Two Paradoxes of Satisfaction

There are two paradoxes of satisfaction, and they are of different kinds. The classic satisfaction paradox is a version of Grelling's: does 'does not satisfy itself ' satisfy itself ? The Unsatisfied paradox finds a predicate, P, such that Px if and onl

Paradoxes and Hypodoxes of Time Travel

I distinguish paradoxes and hypodoxes among the conundrums of time travel. I introduce ‘hypodoxes’ as a term for seemingly consistent conundrums that seem to be related to various paradoxes, as the Truth-teller is related to the Liar. In this article, I briefly compare paradoxes and hypodoxes of time travel with Liar paradoxes and Truth-teller hypodoxes. I also discuss Lewis’ treatment of time travel paradoxes, which I characterise as a Laissez Faire theory of time travel. Time travel paradoxes are impossible according to Laissez Faire theories, while it seems hypodoxes are possible

SN 2011ht: Confirming a Class of Interacting Supernovae with Plateau Light Curves (Type IIn-P)

We present photometry and spectroscopy of the Type IIn supernova (SN) 2011ht, identified previously as a SN impostor. The light curve exhibits an abrupt transition from a well-defined ~120 day plateau to a steep bolometric decline. Leading up to peak brightness, a hot emission-line spectrum exhibits signs of interaction with circumstellar material (CSM), in the form of relatively narrow P-Cygni features of H I and He I superimposed on broad Lorentzian wings. For the remainder of the plateau phase the spectrum exhibits strengthening P-Cygni profiles of Fe II, Ca II, and H-alpha. By day 147, after the plateau has ended, the SN entered the nebular phase, heralded by the appearance of forbidden transitions of [O I], [O II], and [Ca II] over a weak continuum. At this stage, the light curve exhibits a low luminosity that is comparable to that sub-luminous Type II-P supernovae, and a relatively fast visual-wavelength decline that is significantly steeper than the Co-56 decay rate. However, the total bolometric decline, including the IR luminosity, is consistent with Co-56 decay, and implies a low Ni-56 mass of ~0.01 M(Sun). We therefore characterize SN 2011ht as a bona-fide core-collapse SN very similar to the peculiar SNe IIn 1994W and 2009kn. These three SNe define a subclass, which are Type IIn based on their spectrum, but that also exhibit well-defined plateaus and produce low Ni-56 yields. We therefore suggest Type IIn-P as a name for this subclass. Possible progenitors of SNe IIn-P, consistent with the available data, include 8-10 M(Sun) stars, which undergo core collapse as a result of electron capture after a brief phase of enhanced mass loss, or more massive M>25 M(Sun) progenitors, which experience substantial fallback of the metal-rich radioactive ejecta. In either case, the energy radiated by these three SNe during their plateau must be dominated by CSM interaction (abridged).Comment: accepted, post-proof version (includes new data

Systematic techniques for assisting recruitment to trials (START): study protocol for embedded, randomized controlled trials

BACKGROUND: Randomized controlled trials play a central role in evidence-based practice, but recruitment of participants, and retention of them once in the trial, is challenging. Moreover, there is a dearth of evidence that research teams can use to inform the development of their recruitment and retention strategies. As with other healthcare initiatives, the fairest test of the effectiveness of a recruitment strategy is a trial comparing alternatives, which for recruitment would mean embedding a recruitment trial within an ongoing host trial. Systematic reviews indicate that such studies are rare. Embedded trials are largely delivered in an ad hoc way, with interventions almost always developed in isolation and tested in the context of a single host trial, limiting their ability to contribute to a body of evidence with regard to a single recruitment intervention and to researchers working in different contexts. METHODS/DESIGN: The Systematic Techniques for Assisting Recruitment to Trials (START) program is funded by the United Kingdom Medical Research Council (MRC) Methodology Research Programme to support the routine adoption of embedded trials to test standardized recruitment interventions across ongoing host trials. To achieve this aim, the program involves three interrelated work packages: (1) methodology - to develop guidelines for the design, analysis and reporting of embedded recruitment studies; (2) interventions - to develop effective and useful recruitment interventions; and (3) implementation - to recruit host trials and test interventions through embedded studies. DISCUSSION: Successful completion of the START program will provide a model for a platform for the wider trials community to use to evaluate recruitment interventions or, potentially, other types of intervention linked to trial conduct. It will also increase the evidence base for two types of recruitment intervention. TRIAL REGISTRATION: The START protocol covers the methodology for embedded trials. Each embedded trial is registered separately or as a substudy of the host trial

