SGLT2 inhibitor plus DPP‐4 inhibitor as combination therapy for type 2 diabetes: A systematic review and meta‐analysis

To assess the efficacy and safety of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors plus a dipeptidyl peptidase‐4 (DPP‐4) inhibitor in patients with type 2 diabetes mellitus (T2DM), we performed a systematic review and meta‐analysis of 14 randomized controlled trials (RCTs) involving 4828 patients. Compared with a DPP‐4 inhibitor, SGLT2 inhibitor/DPP‐4 inhibitor combination therapy was significantly associated with a decrease in glycaemic control (HbA1c, −0.71%; fasting plasma glucose [FPG], −25.62 mg/dL; postprandial plasma glucose, −44.00 mg/dL), body weight (−2.05 kg) and systolic blood pressure (−5.90 mm Hg), but an increase in total cholesterol (TC) of 3.24%, high‐density lipoprotein of 6.15% and low‐density lipoprotein of 2.55%. Adding a DPP‐4 inhibitor to an SGLT2 inhibitor could reduce HbA1c by −0.31%, FPG by −8.94 mg/dL, TC by −1.48% and triglycerides by −3.25%. Interestingly, low doses of an SGLT2 inhibitor in the combination has similar or even better efficacy in some aspects than high doses. Similar adverse events were observed for the combination therapy, with the exception of genital infection vs DPP‐4 inhibitor (risk ratio [RR], 5.31) and consistent genital infection vs an SGLT2 inhibitor (RR, 0.61). Further studies are warranted to confirm these results

Voriconazole exposure and risk of cutaneous squamous cell carcinoma among lung or hematopoietic cell transplant patients: A systematic review and meta-analysis

Background Current evidence about the association between voriconazole and risk of cutaneous squamous cell carcinoma (SCC) remains inconsistent. Objective To assess the association between voriconazole use and risk of SCC. Methods We systematically searched PubMed and Embase and performed a random effects model meta-analysis to calculate the pooled relative risk (RR) with a 95% confidence interval (CI). Results Of the 8 studies involving a total of 3710 individuals with a lung transplant or hematopoietic cell transplant that were included in the qualitative analysis, 5 were included in the meta-analysis. Use of voriconazole was significantly associated with increased risk of SCC (RR, 1.86; 95% CI, 1.36-2.55). The increased risk did not differ according to type of transplantation or adjustment for sun exposure. Longer duration of voriconazole use was found to be positively associated with risk of SCC (RR, 1.72; 95% CI, 1.09-2.72). Voriconazole use was not associated with increased risk of basal cell carcinoma (RR, 0.84; 95% CI, 0.41-1.71). Limitations There were some heterogeneities in the retrospective observational studies. Conclusions Our findings support an increased risk of SCC associated with voriconazole in individuals with a lung transplant or hematopoietic cell transplant. Routine dermatologic surveillance should be performed, especially among individuals at high risk of developing SCC

HieNet: Bidirectional Hierarchy Framework for Automated ICD Coding

International Classification of Diseases (ICD) is a set of classification codes for medical records. Automated ICD coding, which assigns unique International Classification of Diseases codes with each medical record, is widely used recently for its efficiency and error-prone avoidance. However, there are challenges that remain such as heterogeneity, label unbalance, and complex relationships between ICD codes. In this work, we proposed a novel Bidirectional Hierarchy Framework(HieNet) to address the challenges. Specifically, a personalized PageRank routine is developed to capture the co-relation of codes, a bidirectional hierarchy passage encoder to capture the codes' hierarchical representations, and a progressive predicting method is then proposed to narrow down the semantic searching space of prediction. We validate our method on two widely used datasets. Experimental results on two authoritative public datasets demonstrate that our proposed method boosts state-of-the-art performance by a large margin

SGLT2 inhibitors and risk of cancer in type 2 diabetes: a systematic review and meta-analysis of randomised controlled trials

