1.020-1.049, p < 0.001), higher preoperative PSQI score (OR = 1.047, 95%CI: 1.014-1.080, p = 0.005), and P-tau (OR = 1.015, 95%CI: 1.002-1.028, p = 0.021) were risk factors for SCD, and subsequent sensitivity analysis confirmed this result after adjustment for ASA grade, height, and weight. Conclusion: Patients with SCD are more likely to develop POD undergoing total hip replacement, and SCD can mediate the occurrence of POD via P-tau. Clinical trial registration: This study was registered at China Clinical Trial Registry (Chictr2000033439).

The effect of neostigmine on postoperative delirium after colon carcinoma surgery: a randomized, double-blind, controlled trial.

BACKGROUND: Postoperative delirium (POD) is a critical complication in patients accepting colon carcinoma surgery. Neostigmine, as a cholinesterase inhibitor, can enhance the transmission of cholinergic transmitters in synaptic space, and play an important role in maintaining the normal level of cognition, attention and consciousness. The objective of this study was to investigate the effect of neostigmine on POD and clinical prognosis. METHODS: A randomized, double-blind controlled trial was implemented in Qingdao Municipal Hospital Affiliated to Qingdao University. A total of 454 patients aged 40 to 90 years old accepted colon carcinoma surgery were enrolled between June 7, 2020, and June 7, 2021, with final follow-up on December 8, 2021. Patients were randomly assigned to two groups: the neostigmine group (group N) and the placebo group (group P), the patients in group N were injected with 0.04 mg/kg neostigmine and 0.02 mg/kg atropine intravenously. The primary endpoint was the incidence of POD, researchers evaluated the occurrence of POD by the Confusion Assessment Method (CAM) twice daily (at 10 a.m. and 2 p.m.) during the first 7 postoperative days, POD severity was assessed by the Memorial Delirium Assessment Scale (MDAS). The secondary endpoints were the extubating time, postanesthesia care unit (PACU) time, the incidence of various postoperative complications, length of hospital stays, and 6 months postoperative mortality. RESULTS: The incidence of POD was 20.20% (81/401), including 19.39% (38/196) in group N and 20.98% (43/205) in group P. There was no significant statistical significance in the incidence of POD between group N and group P (P > 0.05); Compared to group P, the extubating time and PACU time in group N were significantly reduced (P < 0.001), the incidence of postoperative pulmonary complications (POPCs) decreased significantly in group N (P < 0.05), while no significant differences were observed in postoperative hospital stay and mortality in 6 months between the two groups (P > 0.05). CONCLUSION: For patients accepted colon carcinoma surgery, neostigmine did not significantly reduce the incidence of POD, postoperative mortality and postoperative hospital stay, while it indeed reduced the extubating time, PACU time and the incidence of POPCs. TRIAL REGISTRATION: The randomized, double-blind, controlled trial was registered retrospectively at www.chictr.org.cn on 07/06/2020 (ChiCTR2000033639).

Potential Value of Serum Lipid in the Identication of Postoperative Delirium Undergoing Knee/Hip Arthroplasty: The Perioperative Neurocognitive Disorder and Biomarker Lifestyle Study.

