Extending DerSimonian and Laird's methodology to perform network meta-analyses with random inconsistency effects.

Network meta-analysis is becoming more popular as a way to compare multiple treatments simultaneously. Here, we develop a new estimation method for fitting models for network meta-analysis with random inconsistency effects. This method is an extension of the procedure originally proposed by DerSimonian and Laird. Our methodology allows for inconsistency within the network. The proposed procedure is semi-parametric, non-iterative, fast and highly accessible to applied researchers. The methodology is found to perform satisfactorily in a simulation study provided that the sample size is large enough and the extent of the inconsistency is not very severe. We apply our approach to two real examples.DJ, RT and IRW are employed by the UK Medical Research Council (code U105260558). JB is supported by the UK MRC grant numbers G0902100 and MR/K014811/1.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/sim.675

Phase I, open-label study of pasireotide in patients with <i>BRAF-</i>wild type and <i>NRAS</i>-wild type, unresectable and/or metastatic melanoma.

Somatostatin analogues exert antitumour activity via direct and indirect mechanisms. The present study was designed to assess the safety and efficacy of pasireotide in patients with &lt;i&gt;BRAF&lt;/i&gt; -wild type (WT) and &lt;i&gt;NRAS&lt;/i&gt; -WT metastatic melanoma. Patients with unresectable and/or metastatic melanoma or Merkel cell carcinoma were eligible. Pasireotide was administered at different doses for ≤8 weeks in dose-escalation phase, followed by long-acting pasireotide 80 mg or lower dose in case of toxicity in follow-up phase up to six additional months. Primary endpoint was safety in the first 8 weeks of dose-escalation phase. The study was terminated early due to slow recruitment. Of the 10 patients with metastatic melanoma enrolled, only four reached the high dose level: two patients reached 3600 µg in dose-escalation and follow-up phases and two patients reached 3600 µg in dose-escalation and long-acting pasireotide 80 mg in follow-up phases and were stable for &gt;5 months. Most common adverse events (AEs) during dose-escalation phase in ≥2 patients (20%) were: diarrhoea (50%), nausea (50%), fatigue (20%), hyperglycaemia (20%), hypophosphatemia (20%), chills (20%) and tumour pain (20%). Grade 3 or 4 study drug-related AEs were diarrhoea and nausea, reported in one patient. Partial response was documented in one patient and stable disease in another. Pasireotide was well tolerated, and safety results were similar to those previously reported in other indications. Further studies are needed to evaluate its antitumour activity alone and in combination with other drugs in melanoma

A Bayesian analysis of pentaquark signals from CLAS data

We examine the results of two measurements by the CLAS collaboration, one of which claimed evidence for a $\Theta^{+}$ pentaquark, whilst the other found no such evidence. The unique feature of these two experiments was that they were performed with the same experimental setup. Using a Bayesian analysis we find that the results of the two experiments are in fact compatible with each other, but that the first measurement did not contain sufficient information to determine unambiguously the existence of a $\Theta^{+}$. Further, we suggest a means by which the existence of a new candidate particle can be tested in a rigorous manner.Comment: 5 pages, 3 figure

Search for medium modification of the ρ\rho meson

The photoproduction of vector mesons on various nuclei has been studied using the CEBAF Large Acceptance Spectrometer (CLAS) at Jefferson Laboratory. The vector mesons, $\rho$, $\omega$, and $\phi$, are observed via their decay to $e^+e^-$, in order to reduce the effects of final state interactions in the nucleus. Of particular interest are possible in-medium effects on the properties of the $\rho$ meson. The $\rho$ spectral function is extracted from the data on various nuclei, carbon, iron, and titanium, and compared to the spectrum from liquid deuterium, which is relatively free of nuclear effects. We observe no significant mass shift for the $\rho$ meson; however, there is some widening of the resonance in titanium and iron, which is consistent with expected collisional broadening.Comment: 8 pages, 4 figure

First measurement of coherent ϕ\phi-meson photoproduction on deuteron at low energies

The cross section and decay angular distributions for the coherent \phi meson photoproduction on the deuteron have been measured for the first time up to a squared four-momentum transfer t =(p_{\gamma}-p_{\phi})^2 =-2 GeV^2/c^2, using the CLAS detector at the Thomas Jefferson National Accelerator Facility. The cross sections are compared with predictions from a re-scattering model. In a framework of vector meson dominance, the data are consistent with the total \phi-N cross section \sigma_{\phi N} at about 10 mb. If vector meson dominance is violated, a larger \sigma_{\phi N} is possible by introducing larger t-slope for the \phi N \to \phi N process than that for the \gamma N \to \phi N process. The decay angular distributions of the \phi are consistent with helicity conservation.Comment: 6 page

