Many-particle Brownian and Langevin Dynamics Simulations with the Brownmove package

<p>Abstract</p> <p>Background</p> <p>Brownian Dynamics (BD) is a coarse-grained implicit-solvent simulation method that is routinely used to investigate binary protein association dynamics, but due to its efficiency in handling large simulation volumes and particle numbers it is well suited to also describe many-protein scenarios as they often occur in biological cells.</p> <p>Results</p> <p>Here we introduce our "brownmove" simulation package which was designed to handle many-particle problems with varying particle numbers and allows for a very flexible definition of rigid and flexible protein and polymer models. Both a Brownian and a Langevin dynamics (LD) propagation scheme can be used and hydrodynamic interactions are treated efficiently with our recently introduced TEA-HI ansatz [Geyer, Winter, JCP 130 (2009) 114905]. With simulations of constrained polymers and flexible models of spherical proteins we demonstrate that it is crucial to include hydrodynamics when multi-bead models are used in BD or LD simulations. Only then both the translational and the rotational diffusion coefficients and the timescales of the internal dynamics can be reproduced correctly. In the third example project we show how constant density boundary conditions [Geyer et al, JCP 120 (2004) 4573] can be used to set up a non-equilibrium simulation of diffusional transport across an array of fixed obstacles. Finally, we demonstrate how the agglomeration dynamics of multiple particles with attractive patches can be analysed conveniently with the help of a dynamic interaction network.</p> <p>Conclusions</p> <p>Combining BD and LD propagation, fast hydrodynamics, a flexible protein model, and interfaces for "open" simulation settings, our freely available "brownmove" simulation package constitutes a new platform for coarse-grained many-particle simulations of biologically relevant diffusion and transport processes.</p

Down-titration of biologics for the treatment of rheumatoid arthritis: A systematic literature review

Biologic therapies have improved the management of rheumatoid arthritis (RA) and the treat-to-target approach has resulted in many patients achieving remission. In the current treatment landscape, clinicians have begun considering dose reduction/tapering for their patients. Rheumatology guidelines in Asia, Europe, and the United States include down-titration of biologics but admit that the level of evidence is moderate. We conducted a systematic literature review to assess the published studies that evaluate down-titration of biologics in RA. The published literature was searched for studies that down-titrated the following biologics: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab. Eligible studies included randomized controlled trials (RCTs), non-RCTs, observational, and pharmacoeconomic studies. The outcomes of interest were (1) efficacy and health-related quality of life, (2) disease flares, and (3) impact on cost. Eleven full-text publications were identified; only three were RCTs. Study results suggest that dosing down may be an option in many patients who have achieved remission or low disease activity. However, some patients are likely to experience a disease flare. Across the studies, the definition of disease flare and the down-titration criteria were inconsistent, making it difficult to conclude which patients may be appropriate and when to attempt down-titration. Studies have evaluated the practice of dosing down biologic therapy in patients with RA; however, a relatively small number of RCTs have been published. Although down-titration may be an option for some patients in LDA or remission, additional RCTs are needed to provide guidance on this practice

Impact of a multifaceted intervention to improve the clinical management of osteoporosis. The ESOSVAL-F study

<p>Abstract</p> <p>Background</p> <p>A study to evaluate the impact of a combined intervention (in-class and on-line training courses, a practicum and economic incentives) to improve anti-osteoporosis treatment and to improve recordkeeping for specific information about osteoporosis.</p> <p>Methods/design</p> <p>A before/after study with a non-equivalent control group to evaluate the impact of the interventions associated with participation in the ESOSVAL-R cohort study (intervention group) compared to a group receiving no intervention (control group). The units of analysis are medical practices identified by a Healthcare Position Code (HPC) referring to a specific medical position in primary care general medicine in a Healthcare Department of the Region of Valencia, Spain. The subjects of the study are the 400 participating "practices" (population assigned to health care professionals, doctors and/or nurses) selected by the Healthcare Departments of the Valencia Healthcare Agency for participation as associate researchers in the ESOSVAL-R study (intervention group), compared to 400 participating "practices" assigned to primary care professionals NOT selected for participation as associate researchers in the ESOSVAL-R study, who are selected on the basis of their working in the same Healthcare Centers as the practices receiving the interventions (control group). The study's primary endpoint is the appropriateness of treatment according by the Spanish National Health System guide (2010) and the National Osteoporosis Foundation (NOF, 2008) and International Osteoporosis Foundation guidance (IOF, 2008).</p> <p>The study will also evaluate a series of secondary and tertiary endpoints. The former are the suitability of treatment and evaluation of the risk of fracture; and the latter are the volume of information registered in the electronic clinical records, and the evaluation of risks and the suitability of treatment.</p

