Search

The equilibrium and kinetics of the furan-maleimide Diels-Alder (DA) reaction for the formation of a reversible network were studied by calorimetry between 25 °C and 90 °C using an amorphous bismaleimide eliminating solvent use. The relationship between the equilibrium conversion x eq with temperature and the effect of dilution were simulated. The glass transition-conversion relationship of the reversible network was established. The thermophysical properties of the reversible network were linked to the kinetics and equilibrium of the DA system, and studied by dynamic mechanical analysis (DMA), dielectric analysis (DEA) and rheometry. Below T g the reversible network behaves like an irreversible network; however, above T g , a decrease in the rubber tensile storage modulus was observed due to a reduction of cross-link density caused by the retro DA reaction. DEA revealed that above T g , an interface is formed between released bismaleimide molecules and the remaining network. The rheological behavior is related to x eq and the lifetime of the reversible covalent bonds. When x eq is higher than the gelation conversion x gel (below 90 °C), the system gels at constant x gel . An elastic strengthening effect is observed in a transition region between 90 °C and 115 °C. Above 115 °C the system is reaching a viscous melt behavior. These observations are important for the application of this network as a self-healing material and as a recyclable elastomer or thermoset. [ABSTRACT FROM AUTHOR]

Previously determined degradation mechanisms of a model polymer compound, poly(vinyl acetate) (PVAc), blended with two different flame retardants, ammonium poly(phosphate) (APP) and melamine isocyanurate (MIC), were used for reaction rate parameter optimization using a kinetic modelling and simulation software. Rate parameters for all different decomposition reactions were established for inert and oxidative conditions, giving insight into all interactions between flame retardants and polymer. Analyzing kinetic data, it was found that APP catalyzes the deacetylation reaction of PVAc, independent from the mixing ratio, and has a higher catalyzing effect than oxygen. Down to ten parts APP per one hundred parts of PVAc, APP is also a very efficient crosslinker with PVAc upon decomposition. MIC on the other hand acts in two ways: as heat-sink flame retardant during deacetylation and charring of the polymer, whereas during this charring step, another part of MIC crosslinks with PVAc. Simulations using kinetic parameter sets of PVAc/MIC and PVAc/APP blends showed that MIC and APP interact independently with PVAc when both flame retardants are mixed together into PVAc. A very efficient flame retarded composite is as such obtained at low loading levels. [ABSTRACT FROM AUTHOR]

Fast scanning chip calorimetry was utilized to investigate the thermal behaviour of a submicron layer of P3HT, an important polymer for organic electronics, when isothermally treated below and inside the glass transition region. A similar study was performed on the conventional polyester PBT, for comparison. It was observed that a heating and cooling rate of 30 000 K s −1 was sufficient to avoid all non-isothermal effects for P3HT, while the faster reordering kinetics of PBT still allowed reordering upon heating at these scanning rates. For both materials, treatments clearly below the glass transition region yield enthalpic relaxation of the glass phase. When treatments are performed inside the glass transition region, however, a combined process of both enthalpic relaxation and the melting of small (nano-sized), imperfect crystals is observed. Due to the influence of the glass phase on the crystallization process, it seems that large, more stable crystals can not be formed. Significant isothermal perfectioning can be observed for the imperfect crystals in P3HT, while very fast non-isothermal reordering upon heating is seen for PBT. An approach based on a 2-step nucleation mechanism of crystallization may be used to interpret the observations of polymer crystallization around and in the glass transition region. [ABSTRACT FROM AUTHOR]

Using the advanced thermal analysis technique of fast scanning chip calorimetry, an isothermal crystallization study was undertaken on poly(3-hexyl thiophene) (P3HT), a workhorse material for organic photovoltaics (OPVs). As a model system, poly(butylene terephthalate) (PBT), a polyester with similar transition temperatures was first analyzed. By using gold foil as a substrate, it was possible to perform this study on thin layers, making the results more applicable for actual OPVs, where thin layers are used for charge generation. Using heating and cooling rates of 30 000 K s −1 , all non-isothermal processes could be avoided, and the evolution of isothermally formed crystals could be analyzed. The bell-shaped curve of crystallization rate as a function of isothermal crystallization temperature was constructed for a ca. 550 nm thin P3HT layer. [ABSTRACT FROM AUTHOR]

Aim Diarrhoea with urgency is a debilitating long-term complication of ileal pouch anal anastomosis (IPAA) after a proctocolectomy. Somatostatin analogues are used to control diarrhoea and high-output ostomies. Hence, we designed a prospective, double-blind, crossover trial to explore the efficacy and tolerability of octreotide to reduce diarrhoea in adult patients with IPAA. Method Patients were randomized to octreotide subcutaneously (SC), 500 μg three times daily (t.i.d.), or matching placebo SC for 7 days. Responders (a reduction in stool frequency of three or more stools per 24-h period and with a reduction in stool frequency of at least 30% after 7 days of treatment compared with baseline; the primary end-point) remained in the same group and nonresponders could cross over to the alternative treatment for 7 days. Open-label octeotide LAR 30 mg was offered to all responders on day 14. Flexible pouchoscopy with biopsies was performed at baseline in all patients and was repeated on days 7 and 14 in patients with pouchitis. Results Fifteen patients (11 men, median age 52 years), all with ulcerative colitis, were randomized. Three patients were withdrawn for side effects during the blinded phase. Response was achieved by two of 12 and two of 11 patients treated with octreotide or placebo, respectively (including crossover, P = 0.9). The median stool frequency remained stable in both groups [Δoctreotide: 0 (IQR, −4 to 0), Δplacebo: −1 (IQR, −1 to 1), P = 0.45]. Octreotide had no effect on the modified pouch disease activity index (mPDAI), and pouchitis persisted in five of six subjects with pouchitis at onset. One subject received open-label octreotide LAR. Conclusion Octreotide has no clear beneficial effect on the stool pattern or on pouchitis severity in patients with high stool frequency after IPAA. [ABSTRACT FROM AUTHOR]

