A meta-analysis of the efficacy of programmed cell death 1/its ligand inhibitors plus cytotoxic T-lymphocyte-associated antigen 4 inhibitors in non-small cell lung cancer.

Background: Immune checkpoint inhibitors (ICIs), either as monotherapy or in combination with chemotherapy, have improved the therapeutic outcome for non-small cell lung cancer (NSCLC). However, the efficacy of combination therapies, such as programmed cell death 1(PD-1)/its ligand (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors, in targeting different pathways remains unclear. We performed a meta-analysis to determine whether the addition of a CTLA-4 inhibitor to PD-1/PD-L1 therapy improves the efficacy of PD-1/PD-L1 monotherapy in NSCLC. Methods: We systematically searched various electronic databases for suitable trials. Only randomized controlled trials (RCTs) comparing the clinical efficacy of PD-1/PD-L1 with and without CTLA-4 were included in the analyses. The meta-analysis software RevMan 5.3 was used for statistical analyses. Results: A total of seven RCTs were retrieved. The results suggested that the combination of CTLA-4 and PD-1/PDL-1 inhibitors did not show enhanced efficacy over PD1/PDL-1 inhibitor monotherapy as determined by overall survival (OS) (HR = 0.98, 95% CI = 0.84-1.14, p = 0.79), progression-free survival (PFS) (HR = 0.92, 95% CI = 0.81-1.06, p = 0.25), and objective response rate (ORR) (HR = 1.08, 95% CI = 0.96-1.21, p = 0.19). Furthermore, the combination immunotherapy was associated increased toxicity as evidenced by increased incidence of any type adverse events (AEs) (RR = 1.06, 95% CI = 1.00-1.13, p = 0.03), grade ≥3 immune-mediated AEs (RR = 1.58, 95% CI = 1.36-1.82, p < 0.05), and treatment discontinuation (RR = 1.83, 95% CI = 1.46-2.28, p < 0.05). Conclusion: Combining anti-CTLA-4 with anti-PD-1/PD-L1 therapy did not improve the therapeutic efficacy, and was associated with greater toxicity than anti-PD-1/PD-L1 monotherapy in patients with advanced NSCLC. Further investigation of the combination immunotherapy in specific subsets of patients is warranted to identify and define the patient-specific benefits of this combination. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023435399.

Head-to-head comparison of azvudine and nirmatrelvir/ritonavir for the hospitalized patients with COVID-19: a real-world retrospective cohort study with propensity score matching.

Background: Nirmatrelvir/ritonavir and azvudine have been approved for the early treatment of COVID-19 in China, however, limited real-world data exists regarding their effectiveness and safety. Methods: We conducted a retrospective cohort study involving the hospitalized COVID-19 patients in China between December 2022 and January 2023. Demographic, clinical, and safety variables were recorded. Results: Among the 6,616 hospitalized COVID-19 patients, we included a total of 725 patients including azvudine recipients (N = 461) and nirmatrelvir/ritonavir (N = 264) recipients after exclusions and propensity score matching (1:2). There was no significant difference in the composite disease progression events between azvudine (98, 21.26%) and nirmatrelvir/ritonavir (72, 27.27%) groups (p = 0.066). Azvudine was associated with a significant reduction in secondary outcomes, including the percentage of intensive care unit admission (p = 0.038) and the need for invasive mechanical ventilation (p = 0.035), while the in-hospital death event did not significantly differ (p = 0.991). As for safety outcomes, 33 out of 461 patients (7.16%) in azvudine group and 22 out of 264 patients (8.33%) in nirmatrelvir/ritonavir group experienced drug-related adverse events between the day of admission (p = 0.565). Conclusion: In our real-world setting, azvudine treatment demonstrated similar safety compared to nirmatrelvir/ritonavir in hospitalized COVID-19 patients. Additionally, it showed slightly better clinical benefits in this population. However, further confirmation through additional clinical trials is necessary.

Cost-effectiveness of empagliflozin for the treatment of heart failure: a systematic review.