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

Background: Preoperative chemoradiotherapy (CRT) followed by surgery is the standard care for locally advanced rectal cancer, but tumour response to CRT and disease outcome are variable. The current study aimed to investigate the effectiveness of plasma telomerase reverse transcriptase (TERT) levels in predicting tumour response and clinical outcome. Methods: 176 rectal cancer patients were included. Plasma samples were collected at baseline (before CRT\ubcT0), 2 weeks after CRT was initiated (T1), post-CRT and before surgery (T2), and 4\u20138 months after surgery (T3) time points. Plasma TERT mRNA levels and total cell-free RNA were determined using real-time PCR. Results: Plasma levels of TERT were significantly lower at T2 (Po0.0001) in responders than in non-responders. Post-CRT TERT levels and the differences between pre- and post-CRT TERT levels independently predicted tumour response, and the prediction model had an area under curve of 0.80 (95% confidence interval (CI) 0.73\u20130.87). Multiple analysis demonstrated that patients with detectable TERT levels at T2 and T3 time points had a risk of disease progression 2.13 (95% CI 1.10\u20134.11)-fold and 4.55 (95% CI 1.48\u201313.95)-fold higher, respectively, than those with undetectable plasma TERT levels. Conclusions: Plasma TERT levels are independent markers of tumour response and are prognostic of disease progression in rectal cancer patients who undergo neoadjuvant therapy

Comparison of intravascular ultrasound guided versus angiography guided drug eluting stent implantation: a systematic review and meta-analysis

BACKGROUND: Intravascular ultrasound (IVUS) can be a useful tool during drug-eluting stents (DES) implantation as it allows accurate assessment of lesion severity and optimal treatment planning. However, numerous reports have shown that IVUS guided percutaneous coronary intervention is not associated with improved clinical outcomes, especially in non-complex patients and lesions. METHODS: We searched the literature in Medline, the Cochrane Library, and other internet sources to identify studies that compare clinical outcomes between IVUS-guided and angiography-guided DES implantation. Random-effects model was used to assess treatment effect. RESULTS: Twenty eligible studies with a total of 29,068 patients were included in this meta-analysis. The use of IVUS was associated with significant reductions in major adverse cardiovascular events (MACE, odds ratios [OR] 0.77, 95 % confidence intervals [CI] 0.71-0.83, P < 0.001), death (OR 0.62, 95 % CI 0.54-0.71, p < 0.001), and stent thrombosis (OR 0.59, 95 % CI: 0.47-0.73, P < 0.001). The benefit was also seen in the repeated analysis of matched and randomized studies. In stratified analysis, IVUS guidance appeared to be beneficial not only in patients with complex lesions or acute coronary syndromes (ACS) but also patients with mixed lesions or presentations (MACE: OR 0.69, 95 % CI: 0.60-0.79, p < 0.001, OR 0.81, 95 % CI 0.74-0.90, p < 0.001, respectively). By employing meta-regression analysis, the benefit of IVUS is significantly pronounced in patients with complex lesions or ACS with respect to death (p = 0.048). CONCLUSIONS: IVUS guidance was associated with improved clinical outcomes, especially in patients with complex lesions admitted with ACS. Large, randomized clinical trials are warranted to identify populations and lesion characteristics where IVUS guidance would be associated with better outcomes

Gene Expression Profiling in Limb-Girdle Muscular Dystrophy 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that β-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT