Aims: Despite their overall favourable safety profile, the intraocular pressure increases after any routes of triamcinolone acetonide application are not rare. We designed a systematic review and network meta-analysis to compare risk of IOP elevation among TA for different routes of administration used by patients diagnosed with macular edema. Methods: We obtained data from the PubMed, MEDLINE, Embase, and Cochrane Library. We performed random-effects model and consistency model network meta-analyses to summarize the evidence. The Bayesian approach was used for direct and indirect comparisons, and the treatments were ranked by the surface under the cumulative ranking curve. The study was registered with PROSPERO, CRD42022366513 Results: Sixteen studies were included in the network meta-analysis. There was a significant difference in IOP between IVTA and STiTA (MD, 1.67 [95% CrI, 0.25, 3.15]) at the 12th week. At the 24th week, compared with the placebo group, IVTA, SCTA and STiTA had statistically significant effect on IOP (MD, 1.35 [95% CrI, 0.23, 2.30], 2.42 [95% CrI, 4.53, 0.19], and 1.31 [95% CrI, 2.49, 0.02]). The probabilities of rankings and SUCRA showed that IVTA and SCTA were generally considered the higher risk of IOP elevation than the other routes of injection therapy. In addition, RITA was shown to be safer. Conclusion: IVTA and SCTA appeared as the least safe routes of injection therapy for ME, which being more prone to increase the risk of IOP elevation. RITA demonstrated a safer profile. However, more high-quality randomized controlled trials will be necessary to further confirm this.

BackgroundThe benefits of sodium-glucose-cotransporter-2 (SGLT2) inhibitors in the treatment of type 1 diabetes mellitus (T1DM) have been demonstrated, but the occurrence of diabetic ketoacidosis (DKA) limits their use. The risk of DKA associated with different doses of SGLT2 inhibitous in the treatment of T1DM is unknown. We conducted a network meta-analysis to evaluate the incidence of DKA at different doses in the treatment of T1DM.MethodsWe searched electronic databases and clinical trial registries, including PubMed, Embase (Ovid SP), the Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov, for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T1DM from inception to December 2023. Literature screening, quality assessment and data extraction were carried out independently by 2 researchers based on the inclusion and exclusion criteria, and statistical analysis was performed using Stata 15.1 software and R 4.1.3.ResultsNineteen clinical studies and one clinical trial were ultimately included. The study involved five different SGLT2 inhibitors. The incidence of DKA in dapagliflozin 5 mg (OR: 2.57, 95% CI: 1.04 to 6.33; P<0.00001), empagliflozin 10 mg (OR: 2.68, 95% CI: 1.11 to 6.49; P<0.00001), sogliflozin 200mg (OR: 4.04, 95% CI: 1.15 to14.18; P<0.00001) and sogliflozin 400mg (OR: 5.96, 95% CI: 2.06 to17.20; P<0.00001) were higher than for the placebo. According to the P scores, SGLT2 inhibitors triggered a lower incidence of DKA than did the placebo. Treatment with 300 mg canagliflozin had the lowest incidence of DKA (P score = 0.8563).ConclusionAccording to our study, 5 mg dapagliflozin,10 mg empagliflozin 200mg sogliflozin and 400mg sogliflozin resulted in DKA when adjunctive insulin was used to treat T1DM. Other SGLT2 inhibitors seem to be safe. However, SGLT2 inhibitors for treating T1DM are off label in China, and adverse reactions should be closely monitored during administration.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/#loginpage, identifier CRD42023416227.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors can decrease serum uric acid (sUA) levels and have potential in the management of glucose levels and cardiorenal protection in patients. This systematic review and network meta-analysis aimed to investigate the effects of SGLT-2 inhibitors on sUA levels and incidence of gout in patients with or without type 2 diabetes. A systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and Clinical Trials databases was performed to retrieve relevant articles published from inception to April 27, 2025, focusing on the impact of SGLT-2 inhibitors on sUA levels or the incidence of gout in the study participants. We performed a Bayesian random-effects network meta-analysis of the included studies using the Markov Chain Monte Carlo simulation techniques. The grading of recommendations, assessment, development, and evaluation approach was used to assess the certainty of the evidence. A total of 57 trials were included. All SGLT-2 inhibitors reduced sUA levels. These inhibitors demonstrated a spectrum of sUA-lowering effects, with empagliflozin and dapagliflozin exhibiting particularly robust efficacy. Specifically, empagliflozin (10 mg: − 43 [95