Objective: This study aims to synthesize evidence on the cost-effectiveness of empagliflozin for heart failure (HF). Methods: MEDLINE, Embase, the Cochrane Library, EconLit, CNKI, Wanfang Data and Chongqing VIP were searched to identify original articles on cost-effectiveness of empagliflozin for HF, and literature surveillance ended on 20 November 2022. The reporting quality of the included articles was determined using the Consolidated Health Economic Evaluation Reporting Standards statement. Results: Of 97 articles identified, 11 studies published from 2020 to 2022 met the inclusion criteria, and the overall quality was accepted. The studies were conducted in 8 countries (China, Japan, Korea, Singapore, Thailand, Australia, United States, and United Kingdom). This body of evidence suggested that add-on empagliflozin was cost effective for HF with reduced ejection fraction (HFrEF) patients compared to standard of care alone in all the related studies including China, Japan, Korea, Singapore, Thailand, and Australia. For HF with preserved ejection fraction (HFpEF) patients, add-on empagliflozin was cost effective in China and Australia, but not in United States and Thailand. For HF with diabetes, add-on empagliflozin was cost effective in United Kingdom. Moreover, the incremental cost-effectiveness ratios (ICER) were lower for patients with diabetes than without in subgroup analysis. In the uncertainty analysis of all included studies, the ICERs were most sensitive to the cost of empagliflozin and cardiovascular mortality, followed by the cost of the standard treatment, hazard ratio of HF hospitalization. Conclusion: add-on empagliflozin for HFrEF might be cost-effective or dominant compared with standard of care alone. However, for HFpEF patients, add-on empagliflozin might be cost-effective in China and Australian, but not cost-effective in United States and Thailand.

Peripherally inserted central catheters versus implantable port catheters for cancer patients: a meta-analysis.

Background: The implanted vascular access ports (PORTs) were compared with peripherally inserted central catheters (PICCs) as the administration of chemotherapy regarding different clinical effects and adverse effects. Which is better is debatable. Hence, the current study was conducted to assess the safety and efficacy of these two optimal vascular access strategies. Methods: The following electronic databases were searched: PubMed, Embase, and the Cochrane Library updated in May 2023. Studies on the differences in complication rates in patients with cancer using either PICC or PORT for chemotherapy were included. Meta-analysis Revman 5.3 software was used for statistical analysis. Results: A total of 22 articles were retrieved. The results suggested that PORT has a superior safety profile, with lower incidences of overall adverse effects (OR=2.72, 95% CI=1.56-4.72 P=0.0004), catheter-related thrombosis (OR=2.84, 95% CI=1.97-4.11, P<0.00001), and allergic reactions (OR=6.26, 95% CI=1.86-21.09, P=0.003) than typically expected with PICC. Moreover, PICC was non-inferior to the PORT group with respect to DVT (OR=2.00, 95% CI=0.86-4.65, P=0.11) and infection (OR=1.55, 95% CI=0.75-3.22, P=0.24). Conclusion: PORT achieved safety benefits compared with chemotherapy through PICC. Therefore, PORT is regarded as safe and effective vascular access for the administration of chemotherapy. When considering economic factors and some key elements, more high-quality research would help verify these clinical benefits. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identififier CRD42023421690.

Controlled synthesis of monodisperse gold nanorods with a small diameter of around 10 nm and largest plasmon wavelength of 1200 nm.

Gold nanorods have been widely used in various fields due to their tunable anisotropic localized surface plasmon resonance (SPR) property. The facile preparation of gold nanorods with a tunable SPR wavelength extending to a near-infrared window, and at the same time, a relatively small particle size for facilitating applications especially in the biomedical field is of great value yet highly challenging. In this work, a new reducing agent, 1,6-dihydroxynaphthalene, is proposed for the synthesis of gold nanorods. The results indicate that gold nanorods with good monodispersity, high shape yield, maximum SPR wavelength of 1200 nm, and especially small diameter of around 10 nm can be acquired simultaneously. In terms of spectral and size controls, by respectively varying the experimental parameters including the amount of silver ions, reducing agents, and gold seeds not only can a good linear correlation be acquired corresponding to a SPR wavelength ranging from around 600 nm to 1200 nm, but a regular change in the particle diameter from 10.5 nm to 7.5 nm could also be observed. The structural and morphological evolutions of the particle for each changed parameter were carefully studied, and insights were gained into the growth mechanism based on the detailed analysis of particle evolution at a specific stage of the growth process.