Objective: We aimed to investigate the relationship between preoperative lipid level and postoperative delirium (POD) and explore whether lipid's effect on POD is mediated by POD core protein. Methods: A total of 635 patients who were planned to undergo knee/hip arthroplasty under combined spinal-epidural anesthesia, regardless of gender, were selected. The patients were aged 40-90 years with American Society of Anesthesiologists physical status I II. The Mini-Mental State Examination (MMSE) was completed 1 day before the operation. Five milliliter elbow venous blood was taken from the patients before anesthesia, and serum levels of total cholesterol (TG), triglyceride (TC), low-density lipoprotein (LDL-C), and high-density lipoprotein (HDL-C) were detected. Cerebrospinal fluid (CSF) was extracted after successful spinal-epidural combined puncture, and amyloid beta40 (Aß40), amyloid beta42 (Aß42), total Tau (t-Tau), and phosphorylated Tau (p-Tau) in the CSF were measured by enzyme-linked immunosorbent assays (ELISA). After the operation, the occurrence and severity of POD were assessed using the Confusion Assessment Method and the Memorial Delirium Assessment Scale (MDAS), respectively. Patients were categorized into POD group and NPOD group. Logistic regression was used to analyze the relationship between POD and TC, TG, LDL-C, and HDL-C, and the mediating effect was used to analyze the role of POD core proteins in the relationship between lipid and MDAS. We used the receiver operating characteristic (ROC) and the precision-recall curve (PRC) analysis to assess the ability of TC, TG, LDL-C, and HDL-C ability to predict POD. Finally, we performed a sensitivity analysis to assess the stability of the results. Results: A total of 562 patients were finally enrolled in this study, and 66 patients developed POD, with an incidence of 11.7%. Logistic regression analysis showed that high concentration of TC (OR = 3.148, 95%CI 1.858∼5.333, P < 0.001), TG (OR = 2.483, 95%CI 1.573∼3.918, P < 0.001), and LDL-C (OR = 2.469, 95%CI 1.310∼4.656, P = 0.005) in serum were risk factors for POD. A high concentration of HDL-C (OR = 0.258, 95%CI 0.112∼0.594, P = 0.001) was a protective factor for POD after adjusted for age, sex, education, and MMSE score. ROC curves showed that HDL-C have the highest sensitivity and specificity in predicting POD. For these four lipid markers, the PRC range from 0.602 to 0.731, respectively. The mediating analysis showed that POD core proteins could partially mediate the relationship between lipid and POD (effect value: 16.19∼91.04%). The results were barely changed in the sensitivity analysis, and the sensitivity analysis has shown that the results were stable. Conclusion: The increase of serum TG, TC, and LDL-C concentration is a risk factor for POD development, while high HDL-C concentration is a protective factor for POD, and the occurrence of POD is caused by hyperlipidemia may be caused by POD core proteins. Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [Chictr200033439].

Correlation between microRNA-320 and postoperative delirium in patients undergoing tibial fracture internal fixation surgery.

BACKGROUND: Although the incidence of postoperative delirium (POD) in the elderly after surgery are rising as individuals are living longer, the pathogenesis of POD remains poorly understood. It has been suggested that miRNA-320 may play a role in POD based on animal study and human study. METHODS: We first carried out an animal study, and designed and conducted a human study based on the result of animal study. The aged rats were randomly assigned to five groups: the control (C), anesthesia and surgery (AS), saline (NS), agomir-320 (AG), and antagomir-320 (AT) groups. Postoperative spatial learning and memory in rats were analyzed by the Morris water maze and the open field tests. The plasma levels of insulin-like growth factor-1 (IGF-1), amyloid precursor protein (APP) proteins, miRNA320 and IGF-1mRNA were measured by ELISA and qRT-PCR, respectively. A total of 240 Chinese Han patients over 65 years who underwent tibial fracture internal fixation were included in the PNDABLE study. POD cases and non-POD controls (1:1 matched) were selected by an anesthesiologist using Confusion Assessment Method. RESULTS: For Group AS, the escape latency was significantly longer and the ratio of time spent in the target quadrant was significantly reduced, APP and miR-320 were upregulated and IGF-1mRNA was downregulated compared with Group C. For Group AG, the escape latency was significantly longer and the ratio of time spent in the target quadrant was significantly reduced, APP and miR-320 were upregulated and IGF-1mRNA was downregulated compared with Group AS. For Group AT, the escape latency was significantly reduced and the ratio of time spent in the target quadrant was significantly longer, APP and miR-320 were downregulated and IGF-1mRNAwas upregulated compared with Group AS. Compared with NPOD patients, the expressions of plasma miR-320 and APP protein were increased and the expression of plasma IGF-1 mRNA was decreased in POD patients after surgery. CONCLUSIONS: MiRNA-320 might play a role in up-regulating the levels of IGF-1mRNA and APP protein, which offered a new target for POD treatment. TRIAL REGISTRATION: Correlation of perioperative neurocognitive disorders with lifestyle and biomarkers. ChiCTR2000033439 . Registered 1 June 2020.

The relationship between body mass index and postoperative delirium.

PURPOSE: We aimed to investigate the relevance of body mass index (BMI) to postoperative delirium (POD), and to test whether the influences of BMI on POD were mediated by cerebrospinal fluid (CSF) biomarkers. PATIENTS AND METHODS: Our study recruited 682 and 761 cognitively intact individuals from the perioperative neurocognitive disorder risk factor and prognosis (PNDRFAP) study and the perioperative neurocognitive disorder and biomarker lifestyle (PNDABLE) study, respectively. The incidence of POD was evaluated by using Confusion Assessment Method (CAM), and POD severity was measured by using the Memorial Delirium Assessment Scale (MDAS). Logistic regression was used to analyze the relationship between BMI and POD. The levels of Aß40, Aß42, T-tau, and P-tau in preoperative CSF were measured by enzyme-linked immune-sorbent assay (ELISA) in the PNDABLE study. Mediation analysis with 5000 bootstrapped iterations was used to explore the mediation effects. RESULTS: In the PNDRFAP study, the incidence of POD was 16.3%, with logistic regression analysis showing that BMI (odds ratio [OR] = 0.900, 95% confidence interval [CI] 0.823-0.985, p = .022) is a protective factor of POD. In the PNDABLE study, the incidence of POD was 18.7%, and regression analysis confirmed that BMI (OR = 0.832, 95% CI 0.761-0.910, p < .001) is a protective factor of POD, while T-tau (OR = 1.005, 95% CI 1.003-1.006, p < .001) and P-tau (OR = 1.037, 95% CI 1.024-1.050, p < .001) were risk factors of POD. Mediation analyses revealed that the association between BMI and POD was partially mediated by T-tau (proportion: 36%) and P-tau (proportion: 24%). CONCLUSION: Higher BMI mediated protective effects on POD through CSF biomarkers (T-tau and P-tau).

Differential hippocampal protein expression between normal mice and mice with the perioperative neurocognitive disorder: a proteomic analysis.

OBJECTIVES: To compare differential expression protein in hippocampal tissues from mice of perioperative neurocognitive disorder (PND) and normal control mice and to explore the possible mechanism of PND. METHODS: Mice were randomly divided into a PND group (n = 9) and a control group (n = 9).The mice in the PND group were treated with open tibial fracture with intramedullary fixation under isoflurane anesthesia, while the mice in the control group received pure oxygen without surgery. The cognitive functions of the two groups were examined using Morris water maze experiment, Open field test and Fear conditioning test. The protein expression of the hippocampus of mice was analyzed by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed to explore the principal functions of dysregulated proteins. RESULTS: A total of 21 proteins were differentially expressed between PND and control mice on days 1, 3, and 7 after the operation. These proteins were involved in many pathological processes, such as neuroinflammatory responses, mitochondrial oxidative stress, impaired synaptic plasticity, and neuronal cell apoptosis. Also, the dysregulated proteins were involved in MAPK, AMPK, and ErbB signaling pathways. CONCLUSION: The occurrence of PND could be attributed to multiple mechanisms.

[China's Reuse Water Development and Utilization Potential Based on the RDA-REM Model].

