The power and value of placebo and nocebo in painful osteoarthritis.

This paper reviews some recent advances in our understanding of the effects of sham or dummy interventions on pain and other symptoms in osteoarthritis (OA), and outlines two new approaches to the investigation of placebo and nocebo effects. We argue that the placebo effect provides us with a valuable way of investigating the nature of conditions like OA. For example, by examining which symptoms, biochemical markers or imaging features do or do not respond to placebo, we might learn more about the relationships between pathology and symptoms in OA. Placebo and nocebo effects are positive or negative outcomes resulting from the human interactions and contexts in which healthcare consultations take place. Subtle changes in behaviours and the environments in which consultations take place can have major effects on pain and other symptoms being experienced by people with OA. Nocebo effects are particularly powerful, leading to many health-care professionals (HCPs) causing unintended harm to their clients. Based on our own research, we conclude that beneficial outcomes are most likely to occur when both the (HCP) and the client feel safe and relaxed, and when the experiences of the client are validated by the (HCP). These findings have important implications for clinical practice. We believe that research in this field needs to be 'trans-disciplinary', escaping from the constraints of the purely biomedical, deterministic, positivist paradigm of most medical research. We provide the example of our own work which combines performance studies and scholarship, with psychology and medicine

Modal Ω-Logic: Automata, Neo-Logicism, and Set-Theoretic Realism

This essay examines the philosophical significance of $\Omega$-logic in Zermelo-Fraenkel set theory with choice (ZFC). The duality between coalgebra and algebra permits Boolean-valued algebraic models of ZFC to be interpreted as coalgebras. The modal profile of $\Omega$-logical validity can then be countenanced within a coalgebraic logic, and $\Omega$-logical validity can be defined via deterministic automata. I argue that the philosophical significance of the foregoing is two-fold. First, because the epistemic and modal profiles of $\Omega$-logical validity correspond to those of second-order logical consequence, $\Omega$-logical validity is genuinely logical, and thus vindicates a neo-logicist conception of mathematical truth in the set-theoretic multiverse. Second, the foregoing provides a modal-computational account of the interpretation of mathematical vocabulary, adducing in favor of a realist conception of the cumulative hierarchy of sets

Quine, Ontology, and Physicalism

Quine's views on ontology and naturalism are well-known but rarely considered in tandem. According to my interpretation the connection between them is vital. I read Quine as a global epistemic structuralist. Quine thought we only ever know objects qua solutions to puzzles about significant intersections in observations. Objects are always accessed descriptively, via their roles in our best theory. Quine's Kant lectures contain an early version of epistemic structuralism with uncharacteristic remarks about the mental. Here Quine embraces mitigated anomalous monism, allowing introspection and the availability in principle of full physical descriptions of the perceptual states which get science off the ground. Later versions abandon these ideas. My epistemic-structural interpretation explains why. I argue first-personal introspective access to mental states is incompatible with global epistemic structuralism

The power of invalidating communication: Receiving invalidating feedback predicts threat-related emotional, physiological, and social responses

© 2016 Guilford Publications, Inc. Previous studies have found that communicating acceptance and understanding (validation) enhances the recipient's psychological and physiological wellbeing compared with receiving nonunderstanding feedback (invalidation). Yet, such studies have not established whether it is validation or absence of invalidation that is beneficial. This study examined the social, physiological, and emotional effects of validating and invalidating feedback in more detail, by employing a control group. Ninety healthy volunteers were randomly allocated to receive validating, invalidating, or no feedback during a series of stressor tasks. Self-report ratings, psychophysiological measurements and social engagement behaviors were recorded. While there were no significant differences between validated and control participants, invalidated participants showed increased physiological and psychological arousal on several measures and reduced social engagement behaviors compared with the other two groups. the relevance of these findings for understanding adverse effects of invalidation during clinical interactions is discussed

Hard and Blind: On Wittgenstein's Genealogical View of Logical Necessity

My main aim is to sketch a certain reading (‘genealogical') of later Wittgenstein's views on logical necessity. Along the way, I engage with the inferentialism currently debated in the literature on the epistemology of deductive logic.publishedVersio

