Integration of Material Characterization, Thermoforming Simulation, and As-Formed Structural Analysis for Thermoplastic Composites.

An improved simulation-based thermoforming design process based on the integration of material characterization and as-formed structural analysis is proposed. The tendency of thermoplastic composites to wrinkle during forming has made simulation critical to optimized manufacturing, but the material models required are complex and time consuming to create. A suite of experimental methods has been developed for measurement of several required properties of the molten thermoplastic composite. These methods have the potential to enhance thermoplastic composites manufacturing by simplifying and expediting the process. These material properties have been verified by application to thermomechanical forming predictions using commercial simulation software. The forming predictions showed improved agreement with experimental results compared to those using representative material properties. A tool for using thermoforming simulations to inform more accurate structural models has been tested on a simple case study, and produced results that clearly differ from those of models using idealized fiber orientations and thicknesses. This provides evidence that this type of as-formed analysis may be necessary in some cases, and may be further investigated as an open source alternative to commercial analysis software.

Apomorphine subcutaneous infusion in patients with Parkinson's disease with persistent motor fluctuations (TOLEDO): a multicentre, double-blind, randomised, placebo-controlled trial.

BACKGROUND: Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment. METHODS: In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121). FINDINGS: Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events. INTERPRETATION: Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy. FUNDING: Britannia Pharmaceuticals.

Clinical significance of C-reactive protein levels in predicting responsiveness to iron therapy in patients with inflammatory bowel disease and iron deficiency anemia.

BACKGROUND: Iron deficiency anemia (IDA) is a common complication of inflammatory bowel disease (IBD). In clinical practice, many patients receive initial treatment with iron tablets although intravenous (i.v.) iron supplementation is often preferable. AIM: This study investigated whether systemic inflammation at initiation of treatment (assessed by C-reactive protein [CRP] and interleukin-6 [IL-6] measurements) predicts response to iron therapy. METHODS: Data from a previously published phase III trial were retrospectively analyzed after stratification of patients according to baseline CRP (> 4 vs. ≤ 4 mg/L) and IL-6 (> 6 vs. ≤ 6 pg/mL) levels. The study population consisted of patients with Crohn's disease or ulcerative colitis and IDA (Hb ≤ 110 g/L and TSAT < 20 % or serum ferritin < 100 ng/mL), randomized to either oral (ferrous sulfate) or i.v. iron (ferric carboxymaltose). RESULTS: A total of 196 patients were evaluated (oral iron: n = 60; i.v. iron: n = 136). Baseline CRP and IL-6 levels were independent of patients' initial Hb levels and iron status (serum ferritin and TSAT; all p > 0.05). Among iron tablet-treated patients, Hb increase was significantly smaller in the high- versus low-CRP subgroup (1.1 vs. 2.0, 2.3 vs. 3.1, and 3.0 vs. 4.0 g/dL at weeks 2, 4, and 8, respectively; all p < 0.05). Differences were less pronounced with stratification according to baseline IL-6. Response to i.v. iron was mainly independent of inflammation. CONCLUSIONS: Patients with high baseline CRP achieved a lower Hb response with oral iron therapy. Our results suggest that CRP may be useful to identify IBD patients who can benefit from first-line treatment with i.v. iron to improve their IDA.

Anaemia from a patient perspective in inflammatory bowel disease: results from the European Federation of Crohn's and Ulcerative Colitis Association's online survey.

OBJECTIVE: Anaemia is frequently seen in inflammatory bowel disease (IBD) and needs appropriate treatment. This online questionnaire investigated the patients' perceptions of anaemia: symptoms, prevalence, treatment and impact on quality of life. METHODS: Patients participated in this survey in 2012. Respondents were mainly from Europe, but also from North America and Asia Pacific. RESULTS: A total of 631 patients completed the questionnaire; most had Crohn's disease, and 41.2% were in remission, 29.8% had mildly active flares, 16.8% had moderately active flares, and 5.4% had severely active flares. When asked about anaemia, 67% believed that anaemia occurred frequently in IBD and was associated with blood loss (45%), iron deficiency (31%), or inflammation (18%). Symptoms commonly reported by patients with anaemia were fatigue and weakness. Fatigue associated with anaemia occurred daily in 53% of patients and negatively impacted the quality of life.A number of patients had not discussed anaemia with a healthcare professional, and 33% of patients with anaemia had not received treatment. Of those treated, 42% took oral prescription iron, 27% intravenous iron, 19% nonprescription iron supplements and 10% prescription liquid or syrup iron. The majority of patients taking liquid or syrup iron (77%), oral iron (74%) and iron supplements (68%) were dissatisfied with their treatment, primarily because of poor tolerability. In contrast, 72% were satisfied with intravenous iron treatment. CONCLUSION: IBD patients are mostly aware of the main signs and symptoms of anaemia. Oral iron is most commonly prescribed, but may cause dissatisfaction because of tolerability issues. Most patients prescribed intravenous iron are satisfied with treatment.