Association between immune-related adverse events and immunotherapy efficacy in non-small-cell lung cancer: a meta-analysis.

Objective: Our study aimed to identify potential correlations between anti-tumor efficacy and immune-related adverse events (irAEs) in non-small-cell lung cancer (NSCLC). Methods: We conducted a comprehensive search of online electronic databases up to March 2023 to identify any correlations between irAEs and immune checkpoint inhibitor (ICI) efficacy in NSCLC. We used meta-analysis RevMan 5.3 software to calculate pooled results. Results: Our meta-analysis of 54 studies revealed that patients who experienced irAEs achieved a significantly higher objective response rate (p < 0.00001) and longer progression-free survival (PFS) (p < 0.00001) and overall survival (OS) (p < 0.00001) than those who did not experience irAEs. Additionally, patients with ≥2 irAEs had better PFS, whereas no significant difference was observed between patients with or without squamous cell carcinoma. Subgroup analysis of irAE types indicated that irAEs (thyroid dysfunction and gastrointestinal, skin, or endocrine irAEs) were associated with better PFS and OS. However, no significant differences were observed between patients with pneumonitis or hepatobiliary irAEs. Conclusion: Our study showed that the occurrence of irAEs was a strong predictor of survival efficacy in patients with NSCLC treated with ICIs. Specifically, patients with ≥2 irAEs and those with thyroid dysfunction and gastrointestinal, skin, or endocrine irAEs achieved a better survival benefit. Systematic Review Registration: Website: https://www.crd.york.ac.uk/prospero/, Identifier: CRD42023421690.

Clinical, economic and humanistic outcomes of medication therapy management services: A systematic review and meta-analysis.

Background: Medication therapy management (MTM) services is a method that can effectively improve patients' conditions, but the efficacy of economic and humanistic outcomes remain unclear. This systematic review and meta-analysis aim to use economic, clinical and humanistic outcomes to evaluate the multi-benefits of MTM services. Method: A systematic review and meta-analysis was conducted by retrieving PubMed, EMBASE, the Cochrane Library and ClinicalTrial.gov from the inception to April 2022. There were two reviewers screening the records, extracting the data, and assessing the quality of studies independently. Results: A total of 81 studies with 60,753 participants were included. MTM services were more effective in clinical outcomes with decreasing the rate of readmission (OR: 0.78; 95% CI: 0.73 to 0.83; I2 = 56%), emergency department visit (OR: 0.88; 95% CI: 0.81 to 0.96; I2 = 32%), adverse drug events (All-cause: OR: 0.68; 95% CI: 0.56 to 0.84; I2 = 61%; SAE: OR: 0.51; 95% CI: 0.33 to 0.79; I2 = 35%) and drug-related problems (MD: -1.37; 95% CI: -2.24 to -0.5; I2 = 95%), reducing the length of stay in hospital (MD: -0.74; 95% CI: -1.37 to -0.13; I2 = 70%), while the economic and humanistic outcomes were less effective. Conclusion: Our systematic review and meta-analysis demonstrated that MTM services had great ability to improve patients' clinical conditions while the efficacy of economic and humanistic outcomes, with some of the outcomes showing high degree of heterogeneity and possible publication bias, required more future studies to provide stronger evidence. Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=349050], identifier [CRD42022349050].

Spectrum and size controllable synthesis of high-quality gold nanorods using 1,7-dihydroxynaphthalene as a reducing agent.

