Efficacy and safety of golimumab in patients with non-radiographic axial spondyloarthritis: a withdrawal and retreatment study (GO-BACK).

OBJECTIVES: The GO-BACK study was designed to evaluate the efficacy and safety of golimumab (GLM) treatment withdrawal in adults with non-radiographic axial spondyloarthritis (nr-axSpA) who demonstrate inactive disease during a 10-month open-label (OL) GLM run-in. METHODS: Eligible participants received OL GLM in period 1. In period 2, participants who achieved inactive disease were randomized 1:1:1 to receive double-blind (DB) treatment with monthly placebo (PBO, treatment withdrawal) or continued GLM treatment given monthly (GLM QMT) or every 2 months (GLM Q2MT). Participants who did not have a disease flare continued DB treatment for ∼12 months. Participants with a disease flare discontinued DB treatment and resumed monthly OL GLM. Primary endpoint compared the proportion of participants without a disease flare in the continued GLM treatment groups (QMT or Q2MT) vs PBO in a multiplicity-controlled, step-down fashion. Safety follow-up continued for ∼3 months after last treatment. RESULTS: A total of 188 patients, out of the 323 enrolled, were eligible for participation in period 2. Both GLM QMT and GLM Q2MT were superior to treatment withdrawal (PBO) in preventing disease flare (P < 0.001), with a treatment-difference vs PBO of 50.4% and 34.4% for the GLM QMT and GLM Q2MT groups, respectively. The time-to-first flare was significantly longer (log-rank P < 0.0001) with GLM treatment compared with PBO. Of 53 participants (in Q2MT or PBO) who had a confirmed disease flare, 51 (96.2%) attained a clinical response within 3 months of restarting OL GLM. Adverse events were consistent with the known GLM safety profile. CONCLUSION: Among participants with active nr-axSpA who attained inactive disease after 10 months of GLM treatment, continued GLM treatment is well tolerated and provides superior protection against disease flares compared with GLM withdrawal. (EudraCT: 2015-004020-65, registered on 30 March 2022; NCT: 03253796, registered on 18 August 2017.).

Long-term tolerability and efficacy of golimumab in active non-radiographic axial spondyloarthritis: results from open-label extension.

OBJECTIVES: We report the open-label extension (OLE) of the GO-AHEAD study evaluating the long-term efficacy and safety of golimumab (GLM) in patients with non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients [both GLM- and placebo (PBO)-treated in the double-blind phase] received GLM 50 mg every 4 weeks during the OLE (36-week treatment; additional 8-week safety follow-up; GLM/GLM and PBO/GLM groups). All patients who entered and received ≥1 dose of study treatment in the OLE were included in the efficacy and safety analyses. The primary efficacy evaluations were the proportions of patients achieving 20% and 40% improvement in the ASAS criteria (ASAS20 and ASAS40, respectively). Responders' analyses were calculated using a non-responder imputation approach. RESULTS: Of 198 patients randomised, 189/198 (95.5%) entered the OLE; 174/198 patients (87.9%) completed all visits. Although the proportion of responders increased from week 16 to week 52 in the OLE in both GLM/GLM and PBO/GLM groups, the GLM/GLM group had a higher proportion of responders than the PBO/GLM group throughout the OLE from week 16 to week 52 (ASAS20: 71.1% to 83.9% vs 40.0% to 75.0%, respectively; ASAS40: 56.7% to 76.3% vs 23.0% to 59.4%, respectively; ASAS partial remission: 33.0% to 53.8% and 18.0% to 45.8%). In the OLE, the overall incidence of AEs was lower in the GLM/GLM vs PBO/GLM groups (41.9% and 54.2%). CONCLUSIONS: Sustained improvement in clinical efficacy was observed at 52 weeks in patients with nr-axSpA following GLM treatment. GLM was well tolerated and provided substantial long-term benefits to patients with nr-axSpA. TRIAL REGISTRATION: NCT01453725; United States National Library of Medicine clinical trials database; www.clinicaltrials.gov.

Congenital Ewing Sarcoma Presenting as a Rapidly Growing Neck Mass in a Newborn.

BACKGROUND: Ewing sarcoma (EWS) is an aggressive soft-tissue and bone malignancy. Congenital EWS is extremely rare, and its presenting features can be unique from that of EWS occurring in older children. CLINICAL FINDINGS: A full-term female infant with a neck mass present at birth was admitted to a level I nursery with an otherwise well appearance and normal vital signs. After consultation with a neonatologist, she was transferred to a neonatal intensive care unit where she developed sudden respiratory collapse from rapid growth of the mass causing airway obstruction, leading to emergent intubation. Ultrasound and MRI scans of the neck mass demonstrated cystic and vascular components, and a timely biopsy revealed small round blue cells with diffuse CD99 expression and chromosomal translocation 11;22. PRIMARY DIAGNOSIS: Ewing sarcoma. INTERVENTIONS: An accelerated workup for EWS was done due to the patient's critical status. On day of life (DOL) 8, she was started on treatment of EWS as per the current standard-of-care AEWS0031. On DOL 24, she underwent tracheostomy placement. OUTCOMES: The patient completed 14 total cycles of chemotherapy and is more than 12 months old. Her tracheostomy was decannulated at 6 months of age. PRACTICE RECOMMENDATIONS: The rarity of EWS in neonates and its presentation as a neck mass make this disease difficult to recognize unless clinicians have a high index of suspicion. The aims of this case report are to increase awareness of malignancy as a potential cause of neck masses in neonates and to prompt nurses and physicians to prepare for airway stabilization at appropriate levels of care if a neck mass is present at birth.

Causal effects of body mass index on cardiometabolic traits and events: a Mendelian randomization analysis.

Elevated body mass index (BMI) associates with cardiometabolic traits on observational analysis, yet the underlying causal relationships remain unclear. We conducted Mendelian randomization analyses by using a genetic score (GS) comprising 14 BMI-associated SNPs from a recent discovery analysis to investigate the causal role of BMI in cardiometabolic traits and events. We used eight population-based cohorts, including 34,538 European-descent individuals (4,407 type 2 diabetes (T2D), 6,073 coronary heart disease (CHD), and 3,813 stroke cases). A 1 kg/m(2) genetically elevated BMI increased fasting glucose (0.18 mmol/l; 95% confidence interval (CI) = 0.12-0.24), fasting insulin (8.5%; 95% CI = 5.9-11.1), interleukin-6 (7.0%; 95% CI = 4.0-10.1), and systolic blood pressure (0.70 mmHg; 95% CI = 0.24-1.16) and reduced high-density lipoprotein cholesterol (-0.02 mmol/l; 95% CI = -0.03 to -0.01) and low-density lipoprotein cholesterol (LDL-C; -0.04 mmol/l; 95% CI = -0.07 to -0.01). Observational and causal estimates were directionally concordant, except for LDL-C. A 1 kg/m(2) genetically elevated BMI increased the odds of T2D (odds ratio [OR] = 1.27; 95% CI = 1.18-1.36) but did not alter risk of CHD (OR 1.01; 95% CI = 0.94-1.08) or stroke (OR = 1.03; 95% CI = 0.95-1.12). A meta-analysis incorporating published studies reporting 27,465 CHD events in 219,423 individuals yielded a pooled OR of 1.04 (95% CI = 0.97-1.12) per 1 kg/m(2) increase in BMI. In conclusion, we identified causal effects of BMI on several cardiometabolic traits; however, whether BMI causally impacts CHD risk requires further evidence.

In vitro efficacy of 2,N-bisarylated 2-ethoxyacetamides against Plasmodium falciparum.

Investigation of a series of 2,N-bisarylated 2-ethoxyacetamides resulted in the identification of four inhibitors 5, 20, 24, 29 with single-digit micromolar in vitro efficacy against two drug-resistant Plasmodium falciparum strains. These compounds are analogs of structurally-related 1,3-bisaryl-2-propen-1-ones (chalcones), the latter showing efficacy in vitro but not in a malaria-infected mouse. The 2,N-bisarylated 2-ethoxyacetamides (e.g., 2, 5, 20) were shown to possess significantly greater stability in the presence of metabolizing enzymes than the corresponding 1,3-bisaryl-2-propen-1-ones (e.g., 1, 3, 18).

Lung eQTLs to help reveal the molecular underpinnings of asthma.

Genome-wide association studies (GWAS) have identified loci reproducibly associated with pulmonary diseases; however, the molecular mechanism underlying these associations are largely unknown. The objectives of this study were to discover genetic variants affecting gene expression in human lung tissue, to refine susceptibility loci for asthma identified in GWAS studies, and to use the genetics of gene expression and network analyses to find key molecular drivers of asthma. We performed a genome-wide search for expression quantitative trait loci (eQTL) in 1,111 human lung samples. The lung eQTL dataset was then used to inform asthma genetic studies reported in the literature. The top ranked lung eQTLs were integrated with the GWAS on asthma reported by the GABRIEL consortium to generate a Bayesian gene expression network for discovery of novel molecular pathways underpinning asthma. We detected 17,178 cis- and 593 trans- lung eQTLs, which can be used to explore the functional consequences of loci associated with lung diseases and traits. Some strong eQTLs are also asthma susceptibility loci. For example, rs3859192 on chr17q21 is robustly associated with the mRNA levels of GSDMA (P = 3.55 × 10(-151)). The genetic-gene expression network identified the SOCS3 pathway as one of the key drivers of asthma. The eQTLs and gene networks identified in this study are powerful tools for elucidating the causal mechanisms underlying pulmonary disease. This data resource offers much-needed support to pinpoint the causal genes and characterize the molecular function of gene variants associated with lung diseases.

Evaluation of etoricoxib in patients undergoing total knee replacement surgery in a double-blind, randomized controlled trial.

BACKGROUND: Optimal postoperative pain management is important to ensure patient comfort and early mobilization. METHODS: In this double-blind, placebo- and active-controlled, randomized clinical trial, we evaluated postoperative pain following knee replacement in patients receiving placebo, etoricoxib (90 or 120 mg), or ibuprofen 1800 mg daily for 7 days. Patients ≥18 years of age who had pain at rest ≥5 (0-10 Numerical Rating Scale [NRS]) after unilateral total knee replacement were randomly assigned to placebo (N = 98), etoricoxib 90 mg (N = 224), etoricoxib 120 mg (N = 230), or ibuprofen 1800 mg (N = 224) postoperatively. Co-primary endpoints included Average Pain Intensity Difference at Rest over Days 1-3 (0- to 10-point NRS) and Average Total Daily Dose of Morphine over Days 1-3. Pain upon movement was evaluated using Average Pain Intensity Difference upon Knee Flexion (0- to 10-point NRS). The primary objective was to demonstrate analgesic superiority for the etoricoxib doses vs. placebo; the secondary objective was to demonstrate that the analgesic effect of the etoricoxib doses was non-inferior to ibuprofen. Adverse experiences (AEs) including opioid-related AEs were evaluated. RESULTS: The least squares (LS) mean (95% CI) differences from placebo for Pain Intensity Difference at Rest over Days 1-3 were -0.54 (-0.95, -0.14); -0.49 (-0.89, -0.08); and -0.45 (-0.85, -0.04) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.05 for etoricoxib vs. placebo). Differences in LS Geometric Mean Ratio morphine use over Days 1-3 from placebo were 0.66 (0.54, 0.82); 0.69 (0.56, 0.85); and 0.66 (0.53, 0.81) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively (p < 0.001 for etoricoxib vs. placebo). Differences in LS Mean Pain Intensity upon Knee Flexion were -0.37 (-0.85, 0.11); -0.46 (-0.94, 0.01); and -0.42 (-0.90, 0.06) for etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. Opioid-related AEs occurred in 41.8%, 34.7%, 36.5%, and 36.3% of patients on placebo, etoricoxib 90 mg, etoricoxib 120 mg, and ibuprofen, respectively. CONCLUSIONS: Postoperative use of etoricoxib 90 and 120 mg in patients undergoing total knee replacement is both superior to placebo and non-inferior to ibuprofen in reducing pain at rest and also reduces opioid (morphine) consumption. CLINICAL TRIAL REGISTRATION: NCT00820027.

In vitro biotransformation, in vivo efficacy and pharmacokinetics of antimalarial chalcones.

4'-n-Butoxy-2,4-dimethoxy-chalcone (MBC) has been described as protecting mice from an otherwise lethal infection with Plasmodium yoelii when dosed orally at 50 mg/kg/dose, daily for 5 days. In contrast, we found that oral dosing of MBC at 640 mg/kg/dose, daily for 5 days, failed to extend the survivability of P. berghei-infected mice. The timing of compound administration and metabolic activation likely contribute to the outcome of efficacy testing in vivo. Microsomal digest of MBC yielded 4'-n-butoxy-4-hydroxy-2-methoxy-chalcone and 4'-(1-hydroxy-n-butoxy)-2,4-dimethoxy-chalcone. We propose that the latter will hydrolyze in vivo to 4'-hydroxy-2,4-dimethoxy-chalcone, which has greater efficacy than MBC in our P. berghei-infected mouse model and was detected in plasma following oral dosing of mice with MBC. Pharmacokinetic parameters suggest that poor absorption, distribution, metabolism and excretion properties contribute to the limited in vivo efficacy observed for MBC and its analogs.

Lower gastrointestinal events in a double-blind trial of the cyclo-oxygenase-2 selective inhibitor etoricoxib and the traditional nonsteroidal anti-inflammatory drug diclofenac.

BACKGROUND & AIMS: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause lower gastrointestinal (GI) clinical events such as bleeding. Cyclo-oxygenase (COX)-2 selective inhibitors decrease upper GI events, but no prospective trial has prespecified assessment of lower GI clinical events. METHODS: Patients >or=50 years old with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd). Lower GI clinical events, confirmed by a blinded adjudication committee, included perforation or obstruction requiring hospitalization or bleeding (gross or occult rectal bleeding without upper GI cause associated with hypotension, orthostatic changes in heart rate [>20 beats per minute] or blood pressure [>20 mmHg systolic or >10 mmHg diastolic], hemoglobin drop >or=2 g/dl, or transfusion; or observed active bleeding or stigmata of hemorrhage). RESULTS: We enrolled 34,701 patients with mean duration of therapy of 18 months. Rates were 0.32 and 0.38 lower GI clinical events per 100 patient-years for etoricoxib and diclofenac (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.63-1.13). Bleeding was the most common event (rates of 0.19 and 0.23 per 100 patient-years, respectively). Multivariable analysis revealed significant risk factors to be prior lower GI event (HR = 4.06; 95% CI, 2.93-5.62) and age >or=65 years (HR = 1.98; 95% CI, 1.45-2.71). CONCLUSIONS: A statistically significant decrease in lower GI clinical events was not seen with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. The risk of a lower GI clinical event with NSAID use seems to be constant over time, and the major risk factors are a prior lower GI event and older age.

How common is diclofenac-associated liver injury? Analysis of 17,289 arthritis patients in a long-term prospective clinical trial.

OBJECTIVES: Few data are available from prospective trials to define the hepatotoxicity of diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world. We determined the rate of laboratory and clinical adverse hepatic effects in a large double-blind trial of diclofenac. METHODS: Patients > or = 50 years with rheumatoid arthritis or osteoarthritis were randomly assigned to diclofenac (150 mg daily) or etoricoxib (60 or 90 mg daily). Patients with hepatic disease or who reported > or = 14 alcoholic drinks weekly were excluded. Patients had visits (with liver tests) every 4 months and were contacted by phone between visits and every 6 months after discontinuation until the end of the study. Causality assessment was performed for liver-related hospitalizations, Hy's cases (serious adverse events with AST or ALT >3 x upper limit of normal (ULN) and bilirubin >2 xULN), and liver failure/transplant/death. RESULTS: A total of 17,289 patients received diclofenac for a mean of 18 months. Liver end points with diclofenac were ALT/AST>3 xULN: 527(3.1%); ALT/AST >10 xULN: 86(0.5%); liver-related hospitalizations: 4(0.023%); Hy's cases: 2(0.012%); liver failure/death/transplant: 0. Aminotransferase elevations occurred primarily within the first 4-6 months of therapy, whereas liver-related hospitalizations occurred between 9 days and 21 months. CONCLUSIONS: Diclofenac is commonly associated with aminotransferase elevations, generally in the first 4-6 months of therapy. Clinical liver events requiring hospitalization are relatively rare (23/100,000 patients), but may develop early or late in therapy. The markedly increased rate of aminotransferase elevation with diclofenac may not be paralleled by a proportional marked increase in clinical liver events, although clinical events potentially also may be decreased with regular monitoring in a clinical trial setting.

Cardiovascular safety and gastrointestinal tolerability of etoricoxib vs diclofenac in a randomized controlled clinical trial (The MEDAL study).

OBJECTIVE: To compare cardiovascular (CV) and other safety and efficacy parameters of etoricoxib 60 and 90 mg, and diclofenac 150 mg. METHODS: This double-blind study randomized OA patients to etoricoxib 90 mg, then to 60 mg once daily vs diclofenac 75 mg twice daily; RA patients were randomized to etoricoxib 90 mg once daily or diclofenac 75 mg twice daily. The primary endpoint was non-inferiority of etoricoxib vs diclofenac for thrombotic CV events (95% CI upper bound of hazard ratio <1.30). Other safety and efficacy parameters were evaluated in cohorts of patients based on etoricoxib dose and disease. RESULTS: A total of 23 504 patients were randomized with mean treatment duration from 19.4 to 20.8 months. The thrombotic CV risk hazard ratio (HR) (etoricoxib to diclofenac) was 0.96 (95% CI 0.81, 1.15), consistent with non-inferiority of etoricoxib to diclofenac. The cumulative gastrointestinal (GI)/liver adverse events (AEs) discontinuation rate was significantly lower for etoricoxib than diclofenac in each patient cohort; HR (95% CI) of 0.46 (0.39, 0.54), 0.52 (0.42, 0.63) and 0.49 (0.39, 0.62) for the 60 mg OA, 90 mg OA and RA cohorts. The maximum average change in systolic blood pressure (BP) with etoricoxib was 3.4-3.6 mmHg (diastolic BP: 1.0-1.5 mmHg), while diclofenac produced a maximum average change of 0.9-1.9 mmHg (diastolic BP: 0.0-0.5 mmHg). Both agents resulted in similar efficacy regardless of etoricoxib dose. CONCLUSION: Long-term etoricoxib use is associated with a risk of thrombotic CV events comparable with that of diclofenac. Compared with diclofenac, etoricoxib demonstrated a greater risk of renovascular AEs, but a more favourable GI/liver tolerability profile.

Baseline factors associated with congestive heart failure in patients receiving etoricoxib or diclofenac: multivariate analysis of the MEDAL program.

AIMS: Non-steroidal anti-inflammatory drugs have been associated with increased risk of congestive heart failure (CHF). We aimed to assess the impact of treatment with etoricoxib or diclofenac on risk of CHF relative to baseline risk factors. METHODS AND RESULTS: We performed a multivariate analysis of 34 701 patients with arthritis receiving etoricoxib 60 or 90 mg, or diclofenac 150 mg, daily for a mean of 18 months, to assess the incidence of confirmed, adjudicated CHF events resulting in emergency room visit or hospitalization. Analyses were performed using a Cox proportional hazard model to evaluate the hazard ratio (HR) between the levels of each risk marker for the incidence of CHF. Significant risk markers included history of CHF (HR: 6.69, 95% CI 3.59-12.47; P <0.0001), age > or = 65 years (2.56, 1.65-3.98; P <0.0001), and history of hypertension (1.83, 1.16-2.89; P = 0.0094) or diabetes (1.83, 1.15-2.94; P = 0.0116). Etoricoxib vs. diclofenac was a significant risk factor only when pooling the etoricoxib 90 mg cohorts (1.88; 1.13-3.10; P = 0.0143). Etoricoxib 60 mg did not significantly increase risk vs. diclofenac. CONCLUSION: History of CHF was highly associated with risk for CHF hospitalization. Hypertension, diabetes, and older age also increased risk modestly. There appeared to be a dose-related increase in CHF with etoricoxib compared with diclofenac, which reached statistical significance when the etoricoxib 90 mg groups (osteoarthritis and rheumatoid arthritis) were pooled.

ICCD: interactive continuous collision detection between deformable models using connectivity-based culling.

We present an interactive algorithm for continuous collision detection between deformable models. We introduce multiple techniques to improve the culling efficiency and the overall performance of continuous collision detection. First, we present a novel formulation for continuous normal cones and use these normal cones to efficiently cull large regions of the mesh as part of self-collision tests. Second, we introduce the concept of "procedural representative triangles" to remove all redundant elementary tests between nonadjacent triangles. Finally, we exploit the mesh connectivity and introduce the concept of "orphan sets" to eliminate redundant elementary tests between adjacent triangle primitives. In practice, we can reduce the number of elementary tests by two orders of magnitude. These culling techniques have been combined with bounding volume hierarchies and can result in one order of magnitude performance improvement as compared to prior collision detection algorithms for deformable models. We highlight the performance of our algorithm on several benchmarks, including cloth simulations, N-body simulations, and breaking objects.

Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison.

BACKGROUND: Upper gastrointestinal safety of cyclo-oxygenase (COX)-2 selective inhibitors versus traditional non-steroidal anti-inflammatory drugs (NSAIDs) has not been assessed in trials that simulate standard clinical practice. Our aim was to assess the effects of these drugs on gastrointestinal outcomes in a population that includes patients taking gastrointestinal protective therapy. METHODS: A prespecified pooled intent-to-treat analysis of three double-blind randomised comparisons of etoricoxib (60 or 90 mg daily) and diclofenac (150 mg daily) in 34 701 patients with osteoarthritis or rheumatoid arthritis was done for upper gastrointestinal clinical events (bleeding, perforation, obstruction, or ulcer) and the subset of complicated events (perforation, obstruction, witnessed ulcer bleeding, or significant bleeding). We also assessed such outcomes in patients who were taking concomitant proton pump inhibitors (PPIs) or low-dose aspirin. These trials are registered with , with the numbers , , and . FINDINGS: Overall upper gastrointestinal clinical events were significantly less common with etoricoxib than with diclofenac (hazard ratio [HR] 0.69, 95% CI 0.57-0.83; p=0.0001). There were significantly fewer uncomplicated gastrointestinal events with etoricoxib than there were with diclofenac (0.57, 0.45-0.74; p<0.0001); there was no difference in complicated events (0.91, 0.67-1.24; p=0.561). PPIs were used concomitantly for at least 75% of the study period by 13 862 (40%) and low-dose aspirin by 11 418 (33%) patients; treatment effects did not differ significantly in these individuals. INTERPRETATION: There were significantly fewer upper gastrointestinal clinical events with the COX-2 selective inhibitor etoricoxib than with the traditional NSAID diclofenac due to a decrease in uncomplicated events, but not in the more serious complicated events. The reduction in uncomplicated events with etoricoxib is maintained in patients treated with PPIs and is also observed with regular low-dose aspirin use.

Real-time path planning in dynamic virtual environments using multiagent navigation graphs.

We present a novel approach for efficient path planning and navigation of multiple virtual agents in complex dynamic scenes. We introduce a new data structure, Multi-agent Navigation Graph (MaNG), which is constructed using first- and second-order Voronoi diagrams. The MaNG is used to perform route planning and proximity computations for each agent in real time. Moreover, we use the path information and proximity relationships for local dynamics computation of each agent by extending a social force model [Helbing05]. We compute the MaNG using graphics hardware and present culling techniques to accelerate the computation. We also address undersampling issues and present techniques to improve the accuracy of our algorithm. Our algorithm is used for real-time multi-agent planning in pursuit-evasion, terrain exploration and crowd simulation scenarios consisting of hundreds of moving agents, each with a distinct goal.

Investigation of smoothness-increasing accuracy-conserving filters for improving streamline integration through discontinuous fields.

Streamline integration of fields produced by computational fluid mechanics simulations is a commonly used tool for the investigation and analysis of fluid flow phenomena. Integration is often accomplished through the application of ordinary differential equation (ODE) integrators--integrators whose error characteristics are predicated on the smoothness of the field through which the streamline is being integrated--smoothness which is not available at the inter-element level of finite volume and finite element data. Adaptive error control techniques are often used to ameliorate the challenge posed by inter-element discontinuities. As the root of the difficulties is the discontinuous nature of the data, we present a complementary approach of applying smoothness-enhancing accuracy-conserving filters to the data prior to streamline integration. We investigate whether such an approach applied to uniform quadrilateral discontinuous Galerkin (high-order finite volume) data can be used to augment current adaptive error control approaches. We discuss and demonstrate through numerical example the computational trade-offs exhibited when one applies such a strategy.

Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison.

BACKGROUND: Cyclo-oxygenase-2 (COX-2) selective inhibitors have been associated with an increased risk of thrombotic cardiovascular events in placebo-controlled trials, but no clinical trial has been reported with the primary aim of assessing relative cardiovascular risk of these drugs compared with traditional non-steroidal anti-inflammatory drugs (NSAIDs). The MEDAL programme was designed to provide a precise estimate of thrombotic cardiovascular events with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. METHODS: We designed a prespecified pooled analysis of data from three trials in which patients with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac (150 mg daily). The primary hypothesis stated that etoricoxib is not inferior to diclofenac, defined as an upper boundary of less than 1.30 for the 95% CI of the hazard ratio for thrombotic cardiovascular events in the per-protocol analysis. Intention-to-treat analyses were also done to assess consistency of results. These trials are registered at http://www.clinicaltrials.gov with the numbers NCT00092703, NCT00092742, and NCT00250445. FINDINGS: 34 701 patients (24 913 with osteoarthritis and 9 787 with rheumatoid arthritis) were enrolled. Average treatment duration was 18 months (SD 11.8). 320 patients in the etoricoxib group and 323 in the diclofenac group had thrombotic cardiovascular events, yielding event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 (95% CI 0.81-1.11) for etoricoxib compared with diclofenac. Rates of upper gastrointestinal clinical events (perforation, bleeding, obstruction, ulcer) were lower with etoricoxib than with diclofenac (0.67 vs 0.97 per 100 patient-years; hazard ratio 0.69 [0.57-0.83]), but the rates of complicated upper gastrointestinal events were similar for etoricoxib (0.30) and diclofenac (0.32). INTERPRETATION: Rates of thrombotic cardiovascular events in patients with arthritis on etoricoxib are similar to those in patients on diclofenac with long-term use of these drugs.

Clinical trial design and patient demographics of the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) study program: cardiovascular outcomes with etoricoxib versus diclofenac in patients with osteoarthritis and rheumatoid arthritis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently needed for the treatment of patients with arthritis. However, long-term use of such drugs that are cyclooxygenase-2 (COX-2) selective inhibitors has been reported to increase cardiovascular risk as compared with placebo, whereas long-term, randomized controlled trials assessing the risk of traditional NSAIDs versus placebo are lacking. The MEDAL program is designed to provide a precise estimate of the relative cardiovascular event rates with the COX-2 selective inhibitor etoricoxib in comparison to the traditional NSAID diclofenac in patients with osteoarthritis and rheumatoid arthritis. The MEDAL program consists of 3 multinational, randomized, double-blind trials in patients with osteoarthritis and rheumatoid arthritis comparing etoricoxib (60 or 90 mg daily) to diclofenac (150 mg daily). All investigator-reported thrombotic cardiovascular events will be adjudicated by an independent panel of experts blinded to treatment assignment. The primary analysis is a noninferiority comparison of etoricoxib versus diclofenac for confirmed thrombotic cardiovascular events, defined as an upper bound of the 95% CI for a hazard ratio of < 1.30. With the planned 635 observed events from approximately 40,000 patient-years of exposure, using an estimated annual event rate of 1.30% in the control arm, the maximum annual event rate for etoricoxib that would meet the noninferiority criteria would be approximately 1.46%, yielding a hazard ratio of 1.12. A total of 34,701 patients have been enrolled in the MEDAL program. Roughly 13,000 and 10,000 patients will, respectively, have had > or = 18 or > or = 24 months of exposure, with maximum exposure of approximately 40 months. The MEDAL program will help to better define the risk-to-benefit ratio of 2 NSAIDs, that differ in their selectivity for COX-2, notably diclofenac and etoricoxib.

Designed cocrystals based on the pyridine-iodoalkyne halogen bond.

Diiodobutadiyne (1) and diiodohexatriyne (2) form cocrystals with bispyridyl oxalamides and ureas, based on the halogen bond between the alkynyl iodine and pyridine nitrogen. In each cocrystal, the oxalamide or urea host forms one-dimensional hydrogen-bonded networks, aligning the diiodopolyyne for potential topochemical polymerization with a repeat distance matching the host repeat.