Prevalence and Risk Factors of Cardiovascular Autonomic Neuropathy in Individuals with Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

Background: Cardiac autonomic neuropathy (CAN) is a severe complication of type 1 diabetes mellitus (T1DM). This meta-analysis aimed to synthesize relevant literature on the prevalence of CAN and its risk factors in individuals with T1DM. Methods: We screened relevant literature from databases based on predefined search criteria until June 28, 2022. Data extraction and quality assessment were conducted independently by two reviewers. A meta-analysis was conducted to determine the prevalence of CAN and its risk factors in individuals with T1DM using a random-effects model. A subgroup analysis was conducted to assess variations in CAN prevalence based on diabetes duration, diagnostic criteria, study quality, study design, and geographic region of the participants. Results: A total of 21 studies provided information on the prevalence of CAN, while 18 studies explored the potential risk factors for CAN. The overall estimated prevalence of CAN in individuals with T1DM was 25.8% (95% confidence interval (95% CI): 0.208-0.307), with no significant differences observed among the five regions. Additionally, smoking, lipid abnormalities, hypertension, duration of diabetes, increased body mass index, elevated glycated haemoglobin concentrations, and presence of chronic complications of diabetes, such as diabetic retinopathy, diabetic neuropathy, and diabetic nephropathy, were associated with a higher prevalence of CAN in individuals with diabetes. Conclusions: CAN is prevalent in individuals with T1DM worldwide. Efforts should be made to improve early screening and intervention for CAN, as well as to implement strategies aimed at improving or controlling early risk factors associated with CAN.

Early Mobilization after Cardiac Catheterization via Femoral Artery: A Systematic Review and Meta-Analysis.

Background: Early mobilization is one of the essential components of enhanced recovery after surgery (ERAS) pathways and has been shown to reduce complications and optimize patient outcomes. However, the effect of early mobilization for patients who undergo trans-femoral cardiac catheterization and the time for optimal mobilization timing remains controversial. We aimed to identify the safety of early mobilization and provide the optimum timing for early mobilization for patients undergoing trans-femoral cardiac catheterization. Methods: We searched MEDLINE, EMBASE, PubMed, Web of Science, Cochrane databases of systematic reviews, CINAHL, SCOPUS, China National Knowledge Infrastructure (CNKI), Wan Fang Database, and Chinese Science and Technology Periodical Database (VIP) comprehensively for randomized controlled trials associated with early mobilization, to explore its effects on patients after a trans-femoral cardiac catheterization. The risk of bias and heterogeneity of studies was assessed using the Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) and I 2 index, respectively. The comprehensive Meta-analysis (CMA) was adopted to perform the meta-analysis. Results: We identified 14 trials with 2653 participants. Early mobilization was associated with significant decrease in back pain (mean difference (MD) = 0.634, 95% CI: 0.23-1.038; p = 0.002), especially in patients receiving instruction for early mobilization in 3 h~4 h versus 5 h~6 h (MD = 0.737, 95% CI: 0.431-1.043; p = 0.000) and 12 h versus 24 h (OR = 5.504, 95% CI: 1.646-18.407; p = 0.006) categories. The results of subgroup analysis also showed a significant risk reduction in urinary retention by early mobilization in 12 h versus 24 h (OR = 5.707, 95% CI: 1.859-17.521; p = 0.002) category. Conclusions: Early mobilization has not been shown to increase the risk of bleeding, hematoma, pseudoaneurysm, urinary retention, and pain at the puncture site after trans-femoral cardiac catheterization. Early mobilization is a practical initiative in ERAS, and it may be safe and feasible to advance the mobilization to 2 h~4 h.

Antibiotic prophylaxis for surgical wound infections in clean and clean-contaminated surgery: an updated systematic review and meta-analysis.

BACKGROUND: The efficacy and necessity of prophylactic antibiotics in clean and clean-contaminated surgery remains controversial. METHODS: The studies were screened and extracted using databases including PubMed, Embase, Cochrane Library, Web of Science, and Clinical Trials.gov according to predefined eligibility criteria. Randomized controlled trials (RCTs) comparing the effect of preoperative and postoperative prophylactic antibiotic use on the incidence of surgical site infections (SSIs) in patients undergoing any clean or clean-contaminated surgery. RESULTS: A total of 16 189 participants in 48 RCTs were included in the primary meta-analysis following the eligibility criteria. The pooled odds ratio (OR) for SSI with antibiotic prophylaxis versus placebo was 0.60 (95% CI: 0.53-0.68). The pooled OR among gastrointestinal, oncology, orthopedics, neurosurgery, oral, and urology surgery was 3.06 (95% CI: 1.05-8.91), 1.16 (95% CI: 0.89-1.50), 2.04 (95% CI: 1.09-3.81), 3.05 (95% CI: 1.25-7.47), 3.55 (95% CI: 1.78-7.06), and 2.26 (95% CI: 1.12-4.55), respectively. Furthermore, the summary mean difference (MD) for patients' length of hospitalization was -0.91 (95% CI: -1.61, -0.16). The results of sensitivity analyses for all combined effect sizes showed good stability. CONCLUSION: Antibiotics are both effective, safe, and necessary in preventing surgical wound infections in clean and clean-contaminated procedures, attributed to their reduction in the incidence of surgical site infections as well as the length of patient hospitalization.

Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.

Background: The excessive accumulation of lactate within the tumor microenvironment (TME) has been demonstrated to facilitate tumor advancement and evade the immune system. Nonetheless, the metabolic status of lactate in lung adenocarcinoma (LUAD) remains uncertain. Method: By analyzing the transcriptome profile of patients with LUAD, we created a lactate metabolism score (LMS) to predict survival. We then conducted a comprehensive examination of the biological functions and immune infiltration among different LMS patient groups. Moreover, we assessed the LMS predictive efficacy in chemotherapy and immunotherapy. Finally, we validated the detrimental phenotypic effects of SLC16A3 on LUAD cell lines (PC9 and A549) through in vitro experiments. We collected clinical samples to assess the prognostic impact of SLC16A3. Results: We constructed an LMS model with 6 lactate metabolism regulatory factors using LASSO regression. The high LMS model indicates worse clinical outcomes for LUAD patients. High LMS patients are associated with metabolic dysregulation and increased infiltration of M0 and M1 macrophages. Low LMS patients are related to upregulated citric acid metabolism pathways and memory immune cells. High LMS patients are suitable for traditional chemotherapy, while patients with low LMS are more likely to benefit from immunotherapy. Lastly, downregulating SLC16A3 significantly reduces the proliferative and invasive capabilities of LUAD cell lines. Clinical cohort shows that patients with high expression of SLC16A3 have a worse prognosis. Conclusions: The LMS model constructed based on the lactate metabolism pathway displays high effectiveness in predicting the outcome of patients with LUAD. LMS can offer direction regarding chemotherapy as well as immunotherapy in LUAD.

Changing profiles of the burden of Alzheimer's disease and other dementias attributable to smoking in the belt and road initiative countries: A secondary analysis of global burden of disease 2019.

Objectives: This study was aimed at analyzing the burden and trend of Alzheimer's disease and other dementias attributed to smoking (SADD) in the Belt and Road Initiative (BRI) countries during 1990-2019. Methods: Data from The 2019 Global Burden of Disease Study was used to extract information on the burden of SADD in terms of the numbers and age-standardized rate of mortality (ASMR) and disability-adjusted life years (ASDALR) in the BRI countries for 1990-2019. The average annual percent change (AAPC) was used to analyze the temporal trends of ASDALR from 1990 to 2019 and in the final decade by Joinpoint regression analysis. Results: The DALYs of SADD were the highest in China, India, and the Russian Federation in 1990 and in Lebanon, Montenegro and Bosnia, and Herzegovina in 2019. From 1990 to 2019, the ASDALR in China had increased from 55.50/105 to 66.18/105, but decreased from 2010 to 2019, while that of India had declined from 32.84/105 to 29.35/105, but increased from 2010 to 2019. The ASDALR showed the fastest increase in the Russian Federation, with AAPC of 1.97% (95% confidence interval [CI]: 1.77%, 2.16%), and the fastest decline in Sri Lanka, with AAPC of -2.69% (95% CI: 2.79%, -2.59%). ASMR and ASDALR from SADD showed a substantial decline during 1990-2019 both globally and in the different socio-demographic index (SDI) regions (all P < 0.05, except for the high-middle-SDI region). Compared to the rates in males, the AAPC in ASDALR of females was significantly greater in 20 countries(all P < 0.05). In the age group of 20-54 years, the DALYs rate showed a decreasing trend only in 13 members in the low-SDI region (all P < 0.05). Conclusion: Under the premise of eliminating the differences, mobilizing resources in the country itself, the BRI organization, and globally will help reduce the global SADD burden and achieve healthy and sustainable development.

The Absence of Intra-Tumoral Tertiary Lymphoid Structures is Associated with a Worse Prognosis and mTOR Signaling Activation in Hepatocellular Carcinoma with Liver Transplantation: A Multicenter Retrospective Study.

