Methods of Blinding in Reports of Randomized Controlled Trials Assessing Pharmacologic Treatments: A Systematic Review

BACKGROUND: Blinding is a cornerstone of therapeutic evaluation because lack of blinding can bias treatment effect estimates. An inventory of the blinding methods would help trialists conduct high-quality clinical trials and readers appraise the quality of results of published trials. We aimed to systematically classify and describe methods to establish and maintain blinding of patients and health care providers and methods to obtain blinding of outcome assessors in randomized controlled trials of pharmacologic treatments. METHODS AND FINDINGS: We undertook a systematic review of all reports of randomized controlled trials assessing pharmacologic treatments with blinding published in 2004 in high impact-factor journals from Medline and the Cochrane Methodology Register. We used a standardized data collection form to extract data. The blinding methods were classified according to whether they primarily (1) established blinding of patients or health care providers, (2) maintained the blinding of patients or health care providers, and (3) obtained blinding of assessors of the main outcomes. We identified 819 articles, with 472 (58%) describing the method of blinding. Methods to establish blinding of patients and/or health care providers concerned mainly treatments provided in identical form, specific methods to mask some characteristics of the treatments (e.g., added flavor or opaque coverage), or use of double dummy procedures or simulation of an injection. Methods to avoid unblinding of patients and/or health care providers involved use of active placebo, centralized assessment of side effects, patients informed only in part about the potential side effects of each treatment, centralized adapted dosage, or provision of sham results of complementary investigations. The methods reported for blinding outcome assessors mainly relied on a centralized assessment of complementary investigations, clinical examination (i.e., use of video, audiotape, or photography), or adjudication of clinical events. CONCLUSIONS: This review classifies blinding methods and provides a detailed description of methods that could help trialists overcome some barriers to blinding in clinical trials and readers interpret the quality of pharmalogic trials

Developing, delivering and documenting rehabilitation in a multi-centre randomised controlled surgical trial: experiences from the ProFHER trial

OBJECTIVES: A rigorous approach to developing, delivering and documenting rehabilitation within randomised controlled trials of surgical interventions is required to underpin the generation of reliable and usable evidence. This article describes the key processes used to ensure provision of good quality and comparable rehabilitation to all participants of a multi-centre randomised controlled trial comparing surgery with conservative treatment of proximal humeral fractures in adults. METHODS: These processes included the development of a patient information leaflet on self-care during sling immobilisation, the development of a basic treatment physiotherapy protocol that received input and endorsement by specialist physiotherapists providing patient care, and establishing an expectation for the provision of home exercises. Specially designed forms were also developed to facilitate reliable reporting of the physiotherapy care that patients received. RESULTS: All three initiatives were successfully implemented, alongside the measures to optimise the documentation of physiotherapy. Thus, all participating sites that recruited patients provided the sling immobilisation leaflet, all adhered to the physiotherapy protocol and all provided home exercises. There was exemplary completion of the physiotherapy forms that often reflected a complex patient care pathway. These data demonstrated equal and high access to and implementation of physiotherapy between groups, including the performance of home exercises. CONCLUSION: In order to increase the validity and relevance of the evidence from trials of surgical interventions and meet international reporting standards, careful attention to study design, conduct and reporting of the intrinsic rehabilitation components is required. The involvement of rehabilitation specialists is crucial to achieving this. Cite this article: Bone Joint Res 2014;3:335–40

The World Hip Trauma Evaluation Study 3 HEMIARTHROPLASTY EVALUATION BY MULTICENTRE INVESTIGATION - WHiTE 3: HEMI - AN ABRIDGED PROTOCOL

