Evidence of potential pro-haemorrhagic drug interactions between CYP3A4 inhibitors and direct oral anticoagulants: Analysis of the FAERS database.

AIMS: There is no consensus on the haemorrhagic risk associated with potential interactions between commonly used CYP3A4 inhibitors and direct oral anticoagulants (DOACs). METHODS: Macrolide antibiotics and azole antimycotics were investigated in this study. Data from Food and Drug Administration Adverse Event Reporting System were retrieved from July 2010 to September 2021. Haemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals (CIs) based on the interaction/noninteraction methodology as (a/c) / (b/d) and considered significant when the lower limit of 95% CI was >1 and the case number of interaction group was ≥3. Subgroup analyses and logistic regression were conducted by adjusting associated factors in haemorrhagic events. RESULTS: From the third quarter of 2010 to the first quarter of 2021, we retrieved 382 853 distinct cases of adverse events associated with DOACs, in which 1128 cases of bleeding were associated with coadministration of CYP3A4 inhibitors and DOACs. The haemorrhagic signal was significant for apixaban when coadministered with clarithromycin (ROR 1.60, 95% CI 1.16-2.20) and posaconazole (ROR 2.69, 95% CI 1.37-5.28). For dabigatran, coadministration with azithromycin (ROR 4.06, 95% CI 2.77-5.95), fluconazole (ROR 2.26, 95% CI 1.52-3.37), itraconazole (ROR 7.52, 95% CI 1.51-37.46) and ketoconazole (ROR 2.06, 95% CI 1.25-3.41) was associated with significantly higher risks of haemorrhages. At the same time, addition of itraconazole to rivaroxaban also indicated significant haemorrhagic signal (ROR 3.58, 95% CI 1.30-9.85). CONCLUSIONS: Macrolide antibiotics and azole antimycotics have potential but different effects on the bleeding risk of DOACs. Close attention is needed when using these drugs together. Such precautions have already been included in some drug labels.

Safety, efficacy and prognosis of anticoagulant therapy for portal vein thrombosis in cirrhosis: a retrospective cohort study.

BACKGROUND: The role of anticoagulants in the treatment of cirrhotic PVT remains controversial. This study aimed to analyze the safety and efficacy of anticoagulant therapy in patients with cirrhotic portal vein thrombosis (PVT) and its impact on prognosis. METHODS: A retrospective cohort study was conducted for PVT patients with liver cirrhosis in our hospital. The primary outcome of the study was the PVT recanalization rate. Other outcomes included bleeding rate, liver function, and mortality. Cox and Logistic regression were used to explore the risk factors of outcomes. RESULTS: This study included 77 patients that 27 patients in the anticoagulant group and 50 in the non-anticoagulant group. Anticoagulant therapy was associated with higher rate of PVT recanalization (44.4% vs 20.0%, log-rank P = 0.016) and lower rate of PVT progression (7.4% vs 30.0%, log-rank P = 0.026), and without increasing the rate of total bleeding (14.8% vs 24%, P = 0.343), major bleeding (3.7% vs 6%, P = 0.665) and variceal bleeding (3.7% vs 16%, P = 0.109). The safety and efficacy of different anticoagulants were similar. The Child-Pugh grade of the anticoagulant therapy group was better than that of the non-anticoagulant therapy group (P = 0.030). There was no significant difference in the 2-year survival rate of the two groups. CONCLUSION: Anticoagulants could increase the PVT recanalization rate and reduce the PVT progression rate without increasing the rate of bleeding. Anticoagulants may be beneficial to improving the liver function of patients with cirrhotic PVT. There was no significant difference in the safety and efficacy of different anticoagulants in the treatment of cirrhotic PVT.

Immunosuppressive therapy for progressive idiopathic membranous nephropathy: a cost-effectiveness analysis in China.