Tertiary lymphoid structure (TLS) can predict the prognosis and sensitivity of tumors to immune checkpoint inhibitors (ICIs) therapy, whether it can be noninvasively predicted by radiomics in hepatocellular carcinoma with liver transplantation (HCC-LT) has not been explored. In this study, it is found that intra-tumoral TLS abundance is significantly correlated with recurrence-free survival (RFS) and overall survival (OS). Tumor tissues with TLS are characterized by inflammatory signatures and high infiltration of antitumor immune cells, while those without TLS exhibit uncontrolled cell cycle progression and activated mTOR signaling by bulk and single-cell RNA-seq analyses. The regulators involved in mTOR signaling (RHEB and LAMTOR4) and S-phase (RFC2, PSMC2, and ORC5) are highly expressed in HCC with low TLS. In addition, the largest cohort of HCC patients is studied with available radiomics data, and a classifier is built to detect the presence of TLS in a non-invasive manner. The classifier demonstrates remarkable performance in predicting intra-tumoral TLS abundance in both training and test sets, achieving areas under receiver operating characteristic curve (AUCs) of 92.9% and 90.2% respectively. In summary, the absence of intra-tumoral TLS abundance is associated with mTOR signaling activation and uncontrolled cell cycle progression in tumor cells, indicating unfavorable prognosis in HCC-LT.

A pathway-based computational framework for identification of a new modal of multi-omics biomarkers and its application in esophageal cancer.

BACKGROUND: The pathway-based strategy has been recently proposed for identifying biomarkers with the advantages of higher biological interpretability and cross-data robustness than the conventional gene-based strategy. However, its utility in clinical applications has been limited due to the high computational complexity and ill-defined performance. OBJECTIVE: The current study presents a machine learning-based computational framework using multi-omics data for identifying a new modal of biomarkers, called pathway-derived core biomarkers, which have the advantages of both gene-based and pathway-based biomarkers. METHODS: Machine-learning methods and gene-pathway network were integrated to select the pathway-derived core biomarkers. Multiple machine-learning algorithms were used to construct and validate the diagnostic models of the biomarkers based on more than 1400 multi-omics clinical samples of esophageal squamous cell carcinoma (ESCC). RESULTS: The results showed that the classifier models based on the new modal biomarkers achieved superior performance in the training datasets with an average AUC/accuracy of 0.98/0.95 and 0.89/0.81 for mRNAs and miRNA, respectively, higher than the currently known classifier models based on the conventional gene-based strategy and pathway-based strategy. In the testing cohorts, the AUC/accuracy increased by 6.1 %/7.3 % than the models based on the native gene-based biomarkers. The improved performance was further confirmed in independent validation cohorts. Specifically, the sensitivity/specificity increased by ∼3 % and the variance significantly decreased by ∼69 % compared with that of the native gene-based biomarkers. Importantly, the pathway-derived core biomarkers also recovered 45 % more previously reported biomarkers than the gene-based biomarkers and are more functionally relevant to the ESCC etiology (involved in 14 versus 7 pathways related with ESCC or other cancer), highlighting the cross-data robustness of this new modal of biomarkers via enhanced functional relevance. CONCLUSIONS: The results demonstrated that the new modal of biomarkers not only have improved predicting performance and robustness, but also exhibit higher functional interpretability thus leading to the potential application in cancer diagnosis.

Tri©DB: an integrated platform of knowledgebase and reporting system for cancer precision medicine.

BACKGROUND: With the development of cancer precision medicine, a huge amount of high-dimensional cancer information has rapidly accumulated regarding gene alterations, diseases, therapeutic interventions and various annotations. The information is highly fragmented across multiple different sources, making it highly challenging to effectively utilize and exchange the information. Therefore, it is essential to create a resource platform containing well-aggregated, carefully mined, and easily accessible data for effective knowledge sharing. METHODS: In this study, we have developed "Consensus Cancer Core" (Tri©DB), a new integrative cancer precision medicine knowledgebase and reporting system by mining and harmonizing multifaceted cancer data sources, and presenting them in a centralized platform with enhanced functionalities for accessibility, annotation and analysis. RESULTS: The knowledgebase provides the currently most comprehensive information on cancer precision medicine covering more than 40 annotation entities, many of which are novel and have never been explored previously. Tri©DB offers several unique features: (i) harmonizing the cancer-related information from more than 30 data sources into one integrative platform for easy access; (ii) utilizing a variety of data analysis and graphical tools for enhanced user interaction with the high-dimensional data; (iii) containing a newly developed reporting system for automated annotation and therapy matching for external patient genomic data. Benchmark test indicated that Tri©DB is able to annotate 46% more treatments than two officially recognized resources, oncoKB and MCG. Tri©DB was further shown to have achieved 94.9% concordance with administered treatments in a real clinical trial. CONCLUSIONS: The novel features and rich functionalities of the new platform will facilitate full access to cancer precision medicine data in one single platform and accommodate the needs of a broad range of researchers not only in translational medicine, but also in basic biomedical research. We believe that it will help to promote knowledge sharing in cancer precision medicine. Tri©DB is freely available at www.biomeddb.org , and is hosted on a cutting-edge technology architecture supporting all major browsers and mobile handsets.

