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To explore the role of neurotrophin-3 (NT-3) during cerebral ischemia, NT-3-deficient brains were subjected to transient focal ischemia. Conditional mutant brains produced undetectable amounts of NT-3 mRNA, whereas the expression of the neurotrophin, BDNF, the NT-3 receptor, TrkC, and the nonselective, low-affinity neurotrophin receptor p75NTR, were comparable to wild-type. Baseline absolute blood flow, vascular and neuroanatomical features, as well as physiological measurements were also indistinguishable from wild-type. Interestingly, the absence of NT-3 led to a significantly decreased infarct volume 23 h after middle cerebral artery occlusion. Consistent with this, the addition of NT-3 to primary cortical cell cultures exacerbated neuronal death caused by oxygen-glucose deprivation. Coincubation with the oxygen free radical chelator, trolox, diminished potentiation of neuronal death. NT-3 also enhanced neuronal cell death and the production of reactive oxygen species caused by oxidative damage inducing agents. We conclude that endogenous NT-3 enhanced neuronal injury during acute stroke, possible by increasing oxygen-radical mediated cell death.

Background Pediatric patients with recurrent/metastatic Ewing sarcoma (ES) have a dismal 5-year survival. Novel therapeutic approaches are desperately needed. Natural killer (NK) cell number and function are low in ES patient tumors, in large part due to the immunosuppressive tumor microenvironment (TME). Melanoma cell adhesion molecule (MCAM) is highly expressed on ES and associated with ES metastasis. NKTR-255 is a polymer-conjugated recombinant human interleukin-15 (IL-15) agonist improving NK cell activity and persistence. Magrolimab (MAG) is a CD47 blockade that reactivates the phagocytic activity of macrophages.Methods Transcriptome profiling coupled with CIBERSORT analyses in both ES mouse xenografts and human patient tumors were performed to identify mechanisms of NK resistance in ES TME. A chimeric antigen receptor (CAR) NK cell targeting MCAM was engineered by CAR mRNA electroporation into ex vivo expanded NK cells. In vitro cytotoxicity assays were performed to investigate the efficacy of anti-MCAM-CAR-NK cell alone or combined with NKTR-255 against ES cells. Interferon-γ and perforin levels were measured by ELISA. The effect of MAG on macrophage phagocytosis of ES cells was evaluated by in vitro phagocytosis assays. Cell-based and patient-derived xenograft (PDX)-based xenograft mouse models of ES were used to investigate the antitumor efficacy of CAR-NK alone and combined with NKTR-255 and MAG in vivo.Results We found that NK cell infiltration and activity were negatively regulated by tumor-associated macrophages (TAM) in ES TME. Expression of anti-MCAM CAR significantly and specifically enhanced NK cytotoxic activity against MCAMhigh but not MCAM-knockout ES cells in vitro, and significantly reduced lung metastasis and extended animal survival in vivo. NKTR-255 and MAG significantly enhanced in vitro CAR-NK cytotoxicity and macrophage phagocytic activity against ES cells, respectively. By combining with NKTR-255 and MAG, the anti-MCAM-CAR-NK cell significantly decreased primary tumor growth and prolonged animal survival in both cell- and PDX-based ES xenograft mouse models.Conclusions Our preclinical studies demonstrate that immunotherapy via the innate immune system by combining tumor-targeting CAR-NK cells with an IL-15 agonist and a CD47 blockade is a promising novel therapeutic approach to targeting MCAMhigh malignant metastatic ES.

Compared with time-independent Hamiltonians, the dynamics of generic quantum Hamiltonians H(t) are complicated by the presence of time ordering in the evolution operator. In the context of digital quantum simulation, this difficulty prevents a direct adaptation of many time-independent simulation algorithms for time-dependent simulation. However, there exists a framework within the theory of dynamical systems that eliminates time ordering by adding a “clock” degree of freedom. In this work, we provide a computational framework, based on this reduction, for encoding time-dependent dynamics as time-independent systems. As a result, we make two advances in digital Hamiltonian simulation. First, we create a time-dependent simulation algorithm based on performing qubitization on the augmented clock system and, in doing so, provide the first qubitization-based approach to time-dependent Hamiltonians that goes beyond Trotterization of the ordered exponential. Second, we define a natural generalization of multiproduct formulas for time-ordered exponentials and then propose and analyze an algorithm based on these formulas. Unlike other algorithms of similar accuracy, the multiproduct approach achieves commutator scaling, meaning that this method outperforms existing methods for physically local time-dependent Hamiltonians with sufficient smoothness. Our work reduces the disparity between time-dependent and time-independent simulation and indicates a step toward optimal quantum simulation of time-dependent Hamiltonians.

We present a systematic ab initio study of clustering in hot dilute nuclear matter using nuclear lattice effective field theory with an SU(4)-symmetric interaction. We introduce a method called light-cluster distillation to determine the abundances of dimers, trimers, and alpha clusters as a function of density and temperature. Our lattice results are compared with an ideal gas model composed of free nucleons and clusters. Excellent agreement is found at very low density, while deviations from ideal gas abundances appear at increasing density due to cluster-nucleon and cluster-cluster interactions. In addition to determining the composition of hot dilute nuclear matter as a function of density and temperature, the lattice calculations also serve as benchmarks for virial expansion calculations, statistical models, and transport models of fragmentation and clustering in nucleus-nucleus collisions.

Abstract The carbon atom provides the backbone for the complex organic chemistry composing the building blocks of life. The physics of the carbon nucleus in its predominant isotope, 12C, is similarly full of multifaceted complexity. Here we provide a model-independent density map of the geometry of the nuclear states of 12C using the ab initio framework of nuclear lattice effective field theory. We find that the well-known but enigmatic Hoyle state is composed of a “bent-arm” or obtuse triangular arrangement of alpha clusters. We identify all of the low-lying nuclear states of 12C as having an intrinsic shape composed of three alpha clusters forming either an equilateral triangle or an obtuse triangle. The states with the equilateral triangle formation also have a dual description in terms of particle-hole excitations in the mean-field picture.