Background Endoscopic dilatation of Crohn's diseaserelated strictures is an alternative to surgical resection in selected patients. The influence of disease activity and concomitant medical therapy on long-term outcomes is largely unknown. Aim and methods To study the long-term safety and efficacy of stricture dilatation in a single centre cohort. Results Between 1995 and 2006, 237 dilatations where performed in 138 patients (mean age 50.6613.4, 56% female) for a clinically obstructive stricture (<5 cm, 84% anastomotic). Immediate success of a first dilatation was 97% with a 5% serious complication rate. After a median follow-up of 5.8 years (IQR 3.0e8.4), recurrent obstructive symptoms led to a new dilatation in 46% or surgery in 24%. Niether elevated levels of C-reactive protein nor endoscopic disease activity predicted the need for new intervention. None of the concomitant therapies influenced the outcome. Conclusion This largest series ever reported confirms that long term efficacy of endoscopic dilatation of Crohn's disease outweighs the complication risk. Neither active disease at the time of dilatation nor medical therapy afterwards predict recurrent dilatation or surgery. [ABSTRACT FROM AUTHOR]

Abstract: Shape memory polyurethanes (SMPUs) have been synthesised via a novel synthetic methodology, resulting in an improvement of the phase separation in the multi-block structure of the polyurethane and in its shape memory properties. ABA block copolymers based on semi-crystalline poly(ɛ-caprolactone) and amorphous poly(propylene oxide) (PPO) were used as precursor for the SMPUs. For their synthesis, poly(ɛ-caprolactone) diols have been converted into isocyanate end-capped prepolymers by using a mixture of 3(4) isocyanato-1-methyl-cyclohexylisocyanate isomers, after which a coupling with low-T g poly(propylene oxide) oligomers is done. The shape memory polymers are obtained by reaction of the ABA block copolymers with hexamethylenediisocyanate and 1,4-butanediol as chain extender. Using this new strategy, a flexible segment (PPO) was introduced between the hard and the switching segments of the SMPU. For comparison, SMPUs without flexible segment have also been prepared with the conventional synthetic route. DSC, isostrain experiments and cyclic shape memory tests revealed narrower switching temperatures for the SMPUs including a flexible segment. [Copyright &y& Elsevier]

Background The natural course of Crohn's disease is characterized by flare-ups altered with periods of remission. The majority of Crohn's disease patients need surgery within 10 years of diagnosis. Major advances in treatment options over the past years have made our treatment goals more ambitious and modification of the natural course has become the ultimate endpoint. Aim To review the evidence of existing therapies for Crohn's disease for changing the natural history. Methods A Medline search was undertaken by using ‘natural history’, ‘Crohn's disease’, ‘therapy’ (corticosteroids, azathioprine, methotrexate, infliximab and enteral feeding), ‘surgery’, ‘hospitalizations’ and ‘mucosal healing’. Results Corticosteroids do not alter the disease course and maintenance therapy with corticosteroids should be avoided given their side effects. The immunomodulators azathioprine and methotrexate heal the mucosa but their onset of action is slow. Infliximab therapy introduces rapid mucosal healing and is associated with decreased hospitalizations and surgical interventions. Despite the fact that immunomodulators and infliximab are effective in maintaining clinical and endoscopic remission, there is little hard evidence at present that these therapies alter the natural history of the disease. The main reason being the fact that these therapies have so far been used only in refractory patients and that early initiation in the right patient is crucial in order to change the disease course. Conclusion Prospective studies should validate predictors of complicated disease and randomized studies in high-risk groups should be performed to answer if early introduction of immunomodulators or biological therapies slows down disease progression and alters natural history. [ABSTRACT FROM AUTHOR]

Background: An uncontrolled pilot study demonstrated that daclizumab, a humanised monoclonal antibody to the interleukin 2 receptor (CD25), might be effective for the treatment of active ulcerative colitis. Methods: A randomised, double blind, placebo controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis. A total of 159 patients with moderate ulcerative colitis were randomised to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4, and 6, or placebo. The primary end point was induction of remission at week 8. Remission was defined as a Mayo score of 0 on both endoscopy and rectal bleeding components and a score of 0 or 1 on stool frequency and physician's global assessment components. Response was defined as a decrease from baseline in the Mayo score of at least 3 points. Results: Two per cent of patients receiving daclizumab 1 mg/kg (p = 0.11 v placebo) and 7% of patients receiving 2 mg/kg (p=0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p=0.04) and in 33% of patients receiving 2 mg/kg (p=0.30) versus 44% of those receiving placebo. Daclizumab was well tolerated. The most frequently reported adverse events in daclizumab treated patients compared with placebo treated patients were nasopharyngitis (14.6%) and pyrexia (10.7%). Conclusion: Patients with moderate ulcerative colitis who are treated with daclizumab are not more likely to be in remission or response at eight weeks than patients treated with placebo. [ABSTRACT FROM AUTHOR]

Laboratory markers have been investigated in inflammatory bowel disease (IBD) for diagnostic and differential diagnostic purposes, for assessment of disease activity and risk of complications, for prediction of relapse, and for monitoring the effect of therapy. The introduction of biological therapies in IBD has renewed interest in inflammatory markers (especially C reactive protein (CRP)), given their potential to select responders to these treatments. Of all the laboratory markers, CRP is the most studied and has been shown to have the best overall performance. CRP is an objective marker of inflammation and correlates well with disease activity in Crohn's disease (CD). Increased CRP levels are associated with better response rates and normal CRP levels predict high placebo response rates in clinical trials with biologicals. However, despite the advantages of CRP over other markers, it is still far from ideal. Furthermore, CRP correlates less well with disease activity in patients with ulcerative colitis (UC) as compared with CD. Other laboratory markers, including erythrocyte sedimentation rate (ESR), leucocyte and platelet count, albumin, and α1 acid glycoprotein (orosomucoid), have been studied either less extensively in IBD or have proven to be less useful than CRP. Faecal markers seem promising and may be more specific in detecting gut inflammation in patients with established IBD. Promising results have been reported with the use of faecal calprotectin in CD as well as in UC. Recent data however suggest that the performance of the faecal calprotectin test is superior for UC than for CD. Taken together, laboratory markers are useful and should be part of the global management of our IBD patients. They are however not magic and until more data become available, the use of CRP and other laboratory markers should be seen as an additive tool to clinical observation and physical examination rather than a replacement. [ABSTRACT FROM AUTHOR]

Micro[hyphen]thermal analysis was used for studying interphases formed in particle[hyphen]filled composites based on an epoxy resin matrix. The subsurface distribution of the particles can be observed in the conductivity images, while spatial variations in thermal properties can be determined by local thermal analyses.For an anhydride[hyphen]cured epoxy system filled with porous silica particles, an interphase is observed around the particles. In the ca. 60 μm wide interphase, the glass transition temperature gradually decreases from the bulk value to a value about 10 °C lower. The less densely cross[hyphen]linked interphase can be detected in the thermal conductivity images and in the local thermal analyses. The interphase formation is attributed to the effect of adsorbed water on the polymerisation mechanism. [Copyright &y& Elsevier]

