Impact of using concomitant conventional DMARDs on adherence to biologic DMARD treatment in rheumatoid arthritis: Multi-centre,population-based cohort study

PurposeTo evaluate the impact of concomitant use of conventional synthetic DMARDs (csCMARD) on adherence, switching and dose of biologic disease modifying antirheumatic drugs (bDMARD) in rheumatoid arthritis (RA) patients treated with bDMARDs.Patients and methodsThis was a population-based cohort study conducted in five provinces of Canada (Alberta, Manitoba, Ontario, Quebec, and Saskatchewan), and one American database (IBM® MarketScan® Databases). Adult RA patients entered the study after a 3-month initiation period of bDMARDs between 1 January 2007, and 30 March 2014. Concomitant csDMARD exposure was compared to non-csDMARD exposure on the following outcomes: discontinuation of bDMARD therapy, switching of bDMARDs, and percent change in dose of bDMARD compared to initial dose. The effect of the time-varying changes in csDMARD exposure was analyzed using marginal structural models. Dose change was analyzed using linear regression. Results from each participating site were combined using likelihood ratio meta-analysis.ResultsThe study population comprised 20,221 new users of bDMARDs: adalimumab (7609), etanercept (9809), abatacept (1024), infliximab (1779). Concomitant use of csDMARD therapy was not significantly associated with reduced discontinuation of bDMARD treatment (hazard ratio 0.90, 95% intrinsic confidence interval 0.79 to 1.02) or reduced switching of bDMARDs (hazard ratio 0.95, 95% intrinsic confidence interval 0.80 to 1.11), but was associated with a small increase in bDMARD dose compared to the mean dose over the first three months of treatment (mean percentage change in dose +0.56% mg/day, 95% intrinsic confidence interval +0.14% to +0.97%).ConclusionIn this large study of RA patients using bDMARDs in Canada and the United States, we found no clear evidence that patients who received concomitant csDMARD therapy were less likely to discontinue, switch or increase their dose of bDMARD.     

Intravenous Thrombolysis and Mechanical Thrombectomy in Patients with Stroke after TAVI: A Report of Two Cases

Transcatheter Aortic Valve Implantation (TAVI) is an increasingly treatment modality for severe aortic stenosis, which is associated with a considerable peri-procedural risk of stroke. To date, the clinical safety and efficacy of Tissue plasminogen activator (tPA) and mechanical thrombectomy in stroke post-TAVI is not established. We describe 2 cases of patients with stroke after TAVI who received tPA therapy and mechanical thrombectomy.     

Associations of HLA and drug-metabolizing enzyme genes in co-trimoxazole-induced severe cutaneous adverse reactions

Co-trimoxazole is mainly used as a first-line drug for treatment and prophylaxis against Pneumocystis jiroveci pneumonia. This drug, however, has been reported as the most common causative drug for severe cutaneous adverse reactions (SCARs). This study aimed to extensively elucidate the associations between genetic polymorphisms of HLA class I and genes involved in bioactivation and detoxification of co-trimoxazole on co-trimoxazole-induced SCARS in a large sample size and well-defined Thai SCARs patients. A total of 67 patients with co-trimoxazole-induced SCARs, consisting of 51 SJS/TEN patients and 16 DRESS patients, and 91 co-trimoxazole tolerant controls were enrolled in the study. The results clearly demonstrated that the HLA-B¹13:01 allele was significantly associated with co-trimoxazole-induced SCARs, especially with DRESS (OR = 8.44, 95% CI = 2.66–26.77, P = 2.94 × 10⁻⁴, Pc = 0.0126). Moreover, the HLA-C¹08:01 allele was significantly associated with co-trimoxazole-induced SJS/TEN in the HIV/AIDS patients with an OR of 8.51 (95% CI = 2.18–33.14, P = 8.60 × 10⁻⁴, Pc = 0.0241). None of the genes involved in the bioactivation and detoxification of co-trimoxazole investigated in this study play any major role in the development of all phenotypes of SCARs.     

Investigation of the mechanisms of Genkwa Flos hepatotoxicity by a cell metabolomics strategy combined with serum pharmacology in HL-7702 liver cells

1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study.