The accurate determination of the free nicotine content in cigarette smoke is crucial for assessing cigarette quality, studying harm and addiction, and reducing tar levels. Currently, the determination of free nicotine in tobacco products primarily relies on methods such as pH calculation, nuclear magnetic resonance (NMR) spectroscopy, headspace solid-phase microextraction (HS-SPME), and traditional solvent extraction. However, these methods have limitations that restrict their widespread application. In this study, the free nicotine in cigarette smoke was directly extracted by using cyclohexane according to the traditional solvent extraction method and detected via gas chromatography-mass spectrometry. Compared with the traditional two-phase solvent extraction, our experimental method is easy to execute and eliminates the influence of aqueous solutions on the original distribution of nicotine in cigarette smoke particulate matter. Furthermore, the presence of protonated nicotine in tobacco does not affect the determination. Compared with HS-SPME and NMR spectroscopy, our approach, which involves solvent extraction followed by chromatographic separation and instrumental detection, offers simplicity, improved precision, better detection limits, and reduced interference during the instrumental detection stage. The standard addition recoveries in the conducted experiment ranged from 96.2% to 102.5%. The limit of detection was 2.8 μg/cig, and the correlation coefficient R2 for the quadratic regression of the standard curve exceeded 0.999. The relative standard deviation for parallel samples was between 1.7% and 3.4% (n = 5), fully meeting the requirements for the determination of free nicotine in cigarette smoke. Analysis of cigarette samples from 38 commercially available brands revealed that the content of free nicotine ranged from 0.376 to 0.716 mg/cig, with an average of 0.540 mg/cig, and free nicotine accounted for 39.1%–88.8% of the total nicotine content.

Abstract We investigate the phase shifts of low-energy α-α scattering under variations of the fundamental parameters of the Standard Model, namely the light quark mass, the electromagnetic fine-structure constant as well as the QCD θ-angle. As a first step, we recalculate α-α scattering in our Universe utilizing various improvements in the adiabatic projection method, which leads to an improved, parameter-free prediction of the S- and D-wave phase shifts for laboratory energies below 10 MeV. We find that positive shifts in the pion mass have a small effect on the S-wave phase shift, whereas lowering the pion mass adds some repulsion in the two-alpha system. The effect on the D-wave phase shift turns out to be more pronounced as signaled by the D-wave resonance parameters. Variations of the fine-structure constant have almost no effect on the low-energy α-α phase shifts. We further show that up-to-and-including next-to-leading order in the chiral expansion, variations of these phase shifts with respect to the QCD θ-angle can be expressed in terms of the θ-dependent pion mass.

Solving the generalized eigenvalue problem is a useful method for finding energy eigenstates of large quantum systems. It uses projection onto a set of basis states which are typically not orthogonal. One needs to invert a matrix whose entries are inner products of the basis states, and the process is unfortunately susceptible to even small errors. The problem is especially bad when matrix elements are evaluated using stochastic methods and have significant error bars. In this work, we introduce the trimmed sampling algorithm in order to solve this problem. Using the framework of Bayesian inference, we sample prior probability distributions determined by uncertainty estimates of the various matrix elements and likelihood functions composed of physics-informed constraints. The result is a probability distribution for the eigenvectors and observables which automatically comes with a reliable estimate of the error and performs far better than standard regularization methods. The method should have immediate use for a wide range of applications involving classical and quantum computing calculations of large quantum systems.

While these facts are generally ignored, nonbinary gender is a theme in fan spaces, and Judith Butler's theory of gender creation mostly excludes the possibility of any genders outside of the binary. When brought together, classic queer studies and fan studies texts offer explanations for both and indicate that nonbinary genders are at the core of fan fiction. Fan fiction communities, although often transphobic, practice bringing into the world genders outside of the binary gender system. Judith Butler's gender theory and classic fan studies research inform one another; when they are brought together, it is clear that fandom is a ground for the creation of genders, which in turn are embodied outside of fandom and are objects of attraction that exist outside of binary-gendered attraction models.

Background: The presence of pharmaceuticals in the environment is a growing global concern and although environmental risk assessment is required for approval of new drugs in Europe and the USA, the adequacy of the current triggers and the effects-based assessments has been questioned. Objective: To provide a comprehensive analysis of all regulatory compliant aquatic ecotoxicity data and evaluate the current triggers and effects-based environmental assessments to facilitate the development of more efficient approaches for pharmaceuticals toxicity testing. Methods: Publicly-available regulatory compliant ecotoxicity data for drugs targeting human proteins was compiled together with pharmacological information including drug targets, Cmax and lipophilicity. Possible links between these factors and the ecotoxicity data for effects on, growth, mortality and/or reproduction, were evaluated. The environmental risks were then assessed based on a combined analysis of drug toxicity and predicted environmental concentrations based on European patient consumption data. Results: For most (88%) of the of 975 approved small molecule drugs targeting human proteins a complete set of regulatory compliant ecotoxicity data in the public domain was lacking, highlighting the need for both intelligent approaches to prioritize legacy human drugs for a tailored environmental risk assessment and a transparent database that captures environmental data. We show that presence/absence of drug-target orthologues are predictive of susceptible species for the more potent drugs. Drugs that target the endocrine system represent the highest potency and greatest risk. However, for most drugs (>80%) with a full set of ecotoxicity data, risk quotients assuming worst-case exposure assessments were below one in all European countries indicating low environmental risks for the endpoints assessed. Conclusion: We believe that the presented analysis can guide improvements to current testing procedures, and provide valuable approaches for prioritising legacy drugs (i.e. those registered before 2006) for further ecotoxicity testing. For drugs where effects of possible concern (e.g. behaviour) are not captured in regulatory tests, additional mechanistic testing may be required to provide the highest confidence for avoiding environmental impacts.

Introduction: SARS-CoV-2 antibody detection serves as an important diagnostic marker for past SARS-CoV-2 infection and is essential to determine the spread of COVID-19, monitor potential COVID-19 long-term effects, and to evaluate possible protection from reinfection. A study was conducted across three hospital sites in a large central London NHS Trust in the UK, to evaluate the prevalence and duration of SARS-CoV-2 IgG antibody positivity in healthcare workers.Methods: A matrix equivalence study consisting of 228 participants was undertaken to evaluate the Abbott Panbio™ COVID-19 IgG/IgM rapid test device. Subsequently, 2001 evaluable healthcare workers (HCW), representing a diverse population, were enrolled in a HCW study between June and August 2020. A plasma sample from each HCW was evaluated using the Abbott Panbio™ COVID-19 IgG/IgM rapid test device, with confirmation of IgG-positive results by the Abbott ArchitectTM SARS-CoV-2 IgG assay. 545 participants, of whom 399 were antibody positive at enrolment, were followed up at 3 months.Results: The Panbio™ COVID-19 IgG/IgM rapid test device demonstrated a high concordance with laboratory tests. SARS-CoV-2 antibodies were detected in 506 participants (25.3%) at enrolment, with a higher prevalence in COVID-19 frontline (28.3%) than non-frontline (19.9%) staff. At follow-up, 274/399 antibody positive participants (68.7%) retained antibodies; 4/146 participants negative at enrolment (2.7%) had seroconverted. Non-white ethnicity, older age, hypertension and COVID-19 symptoms were independent predictors of higher antibody levels (OR 1.881, 2.422–3.034, 2.128, and 1.869 respectively), based on Architect™ index quartiles; participants in the first three categories also showed a greater antibody persistence at 3 months.Conclusion: The SARS-CoV-2 anti-nucleocapsid IgG positivity rate among healthcare staff was high, declining by 31.3% during the 3-month follow-up interval. Interestingly, the IgG-positive participants with certain risk factors for severe COVID-19 illness (older age, Black or Asian Ethnicity hypertension) demonstrated greater persistence over time when compared to the IgG-positive participants without these risk factors.