Mirror Symmetry and Other Miracles in Superstring Theory

The dominance of string theory in the research landscape of quantum gravity physics (despite any direct experimental evidence) can, I think, be justified in a variety of ways. Here I focus on an argument from mathematical fertility, broadly similar to Hilary Putnam's 'no miracles argument' that, I argue, many string theorists in fact espouse. String theory leads to many surprising, useful, and well-confirmed mathematical 'predictions' - here I focus on mirror symmetry. These predictions are made on the basis of general physical principles entering into string theory. The success of the mathematical predictions are then seen as evidence for framework that generated them. I attempt to defend this argument, but there are nonetheless some serious objections to be faced. These objections can only be evaded at a high (philosophical) price.Comment: For submission to a Foundations of Physics special issue on "Forty Years Of String Theory: Reflecting On the Foundations" (edited by G. `t Hooft, E. Verlinde, D. Dieks and S. de Haro)

What trial participants need to be told about placebo effects to give informed consent: a survey to establish existing knowledge among patients with back pain.

INTRODUCTION: Patients require an accurate knowledge about placebos and their possible effects to ensure consent for placebo-controlled clinical trials is adequately informed. However, few previous studies have explored patients' baseline (ie, pretrial recruitment) levels of understanding and knowledge about placebos. The present online survey aimed to assess knowledge about placebos among patients with a history of back pain. DESIGN: A 15-item questionnaire was constructed to measure knowledge about placebos. Additional questions assessed sociodemographic characteristics, duration and severity of back pain, and previous experience of receiving placebos. SETTING: Participants recruited from community settings completed the study online. RESULTS: 210 participants completed the questionnaire. 86.7% had back pain in the past 6 months, 44.3% currently had back pain. 4.3% had received a placebo intervention as part of a clinical trial and 68.1% had previously read or heard information about placebos. Overall knowledge of placebos was high, with participants on average answering 12.07 of 15 questions about placebos correctly (SD=2.35). However, few participants correctly answered questions about the nocebo effect (31.9% correct) and the impact of the colour of a placebo pill (55.2% correct). CONCLUSIONS: The findings identified key gaps in knowledge about placebos. The lack of understanding of the nocebo effect in particular has implications for the informed consent of trial participants. Research ethics committees and investigators should prioritise amending informed consent procedures to incorporate the fact that participants in the placebo arm might experience adverse side effects

The light chains of kinesin-1 are autoinhibited

The light chains (KLCs) of the microtubule motor kinesin-1 bind cargoes and regulate its activity. Through their tetratricopeptide repeat domain (KLCTPR), they can recognize short linear peptide motifs found in many cargo proteins characterized by a central tryptophan flanked by aspartic/glutamic acid residues (W-acidic). Using a fluorescence resonance energy transfer biosensor in combination with X-ray crystallographic, biochemical, and biophysical approaches, we describe how an intramolecular interaction between the KLC2TPR domain and a conserved peptide motif within an unstructured region of the molecule, partly occludes the W-acidic binding site on the TPR domain. Cargo binding displaces this interaction, effecting a global conformational change in KLCs resulting in a more extended conformation. Thus, like the motor-bearing kinesin heavy chains, KLCs exist in a dynamic conformational state that is regulated by self-interaction and cargo binding. We propose a model by which, via this molecular switch, W-acidic cargo binding regulates the activity of the holoenzyme

Lamellipodia are crucial for haptotactic sensing and response

Haptotaxis is the process by which cells respond to gradients of substrate-bound cues, such as extracellular matrix proteins (ECM); however, the cellular mechanism of this response remains poorly understood and has mainly been studied by comparing cell behavior on uniform ECMs with different concentrations of components. To study haptotaxis in response to gradients, we utilized microfluidic chambers to generate gradients of the ECM protein fibronectin, and imaged the cell migration response. Lamellipodia are fan-shaped protrusions that are common in migrating cells. Here, we define a new function for lamellipodia and the cellular mechanism required for haptotaxis – differential actin and lamellipodial protrusion dynamics lead to biased cell migration. Modest differences in lamellipodial dynamics occurring over time periods of seconds to minutes are summed over hours to produce differential whole cell movement towards higher concentrations of fibronectin. We identify a specific subset of lamellipodia regulators as being crucial for haptotaxis. Numerous studies have linked components of this pathway to cancer metastasis and, consistent with this, we find that expression of the oncogenic Rac1 P29S mutation abrogates haptotaxis. Finally, we show that haptotaxis also operates through this pathway in 3D environments