BACKGROUND: This study aims to evaluate the cost-effectiveness of immunosuppressive therapy for patients with progressive idiopathic membranous nephropathy (IMN) from the Chinese healthcare system perspective. METHODS: To estimate the cost-effectiveness of four regimens namely cyclophosphamide, cyclosporine, rituximab and tacrolimus-rituximab in treatment of IMN recommended by the updated Kidney Disease: Improving Global Outcomes (KDIGO) guideline 2021, a Markov model with five discrete states (active disease, remission, dialysis, kidney transplant and death) based on IMN patients aged 50 or above over a 30-years time horizon was constructed. Total costs were imputed from the Chinese healthcare system perspective, and health outcomes were converted into quality-adjusted life years (QALYs). The incremental cost-effectiveness ratio (ICER) was used to describe the results. The willingness-to-pay (WTP) threshold was set at $12,044 (China's 2021 Gross Domestic Product per capita). Sensitivity analyses were performed to test the uncertainties of the results. RESULT: Compared with cyclophosphamide, both cyclosporine (incremental cost $28,337.09, incremental QALY-1.63) and tacrolimus-rituximab (incremental cost $28,324.13, incremental QALY -0.46) were considered at strictly dominated for their negative values in QALYs, and the ICER value of rituximab was positive (incremental cost $9,162.19, incremental QALY 0.44). Since the ICER of rituximab exceeds the pre-determined threshold, cyclophosphamide was likely to be the best choice for the treatment of IMN within the acceptable threshold range. The results of the sensitivity analysis revealed that the model outcome was mostly affected by the probability of remission in rituximab. In a probabilistic sensitivity analysis, cyclophosphamide had 62.4% probability of being cost-effective compared with other regimens when the WTP was $12,044 per QALY. When WTP exceeded $18,300, rituximab was more cost-effective than cyclophosphamide. CONCLUSION: Compared with cyclosporine, rituximab and tacrolimus-rituximab, our model results indicated that cyclophosphamide represented the most cost-effective regimen for patients with progressive IMN in China.

Coagulation dysfunction events associated with tigecycline: a real-world study from FDA adverse event reporting system (FAERS) database.

BACKGROUND: Tigecycline has broad-spectrum anti-bacterial activity and often used for critically ill patients with complicated infections. Only a few clinical studies have reported the coagulation disorder induced by tigecycline. The aim of this study was to investigate the association between tigecycline and coagulation dysfunction using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHOD: Data from January 2005 to December 2020 in FAERS were retrieved. We investigated the clinical characteristics of the coagulation dysfunction events and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare tigecycline with the full database and other antibiotics. RESULTS: The total number of reports of coagulation dysfunction related to tigecycline as the primary suspect drug was 223. The median time to event of the coagulation dysfunction events was 10 (interquartile range [IQR] 6.75-13) days. 80.72% coagulation-related adverse events appeared within the first 14 days since the initiation of tigecycline administration. The overall ROR (95% CI) for coagulation-related adverse events was 3.55 (3.08, 4.09). The RORs (95% CI) for thrombocytopenia, hypofibrinogenaemia, coagulopathy, activated partial thromboplastin time prolonged, international normalized ratio increased, prothrombin time prolonged were 8.21 (6.34, 10.62), 705.41 (526.81, 944.54), 30.67 (21.92, 42.92), 42.98 (24.85, 74.31), 4.67 (2.51, 8.71), and 27.99 (15.01, 52.19), respectively. In analyses stratified on comparing tigecycline to vancomycin and daptomycin, significant coagulation dysfunction signals were found with the RORs (95% CI) 2.74 (2.34, 3.22) and 3.08 (2.57, 3.70). CONCLUSIONS: We found a strong signal of high frequency of reporting coagulation dysfunction in tigecycline. Health professionals should be aware of the potential coagulation disorders risk and monitor coagulation parameters during anti-bacterial therapy with tigecycline, particularly the need to monitor fibrinogen levels.

Central nervous system adverse events of ceftazidime/avibactam: A retrospective study using Food and Drug Administration Adverse Event Reporting System.

WHAT IS KNOWN AND OBJECTIVE: Many antibiotics are well known for being associated with adverse events (AEs) of central nervous system, ceftazidime/avibactam (CAZ/AVI) is a novel ß-lactam/ß-lactamase inhibitor combinations. In this commentary, we analyzed reports of nervous system disorders associated with CAZ/AVI, meropenem, imipenem, ceftazidime, ceftriaxone, and cefepime in the Food and Drug Administration (FDA) Adverse Event Reporting System database from January 2015 to March 2022. COMMENT: The reporting odds ratios (RORs) method was used to detect the safety signals. Up to 15.62% of CAZ/AVI AEs exhibit nervous system disorders associated with CAZ/AVI. A nervous system disorder signal was detected for CAZ/AVI compared with meropenem, ceftazidime, and ceftriaxone. Compared with meropenem, imipenem, ceftazidime, and ceftriaxone, encephalopathy, myoclonus, reported with CAZ/AVI exhibited significant RORs. WHAT IS NEW AND CONCLUSION: This study found that CAZ/AVI showed a relatively stronger sign nervous system disorder than meropenem, ceftazidime, and ceftriaxone in the real world. The poor clinical outcome of these events should attract clinical attention, especially for patients with older than 65 years old and long treatment courses.

Cost-effectiveness analysis of dabigatran, rivaroxaban and warfarin in the prevention of stroke in patients with atrial fibrillation in China.

