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This is the first book-length English-language study of a group of five artists closely linked with the Spanish avant-garde in the 1920s and 1930s.

Gefapixant is an oral P2X3 receptor antagonist that has previously shown efficacy and safety in refractory chronic cough and unexplained chronic cough. We therefore aim to confirm the efficacy and safety of gefapixant in participants with refractory chronic cough and unexplained chronic cough. COUGH-1 and COUGH-2 were both double-blind, randomised, parallel-group, placebo-controlled, phase 3 trials. COUGH-1 was done in 156 sites in 17 countries and COUGH-2 in 175 sites in 20 countries. We enrolled participants who were 18 years or older with a diagnosis of refractory chronic cough or unexplained chronic cough of 1 year duration or more. Participants were also required to have a cough severity visual analogue scale score of 40 mm or more at screening and baseline. Eligible participants were randomly allocated (1:1:1), using a computer-generated allocation schedule, to one of three treatment groups: placebo, gefapixant 15 mg twice per day, or gefapixant 45 mg twice per day. All study treatments were given orally. Participants were treated over a 12-week main study period in COUGH-1 and a 24-week main study period in COUGH-2; followed by extension periods for a total of up to 52 weeks of treatment in both trials. The primary outcome was placebo-adjusted mean change in 24-h cough frequency at 12 weeks in COUGH-1 and 24 weeks in COUGH-2. Both studies were registered with ClinicalTrials.gov, NCT03449134 (COUGH-1) and NCT03449147 (COUGH-2). From March 14, 2018, (first participant screened) to July 26, 2019, (last participant screened) 732 patients were recruited in COUGH-1 and 1317 in COUGH-2. COUGH-1 randomly assigned and treated 730 participants (243 [33×3%] with placebo, 244 [33×4%] with gefapixant 15 mg twice per day, and 243 [33×3%] with gefapixant 45 mg twice per day); COUGH-2 randomly assigned and treated 1314 participants (435 [33×1%] with placebo, 440 [33×5%] with gefapixant 15 mg twice per day, and 439 [33×4%] with gefapixant 45 mg twice per day). Participants were mostly female (542 [74×2%] of 730 in COUGH-1 and 984 [74×9%] of 1314 in COUGH-2). The mean age was 59×0 years (SD 12×6) in COUGH-1 and 58×1 years (12×1) in COUGH-2, and the mean cough duration was 11·6 years (SD 9·5) in COUGH-1 and 11·2 years (9·8) in COUGH-2. Gefapixant 45 mg twice per day showed significant reductions in 24-h cough frequency compared with placebo at week 12 in COUGH-1 (18·5% [95% CI 32·9–0·9]; p=0·041) and at week 24 in COUGH-2 (14·6% [26·1–1·4]; p=0·031). Gefapixant 15 mg twice per day did not show a significant reduction in cough frequency versus placebo in both studies. The most common adverse events were related to taste disturbance: ageusia (36 [4·9%] of 730 in COUGH-1 and 86 [6·5%] of 1314 in COUGH-2), dysgeusia (118 [16·2%] in COUGH-1 and 277 [21·1%] in COUGH-2), hypergeusia (3 [0·4%] in COUGH-1 and 6 [0×5%] in COUGH-2), hypogeusia (19 [2·6%] in COUGH-1 and 80 [6·1%] in COUGH-2), and taste disorder (28 [3·8%] in COUGH-1 and 46 [3·5%] in COUGH-2). Gefapixant 45 mg twice per day is the first treatment to show efficacy with an acceptable safety profile in phase 3 clinical trials for refractory chronic cough or unexplained chronic cough. Merck Sharp & Dohme.

\"The book sets out deliberately to challenge current directions in construction management, confronting the assumption that knowledge is uni-dimensional and accumulative. It will be argued that any understanding of construction management depends upon a critical orientation that does not subjugate understanding to performance. The book will initially set out the justification for adopting a critical perspective with reference to the broader literature on Construction Management Studies. Current trends in construction management will be set in the context of social, economic and political change over the past thirty years. A recurring theme throughout the book will be the complex interplay between the espoused managerial rhetoric and the realities of structural change in the construction sector. The discourse of construction management shapes, and is shaped by, the changing reality of the workplace. Linkages will also be made to the emergence of the enterprise culture and rhetoric of the global marketplace. Following the development of a critical perspective on construction management as a whole, specific chapters will be devoted to: business process re-engineering, lean construction, partnering, collaborative working, performance measurement and the assumed need for culture change\"-- Provided by publisher.

E3 ubiquitin ligases are critical to the protein degradation pathway by catalyzing the final step in protein ubiquitination by mediating ubiquitin transfer from E2 enzymes to target proteins. Nedd4 is a HECT domain-containing E3 ubiquitin ligase with a wide range of protein targets, the dysregulation of which has been implicated in myriad pathologies, including cancer and Parkinson's disease. Towards the discovery of compounds disrupting the auto-ubiquitination activity of Nedd4, we developed and optimized a TR-FRET assay for high-throughput screening. Through selective screening of a library of potentially covalent compounds, compounds 25 and 81 demonstrated apparent IC 50 values of 52 µM and 31 µM, respectively. Tandem mass spectrometry (MS/MS) analysis confirmed that 25 and 81 were covalently bound to Nedd4 cysteine residues (Cys182 and Cys867). In addition, 81 also adducted to Cys627. Auto-ubiquitination assays of Nedd4 mutants featuring alanine substitutions for each of these cysteines suggested that the mode of inhibition of these compounds occurs through blocking the catalytic Cys867. The discovery of these inhibitors could enable the development of therapeutics for various diseases caused by Nedd4 E3 ligase dysregulation.