BackgroundThis study aimed to systematically review the research on home pharmaceutical care and to identify emerging trends and research hotspots using bibliometric methods.MethodsPublications related to home pharmaceutical care, published from inception to 6 February 2025, were extracted from the Web of Science Core Collection (WoSCC). The bibliometric tool CiteSpace was employed to analyze various metrics, including the number of publications, contributing countries, institutions, authors, keywords, cited references, and research trends in the field of home pharmaceutical care.ResultsA total of 812 relevant articles were retrieved from the WoSCC. The most prolific contributors were Hughes CM, Nishtala, PS, and Lapane KL. The United States emerged as the leading country in the field, with Queen’s University Belfast identified as the most productive institution. The keyword with the highest frequency was “pharmaceutical care.” The research hotspots in this field were centered around “polypharmacy,” “medication reconciliation,” and “drug-related problems.”ConclusionThis study utilized CiteSpace to analyze research trends and hotspots in the field of home pharmaceutical care. The findings suggest that “polypharmacy” and “care homes” are likely to become focal points of future research. Additionally, the development of research in developing countries lags behind that in developed countries. Therefore, it is crucial for developing countries to learn from the advances made by developed nations in this field, and to foster greater international collaboration and research efforts.

PURPOSE:To compare structural and vascular differences in the macular region of the retina using optical coherence tomography (OCT)/OCT angiography (OCTA) between coronary angiography (CAG)-confirmed coronary heart disease (CHD) patients and non-CHD individuals. METHODS:The study included 340 eyes from 180 CHD patients and 136 eyes from 68 controls. Imaging was conducted using the AngioVue OCT device with a macula-centered 6 mm ∗ 6 mm field of view. Retinal thickness and 2D/3D vascular-related biomarkers were derived using existing retinal layer segmentation software, and our previously proposed 2D/3D vascular and 3D foveal avascular zone segmentation methods. Statistical analyses included t-tests, Mann-Whitney U tests, chi-square tests, and Pearson's correlation. RESULTS:The CHD group exhibited significantly lower retinal nerve fiber layer (RNFL) thickness (r = -0.20, P < 0.001) in the inner inferior (I) region, based on macular region layer segmentation. For the 3D OCT images, as defined by the ETDRS grid, both the inner and outer retina layers in the outer superior (out-S) region were significantly thinner in the CHD group. The CHD group showed significantly lower overall 2D fractal dimension (FD) (1.72 ± 0.03 vs. 1.73 ± 0.02, P < 0.001) and vessel skeleton density (VSD) (26.61 ± 4.52 vs. 28.50 ± 3.40, P < 0.001) compared to the control group. The proposed 3D vascular density (VD) feature showed a significant difference between the groups (19.23 ± 5.67 vs. 20.69 ± 5.15, P = 0.048). CONCLUSION:Thinning of retinal thickness and reduced vascular density are associated with CHD and may serve as valuable, cost-effective biomarkers for assessing coronary artery disease assessment.