Cerebrospinal Fluid from Patients After Craniotomy with the Appearance of Interleukin-6 Storm Can Activate Microglia to Damage the Hypothalamic Neurons in Mice.

We monitored CSF (cerebrospinal fluid) for Th1/Th2 inflammatory cytokines in a patient with unexplained postoperative disturbance of consciousness after craniotomy and found that the level of IL-6 (interleukin-6) concentrations was extremely high, meeting the traditional criteria for an inflammatory cytokine storm. Subsequently, the cerebrospinal fluid specimens of several patients were tested, and it was found that IL-6 levels were increased in different degrees after craniotomy. Previous studies have focused more on mild and long-term IL-6 elevation, but less on the effects of this short-term IL-6 inflammatory cytokine storm. Cerebrospinal fluid rich in IL-6 may play a significant role in patients after craniotomy. The objective is to explore the degree of IL-6 elevation and the incidence of IL-6 inflammatory cytokine storm in patients after craniotomy, as well as the effect of IL-6 elevation on the brain. In this study, the levels and clinical manifestations of inflammatory factors in cerebrospinal fluid after craniotomy were statistically classified, and the underlying mechanisms were discussed preliminarily. CSF specimens of patients after craniotomy were collected, IL-6 level was measured at 1, 5, and 10 days after operation, and cognitive function was analyzed at 1, 10, and 180 days after surgery. Craniotomy mouse model, cerebrospinal fluid of patients with the appearance of IL-6 storm after craniotomy, and IL-6 at the same concentration stimulation model were established. Behavioral tests, fluorescence in situ hybridization (FISH), pathological means, western blot, and ELISA (enzyme-linked immune-sorbent assay) were performed for verification. CSF from patients after craniotomy caused disturbance of consciousness in mice, affected neuronal damage in the hypothalamus, activation of microglia in the hypothalamus, and decreased expression of barrier proteins in the hypothalamus and brain. The large amount of interleukin-6 in CSF after craniotomy was found to be mainly derived from astrocytes. The IL-6 level in CSF after craniotomy correlated inversely with patients' performance in MoCA test. High levels of IL-6 in the cerebrospinal fluid derived from astrocytes after craniotomy may lead to disruption of the brain-cerebrospinal fluid barrier, most notably around the hypothalamus, which might result in inflammatory activation of microglia to damage the hypothalamic neurons and impaired cognitive function/more gradual cognitive repairment in patients after craniotomy with the appearance of IL-6 storm.

Proximal femoral tumor resection followed by joint prosthesis replacement: a systematic review and meta-analysis.

BACKGROUND: This study aimed to determine the prognostic outcome of hip joint replacement after resection of proximal femoral tumors by reviewing original studies. METHODS: Two researchers independently searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to July 17, 2022. Then, the literature was screened by inclusion criteria. The basic information, primary outcomes, and secondary outcomes were extracted for weighted combined analysis. The quality of the included literature was evaluated using the Newcastle-Ottawa scale. RESULTS: Twenty-four retrospective cohort studies comprising 2081 patients were included. The limb salvage rate was 98%. The survival rates at 1, 2, 3, 4, and 5 years were 80, 72, 65, 64, and 55% for patients with primary tumors and the rate at 1, 2, 3, 4, and 5 years were 44, 25, 17, 14, and 11% for patients with bone metastases, respectively. CONCLUSION: As chemotherapy and radiotherapy treatment progressed, joint reconstruction after proximal femoral tumor resection improved patients' function and quality of life.

Esophagogastric Junction Outflow Obstruction Is Likely to Be a Local Manifestation of Other Primary Diseases: Analysis of Single-Center 4-Year Follow-Up Data.