The spectrum and size controllable synthesis of gold nanorods is of great value for their widely applicable aspect ratio dependence of anisotropic surface plasmon resonance. Herein, 1,7-dihydroxynaphthalene with a relatively strong reducibility is proposed as a reducing agent for the controllable synthesis of gold nanorods. The result indicated that gold nanorods with high monodispersity, high shape yield, relatively small diameters, and maximum plasmon resonance wavelength of above 1000 nm can be acquired. More importantly, by virtue of the reducing agent used, fine and precise controls over the plasmon wavelength and diameter of the rod can be achieved via changes in experimental conditions. In particular, increases in the concentration of both silver ions and cetyltrimethylammonium bromide (CTAB) can increase the plasmon wavelength from around 600 nm to 1000 nm but respectively show a decreased diameter with the smallest value of around 14.3 nm and a mildly increased diameter from around 9.0 nm to 14.3 nm; moreover, increasing the concentration of reducing agents and gold seeds can simultaneously cause decreases in the plasmon wavelength from around 1000 nm to 800 nm and the diameters from around 14.3 nm to 9.0 and 7.3 nm, respectively. This powerful and efficient method of controllable synthesis of AuNRs could be valuable and attractive for the application of the as-obtained particles.

Multiple beneficial outcomes of medication therapy management interventions in randomized control trials and non-randomized control trials: A protocol for systematic review and meta-analysis.

BACKGROUND: Medication therapy management (MTM) service is an effective method to reduce medication-related problems and improve patients' multiple kinds of outcomes. However, the lack of comprehensive review for MTM services has hindered its development. As a result, we are aiming to evaluate the current benefits of MTM services with multiple outcomes. METHOD: An electronic search will be performed for randomized controlled trials (RCTs) or non-randomized control trials (NRCTs) that reported MTM services or pharmaceutical services as interventions from PubMed, The Cochrane Library, Embase, and ClinicalTrial. gov. The odds ratios, mean differences, and standard mean differences and their 95% confidence intervals (95% confidence intervals) will be calculated with fixed or random effect models. RESULTS: This study will evaluate the multiple benefits of MTM services in clinical endpoints, quality of life, economy, and drug-related problems. CONCLUSION: The results will review eligible studies released in the past twenty years and provide more comprehensive evidence of the efficacy of MTM services. ETHICS AND DISSEMINATION: Ethical approval is not applicable for this study.

Effect of drug combination on tacrolimus target dose in renal transplant patients with different CYP3A5 genotypes.

Various factors, including genetic polymorphisms, drug-drug interactions, and patient characteristics influence the blood concentrations of tacrolimus in renal transplant patients. In the present study, we established a population pharmacokinetic model to explore the effect of combined use of Wuzhi capsules/echinocandins and the patients' biochemical parameters such as haematocrit on blood concentrations and target doses of tacrolimus in renal transplant patients with different CYP3A5 genotypes. The aim of the study was to propose an individualised tacrolimus administration regimen for early renal transplant recipients.In this retrospective cohort study, we included 240 renal transplant recipients within 21 days of surgery (174 males and 66 females, mean age 39.4 years), who received tacrolimus alone (n = 54), in combination with Wuzhi capsules (99) or caspofungin (57) or micafungin (30). We collected demographic characteristics, clinical indicators, CYP3A5 genotypes, and 1950 steady-state concentrations of tacrolimus and included them in population pharmacokinetic model. An additional 110 renal transplant recipients and 625 steady-state concentrations of tacrolimus were included for external validation of the model. The population pharmacokinetic model was established and Monte Carlo was used to simulate probabilities for achieving the target concentration for individual tacrolimus administration.A two-compartment model of first-order absorption and elimination was developed to describe the population pharmacokinetics of tacrolimus. CYP3A5 genotypes and co-administration of Wuzhi capsules, as well as time after renal transplantation and haematocrit, were important factors affecting the clearance of tacrolimus. We found no obvious change in trend in the scatter plot of tacrolimus clearance rate vs. haematocrit. The Monte Carlo simulation indicated the following recommended doses of tacrolimus alone: 0.14 mg⋅kg-1⋅d-1 for genotype CYP3A5*1*1, 0.12 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.10 mg⋅kg-1⋅d-1 for CYP3A5*3*3. For patients receiving the combination with Wuzhi capsules, the recommended doses of tacrolimus were 0.10 mg⋅kg-1⋅d-1 for CYP3A5*1*1, 0.08 mg⋅kg-1⋅d-1 for CYP3A5*1*3, and 0.06 mg⋅kg-1⋅d-1 for CYP3A5*3*3 genotypes. Caspofungin or micafungin had no effect on the clearance of tacrolimus in renal transplant recipients.The population pharmacokinetics of tacrolimus in renal transplant patients was evaluated and the individual administration regimen of tacrolimus was simulated. For early kidney transplant recipients receiving tacrolimus treatment, not only body weight, but also CYP3A5 genotypes and drugs used in combination should be considered when determining the target dose of tacrolimus.

