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IntroductionPatients presenting with acute undifferentiated breathlessness are commonly encountered in admissions units across the UK. Existing blood biomarkers have clinical utility in distinguishing patients with single organ pathologies but have poor discriminatory power in multifactorial presentations. Evaluation of volatile organic compounds (VOCs) in exhaled breath offers the potential to develop biomarkers of disease states that underpin acute cardiorespiratory breathlessness, owing to their proximity to the cardiorespiratory system. To date, there has been no systematic evaluation of VOC in acute cardiorespiratory breathlessness. The proposed study will seek to use both offline and online VOC technologies to evaluate the predictive value of VOC in identifying common conditions that present with acute cardiorespiratory breathlessness.Methods and analysisA prospective real-world observational study carried out across three acute admissions units within Leicestershire. Participants with self-reported acute breathlessness, with a confirmed primary diagnosis of either acute heart failure, community-acquired pneumonia and acute exacerbation of asthma or chronic obstructive pulmonary disease will be recruited within 24 hours of admission. Additionally, school-age children admitted with severe asthma will be evaluated. All participants will undergo breath sampling on admission and on recovery following discharge. A range of online technologies including: proton transfer reaction mass spectrometry, gas chromatography ion mobility spectrometry, atmospheric pressure chemical ionisation-mass spectrometry and offline technologies including gas chromatography mass spectroscopy and comprehensive two-dimensional gas chromatography-mass spectrometry will be used for VOC discovery and replication. For offline technologies, a standardised CE-marked breath sampling device (ReCIVA) will be used. All recruited participants will be characterised using existing blood biomarkers including C reactive protein, brain-derived natriuretic peptide, troponin-I and blood eosinophil levels and further evaluated using a range of standardised questionnaires, lung function testing, sputum cell counts and other diagnostic tests pertinent to acute disease.Ethics and disseminationThe National Research Ethics Service Committee East Midlands has approved the study protocol (REC number: 16/LO/1747). Integrated Research Approval System (IRAS) 198921. Findings will be presented at academic conferences and published in peer-reviewed scientific journals. Dissemination will be facilitated via a partnership with the East Midlands Academic Health Sciences Network and via interaction with all UK-funded Medical Research Council and Engineering and Physical Sciences Research Council molecular pathology nodes.Trial registration numberNCT03672994.

Programming.Architecture is a simple and concise introduction to the history of computing and computational design, explaining the basics of algorithmic thinking and the use of the computer as a tool for design and architecture. Paul Coates, a pioneer of CAAD, demonstrates algorithmic thinking through projects and student work collated through his years of teaching students of computing and design. The book takes a detailed and practical look at what the techniques and philosophy of coding entail, and gives the reader many \"glimpses under the hood\" in the form of code snippets and examples of algorithms. This is essential reading for student and professional architects and designers interested in how the development of computers has influenced the way we think about, and design for, the built environment. Paul Coates is Senior Lecturer at the University of East London (UEL). He is also Programme leader of the MSc Architecture: Computing and design programme and Head of CECA (the Centre for Evolutionary Computing in Architecture), a research centre at the School of Architecture and the Visual Arts, UEL. Introduction 1. Falling Between Two Stools 2. Rethinking Representation 3. In the Beginning was the Word 4. The Mystery of the Machine that Invents Itself 5. Evolving the Text - Being even Lazier 6. The Text of the Vernacular. Epilogue. Glossary \" Programming Architecture is a good book. It makes an invaluable contribution to the field of generative design. I recommend this book to designers interested in the history of computing and computational design and to computer experts in genetic programming interested to explore a new field of application such as architectural design.\" – Benachir Medjdoub, Genetic Programming and Evolvable Machines