Background:Elevated serum uric acid (SUA) is strongly associated with adverse clinical outcomes. Sodium-glucose-cotransporter-2 (SGLT2) inhibitors not only lower blood glucose levels but also reduce UA. However, comparative data on the SUA-lowering effects among different SGLT2 inhibitors remain sparse, hindering evidence-based drug selection. This study aimed to systematically evaluate the effects of various SGLT2 inhibitors on SUA. Methods:We searched the Cochrane Central Register of Controlled Trials (Ovid SP), Embase (Ovid SP), PubMed, and ClinicalTrials.gov up to March 2024 for randomized controlled trials (RCTs) evaluating SGLT2 inhibitors in patients with or without type 2 diabetes mellitus (T2DM). The primary outcome was the change in SUA levels compared with placebo. Data were analyzed using Review Manager 5.4. Pooled mean differences (MDs) for continuous outcomes (SUA change) and relative risk (RR) for dichotomous outcomes (gout incidence) were calculated. Study quality was evaluated using the Cochrane Risk of Bias tool (RoB 2), and the overall evidence quality was evaluated using the GRADE approach. Results:A total of 51 RCTs were included in the meta-analysis. The SUA levels were significantly lower in all SGLT2 inhibitors groups than in the placebo groups. SGLT2 inhibitors have superior efficacy in lowering SUA levels compared with placebo [MD = -32.14 μmol/L, 95% CI (-35.96 to -28.31); P < 0.001]. Subgroup analysis showed empagliflozin achieved the greatest reduction in SUA [MD = -45.61 μmol/L, 95% CI (-52.26 to -38.97); P < 0.00001], while sotagliflozin had the least effect [MD = -13.72 μmol/L, 95% CI (-19.16 to -8.29); P < 0.00001]. The GRADE profiles indicated low-quality evidence for reduction in SUA levels. However, there was no difference in the incidence of gout between the two groups [RR = 0.96, 95% CI (0.77-1.21), P = 0.75]. Conclusion:SGLT2 inhibitors demonstrated greater SUA reduction than placebo, highlighting their potential as multifactorial therapies in high-risk populations. Systematic Review Registration:https://www.crd.york.ac.uk/prospero/#loginpage, identifier CRD42023458993.

ObjectivesThis study aimed to identify the risk factors for pancreatic cancer through machine learning.MethodsWe investigated the relationships between different risk factors and pancreatic cancer using a real-world retrospective cohort study conducted at West China Hospital of Sichuan University. Multivariable logistic regression, with pancreatic cancer as the outcome, was used to identify covariates associated with pancreatic cancer. The machine learning model extreme gradient boosting (XGBoost) was adopted as the final model for its high performance. Shapley additive explanations (SHAPs) were utilized to visualize the relationships between these potential risk factors and pancreatic cancer.ResultsThe cohort included 1,982 patients. The median ages for pancreatic cancer and nonpancreatic cancer groups were 58.1 years (IQR: 51.3–64.4) and 57.5 years (IQR: 49.5–64.9), respectively. Multivariable logistic regression indicated that kirsten rats arcomaviral oncogene homolog (KRAS) gene mutation, hyperlipidaemia, pancreatitis, and pancreatic cysts are significantly correlated with an increased risk of pancreatic cancer. The five most highly ranked features in the XGBoost model were KRAS gene mutation status, age, alcohol consumption status, pancreatitis status, and hyperlipidaemia status.ConclusionMachine learning algorithms confirmed that KRAS gene mutation, hyperlipidaemia, and pancreatitis are potential risk factors for pancreatic cancer. Additionally, the coexistence of KRAS gene mutation and pancreatitis, as well as KRAS gene mutation and pancreatic cysts, is associated with an increased risk of pancreatic cancer. Our findings offered valuable implications for public health strategies targeting the prevention and early detection of pancreatic cancer.

Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors have proven to be effective in improving glycemic control in patients with type 2 diabetes mellitus (T2DM). However, the risk of diabetic ketoacidosis (DKA) in patients remains unclear. The purpose of this study is to conduct this systematic review and network meta-analysis for the risk of DKA of SGLT2 inhibitors in patients with T2DM.Methods: We searched for randomized controlled trials (RCTs) concerning SGLT2 inhibitors in patients with T2DM in PubMed, EMBASE (Ovid SP), Cochrane Central Register of Controlled Trials (Ovid SP), and ClinicalTrials.gov from inception to January 2022. The primary outcomes were the risk of DKA. We assessed the sparse network with a fixed-effect model and consistency model in a frequentist framework with a graph-theoretical method by the netmeta package in R. We assessed the evidence quality of evidence of outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE).Results: In total, 36 studies involving 52,264 patients were included. The network showed that there was no significant difference observed among SGLT2 inhibitors, other active antidiabetic drugs, and placebo in the risk of DKA. There was no significant difference in the DKA risk between different doses of SGLT2 inhibitors. The certainty of the evidence ranged from very low to moderate. The probabilities of rankings and P-score showed that compared to placebo, SGLT2 inhibitors might increase the risk of DKA (P-score = 0.5298). Canagliflozin might have a higher DKA risk than other SGLT2 inhibitors (P-score = 0.7388).Conclusion: Neither SGLT2 inhibitors nor other active antidiabetic drugs were associated with an increased risk of DKA compared to placebo, and the risk of DKA with SGLT2 inhibitors was not found to be dose-dependent. In addition, the use of canagliflozin was less advisable than other SGLT2 inhibitors according to the rankings and P-score.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/, identifier PROSPERO, CRD42021297081.