Emulators that can bypass computationally expensive scientific calculations with high accuracy and speed can enable new studies of fundamental science as well as more potential applications. In this work we discuss solving a system of constraint equations efficiently using a self-learning emulator. A self-learning emulator is an active learning protocol that can be used with any emulator that faithfully reproduces the exact solution at selected training points. The key ingredient is a fast estimate of the emulator error that becomes progressively more accurate as the emulator is improved, and the accuracy of the error estimate can be corrected using machine learning. We illustrate with three examples. The first uses cubic spline interpolation to find the solution of a transcendental equation with variable coefficients. The second example compares a spline emulator and a reduced basis method emulator to find solutions of a parametrized differential equation. The third example uses eigenvector continuation to find the eigenvectors and eigenvalues of a large Hamiltonian matrix that depends on several control parameters.

Background The prognosis of patients with relapsed or progressive B cell (CD20+) non-Hodgkin’s lymphoma (B-NHL), including Burkitt lymphoma (BL), is dismal due to chemoradiotherapy resistance. Novel therapeutic strategies are urgently needed. N-820 is a fusion protein of N-803 (formerly known as ALT-803) to four single-chains of rituximab. This agent has tri-specific binding activity to CD20 and enhanced antibody-dependent cell-mediated cytotoxicity.Methods We investigated the anti-tumor combinatorial effects of N-820 with ex vivo expanded peripheral blood natural killer (exPBNK) cells against rituximab-sensitive and rituximab-resistant CD20+ BL in vitro using cytoxicity assays and in vivo using human BL xenografted NOD/SCID/IL2rγnull (NSG) mice. We also investigated the cytokines/chemokines/growth factors released using ELISA and multiplex assay. Gene expression changes were examined using real-time PCR arrays.Results N-820 significantly enhanced the expression of NK activating receptors (p

In the current era of noisy quantum devices, there is a need for quantum algorithms that are efficient and robust against noise. Towards this end, we introduce the projected cooling algorithm for quantum computation. The projected cooling algorithm is able to construct the localized ground state of any Hamiltonian with a translationally-invariant kinetic energy and interactions that vanish at large distances. The term “localized” refers to localization in position space. The method can be viewed as the quantum analog of evaporative cooling. We start with an initial state with support over a compact region of a large volume. We then drive the excited quantum states to disperse and measure the remaining portion of the wave function left behind. For the nontrivial examples we consider here, the improvement over other methods is substantial. The only additional resource required is performing the operations in a volume significantly larger than the size of the localized state. These characteristics make the projected cooling algorithm a promising tool for calculations of self-bound systems such as atomic nuclei.

We review several recent results on lattice simulations by the Nuclear Lattice Effective Field Theory Collaboration. In the first part we discuss the implementation of nuclear forces on the lattice using chiral effective field theory. The new development we highlight is the use of non-local lattice operators to achieve a simpler spin channel decomposition, in contrast with previous studies that considered only local interactions. In the second part, we present evidence that nuclear physics is close to a quantum phase transition. This development is also linked to the study of the differences between local and non-local interactions. In the final part we further explore the link between the nuclear forces and nuclear structure. We consider the simplest possible nuclear interaction which can accurately reproduce the ground state energies of neutron matter, light nuclei, and medium-mass nuclei. We discuss what these recent developments say about the emergence of nuclear structure from nuclear forces and the road ahead for nuclear lattice simulations.

Abstract Background This study assessed the feasibility and acceptability of two common types of exercise training—high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT)—in adults with Crohn’s disease (CD). Methods In this mixed-methods pilot trial, participants with quiescent or mildly-active CD were randomly assigned 1:1:1 to HIIT, MICT or usual care control, and followed up for 6 months. The HIIT and MICT groups were offered three exercise sessions per week for the first 12 weeks. Feasibility outcomes included rates of recruitment, retention, outcome completion, and exercise attendance. Data were collected on cardiorespiratory fitness (e.g., peak oxygen uptake), disease activity, fatigue, quality of life, adverse events, and intervention acceptability (via interviews). Results Over 17 months, 53 patients were assessed for eligibility and 36 (68%) were randomised (47% male; mean age 36.9 [SD 11.2] years); 13 to HIIT, 12 to MICT, and 11 to control. The exercise session attendance rate was 62% for HIIT (288/465) and 75% for MICT (320/429), with 62% of HIIT participants (8/13) and 67% of MICT participants (8/12) completing at least 24 of 36 sessions. One participant was lost to follow-up. Outcome completion rates ranged from 89 to 97%. The mean increase in peak oxygen uptake, relative to control, was greater following HIIT than MICT (2.4 vs. 0.7 mL/kg/min). There were three non-serious exercise-related adverse events, and two exercise participants experienced disease relapse during follow-up. Conclusions The findings support the feasibility and acceptability of the exercise programmes and trial procedures. A definitive trial is warranted. Physical exercise remains a potentially useful adjunct therapy in CD. [ID: ISRCTN13021107].

The main objective of this article is to raise questions regarding the complex interactions between local and creative economies. To do so, a review of the literature dealing with the creative economy from a geographical perspective is carried out, with emphasis on authors such as Richard Florida, Amaral Filho, Ana Fani Carlos and Milton Santos. Special attention is given to approaches that address the issues of mode of production, trajectories and other characteristics associated with the identity of the place that affect the development of creative economies. Also treated are those approaches that deal with the many ventures associated with the creative economy and how labour relations manifest themselves in geographic space. Also noteworthy are the studies of Economic Geography that seek to understand the relations between creative economy and society based on principles that emphasize the importance of local. Finally, given the importance of factors such as the structure and spatial dynamics of networks, territoriality and locality, the relevance of studies that address the creative economy from a geographic perspective is explored, especially by its capacity to explain how the different realities or manifestations of this type of economy reflect in inequalities and conditions that at the same time characterize the place and mark the differences between the localities.