Light Vector Mesons in the Nuclear Medium

The light vector mesons ($\rho$, $\omega$, and $\phi$) were produced in deuterium, carbon, titanium, and iron targets in a search for possible in-medium modifications to the properties of the $\rho$ meson at normal nuclear densities and zero temperature. The vector mesons were detected with the CEBAF Large Acceptance Spectrometer (CLAS) via their decays to $e^{+}e^{-}$. The rare leptonic decay was chosen to reduce final-state interactions. A combinatorial background was subtracted from the invariant mass spectra using a well-established event-mixing technique. The $\rho$ meson mass spectrum was extracted after the $\omega$ and $\phi$ signals were removed in a nearly model-independent way. Comparisons were made between the $\rho$ mass spectra from the heavy targets ($A > 2$) with the mass spectrum extracted from the deuterium target. With respect to the $\rho$-meson mass, we obtain a small shift compatible with zero. Also, we measure widths consistent with standard nuclear many-body effects such as collisional broadening and Fermi motion.Comment: 15 pages, 18 figures, 3 table

Structural basis for pre-tRNA recognition and processing by the human tRNA splicing endonuclease complex

Throughout bacteria, archaea and eukarya, certain tRNA transcripts contain introns. Pre-tRNAs with introns require splicing to form the mature anticodon stem loop. In eukaryotes, tRNA splicing is initiated by the heterotetrameric tRNA splicing endonuclease (TSEN) complex. All TSEN subunits are essential, and mutations within the complex are associated with a family of neurodevelopmental disorders known as pontocerebellar hypoplasia (PCH). Here, we report cryo-electron microscopy structures of the human TSEN–pre-tRNA complex. These structures reveal the overall architecture of the complex and the extensive tRNA binding interfaces. The structures share homology with archaeal TSENs but contain additional features important for pre-tRNA recognition. The TSEN54 subunit functions as a pivotal scaffold for the pre-tRNA and the two endonuclease subunits. Finally, the TSEN structures enable visualization of the molecular environments of PCH-causing missense mutations, providing insight into the mechanism of pre-tRNA splicing and PCH

Dual equipoise shared decision making: definitions for decision and behaviour support interventions

Contains fulltext : 80919.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: There is increasing interest in interventions that can support patients who face difficult decisions and individuals who need to modify their behaviour to achieve better outcomes. Evidence for effectiveness is used to categorise patients care. Effective care is where evidence of benefit outweighs harm: patients should always receive this type of care, where indicated. Preference-sensitive care describes a situation where the evidence for the superiority of one treatment over another is either not available or does not allow differentiation; in this situation, there are two or more valid approaches, and the best choice depends on how individuals value the risks and benefits of treatments. DISCUSSION: Preference-sensitive decisions are defined by equipoise: situations where options need to be deliberated. Moreover, where both healthcare professionals and patients agree that equipoise exists, situations may be regarded as having 'dual equipoise'. Such conditions are ideal for shared decision making. However, there are many situations in medicine where dual equipoise does not exist, where health professionals hold the view that scientific evidence for benefit strongly outweighs harm. This is often the case where people suffer from chronic conditions, and where behaviour change is recommended to improve outcomes. However, some patients, are either ambivalent or find it difficult to sustain optimal behaviours, i.e., patients will be in varying degrees of equipoise. Therefore, situations where dual equipoise exists (or not) help to clarify the definitions of two classes of support, namely, decision and behaviour change support interventions. Decision support interventions help people think about choices they face; they describe where and why choice exists, in short, conditions of dual equipoise; they provide information about options, including, where reasonable, the option of taking no action. These interventions help people to deliberate, independently or in collaboration with others, about options by considering relevant attributes; they support people to forecast how they might feel about short, intermediate, and long-term outcomes that have relevant consequences, in ways that help the process of constructing preferences and eventual decision making appropriate to their individual situation. Whereas, behavioural support interventions describe, justify, and recommend actions that, over time, lead to predictable outcomes over short, intermediate, and long-term timeframes, and that have relevant and important consequences for those who are considering behaviour change. SUMMARY: Decision and behaviour support interventions have divergent aims, different relationships to equipoise, and form two classes of interventions