Background: Although with the application of etanercept biosimilars in the field of rheumatoid arthritis, the evidences of their efficacy, safety, and immunogenicity are still limited. We conducted this meta-analysis to evaluate the efficacy, safety and immunogenicity of etanercept biosimilars for treating active rheumatoid arthritis compared to reference biologics (Enbrel®). Methods: PubMed, Embase, Central, and ClinicalTrials.gov were searched for randomized controlled trials of etanercept biosimilars treated in adult patients diagnosed with rheumatoid arthritis from their earliest records to 15 August 2022. The outcomes included ACR20, ACR50, and ACR70 response rate at different time points from FAS or PPS, adverse events, and proportion of patients developed anti-drug antibodies. The risk of bias of each included study was assessed using the revised Cochrane Risk of Bias in Randomised Trials tool, and the certainty of evidence was rated according to the Grading of Recommendation Assessment, Development, and Evaluation. Results: Six RCTs with 2432 patients were included in this meta-analysis. Etanercept biosimilars showed more benefits in ACR50 at 24 weeks from PPS [5 RCTs, OR = 1.22 (1.01, 1.47), p = 0.04, I2 = 49%, high certainty], ACR50 at 1 year from PPS [3 RCTs, OR = 1.43 (1.10, 1.86), p < 0.01, I2 = 0%, high certainty] or FAS [2 RCTs, OR = 1.36 (1.04, 1.78), p = 0.03, I2 = 0%, high certainty], and ACR70 at 1 year from PPS [3 RCTs, OR = 1.32 (1.01, 1.71), p = 0.04, I2 = 0%, high certainty]. In terms of other outcomes about efficacy, safety, and immunogenicity, the results showed that there was no significant difference between etanercept biosimilars and reference biologics, and the certainty of evidences ranged from low to moderate. Conclusion: Etanercept biosimilars showed more benefits in ACR50 response rate at 1 year than reference biologics (Enbrel®), other outcomes for clinical efficacy, safety, and immunogenicity of etanercept biosimilars were comparable with originator in patients with rheumatoid arthritis. Systematic Review Registration: PROSPERO, identifier CRD42022358709.

Lysine-specific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cell-derived and patient-derived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damage-inducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, co-administration of ZY0511 and DTP3, which specifically enhanced the pro-apoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC.

Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively active in ovarian cancer (OC) with homologous recombination (HR) deficiency (HRD) caused by mutations in BRCA1/2 and other DNA repair pathway members. We sought molecular targeted therapy that induce HRD in HR-proficient cells to induce synthetic lethality with PARPi and extend the utility of PARPi. Here, we demonstrate that lysine-specific demethylase 1 (LSD1) is an important regulator for OC. Importantly, genetic depletion or pharmacological inhibition of LSD1 induces HRD and sensitizes HR-proficient OC cells to PARPi in vitro and in multiple in vivo models. Mechanistically, LSD1 inhibition directly impairs transcription of BRCA1/2 and RAD51, three genes essential for HR, dependently of its canonical demethylase function. Collectively, our work indicates combination with LSD1 inhibitor could greatly expand the utility of PARPi to patients with HR-proficient tumor, warranting assessment in human clinical trials.

AbstractBackgroundOverweight and obesity are widespread among children and adolescents. We aimed to summarize the evidence for the pharmacotherapy as an adjunct to lifestyle interventions in overweight or obese children and adolescents by comparing the benefits and harms.MethodsRCTs (randomized controlled trials) were sourced from PubMed, Embase (using the OVID platform), the Cochrane Library (CENTRAL), as well as the trial registers ICTRP (WHO) and ClinicalTrials.gov. Searches were undertaken from inception to April 25, 2023. A network meta-analysis was performed using the frequentists framework based on random-effects model. We used GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach to evaluate the overall certainty of evidence and categorized the interventions.ResultsIn total, 42 RCTs (n=3883) comparing 8 different pharmacotherapy strategies were included in this study. Evidence strongly suggested that phentermine-topiramate reduced BMI the most (the mean difference (MD) -4.83 [95% CI, -7.46 to -2.20] kg/m2) and weight (MD, -14.59 [95% CI, -19.37, -9.81] kg) in children and adolescents with overweight or obesity. Compared to lifestyle intervention alone, phentermine-topiramate was associated with an additional 557 events per 1000 person-years in terms of the proportion of participants achieving a BMI reduction of ≥5%, but there was no increased harm in total gastrointestinal adverse effects and discontinuation due to adverse events.ConclusionsPhentermine-topiramate was closely related to weight loss and showed a good tolerability, proving to be the optimal treatment strategy for overweight or obese children and adolescents.RegistrationPROSPERO registry number: CRD42022329226

Background: Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete determination of their cardiovascular safety remains inconclusive. Hence, the primary objective of this network meta-analysis is to meticulously assess and juxtapose the cardiovascular risks linked to distinct JAK inhibitors employed in RA patients. Methods: A systematic review and network meta-analysis were meticulously conducted, encompassing a collection of randomized controlled trials (RCTs) that focused on investigating the incidence of major adverse cardiovascular events (MACE) and all-cause mortality associated with Janus kinase (JAK) inhibitors administered to patients with rheumatoid arthritis (RA). Extensive exploration was performed across multiple electronic databases, incorporating studies published until March 2023. To be included in this analysis, the RCTs were required to involve adult participants diagnosed with RA who received treatment with JAK inhibitors. To ensure accuracy, two authors independently undertook the selection of eligible RCTs and meticulously extracted aggregate data. In order to examine the outcomes of MACE and all-cause mortality, a frequentist graph theoretical approach within network meta-analyses was employed, utilizing random-effects models. Third study has been registered on PROSPERO under the reference CRD42022384611. Findings: A specific selection encompassing a total of 14 meticulously chosen randomized controlled trials was undertaken, wherein 13,524 patients were assigned randomly to distinct treatment interventions. The analysis revealed no notable disparity in the occurrence of major adverse cardiovascular events (MACE) between the interventions and the placebo group. However, in comparison to adalimumab, the employment of JAK inhibitors exhibited an association with higher rates of all-cause mortality [odds ratio (OR): 1.7, 95% confidence interval (CI): 1.02-2.81]. This observed increase in risk primarily stemmed from the usage of tofacitinib (OR: 1.9, 95% CI: 1.12-3.23). None of the other JAK inhibitors exhibited a statistically significant variance in all-cause mortality when compared to adalimumab. Interpretation: Our study suggests that JAK inhibitors may not increase the risk of MACE in RA patients but may be associated with a higher risk of all-cause mortality compared to adalimumab, primarily due to tofacitinib use. Rheumatologists should carefully consider the cardiovascular risks when prescribing JAK inhibitors, particularly tofacitinib, for RA patients. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384611, CRD42022384611.

Objective:Our study aimed to evaluate the cost-effectiveness of the addition of serplulimab to chemotherapy (cisplatin and fluorouracil) for programmed death-ligand 1 (PD-L1) positive advanced esophageal squamous cell carcinoma (ESCC) as the first-line treatment in China.Methods:A three-state Markov model was established to assess the incremental cost-effectiveness ratio (ICER) for serplulimab plus chemotherapy versus chemotherapy alone. Survival data were extrapolated from the ASTRUM-007 trial, cost data were derived from local sources, and utilities were derived from published literature. Health outcomes were measured as quality-adjusted life-years (QALYs). Sensitivity and probability sensitivity analyses were used to investigate the robustness of the model.Results:In the base-case analysis, compared with chemotherapy alone, serplulimab gained an additional 0.16 QALYs with an incremental cost of $29,547.88, leading to an ICER of $184,674.25/QALY. Additionally, the subgroup analyses presented that the ICERs of serplulimab plus chemotherapy were $157,892.50/QALY and $127,996.45/QALY in advanced ESCC patients with 1≤ CPS< 10 and CPS≥ 10, respectively. These ICERs significantly exceeded the Chinese willingness-to-pay (WTP) threshold. The deterministic sensitivity analysis illustrated that the cost of progression-free survival in serplulimab plus chemotherapy group was the parameter with the strongest influence on the ICERs.Conclusion:In the Chinese health care system, with 3 times China's per capita gross domestic product as the WTP threshold, compared with chemotherapy alone, serplulimab combined chemotherapy is not economical for PD-L1-positive advanced ESCC in the first-line setting.

ObjectiveTo determine the harms of ezetimibe in people who need lipid-lowering treatment.DesignSystematic review and meta-analysis.Data sourcesRandomised controlled trials and cohort studies.Eligibility criteria for selecting studiesStudies comparing ezetimibe with placebo, standard care, or other lipid-lowering agents in people who need lipid-lowering treatment with a follow-up duration of at least six months (or 24 weeks). The relative effects for potential harms of ezetimibe were pooled by use of random effect pairwise meta-analyses for randomised controlled trials and the evidence from observational studies was narratively summarised. The certainty of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation.Results48 randomised controlled trials with 28 444 participants (median follow-up 34 weeks, range 24-312 weeks) and four observational studies with 1667 participants (median follow-up 282 weeks, range 72-400 weeks) were included. The meta-analyses of randomised trials showed moderate to high certainty that ezetimibe was not associated with cancer (relative risk 1.01; 95% confidence interval 0.92 to 1.11), fractures (0.90; 0.74 to 1.10), discontinuation due to any adverse event (0.87; 0.74 to 1.03), gastrointestinal adverse events leading to discontinuation (1.34; 0.58 to 3.08), myalgia or muscular pain leading to discontinuation (0.82; 0.51 to 1.33), neurocognitive events (1.48; 0.58 to 3.81), or new-onset diabetes (0.88; 0.61 to 1.28). The narrative analysis of observational studies provided consistent findings. No credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials.ConclusionsEzetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents.Review registrationPROSPERO CRD42020187437.

Blocking the de novo biosynthesis of pyrimidine by inhibiting human dihydroorotate dehydrogenase (hDHODH) is an effective way to suppress the proliferation of cancer cells and activated lymphocytes. Herein, eighteen teriflunomide derivatives and four ASLAN003 derivatives were designed and synthesized as novel hDHODH inhibitors based on a benzophenone scaffold. The optimal compound 7d showed a potent hDHODH inhibitory activity with an IC50 value of 10.9 nM, and displayed promising antiproliferative activities against multiple human cancer cells with IC50 values of 0.1-0.8 μM. Supplementation of exogenous uridine rescued the cell viability of 7d-treated Raji and HCT116 cells. Meanwhile, 7d significantly induced cell cycle S-phase arrest in Raji and HCT116 cells. Furthermore, 7d exhibited favorable safety profiles in mice and displayed effective antitumor activities with tumor growth inhibition (TGI) rates of 58.3% and 42.1% at an oral dosage of 30 mg/kg in Raji and HCT116 cells xenograft models, respectively. Taken together, these findings provide a promising hDHODH inhibitor 7d with potential activities against some tumors.

Objective Camrelizumab is a selective, humanised, high-affinity IgG 4 kappa monoclonal antibody against programmed cell death 1 that shows effective antitumour activity with acceptable toxicity in multiple tumour types. The CameL trial demonstrated that camrelizumab plus chemotherapy (CC) significantly prolonged the median progression-free survival and median overall survival versus chemotherapy alone (CA) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Our study was conducted to investigate the cost-effectiveness of the two strategies in chemotherapy-naive patients with advanced non-squamous NSCLC. Design, setting and participants A Markov simulation model was generated based on the CameL trial. The two simulated treatments included CC and CA. Primary and secondary outcome measures Utility was derived from published literature, and costs were calculated based on those at our hospital in Chengdu, China. Incremental cost-effectiveness ratios (ICERs) were calculated to compare the cost-effectiveness of the two treatment arms. Results In the overall population, the total costs were $27 223.40 and $13 740.10 for CC and CA treatment, respectively. The CC treatment produced 1.37 quality-adjusted life years (QALYs), and the CA treatment produced 1.17 QALYs. Hence, patients who were in the CC group spent an additional $13 483.30 and generated an increase of 0.20 QALYs, resulting in an ICER of $67 416.50 per QALY. Conclusions For chemotherapy-naive patients with advanced non-squamous NSCLC, CC is not considered a cost-effective treatment versus CA in China when considering a willingness-to-pay threshold of $31 500 per QALY. Trial registration number NCT03134872

Background: Gout is a common disease and is usually treated with uric acid-lowering drugs (the most commonly used of which are febuxostat and allopurinol). However, the cardiovascular safety of febuxostat and allopurinol is still controversial. The purpose of our study is to evaluate the cardiovascular safety of the two drugs in patients with gout using one-stage and two-stage meta-analysis. Methods: PubMed, Embase, CBM, CNKI, WanFang, Central, and VIP were searched from inception to 30 January 2022. Randomized controlled trials which evaluated the cardiovascular safety of febuxostat or allopurinol for treating patients with gout were included. Based on the Kaplan–Meier curves of the two studies, individual patient data (IPD) were extracted and reconstructed. We used time-varying risk ratios (RRs) to summarize time-to-event outcomes, and the RRs of MACE incidence, cardiovascular mortality, and all-cause mortality were calculated by a multi-level flexible hazard regression model in 1-stage meta-analyses. p values were calculated using a log-rank test. At the same time, using the reconstructed IPD, we performed 2-stage meta-analyses to inform the quantitative estimates of time-specific relative risks at the six time points (1 , 2, 3, 4, 5, and 6 years) based on a random-effects model. Results: Two RCTs with 12,318 participants were included. In the incidence of major adverse cardiovascular events between the two regimens, there was no significant difference [RR = 0.99 (95% CI, 0.89–1.11), p = 0.87]; at the same time, there was no significant difference in cardiovascular mortality [RR = 1.17 (95% CI, 0.98–1.40),p = 0.08] or all-cause mortality [RR = 1.03 (95% CI, 0.91–1.17),p = 0.62]. In terms of 2-stage meta-analyses, there was no significant difference in any outcomes at any time point (moderate-to low-certainty evidence). Conclusion: In patients without atherosclerotic disease, febuxostat likely has a similar cardiovascular profile to allopurinol. However, in patients with a history of cardiovascular disease, allopurinol treatment is associated with less cardiovascular mortality as compared with febuxostat. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/#loginpage, identifier PROSPERO, CRD42022325656.

Objective To determine the harms of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors in people who need lipid-lowering therapy. Methods This systematic review included randomised controlled trials that compared PCSK9 inhibitors with placebo, standard care or active lipid-lowering comparators in people who need lipid-lowering therapy with the follow-up duration of at least 24 weeks. We summarised the relative effects for potential harms from PCSK9 inhibitors using random-effect pairwise meta-analyses and assessed the certainty of evidence using GRADE (Grading of Recommendation Assessment, Development and Evaluation) for each outcome. Results We included 32 trials with 65 861 participants (with the median follow-up duration of 40 weeks, ranging from 24 to 146 weeks). The meta-analysis showed an incidence of injection-site reaction leading to discontinuation (absolute incidence of 15 events (95% CI 11 to 20) per 1000 persons in a 5-year time frame, high certainty evidence). PCSK9 inhibitors do not increase the risk of new-onset diabetes mellitus, neurocognitive events, cataracts or gastrointestinal haemorrhage with high certainty evidence. PCSK9 inhibitors probably do not increase the risks of myalgia or muscular pain leading to discontinuation or any adverse events leading to discontinuation with moderate evidence certainty. Given very limited evidence, PCSK9 inhibitors might not increase influenza-like symptoms leading to discontinuation (risk ratio 1.5; 95% CI 0.06 to 36.58). We did not identify credible subgroup analyses results, including shorter versus longer follow-up duration of trials. Conclusions PCSK9 inhibitors slightly increase the risk of severe injection-site reaction but not cataracts, gastrointestinal haemorrhage, neurocognitive events, new-onset diabetes or severe myalgia or muscular pain.