We derive the finite-volume correction to the binding energy of an N-particle quantum bound state in a cubic periodic volume. Our results are applicable to bound states with arbitrary composition and total angular momentum, and in any number of spatial dimensions. The only assumptions are that the interactions have finite range. The finite-volume correction is a sum of contributions from all possible breakup channels. In the case where the separation is into two bound clusters, our result gives the leading volume dependence up to exponentially small corrections. If the separation is into three or more clusters, there is a power-law factor that is beyond the scope of this work, however our result again determines the leading exponential dependence. We also present two independent methods that use finite-volume data to determine asymptotic normalization coefficients. The coefficients are useful to determine low-energy capture reactions into weakly bound states relevant for nuclear astrophysics. Using the techniques introduced here, one can even extract the infinite-volume energy limit using data from a single-volume calculation. The derived relations are tested using several exactly solvable systems and numerical examples. We anticipate immediate applications to lattice calculations of hadronic, nuclear, and cold atomic systems. Keywords: Finite-volume correction, Bound states, Lattice field theory

We consider two-component fermions with short-range interactions and large scattering length. This system has universal properties that are realized in several different fields of physics. In the limit of large fermion–fermion scattering length aff and zero-range interaction, all properties of the system scale proportionally with aff. For the case with shallow bound dimers, we calculate the dimer–dimer scattering phase shifts using lattice effective field theory. We extract the universal dimer–dimer scattering length add/aff=0.618(30) and effective range rdd/aff=−0.431(48). This result for the effective range is the first calculation with quantified and controlled systematic errors. We also benchmark our methods by computing the fermion–dimer scattering parameters and testing some predictions of conformal scaling of irrelevant operators near the unitarity limit.

How does nuclear binding emerge from first principles? Our current best understanding of nuclear forces is based on a systematic low-energy expansion called chiral effective field theory. However, recent ab initio calculations of nuclear structure have found that not all chiral effective field theory interactions give accurate predictions with increasing nuclear density. In this letter we address the reason for this problem and the first steps toward a solution. Using nuclear lattice simulations, we deduce the minimal nuclear interaction that can reproduce the ground state properties of light nuclei, medium-mass nuclei, and neutron matter simultaneously with no more than a few percent error in the energies and charge radii. We find that only four parameters are needed. With these four parameters one can accurately describe neutron matter up to saturation density and the ground state properties of nuclei up to calcium. Given the absence of sign oscillations in these lattice Monte Carlo simulations and the mild scaling of computational effort scaling with nucleon number, this work provides a pathway to high-quality simulations in the future with as many as one or two hundred nucleons.

We introduce a general and accurate method for determining lattice phase shifts and mixing angles, which is applicable to arbitrary, non-cubic lattices. Our method combines angular momentum projection, spherical wall boundaries and an adjustable auxiliary potential. This allows us to construct radial lattice wave functions and to determine phase shifts at arbitrary energies. For coupled partial waves, we use a complex-valued auxiliary potential that breaks time-reversal invariance. We benchmark our method using a system of two spin-1/2 particles interacting through a finite-range potential with a strong tensor component. We are able to extract phase shifts and mixing angles for all angular momenta and energies, with precision greater than that of extant methods. We discuss a wide range of applications from nuclear lattice simulations to optical lattice experiments.

We investigate the impact of the QCD vacuum at nonzero θ on the properties of light nuclei, Big Bang nucleosynthesis, and stellar nucleosynthesis. Our analysis starts with a calculation of the θ-dependence of the neutron-proton mass difference and neutron decay using chiral perturbation theory. We then discuss the θ-dependence of the nucleon-nucleon interaction using a one-boson-exchange model and compute the properties of the two-nucleon system. Using the universal properties of four-component fermions at large scattering length, we then deduce the binding energies of the three-nucleon and four-nucleon systems. Based on these results, we discuss the implications for primordial abundances of light nuclei, the production of nuclei in stellar environments, and implications for an anthropic view of the universe.

The aim was to undertake secondary data analysis from a three-arm randomised feasibility trial of high intensity interval training (HIIT), moderate intensity continuous training (MICT), and usual care control in adults with Crohn's disease (CD; n = 36), with a primary focus on exploring affective and enjoyment responses. Twenty-five participants with quiescent or mildly-active CD were randomised to one of the two exercise groups: HIIT (n = 13) and MICT (n = 12). Both groups were offered thrice weekly sessions for 12 weeks. MICT consisted of cycling for 30 minutes at 35% peak power (Wpeak), whereas HIIT involved ten 1-minute bouts at 90% Wpeak, interspersed with 1-minute bouts at 15% Wpeak. Heart rate (HR), differentiated ratings of perceived exertion for legs (RPE-L) and central (RPE-C), along with feeling state (Feeling Scale; FS) were measured at 92.5% of each session. Enjoyment was measured at the end of training using the Physical Activity Enjoyment Scale (PACES). Post-hoc exploratory analysis involved a mixed-model two-way ANOVA to compare HR, RPE-L, RPE-C and FS for the exercise sessions in weeks 1, 6 and 12 between groups. Overall, HR was greater (p < 0.01) during HIIT (173 ± 8 bpm) compared with MICT (128 ± 6 bpm). Similarly, RPE-L and RPE-C responses were greater overall (p = 0.03 and p = 0.03, respectively) during HIIT (5.5 ± 1.6 and 5.1 ± 1.7, respectively) compared to MICT (3.3 ± 1.5 and 2.9 ± 1.5, respectively). Overall, FS was 2.2 ± 1.9 for HIIT and 2.1 ± 1.4 for MICT with no effect of treatment group (p = 0.25) or time (p = 0.94). There was also no significant difference in PACES scores between HIIT (99.4 ± 12.9) and MICT (101.3 ± 17.4; p = 0.78). The findings suggest HIIT and MICT protocols elicited similar enjoyment and affect in adults with quiescent or mildly-active CD.

Muramyl tripeptide phos-phatidylethanolamine (MTP-PE) is a synthetic analogue of muramyl dipep-tide (MDP), a component of bacterial cell walls that has potent in vitro monocyte-activating properties. We conducted a phase II clinical trial of MTP-PE in 30 patients with metastatic melanoma. Our purpose was to define a clinical response rate for this agent in patients with advanced melanoma and to evaluate the agent's immunomodulatory properties. Patients were randomly assigned to 1-or 4-mg dose levels of MTP-PE and received the drug intravenously once a week for 12–24 weeks. Immunological monitoring consisted of measurement of plasma tumor necrosis factor-a (TNF-α), neopterin, interleukin-l-β, inter-leukin-6 (IL-6), and β-microglobulin levels; phenotyping analysis of expression of human HLA-DR, CD-14 on mono-nuclear cells; and measurement of in vitro monocyte cytotoxicity against SKMel28 targets cells. MTP-PE was well tolerated; fever and chills were the major toxic effects. Plasma TNF-a levels increased 16-fold 2 hours after the first MTP-PE treatment. Increases in TNF-a levels after MTP-PE administration continued through week 12, but changes were of a lower magnitude after week 1. Plasma neopterin levels were significantly increased 24 hours after treatment at weeks 1, 6, and 12. A marked increase in IL-6 and a modest rise in β-microglobulin levels were also seen at week 1. No significant changes from baseline IL-1β were observed. In the cytotoxicity assay, monocyte cytotoxic activity was significantly increased at weeks 4 and 6. Surface immuno-phenotyping revealed a consistent transient reduction in the number of circulating monocytes 2 hours after MTP-PE was administered. In addition, we observed a down-regulation (i.e., a decrease) in the expression of Leu M3 and HLA-DR on monocytes 2 hours after MTP-PE treatment, followed by a recovery 24 hours after treatment. No objective clinical responses were seen in this advanced disease population. We conclude that MTP-PE has pleiotropic and potentially beneficial biologic effects and that further clinical investigations of MTP-PE are justified. In view of the clear immunomodulatory actions seen in our study and in earlier clinical trials, we believe that MTP-PE deserves further study in the adjuvant setting. [J Natl Cancer Inst 84:694–699, 1992] [ABSTRACT FROM PUBLISHER]

