Methodological bias in cluster randomised trials

Background: Cluster randomised trials can be susceptible to a range of methodological problems. These problems are not commonly recognised by many researchers. In this paper we discuss the issues that can lead to bias in cluster trials. Methods: We used a sample of cluster randomised trials from a recent review and from a systematic review of hip protectors. We compared the mean age of participants between intervention groups in a sample of 'good' cluster trials with a sample of potentially biased trials. We also compared the effect sizes, in a funnel plot, between hip protector trials that used individual randomisation compared with those that used cluster randomisation. Results: There is a tendency for cluster trials, with evidence methodological biases, to also show an age imbalance between treatment groups. In a funnel plot we show that all cluster trials show a large positive effect of hip protectors whilst individually randomised trials show a range of positive and negative effects, suggesting that cluster trials may be producing a biased estimate of effect. Conclusion: Methodological biases in the design and execution of cluster randomised trials is frequent. Some of these biases associated with the use of cluster designs can be avoided through careful attention to the design of cluster trials. Firstly, if possible, individual allocation should be used. Secondly, if cluster allocation is required, then ideally participants should be identified before random allocation of the clusters. Third, if prior identification is not possible, then an independent recruiter should be used to recruit participants

Outcome of Occupational Latex Allergy—Work Ability and Quality of Life

OBJECTIVE: The quality of life (QOL) and work ability of health care workers allergic to natural rubber latex (NRL) were assessed after implementation of regulations on powder-free NRL gloves in Germany. METHODS: 196 HCW with reported NRL allergy answered a questionnaire (response rate 58%) containing the Work Ability Index (WAI), Mini Asthma Quality of Life Questionnaire (MiniAQLQ), and Dermatology Life Quality Index (DLQI). RESULTS: 63.2% still had NRL-related symptoms during the last 6 month. However on a scale from 0 to 10, the intensity of NRL-related symptoms decreased from 8.5 before to 2.3 after implementation of regulations on powder-free NRL gloves. A higher number of subjects were able to avoid NRL in the private than in the work environment (85% vs. 61%). NRL-related symptoms decreased and WAI increased with successful avoidance of NRL at workplace (b = 0.23, p = 0.003). QOL was only little affected by NRL allergy (mean: MiniAQLQ = 6.0; DLQI = 4.1). CONCLUSIONS: Although there was improvement after implementation of powder-free NRL gloves, there is still a considerable number of HCW with NRL-related symptoms. Further investigations on latex avoidance and the cause of persisiting allergic symptoms in HCW with NRL allergy are therefore needed

Trabecular Reorganization in Consecutive Iliac Crest Biopsies when Switching from Bisphosphonate to Strontium Ranelate Treatment

BACKGROUND: Several agents are available to treat osteoporosis while addressing patient-specific medical needs. Individuals' residual risk to severe fracture may require changes in treatment strategy. Data at osseous cellular and microstructural levels due to a therapy switch between agents with different modes of action are rare. Our study on a series of five consecutively taken bone biopsies from an osteoporotic individual over a six-year period analyzes changes in cellular characteristics, bone microstructure and mineralization caused by a therapy switch from an antiresorptive (bisphosphonate) to a dual action bone agent (strontium ranelate). METHODOLOGY/PRINCIPAL FINDINGS: Biopsies were progressively taken from the iliac crest of a female patient. Four biopsies were taken during bisphosphonate therapy and one biopsy was taken after one year of strontium ranelate (SR) treatment. Furthermore, serum bone markers and dual x-ray absorptiometry measurements were acquired. Undecalcified histology was used to assess osteoid parameters and bone turnover. Structural indices and degree of mineralization were determined using microcomputed tomography, quantitative backscattered electron imaging, and combined energy dispersive x-ray/µ-x-ray-fluorescence microanalysis. CONCLUSIONS/SIGNIFICANCE: Microstructural data revealed a notable increase in bone volume fraction after one year of SR treatment compared to the bisphosphonate treatment period. Indices of connectivity density, structure model index and trabecular bone pattern factor were predominantly enhanced indicating that the architectural transformation from trabecular rods to plates was responsible for the bone volume increase and less due to changes in trabecular thickness and number. Administration of SR following bisphosphonates led to a maintained mineralization profile with an uptake of strontium on the bone surface level. Reactivated osteoclasts designed tunneling, hook-like intratrabecular resorption sites. The appearance of tunneling resorption lacunae and the formation of both mini-modeling units and osteon-like structures within increased plate-like cancellous bone mass provides additional information on the mechanisms of strontium ranelate following bisphosphonate treatment, which may deserve special attention when monitoring a treatment switch

AHR2 Mutant Reveals Functional Diversity of Aryl Hydrocarbon Receptors in Zebrafish