Aims/hypothesis The association between sodium–glucose cotransporter 2 (SGLT2) inhibitors and the risk of cancer in individuals with type 2 diabetes remains uncertain. This study aimed to evaluate the risk of cancer associated with SGLT2 inhibitor treatment of type 2 diabetes. Methods We systematically searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov from inception to 15 February 2017 to identify eligible randomised controlled trials (RCTs) that report cancer events in individuals with type 2 diabetes treated with SGLT2 inhibitors for at least 24 weeks. We performed pairwise and network meta-analyses as well as a cumulative meta-analysis to calculate ORs and 95% CIs. Results In total, 580 incidences of cancer among 34,569 individuals were identified from 46 independent RCTs with a mean trial duration of 61 weeks. When compared with comparators (placebo or other active glucose-lowering treatments), SGLT2 inhibitors were not significantly associated with an increased risk of overall cancer (OR 1.14 [95% CI 0.96, 1.36]). For pre-specified cancer types, the risk of bladder cancer might be increased with SGLT2 inhibitors (OR 3.87 [95% CI 1.48, 10.08]), especially empagliflozin (OR 4.49 [95% CI 1.21, 16.73]). Interestingly, canagliflozin might be protective against gastrointestinal cancers (OR 0.15 [95% CI 0.04, 0.60]). Conclusions/interpretation Current evidence from short-term RCTs did not indicate a significantly increased risk of overall cancer among individuals with type 2 diabetes using SGLT2 inhibitors. Given the short-term trial durations and uncertainty of evidence, future long-term prospective studies and post-marketing surveillance studies are warranted

Pioglitazone and bladder cancer risk: a systematic review and meta-analysis

Current evidence about the association between pioglitazone and bladder cancer risk remains conflict. We aimed to assess the risk of bladder cancer associated with the use of pioglitazone and identify modifiers that affect the results. We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to 25 August 2016 for randomized controlled trials (RCTs) and observational studies that evaluated the association between pioglitazone and bladder cancer risk. Conventional and cumulative meta-analyses were used to calculate the odds ratio (OR) with 95% confidence interval (CI). A restricted spline regression analysis was used to examine the dose-response relationship with a generalized least-squares trend test. We included two RCTs involving 9114 patients and 20 observational studies (n = 4,846,088 individuals). An increased risk of bladder cancer in patients treated with pioglitazone versus placebo was noted from RCTs (OR, 1.84; 95%CI, 0.99 to 3.42). In observational studies, the increased risk of bladder cancer was slight but significant among ever-users of pioglitazone versus never-users (OR, 1.13; 95%CI, 1.03 to 1.25), which appeared to be both time- (P = 0.003) and dose-dependent (P = 0.05). In addition, we observed the association differed by region of studies (Europe, United States, or Asia) or source of funding (sponsored by industry or not). Current evidence suggests that pioglitazone may increase the risk of bladder cancer, possibly in a dose- and time-dependent manner. Patients with long-term and high-dose exposure to pioglitazone should be monitored regularly for signs of bladder cancer

Comparisons of diabetic retinopathy events associated with glucose‐lowering drugs in patients with type 2 diabetes mellitus: A network meta‐analysis

Aim To assess the comparative effects of glucose‐lowering drugs (GLDs) on the risk of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods We systematically searched Cochrane Central Register of Controlled Trials, PUBMED and EMBASE from inception to January 17, 2017 to identify randomized controlled trials (RCTs) that reported DR events among T2DM patients receiving any GLD. Random‐effects pairwise and network meta‐analyses were performed to calculate odds ratios (ORs) with 95% confidence intervals (CIs). Results A total of 37 independent RCTs with 1806 DR events among 100 928 patients with T2DM were included. The mean duration of diabetes was 8.7 years and mean baseline HbA1c was 8.2% (SD, 0.5%). Our network meta‐analysis found that DPP‐4i (OR, 1.20; 95% CI, 0.87‐1.65), GLP‐1RA (OR, 1.19; 95% CI, 0.94‐1.52) and SGLT2 inhibitors (OR, 0.79; 95% CI, 0.49‐1.28) were not associated with a higher risk of DR than placebo; however, a significantly increased risk of DR was associated with DPP‐4i in the pairwise meta‐analysis (OR, 1.27; 95% CI, 1.05‐1.53). Sulfonylureas, on the other hand, were associated with a significantly increased risk of DR compared to placebo (OR, 1.67; 95% CI, 1.01‐2.76). Conclusions Current evidence indicates that the association between DPP‐4i, GLP‐1RA or SGLT2 inhibitors and risk of DR remains uncertain in patients with T2DM. Some evidence suggests that sulfonylureas may be associated with increased risk of DR. However, given that DR events were not systematically assessed, these effects should be explored further in large‐scale, well‐designed studies