Genetically modified pigs have been considered favorable resources in xenotransplantation. Microinjection of randomly integrating transgenes into zygotes, somatic cell nuclear transfer, homologous recombination, zinc finger nucleases, transcription activator-like effector nucleases, and most recently, clustered regularly interspaced short palindromic repeats-cas9 (CRISPR/Cas9) are the techniques that have been used to generate these animals. Here, we provide an overview of the CRISPR approaches that have been used to modify genes which are vital in improving xenograft survival rate, including cytidine monophosphate-N-acetylneuraminic acid hydroxylase, B1,4N-acetylgalactosaminyltransferase, isoglobotrihexosylceramide synthase, class I MHC, von Willebrand factor, C3, and porcine endogenous retroviruses. In addition, we will mention the importance of potential candidate genes which could be targeted using CRISPR/Cas9.

We investigate Nuclear Lattice Effective Field Theory for the two-body system for several lattice spacings at lowest order in the pionless as well as in the pionful theory. We discuss issues of regularizations and predictions for the effective range expansion. In the pionless case, a simple Gaussian smearing allows to demonstrate lattice spacing independence over a wide range of lattice spacings. We show that regularization methods known from the continuum formulation are necessary as well as feasible for the pionful approach.

Governments and organizations around the world are increasingly turning to knowledge and information sharing as a lead strategy for developing response capacity to address issues in a wide range of programs and policy areas. The sharing of information and knowledge within organizations may be influenced by a range of factors, one being trust. This paper seeks, firstly, to identify and explore some key theoretic approaches to trust applied in the broader social sciences literature, including trust as a “leap of faith” or willingness to vulnerability; trust as a key component of social capital; and trust as a component of the concept of power-knowledge and truth- telling as found in the work of Michel Foucault. Second, the paper presents the findings of a meta-analysis conducted of recent library and information science (LIS) literature in order to analyze how these three theoretical approaches are represented. Findings of the meta-analysis indicate that the trust definitions offered by two of the three theoretical perspectives investigated are well represented in recent LIS research; that other simpler definitions of trust are also represented; and that over one quarter of the sample were found to offer no explicit definition of trust. Analysis of these latter studies suggest that trust is represented by the implicit views and assumptions of researchers and the focus is more on the embedded authority of the information or abstract system rather than on the trustor as an essential component of the trust dynamic. DOI: http://dx.doi.org/10.5130/ccs.v5i3.3430

A deceptive aspect of the ‘writing about music is like dancing about architecture’ cliché is the function of the preposition ‘about’. Literature and music, dance and architecture, painting and film – all are discrete aesthetic forms that nonetheless simultaneously feed off and provide nourishment for each other as part of art’s perpetual drive toward diversity and innovation. Nowhere is the aptness of the association between writing and music more obvious than in the phenomenon of album liner notes. Rather than merely an attempt at describing or translating musical experience, liner notes contribute to the dialogue between composer and listener and are a significant part of the culture of contemporary music.

Polychlorinated biphenyls (PCBs), such as PCB52, are hazardous environmental contaminants present in indoor and outdoor environments. Oral PCB exposure affects the colon microbiome; however, it is unknown if inhalation of PCBs alters the intestinal microbiome. We hypothesize that sub-acute inhalation of PCB52 affects microbial communities depending on the location in the (GI) gastrointestinal tract and the local profiles of PCB52 and its metabolites present in the GI tract following mucociliary clearance and biliary or intestinal excretion. Sprague-Dawley rats were exposed via nose-only inhalation 4 h per day, 7 days per week, for 4 weeks to either filtered air or PCB52. After 28 days, differences in the microbiome and levels of PCB52 and its metabolites were characterized throughout the GI tract. PCB52 inhalation altered taxa abundances and predicted functions altered throughout the gut, with most alterations occurring in the large intestine. PCB52 and metabolite levels varied across the GI tract, resulting in differing PCB × microbiome networks. Thus, the presence of different levels of PCB52 and its metabolites in different parts of the GI tract has varying effects on the composition and predicted function of microbial communities. Future studies need to investigate whether these changes lead to adverse outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Author AM is the inventor of a technology claiming the use of Prevotella histicola for the treatment of autoimmune diseases. The patent for the technology is owned by Mayo Clinic, which has given an exclusive license to Evelo Biosciences. AM received royalties from Mayo Clinic (paid by Evelo Biosciences). However, no funds or products from the patent were used in the present study. The remaining authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exposure to polychlorinated biphenyls (PCBs) is associated with developmental neurotoxicity and neurodegenerative disorders; however, the underlying mechanisms of pathogenesis are unknown. Existing literature has focused mainly on using neurons as a model system to study mechanisms of PCB-mediated neurotoxicity, overlooking the role of glial cells, such as astrocytes. As normal brain function is largely astrocyte-dependent, we hypothesize that astrocytes play an important role in PCB-mediated injury to neurons. We assessed the toxicity of two commercial PCB mixtures, Aroclor 1016 and Aroclor 1254, and a non-Aroclor PCB mixture found in residential air called the Cabinet mixture, all of which contain lower chlorinated PCBs (LC-PCBs) found in indoor and outdoor air. We further assessed the toxicity of five abundant airborne LC-PCBs and their corresponding human-relevant metabolites in vitro models of astrocytes, namely, the C6 cell line and primary astrocytes isolated from Sprague-Dawley rats and C57BL/6 mice. PCB52 and its human-relevant hydroxylated and sulfated metabolites were found to be the most toxic compounds. No significant sex-dependent cell viability differences were observed in rat primary astrocytes. Based on the equilibrium partitioning model, it was predicted that the partitioning of LC-PCBs and their corresponding metabolites in biotic and abiotic compartments of the cell culture system is structure-dependent and that the observed toxicity is consistent with this prediction. This study, for the first time, shows that astrocytes are sensitive targets of LC-PCBs and their human-relevant metabolites and that further research to identify mechanistic targets of PCB exposure in glial cells is necessary.

