19 research outputs found
Copyright & Risk: Scoping the Wellcome Digital Library Project
No full textCopyright & Risk: Scoping the Wellcome Digital Library is a comprehensive case study which aims to assess the merits of the risk-managed approach to copyright clearance adopted by the Wellcome Library (WL) in the course of their pilot digitisation project Codebreakers: Makers of Modern Genetics.
Whilst the WL clearly identifies as a library, as a collecting institution it extends from books and periodicals to include archives and manuscripts, art, the moving image and sound associated with the biomedical sciences and the medical humanities.[1] In this case study we consider the digitisation of both library (books) and archive material as part of the Codebreakers project, although our principal interest lies with the archive digitisation strand.
This report assesses the merits of the WL’s approach to copyright compliance by:
Introducing the WL and the Codebreakers mass digitisation project
Outlining the copyright challenges presented by the mass-digitisation effort
Discussing the risk management methods used by the WL in determining which rights should be cleared
Examining the results of the risk-managed copyright clearance process
As a result of this analysis, the research aims to:
Compare the Wellcome experience on Codebreakers to rights clearance exercises attempted by other cultural heritage institutions
Provide policy makers with useful data and insights to inform the debate on copyright exceptions for cultural heritage institutions
Discuss the relevance of this approach for other UK archive institutions
Prior to the preparation of this case study, CREATe published a working paper in March 2013[2], reviewing current and proposed changes to UK copyright law, and specifically exceptions provided for libraries and archives. This was further extended by a review of available literature on the digitisation of archival and library collections for publication online, contextualized with specific examples.
Existing literature reveals that rights clearance procedures impose prohibitive burdens on cultural institutions, through the cost of staff time and training in both diligent search and the process of contacting rightsholders.[3] It also indicates that in most cases, the results of rights clearance processes are unsatisfactory: either copyright holders cannot be identified and traced; or those who are contacted, do not respond to permission requests. Archives, in contrast to libraries, have the added complication of dealing with larger and more varied collections of material, the majority of which has been created for non-commercial purposes; this material is often unpublished at the point of deposit with the archive, and typically includes higher proportions of orphan works (when compared with traditional library collections).[4]
Documented examples of archival rights clearance projects are scarce, and where studies do exist, they have generally been conducted at a large-scale level, and do not contain sufficient detail to enable in-depth analysis of the rights clearance process.[5] Anna Vuopala’s excellent Orphan Works study[6] includes examples of rights clearance projects at 19 institutions, and focuses almost exclusively on the time and cost required to clear rights, which is extremely useful, but leaves out other valuable details about the right clearance process: for example, the number of rightsholders’ contact details found; the refusal rates and reasons given for refusal at each institution; and the number of rightsholders who do not respond to permission requests.
In general, there is a lack of detailed evidence concerning rights clearance in archival digitisation, and especially in relation to projects that employ risk-management strategies in a sector which is known to be highly risk averse. The WL was chosen as an appropriate subject for this case study given the scale of their digitisation aims, and their use of a risk managed approach to copyright compliance.
Codebreakers, as a digitisation project, was never designed to facilitate a study of the process of rights clearance – by the time data collection for the Copyright and Risk Project began, Codebreakers was entering its final stages, with the official launch of the project website taking place in February 2013. As a result, semi-structured interviews were chosen as the most effective method of obtaining data about the project. Interviews were conducted with key project staff at the WL as well as with staff from five partner archives involved in delivering the Codebreakers project.
The semi-structured format of the interviews was chosen for its flexibility; a list of questions was chosen, but given the length of the interviews, it was possible to divert from these questions and follow up on unexpected lines of enquiry raised by the interview subjects. Also, by working from a set list of questions, it was still possible to collate the answers to specific questions, thereby producing some quantifiable data. The questions were generated through a discussion of the aims of the project, and through consultation of other similar projects: specifically Jean Dryden’s doctoral research on the practices of Canadian repositories when making their archival material available online.[7]
The interviews covered five specific areas: the respondents’ role within their place of work; their role working on the Codebreakers project; the rights clearance challenges posed by the project; the development of policies and practices over the timeframe of the project; and finally, the respondents’ own views and experience of copyright, divorced from an institutional perspective.