BACKGROUND AND OBJECTIVE: To evaluate the cost-effectiveness of new anticoagulants and warfarin in the prevention of stroke in Chinese patients with atrial fibrillation (AF). METHODS: The Markov model was constructed to compare patients' quality-adjusted life-years (QALYs) using drug cost, the cost of the examination after taking a drug, and the incremental cost of other treatments. Both dabigatran (110 and 150 mg, twice a day) and rivaroxaban (20 mg, once a day) were compared with warfarin (3-6 mg, once a day). Willingness to pay, three times the 2018 China GDP per capita (9481.88 $), was the cost-effect threshold in our study. RESULTS: The total cost were was 5317.31$, 29673.33$, 23615.49$, and 34324.91$ for warfarin, rivaroxaban, dabigatran 110 mg bid, and dabigatran 150 mg bid, respectively. The QALYs for each of the four interventions were 11.07 years, 15.46 years, 12.4 years, and 15 years, respectively. The cost-effectiveness analysis of the three new oral anticoagulants and warfarin showed that the incremental cost-effectiveness ratio (ICER) was 5548.07$/QALY when rivaroxaban was compared with warfarin. Rivaroxaban was the most cost-effective choice and warfarin was the least. CONCLUSIONS: In Chinese patients with AF, although warfarin is cheaper, rivaroxaban has a better cost-effectiveness advantage from an economic point of view.

Thalidomide as a treatment for inflammatory bowel disease in children and adolescents: A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Thalidomide is used off-label for the treatment of inflammatory bowel disease (IBD) and not as a first-line treatment option. The instructions clearly state that thalidomide is contraindicated in children because its safety and effectiveness in children are unknown. In this article, we review the efficacy and safety of thalidomide as a treatment for IBD in children and adolescents. METHODS: We searched PubMed, Embase, the Cochrane Library, CNKI, WanFang Data, CBM database [from the date of database establishment to June 2019] and clinical trials [systematic review and meta-analysis, randomized controlled trials (RCTs), cohort studies, case-control studies and case series studies] for studies concerning the use of thalidomide as a treatment for IBD in children and adolescents. RESULTS AND DISCUSSION: Seven studies (two RCTs and five case series), which included 134 children and adolescents (32 with ulcerative colitis, 102 with Crohn's disease), met the inclusion criteria. The included studies showed that the clinical remission rate of thalidomide was 44%-100% and the steroid tapering rate was 50%-100% in children and adolescents with refractory IBD. Peripheral neuropathy was the most common major adverse reaction, and it appeared to be cumulative dose-dependent. WHAT IS NEW AND CONCLUSION: Thalidomide as a treatment for refractory IBD in children and adolescents can improve clinical remission and achieve longer-term maintenance of remission. Peripheral neuropathy is the main adverse drug reaction, and it can be monitored and prevented. It is necessary to fully communicate with parents and obtain informed consent before using this drug.

Antidepressant Use and Risk of Venous Thromboembolism: A Systematic Review and Meta-Analysis.

PURPOSE: Studies provided conflicting results on whether antidepressant use increased the risk of venous thromboembolism (VTE). Our aim was to examine the association between antidepressant use and the risk of VTE. METHODS: Pubmed, Embase, and the Cochrane Library were searched up to March 13, 2018. Case-control studies and cohort studies that examined the association between antidepressant use and the risk of VTE, deep vein thrombosis or pulmonary embolism were included. Several subgroup analyses and sensitivity analyses were conducted. GRADE approach was used to assess the quality of evidence. RESULTS: Nine studies (six case-control studies and three cohort studies) were included. Overall, antidepressant use may be associated with an increased risk of VTE (OR 1.27, 95% CI 1.09 to 1.49); however, no association was observed in studies with low risk of bias (OR 1.27, 95% CI 0.84 to 1.92). No association between selective serotonin reuptake inhibitor use and VTE risk was detected in the overall analysis (OR 1.10, 95% CI 0.90 to 1.34) and in subgroup analysis of studies with low risk of bias. Tricyclic antidepressant may be associated with an increased VTE risk (OR 1.26, 95% CI 1.02 to 1.57), and the quality of evidence was rated as very low by GRADE approach; however, no association was observed when we only included studies with low risk of bias. CONCLUSIONS: There was no association between selective serotonin reuptake inhibitor use and VTE risk. Tricyclic antidepressant may be associated with an increased VTE risk, but the quality of evidence was very low.

Rh-endostatin Concomitant with Chemotherapy Versus Single Agent Chemotherapy for Treating Soft Tissue and Bone Sarcomas: A Systematic Review and Meta-Analysis.