Objective: To determine, among patients with axial spondyloarthritis (axSpA), whether the risk of inflammatory bowel disease (IBD) varies between patients treated with biologic therapies and those treated with other therapies and, specifically, whether the risk is higher in patients treated with etanercept (ETN)., Methods: The British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS) was used to determine the incidence of IBD during follow-up and to calculate the incidence rate difference (IRD) per 1000 person-years (PY), between biologic treatment and other treatment groups. We then conducted a systematic review, involving observational studies and randomized controlled trials (RCTs), to perform a metaanalysis to quantify the difference in incidence of IBD between treatment groups., Results: According to the BSRBR-AS, among people with axSpA, exposure to biologic therapy was associated with an increased incidence of IBD compared to those who were not exposed to biologic therapy (IRD 11.9, 95% CI 4.3-19.6). This finding was replicated across observational studies but was not seen in placebo-controlled RCTs (IRD 2.2, 95% CI -4.1 to 8.5). Data from the BSRBR-AS do not suggest that excess incidence of IBD is associated with exposure to ETN compared to other anti-tumor necrosis factor (TNF) therapies (IRD -6.5, 95% CI -21.3 to 8.5). RCTs and their extensions suggest a small-yet not statistically significant-absolute increased incidence associated with ETN of between 2.1 and 5.8 per 1000 PY compared to other anti-TNF therapies., Conclusion: There was an excess risk of IBD among persons treated with biologics in observational studies. Only evidence from RCTs suggested that ETN was associated with an increased risk compared to other anti-TNF therapies, albeit with considerable uncertainty., (Copyright © 2023 by the Journal of Rheumatology.)

Chiral polychlorinated biphenyls (PCB) are environmentally relevant developmental neurotoxicants. Because their hydroxylated metabolites (OH-PCBs) are also neurotoxic, it is necessary to determine how PCB metabolism affects the developing brain, for example, in mouse models. Because the cytochrome P450 isoforms involved in the metabolism of chiral PCBs remain unexplored, we investigated the metabolism of PCB 91 (2,2',3,4',6-pentachlorobiphenyl), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 132 (2,2',3,3',4,6'-hexachlorobiphenyl), and PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl) using liver microsomes from male and female Cyp2a(4/5)bgs -null, Cyp2f2 -null, and wild-type mice. Microsomes, pooled by sex, were incubated with 50 μM PCB for 30 min, and the levels and enantiomeric fractions of the OH-PCBs were determined gas chromatographically. All four PCB congeners appear to be atropselectively metabolized by CYP2A(4/5)BGS and CYP2F2 enzymes in a congener- and sex-dependent manner. The OH-PCB metabolite profiles of PCB 91 and PCB 132, PCB congeners with one para -chlorine substituent, differed between null and wild-type mice. No differences in the metabolite profiles were observed for PCB 95 and PCB 136, PCB congeners without a para -chlorine group. These findings suggest that Cyp2a(4/5)bgs -null and Cyp2f2 -null mice can be used to study how a loss of a specific metabolic function (e.g., deletion of Cyp2a(4/5)bgs or Cyp2f2 ) affects the toxicity of chiral PCB congeners.

Objective: To determine among patients with axial spondyloarthritis (SpA) the factors associated with decreased spinal mobility and to determine whether poor mobility is a predictor of response to anti-tumor necrosis factor (anti-TNF) therapy., Methods: This was a prospective UK cohort study of persons meeting Assessment of Spondylarthritis international Society (ASAS) criteria for axial SpA. At recruitment, clinical and patient-reported factors independently associated with spinal mobility (measured by the Bath Ankylosing Spondylitis Metrology Index [BASMI]) were determined. Among those commencing anti-TNF therapy, factors that were independent predictors of response were determined using ASAS criteria, quality of life, and Ankylosing Spondylitis Disease Activity Score (ASDAS) response criteria., Results: A total of 1,960 participants were eligible; 70% were male, the median age was 48 years (interquartile range [IQR] 37, 59), and the median BASMI score 3.6 (IQR 2.2, 5.3). Factors independently associated with poor spinal mobility were poorer function, meeting radiographic criteria for AS, longer symptom duration, higher levels of inflammation (measured by C-reactive protein level), older age, male sex, not being currently employed, and lower levels of education. For 51% of participants, the measured BASMI score was within 1 of that estimated. Poorer mobility (higher BASMI score) was an independent predictor of not meeting response criteria for ASAS 20% improvement (odds ratio [OR] per increasing score 0.80 [IQR 0.66, 0.98]), ASAS 40% improvement (OR 0.69 [IQR 0.50, 0.95]), and quality of life (measured by the Ankylosing Spondylitis Quality of Life Questionnaire) (β = 0.64 [IQR 0.26, 1.02]), but was not related to meeting ASDAS response criteria., Conclusion: The BASMI score was estimated moderately well by other routinely measured factors in patients with axial SpA and was an independent predictor of response to biologic therapy for some, but not all, commonly used measures. Consensus around its role in disease monitoring and clinical decisions, particularly in the likely context of face-to-face consultations becoming less frequent, remains to be established., (© 2020 American College of Rheumatology.)