To promote the efficient utilization of China's reuse water resources and optimize the allocation of water resources, an analysis of factors influencing the development and utilization of reuse water resources was conducted. The uniqueness and competitiveness of reuse water resources were analyzed, and the driving and constraint mechanisms were revealed. A potential indicator system for the bilateral coordination of the supply and demand of reuse water was also established. Based on redundancy analysis (RDA), key indicators for the prediction of reuse water development and utilization potential were screened. On this basis, a national-scale reuse water development and utilization potential prediction model was constructed (the random effects model, REM). Given some uncertainty in the parameters of the REM model, the confidence interval ranges of the parameters at the 10%-90% quartile levels were identified. The results show that four indicators (ecological water consumption, density of water supply pipelines in built-up areas, fixed asset investment in the construction of reuse water treatment facilities, and total wastewater treatment) are closely related to the development and utilization of reuse water and, hence, are key indicators. The REM for the potential prediction has a high fitting accuracy, which can effectively reflect the fluctuations in the observed values with a maximum fitting error of -8.5%. China's reuse water development and utilization will continue to maintain rapid growth long into the future, reaching 12.9 billion m3 by 2025. This will help optimize national urban water supply structures and improve the reuse rate of regional water resources.

Potential Value of Cerebrospinal Fluid Progranulin in the Identification of Postoperative Delirium in Geriatrics Patients Undergoing Knee Replacement: The Perioperative Neurocognitive Disorder and Biomarker LifestylE Study.

Objective: The aim of this study was to investigate whether progranulin (PGRN) levels in cerebrospinal fluid (CSF) were associated with postoperative delirium (POD) in geriatric patients undergoing knee replacement. Method: A total of 600 Han Chinese patients aged 65-90 years and who underwent unilateral total knee arthroplasty were included in the Perioperative Neurocognitive Disorder And Biomarker LifestylE (PNDABLE) study from June 2020 to November 2020. All participants were assessed using the Confusion Assessment Method and the Memorial Delirium Assessment Scale on postoperative days 1-7 (or before discharge) by an anesthesiologist. CSF PGRN and CSF biomarkers of POD were measured by ELISA. We analyzed the risk and protective factors of POD using the multivariate logistic regression, and the associations between CSF PGRN and CSF biomarkers of POD using multiple linear regression. We also explored whether the influence of CSF PGRN on POD was mediated by POD core pathology in linear regression models. Results: Postoperative delirium incidence was 9.7% (53/545). There were significant differences in preoperative CSF PGRN between patients with POD and non-POD (NPOD). As for CSF biomarkers, CSF Aß40, T-tau, and P-tau were risk factors for POD, while CSF PGRN, Aß42, and Aß42/Aß40 were protective factors for POD, as shown by the multivariate logistic regression analysis. CSF PGRN was positively associated with CSF Aß42 and was negatively associated with CSF Aß40, T-tau, and P-tau in patients with POD. We found that the AUC was 0.795 (95% CI = 0.706, 0.867) for PGRN between POD and NPOD groups. We found the influence of CSF PGRN on POD was mediated by POD core pathology. The effect was considered partial mediation with the proportion of mediation varying from 44.92 to 62.07%. Conclusion: Cerebrospinal fluid PGRN may be a reasonably good prognostic factor for POD development. Overall, amyloid pathology and tau protein might partially mediate the influence of PGRN on POD. Clinical Trial Registration: www.clinicaltrials.gov, identifier ChiCTR2000033439.

Assessment and uncertainty analysis of groundwater risk.

Groundwater with relatively stable quantity and quality is commonly used by human being. However, as the over-mining of groundwater, problems such as groundwater funnel, land subsidence and salt water intrusion have emerged. In order to avoid further deterioration of hydrogeological problems in over-mining regions, it is necessary to conduct the assessment of groundwater risk. In this paper, risks of shallow and deep groundwater in the water intake area of the South-to-North Water Transfer Project in Tianjin, China, were evaluated. Firstly, two sets of four-level evaluation index system were constructed based on the different characteristics of shallow and deep groundwater. Secondly, based on the normalized factor values and the synthetic weights, the risk values of shallow and deep groundwater were calculated. Lastly, the uncertainty of groundwater risk assessment was analyzed by indicator kriging method. The results meet the decision maker's demand for risk information, and overcome previous risk assessment results expressed in the form of deterministic point estimations, which ignore the uncertainty of risk assessment.