OBJECTIVES: Endostar (recombinant human endostatin (rh-endostatin)), a 20-kDa proteolytic fragment of collagen XVIII, was approved for the treatment of non-small cell lung cancer (NSCLC). Recently, several studies have evaluated the efficacy of rh-endostatin combined with chemotherapy in the treatment of bone and soft tissue sarcomas. Here, we conducted a systematic review and meta-analysis to assess available evidence. Methods: Pubmed, Embase, Web of Sciences, the Cochrane Library and two Chinese literature databases (CNKI, WanFang) were systematically searched till May 20, 2018. Randomized controlled trials (RCTs) and cohort studies which compared the outcomes of rh-endostatin combined with chemotherapy versus chemotherapy alone for treating bone sarcomas or soft tissue sarcomas were included. The primary outcome was overall survival rate (OSR). Secondary outcomes included objectiveremissionrate(ORR), clinical benefit rate (CBR), disease control rate (DCR), distant metastasis rate (DMR) and adverse effects (AEs). The methodological quality of the included studies was evaluated. Data analysis was performed by Revman 5.3 software. Results: 9 studies comprising 839 patients were included. The pooled results indicated that, compared with chemotherapeutic agents alone, rh-endostatin combined group had a significant benefit in 1-year and 2-year OSR. However, there were no difference between 5-year OSR. OR, CBR and DMR were higher in rh-endostatin combined group. No significant difference was observed in the incidence of AEs. Conclusions: Rh-endostatin combined chemotherapeutic agents significantly improved clinical efficacy compared with chemotherapeutic agents alone in treating bone and soft tissue sarcomas. Moreover, combination of rh-endostatin with chemotherapy didn't increase the incidence of AEs. But more high quality RCTs with  large  sample  size  should  be  done  in  the  future  to confirm the conclusion.

Effects of Canagliflozin on Fatty Liver Indexes in Patients with Type 2 Diabetes: A Meta-analysis of Randomized Controlled Trials.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) affects about 75% of patients with type 2 diabetes mellitus (T2DM). We conducted a meta-analysis to determine the effect of canagliflozin on fatty liver indexes in T2DM patients. METHODS: A literature search of PubMed, Embase and Cochrane was conducted up to March 30, 2017. The liver function test and lipid profile were extracted from randomized controlled trials (RCTs) to evaluate the effect of canagliflozin on fatty liver. Weighted mean differences (WMDs) or relative risks and 95% confidence intervals (CIs) were computed by using either fixed or random-effects models. Sensitivity analysis and publication bias were evaluated. RESULTS: Our results showed that canagliflozin decreased serum concentrations of  alanine amino transferase (WMD: -11.68 [95% CI: -18.95, -10.95]; P<0.001), aspartate amino transferase (WMD: -7.50 [95% CI: -10.61, -4.38]; P<0.001), gamma-glutamyl transferase (WMD: -15.17 [95% CI: -17.73, -12.61]; P<0.001), triglycerides (WMD: -0.10 [95% CI: -0.15, -0.05]; P<0.001) but increased low-density lipoprotein cholesterol (WMD: 0.1 [95% CI: 0.06, 0.13]; P<0.001), high-density lipoprotein cholesterol (WMD: 0.06 [95% CI: 0.05, 0.07]; P<0.001) at week 26 or 52. CONCLUSIONS: Our results indicated that canagliflozin may have a protective effect on fatty liver in T2DM patients. The limitation was that the liver biopsy was hard to obtain in published studies. More RCTs specified on NAFLD are needed to get further information. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Effectiveness of Pharmacist-led Anticoagulation Management on Clinical Outcomes: A Systematic Review and Meta-Analysis.

OBJECTIVES: We performed this systematic review and meta-analysis to confirm whether patients benefit more from pharmacist-led anticoagulation management than other models. METHODS: We searched PubMed, Embase, Cochrane Library and reference lists of yielded results conducted up to April 25, 2017. RCTs and observational cohort studies and case-control studies which compared the percentage of time within the target therapeutic range (TTR), the percentage of time within the expanded therapeutic range (TER), haemorrhage events, thrombosis events, mortality, patient satisfaction and/or medicine cost saving of pharmacist-led anticoagulation management with other models, and species were limited to humans. Two investigators evaluated methodology and extracted data from included studies independently. Data analysis were performed by STATA 12.0 software and quality of evidence assessment was performed by GRADEprofiler software. RESULTS: 8 RCTs and 9 observational cohort studies with 9919 patients were included eventually with high quality and no publication bias. In RCTs pooled results, TTR (p=0.548 moderate-quality), TER (p=0.285, moderate-quality), total haemorrhage events (p=0.140, low-quality), minor haemorrhage events (p=0.162, low-quality), major haemorrhage events (p=0.237, low-quality), thrombosis events (p=0.615, low-quality) and mortality (p=0.876, low-quality) was not significant between two groups. In observational studies pooled results, TTR (p=0.000, low-quality) was significant higher in pharmacist-led management group and the risk of total haemorrhage events (p=0.000, moderate-quality), minor haemorrhage events (p=0.000, moderate-quality) and thrombosis events (p=0.000, moderate-quality) were significant lower in pharmacist-led management group. Patient satisfaction and medicine cost saving were descriptively reviewed. CONCLUSIONS: According to the grading of evidence, we concluded that the risk of total haemorrhage events, minor haemorrhage events and thrombosis events significantly decreased in pharmacist-led anticoagulation management group compared with other management models and no significant difference in TTR, TER, major haemorrhage events and mortality between two groups. Longer follow-up period RCT studies with large sample size should be done in the future to confirm effectiveness of pharmacist-led anticoagulation management model. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Reduced peripheral blood mtDNA content is associated with impaired glucose-stimulated islet ß cell function in a Chinese population with different degrees of glucose tolerance.

AIMS: Our aim is to explore the associations between mitochondrial DNA (mtDNA) content and basal plasma glucose, plasma glucose after oral glucose administration and oxidative stress in a Chinese population with different levels of glucose tolerance. We also aimed to investigate the effect of mtDNA content on basal and oral glucose-stimulated insulin secretion. METHODS: Five hundred and fifty-six Chinese subjects underwent a 75-g, 2-h oral glucose tolerance test. Subjects with diabetes (n = 159), pre-diabetes (n = 197) and normal glucose tolerance (n = 200) were screened. Blood lipid profile was assessed, and levels of the oxidative stress indicators superoxide dismutase, glutathione reductase (GR) and 8-oxo-2'-deoxyguanosine (8-oxo-dG) were measured. Levels of HbA1c , plasma glucose, insulin and C-peptide were also determined. Measurements were taken at 0, 30, 60 and 120 min after 75 g oral glucose tolerance test. Peripheral blood mtDNA content was assessed using a real-time polymerase chain reaction assay. Insulin sensitivity was evaluated by homeostatic model assessment of insulin resistance and Matsuda index (ISIM ). Basal insulin secretion index (HOMA-ß), early phase disposition index (DI30 ) and total phase disposition index (DI120 ) indicate insulin levels at different phases of insulin secretion. RESULTS: Peripheral blood mtDNA content was positively associated with DI30 and DI120 and was negatively associated with plasma glucose measured 30, 60 and 120 min after oral glucose administration. However, there was no correlation between mtDNA content and basal insulin secretion (HOMA-ß), serum lipid or oxidative stress indicators (8-oxo-dG, superoxide dismutase, GR). HbA1c was negatively associated with GR (r = -0.136, p = 0.001). Multiple linear regression analysis showed that reduced peripheral blood mtDNA content increased the risk of impaired glucose-stimulated ß cell function (DI30 : ß = 0.104, p = 0.019; DI120 : ß = 0.116, p = 0.009). CONCLUSIONS: Decreased peripheral blood mtDNA content was more closely associated with glucose-stimulated insulin secretion than with basal secretion. Reduction in glucose-stimulated insulin secretion causes postprandial hyperglycaemia. The oxidative stress was probably largely influenced by hyperglycaemia; it was probably that the decreased mt DNA content led to hyperglycaemia, which caused elevated oxidative stress. © 2016 The Authors. Diabetes/Metabolism Research and Reviews Published by John Wiley & Sons Ltd.

Evaluation Outcomes Associated with Alternative Dosing Strategies for Piperacillin/Tazobactam: A Systematic Review and Meta-Analysis.

