Tacrolimus versus mycophenolate for AutoImmune hepatitis patients with incompLete response On first-line therapy (TAILOR study): a study protocol for a phase III, open-label, multicentre, randomised controlled trial.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. METHODS: The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. DISCUSSION: This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. TRIAL REGISTRATION: ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021-003420-33. Prospectively registered on 16 June 2021.

Controlling the Oxygen Defects Concentration in a Pure BiFeO3 Bulk Ceramic.

BiFeO3 is a multiferroic material with a perovskite structure that has a lot of potential for use in sensors and transducers. However, obtaining pure single-phase BiFeO3 ceramic with a low electrical conductivity via solid-state reactions remains a problem that limits its application. In this work, the suppression of secondary phases in BiFeO3 was studied by varying the compositional parameters and the sintering temperature. The addition of 1% Bi2O3 to the stoichiometric precursor mixture prevented the formation of secondary phases observed when sintering stoichiometric precursors. The pure phase ceramic had a p-type conductivity and a three-decade lower electrical conductivity as measured by impedance spectroscopy. Annealing of optimally synthesized material at different partial pressures of oxygen in an oxygen−nitrogen gas atmosphere showed that the reason for this type of conductivity lies in the high concentration of defects associated with oxygen. By annealing in various mixtures of nitrogen and oxygen, it is possible to control the concentration of these defects and hence the conductivity, which can go down another two decades. At a pO2 ≤10%, the conductivity is determined by intrinsic charge carriers in the material itself.

New chemistry supporting portable solutions for end-stage renal disease dialysis treatment.

A new polymeric adsorbent to improve portable dialysis treatment by simplifying urea removal at the dialysate regeneration step is proposed. An adsorbent to remove urea was synthesized by molecular imprinting technology that can potentially overcome drawbacks existing in urease enzyme-based dialysate regeneration technology. Molecularly imprinted polymer (MIP) for urea generates cavities both in shape and in size targeted for urea. Using the synthesized MIP, we have shown removal of urea present in the dialysate buffer. Various experimental conditions such as choice of monomers, porogen, and template to monomer ratios were optimized to achieve highest binding capacity on a column flow through system monitored using high-performance liquid chromatography (HPLC). Taking advantage of the basicity of urea molecule, monomers having Brønsted acidic groups such as acrylic acid, methacrylic acid and itaconic acid were screened. The MIP synthesized using urea:acrylic acid:EGDMA (1:4:12) in acetonitrile:ethylene dichloride (1:1) as porogen gave highest binding capacity of 24.5 g/kg of urea in the dialysate buffer matrix.

A LEAN approach toward automated analysis and data processing of polymers using proton NMR spectroscopy.

To maximize utilization of expensive laboratory instruments and to make most effective use of skilled human resources, the entire chain of data processing, calculation, and reporting that is needed to transform raw NMR data into meaningful results was automated. The LEAN process improvement tools were used to identify non-value-added steps in the existing process. These steps were eliminated using an in-house developed software package, which allowed us to meet the key requirement of improving quality and reliability compared with the existing process while freeing up valuable human resources and increasing productivity. Reliability and quality were improved by the consistent data treatment as performed by the software and the uniform administration of results. Automating a single NMR spectrophotometer led to a reduction in operator time of 35%, doubling of the annual sample throughput from 1400 to 2800, and reducing the turn around time from 6 days to less than 2.

On the synergistic catalytic properties of bimetallic mesoporous materials containing aluminum and zirconium: the Prins cyclisation of citronellal.