Association of DNA polymorphisms within the CYP11B2/CYP11B1 locus and postoperative hypertension risk in the patients with aldosterone-producing adenomas.

OBJECTIVES: Hypertension often persists after adrenalectomy for primary aldosteronism. Traditional factors associated with postoperative hypertension were evaluated, but whether genetic determinants were involved remains poorly understood. The aim of this study was to investigate the association of DNA polymorphisms within steroid synthesis genes (CYP11B2, CYP11B1) and the postoperative resolution of hypertension in Chinese patients undergoing adrenalectomy for aldosterone-producing adenomas (APA). METHODS: Ninety-three patients with APA were assessed for postoperative resolution of hypertension. All patients were genotyped for rs1799998 (C-344 T), intron 2 conversion, rs4539 (A2718G) within CYP11B2 and rs6410 (G22 5A), rs6387 (A2803G) within CYP11B1. The associations between CYPB11B2/CYP11B1 polymorphisms and persistent postoperative hypertension were assessed by multivariate analysis. RESULTS: CYP11B2-CYP11B1 haplotype was associated with persistent postoperative hypertension in Chinese patients undergoing adrenalectomy with APA (P = .006). Specifically, the rs4539 (AA) polymorphism was associated with persistent postoperative hypertension (P = .002). Multivariate logistic regression revealed the common haplotypes H1 (AGACT), H2 (AGAWT), and H3 (AGAWC) were associated with the persistent postoperative hypertension (P = .01, 0.03, 0.005 after Bonferroni correction). Additional predictors of persistent postoperative hypertension included duration of hypertension (P <.0005), family history of hypertension (P = .001), and elevated systolic blood pressure (P = .015). CONCLUSIONS: The rs4539 (AA), H1, H2, and H3 are genetic predictors for postoperative persistence of hypertension for Chinese patients treated by adrenalectomy with APA. DNA polymorphisms at CYP11B2/B1 locus may confer susceptibility to postoperative hypertension of patients with APA.

Polymorphisms in CYP11B2 and CYP11B1 genes associated with primary hyperaldosteronism.

Several frequent polymorphisms in the CYP11B2 gene are suggested to be associated with essential hypertension and aldosterone secretion. In this study, we investigated the association of polymorphisms in CYP11B2 and CYP11B1 genes with the risk of primary hyperaldosteronism (PH). Three polymorphisms in the CYP11B2 gene (intron 2 conversion, rs1799998 and rs4539) and two polymorphisms in the CYP11B1 gene (rs6410 and rs6387) were analyzed in patients with PH and in the normal population. The rs6410 allelic frequencies in patients with aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were significantly different from those in controls at P=1.09 x 10(-5) and 0.015, respectively. There was a relative excess of AA homozygotes and AG heterozygotes of the rs6410 allele in the APA group as compared with the control group (P=2.19 x 10(-4)). There were significantly different genotypes, AA and AG, of the rs6410 allele between the patients with IHA and the controls only after adjustments for age, gender and body mass index (odds ratio (OR)=4.06, 95% confidence interval (CI) 1.31-12.66; OR=2.41, 95% CI 1.02-5.72). One susceptible haplotype, AAAWT, was identified to be significantly associated with APA (OR=1.44, 95% CI 1.19-1.76), and three susceptible haplotypes, AAAWT, AGGWT and AGAWC, were identified to be significantly associated with IHA (OR=1.55, 95% CI 1.23-1.96; OR=1.49, 95% CI 1.17-1.89; OR=1.40, 95% CI 1.04-1.88). In contrast, one protective haplotype, GGAWT, showed a significant difference between the patients with APA and controls (OR=0.73, 95% CI 0.55-0.97). Several haplotypes were associated with ARR in both the controls and cases. Our data demonstrated that there was a significant association between polymorphisms in the CYP11B2 and CYP11B1 genes and a genetic predisposition to PH. The association with IHA seemed closer compared with APA.