Diffusion limitations have an impact on epoxy cure reactions near vitrification. The effects of diffusion control on the rate of reaction can be described by the evolution of a mobility factor, which is directly based on the experimental heat capacity evolution measured with differential (scanning) temperature modulated calorimetry (D(S)TMC) as diffusion and mobility factor coincide for the epoxy resins studied. A model based on the free volume theory and the Rabinowitch activated complex theory is presented here. It relates the apparent rate constant to the difference between the reaction temperature and Tg. Very good correlations are derived between model calculations and the experimental normalized mobility factor measured at 1/60 Hz. A further extension of the model to allow for experimental mobility factors measured at different modulation frequencies is also proposed. The model successfully predicts the deceleration of reactions due to diffusion limitations, which demonstrates the applicability of D(S)TMC to estimate the effect of the reaction-induced vitrification on the polymerization and to model the overall cure kinetics. [Copyright &y& Elsevier]

Motilin has excitatory effects on the colon of the rabbit and the dog, but little is known of its effect on the human colon. The aim of this study was to investigate the effects induced by motilin and erythromycin A (EMA) on muscle strips and on single cells from primary cultures from human colon. Isotonic contraction was recorded in circular muscle strips from macroscopically normal resection specimens of patients operated on for colonic neoplasm. Agonist-induced intracellular Ca2+ ([Ca2+]i) signalling was studied in primary cultures of colonic smooth-muscle cells using the ratiometric Ca2+ indicator Indo 1, on a laser-scanning confocal epifluorescence microscope. In circular muscle strips, norleucine13-porcine motilin ([Nle13]-pm)and EMA induced tonic contractions with an EC50 of 92 ± 21 nmol L-1 and 31 ± 16 μmol L-1, respectively. The maximal contraction was 21 ± 4% (motilin) and 33 ± 12% (EMA) of the response to 10-4 mol L-1 acetylcholine (ACh). The motilin antagonist OHM-11526 (10-5.5 mol L-1) abolished the effects of both [Nle13]-pm and EMA. Neither tetrodotoxin (10-5.5 mol L-1), L-nitro-D-arginine methyl ester (L-NAME) (10-3.5 mol L-1) nor guanethidine (10-5 mol L-1) interfered with the effects of [Nle13]-pm or EMA. [Nle13]-pm (10-11-10-6 mol L-1) induced rises of [Ca2+]i in cultured colonic myocytes. At 10-6 mol L-1, 94% of the cells responded, and half of the cells responded at 1.4 nmol L-1 [Nle13]-pm. 81% (35/43) and 95% (75/79) responded to EMA (10-6 mol L-1) and acetylcholine (ACh, 10-4 mol L-1), respectively. The motilin antagonist GM-109 inhibited motilin- and EMA-induced [Ca2+]i rises. In the absence of extracellular Ca2+, only 13% (7/52) of the cells responded to [Nle13]-pm (10-6 mol L-1) vs. 90% (47/52) to ACh (10-4 mol L-1). Motilin and EMA have direct excitatory effects on circular smooth muscle from the human colon and these effects are mediated via a smooth-muscle motilin receptor. These findings suggest that motilin may regulate colonic motility and that motilides may have therapeutic potential for the treatment of colonic hypomotility. [ABSTRACT FROM AUTHOR]

Trinitrobenzenesulphonic acid (TNBS)-induced colitis decreases the contractile response of the rabbit colon to motilin, and inflammation may increase plasma motilin levels. We studied whether the decreased contractility could be due to a down-regulation of motilin receptors, caused by increased plasma motilin levels. As this would affect all tissues, uninflamed sites were studied as well. Colitis was induced by different doses (100–150 mg kg-1) of TNBS. In the colon, the TNBS dose-dependent decrease of the contractile response towards motilin was reflected in a decrease in motilin receptor density. In contrast, in the antrum, receptors were upregulated by 150 mg kg-1 TNBS, while central motilin receptors in the cerebellum were not affected. Plasma motilin levels were not influenced by inflammation, although the motilin content and mRNA expression in the duodenal and jejunal mucosa, but not in the colon, was significantly increased. The opposite was true for interleukin-1β and interleukin receptor antagonist mRNA expression. We conclude that the decreased motilin contractility in rabbit colitis is due to a downregulation of motilin receptors in the colon, but this is not caused by chronic hormonal stimulation. [ABSTRACT FROM AUTHOR]

Abstract The healing behavior of a dynamically reversible covalent polymer network with a T g of 3 °C, based on the reversible Diels-Alder (DA) cycloaddition between furan and maleimide moieties is reported, for both room-temperature and heating-mediated healing. In previous work the dynamic character of the DA cycloaddition reaction in a polymer network was studied, those findings are used to understand its healing ability. The recovery of mechanical properties by intrinsic healing is studied by Dynamic Mechanical Analysis, quantifying the loss in properties due to incurred damage and assessing their recovery with respect to the original material. The DA cycloadduct bonds in the network can be mechanically activated to autonomously heal damage at room temperature if the damage surfaces remain activated. If the damage surfaces are not brought in contact fast enough they reestablish equilibrium (aging) and lose their autonomous healing potential. In the latter case, only heating-mediated healing can occur, reactivating the healing ability. Controlled damage formation and subsequent sealing of the damage of network coatings is monitored by Atomic Force Microscopy and optical microscopy. The repeatability for both mechanical activation, studied by tensile testing, and thermal cycling, studied by Differential Scanning Calorimetry, is reported. Graphical abstract Image 1 Highlights • Room-temperature healing of a reversible polymer network with Diels-Alder bonds. • Heating-mediated healing of aged surfaces, reactivating the healing potential. • Dynamic character of the Diels-Alder reaction with furan/maleimide moieties. • Establishing the relaxation time of the Diels-Alder equilibrium reaction τ DA. • Correlation of τ DA and τ rDA with heating-mediated or room-temperature healing. [ABSTRACT FROM AUTHOR]

To increase the durability and reliability of thermosets, self-healing via a vascular network, is developed. A judicious choice of healing agents proves to be necessary to achieve the best recovery of properties. Four low viscosity two-component epoxy-amine healing systems were compared, to check which glass transition temperature range would be best to recover mechanical properties (T g ranging from −8 to 68 °C). Interdiffusion experiments show that all systems react sufficiently slowly at room temperature to allow interdiffusion of epoxy and amine over more than 1 mm before the diffusion is stopped by vitrification. Swelling tests revealed that most of the selected healing agents diffuse into the surrounding matrix and swell it. This might be beneficial for crack closure and improved adhesion between healing system and matrix. Flexural tests demonstrated that, the higher the glass transition temperature of the fully cured healing system, the higher the healing capability. [ABSTRACT FROM AUTHOR]

The authors discuss the study conducted by E. Bultman and colleagues on the predictors of dose escalation in Crohn's disease patients treated with adalimumab. The authors say that clinical trials with infliximab and adalimumab in Crohn's disease have shown a response loss with need for dose optimization. They note that the study show 39% of 122 patients needed adalimumab dose optimization after a year. Moreover, the relation of body mass index (BMI) to adalimumab is discussed.