\"Brings together leading thinking on issues of new professional practice and on the future of a sustainable built environment This book focuses on both construction and development issues, and examines how we can transition to a sustainable future by the year 2050bringing together leading research and practice at building, neighbourhood, and city levels. It deftly analyses how emerging socio-economic, technological, and environmental trends will influence the built environment of the future. The book covers a broad spectrum of interests across the scales of buildings, communities and cities, including how professional practice will need to adapt to these trends. The broader context is provided by an analysis of emergent business models and the changing requirements for expert advice from clients. Sustainable Futures in the Built Environment to 2050: A Foresight Approach to Construction and Development features chapters covering: data and trends, including historical data and UK and international case studies; policies and practice related to the field; current state of scientific understanding; key challenges; key technological advances (including disruptive and systemic technological innovations); change issues and critical uncertainties; and future visions. It provides: A strong conceptual framework based on a Foresight' approach Discussion of the key data and trends that underpin each chapter, Coverage of both construction and property development Specially commissioned chapters by academics, and practitioners, A synthesis of the main findings in the book and key insights for the future to 2050 Sustainable Futures in the Built Environment to 2050: A Foresight Approach to Construction and Development is an important book for postgraduate students and researchers, construction, real estate and property development specialists, engineers, planners, architects, foresight and futures studies specialists, and anyone involved in sustainable buildings\"-- Provided by publisher.

Tildrakizumab is a high-affinity, humanised, IgG1 κ antibody targeting interleukin 23 p19 that represents an evolving treatment strategy in chronic plaque psoriasis. Previous research suggested clinical improvement with inhibition of interleukin 23 p19. We did two phase 3 trials to investigate whether tildrakizumab is superior to placebo and etanercept in the treatment of chronic plaque psoriasis. We did two three-part, parallel group, double-blind, randomised controlled studies, reSURFACE 1 (at 118 sites in Australia, Canada, Japan, the UK, and the USA) and reSURFACE 2 (at 132 sites in Europe, Israel, and the USA). Participants aged 18 years or older with moderate-to-severe chronic plaque psoriasis (body surface area involvement ≥10%, Physician's Global Assessment [PGA] score ≥3, and Psoriasis Area and Severity Index [PASI] score ≥12) were randomised (via interactive voice and web response system) to tildrakizumab 200 mg, tildrakizumab 100 mg, or placebo in reSURFACE 1 (2:2:1), or to tildrakizumab 200 mg, tildrakizumab 100 mg, placebo, or etanercept 50 mg (2:2:1:2). Randomisation was done by region and stratified for bodyweight (≤90 kg or >90 kg) and previous exposure to biologics therapy for psoriasis. Investigators, participants, and study personnel were blinded to group allocation and remained blinded until completion of the studies. Assigned medication was identical in appearance and packaging. Tildrakizumab was administered subcutaneously at weeks 0 and 4 during part 1 and at week 16 during part 2 (weeks 12 and 16 for participants re-randomised from placebo to tildrakizumab; etanercept was given twice weekly in part 1 of reSURFACE 2 and once weekly during part 2). The co-primary endpoints were the proportion of patients achieving PASI 75 and PGA response (score of 0 or 1 with ≥2 grade score reduction from baseline) at week 12. Safety was assessed in the all-participants-as-treated population, and efficacy in the full-analysis set. These trials are registered with ClinicalTrials.gov, numbers NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). These studies are completed, but extension studies are ongoing. reSURFACE 1 ran from Dec 10, 2012, to Oct 28, 2015. reSURFACE 2 ran from Feb 12, 2013, to Sept 28, 2015. In reSURFACE 1, 772 patients were randomly assigned, 308 to tildrakizumab 200 mg, 309 to tildrakizumab 100 mg, and 155 to placebo. At week 12, 192 patients (62%) in the 200 mg group and 197 patients (64%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). 182 patients (59%) in the 200 mg group and 179 patients (58%) in the 100 mg group achieved PGA responses, compared with 11 patients (7%) in the placebo group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo). In reSURFACE 2, 1090 patients were randomly assigned, 314 to tildrakizumab 200 mg, 307 to tildrakizumab 100 mg, 156 to placebo, and 313 to etanercept. At week 12, 206 patients (66%) in the 200 mg group, and 188 patients (61%) in the 100 mg group achieved PASI 75, compared with 9 patients (6%) in the placebo group and 151 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p<0·0001 for 200 mg vs etanercept and p=0·0010 for 100 mg vs etanercept). 186 patients (59%) in the 200 mg group, and 168 patients (55%) in the 100 mg group achieved a PGA response, compared with 7 patients (4%) in the placebo group and 149 patients (48%) in the etanercept group (p<0·0001 for comparisons of both tildrakizumab groups vs placebo; p=0·0031 for 200 mg vs etanercept and p=0·0663 for 100 mg vs etanercept). Serious adverse events were similar and low in all groups in both trials. One patient died in reSURFACE 2, in the tildrakizumab 100 mg group; the patient had alcoholic cardiomyopathy and steatohepatitis, and adjudication was unable to determine the cause of death. In two phase 3 trials, tildrakizumab 200 mg and 100 mg were efficacious compared with placebo and etanercept and were well tolerated in the treatment of patients with moderate-to-severe chronic plaque psoriasis. Merck & Co.