CSAR Benchmark Exercise of 2010: Selection of the Protein–Ligand Complexes

ABSTRACT: A major goal in drug design is the improvement of computational methods for docking and scoring. The Community Structure Activity Resource (CSAR) aims to collect available data from industry and academia which may be used for this purpose (www.csardock.org). Also, CSAR is charged with organizing community-wide exercises based on the collected data. The first of these exercises was aimed to gauge the overall state of docking and scoring, using a large and diverse data set of protein ligand complexes. Participants were asked to calculate the affinity of the complexes as provided and then recalculate with changes which may improve their specific method. This first data set was selected from existing PDB entries which had binding data (Kd or Ki) in Binding MOAD, augmented with entries from PDBbind. The final data set contains 343 diverse protein ligand complexes and spans 14 pKd. Sixteen proteins have three or more complexes in the data set, from which a user could start an inspection of congeneric series. Inherent experimental error limits the possible correlation between scores and measured affinity; R 2 is limited to ∼0.9 when fitting to the data set without over parametrizing. R 2 is limited to ∼0.8 when scoring the data set with a method trained on outside data. The details of how the data set was initially selected, and the process by which it matured t

A comparative analysis of whole genome sequencing of esophageal adenocarcinoma pre- and post-chemotherapy

The scientific community has avoided using tissue samples from patients that have been exposed to systemic chemotherapy to infer the genomic landscape of a given cancer. Esophageal adenocarcinoma is a heterogeneous, chemoresistant tumor for which the availability and size of pretreatment endoscopic samples are limiting. This study compares whole-genome sequencing data obtained from chemo-naive and chemo-treated samples. The quality of whole-genomic sequencing data is comparable across all samples regardless of chemotherapy status. Inclusion of samples collected post-chemotherapy increased the proportion of late-stage tumors. When comparing matched pre- and post-chemotherapy samples from 10 cases, the mutational signatures, copy number, and SNV mutational profiles reflect the expected heterogeneity in this disease. Analysis of SNVs in relation to allele-specific copy-number changes pinpoints the common ancestor to a point prior to chemotherapy. For cases in which pre- and post-chemotherapy samples do show substantial differences, the timing of the divergence is near-synchronous with endoreduplication. Comparison across a large prospective cohort (62 treatment-naive, 58 chemotherapy-treated samples) reveals no significant differences in the overall mutation rate, mutation signatures, specific recurrent point mutations, or copy-number events in respect to chemotherapy status. In conclusion, whole-genome sequencing of samples obtained following neoadjuvant chemotherapy is representative of the genomic landscape of esophageal adenocarcinoma. Excluding these samples reduces the material available for cataloging and introduces a bias toward the earlier stages of cancer.This study was partly funded by a project grant from Cancer Research UK. R.C.F. is funded by an NIHR Professorship and receives core funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Cancer Medicine Centre. We acknowledge the support of The University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited

Optimal primary care management of clinical osteoarthritis and joint pain in older people: a mixed-methods programme of systematic reviews, observational and qualitative studies, and randomised controlled trials