Hiding inside? Intracellular expression of non-glycosylated c-kit protein in cardiac progenitor cells

Cardiac progenitor cells including c-kit(+) cells and cardiosphere-derived cells (CDCs) play important roles in cardiac repair and regeneration. CDCs were reported to contain only small subpopulations of c-kit(+) cells and recent publications suggested that depletion of the c-kit(+) subpopulation of cells has no effect on regenerative properties of CDCs. However, our current study showed that the vast majority of CDCs from murine heart actually express c-kit, albeit, in an intracellular and non-glycosylated form. Immunostaining and flow cytometry showed that the fluorescent signal indicative of c-kit immunostaining significantly increased when cell membranes were permeabilized. Western blots further demonstrated that glycosylation of c-kit was increased during endothelial differentiation in a time dependent manner. Glycosylation inhibition by 1-deoxymannojirimycin hydrochloride (1-DMM) blocked c-kit glycosylation and reduced expression of endothelial cell markers such as Flk-1 and CD31 during differentiation. Pretreatment of these cells with a c-kit kinase inhibitor (imatinib mesylate) also attenuated Flk-1 and CD31 expression. These results suggest that c-kit glycosylation and its kinase activity are likely needed for these cells to differentiate into an endothelial lineage. In vivo, we found that intracellular c-kit expressing cells are located in the wall of cardiac blood vessels in mice subjected to myocardial infarction. In summary, our work demonstrated for the first time that c-kit is not only expressed in CDCs but may also directly participate in CDC differentiation into an endothelial lineage

On the Changing Contribution of Snow to the Hydrology of the Fraser River Basin, Canada

This paper presents an application of the Variable Infiltration Capacity (VIC) model to the Fraser River basin (FRB) of British Columbia (BC), Canada, over the latter half of the twentieth century. The Fraser River is the longest waterway in BC and supports the world’s most abundant Pacific Ocean salmon populations. Previous modeling and observational studies have demonstrated that the FRB is a snow-dominated system, but with climate change, it may evolve to a pluvial regime. Thus, the goal of this study is to evaluate the changing contribution of snow to the hydrology of the FRB over the latter half of the twentieth century. To this end, a 0.25° atmospheric forcing dataset is used to drive the VIC model from 1949 to 2006 (water years) at a daily time step over a domain covering the entire FRB. A model evaluation is first conducted over 11 major subwatersheds of the FRB to quantitatively assess the spatial variations of snow water equivalent (SWE) and runoff (R). The ratio of the spatially averaged maximum SWE to R (RSR) is used to quantify the contribution of snow to the runoff in the 11 subwatersheds of interest. From 1949 to 2006, RSR exhibits a significant decline in 9 of the 11 subwatersheds (with p < 0.05 according to the Mann–Kendall test statistics). To determine the sensitivity of RSR, the air temperature and precipitation in the forcing dataset are then perturbed. The ratio RSR decreases more significantly, especially during the 1990s and 2000s, when air temperatures have warmed considerably compared to the 1950s. On the other hand, increasing precipitation by a multiplicative factor of 1.1 causes RSR to decrease. As the climate continues to warm, ecological processes and human usage of natural resources in the FRB may be substantially affected by its transition from a snow to a hybrid (nival/pluvial) and even a rain-dominated system