Apoptosis induced by DICO, a novel non-aromatic B-ring flavonoid via a ROS-dependent mechanism in human colon cancer cells.

5,7-Dihydroxy-2-(1,2-isopropyldioxy-4-oxo-cyclohex-5-enyl)-chromen-4-one (DICO) is a novel non-aromatic B-ring flavonoid, isolated mainly from Macrothelypteris viridifrons and has anti-tumour properties. In this study, we investigated the cytotoxicity and underlying biochemical pathways leading to cell death, in response to DICO treatment of a human colon cancer cell line HT-29. Our results indicated that DICO induced apoptosis by elevating the generation of reactive oxygen species, which could be quenched by the antioxidants N-acetyl cysteine. In addition, activation of signal transducer and activator of transcription 3 and suppression of nuclear factor kappa B played a crucial role in DICO-induced apoptosis. Overall, our results provide mechanistic insights into the apoptotic action of a potential anti-tumour drug, DICO.

Does Having a Usual Primary Care Provider Reduce Polypharmacy Behaviors of Patients With Chronic Disease? A Retrospective Study in Hubei Province, China.

Background: Within China's hierarchical medical system, many patients seek medical care in different hospitals independently without integrated management. As a result, multi-hospital visiting is associated with fragmented service utilization and increased incidence of polypharmacy behaviors, especially for patients with chronic disease. It has been confirmed that factors from the perspective of patients may cause polypharmacy behaviors in Chinese community patients; whether having a usual primary care provider for chronic disease patients could reduce the polypharmacy behaviors and the effect size remains unanswered, and that is what our study aimed to answer. Methods: Our study adopted a cluster sampling method to select 1,196 patients with hypertension or diabetes and measured some information about them. The propensity score weighting method was adopted to eliminate the influence of confounding bias, and then a multivariate logistic regression model was conducted to test the relationship between having a usual primary care provider and polypharmacy behaviors. Results: Patients without usual primary care providers were significantly correlated with polypharmacy behaviors (OR = 2.40, 95%CI: 1.74-3.32, p < 0.001), and the corresponding marginal effect is 0.09 (95%CI: 0.06-0.12). Patients who suffer from two kinds of diseases (OR = 3.05, 95%CI: 1.87-5.10, p < 0.001), with more than three kinds of diseases (OR = 21.03, 95%CI: 12.83-35.65, p < 0.001), with disease history of 20 years and above (OR = 1.66, 95%CI: 1.14-2.42, p = 0.008), who communicate frequently with doctors (OR = 3.14, 95%CI: 1.62-6.19, p < 0.001), alcoholic patients (OR = 2.14, 95%CI: 1.08-4.19, p = 0.027), who used to have meat-based food (OR = 1.42, 95%CI: 1.00-2.00, p = 0.049), and have vegetarian-based diet (OR = 1.42, 95%CI: 1.00-2.00, p = 0.049) are more likely to have polypharmacy behaviors, while patients aged between 65 and 75 years (OR = 0.50, 95%CI: 0.33-0.77, p = 0.020), used to be brain workers (OR = 0.67, 95%CI: 0.45-0.99, p = 0.048), with disease history between 10 and 20 years (OR = 0.56, 95%CI: 0.37-0.83, p = 0.005), have had adverse drug reactions (OR = 0.64, 95%CI: 0.45-0.93, p = 0.019), and participated in medical insurance for urban and rural residents (OR = 0.35, 95%CI: 0.21-0.58, p < 0.001) were less likely to have polypharmacy behaviors. Conclusion: The results suggest that having a usual primary care provider may reduce the incidence of having polypharmacy behaviors; we can take intervention measures to promote establishing a long-term relationship between patients and primary care providers.