The aryl hydrocarbon receptor (AHR) is well known for mediating the toxic effects of TCDD and has been a subject of intense research for over 30 years. Current investigations continue to uncover its endogenous and regulatory roles in a wide variety of cellular and molecular signaling processes. A zebrafish line with a mutation in ahr2 (ahr2hu3335), encoding the AHR paralogue responsible for mediating TCDD toxicity in zebrafish, was developed via Targeting Induced Local Lesions IN Genomes (TILLING) and predicted to express a non-functional AHR2 protein. We characterized AHR activity in the mutant line using TCDD and leflunomide as toxicological probes to investigate function, ligand binding and CYP1A induction patterns of paralogues AHR2, AHR1A and AHR1B. By evaluating TCDD-induced developmental toxicity, mRNA expression changes and CYP1A protein in the AHR2 mutant line, we determined that ahr2hu3335 zebrafish are functionally null. In silico modeling predicted differential binding of TCDD and leflunomide to the AHR paralogues. AHR1A is considered a non-functional pseudogene as it does not bind TCCD or mediate in vivo TCDD toxicity. Homology modeling, however, predicted a ligand binding conformation of AHR1A with leflunomide. AHR1A-dependent CYP1A immunohistochemical expression in the liver provided in vivo confirmation of the in silico docking studies. The ahr2hu3335 functional knockout line expands the experimental power of zebrafish to unravel the role of the AHR during development, as well as highlights potential activity of the other AHR paralogues in ligand-specific toxicological responses

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Search for R-parity-violating supersymmetry in events with four or more leptons in sqrt(s) =7 TeV pp collisions with the ATLAS detector

A search for new phenomena in final states with four or more leptons (electrons or muons) is presented. The analysis is based on 4.7 fb−1 of $\sqrt{s}=7\;\mathrm{TeV}$ proton-proton collisions delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in two signal regions: one that requires moderate values of missing transverse momentum and another that requires large effective mass. The results are interpreted in a simplified model of R-parity-violating supersymmetry in which a 95% CL exclusion region is set for charged wino masses up to 540 GeV. In an R-parity-violating MSUGRA/CMSSM model, values of m 1/2 up to 820 GeV are excluded for 10 < tan β < 40

Search for high-mass resonances decaying to dilepton final states in pp collisions at s√=7 TeV with the ATLAS detector

The ATLAS detector at the Large Hadron Collider is used to search for high-mass resonances decaying to an electron-positron pair or a muon-antimuon pair. The search is sensitive to heavy neutral Z′ gauge bosons, Randall-Sundrum gravitons, Z * bosons, techni-mesons, Kaluza-Klein Z/γ bosons, and bosons predicted by Torsion models. Results are presented based on an analysis of pp collisions at a center-of-mass energy of 7 TeV corresponding to an integrated luminosity of 4.9 fb−1 in the e + e − channel and 5.0 fb−1 in the μ + μ −channel. A Z ′ boson with Standard Model-like couplings is excluded at 95 % confidence level for masses below 2.22 TeV. A Randall-Sundrum graviton with coupling k/MPl=0.1 is excluded at 95 % confidence level for masses below 2.16 TeV. Limits on the other models are also presented, including Technicolor and Minimal Z′ Models

Robustness Analysis and Behavior Discrimination in Enzymatic Reaction Networks

Characterizing the behavior and robustness of enzymatic networks with numerous variables and unknown parameter values is a major challenge in biology, especially when some enzymes have counter-intuitive properties or switch-like behavior between activation and inhibition. In this paper, we propose new methodological and tool-supported contributions, based on the intuitive formalism of temporal logic, to express in a rigorous manner arbitrarily complex dynamical properties. Our multi-step analysis allows efficient sampling of the parameter space in order to define feasible regions in which the model exhibits imposed or experimentally observed behaviors. In a first step, an algorithmic methodology involving sensitivity analysis is conducted to determine bifurcation thresholds for a limited number of model parameters or initial conditions. In a second step, this boundary detection is supplemented by a global robustness analysis, based on quasi-Monte Carlo approach that takes into account all model parameters. We apply this method to a well-documented enzymatic reaction network describing collagen proteolysis by matrix metalloproteinase MMP2 and membrane type 1 metalloproteinase (MT1-MMP) in the presence of tissue inhibitor of metalloproteinase TIMP2. For this model, our method provides an extended analysis and quantification of network robustness toward paradoxical TIMP2 switching activity between activation or inhibition of MMP2 production. Further implication of our approach is illustrated by demonstrating and analyzing the possible existence of oscillatory behaviors when considering an extended open configuration of the enzymatic network. Notably, we construct bifurcation diagrams that specify key parameters values controlling the co-existence of stable steady and non-steady oscillatory proteolytic dynamics

Ca2+-induced changes in energy metabolism and viability of melanoma cells

Cancer cells are characterized by a high rate of glycolysis, which is their primary energy source. We show here that a rise in intracellular-free calcium ion (Ca2+), induced by Ca2+-ionophore A23187, exerted a deleterious effect on glycolysis and viability of B16 melanoma cells. Ca2+-ionophore caused a dose-dependent detachment of phosphofructokinase (EC 2.7.1.11), one of the key enzymes of glycolysis, from cytoskeleton. It also induced a decrease in the levels of glucose 1,6-bisphosphate and fructose 1,6-bisphosphate, the two stimulatory signal molecules of glycolysis. All these changes occurred at lower concentrations of the drug than those required to induce a reduction in viability of melanoma cells. We also found that low concentrations of Ca2+-ionophore induced an increase in adenosine 5′-triphosphate (ATP), which most probably resulted from the increase in mitochondrial-bound hexokinase, which reflects a defence mechanism. This mechanism can no longer operate at high concentrations of the Ca2+-ionophore, which causes a decrease in mitochondrial and cytosolic hexokinase, leading to a drastic fall in ATP and melanoma cell death. The present results suggest that drugs which are capable of inducing accumulation of intracellular-free Ca2+ in melanoma cells would cause a reduction in energy-producing systems, leading to melanoma cell death. © 1999 Cancer Research Campaig