A better dosing strategy can improve clinical outcomes for patients. We systematically reviewed the literatures to determine whether any clinical benefits exist for piperacillin/tazobactam by extended or continuous infusion. Methods - A search of PubMed, Web of Science, ProQuest, ScienceDirect, Cochrane, Embase and related ICAAC and ACCP conferences were conducted up to September 5, 2015. Randomized controlled and observational studies that compared extended or continuous infusion with conventional intermittent infusion of piperacillin/tazobactam were identified from the databases above and analyzed. Two reviewers independently evaluated the methodology and extracted data from primary studies. A meta-analysis was performed using Revman 5.2 software. The quality of each study was assessed. Sensitivity analysis and publication bias were evaluated. Results - Three randomized controlled trials and twelve observational studies were included in this study. All included studies had high quality and no publication bias was found. Compared to the conventional intermittent infusion approach, the extended or continuous infusion group had a significant cost effectiveness (OR -0.89.02, CI (-114.69,-63.35), P<0.00001). No statistical difference was observed for clinical cure rate (OR 1.64, 95% CI (0.88, 3.30), P=0.12) between the two dosing regimens. The sensitivity analysis showed the results were stable. Conclusions - Our systematic review and meta-analysis found that the outcomes associated with alternative dosing strategies of piperacillin/tazobactam have changed compared with conclusions before for several literatures with large samples published. Further data on the outcomes should be generated for a better understanding of the extended or continuous infusion strategy. On the whole, our meta-analysis suggested that the extended or continuous infusion should be recommended for clinical use only considering its economic advantage, but there was no significantly higher clinical cure rate and lower mortality rate compared with the conventional intermittent infusion. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Influence of diet on leukocyte telomere length, markers of inflammation and oxidative stress in individuals with varied glucose tolerance: a Chinese population study.

OBJECTIVES: To explore influence of carbohydrates/fat proportions, dietary ingredients on telomere length shortening, oxidative stress and inflammation in a Chinese population with different glucose tolerance status. METHODS: Five hundred and fifty-six Chinese subjects without diabetes history underwent a 75 g, 2 h Oral Glucose Tolerance Test (OGTT). Subjects with diabetes (n = 159), pre-diabetes (n = 197), and normal glucose tolerance (n = 200) were screened. Dietary intakes were evaluated using a semi-quantitative food frequency questionnaire (FFQ). Peripheral blood leukocyte telomere length (LTL) was assessed using a real-time PCR assay. Blood lipid profile, levels of the oxidative stress indicators superoxide dismutase (SOD), glutathione reductase (GR), 8-oxo-2'-deoxyguanosine (8-oxo-dG) and inflammation indicators tumor necrosis factor (TNF-ɑ), interleukine-6 (IL-6) were measured. Levels of HbA1c, plasma glucose, insulin, and C peptide were also determined. Measurements were taken at 0 min, 30 min, 60 min, and 120 min after 75 g OGTT. Insulin sensitivity was evaluated by HOMA-IR. Basal insulin secretion index (HOMA-ß), early phase disposition index (DI30) and total phase disposition index (DI120) indicate insulin levels at different phases of insulin secretion. RESULTS: In patients with newly diagnosed diabetes, LTL adjusted by age was longer in HbA1c < 7 % group (log (LTL):1.93 ± 0.25) than in HbA1c ≥ 7 % group (log (LTL):1.82 ± 0.29). LTL was not associated with daily energy intake, diet fat, carbohydrates and protein proportions. Multiple linear regression analysis indicated that legumes, nuts, fish and seaweeds were protective factors for LTL shortening, and sweetened carbonated beverage was a risk factor for LTL shortening ( legumes: ß = 0.105, p = 0.018; nuts: ß = 0.110, p = 0.011; fish: ß = 0.118, p = 0.007; seaweeds: ß = 0.116, p = 0.009; sweetened carbonated beverage: ß = -0.120, p = 0.004 ). Daily energy intake was positively associated with TNF-ɑ, IL-6 (TNF-ɑ: r = 0.125, p = 0.006;IL-6: r = 0.092, p =0.04). Fat, carbohydrate proportions were positively associated with TNF-ɑ (fat: r = 0.119, p = 0.008 ; carbohydrate: r = 0.094, p = 0.043). Seaweeds and dairy intake were negatively associated with 8-oxo-dG (seaweed: r = -0.496, p = 0.001;dairy: r = -0.246, p = 0.046 ), vegetables and fruits were positively associated with GR ( vegetables: r = 0.101, p = 0.034;fruits: r = 0.125, p = 0.045). Cereal, meat were positively associated with TNF-ɑ ( cereal: r = 0.091, p = 0.048 ; meat: r = 0.405, p = 0.009). CONCLUSION: Diabetes patients with better plasma glucose (HbA1c < 7 %) had longer LTL, LTL could reflect plasma glucose status in diabetes patients. LTL were probably not influenced by diet carbohydrates/fat proportions but was associated with diet ingredients. Diet ingredients significantly impacted on markers of inflammation and oxidative stress, which probably had an effect on LTL.

The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio as a predictor of insulin resistance but not of ß cell function in a Chinese population with different glucose tolerance status.