Direct versus conventional anticoagulants for treatment of cancer associated thrombosis: a pooled and interaction analysis between observational studies and randomized clinical trials.

BACKGROUND: There are emerging observational studies (OSs) to assess real-world comparative effectiveness and safety of direct oral anticoagulants (DOACs) in cancer associated thrombosis (CAT). We conducted a pooled and interaction analysis to compare the treatment effect estimates of DOACs between OSs and randomized controlled trials (RCTs). METHODS: We systematically searched PUBMED, EMBASE and Cochrane Library for OSs and RCTs that reported recurrent venous thromboembolism (VTE) and/or major bleeding events in CAT patients receiving DOACs and conventional anticoagulants [warfarin or low molecular-weight heparins (LMWHs)]. Relative risks (RRs) for OSs and RCTs were calculated using random-effects models separately, and interaction analyses were afterward applied to assess the comparability between OSs and RCTs. RESULTS: Baseline characteristic was comparable between identified 10 OSs (35,142 patients) and 8 RCTs (2,602 patients). Overall, no significant difference of treatment effect estimates between OSs and RCTs was detected (Pinteraction: 0.42 for recurrent VTE; Pinteraction: 0.38 for major bleeding). DOACs significantly decreased the risk of recurrent VTE compared with conventional anticoagulants in CAT patients (RR: 0.74, 95% CI: 0.63-0.86, I2: 0% for OSs; RR: 0.65, 95% CI: 0.49-0.86; I2: 0% for RCTs), without increasing major bleeding risk (RR: 0.90, 95% CI: 0.76-1.07, I2: 24.0% for OSs; RR: 1.17, 95% CI: 0.72-1.88, I2: 26.2% for RCTs). Whereas, increased risk of gastrointestinal bleeding (GIB) was found with DOACs versus conventional anticoagulants in CAT patients (RR: 2.77, 95% CI: 1.35-5.68, I2: 0% for RCTs). Analyses of subgroups, based on comparators and follow-up duration, did not significantly affect results. CONCLUSIONS: In this study, effectiveness and safety of DOACs versus conventional anticoagulants in CAT from OSs are in agreement with those from RCTs, confirming a low risk of recurrent VTE and similar risk of major bleeding in CAT patients receiving DOACs.

Risk of Major Gastrointestinal Bleeding With New vs Conventional Oral Anticoagulants: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: There is controversy over whether use of non-vitamin K antagonist oral anticoagulants (NOACs) associates with increased risk of major gastrointestinal bleeding (GIB) compared with conventional therapies (such as vitamin K antagonists or anti-platelet agents). We performed a systematic review and meta-analysis of data from randomized controlled trials and high-quality real-world studies. METHODS: We performed a systematic search of the MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov Website databases (through Oct 12, 2018) for randomized controlled trials and high-quality real-world studies that reported major GIB events in patients given NOACs or conventional therapy. Relative risks (RRs) for randomized controlled trials and adjusted hazard ratios (aHRs) for real-world studies were calculated separately using random-effects models. RESULTS: We analyzed data from 43 randomized controlled trials (183,752 patients) and 41 real-world studies (1,879,428 patients). The pooled major rates of GIB for patients on NOACs (1.19%) vs conventional treatment (0.92%) did not differ significantly (RR from randomized controlled trials, 1.09; 95% CI, 0.91-1.31 and aHR from real-world studies, 1.02; 95% CI, 0.94-1.10; Pinteraction=.52). Rivaroxaban, but not other NOACs, was associated with an increased risk for major GIB (RR from randomized controlled trials, 1.39; 95% CI, 1.17-1.65 and aHR from real-world studies, 1.14; 95% CI, 1.04-1.23; Pinteraction = .06). Analyses of subgroups, such as patients with different indications, dosage, or follow-up time, did not significantly affect results. Meta-regression analysis failed to detect any potential confounding to impact the primacy outcome. CONCLUSIONS: In a systematic review and meta-analysis of data from randomized controlled trials and real-world studies, we confirmed that there is no significant difference in risk of major GIB between patients receiving NOACs vs conventional treatment. Rivaroxaban users had a 39% increase in risk for major GIB.

