Mycophenolate mofetil versus azathioprine for prevention of acute rejection in renal transplantation (MYSS): a randomised trial.

BACKGROUND: Mycophenolate mofetil has replaced azathioprine in immunosuppression regimens worldwide to prevent graft rejection. However, evidence that its antirejection activity is better than that of azathioprine has been provided only by registration trials with an old formulation of ciclosporin and steroid. We aimed to compare the antirejection activity of these two drugs with a new formulation of ciclosporin. METHODS: The mycophenolate steroids sparing multicentre, prospective, randomised, parallel-group trial compared acute rejections and adverse events in recipients of cadaver-kidney transplants over 6-month treatment with mycophenolate mofetil or azathioprine along with ciclosporin microemulsion (Neoral) and steroids (phase A), and over 15 more months without steroids (phase B). The primary endpoint was occurrence of acute rejection episodes. Analysis was by intention to treat. FINDINGS: 168 patients per group entered phase A. 56 (34%) assigned mycophenolate mofetil and 58 (35%) assigned azathioprine had clinical rejections (risk reduction [RR] on mycophenolate mofetil compared with azathioprine 13.7% [95% CI -25.7% to 40.7%], p=0.44). 88 patients in the mycophenolate mofetil group and 89 in the azathioprine group entered phase B. 14 (16%) taking mycophenolate mofetil and 11 (12%) taking azathioprine had clinical rejections (RR -16.2%, [-157.5% to 47.5%], p=0.71). Average per-patient costs of mycophenolate mofetil treatment greatly exceeded those of azathioprine (phase A 2665 Euros [SD 586] vs Euros 184 [62]; phase B 5095 Euros [2658] vs 322 Euros [170], p<0.0001 for both). INTERPRETATION: In recipients of cadaver kidney-transplants given ciclosporin microemulsion, mycophenolate mofetil offers no advantages over azathioprine in preventing acute rejections and is about 15 times more expensive. Standard immunosuppression regimens for transplantation should perhaps include azathioprine rather than mycophenolate mofetil, at least for kidney graft

The effect of neoadjuvant chemotherapy and chemoradiotherapy on exercise capacity and outcome following upper gastrointestinal cancer surgery: an observational cohort study

Background: In 2014 approximately 21,200 patients were diagnosed with oesophageal and gastric cancer in England and Wales, of whom 37 % underwent planned curative treatments. Potentially curative surgical resection is associated with significant morbidity and mortality. For operable locally advanced disease, neoadjuvant chemotherapy (NAC) improves survival over surgery alone. However, NAC carries the risk of toxicity and is associated with a decrease in physical fitness, which may in turn influence subsequent clinical outcome. Lower levels of physical fitness are associated with worse outcome following major surgery in general and Upper Gastrointestinal Surgery (UGI) surgery in particular. Cardiopulmonary exercise testing (CPET) provides an objective assessment of physical fitness. The aim of this study is to test the hypothesis that NAC prior to upper gastrointestinal cancer surgery is associated with a decrease in physical fitness and that the magnitude of the change in physical fitness will predict mortality 1 year following surgery.Methods: This study is a multi-centre, prospective, blinded, observational cohort study of participants with oesophageal and gastric cancer scheduled for neoadjuvant cancer treatment (chemo- and chemoradiotherapy) and surgery. The primary endpoints are physical fitness (oxygen uptake at lactate threshold measured using CPET) and 1-year mortality following surgery; secondary endpoints include post-operative morbidity (Post-Operative Morbidity Survey (POMS)) 5 days after surgery and patient related quality of life (EQ-5D-5 L).Discussion: The principal benefits of this study, if the underlying hypothesis is correct, will be to facilitate better selection of treatments (e.g. NAC, Surgery) in patients with oesophageal or gastric cancer. It may also be possible to develop new treatments to reduce the effects of neoadjuvant cancer treatment on physical fitness. These results will contribute to the design of a large, multi-centre trial to determine whether an in-hospital exercise-training programme that increases physical fitness leads to improved overall survival.<br/

Quantitative Prediction of miRNA-mRNA Interaction Based on Equilibrium Concentrations

MicroRNAs (miRNAs) suppress gene expression by forming a duplex with a target messenger RNA (mRNA), blocking translation or initiating cleavage. Computational approaches have proven valuable for predicting which mRNAs can be targeted by a given miRNA, but currently available prediction methods do not address the extent of duplex formation under physiological conditions. Some miRNAs can at low concentrations bind to target mRNAs, whereas others are unlikely to bind within a physiologically relevant concentration range. Here we present a novel approach in which we find potential target sites on mRNA that minimize the calculated free energy of duplex formation, compute the free energy change involved in unfolding these sites, and use these energies to estimate the extent of duplex formation at specified initial concentrations of both species. We compare our predictions to experimentally confirmed miRNA-mRNA interactions (and non-interactions) in Drosophila melanogaster and in human. Although our method does not predict whether the targeted mRNA is degraded and/or its translation to protein inhibited, our quantitative estimates generally track experimentally supported results, indicating that this approach can be used to predict whether an interaction occurs at specified concentrations. Our approach offers a more-quantitative understanding of post-translational regulation in different cell types, tissues, and developmental conditions