Objectives Alcohol misuse is a complex systemic problem. The aim of this study was to explore the feasibility of using a transparent and participatory agent-based modelling approach to develop a robust decision support tool to test alcohol policy scenarios before they are implemented in the real world. Methods A consortium of Australia’s leading alcohol experts was engaged to collaboratively develop an agent-based model of alcohol consumption behaviour and related harms. As a case study, four policy scenarios were examined. Results A 19.5 ± 2.5% reduction in acute alcohol-related harms was estimated with the implementation of a 3 a.m. licensed venue closing time plus 1 a.m. lockout; and a 9 ± 2.6% reduction in incidence was estimated with expansion of treatment services to reach 20% of heavy drinkers. Combining the two scenarios produced a 33.3 ± 2.7% reduction in the incidence of acute alcohol-related harms, suggesting a synergistic effect. Conclusions This study demonstrates the feasibility of participatory development of a contextually relevant computer simulation model of alcohol-related harms and highlights the value of the approach in identifying potential policy responses that best leverage limited resources.

Written by a pioneer of CAAD, this is essential reading for all those interested in the history of computing and computational design.

Many of the scientific and regulatory challenges that exist in research on the safety, quality and efficacy of dietary supplements are common to all countries as the marketplace for them becomes increasingly global. This article summarizes some of the challenges in supplement science and provides a case study of research at the Office of Dietary Supplements at the National Institutes of Health, USA, along with some resources it has developed that are available to all scientists. It includes examples of some of the regulatory challenges faced and some resources for those who wish to learn more about them.

Early intervention and tight control of inflammation optimise outcomes in rheumatoid arthritis but these approaches have not yet been studied in psoriatic arthritis. We aimed to assess the effect of tight control on early psoriatic arthritis using a treat-to-target approach. For this open-label multicentre randomised controlled trial, adult patients (aged ≥18 years) with early psoriatic arthritis (<24 months symptom duration), who had not previously received treatment with any disease-modifying anti-rheumatic drugs, were enrolled from eight secondary care rheumatology centres in the UK. Enrolled patients were randomly assigned in a 1:1 ratio to receive either tight control (with review every 4 weeks and with escalation of treatment if minimal disease activity criteria not met) or standard care (standard therapy according to the treating clinician, with review every 12 weeks) for 48 weeks. Randomisation was done by minimisation incorporating a random element, to ensure treatment groups were balanced for randomising centre and pattern of arthritis (oligoarticular vs polyarticular). The randomisation procedure was done through a central 24-h automated telephone system based at the Leeds Institute of Clinical Trials Research (Leeds, UK). This was an open-label study in which patients and clinicians were aware of treatment group assignment. Clinical outcomes were recorded by a masked assessor every 12 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology (ACR) 20% (ACR20) response at 48 weeks, analysed by intention to treat with multiple imputation for missing ACR components. Cost-effectiveness was also assessed. This trial is registered with ClinicalTrials.gov, number NCT01106079, and the ISCRCTN registry, number ISCRCTN30147736. Between May 28, 2008, and March 21, 2012, 206 eligible patients were enrolled and randomly assigned to receive tight control (n=101) or standard care (n=105). In the intention-to-treat patient population, the odds of achieving an ACR20 response at 48 weeks were higher in the tight control group than in the standard care group (odds ratio 1·91, 95% CI 1·03–3·55; p=0·0392). Serious adverse events were reported by 20 (10%) patients (25 events in 14 [14%] patients in the tight control group and eight events in six [6%] patients in the standard care group) during the course of the study. No unexpected serious adverse events or deaths occurred. Tight control of psoriatic arthritis disease activity through a treat-to-target approach significantly improves joint outcomes for newly diagnosed patients, with no unexpected serious adverse events reported. Arthritis Research UK and Pfizer.