This article presents information on benefits of high-dose cyclosporine, over low-dose cyclosporine for the treatment of ulcerative colitis. Cyclosporine is known to be highly effective for patients with severe ulcerative colitis, inducing remission in 50% of patients treated acutely. However, sustained remission occurs in only about one third of patients at 1 year. In this study, high-dose intravenous cyclosporine had no additional clinical benefit over low-dose intravenous cyclosporine in treating patients with severe ulcerative colitis. While the response rate with cyclosporine is 50%, it decreases to about one third of the responders in each group after 1 year.

The article discusses a study which examines the outcome of surgery for symptomatic Crohn's rectovaginal fistula (RVF) and the effect of therapy with antibody against tumour necrosis factor (TNF) on healing. The study shows that most patients achieve fistula closure but require more than one operation. It notes that 81 per cent of 52 patients achieve fistula closure and 56 per cent attain primary surgical success rate while 57 per cent achieve secondary surgical success rate.

Abstract: The thermal degradation kinetics of poly(vinyl acetate) (PVAc) and poly(ethylene-co-vinyl acetate) (EVA) copolymers in inert and oxidative conditions are modelled using a simplified mechanistic model. Experimental data originating from isothermal, constant heating rate and high resolution thermogravimetric analysis are used for rate parameter optimisation. The kinetics of the non-catalysed deacetylation reaction of the (co)polymers is studied for EVA with low weight percent vinyl acetate. These results are used to investigate the kinetics of the catalytic deacetylation and deactivation process of PVAc, EVA 73, and EVA 60. The rate parameters of the consecutive degradation of deacetylated PVAc and EVA by chain scission reactions (inert) or the charring and oxidation of char into CO2 (oxidative) are optimised. The reaction mechanism with optimised rate parameters allows the description of the full degradation of PVAc and EVA over a large range of experimental conditions. [Copyright &y& Elsevier]

Abstract: The thermal degradation mechanism of poly(vinyl acetate) (PVAc) and poly(ethylene-co-vinyl acetate) (EVA) copolymers was investigated with solid-state NMR, thermogravimetry coupled with mass spectrometry and differential thermal analysis. Between 300 and 400°C acetic acid is eliminated (deacetylation), leaving a highly unsaturated residue or polyene. The deacetylation of PVAc is autocatalytic. Upon incorporation of ethylene entities into the polymer backbone, autocatalysis disappears. Between 400 and 500°C, the polyene will degrade further by chain scission reactions in inert conditions or aromatise in an oxidative environment into a char, and oxidised eventually into CO2 beyond 500°C. In inert conditions, the deacetylation step as well as the chain scission reaction shows endothermic effects. In an oxidative environment, large exothermal effects are found for each degradation step. This indicates the occurrence of additional oxidation reactions during deacetylation, an important reorganisation of the polyene during char formation and oxidation of the latter into CO2. [Copyright &y& Elsevier]

Abstract: The elimination process of n-alkyl-sulphinyl precursor polymers towards conjugated poly[2-(3′,7′-dimethyloctyloxy)-5-methoxy-1,4-phenylene vinylene], or OC1C10-PPV, was studied with modulated temperature differential scanning calorimetry (MTDSC) and thermogravimetric analysis (TGA), with a focus on the subsequent reactions of the elimination products. The latter reactions were monitored using the non-reversing heat flow and the heat capacity (C p) measured in non-isothermal MTDSC experiments. The disproportionation reaction occurs in a temperature range between 85 and 135°C and is seen as an increase in C p. Water and elimination products released during the elimination reaction act as plasticizers and lower the T g. TGA experiments show that the temperature, film thickness, and the eliminated group play an important role on the diffusion and evaporation of the elimination products. The elimination products can further decompose and interact with the conjugated system to form undesirable crosslinks (network formation) in a temperature range of 140–160°C. [Copyright &y& Elsevier]

Introduction: This study was designed to evaluate the safety of fontolizumab, a humanised anti-interferon y antibody, in patients with moderate to severe Crohn's disease (CD). Patients and methods: Forty five patients with a CD activity index (CDAI) of 250-450 were randomised in a double blind, placebo controlled, dose escalating fashion to receive single doses of fontolizumab (0.1, 1.0, and 4.0 mg/kg) or placebo. By day 29, patients with clinical response were re-randomised to receive three additional doses of one half their initial fontolizumab dose or placebo at four weekly intervals. Primary objectives were safety and tolerability. Secondary outcomes included assessments of immunogenicity, clinical activity, and potential pharmacodynamic surrogates. Results: Treatment was generally well tolerated. There were slightly more reports of chills, flu-like syndrome, asthenia, nausea, and vomiting in the 1.0 mg and 4.0 mg/kg fontolizumab cohorts. Two serious adverse events rated as worsening of CD occurred under fontolizumab. Antibodies to fontolizumab were confirmed in one patient. No differences in clinical activity parameters were noted between any of the active treatment groups and placebo, with the placebo group having a particularly favourable outcome (60% response and 40% remission). By day 29, a more enhanced decrease in median Crohn's disease endoscopic index of severity (p=0.02) and serum C reactive protein (p<0.001) was observed in the 4.0 mg/kg (n = 14) fontolizumab cohort compared with placebo (n = 10). Pharmacodynamic effects were observed by immunohistochemistry. Conclusions: Fontolizumab was well tolerated with minimal immunogenicity at doses of up to 4.0 mg/kg in patients with CD. A biological activity of fontolizumab is suggested. [ABSTRACT FROM AUTHOR]