Bimetallic three-dimensional amorphous mesoporous materials, Al-Zr-TUD-1 materials, were synthesised by using a surfactant-free, one-pot procedure employing triethanolamine (TEA) as a complexing reagent. The amount of aluminium and zirconium was varied in order to study the effect of these metals on the Brønsted and Lewis acidity, as well as on the resulting catalytic activity of the material. The materials were characterised by various techniques, including elemental analysis, X-ray diffraction, high-resolution TEM, N(2) physisorption, temperature-programmed desorption (TPD) of NH(3), and (27) Al MAS NMR, XPS and FT-IR spectroscopy using pyridine and CO as probe molecules. Al-Zr-TUD-1 materials are mesoporous with surface areas ranging from 700-900 m(2) g(-1), an average pore size of around 4 nm and a pore volume of around 0.70 cm(3) g(-1). The synthesised Al-Zr-TUD-1 materials were tested as catalyst materials in the Lewis acid catalysed Meerwein-Ponndorf-Verley reduction of 4-tert-butylcyclohexanone, the intermolecular Prins synthesis of nopol and in the intramolecular Prins cyclisation of citronellal. Although Al-Zr-TUD-1 catalysts possess a lower amount of acid sites than their monometallic counterparts, according to TPD of NH(3), these materials outperformed those of the monometallic Al-TUD-1 as well as Zr-TUD-1 in the Prins cyclisation of citronellal. This proves the existence of synergistic properties of Al-Zr-TUD-1. Due to the intramolecular nature of the Prins cyclisation of citronellal, the hydrophilic surface of the catalyst as well as the presence of both Brønsted and Lewis acid sites synergy could be obtained with bimetallic Al-Zr-TUD-1. Besides spectroscopic investigation of the active sites of the catalyst material a thorough testing of the catalyst in different types of reactions is crucial in identifying its specific active sites.

Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid.

BACKGROUND: The reported incidence of hepatocellular carcinoma (HCC) among patients with primary biliary cirrhosis (PBC) varies from 0.7-3.8%, whereas in cirrhotic patients the risk is considerably higher. Age, male sex, cirrhosis, and portal hypertension are reported risk factors. It has been suggested that ursodeoxycholic acid (UDCA) may protect against HCC. We aimed to define risk factors for the development of HCC at the time of PBC diagnosis and to identify, among patients treated with UDCA for a long term, a subgroup that could benefit from screening. METHODS: Prospective multicenter cohort study of patients with established PBC treated with 13-15 mg/kg/day UDCA. Age, sex, antimitochondrial antibodies, bilirubin, albumin, alkaline phosphatase, alanine aminotransferase, aspartate amino transferase, cirrhosis, portal hypertension, Mayo Risk Score, prognostic class (based on bilirubin and albumin levels), and response to UDCA (normalization of bilirubin and/or albumin levels) were analyzed as potential risk factors in Cox regression analysis. RESULTS: Three hundred and seventy-five patients were included, median follow-up was 9.7 years. HCC occurred in nine patients, corresponding with an annual incidence of 0.2%. The factor significantly associated with the development of HCC was the response to UDCA (P<0.001). The risk for HCC was highest in the group of nonresponders to UDCA: the 10 years incidence of HCC was 9% and the 15 years incidence was 20%. The number needed to screen in this subgroup was 11. CONCLUSION: In UDCA treated PBC patients the risk of HCC is relatively low. The main risk factor for HCC in this study was the absence of biochemical response to UDCA after 1-year treatment.

Evaluation of algorithms for automated phase correction of NMR spectra.

In our attempt to fully automate the data acquisition and processing of NMR analysis of dissolved synthetic polymers, phase correction was found to be the most challenging aspect. Several approaches in literature were evaluated but none of these was found to be capable of phasing NMR spectra with sufficient robustness and high enough accuracy to fully eliminate intervention by a human operator. Step by step, aspects from the process of manual/visual phase correction were translated into mathematical concepts and evaluated. This included area minimization, peak height maximization, negative peak minimization and baseline correction. It was found that not one single approach would lead to acceptable results but that a combination of aspects was required, in line again with the process of manual phase correction. The combination of baseline correction, area minimization and negative area penalization was found to give the desired results. The robustness was found to be 100% which means that the correct zeroth order and first order phasing parameters are returned independent of the position of the starting point of the search in this parameter space. When applied to high signal-to-noise proton spectra, the accuracy was such that the returned phasing parameters were within a distance of 0.1-0.4 degrees in the two dimensional parameter space which resulted in an average error of 0.1% in calculated properties such as copolymer composition and end groups.