2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed. Besides, two signal molecules and four enzymes involved in biosynthesis pathway of lysophosphatidylcholine and the sphingosine kinase/sphingosine-1-phosphate pathway were determined to investigate the relationship between Genkwa Flos hepatotoxicity and these two classic pathways. Finally, the metabolic pathways related to specific biomarkers and two classic metabolic pathways were analyzed to explain the possible mechanism of Genkwa Flos hepatotoxicity.

3. Based on the results, lipid peroxidation and oxidative stress, phospholipase A₂/lysophosphatidylcholine pathway, the disturbance of sphingosine-1-phosphate metabolic profile centered on sphingosine kinase/sphingosine-1-phosphate pathway and fatty acid metabolism might be critical participators in the progression of liver injury induced by Genkwa Flos.     

Evaluation of cisplatin-hydrogel for improving localized antitumor efficacy in gastric cancer

Gastric cancer, one of the most common disease, has become a major public health problem worldwide. Cisplatin (DDP) has been a widely used drug for the treatment of cancer, also usually applied in gastric cancer in clinic. However, the side effects including toxicity and drug-resistance restricted the usage of DDP in clinic, so we prepared a DDP-complexed hydrogel (DDP-Gel) and investigated its efficacy in gastric cancer. For in vivo studies, MKN45-Luc cells were injected into BLAB/C node mice subcutaneously to establish gastric cancer with orthotopically grown tumors. Mice bearing tumors were treated with normal saline, DDP and DDP-Gel. Body weight and survival condition were observed and recorded. The treatment efficacy in vivo was detected by luciferase imaging and histological evaluation was performed by H&E staining of different organs. Additionally, normal ICR mice were treated with different doses of DDP/DDP-Gel to calculate their LD₅₀ in vivo. The results showed that DDP-Gel prolonged survival time and ameliorated body weight changes of mice bearing tumors. DDP-Gel exhibited higher efficacy to inhibit tumor growth and metastasis, compared to DDP. Besides, LD₅₀ of DDP-Gel was 166.0?mg/kg, 13.2 folds higher than DDP. As a conclusion, DDP-Gel showed a more effective and safer function than DDP in gastric cancer, which indicating that DDP-Gel might be a novel strategy for gastric cancer therapy.     

Flavonoids and stilbenoids as a promising arsenal for the management of chronic arsenic toxicity

Rapid industrial and technological development has impacted ecosystem homeostasis strongly. Arsenic is one of the most detrimental environmental toxins and its management with chelating agents remains a matter of concern due to associated adverse effects. Thus, safer and more effective alternative therapy is required to manage arsenic toxicity. Based on existing evidence, native and indigenous plant-based active biomolecules appear as a promising strategy to mitigate arsenic-induced toxicity with an acceptable safety profile. In this regard, various phytochemicals (flavonoids and stilbenoids) are considered important classes of polyphenolic compounds with antioxidant and chelation effects, which may facilitate the removal of arsenic from the body more effectively and safely with regard to conventional approaches. This review presents an overview of conventional chelating agents and the potential role of flavonoids and stilbenoids in ameliorating arsenic toxicity. This report may provide a roadmap for identifying novel prophylactic/therapeutic strategies for managing arsenic toxicity.     

Communication and coping intervention for mothers of adolescents with type 1 diabetes: Rationale and trial design

Mothers of adolescents with type 1 diabetes (T1D) experience high rates of depressive symptoms and diabetes distress, which are established risk factors for deteriorating glycemic control, problems with adherence, increased depressive symptoms, and poor quality of life in adolescents. Given that adolescents are a high-risk population for suboptimal glycemic control, novel interventions to improve outcomes in adolescents with T1D are needed. Building on effective interventions to treat depression in adults, and our own pilot work in this population, we developed a cognitive behavioral intervention, Communication & Coping, to target maternal depressive symptoms and parenting behaviors. The randomized controlled trial compares the telephone and Facebook-delivered Communication & Coping intervention, which promotes the use of adaptive coping strategies and positive parenting practices, to a diabetes education control condition on diabetes outcomes and psychosocial outcomes in adolescents with T1D. This paper describes the study rationale, trial design, and methodology.