Objective To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs). Design Systematic review followed by a one stage bayesian individual patient data meta-analysis. Data sources Studies from Canadian and European healthcare databases. Review methods Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias. Exposure and outcomes Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction. Results A cohort of 446 763 individuals including 61 460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations. Conclusions All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.

Exercise signals neurogenesis in the dentate gyrus of the hippocampus. This phenomenon requires vascular endothelial growth factor (VEGF) originating from outside the blood-brain barrier, but no cellular source has been identified. Thus, we hypothesized that VEGF produced by skeletal myofibers plays a role in regulating hippocampal neuronal precursor cell proliferation following exercise training. This was tested in adult conditional skeletal myofiber-specific VEGF gene-ablated mice (VEGF ) by providing VEGF and non-ablated (VEGF ) littermates with running wheels for 14 days. Following this training period, hippocampal cerebral blood flow (CBF) was measured by functional magnetic resonance imaging (fMRI), and neuronal precursor cells (BrdU+/Nestin+) were detected by immunofluorescence. The VEGF trained group showed improvements in both speed and endurance capacity in acute treadmill running tests (P < 0.05). The VEGF group did not. The number of proliferating neuronal precursor cells was increased with training in VEGF (P < 0.05) but not in VEGF mice. Endothelial cell (CD31+) number did not change in this region with exercise training or skeletal myofiber VEGF gene deletion. However, resting blood flow through the hippocampal region was lower in VEGF mice, both untrained and trained, than untrained VEGF mice (P < 0.05). An acute hypoxic challenge decreased CBF (P < 0.05) in untrained VEGF , untrained VEGF and trained VEGF mice, but not trained VEGF mice. VEGF , but not VEGF , mice were able to acutely run on a treadmill at an intensity sufficient to increase hippocampus VEGF levels. These data suggest that VEGF expressed by skeletal myofibers may directly or indirectly regulate both hippocampal blood flow and neurogenesis.

Background: Prolonged time to treatment initiation (TTI) for patients with curable anal cancer may reduce tumor control. This study investigated demographic disparities in TTI for patients receiving definitive chemoradiation (CRT) for anal squamous cell carcinoma (A-SCC). Methods: Adult patients with A-SCC diagnosed from 2004 to 2014 and treated with definitive CRT were identified in the National Cancer Database (NCDB). TTI was defined as days from diagnosis to start of CRT. A negative binomial regression model estimated predicted TTI (pTTI) values. Cox proportional hazards model evaluated the impact of TTI on overall survival (OS). Results: Overall, 12,546 patients were included with 9% Non-Hispanic Black patients and 4% Hispanic patients. Multivariable analysis (MVA) showed that pTTI varied significantly by race/ethnicity with Non-Hispanic Black patients having a pTTI of 50 vs. 38 days for Non-Hispanic White patients [relative risk (RR), 1.21; 95% confidence interval (CI), 1.17-1.25]. For Hispanic patients, pTTI was 48 days, significantly longer than that of Non-Hispanic White patients (RR, 1.19; 95% CI, 1.14-1.24). Gender, insurance status, education level, urban category, distance to reporting facility, treatment facility type, intensity-modulated radiation therapy (IMRT)/proton use, T/N classification, and comorbidity status were all also associated with significant variation in TTI. TTI was not independently associated with changes in OS on MVA [hazard ratio (HR), 0.999; 95% CI, 0.997-1.002]. Conclusions: Non-Hispanic Black and Hispanic patients have longer delays in starting definitive CRT for A-SCC. While TTI was not associated with OS, future analyses should explore the impact of TTI on local control, metastases, and patient-reported outcomes.

Background: Prolongation of radiotherapy (RT) in the treatment of numerous types of cancer has been shown to reduce overall survival (OS). Treatment delays are common in squamous cell carcinoma of the anus (SCCA) due to the toxicity of definitive chemoradiation (CRT). The effect of these delays on outcomes has not been well evaluated. This study investigated the effects of RT prolongation on OS in patients receiving CRT for SCCA.Methods: The National Cancer Database was queried for adult patients diagnosed with SCCA and treated with CRT from 2004-2014. Cox proportional hazard regression models examined the effect of duration of RT, measured as fractions delivered per week, on OS. Negative binomial regression assessed the effects of demographic and prognostic factors on the duration of RT.Results: A total of 8,948 patients were included in the analysis of factors impacting treatment duration, and 6,429 patients in the OS analysis. Multivariable analysis (MVA) showed female gender, non-private insurance, treatment at a low or intermediate volume facility, Charlson/Deyo score ≥2, and advanced disease were associated with longer RT duration. Treatment with IMRT, with single agent chemotherapy, at an academic center, and in later years were associated with shorter RT duration. A decrease in fractions delivered per week was independently associated with reduced OS with a cutoff of 4.72 fractions per week (about 2 missed fractions over a 30 fraction treatment) delineating the largest differences in OS.Conclusions: Efforts should be made to avoid RT interruptions of any length in SCCA patients and to compensate for treatment breaks to reduce the total duration of RT.