: By temporarily suppressing the immune response, the anti-tumour necrosis factor agent, infliximab, may increase the risk of peri-operative complications. : To test this hypothesis for intestinal resection in a cohort of 313 Crohn's disease patients treated with infliximab. Forty received one or more infusions prior to intestinal resection (31/40 within 12 weeks). : The post-operative events of these patients were compared with those of a control group (infliximab naive) of 39 patients adjusted for age, gender and surgical procedure. Early (10 days) and late (3 months) major or minor complications were identified. : The incidence of early minor (15.0% vs. 12.8%) and major (12.5% vs. 7.7%) and late minor (2.5% vs. 5.1%) and major (17.5% vs. 12.8%) complications and the mean hospital stay after surgery (10.3 ± 4.0 days vs. 9.9 ± 5.5 days) were similar in both groups. A trend towards an increased early infection rate was found in infliximab pre-treated patients (6 vs. 1; P = 0.10), but more patients in this group received corticosteroids and/or immunosuppressives (29 vs. 16 patients; P < 0.05). : The use of infliximab before intestinal resection does not prolong the hospital stay and does not increase the rate of post-operative complications. [ABSTRACT FROM AUTHOR]

Summary Background : Monoclonal antibodies to the pro-inflammatory cytokine tumour necrosis factor-α have shown efficacy in treating Crohn's disease, but can be immunogenic. Soluble tumour necrosis factor-binding proteins are being studied as potential alternative anti-tumour necrosis factor agents in Crohn's disease. Aim : To investigate the safety and efficacy of onercept, a recombinant form of the natural human soluble p55 tumour necrosis factor receptor, in the treatment of patients with active Crohn's disease. Methods : In a pilot study, 12 patients with active Crohn's disease were randomized to receive onercept at either 11.7 or 50 mg three times weekly for 2 weeks. Patients were followed up for 6 months after the end of treatment. Results : The Crohn's disease activity index decreased rapidly during treatment in both groups. Seven responses (Crohn's disease activity index decrease of 100 points) were observed over the first 6 weeks of the study, including five remissions (Crohn's disease activity index decrease of 150 points). Improvement was sustained for 2–4 months after stopping treatment. Treatment was well tolerated. No patients developed antibodies to onercept. Conclusions : Neutralizing the activity of tumour necrosis factor-α with its soluble p55 receptor may be valuable in the treatment of patients with Crohn's disease. Larger placebo-controlled trials are indicated. [ABSTRACT FROM AUTHOR]

Background: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.Methods: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components).Results: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.Conclusions: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.). [ABSTRACT FROM AUTHOR]

In this work, a new finite element modelling (FEM) approach is followed to model spatiotemporally resolved water uptake in organic coatings. To this aim, we start from a physical model, where not only Fickian diffusion of water is taken into account but also the adsorption/desorption reaction of water on the polymer matrix. Starting from a number of important coating properties and crucial model parameters, derived from gravimetric and Fourier transform infrared (FTIR) measurements as the model input, the local water concentration over the coating thickness as a function of time is modelled for a polyethylene glycol diacrylate (PEGDA) coating. The modelled water concentration is then used to calculate virtual capacitance values which are evaluated against experimental capacitance values extracted from impedance measurements. The constraints of the FEM model and ORP-EIS experiments and the discrepancies between them are critically discussed in order to carry out a meaningful model validation, eventually leading to model improvements. • A one-dimensional FEM model is developed predicting the water uptake in organic coatings. • The FEM model is validated by multisine EIS capacitance measurements. • Critical appraisal of the FEM model and the hypotheses is strictly necessary for a reliable model validation. • The effect of ions on the water uptake influences the interpretation of water uptake through EIS measurements. • Model improvements can be obtained by taking more physical phenomena into account. [ABSTRACT FROM AUTHOR]

Summary: Background: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti‐fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. Aim: To standardise definitions, diagnosis and treatment targets for anti‐fibrotic stricture therapies in Chron's disease. Methods: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. Results: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre‐stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post‐prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24‐48 weeks is considered the appropriate endpoint in pharmacological trials. Conclusions: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design. [ABSTRACT FROM AUTHOR]

Summary: Background: The presence of antibodies towards infliximab (ATI) is associated with lower infliximab (IFX) trough concentrations and loss of response. IFX treatment intensification is effective for restoring response in most, but not all patients with Crohn's disease (CD). Aim: To compare outcome, pharmacokinetics and immunogenicity of treatment intensification strategies in patients with CD who lost clinical response to IFX. Methods: A retrospective cohort study was conducted, including 103 patients with CD who lost clinical response during IFX maintenance therapy and therefore received a double dose IFX (10 mg/kg) and/or a next infusion after a shortened interval. IFX and ATI concentrations were measured in consecutive trough samples, just before (T0) and after (T+1) treatment intensification. Results: Clinical response (physicians' global assessment) and biological response and remission (CRP) were restored in 63%, 42% and 24% of patients (evaluated at T+1). Treatment intensification increased IFX trough concentrations from 1.2 μg/mL [0.3‐3.6] at T0 to 3.6 μg/mL [0.5‐10.2] at T+1 (P < .0001). Using a drug tolerant assay, ATI were detected in the T0 sample of 47% of patients. ATI negatively impacted the achieved IFX trough concentration (Spearman r −0.57, P < .0001) and the probability of clinical response (P = 0.034) at T+1. When ATI were quantifiable but <282 ng/mL eq. at T0, combined interval shortening and dose doubling was more effective for restoring therapeutic IFX trough concentrations (≥3 μg/mL at T+1) than dose doubling alone, which in turn was more effective than interval shortening alone (P < .001). Conclusion: Antibodies towards infliximab can guide clinical decision‐making on treatment intensification. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Surgery for ileal pouch–anal anastomosis (IPAA) has evolved over time, especially since the introduction of laparoscopy. The aim of this retrospective study was to report the impact of surgical evolution on outcome over a period of 25 years. Method: All patients who had IPAA surgery for ulcerative colitis from 1990 to 2015 at the University Hospitals of Leuven were included. Patients were divided into three period arms (period A 1990–1999; period B 2000–2009; period C 2010–2015). The main outcome measure was anastomotic leakage. Results: A total of 335 patients (58.8% male) with a median age of 39 years (interquartile range 32–49 years) at surgery were included. Median follow‐up was 5 years (interquartile range 2–10 years). Overall anastomotic leakage (grades A–C) was 14.9%. A significant decrease in leakage rate was observed over time (from 21.4% in period A to 12.1% in period B to 10.0% in period C; P = 0.04). The defunctioning ileostomy rate at the time of pouch construction decreased from 91.7% (period A) to 40.3% (period B) to 11.1% (period C) (P < 0.001). We observed an increase in the use of laparoscopy (23.9% in period A vs 72.6% in period B, vs 84.4% in period C; P = 0.001) and a shift to a modified two‐stage procedure (4.1% in period A, vs 66.7% in period C; P < 0.0001). In a monocentric study with some of the data retrieved retrospectively it was not possible to account for the impact of preoperative nutritional status (weight loss, serum albumin level) or disease burden. Other outcome factors were not measured, for example sexual function and fecundity. Conclusion: A higher rate of laparoscopic IPAA surgery, together with a shift towards modified two‐stage procedures, was associated with a lower leakage rate despite a reduction in the use of defunctioning ileostomy. [ABSTRACT FROM AUTHOR]