Approximately half of all hip fractures are displaced intracapsular fractures. The standard treatment for these fractures is either hemiarthroplasty or total hip arthroplasty. The recent National Institute for Health and Care Excellence (NICE) guidance on hip fracture management recommends the use of 'proven' cemented stem arthroplasty with an Orthopaedic Device Evaluation Panel (ODEP) rating of at least 3B (97% survival at three years). The Thompsons prosthesis is currently lacking an ODEP rating despite over 50 years of clinical use, likely due to the paucity of implant survival data. Nationally, adherence to these guidelines is varied as there is debate as to which prosthesis optimises patient outcomes.This study design is a multi-centre, multi-surgeon, parallel, two arm, standard-of-care pragmatic randomised controlled trial. It will be embedded within the WHiTE Comprehensive Cohort Study (ISRCTN63982700). The main analysis is a two-way equivalence comparison between Hemi-Thompson and Hemi-Exeter polished taper with Unitrax head. Secondary outcomes will include radiological leg length discrepancy measured as per Bidwai and Willett, mortality, re-operation rate and indication for re-operation, length of index hospital stay and revision at four months. This study will be supplemented by the NHFD (National Hip Fracture Database) dataset.Evidence on the optimum choice of prosthesis for hemiarthroplasty of the hip is lacking. National guidance is currently based on expert opinion rather than empirical evidence. The incidence of hip fracture is likely to continue to increase and providing high quality evidence on the optimumCite this article: A. L. Sims. The World Hip Trauma Evaluation Study 3: Hemiarthroplasty Evaluation by Multicentre Investigation - WHITE 3: HEMI - An Abridged Protocol. Bone Joint Res 2016;5:18-25. doi: 10.1302/2046-3758.51.2000473

Quantum Fluctuations in Large-Spin Molecules

A new type of mesoscopic quantum effect in large-spin molecules possessing easy-axis anisotropy, such as Mn12, is predicted. The response of such a system to an external field applied perpendicular to the easy axis is considered. It is shown that the susceptibility of this system exhibits a peculiar peak of purely quantum origin. This effect arises from very general properties of quantum fluctuations in spin systems. We demonstrate that the effect is entirely accessible for contemporary experimental techniques. Our studies show that the many-spin nature of the Mn12 clusters is important for a correct description of this quantum peak.Comment: REVTeX, 3 pages, 6 figures (postscript

Tunneling of a large spin via hyperfine interactions

We consider a large spin \bf S in the magnetic field parallel to the uniaxial crystal field, interacting with N >> 1 nuclear spins \bf I_i via Hamiltonian \cal H = -DS_z^2 - H_zS_z+ A{\bf S}\cdot \sum_{i=1}^N {\bf I}_i with A << D, at temperature T. Tunneling splittings and the selection rules for the resonant values of H_z are obtained perturbatively. The quantum coherence exists at T << ASI while at T >= ASI the coherence is destroyed and the relaxation of \bf S is described by a stretched dependence which can be close to log t under certain conditions. Relevance to Mn-12 acetate is discussed.Comment: 5 PR pages, 4 figures, submitted to PR

Thermally Activated Resonant Magnetization Tunneling in Molecular Magnets: Mn_12Ac and others

The dynamical theory of thermally activated resonant magnetization tunneling in uniaxially anisotropic magnetic molecules such as Mn_12Ac (S=10) is developed.The observed slow dynamics of the system is described by master equations for the populations of spin levels.The latter are obtained by the adiabatic elimination of fast degrees of freedom from the density matrix equation with the help of the perturbation theory developed earlier for the tunneling level splitting [D. A. Garanin, J. Phys. A, 24, L61 (1991)]. There exists a temperature range (thermally activated tunneling) where the escape rate follows the Arrhenius law, but has a nonmonotonic dependence on the bias field due to tunneling at the top of the barrier. At lower temperatures this regime crosses over to the non-Arrhenius law (thermally assisted tunneling). The transition between the two regimes can be first or second order, depending on the transverse field, which can be tested in experiments. In both regimes the resonant maxima of the rate occur when spin levels in the two potential wells match at certain field values. In the thermally activated regime at low dissipation each resonance has a multitower self-similar structure with progressively narrowing peaks mounting on top of each other.Comment: 18 pages, 8 figure

The challenges faced in the design, conduct and analysis of surgical randomised controlled trials

Randomised evaluations of surgical interventions are rare; some interventions have been widely adopted without rigorous evaluation. Unlike other medical areas, the randomised controlled trial (RCT) design has not become the default study design for the evaluation of surgical interventions. Surgical trials are difficult to successfully undertake and pose particular practical and methodological challenges. However, RCTs have played a role in the assessment of surgical innovations and there is scope and need for greater use. This article will consider the design, conduct and analysis of an RCT of a surgical intervention. The issues will be reviewed under three headings: the timing of the evaluation, defining the research question and trial design issues. Recommendations on the conduct of future surgical RCTs are made. Collaboration between research and surgical communities is needed to address the distinct issues raised by the assessmentof surgical interventions and enable the conduct of appropriate and well-designed trials.The Health Services Research Unit is funded by the Scottish Government Health DirectoratesPeer reviewedPublisher PD