Background Osteoarthritis (OA) is the most common long-term condition managed in UK general practice. However, care is suboptimal despite evidence that primary care and community-based interventions can reduce OA pain and disability. Objectives The overall aim was to improve primary care management of OA and the health of patients with OA. Four parallel linked workstreams aimed to (1) develop a health economic decision model for estimating the potential for cost-effective delivery of primary care OA interventions to improve population health, (2) develop and evaluate new health-care models for delivery of core treatments and support for self-management among primary care consulters with OA, and to investigate prioritisation and implementation of OA care among the public, patients, doctors, health-care professionals and NHS trusts, (3) determine the effectiveness of strategies to optimise specific components of core OA treatment using the example of exercise and (4) investigate the effect of interventions to tackle barriers to core OA treatment, using the example of comorbid anxiety and depression in persons with OA. Data sources The North Staffordshire Osteoarthritis Project database, held by Keele University, was the source of data for secondary analyses in workstream 1. Methods Workstream 1 used meta-analysis and synthesis of published evidence about effectiveness of primary care treatments, combined with secondary analysis of existing longitudinal population-based cohort data, to identify predictors of poor long-term outcome (prognostic factors) and design a health economic decision model to estimate cost-effectiveness of different hypothetical strategies for implementing optimal primary care for patients with OA. Workstream 2 used mixed methods to (1) develop and test a ‘model OA consultation’ for primary care health-care professionals (qualitative interviews, consensus, training and evaluation) and (2) evaluate the combined effect of a computerised ‘pop-up’ guideline for general practitioners (GPs) in the consultation and implementing the model OA consultation on practice and patient outcomes (parallel group intervention study). Workstream 3 developed and investigated in a randomised controlled trial (RCT) how to optimise the effect of exercise in persons with knee OA by tailoring it to the individual and improving adherence. Workstream 4 developed and investigated in a cluster RCT the extent to which screening patients for comorbid anxiety and depression can improve OA outcomes. Public and patient involvement included proposal development, project steering and analysis. An OA forum involved public, patient, health professional, social care and researcher representatives to debate the results and formulate proposals for wider implementation and dissemination. Results This programme provides evidence (1) that economic modelling can be used in OA to extrapolate findings of cost-effectiveness beyond the short-term outcomes of clinical trials, (2) about ways of implementing support for self-management and models of optimal primary care informed by National Institute for Health and Care Excellence recommendations, including the beneficial effects of training in a model OA consultation on GP behaviour and of pop-up screens in GP consultations on the quality of prescribing, (3) against adding enhanced interventions to current effective physiotherapy-led exercise for knee OA and (4) against screening for anxiety and depression in patients with musculoskeletal pain as an addition to current best practice for OA. Conclusions Implementation of evidence-based care for patients with OA is feasible in general practice and has an immediate impact on improving the quality of care delivered to patients. However, improved levels of quality of care, changes to current best practice physiotherapy and successful introduction of psychological screening, as achieved by this programme, did not substantially reduce patients’ pain and disability. This poses important challenges for clinical practice and OA research. Limitations The key limitation in this work is the lack of improvement in patient-reported pain and disability despite clear evidence of enhanced delivery of evidence-based care. Future work recommendations (1) New thinking and research is needed into the achievable and desirable long-term goals of care for people with OA, (2) continuing investigation into the resources needed to properly implement clinical guidelines for management of OA as a long-term condition, such as regular monitoring to maintain exercise and physical activity and (3) new research to identify subgroups of patients with OA as a basis for stratified primary care including (i) those with good prognosis who can self-manage with minimal investigation or specialist treatment, (ii) those who will respond to, and benefit from, specific interventions in primary care, such as physiotherapy-led exercise, and (iii) develop research into effective identification and treatment of clinically important anxiety and depression in patients with OA and into the effects of pain management on psychological outcomes in patients with OA. Trial registration Current Controlled Trials ISRCTN06984617, ISRCTN93634563 and ISRCTN40721988. Funding This project was funded by the National Institute for Health Research (NIHR) Programme Grants for Applied Research Programme and will be published in full in Programme Grants for Applied Research Programme; Vol. 6, No. 4. See the NIHR Journals Library website for further project information. </jats:sec

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

The Pinocchio paradox

The Liar paradox is intuitive. Having explained the Liar to my elder children some years ago, I asked them to come up with versions of their own. My son, Leif, then 13, suggested: A policeman asks a suspect whether he is lying, and the criminal just says ‘Yes’. One can see how this would work, and it is similar to a known version of the Liar originating with L. Jonathan Cohen. After some time, my elder daughter, Veronique, then 11, devised the Pinocchio paradox. Pinocchio says ‘My nose will be growing’. Pinocchio’s nose grows, so the story tells us, whenever he tells a lie. The use of a future tense ties in with when Pinocchio’s nose is supposed to grow – after telling a lie. Philosophers will naturally want to know how soon afterwards. (There is an interesting version of the Epimenides though, if one does not restrict how soon Pinocchio’s nose should grow. Imagine Pinocchio says ‘My nose will grow ’ but everything else Pinocchio says is true. Then, Pinocchio’s nose wil