Objective: To describe the baseline characteristics, biologic DMARD (bDMARD) response and drug survival of axial SpA (axSpA) patients in the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS) according to radiographic status., Methods: The BSRBR-AS is a national prospective cohort including axSpA participants classified according to the Assessment of SpondyloArthritis international Society criteria. In this analysis, baseline data of patients starting bDMARDs were compared. Ankylosing Spondylitis Disease Activity Scores (ASDASs) for low disease status, clinically important improvement (CII) and major improvement (MI) at 1 year were used to assess treatment response. Cox proportional hazards analysis was performed after adjusting for clinically relevant confounders., Results: A total of 1145 axSpA patients were included. Higher male prevalence, older age and longer disease duration were seen in the radiographic axSpA (r-axSpA) subgroup. Based on a complete case analysis (290 patients), two-thirds of patients achieved an ASDAS low disease state at 1 year regardless of radiographic status [non-radiographic axSpA (nr-axSpA) 64.2% vs r-axSpA 66.1]. No statistically significant differences were seen between the subgroups in attaining ASDAS CII (nr-axSpA 50.7% vs r-axSpA 44.7%) or MI (nr-axSpA 20% vs r-axSpA 18.7%). Drug survival probability curves were similar for both subgroups and the hazard ratio for nr-axSpA/axSpA was 0.94 (95% CI 0.69, 1.28) when adjusted for sex, age, baseline ASDAS with CRP, smoking status, disease duration, HLA-B27 and prescribed biologic., Conclusions: Although there appeared to be some differences in the baseline characteristics when exploring this cohort according to radiographic status, which are likely related to the natural history of the disease, the level of biologic response and drug survival was comparable between nr-axSpA and r-axSpA., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To identify factors associated with FM development and recovery in patients with axial SpA (axSpA)., Methods: The British Society of Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) recruited patients with axSpA from 83 centres in a prospective study. FM was diagnosed using the self-reported Fibromyalgia Survey Diagnostic Criteria from 2015. Measures of axSpA disease activity and clinical findings were recorded at regular intervals. We identified predictors for FM development and recovery between yearly visits using uni- and multivariable logistic regression models., Results: A total of 801 participants, 247 (30.8%) female, had two or more visits and were eligible for inclusion. A total of 686 participants did not have FM at baseline, of whom 45 had developed FM at follow-up, while 115 participants had FM at baseline, of whom 77 had recovered at follow-up. A high baseline BASDAI score [odds ratio (OR) 1.27 (95% CI 1.08, 1.49)] and Widespread Pain Index (WPI) [OR 1.14 (95% CI 1.02, 1.28)] were significantly associated with FM development in the final multivariable model. A low baseline BASFI score [OR 0.68 (95% CI 0.53, 0.86)] and WPI [OR 0.84 (95% CI 0.720, 0.97)] and starting a TNF inhibitor [OR 3.86 (95% CI 1.54, 9.71)] were significantly associated with FM recovery., Conclusion: High levels of disease activity and the presence of widespread pain is associated with the development of FM in patients with axSpA, while low levels of the same variables and starting a TNF inhibitor are associated with recovery from FM. The presence of comorbid FM should be considered in patients with persistent high axSpA disease activity and widespread pain., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: The aim was to assess the feasibility and acceptability of a telephone-based cognitive behaviour therapy (tCBT) intervention for individuals with axial SpA (axSpA), with and without co-morbid FM, and to measure the change in patient-reported health outcomes., Methods: A convenience sample of individuals recruited from British Society for Rheumatology Biologics Registry for AS (BSRBR-AS) sites were offered a course of tCBT (framed as coaching). Patient-reported outcomes were measured at baseline and on course completion. Semi-structured qualitative interviews assessed intervention acceptability. Thematic analysis was informed by the theoretical framework of acceptability., Results: Forty-two participants attended for initial assessment. Those completing at least one tCBT session ( n  = 28) were younger, more likely to meet classification criteria for FM (57 vs 29%) and reported higher disease activity. Modest improvements were reported across a range of disease activity and wider health measures, with 62% of patients self-rating their health as improved (median 13 weeks post-intervention). Twenty-six participants were interviewed (including six who discontinued after initial assessment). tCBT was widely acceptable, offering a personalized approach. Despite low or unclear expectations, participants described improved sleep and psychological well-being and gained new skills to support self-management. Reasons for non-uptake of tCBT centred on lack of perceived need and fit with individual value systems. Many felt that tCBT would be most useful closer to diagnosis., Conclusion: Higher uptake among axSpA patients with co-morbid FM suggests that these individuals have additional needs. The findings are helpful in identifying patients most likely to engage with and benefit from tCBT and to maximize participation., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Effective management of axial spondyloarthritis (axSpA)-related fatigue is a major unmet clinical need. Anti-TNF therapy may reduce fatigue levels, although any effect has yet to be definitively quantified and predictors of any such improvements are unknown., Methods: The British Society of Rheumatology Register in Axial Spondyloarthritis (BSRBR-AS) prospectively recruited axSpA patients across the UK. Changes in fatigue levels (measured using the Chalder Fatigue Scale) >1 year were compared between those starting anti-TNF therapy at the time of recruitment and those not. Differences between treatment groups were adjusted using propensity score matching. Results were meta-analysed with the extant literature to calculate pooled estimates. Then, among those BSRBR-AS anti-TNF commencers with clinically relevant fatigue, baseline predictors of response were investigated., Results: Of the 998 BSRBR-AS recruits with complete fatigue data, 310 were anti-TNF commencers. At 1-year follow-up, the former group reported a mean fatigue change of -2.6 (95% CI -4.1, -1.9) points while the latter reported a mean worsening of fatigue by 0.2 points. Following propensity score adjustment, those commencing anti-TNF therapy reduced fatigue by 3.0 points compared with those not. Of those with significant fatigue and commencing anti-TNF, poor sleep quality at baseline predicted fatigue improvement. In the meta-analysis, including 1109 subjects, treatment with anti-TNF therapy resulted in a significant improvement in fatigue [Standardized mean difference (SMD) = 0.36, 95% CI 0.15, 1.56]., Conclusion: Anti-TNF therapy results in a significant but modest reduction in fatigue amongst axSpA patients, with those reporting poor sleep quality most likely to report improvement. Effective management will likely require additional approaches., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: While many axSpA patients, eligible to receive anti-TNFα therapy, derive benefit when prescribed them, some patients do not. The current study aims to identify modifiable targets to improve outcome as well as non-modifiable targets that identify groups less likely to derive benefit., Methods: The BSRBR-AS is a prospective cohort study of axSpA patients who, at recruitment, were naïve to biologic therapy. Those in the 'biologic' sub-cohort commenced their first anti-TNFα therapy at recruitment or during follow-up. Prior to commencement, information was collected on socio-economic, clinical and patient-reported factors. Outcome was assessed according to ASAS20, ASAS40, ASDAS reduction and achieving a moderate/inactive ASDAS disease state., Results: 335 participants commenced their first anti-TNFα therapy and were followed up at a median of 14 (inter-quartile range 12-17) weeks. Response varied between 33% and 52% according to criteria used. Adverse socio-economic factors, fewer years in education predicted lower likelihood of response across outcome measures as did not working full-time. Co-morbidities and poor mental health were clinical and patient-reported factors, respectively, associated with lack of response. The models, particularly those using ASDAS, were good at predicting those who did not respond (negative predictive value (NPV) 77%)., Conclusion: Some factors predicting non-response (such as mental health) are modifiable but many (such as social/economic factors) are not modifiable in clinic. They do, however, identify patients who are unlikely to benefit from biologic therapy alone. Priority should focus on how these patients receive the benefits that many derive from such therapies., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: To examine differences in clinical and patient-reported outcomes, including work, in individuals with axial spondyloarthritis (axSpA) living in rural and urban settings., Methods: Using a sequential, explanatory mixed-method design, data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis were used to (1) characterise participants with axSpA living in rural and urban areas and (b) assess any differences in outcome after commencement of