Background Adalimumab is used to treat moderate to severe Crohn's disease ( CD) and ulcerative colitis ( UC) when conventional therapies fail. Aim To update long-term adalimumab safety from CD and UC trials; the previous report was CD only, 3160 patients/3402 patient-years ( PYs). Methods Treatment-emergent adverse events ( AEs; first dose to 70 days after last dose/December 31, 2015) in adults in phase 2/3 and 3/3b trials and open-label extensions were coded using Medical Dictionary for Regulatory Activities (Med DRA-v18.1). Rates were assessed as events/100 (E/100 PYs). Results The database (16 trials; CD, N = 3606; UC, N = 1739) represented 4145 and 3397 PYs of exposure, respectively. For CD, incidences of any AEs with adalimumab were 60.8%-65.1%, depending on dose, and 71.5% with placebo; for UC, the incidences were 53.5%-54.8% and 56.1%, respectively. Rates of any AEs ( CD, 605 E/100 PYs; UC, 361 E/100 PYs), serious AEs ( CD, 36.1 E/100 PYs; UC, 18.9 E/100 PYs), and malignancies ( CD, 1.2 E/100 PYs; UC, 1.0 E/100 PYs) were similar between current and prior analyses. Apparent rate of opportunistic infections was lowered to 0.3 and 0.2 E/100 PYs for CD and UC, respectively, by recent Med DRA changes excluding oral candidiasis and tuberculosis. Standardised incidence ratios for malignancies were similar to the general population ( CD, 1.45 [95% CI, 0.90-2.22]; UC, 1.36 [95% CI, 0.84-2.07]). Demyelinating disorders were uncommon ( CD, 0.1 E/100 PYs; UC, <0.1 E/100 PYs). Conclusions Patients with moderately to severely active Crohn's disease or ulcerative colitis continued to experience acceptable safety with adalimumab, without new safety signals. [ABSTRACT FROM AUTHOR]

Background Despite improvements in medical therapy, the majority of patients with Crohn's disease still require surgery. The aim of this study was to report safety, and clinical and surgical recurrence rates, including predictors of recurrence, after ileocaecal resection for Crohn's disease. Methods This was a cohort analysis of consecutive patients undergoing a first ileocaecal resection for Crohn's disease between 1998 and 2013 at one of two specialist centres. Anastomotic leak rate and associated risk factors were assessed. Kaplan-Meier estimates were used to describe long-term clinical and surgical recurrence. Univariable and multivariable regression analyses were performed to identify risk factors for both endpoints. Results In total, 538 patients underwent primary ileocaecal resection (40·0 per cent male; median age at surgery 31 (i.q.r. 24-42) years). Median follow-up was 6 (2-9) years. Fifteen of 507 patients (3·0 per cent) developed an anastomotic leak. An ASA fitness grade of III (odds ratio ( OR) 4·34, 95 per cent c.i. 1·12 to 16·77; P = 0·033), preoperative antitumour necrosis factor therapy ( OR 3·30, 1·09 to 9·99; P = 0·035) and length of resected bowel specimen ( OR 1·06, 1·03 to 1·09; P < 0·001) were significant risk factors for anastomotic leak. Rates of clinical recurrence were 17·6, 45·4 and 55·0 per cent after 1, 5 and 10 years respectively. Corresponding rates of requirement for further surgery were 0·6, 6·5 and 19·1 per cent. Smoking (hazard ratio ( HR) 1·67, 95 per cent c.i. 1·14 to 2·43; P = 0·008) and a positive microscopic resection margin ( HR 2·16, 1·46 to 3·21; P < 0·001) were independent risk factors for clinical recurrence. Microscopic resection margin positivity was also a risk factor for further surgery ( HR 2·99, 1·36 to 6·54; P = 0·006). Conclusion Ileocaecal resection achieved durable medium-term remission, but smoking and resection margin positivity were risk factors for recurrence. [ABSTRACT FROM AUTHOR]

Background Data on dose de-escalation in patients with Crohn's disease (CD) are limited. Aim To evaluate outcomes of dose de-escalation from adalimumab (ADM) every other week (EOW) to every three weeks (ETW). Methods We selected patients with CD receiving maintenance therapy with ADM 40 mg ETW with serum levels (SL) available before and after dose de-escalation. Sex- and age-matched controls continuing ADM 40 mg EOW were identified. Patient reported outcome, C-reactive protein (CRP) and serum albumin were collected. Results Out of 898 patients, we identified 40 (11 male, median 37 years) who de-escalated to ADM 40 mg ETW for ADM-related adverse events (AE, n = 1), ADM SL >7 μg/mL ( n = 8), or both ( n = 31). Compared to controls, ADM SL dropped significantly within 4 months, without associated clinical or biochemical changes. In 53% of patients, dose de-escalation was associated with disappearance of AE (8/16 skin manifestation, 3/6 arthralgia, 5/7 frequent infectious episodes). During a median follow-up of 24 months, 65% of patients maintained clinical response, but 35% needed dose escalation back to ADM 40 mg EOW because of clinical relapse ( n = 8), ADM SL <4 μg/mL ( n = 2), or both ( n = 4). CRP <3.5 mg/L at dose de-escalation was independently associated with dose escalation-free survival [odds ratio 6.28 (95% CI 1.83-21.59), P = 0.004]. We could not define a minimal ADM SL to consider or maintain dose de-escalation. Conclusions Overall, 65% of patients who de-escalated to adalimumab 40 mg every 3 weeks remained in clinical remission for a median of 24 months. In 53% of patients, adalimumab-related adverse events disappeared after dose de-escalation. Regardless of adalimumab SL, disease remission should be assessed objectively prior to dose de-escalation. [ABSTRACT FROM AUTHOR]