Magnetic properties of the frustrated AFM spinel ZnCr_2O_4 and the spin-glass Zn_{1-x}Cd_xCr_2O_4 (x=0.05,0.10)

The $T$-dependence (2- 400 K) of the electron paramagnetic resonance (EPR), magnetic susceptibility, $\chi (T)$, and specific heat, $C_{v}(T)$, of the $normal$ antiferromagnetic (AFM) spinel ZnCr$_{2}$O$_{4}$ and the spin-glass (SG) Zn$_{1-x}$Cd$_{x}$Cr$_{2}$O$_{4}$ ($x=0.05,0.10$) is reported. These systems behave as a strongly frustrated AFM and SG with $$ $\approx T_{G}\approx 12$ K and -400 K $\gtrsim \Theta_{CW}\gtrsim -500$ K. At high-$T$ the EPR intensity follows the $\chi (T)$ and the $g$-value is $T$-independent. The linewidth broadens as the temperature is lowered, suggesting the existence of short range AFM correlations in the paramagnetic phase. For ZnCr$_{2}$O$_{4}$ the EPR intensity and $\chi (T)$ decreases below 90 K and 50 K, respectively. These results are discussed in terms of nearest-neighbor Cr$^{3+}$ (S $=3/2$%) spin-coupled pairs with an exchange coupling of $| J/k| \approx$ 50 K. The appearance of small resonance modes for $T\lesssim 17$ K, the observation of a sharp drop in $\chi (T)$ and a strong peak in $C_{v}(T)$ at $T_{N}=12$ K confirms, as previously reported, the existence of long range AFM correlations in the low-$T$ phase. A comparison with recent neutron diffraction experiments that found a near dispersionless excitation at 4.5 meV for $T\lesssim T_{N}$ and a continuous gapless spectrum for $T\gtrsim T_{N}$, is also given.Comment: 17 pages, 8 figures, 1 Table. Submitted to Physical Review

Effect of local Coulomb interactions on the electronic structure and exchange interactions in Mn12 magnetic molecules

We have studied the effect of local Coulomb interactions on the electronic structure of the molecular magnet Mn12-acetate within the LDA+U approach. The account of the on-site repulsion results in a finite energy gap and an integer value of the molecule's magnetic moment, both quantities being in a good agreement with the experimental results. The resulting magnetic moments and charge states of non-equivalent manganese ions agree very well with experiments. The calculated values of the intramolecular exchange parameters depend on the molecule's spin configuration, differing by 25-30% between the ferrimagnetic ground state and the completely ferromagnetic configurations. The values of the ground-state exchange coupling parameters are in reasonable agreement with the recent data on the magnetization jumps in megagauss magnetic fields. Simple estimates show that the obtained exchange parameters can be applied, at least qualitatively, to the description of the spin excitations in Mn12-acetate.Comment: RevTeX, LaTeX2e, 4 EPS figure

Quantum-Classical Transition of the Escape Rate of a Uniaxial Spin System in an Arbitrarily Directed Field

The escape rate \Gamma of the large-spin model described by the Hamiltonian H = -DS_z^2 - H_zS_z - H_xS_x is investigated with the help of the mapping onto a particle moving in a double-well potential U(x). The transition-state method yields $\Gamma$ in the moderate-damping case as a Boltzmann average of the quantum transition probabilities. We have shown that the transition from the classical to quantum regimes with lowering temperature is of the first order (d\Gamma/dT discontinuous at the transition temperature T_0) for h_x below the phase boundary line h_x=h_{xc}(h_z), where h_{x,z}\equiv H_{x,z}/(2SD), and of the second order above this line. In the unbiased case (H_z=0) the result is h_{xc}(0)=1/4, i.e., one fourth of the metastability boundary h_{xm}=1, at which the barrier disappears. In the strongly biased limit \delta\equiv 1-h_z << 1, one has h_{xc} \cong (2/3)^{3/4}(\sqrt{3}-\sqrt{2})\delta^{3/2}\cong 0.2345 \delta^{3/2}, which is about one half of the boundary value h_{xm} \cong (2\delta/3)^{3/2} \cong 0.5443 \delta^{3/2}.The latter case is relevant for experiments on small magnetic particles, where the barrier should be lowered to achieve measurable quantum escape rates.Comment: 17 PR pages, 16 figures; published versio