Using this method of enquiry, respondents were asked about policies and practices mandated by the institutions they work for, but also for their own opinions as professionals, built up though work experience, education and training. By encouraging the respondents to reflect on their own experience, it was also possible to use the ‘snowball’ technique to tease out pointers to documentation and other resources used by the respondents, not only in relation to this project, but to their experience working on others as well.
Once completed, the interviews were transcribed to provide usable data. The transcriptions were used for a variety of purposes. Responses to specific questions were logged to give quantifiable results. Where respondents gave specific examples of practices, or policy changes, these are used as evidence in the text of this report. As a result of interviewing respondents at the Wellcome, project documentation was also made available for inclusion in this case study. This material takes two forms: policy documents which were circulated and updated as the project took place; and an internal report produced towards the end of the project, which includes a variety of statistics and more general lessons learned. The documentation has been discussed in the text of the report and examples of specific documents are available in the Appendix.
This combination of anecdotal evidence, combined with results and project documentation, has allowed us to trace the processes by which the WL has used risk management to achieve their digitisation objectives.
[1] The Wellcome Library Collection Development Policy is available athttp://wellcomelibrary.org/content/documents/policy-documents/collection-development-policy.pdf [Accessed: 5 Dec 2013]
[2] Deazley, R., and Stobo, V. (2013) Archives and Copyright: Risk and Reform. Working Paper. CREATe / University of Glasgow, Glasgow, UK.
[3] Ibid
[4] For any work, created by an author who died before 1 January 1969, which was unpublished as of 1 August 1989 (when the CDPA 1988 came into force), the duration of copyright will last until 31 December 2039. CDPA, Schedule 1, s.12(4).
[5] Vuopala, A., “Assessment of the Orphan works issue and Costs for Rights Clearance” (May 2010), available at: and Korn, N., (2009) “In from the Cold” JISC & The Collections Trust, available at: [Accessed: 1 Sep 2013]
[6] Vuopala, A., (2010) – See page 39, and the example of the National Archives ‘Moving Here’ project. 45 rightsholders refused permission, but information regarding the reasons for refusal is not available. As to the rightsholders who could not be identified in relation to 385 documents – it is not made clear whether contact details could not be found for these individuals, or if they were but did not respond to permission requests.
[7] Dryden, J., “Copyright issues in the selection of archival material for internet access” (2008) Archival Science 123-4
COVID-19 platform trials:insight and lessons in clinical trial design
No full textThe COVID-19 pandemic was an unprecedented healthcare event. With a novel pathogen and no proven treatments, it also represented an unprecedented challenge for clinical research, with an urgent need for life-saving treatments and vaccines. In the absence of outstanding candidate therapeutics, trial designs were required which could rapidly evaluate multiple therapies in heterogeneous patient populations. Adaptive platform trials (randomised trials with multiple treatment arms and a single control group) were ideal to deliver this. This approach was heavily used in fields such as oncology pre-pandemic, but was less common in respiratory medicine or infectious diseases. Trials such as RECOVERY and REMAP-CAP delivered dexamethasone, tociliuzumab, baricitinib and antibody therapies as effective treatments for hospitalised patients with COVID-19, while demonstrating lack of effectiveness for a number of drugs that were widely used empirically. The success of adaptive platform trials during COVID-19 has increased interest in their application to other diseases post-pandemic, which may be a lasting legacy of the pandemic for clinical research.</p
Author Correction: The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma
No full textThe original version of this Article mistakenly misspelled “Carolin M. Sauer” from the author list as “Carolyn Sauer,” who is from the ‘CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.’ This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article mistakenly misspelled “Ionut-Gabriel Funingana” from the author list as “Ionat-Gabriel Funingana,” who is from the ‘CRUK Cambridge Institute, University of Cambridge, Cambridge, UK’ and ‘Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.’ This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article contained an error in Fig. 1a, in which a panel indicating copy number event analysis was missing from the study workflow diagram. This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article contained an error in the Methods section which incorrectly read ‘Fastq sequencing reads were aligned to GRCh37 (g1kp2) using bwa samse.’ The correct version states ‘hs37d5’ in place of ‘glkp2.’ This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article contained an error in the Data Availability Statement stating ‘The pre-processed single nucleotide variant and copy number data are available through a Zenodo data repository and can be downloaded here’ which linked to an incorrect version of the Zenodo repository. The correct link is as follows:. This has been corrected in both the PDF and HTML versions of the Article.</p