A combination of fast scanning chip calorimetry and X-ray ptychography is explored to study the effects of thermal annealing on the active layer of bulk heterojunction organic photovoltaics. The well-known P3HT/PC 61 BM 1:1 system is investigated as a test case. By using a custom chip calorimetry setup, it is possible to give a thermal treatment at 127 °C (400 K) to P3HT/PC 61 BM 1:1 thin layers, using a heating and cooling rate of 30000 K s −1 , after which the resulting morphology is investigated with X-ray ptychography. Applying only heating and cooling, without isothermal annealing, yields a featureless morphology. This corresponds well with thermal data which indicate a mixed amorphous phase only. For increasing isothermal annealing times, a well-defined morphology appears with increasing domain size, corresponding to the formation of an endothermal melting trajectory. This melting trajectory is expected to consist of both eutectic melting and melting of coarsened crystals. In contrast to chip calorimetry results, large domain sizes are obtained for heating and cooling without isothermal annealing at a conventional rate of 20 K min −1 . This initial morphology then develops further with increased isothermal annealing. The combination of chip calorimetry and ptychography allows separating the effects of each single thermal step on morphology development. [ABSTRACT FROM AUTHOR]

Background The long-term efficacy of infliximab in patients with Crohn's disease is suboptimal. Aim To study prognostic factors for real-life long-term effcacy of infliximab in Crohn's disease. Methods All consecutive Crohn's disease patients treated with infliximab at a tertiary centre were retrospectively analysed. Only patients who received scheduled infliximab maintenance treatment were considered. Patient- and disease-related factors were used to identify independent predictors of infliximab failure-free survival using Cox proportional hazards regression. Results Of 1031 patients with Crohn's disease, 261 were eligible for inclusion. Median time on infliximab was 2.4 [ IQR 1.4-4.7] years, and 65 (24.9%) patients experienced infliximab failure. Estimated 5-year infliximab failure-free survival was 65.9% (95% CI 58.3-73.5). Multivariate Cox regression identified disease duration ≥1 year ( HR 2.5 (95% CI 1.2-5.2), P = 0.02), L1 disease location [ HR 2.0 (1.1-3.5), P = 0.02], prior anti- TNF use [ HR 2.3 (1.1-4.8), P = 0.03], haemoglobin <13.5 g/dL [ HR 2.3 (1.2-4.4), P = 0.02], not using therapeutic drug monitoring [ HR 8.0 (4.1-15.6), P = 1 × 10−9], and first dose optimisation within first year [ HR 3.7 (2.1-6.6), P = 5 × 10−6] as independent predictors of infliximab failure-free survival. Stratifying patients into risk groups resulted in estimated 3-year infliximab failure-free survival rates ranging from 95.3% (94.2-96.4) to 26.3% (8.6-44.0) depending on the number of risk factors ( P = 8 × 10−13). Conclusions This study identified several easy to obtain predictors of infliximab failure in patients with Crohn's disease, and these are in line with previous reports. Those with a high-risk profile for infliximab failure in whom infliximab initiation is considered, should be treated as early as possible making use of therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background The detrimental effect of smoking on development and progression of Crohn's disease ( CD) is generally accepted. Aim To evaluate the awareness of smoking risks in a Belgian inflammatory bowel disease ( IBD) population. Methods In the out-patient clinic of a tertiary referral centre, 625 consecutive patients with CD, 238 patients with ulcerative colitis ( UC) and 289 non- IBD controls, filled out a simple questionnaire. This questionnaire included data on smoking behaviour and awareness of smoking-related health effects, including effects on IBD. Results At diagnosis, more CD patients were active smokers compared to UC (40% vs. 17%, P < 0.001). Remarkably, smoking cessation rates after diagnosis were similar for CD and UC (both 56%, P = 0.997). The great majority recognised a detrimental influence of smoking on general health (98-99%), lung cancer (95-97%), myocardial infarction (89-92%) and stroke (78-87%). Although CD patients more frequently acknowledged risks of smoking on their disease, only 37% were aware of a link with CD development, 30% of increased surgical rates and 27% of increased post-operative CD recurrence. Active smokers more frequently denied an increased risk of surgery and higher post-operative CD recurrence. Intriguingly, within the active smokers with CD, those not willing to quit smoking most often denied a potential bad influence of smoking. Taking into account disease duration, previous surgery, education level, working status and nicotine dependence, we were unable to define specific subgroups of patients requiring extra education. Conclusion Although patients with Crohn's disease were better informed on the detrimental effects of smoking, the awareness rate was still low. [ABSTRACT FROM AUTHOR]

Background The general increased life expectancy is reflected in the age of patients with inflammatory bowel disease ( IBD). The knowledge about efficacy and safety of anti-tumour necrosis factor ( TNF) therapy in elderly is scarce and conflicting. Aim To assess the efficacy and safety of anti- TNF therapy in elderly patients taking into account eventual comorbidity. Methods Observational and retrospective single-centred study where 66 IBD patients initiating anti- TNF treatment at age ≥65 years (cases: ≥65 anti- TNF) were compared with 112 IBD patients initiating anti- TNF <65 years (controls <65 anti- TNF) and 61 anti- TNF naïve IBD patients treated with immunosuppressants ( IMS) and/or corticosteroids ( CS) ≥65 years (controls ≥65 IMS/ CS). Controls were matched to cases for IBD type, follow-up, disease duration and anti- TNF type. Comorbidity was assessed by using the Charlson Comorbidity Index ( CCI). Both efficacy and safety of treatment were adjusted for comorbidity. Results The short-term clinical response to anti- TNF at 10 weeks was significantly lower in cases: ≥65 anti- TNF (68% vs. 89%; P < 0.001), whereas at ≥6 months, differences were not significant (79.5% vs. 82.8%; P = 0.639). The risk for any severe adverse events was higher in cases: ≥65 anti- TNF than in controls <65 anti- TNF ( RR = 4.7; P < 0.001) or controls ≥65 IMS/ CS ( RR = 3.09; P = 0.0008). Age older than 65 and CCI > 0 were independent risk factors for malignancy and mortality regardless of the medication. Conclusion Elderly patients treated with anti- TNF have a lower rate of short-term clinical response and a higher rate of severe adverse events than the younger patients under the same treatment. [ABSTRACT FROM AUTHOR]