biologic therapy (phase 1). Semistructured interviews (phase 2) further explored the results from phase 1., Results: Patients with axSpA living in rural areas were older and more likely to work in a physical job. Among patients prescribed biologics, there were no differences in response to biologics, but after adjustment for age, sex and local area deprivation rural dwellers reported more presenteeism and overall work impairment. Work effects could be explained by accounting for individual differences in disease activity, fatigue, physical function and job type. Interviews highlighted the complex relationship between clinical factors, contextual factors (work environment, job demands) and work disability. The ability to work and flexibility in terms of what, when and how tasks are undertaken were important. Support from employers was variable and healthcare professionals were often perceived as unsupportive., Conclusions: Patients with axSpA living in rural areas report a greater impact of their disease on work productivity. New measures are needed to capture important contextual factors and comprehensively determine the impact of long-term conditions on work. Future European League Against Rheumatism axSpA recommendations should include support to work as a target to optimise quality of life in patients with axSpA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Management guidelines assume that results from clinical trials can be generalised, although seldom is data available to test this assumption. We aimed to determine the proportion of patients commencing tumour necrosis factor inhibition (TNFi) who would have been eligible for relevant clinical trials, and whether treatment response differs between these groups and the trials themselves. The British Society for Rheumatology Biologics Register for Ankylosing Spondylitis (BSRBR-AS) recruited a real-world cohort of TNFi-naïve spondyloarthritis patients with data collection from clinical records and patient questionnaires. Participant characteristics were extracted from trials identified from a recent Health Technology Assessment of TNFi for ankylosing spondylitis/non-radiographic axial spondyloarthritis. Descriptive statistics were used to determine the differences, including treatment response, between BSRBR-AS participants who would/would not have been eligible for the clinical trials and with trial participants. Among 2420 BSRBR-AS participants, those commencing TNFi (34%) had shorter symptom duration (15 vs 22 years) but more active disease (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 6.4 vs 4.0; Bath Ankylosing Spondylitis Disease Functional Index (BASFI) 6.2 vs 3.8). Of those commencing TNFi, 41% met eligibility criteria for ≥1 of fourteen relevant trials; they reported higher disease activity (BASDAI 6.9 vs 6.1) and poorer function (BASFI 6.6 vs 6.0). 61.7% of trial participants reported a positive treatment response, vs 51.3% of BSRBR-AS patients (difference: 10.4%; 95% CI 4.4% to 16.5%). Potential eligibility for trials did not influence treatment response (difference 2.0%; -9.4% to 13.4%). Fewer patients in the real world respond to TNFi than is reported in the trial literature. This has important implications for the generalisability of trial results, and the cost-effectiveness of TNFi agents., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To determine modifiable factors associated with poor quality of life (QoL) in patients with axial spondyloarthritis (axSpA)., Methods: Analysis of data from the British Society for Rheumatology Biologics Register in Ankylosing Spondylitis (BSRBR-AS) and validation of a previous model using data from 1810 patients with axSpA recruited during 2012-2017. Data collected included clinical and patient-reported measures. QoL was assessed using the Ankylosing Spondylitis Quality of Life (ASQoL) measure. Linear regression models predicting ASQoL scores were used first to validate a previous model from a national study, to extend this with additional information available in BSRBR-AS and finally to identify a 'de novo' model from BSRBR-AS of which factors impact on poor QoL., Results: Four out of five factors included in a previous model of poor QoL in patients with axSpA were confirmed: Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index, fatigue and widespread pain, although the performance of the model was improved by the addition of measures of mood and sleep disturbance. In a de novo model in BSRBR-AS, there were six factors (other than disease activity and function) that predicted ASQoL: depression (β=0.16), sleep disturbance (β=0.08), activity impairment (β=0.04), fibromyalgia (Symptom Severity Scale (β=0.24) and Widespread Pain Index (β=0.10)) and tobacco smoking (β=0.66)., Conclusion: This study confirms that poor QoL in patients with axSpA, in addition to high disease activity and poor function, is independently influenced by sleep disturbance, mood and widespread pain. These additional factors are not considered targets for treatment in current European League Against Rheumatism (EULAR) guidelines for managing the condition., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population-based studies conducted in the United Kingdom. The FM working group established a revised diagnosis of FM and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability, and validity. Revisions of the dimensions will also be required as research advances our understanding of FM. PERSPECTIVE: The ACTTION-APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Around 1 in 8 patients with axial spondyloarthritis (axSpA) also meet criteria for fibromyalgia and such patients have considerable unmet need. Identifying effective therapy is important but to what extent fibromyalgia-like symptoms relate to axSpA disease severity has not been established. The aim of the current analysis was to determine whether distinct clusters of axSpA patients exist and if so to determine a) whether they differ in terms of prevalence of fibromyalgia and b) the features of patients in clusters with high prevalence., Methods: The British Society for Rheumatology Biologics Register (BSRBR-AS) recruited axSpA patients from 83 centres 2012-2017. Clinical data, and information from patients was collected (including research criteria for fibromyalgia). Cluster analysis was undertaken using split samples for development and validation both in the whole population and the sub-group which met fibromyalgia criteria., Results: One thousand three hundred thirty-eight participants were included of whom 23% met research criteria for fibromyalgia. Four clusters were identified. Two exhibited very high disease activity, one which was primarily axial ( n  = 347) and a smaller cluster ( n  = 32) with axial and peripheral disease, and in both groups more than half of members met criteria for fibromyalgia. The remaining two clusters ( n  = 437, n  = 462) had overall less severe disease however the one which showed greater disease activity and poorer quality of life had a higher proportion meeting fibromyalgia criteria (16% v. 4%). Within those meeting fibromyalgia criteria there were three clusters. The two main groups were defined by level of symptom severity with a smaller third cluster noted to have high average swollen and tender joint counts and high levels of comorbidity., Conclusions: The major feature defining clusters with a high proportion of persons meeting criteria for fibromyalgia is high axSpA disease activity although clusters with features of fibromyalgia in the absence of high disease activity also show moderately high prevalence. Management may be most successful with pharmacologic therapy to target inflammation but enhanced by the concurrent use of non-pharmacologic therapy in such patients., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Objective: The effects of smoking on disease manifestations in axial SpA are inadequately described. Utilizing a large and well-characterized cohort, we investigated the association between smoking and extra-axial manifestations, and smoking and disease severity measures., Methods: Baseline data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis were explored. Our analyses focused on extra-axial manifestations and other disease severity measures, including scales for fatigue, sleep, anxiety and depression. Logistic and linear models were used to quantify associations between disease characteristics according to smoking status (current/ex/never) and quantity (heavy/light), adjusting for age, gender, BMI, education, deprivation, comorbidities, symptom duration and alcohol status., Results: A total of 2031 participants were eligible for the current analysis (68% male, mean age 49 years). Of these, 24% were current and 32% ex-smokers. When compared with non-smokers, current smokers had lower odds of uveitis [OR 0.7, 95% CI 0.5-0.9] and higher odds of psoriasis (ORadj 1.6, 95% CI 1.1-2.3). Ex- and current smokers had incrementally more severe disease than never smokers, with higher BASDAI (β = 0.3, 95% CI 0.1-0.6; β = 0.9, 95% CI 0.6-1.2) and BASFI (β = 0.5, 95% CI 0.2-0.8; β = 1.3, 95% CI 1.0-1.6); similar associations were observed for fatigue, sleep, anxiety and depression., Conclusion: In this large cross-sectional study, we observed that smoking is independently associated with an adverse disease profile in axial SpA, including worse fatigue, sleep, anxiety and depression, and higher odds of psoriasis. The paradoxical association between current smoking and reduced odds of uveitis is interesting and warrants further investigation., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)