The COVID-19 disease caused by the SARS-CoV-2 coronavirus has become a pandemic health crisis. An attractive target for antiviral inhibitors is the main protease 3CL M pro due to its essential role in processing the polyproteins translated from viral RNA. Here we report the room temperature X-ray structure of unliganded SARS-CoV-2 3CL M pro , revealing the ligand-free structure of the active site and the conformation of the catalytic site cavity at near-physiological temperature. Comparison with previously reported low-temperature ligand-free and inhibitor-bound structures suggest that the room temperature structure may provide more relevant information at physiological temperatures for aiding in molecular docking studies. The SARS-CoV-2 3CL main protease (3CL M pro ) is a chymotrypsin-like protease that facilitates the production of non-structural proteins, which are essential for viral replication and is therefore of great interest as a drug target. Here, the authors present the 2.30 Å room temperature crystal structure of ligand-free 3CL M pro and compare it with the earlier determined low-temperature ligand-free and inhibitor-bound crystal structures.

This paper offers a partial defence of a Sellarsian-inspired form of scientific realism. It defends the relocation strategy that Sellars adopts in his project of reconciling the manifest and scientific images. It concentrates on defending the causal analysis of perception that is essential to his treatment of sensible qualities. One fundamental metaphysical issue in perception theory concerns the nature of the perceptual relation; it is argued that a philosophical exploration of this issue is continuous with the scientific investigation of perceptual processes. Perception, it is argued, can, and should, be naturalised. A challenge for any account of perception arises from the fact that a subject’s experiences are connected with particular objects. We need to supply principled grounds for identifying which external physical object the subject stands in a perceptual relation to when they have an experience. According to the particularity objection presented in the paper, naive realism (or disjunctivism) does not constitute an independently viable theory since, taken on its own, it is unable to answer the objection. In appealing to a ‘direct experiential relation’, it posits a relation that cannot be identified independently of the underlying causal facts. A proper understanding of one central function of perception, as guiding extended patterns of actions, supports a causal analysis of perception. It allows us to draw up a set of necessary and sufficient conditions for perceiving that avoids well-known counterexamples. An analysis of this kind is congruent with the scientific account, according to which experiences are interpreted as inner states: sensible qualities, such as colours, are in the mind (but not as objects of perception).A Sellarsian version of the relocation story is thus vindicated.

ObjectiveTo evaluate efficacy and safety of guselkumab, an anti-interleukin-23p19-subunit antibody, in patients with psoriatic arthritis (PsA) with prior inadequate response (IR) to tumour necrosis factor inhibitors (TNFi).MethodsAdults with active PsA (≥3 swollen and ≥3 tender joints) who discontinued ≤2 TNFi due to IR (lack of efficacy or intolerance) were randomised (2:1) to subcutaneous guselkumab 100 mg or placebo at week 0, week 4, then every 8 weeks (Q8W) through week 44. Patients receiving placebo crossed over to guselkumab at week 24. The primary (ACR20) and key secondary (change in HAQ-DI, ACR50, change in SF-36 PCS and PASI100) endpoints, at week 24, underwent fixed-sequence testing (two-sided α=0.05). Adverse events (AEs) were assessed through week 56.ResultsAmong 285 participants (female (52%), one (88%) or two (12%) prior TNFi), 88% of 189 guselkumab and 86% of 96 placebo→guselkumab patients completed study agent through week 44. A statistically significantly higher proportion of patients receiving guselkumab (44.4%) than placebo (19.8%) achieved ACR20 (%difference (95% CI): 24.6 (14.1 to 35.2); multiplicity-adjusted p<0.001) at week 24. Guselkumab was superior to placebo for each key secondary endpoint (multiplicity-adjusted p<0.01). ACR20 response (non-responder imputation) in the guselkumab group was 58% at week 48; >80% of week 24 responders maintained response at week 48. Through week 24, serious AEs/serious infections occurred in 3.7%/0.5% of 189 guselkumab-randomised and 3.1%/0% of 96 placebo-randomised patients; the guselkumab safety profile was similar through week 56, with no deaths or opportunistic infections.ConclusionGuselkumab significantly improved joint and skin manifestations and physical function in patients with TNFi-IR PsA. A favourable benefit–risk profile was demonstrated through 1 year.Trial registration number NCT03796858.