Prior optical coherence tomography (OCT) studies of schizophrenia have identified thinning of retinal layers. However, findings have varied across reports, and most studies have had serious methodological limitations. To address unresolved issues, we determined whether: (1) retinal thinning in schizophrenia occurs independently of comorbid medical conditions that affect the retina; (2) thinning is independent of antipsychotic medication dose; (3) optic nerve parameters are abnormal in schizophrenia; and (4) OCT indices are related to visual and cognitive impairments common in schizophrenia. A total of 32 people with schizophrenia and 32 matched controls participated. Spectral domain OCT generated data on retinal nerve fiber layer (RNFL), macula, and ganglion cell-inner plexiform layer (GCL-IPL) thickness, in addition to cup volume and the cup-to-disc ratio at the optic nerve head. Subjects with schizophrenia also completed measures of symptoms, visual processing, and IQ. The groups did not differ on RNFL, macula, or GCL-IPL thickness. However, thinning of these layers was related to the presence of diabetes or hypertension across the sample as a whole. The schizophrenia group demonstrated enlarged cup volume and an enlarged cup-to-disc ratio in both eyes, which were unrelated to medical comorbidity, but were related to increased cognitive symptoms. Past reports of retinal thinning may be artifacts of medical comorbidity that is over-represented in schizophrenia, or other confounds. However, optic nerve head abnormalities may hold promise as biomarkers of central nervous system abnormality, including cognitive decline, in schizophrenia.

Background Clinical guidelines offer an accessible synthesis of the best evidence of effectiveness of interventions, providing recommendations and standards for clinical practice. Many guidelines are relevant to the diagnosis and management of the acutely unwell patient during the first 24–48 h of admission. Care bundles are comprised of a small number of evidence-based interventions that when implemented together aim to achieve better outcomes than when implemented individually. Care bundles that are explicitly developed from guidelines to provide a set of related evidence-based actions have been shown to improve the care of many conditions in emergency, acute and critical care settings. This study aimed to review the implementation of two distinct care bundles in the acute medical setting and identify the factors that supported successful implementation. Methods Two initiatives that had used a systematic approach to quality improvement to successfully implement care bundles within the acute medical setting were selected as case studies. Contemporaneous data generated during the initiatives included the review reports, review minutes and audio recordings of the review meetings at different time points. Data were subject to deductive analysis using three domains of the Consolidated Framework for Implementation Research to identify factors that were important in the implementation of the care bundles. Results Several factors were identified that directly influenced the implementation of the care bundles. Firstly, the availability of resources to support initiatives, which included training to develop quality improvement skills within the team and building capacity within the organisation more generally. Secondly, the perceived sustainability of changes by stakeholders influenced the embedding new care processes into existing clinical systems, maximising their chance of being sustained. Thirdly, senior leadership support was seen as critical not just in supporting implementation but also in sustaining longer-term changes brought about by the initiative. Lastly, practitioner incentives were identified as potential levers to engage junior doctors, a crucial part of the acute medical work force and essential to the initiatives, as there is currently little recognition or reward for involvement Conclusions The factors identified have been shown to be supportive in the successful implementation of care bundles as a mechanism for implementing clinical guidelines. Addressing these factors at a practitioner and organisational level, alongside the use of a systematic quality improvement approach, should increase the likelihood that care bundles will be implemented successfully to deliver evidence based changes in the acute medical setting.

HighlightsModern methods of construction (MMC) comprise a value-laden and highly flexible discourse. Nevertheless, the constituent narratives have long-lasting consequences for the material fabric of the built environment. Current policy sources can be seen to possess an embedded pro-innovation bias that offsets any appetite for evidence-based research, especially that which relates to the mistakes of the past. Many policy narratives in favour of MMC are further characterised by an exaggerated sense of hubris, with an in-built institutionalised preference for disruptive innovation. Liberalised economies are especially prone to technological optimism, with a tendency to cast regulation as a barrier to be overcome. The Grenfell Tower tragedy provides a stark reminder of the limitations of viewing regulation solely through the lens of innovation. Hence, it illustrates how the prevailing built environment research–policy consensus has failed the civil society which it purportedly serves. These failings should be of concern to those who privilege evidence-based research as a means of negating the alarming onset of the post-truth society. Research is required that looks beyond the imperatives of narrowly defined productivity. It is essential that policy narratives such as MMC are fully explored in terms of their short-, medium- and long-term implications.