Estrogen- and Progesterone (P4)-Mediated Epigenetic Modifications of Endometrial Stromal Cells (EnSCs) and/or Mesenchymal Stem/Stromal Cells (MSCs) in the Etiopathogenesis of Endometriosis

Endometriosis is a common chronic inflammatory condition in which endometrial tissue appears outside the uterine cavity. Because ectopic endometriosis cells express both estrogen and progesterone (P4) receptors, they grow and undergo cyclic proliferation and breakdown similar to the endometrium. This debilitating gynecological disease affects up to 15% of reproductive aged women. Despite many years of research, the etiopathogenesis of endometrial lesions remains unclear. Retrograde transport of the viable menstrual endometrial cells with retained ability for attachment within the pelvic cavity, proliferation, differentiation and subsequent invasion into the surrounding tissue constitutes the rationale for widely accepted implantation theory. Accordingly, the most abundant cells in the endometrium are endometrial stromal cells (EnSCs). These cells constitute a particular population with clonogenic activity that resembles properties of mesenchymal stem/stromal cells (MSCs). Thus, a significant role of stem cell-based dysfunction in formation of the initial endometrial lesions is suspected. There is increasing evidence that the role of epigenetic mechanisms and processes in endometriosis have been underestimated. The importance of excess estrogen exposure and P4 resistance in epigenetic homeostasis failure in the endometrial/endometriotic tissue are crucial. Epigenetic alterations regarding transcription factors of estrogen and P4 signaling pathways in MSCs are robust in endometriotic tissue. Thus, perspectives for the future may include MSCs and EnSCs as the targets of epigenetic therapies in the prevention and treatment of endometriosis. Here, we reviewed the current known changes in the epigenetic background of EnSCs and MSCs due to estrogen/P4 imbalances in the context of etiopathogenesis of endometriosis

Managing formalization to increase global team effectiveness and meaningfulness of work in multinational organizations

Global teams may help to integrate across locations, and yet, with formalized rules and procedures, responsiveness to those locations’ effectiveness, and the team members’ experiences of work as meaningful may suffer. We employ a mixed-methods approach to understand how the level and content of formalization can be managed to resolve these tensions in multinationals. In a sample of global teams from a large mining and resources organization operating across 44 countries, interviews, observations, and a quantitative 2-wave survey revealed a great deal of variability between teams in how formalization processes were enacted. Only those formalization processes that promoted knowledge sharing were instrumental in improving team effectiveness. Implementing rules and procedures in the set-up of the teams and projects, rather than during interactions, and utilizing protocols to help establish the global team as a source of identity increased this knowledge sharing. Finally, we found members’ personal need for structure moderated the effect of team formalization on how meaningful individuals found their work within the team. These findings have significant implications for theory and practice in multinational organizations

Computerized adaptive testing of population psychological distress : simulation-based evaluation of GHQ-30

PURPOSE: Goldberg's General Health Questionnaire (GHQ) items are frequently used to assess psychological distress but no study to date has investigated the GHQ-30's potential for adaptive administration. In computerized adaptive testing (CAT) items are matched optimally to the targeted distress level of respondents instead of relying on fixed-length versions of instruments. We therefore calibrate GHQ-30 items and report a simulation study exploring the potential of this instrument for adaptive administration in a longitudinal setting. METHODS: GHQ-30 responses of 3445 participants with 2 completed assessments (baseline, 7-year follow-up) in the UK Health and Lifestyle Survey were calibrated using item response theory. Our simulation study evaluated the efficiency of CAT administration of the items, cross-sectionally and longitudinally, with different estimators, item selection methods, and measurement precision criteria. RESULTS: To yield accurate distress measurements (marginal reliability at least 0.90) nearly all GHQ-30 items need to be administered to most survey respondents in general population samples. When lower accuracy is permissible (marginal reliability of 0.80), adaptive administration saves approximately 2/3 of the items. For longitudinal applications, change scores based on the complete set of GHQ-30 items correlate highly with change scores from adaptive administrations. CONCLUSIONS: The rationale for CAT-GHQ-30 is only supported when the required marginal reliability is lower than 0.9, which is most likely to be the case in cross-sectional and longitudinal studies assessing mean changes in populations. Precise measurement of psychological distress at the individual level can be achieved, but requires the deployment of all 30 items

Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies

HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo

Anisotropic nanomaterials: structure, growth, assembly, and functions

Comprehensive knowledge over the shape of nanomaterials is a critical factor in designing devices with desired functions. Due to this reason, systematic efforts have been made to synthesize materials of diverse shape in the nanoscale regime. Anisotropic nanomaterials are a class of materials in which their properties are direction-dependent and more than one structural parameter is needed to describe them. Their unique and fine-tuned physical and chemical properties make them ideal candidates for devising new applications. In addition, the assembly of ordered one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) arrays of anisotropic nanoparticles brings novel properties into the resulting system, which would be entirely different from the properties of individual nanoparticles. This review presents an overview of current research in the area of anisotropic nanomaterials in general and noble metal nanoparticles in particular. We begin with an introduction to the advancements in this area followed by general aspects of the growth of anisotropic nanoparticles. Then we describe several important synthetic protocols for making anisotropic nanomaterials, followed by a summary of their assemblies, and conclude with major applications