Net clinical benefit of non-vitamin K antagonist oral anticoagulants in atrial fibrillation and chronic kidney disease: a trade-off analysis from four phase III clinical trials.

BACKGROUND: Atrial fibrillation (AF) is quite prevalent in patient with chronic kidney disease (CKD). This study mainly investigated the net clinical benefit (NCB) property of non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with AF and CKD by a pooled-analysis. METHODS: A comprehensive search of Medline, Embase, Cochrane Library and Clinical Trials.gov Website was performed for eligible randomized controlled trials (RCTs) reporting the efficacy and safety outcomes according to renal function of NOACs. Pre-specified outcomes and their number of patients needed to treat (NNT), including stroke/systemic embolism (SSE), major bleeding, and all-cause death, were evaluated using a random-effects model. NCB that balanced SSE and major bleeding was calculated using Singer's method. RESULTS: Four phase III clinical trials including 70,952 patients were enrolled, 45,265 (64%) with CKD, and 25,687 (36%) without CKD; 41,942 (59%) taking NOACs and 29,010 (41%) taking warfarin. Risks of SSE [relative risk (RR): 0.80, 95% confidence interval (CI): 0.73-0.88, P<0.01], major bleeding (RR: 0.79, 95% CI: 0.66-0.96, P=0.017), and all-cause death (RR: 0.91, 95% CI: 0.84-0.99, P=0.031) were significantly lower in CKD patients with NOACs than those with warfarin, accompanying with a high absolute risk reduction (NNT: 182 for SSE; 122 for major bleeding; 196 for all-cause death). While NOACs were not superior to warfarin on SSE, major bleeding, and all-cause death in patients without CKD, the NCB of NOACs versus warfarin was progressively increased with the deterioration of renal function (NCB: 0.72 for no CKD, 1.59 for mild CKD, 2.74 for moderate CKD). Sensitivity analyses did not significantly affect the primacy results. CONCLUSIONS: NOACs, compared with warfarin, provide a better clinical profile on SSE, major bleeding, all-cause death, and NCB in CKD patients.

A network meta-analysis for safety of endothelin receptor antagonists in pulmonary arterial hypertension.

BACKGROUND: Currently, direct comparative safety between endothelin receptor antagonists (ERAs) in pulmonary arterial hypertension (PAH) is limited. Thus, a systematic review with network analysis was conducted. METHODS: An electronic search was performed for randomized controlled trials (RCTs) that reported the interested safety data (abnormal liver function, peripheral edema, and anemia) of ERAs in PAH. Risk ratios (RRs) with their confidence intervals (CIs) and the surface under the cumulative ranking curve (SUCRA) were calculated using a network analysis. RESULTS: Ten RCTs involving 2,288 patients were included. Compared with placebo, bosentan (RR, 2.93; 95% CI, 1.78-4.84) significantly increased the risk of abnormal liver function, ambrisentan (RR, 1.62; 95% CI, 1.23-2.13) significantly increased the risk of peripheral edema, and macitentan (RR, 3.42; 95% CI, 1.65-7.07) significantly increased the risk of anemia. SUCRA analysis suggested that bosentan 125 mg twice daily had the highest risk of abnormal liver function; ambrisentan 10 mg once daily had the highest risk of peripheral edema; macitentan 10 mg once daily had the highest risk of anemia. CONCLUSIONS: Abnormal liver function (bosentan), peripheral edema (ambrisentan), and anemia (macitentan) were the safety indicators of ERAs in patients with PAH. Different monitoring parameters should be considered for individual ERA.