BACKGROUND: Whether esophagogastric junction outflow obstruction (EGJOO) is a variant of achalasia cardia (AC) or an esophageal motility state of certain organic or systemic diseases remains controversial. We aimed to investigate the differences between EGJOO and AC in clinical characteristics and outcomes through a 4-year follow-up. METHODS: Patients diagnosed with primary EGJOO or AC were included. Based on the presence of concomitant disease, EGJOO patients were divided into a functional and an anatomical EGJOO group; similarly, patients with AC were divided into an AC with organic disease group and a true AC group. Disease characteristics and high-resolution manometry (HRM) parameters were retrospectively compared between the groups, and the development of organic diseases that could affect esophageal motility disorders and responses to treatment were examined during the follow-up. Symptom relief was defined as an Eckardt score of ≤3 after the treatment. RESULTS: The study included 79 AC patients and 70 EGJOO patients. Compared with patients with AC, EGJOO patients were older, had shorter disease duration, a lower Eckardt score, and were more likely to have concurrent adenocarcinoma of the esophagogastric junction (AEG) and autoimmune disease (p < 0.05 for all). The severity of dysphagia and Eckardt scores were higher in the anatomical EGJOO group than in the functional EGJOO group. Significant differences were seen in HRM parameters (UES residual pressure, LES basal pressure, and LES residual pressure) between AC and EGJOO patients. However, no significant differences in HRM parameters were observed between the functional EGJOO and anatomical EGJOO groups. Sixty-seven (95.71%) patients with EGJOO and sixty-nine (87.34%) patients with AC experienced symptom relief (p = 0.071). Among patients achieving symptom relief, a relatively large proportion of patients with EGJOO had symptom relief after medications (37/67, 55.22%), the resolution of potential reasons (7/67, 10.45%), and spontaneous relief (15/67, 22.39%), while more patients with AC had symptom relief after POEM (66/69, 95.65%). Among EGJOO patients achieving symptom relief, more patients (7/20, 35%) with anatomical EGJOO had symptom relief after the resolution of potential reasons for EGJOO, while more patients (32/47, 68.09%) with functional EGJOO had symptom relief with medications. CONCLUSIONS: Concurrent AEG and autoimmune diseases are more likely in EGJOO than in AC. A considerable part of EGJOO may be the early manifestation of an organic disease. Anatomical EGJOO patients experience symptom improvement with the resolution of primary diseases, while most functional EGJOO patients experience symptom relief with pharmacotherapy alone or even without any treatment.

Long-term outcomes in lean and non-lean NAFLD patients: a systematic review and meta-analysis.

BACKGROUND: Although nonalcoholic fatty liver disease (NAFLD) commonly occurs in overweight or obese individuals, it is increasingly being identified in the lean population. The association between lean and an increased risk of all-cause mortality among patients with NAFLD remains controversial. We aimed to perform a systematic review and meta-analysis of the literature to evaluate this association and compare the long-term outcomes of lean NAFLD patients and non-lean NAFLD patients. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wan Fang, and Chinese Biomedical Literature Database (CBM) from inception to October 15, 2021, for relevant original research articles without any language restrictions. Our primary outcome was to compare the all-cause mortality in lean NAFLD patients and non-lean NAFLD patients by qualitative synthesis. Relative risks (RRs) and corresponding 95% confidential intervals (CIs) were pooled with a random effect model. Heterogeneity was evaluated using I-squared (I²) statistics while publication bias was determined using Egger's tests. Subgroup and sensitivity analyses were performed. As for secondary outcomes, we estimated total, cardiovascular, and liver-related mortality, as well as the incidence of diabetes, hypertension, cirrhosis, and cancer in lean and non-lean individuals with NAFLD by quantitative synthesis. Person-years of follow-up were used as the denominator to estimate the mortality and incidence. RESULTS: We identified 12 studies (n = 26,329), 7 of which (n = 7924) were used to evaluate the risk of all-cause mortality between lean and non-lean NAFLD patients. Lean patients with NAFLD were found to be at an elevated risk of death compared to non-lean patients (RR = 1.39, 95% CI 1.08-1.82, heterogeneity: I² = 43%). Among the lean NAFLD population, all-cause mortality was 13.3 (95% CI: 6.7-26.1) per 1000 person-years, 3.6 (95% CI: 1.0-11.7) for liver-related mortality, and 7.7 (95% CI: 6.4-9.2) for cardiovascular-related mortality. The incidence of new-onset diabetes was 13.7 (95% CI 8·2-22.7) per 1000 person-years, new-onset hypertension was 56.1 (95% CI: 40.2-77.9), cirrhosis was 2.3 (95% CI: 1.0-5.0), and cancer was 25.7 (95% CI: 20.3-32.4). CONCLUSIONS: Lean patients with NAFLD had a higher risk of all-cause death than non-lean patients. Body mass index (BMI) should not be used as a criterion to determine whether further observation and therapy of patients with NAFLD are warranted.

Analysis and Characterization of Glutathione Peroxidases in an Environmental Microbiome and Isolated Bacterial Microorganisms.