BACKGROUND: Triglyceride/high-density lipoprotein-cholesterol (TG/HDL-C) ratio was a surrogate marker of IR; however, the relationship of TG/HDL-C with IR might vary by ethnicity. This study aims to investigate whether lipid ratios-TG/HDL-C, cholesterol/high-density lipoprotein-cholesterol (TC/HDL-C) ratio, low-density lipoprotein-cholesterol/high-density lipoprotein-cholesterol (LDL-C/HDL-C)) could be potential clinical markers of insulin resistance (IR) and ß cell function and further to explore the optimal cut-offs in a Chinese population with different levels of glucose tolerance. METHODS: Four hundred seventy-nine subjects without a history of diabetes underwent a 75 g 2 h Oral Glucose Tolerance Test (OGTT). New-onset diabetes (n = 101), pre-diabetes (n = 186), and normal glucose tolerance (n = 192) were screened. IR was defined by HOMA-IR > 2.69. Based on indices (HOMA-ß, early-phase disposition index [DI30], (ΔIns30/ΔGlu30)/HOMA-IR and total-phase index [DI120]) that indicated different phases of insulin secretion, the subjects were divided into two groups, and the lower group was defined as having inadequate ß cell compensation. Logistic regression models and accurate estimates of the areas under receiver operating characteristic curves (AUROC) were obtained. RESULTS: In all of the subjects, TG/HDL, TC/HDL-C, LDL-C/HDL-C, and TG were significantly associated with IR. The AUROCs of TG/HDL-C and TG were 0.71 (95 % CI: 0.66-0.75) and 0.71 (95 % CI: 0.65-0.75), respectively. The optimal cut-offs of TG/HDL-C and TG for IR diagnosis were 1.11 and 1.33 mmol/L, respectively. The AUROCs of TC/HDL-C and LDL-C/HDL-C were 0.66 and 0.65, respectively, but they were not acceptable for IR diagnosis. TG/HDL-C,LDL-C/HDL-C and TG were significantly associated with HOMA-ß, but AUROCs were less than 0.50; therefore, the lipid ratios could not be predictors of basal ß cell dysfunction. None of the lipid ratios was associated with early-phase insulin secretion. Only TG/HDL-C and TG were significantly correlated with total-phase insulin secretion, but they also were not acceptable predictors of total-phase insulin secretion (0.60 < AUROC < 0.70). CONCLUSIONS: In a Chinese population with different levels of glucose tolerance, TG/HDL-C and TG could be the predictors of IR. The lipid ratios could not be reliable makers of ß cell function in the population.

Inhibiting protein arginine deiminases has antioxidant consequences.

Ulcerative colitis is a dynamic, idiopathic, chronic inflammatory condition that carries a high colon cancer risk. We previously showed that Cl-amidine, a small-molecule inhibitor of the protein arginine deiminases, suppresses colitis in mice. Because colitis is defined as inflammation of the colon associated with infiltration of white blood cells that release free radicals and citrullination is an inflammation-dependent process, we asked whether Cl-amidine has antioxidant properties. Here we show that colitis induced with azoxymethane via intraperitoneal injection + 2% dextran sulfate sodium in the drinking water is suppressed by Cl-amidine (also given in the drinking water). Inducible nitric oxide synthase, an inflammatory marker, was also downregulated in macrophages by Cl-amidine. Because epithelial cell DNA damage associated with colitis is at least in part a result of an oxidative burst from overactive leukocytes, we tested the hypothesis that Cl-amidine can inhibit leukocyte activation, as well as subsequent target epithelial cell DNA damage in vitro and in vivo. Results are consistent with this hypothesis, and because DNA damage is a procancerous mechanism, our data predict that Cl-amidine will not only suppress colitis, but we hypothesize that it may prevent colon cancer associated with colitis.

Activation of IK1 channel by zacopride attenuates left ventricular remodeling in rats with myocardial infarction.

Activating IK1 channels is considered to be a promising antiarrhythmic strategy. Zacopride has been identified as a selective IK1 channel agonist and can suppress triggered arrhythmias. Whether this drug also exerts a beneficial effect on cardiac remodeling is unknown, and the present study sought to address this question. Cardiac remodeling was induced through coronary ligation-induced myocardial infarction (MI) in male Sprague-Dawley rats. Zacopride (15 µg/kg) was administered (intraperitoneally) daily for 28 days after MI to determine whether it could attenuate MI-induced cardiac remodeling. A 4-week treatment with zacopride attenuated post-MI cardiac remodeling, as shown by the reduced left ventricular end-diastolic dimension and left ventricular end-systolic dimension and the increased ejection fraction and fractional shortening in zacopride-treated animals compared with animals treated with vehicle (all P < 0.05). Furthermore, zacopride significantly decreased myocardial collagen deposition, cardiomyocyte hypertrophy, the plasma level of brain natriuretic peptide, and cardiomyocyte ultrastructural injury. Zacopride also upregulated the expression of the IK1 channel protein and downregulated the expression of phosphorylated p70S6 kinase (p-p70S6K) and mTOR. These beneficial effects of zacopride were partially abolished by the IK1 channel blocker chloroquine. We conclude that the activation of IK1 channel by zacopride attenuates post-MI cardiac remodeling by suppressing mTOR-p70S6 kinase signaling.