Net clinical benefit analysis of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation and chronic kidney disease: Protocol for a systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is increasingly prevalent in chronic kidney disease (CKD) patients. The efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) in AF and CKD patients remains unknown. This systematic review and meta-analysis will mainly assess net clinical benefit (NCB) property of NOACs versus warfarin in patients with AF and CKD by a pooled-analysis. METHODS: We will search Medline, Embase, Cochrane Library, and Clinical Trials.gov Website comprehensively for eligible randomized controlled trials that report the efficacy and safety outcomes according to renal function of NOACs. Relative risks and their 95% confidence intervals will be calculated using fixed- and random-effects models. Subgroup, sensitivity, and regression analyses will be performed to evaluate intertrial heterogeneity and bias of the results. NCB that balance stroke/systemic embolism (SSE) and major bleeding will be calculated using Singer's method. RESULTS: This systemic review and meta-analysis will evaluate the NCB of NOACs versus warfarin via SSE, major bleeding and all-cause death in patients with CKD. CONCLUSIONS: This study will provide new evidence for clinical profile of NOACs on SSE, major bleeding, all-cause death, and NCB in CKD patients. PROSPERO REGISTRATION NUMBER: CRD42019116940.

HPLC analysis, optimization of extraction and purification conditions, biological evaluation of total protoflavones from Macrothelypteris viridifrons.

The present study aims to evaluate phytochemical and pharmacological potential of total protoflavones from Macrothelypteris viridifrons. In the phytochemical study, an HPLC analysis method was established, and the optimal extraction and purification conditions were analyzed. The extractive condition was optimized as follows: the backflow extraction with 20 folds of 70% ethanol at 80◦C for 1 h twice. Moreover, by combining the alkali-extraction and acid-precipitation method with the macroporous resin purification technology, the final purity rate of total protoflavones was no less than 54.85%. In the pharmacological study, the total protoflavones from M. viridifrons showed a significant tumor-inhibitory effect in the H22 hepatoma cells transplantation model with a higher inhibitory rate of 55.76% in high dosage (100mg/kg) treatment group compared with the positive control group (20 mg/kg cyclophosphamide). Taken of all, these results support that protoflavones are the material basis of M. viridifrons as an anticancer folk medicine.

Increased risk of myocardial infarction with dabigatran etexilate: fact or fiction? A critical meta-analysis of over 580,000 patients from integrating randomized controlled trials and real-world studies.

BACKGROUND: The question of whether the use of dabigatran etexilate is associated with a high risk of myocardial infarction (MI) remains unanswered owing to the lack of critical evidences. METHODS: A comprehensive search of databases (Medline, Embase, Cochrane Library databases, and ClinicalTrials.gov Website) was performed for RCTs that reported MI events and observational nationwide database studies that reported adjusted hazard ratio (HR) with dabigatran treatment. Summary HRs and 95% confidence intervals (95% CI) were calculated using random-effects models. Cumulative meta-analysis was conducted for evaluating the results as a continuum, and subgroup analyses were undertaken on the basis of study type, indication, controls, and dosage. RESULTS: Finally, 24 studies including 588,047 patients (44,856 patients in 14 RCTs and 543,191 patients in 10 observational database studies) met the inclusion criteria, among which 222,352 (37.8%) patients receiving dabigatran and 365,695 (62.2%) patients receiving placebo/other anticoagulants. In comparison to controls, no significant association was detected between the use of dabigatran and the higher risk of MI (HR: 0.97, 95% CI: 0.87-1.06; I2 for heterogeneity: 26.3%, P = 0.089). The results were consistent across the key subgroups (indication, controls, and dosage, Pinteraction > 0.05 for each), with the exception of study type (RCTs or database studies, Pinteraction = 0.046). Cumulative meta-analysis was not suggestive of a temporal trend in the effect of dabigatran on MI. CONCLUSIONS: This meta-analysis confirms a low risk of MI in patients exposed to dabigatran, which seems to be validated when pooling over 580,000 patients from RCTs and real-world studies.