Glutathione peroxidases (Gpx) are a group of antioxidant enzymes that protect cells or tissues against damage from reactive oxygen species (ROS). The Gpx proteins identified in mammals exhibit high catalytic activity toward glutathione (GSH). In contrast, a variety of non-mammalian Gpx proteins from diverse organisms, including fungi, plants, insects, and rodent parasites, show specificity for thioredoxin (TRX) rather than GSH and are designated as TRX-dependent peroxiredoxins. However, the study of the properties of Gpx in the environmental microbiome or isolated bacteria is limited. In this study, we analyzed the Gpx sequences, identified the characteristics of sequences and structures, and found that the environmental microbiome Gpx proteins should be classified as TRX-dependent, Gpx-like peroxiredoxins. This classification is based on the following three items of evidence: i) the conservation of the peroxidatic Cys residue; ii) the existence and conservation of the resolving Cys residue that forms the disulfide bond with the peroxidatic cysteine; and iii) the absence of dimeric and tetrameric interface domains. The conservation/divergence pattern of all known bacterial Gpx-like proteins in public databases shows that they share common characteristics with that from the environmental microbiome and are also TRX-dependent. Moreover, phylogenetic analysis shows that the bacterial Gpx-like proteins exhibit a star-like radiating phylogenetic structure forming a highly diverse genetic pool of TRX-dependent, Gpx-like peroxidases.

Intravoxel incoherent motion MRI for rectal cancer: correlation of diffusion and perfusion characteristics with clinical-pathologic factors.

BACKGROUND: Colorectal cancer is the most common cause of cancer-related death worldwide. Magnetic resonance imaging (MRI) has become a promising alternative method for staging the cancer. PURPOSE: To evaluate parameters of intravoxel incoherent motion (IVIM) and their relationships with clinical-pathologic factors in rectal cancers. MATERIAL AND METHODS: A total of 51 patients with histopathologically proven rectal cancer who underwent preoperative pelvic MRI were prospectively enrolled. Parameters (ADC, D, D*, and f) derived from IVIM-diffusion-weighted imaging (DWI) were independently measured by two radiologists. Student's t-test, receiver operating characteristic curves, and Spearman correlation were used for statistical analysis. RESULTS: ADC, D, and D* were significantly higher in pT1-2 tumors than in pT3-4 tumors (1.108 ± 0.233 vs. 0.950 ± 0.176, 0.796 ± 0.199 vs. 0.684 ± 0.114, 0.013 ± 0.005 vs. 0.008 ± 0.003, respectively; P < 0.05). D* exhibited a strong correlation with the tumor stage (r = -0.675, P < 0.001). In poorly differentiated cluster (PDC) grading, ADC, D*, and f were significantly lower in high-grade tumors than in low-grade tumors (0.905 ± 0.148 vs. 1.064 ± 0.200, 0.008 ± 0.002 vs. 0.011 ± 0.005, and 0.252 ± 0.032 vs. 0.348 ± 0.058, respectively; P < 0.05). The f value exhibited a significantly strong correlation with the PDC grades (r = -0.842, P < 0.001), and higher sensitivity and specificity (95.2% and 75.9%) than those shown by the ADC, D, and D* values. CONCLUSION: IVIM parameters, especially f, demonstrated a strong correlation with histologic grades and showed a better performance in differentiating between high- and low-grade rectal cancers. These parameters would be helpful in predicting tumor aggressiveness and prognosis.

Comparison of specimen quality among the standard suction, slow-pull, and wet suction techniques for EUS-FNA: A multicenter, prospective, randomized controlled trial.

Background and Objectives: Standard suction technique (SST), slow-pull technique (SPT), and wet suction technique (WEST) of EUS-FNA are designed to improve the diagnostic yields of solid and solid-cystic lesions. We conducted a multicenter, prospective, randomized crossover trial to compare SST, SPT, and WEST on specimen quality and diagnostic accuracy using a 22G needle. Methods: Patients with solid or solid-cystic lesions referred for EUS-FNA at four tertiary hospitals from December 2017 to August 2019 were considered eligible. All lesions were sampled using a 22G needle by the three techniques performed consecutively in a randomized order. The primary outcome was quality of the specimen acquired by each technique regarding blood contamination, tissue integrity and cellularity for diagnosis, graded on a predefined scale. The secondary outcomes were the diagnostic yield of EUS-FNA and the incidence of adverse events. ClinicalTrial. gov registration number: NCT03567863. Results: A total of 300 patients (mean age, 60.6 years, 188 men) were enrolled. WEST was superior (mean score 4.02 ± 1.51) over SST (3.67 ± 1.57, P = 0.018), but comparable to SPT (3.83 ± 1.55, P = 0.370) in overall specimen quality evaluation. WEST produced better tissue integrity (1.42 ± 0.74) and higher cellularity (1.32 ± 0.80) than SST and SPT. SPT (1.43 ± 0.69) was superior to SST (1.27 ± 0.72, P = 0.004) and WEST (1.28 ± 0.71, P = 0.006) in avoiding blood contamination. WEST achieved a diagnostic accuracy of 74.7%, higher than SST (64.4%, P = 0.007) and SPT (65.0%, P = 0.012). One bleeding event occurred with a pancreatic lesion. Conclusions: WEST was comparable to SPT and superior to SST in the overall quality of the specimen and achieved highest diagnostic yield.

SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis.

OBJECTIVES: Despite advances in treatment, an effective therapeutic strategy for acute kidney injury (AKI) is still lacking. Considering the widely reported clinical benefits of canagliflozin in the kidneys, we assessed the effects of canagliflozin on AKI. METHODS: Lipopolysaccharide was used to induce AKI in the presence of canagliflozin. RESULTS: Canagliflozin treatment reduced blood urea nitrogen and serum creatinine levels and improved the renal tubular structure in mice with lipopolysaccharide-induced septic AKI. Canagliflozin also suppressed the inflammatory response, oxidative stress and tubular cell death in the kidneys during septic AKI. In vitro, canagliflozin supplementation maintained mitochondrial function in lipopolysaccharide-treated HK-2 cells by restoring the mitochondrial membrane potential, inhibiting mitochondrial reactive oxygen species production and normalizing mitochondrial respiratory complex activity. In HK-2 cells, canagliflozin stimulated the adenosine monophosphate-activated protein kinase catalytic subunit alpha 1 (AMPKα1)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway, thus elevating the number of live and healthy mitochondria following lipopolysaccharide treatment. Inhibition of the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway abolished the protective effects of canagliflozin on renal cell mitochondria and tubular viability. Similarly, the protective effects of canagliflozin on kidney function and tubular structure were abrogated in AMPKα1-knockout mice. CONCLUSIONS: Canagliflozin could be used to treat septic AKI by activating the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway.

An Integrative Analysis Framework for Identifying the Prognostic Markers from Multidimensional RNA Data of Clear Cell Renal Cell Carcinoma.

The altered regulatory status of long noncoding RNA (lncRNA), miRNA, and mRNA and their interactions play critical roles in tumor proliferation, metastasis, and progression, which ultimately influence cancer prognosis. However, there are limited studies of comprehensive identification of prognostic biomarkers from combined data sets of the three RNA types in the highly metastatic clear cell renal cell carcinoma (ccRCC). The current study employed an integrative analysis framework of functional genomics approaches and machine learning methods to the lncRNA, miRNA, and mRNA data and identified 16 RNAs (3 lncRNAs, 6 miRNAs, and 7 mRNAs) of prognostic value, with 9 of them novel. A 16 RNA-based score was established for prognosis prediction of ccRCC with significance (P < 0.0001). The area under the curve for the score model was 0.868 to 0.870 in the training cohort and 0.714 to 0.778 in the validation cohort. Construction of the lncRNA-miRNA-mRNA interaction network showed that the downstream mRNAs and upstream lncRNAs in the network initiated from the miRNA or lncRNA markers exhibit significant enrichment in functional classifications associated with cancer metastasis, proliferation, progression, or prognosis. The functional analysis provided clear support for the role of the RNA biomarkers in predicting cancer prognosis. This study provides promising biomarkers for predicting prognosis of ccRCC using multidimensional RNA data, and these findings are expected to facilitate potential clinical applications of the biomarkers.

The expression and survival significance of sodium glucose transporters in pancreatic cancer.

BACKGROUND: Sodium glucose transporters (SGLTs) play vital roles in glucose uptake in many solid cancers, including pancreatic cancer (PC). However, their expression profile in pancreatic cancer and correlation with prognosis are not clear. Thus, we aimed to analyse the expression profile and prognostic significance of SGLT-1 and SGLT-2 in PC. METHODS: Eighty-eight patients with pancreatic ductal adenocarcinoma (PDAC) undergoing surgery in Huashan Hospital, Fudan University, from July 2017 to June 2020 were enrolled in the study. Specimens for immunohistochemistry were obtained through surgical resection. Bioinformatics analysis was performed based on the Gene Expression Omnibus (GEO), Oncomine and The Cancer Genome Atlas (TCGA) databases. The statistics were calculated using IBM SPSS Statistics, version 20 and R 4.1.1. P values lower than 0.05 were considered to indicate statistical significance. RESULTS: SGLT-1 but not SGLT-2 was significantly overexpressed in PDAC. Survival analysis showed that the median overall survival (OS) and progression-free survival (PFS) of patients with high SGLT-1 expression were significantly longer than that of patients with low SGLT-1 expression. Cox regression indicated that high SGLT-1 expression was an independent predictor for a better prognosis, while residual tumour status (R1 and R2) was an independent risk factor for a poor prognosis. Finally, PDZK1-interacting protein 1 (PDZK1IP1), a protein participating in the generation of reactive oxygen species, was overexpressed in PDAC and its expression was significantly correlated with SGLT-1. CONCLUSIONS: SGLT-1 but not SGLT-2 was overexpressed in PDAC, and the overexpression of SGLT-1 could be a predictor of a better prognosis. Residual tumour status (R1 and R2) was a risk factor for poor prognosis and disease progression.