A denoising method based on deep learning for proton radiograph using energy resolved dose function.

Objective.Proton radiograph has been broadly applied in proton radiotherapy which is affected by scattered protons which result in the lower spatial resolution of proton radiographs than that of x-ray images. Traditional image denoising method may lead to the change of water equivalent path length (WEPL) resulting in the lower WEPL measurement accuracy. In this study, we proposed a new denoising method of proton radiographs based on energy resolved dose function curves.Approach.Firstly, the corresponding relationship between the distortion of WEPL characteristic curve, and energy and proportion of scattered protons was established. Then, to improve the accuracy of proton radiographs, deep learning technique was used to remove scattered protons and correct deviated WEPL values. Experiments on a calibration phantom to prove the effectiveness and feasibility of this method were performed. In addition, an anthropomorphic head phantom was selected to demonstrate the clinical relevance of this technology and the denoising effect was analyzed.Main results.The curves of WEPL profiles of proton radiographs became smoother and deviated WEPL values were corrected. For the calibration phantom proton radiograph, the average absolute error of WEPL values decreased from 2.23 to 1.72, the mean percentage difference of all materials of relative stopping power decreased from 1.24 to 0.39, and the average relative WEPL corrected due to the denoising process was 1.06%. In addition, WEPL values correcting were also observed on the proton radiograph for anthropomorphic head phantom due to this denoising process.Significance.The experiments showed that this new method was effective for proton radiograph denoising and had greater advantages than end-to-end image denoising methods, laying the foundation for the implementation of precise proton radiotherapy.

Analysis of new-onset seizures following use of COVID-19 vaccinations in children based on VAERS.

BACKGROUND: Recently, there have been some reports of seizures related with COVID-19 vaccinations. However, no studies have systematically investigated the relationship between seizures and various COVID-19 vaccines. RESEARCH DESIGN AND METHODS: This research aimed to analyze the characteristics and risk signals of new-onset seizures in children caused by various COVID-19 vaccines based on the data of the Vaccine Adverse Event Reporting System (VAERS). To identify potential risk signals, a disproportionality analysis was conducted. The reporting odds ratio (ROR) and the Proportional Reporting Ratio (PRR) were used to detect signals. RESULTS: A total of 695 children with new-onset seizures events associated with COVID-19 vaccinations were retrieved from the VAERS database. Compared with influenza vaccinations, the percentage and rate of COVID-19 vaccinations related seizures was all reduced. The median onset time of seizures was 1 day after COVID-19 vaccines. No signal was detected for an association between the COVID-19 vaccines and new-onset seizures, neither when compared with influenza vaccines nor with non-COVID-19 vaccines. CONCLUSION: No statistically significant risk signal of COVID-19 vaccine-related seizures was found in this study. However, it is still necessary to monitor the possibility of new-onset seizures when children are immunized with COVID-19 vaccines.

Development of a Risk Prediction Model for Infection After Kidney Transplantation Transmitted from Bacterial Contaminated Preservation Solution.

Background: The risk of transplant recipient infection is unknown when the preservation solution culture is positive. Methods: We developed a prediction model to evaluate the infection in kidney transplant recipients within microbial contaminated preservation solution. Univariate logistic regression was utilized to identify risk factors for infection. Both stepwise selection with Akaike information criterion (AIC) was used to identify variables for multivariate logistic regression. Selected variables were incorporated in the nomograms to predict the probability of infection for kidney transplant recipients with microbial contaminated preservation solution. Results: Age, preoperative creatinine, ESKAPE, PCT, hemofiltration, and sirolimus had a strongest association with infection risk, and a nomogram was established with an AUC value of 0.72 (95% confidence interval, 0.64-0.80) and Brier index 0.20 (95% confidence interval, 0.18-0.23). Finally, we found that when the infection probability was between 20% and 80%, the model oriented antibiotic strategy should have higher net benefits than the default strategy using decision curve analysis. Conclusion: Our study developed and validated a risk prediction model for evaluating the infection of microbial contaminated preservation solutions in kidney transplant recipients and demonstrated good net benefits when the total infection probability was between 20% and 80%.