Background Data for adalimumab in ulcerative colitis after prior use of infliximab are scarce. Aims To study adalimumab response rates and predictors of response in ulcerative colitis, including drug concentrations. Methods In this single centre cohort study 73 UC patients, previously exposed to infliximab, were assessed for response to adalimumab at weeks 12 and 52. Serum samples prior to week 12 were available and included in multivariate analysis to predict response. Results Overall clinical response at week 12 and 52 were 75% and 52%, respectively. Adalimumab was continued without need for dose escalation throughout year 1 in 16 patients, 22 needed dose escalation and 35 discontinued treatment within 1 year. Prior response to infliximab and early serum concentrations correlated with response. Receiver operator characteristic curve analysis yielded optimal adalimumab concentrations of 4.58 μg/mL for week 12 and 7.0 μg/mL for week 52. Independent predictors for response at week 12 were primary response to infliximab [odds ratio (OR) 8.33; 95% confidence interval (CI) 1.8-33.3; P = 0.006] and an adalimumab concentration ≥4.58 μg/mL at week 4 (OR 4.85; 95% CI 1.3-18.6; P = 0.009). Positive predictors for week 52 response were primary response to infliximab (OR 5.2; 95% CI 1.14-23.8; P = 0.034) and adalimumab concentration at week 4 of ≥7 μg/mL (OR 3.56; 95% CI 1.17-10.79; P = 0.025). Conclusion Prior response to infliximab and high early adalimumab serum concentrations predict week 12 and year 1 responses to adalimumab in ulcerative colitis. [ABSTRACT FROM AUTHOR]

Background Patients with moderately to severely active ulcerative colitis occasionally do not respond to or lose initial response to maintenance dosing of anti- TNF therapy. Aim To report the efficacy of escalation from every other week ( EOW) to weekly adalimumab dosing in patients from the clinical trial ULTRA 2 ( NCT00408629), by week 8 response (i.e. response after adalimumab induction therapy). Methods Week 52 remission, response, and mucosal healing rates were assessed in ULTRA 2 adalimumab-randomised patients who escalated to weekly dosing. Patients were stratified by week 8 response per partial Mayo score. Kaplan-Meier and logistic regression analyses estimated time to weekly dosing and defined predictors of escalation to weekly dosing, respectively. Adverse events were reported for patients receiving open-label adalimumab. Results The rate of escalation to weekly dosing was 16.3% (20/123) for week 8 responders and 38.4% (48/125) for week 8 nonresponders. Week 52 remission, response and mucosal healing rates with weekly dosing were 20%, 45%, and 45% for week 8 responders and 2.1%, 25% and 29.2% for nonresponders, respectively ( NRI). The median time to weekly dosing was 288 days for week 8 nonresponders and not estimable for responders. Prior anti- TNF use was a significant predictor of escalation to weekly dosing. Treatment-emergent adverse event rates were similar for patients receiving open-label EOW or weekly adalimumab. Conclusions Escalation to weekly adalimumab dosing demonstrated clinical benefits for patients who lost response to therapy and may be beneficial for patients not initially responding to induction therapy. No new safety risks were identified with weekly dosing. [ABSTRACT FROM AUTHOR]

Background Tumour necrosis factor ( TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases ( IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies ( ADAs) may decrease their efficacy. Aim The evidence supporting the use of therapeutic drug monitoring ( TDM) based clinical algorithms for infliximab ( IFX) and their role in clinical practice will be discussed. Methods The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. Results Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. Conclusions Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials. [ABSTRACT FROM AUTHOR]

Abstract: A novel hyphenated RheoDSC combines rheological and calorimetric analyses of samples by performing rheological experiments inside a DSC cell. This enables direct studies of the chemorheological changes of epoxy-amine thermosets during crosslinking. The rheological and calorimetric information can be presented in time–temperature-transformation (TTT) cure diagrams, without the need for making interpretations based on experiments performed on different samples in the different thermal environments of individual rheometers and calorimeters. [Copyright &y& Elsevier]

Abstract: A self-healing polymer network for potential coating applications was designed based on the concept of the reversible Diels–Alder (DA) reaction between a furan functionalized compound and a bismaleimide. The network allows local mobility in a temperature window from ca. 80°C to 120°C by shifting the DA equilibrium towards the initial building blocks. Changing the spacer length in the furan functionalized compound leads to tailor-made properties. Elastomeric model systems were chosen to evaluate the kinetic parameters by Fourier transform infrared spectroscopy. For the DA reaction a pre-exponential factor ln(A DA in kgmol−1 s−1) equal to 13.1±0.8 and an activation energy (E DA) of 55.7±2.3kJmol−1 are found. For the retro-DA reaction, ln(A rDA) and E rDA are 25.8±1.8s−1 and 94.2±4.8kJmol−1, respectively. The enthalpy and entropy of reaction are calculated as −38.6kJmol−1 and −105.3Jmol−1 K−1. The kinetic results are validated by micro-calorimetry. Non-isothermal dynamic rheometry provides the gel-point temperature of the reversible network. The sealing capacity is evaluated by atomic force microscopy for micro-meter sized defects. Repeatability of the non-autonomous healing is checked by micro-calorimetry, ruling out side-reactions below 120°C. [Copyright &y& Elsevier]

Background Patients with moderately-to-severely active ulcerative colitis ( UC) are unlikely to continue anti- TNF therapy in the absence of early therapeutic response. Aim To assess week 52 efficacy, safety and benefit/risk balance of adalimumab treatment in patients with moderately-to-severely active UC failing conventional therapy who achieved clinical response at week 8 in the 52-week ULTRA 2 trial. Methods Patients randomised to adalimumab (160/80 mg, week 0/2; 40 mg, every other week thereafter) in ULTRA 2 who achieved clinical response at week 8 per partial Mayo score (Mayo score without endoscopy subscore) were assessed for week 52 clinical remission, clinical response, mucosal healing, steroid-free remission and steroid discontinuation rates, overall and by prior anti- TNF use. Benefit/risk balance for the overall ITT population (regardless of week 8 responder status) was assessed using 'net efficacy adjusted for risk' ( NEAR) odds ratios. Safety was assessed using adverse event rates. Results Of 248 adalimumab-treated patients, 123 (49.6%) achieved clinical response at week 8. Of these, 30.9%, 49.6%, and 43.1% achieved clinical remission, clinical response, and mucosal healing, respectively, at week 52. Of the week 8 responders using corticosteroids at baseline ( N = 90), 21.1% achieved steroid-free remission and 37.8% were steroid-free at week 52. NEAR odds ratios indicated a positive benefit/risk balance for achievement of week 8 and week 52 response or remission without serious adverse events or serious infections. No safety concerns were identified. Conclusions Adalimumab treatment was associated with a positive benefit/risk balance in the overall population of patients with moderately-to-severely active ulcerative colitis in ULTRA 2; early response was predictive of a positive outcome at 1 year (NCT00408629). [ABSTRACT FROM AUTHOR]