Association Between Gastroesophageal Flap Valve and Endoscopically Diagnosed Gastroesophageal Reflux Disease According to Lyon Consensus: A Meta-analysis of Asian Studies.

BACKGROUND: Lyon Consensus altered the previous understanding of endoscopic gastroesophageal reflux disease (GERD) and pointed out that only high-grade reflux esophagitis (RE) [Los Angeles (LA) grades C or D], Barrett's esophagus or peptic stricturing were considered confirmatory evidence for GERD but low-grade RE (LA grades A or B) was regarded as suspected GERD. We aimed to summarize the possible relationship between gastroesophageal flap valve (GEFV) and endoscopic GERD according to Lyon Consensus using meta-analysis of studies done in Asia. MATERIALS AND METHODS: Comprehensive searches of PubMed, WOS, Embase, SinoMed, and CNKI databases were completed to identify eligible studies published before September 22, 2019. A total of 237 articles have been reviewed and 2 reviewers independently evaluated the eligibility for inclusion, extracted, and analyzed the statistical data. The pooled risk ratios (RRs) with 95% confidence intervals (CI) were measured for the association. Random-effects models were used when observing significant heterogeneity. RESULTS: A total of 15 studies were included and we found that abnormal GEFV (III and IV) could be associated with RE and the correlation become stronger as the grade increases (RE-A vs. controls-RR: 2.186, 95% CI: 1.560-3.064, P<0.001; RE-B vs. RE-A-RR: 1.268, 95% CI: 1.128-1.425, P<0.001; RE-C vs. RE-B-RR: 1.181, 95% CI: 1.000-1.395, P=0.049; RE-D vs. RE-C-RR: 1.471, 95% CI: 1.151-1.879, P=0.002). Both suspected GERD (RR: 2.400, 95% CI: 1.761-3.271, P<0.001) and endoscopic GERD (RR: 1.388, 95% CI: 1.127-1.711, P=0.002) were related to abnormal GEFV. CONCLUSION: Abnormal GEFV could provide useful information for reflux conditions, but it could not distinguish confirmatory GERD from low-grade RE under the upper endoscopy.

Activation of Age-Related Nuclear Factor-κB Signaling Pathway Leads to Chronic Inflammation and Pituitary Fibrosis.

OBJECTIVE: The purpose of the present study was to investigate the mechanism of pituitary fibrosis in elderly people. METHODS: First, 20 pituitary glands obtained from 11 elderly people and 9 young people were studied using Masson's trichrome staining for fibrosis detection. Second, pituitary glands from 12 male rats, including 6 aged rats (OM group) and 6 young rats (YM group), were also studied. Western blotting was performed to detect collagen 1 and phosphorylation of the nuclear factor (NF)-κB subunit p65 in the OM and YM groups. The levels of 8 proinflammatory cytokines (interleukin [IL]-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, interferon-γ, and tumor necrosis factor-α) in the rat pituitary glands were detected using liquid suspension chip technology. Enzyme-linked immunosorbent assays were performed to detect the growth hormone (GH) levels in the venous blood samples from the rats. Next, 12 aged rats were randomly divided into 2 groups: the QNZ (Q)+OM and normal physiological saline (N)+OM groups. The Q+OM and N+OM groups had undergone intervention by intraperitoneally injection of QNZ and physiological saline (1 mg/kg) for 28 days, respectively. Finally, biochemical and histological examinations were performed, including Masson's trichrome staining for fibrosis, Western blotting for phosphorylation of p65, Millipore multiplex bead arrays (Millipore, Billerica, Massachusetts, USA) for proinflammatory cytokine levels, and enzyme-linked immunosorbent assays for GH secretion. RESULTS: Fibrosis was detected in the elderly patient group. Collagen 1, phosphorylation of the NF-κB signaling pathway, and the proinflammatory cytokine levels showed a significant increase in the OM group. Compared with the N+OM group, pituitary fibrosis was alleviated in the Q+OM group, with an increase in GH secretion and decreased proinflammatory cytokine levels and NF-κB. CONCLUSIONS: Pituitary fibrosis was found in the elderly group, and the pathological change was antagonized by decreasing the proinflammatory cytokine levels using QNZ and further increasing GH secretion.