Explorations of structure and choice in taxing capital gains: New Zealand tax experts' perspectives
No full textThis study explores the key issues, aspects, and attributes concerning capital gains tax (CGT) to enable the formulation of policy guidelines that might be used if a CGT were considered in New Zealand. It contends that the development of the New Zealand’s policy on taxing capital gains has continued in a somewhat ad hoc and inconsistent fashion. The lack of a uniform approach to capital gains taxation has resulted in detailed, but complex, legislation which leads to “policy inconsistencies and unintended incentives built into the tax structure” (Oliver, 2001, pp. 80 – 81). The study bridges the divide between theoretical analysis of CGT and implementation issues on operating a CGT. It attempts to address one primary research question and an associated secondary question. The primary research question is: should capital gains be taxed more comprehensively than at present? As a start, it examines the two important issues surrounding income definition and the capital/income distinction. In this regard, the research first attempts to identify the definition(s) of capital gains from the New Zealand perspective(s). This is followed by investigating the key areas of the tax system in order to seek the best way of taxing capital gains. This study also attempts to address the secondary research question, i.e., why (or why not) do the tax experts favour (or oppose) a comprehensive CGT? In this respect, this study identifies 23 factors/issues that are related to the tax experts’ attitudes towards a particular form of a CGT model (i.e., current hybrid approach, a realisation-based CGT or an accrual-based CGT). A mixed-methods design has been adopted in this study involving both a quantitative (survey) and a qualitative (interview) method in analysing the data to determine the tax experts’ overall perceptions of a CGT in New Zealand and the CGT adoption factors which influenced them. One important finding of the comparative analyses was that all tax experts generally agreed that the lack of a comprehensive CGT could provide more significant tax planning opportunities. However, many tax experts did not support the comprehensive income concept as they disagreed with the benefits derived from the gains in horizontal equity through adopting a CGT. This study has identified several important policy issues and reviewed their implication for the adoption of a CGT in New Zealand. The finding of the study revealed that the tax experts strongly supported the exemption of the gains on disposal of a taxpayer’s main residence and the tax preference for inflation adjustment. Another important policy issue is the implementation of an accrual-based CGT. Most tax experts considered a realisation-based CGT would be better than an accrual one. In particular, they were concerned about the liquidity problems and the compliance costs involved in an accrual-based CGT regime i.e., the annual valuation of all assets. These findings represent a first step towards a theoretical CGT framework. It is hoped that the knowledge gained in this study would give a greater understanding into the practical decision-making process that could result in a better public acceptance for a tax reform
Copyright and the Regulation of Orphan Works: A Comparative Review of Seven Jurisdictions, and a Rights Clearance Simulation
No full textAbout
This report is a collaboration between the Centre for Intellectual Property Policy & Management (www.cippm.org.uk), Bournemouth University (BU), the Department for Human Resources & Organisational Behaviour, The Business School, BU, and CREATe, the RCUK Centre for Copyright & New Business Models (www.create.ac.uk).
The Hargreaves Review stated: “The problem of orphan works – works to which access is effectively barred because the copyright holder cannot be traced – represents the starkest failure of the copyright framework to adapt.” (Digital Opportunity: A Review of Intellectual Property and Growth; London: Intellectual Property Office; 2011; p. 38).
This report was commissioned by the Intellectual Property Office to support the implementation of the Hargreaves Review. It aims to offer a clearer understanding of how orphan works are regulated and priced in other jurisdictions, and how a pricing system could be structured to ensure that “parents” are fairly remunerated if they re-appear, and users are incentivised to access and exploit registered orphan works.
Executive Summary
‘Orphan works’ are works in which copyright still subsists, but where the rightholder, whether it be the creator of the work or successor in title, cannot be located.
This report was commissioned to assist the UK government in evaluating policy options in the implementation of the Hargreaves Review of Intellectual Property & Growth (2011) to enable and price the use of orphan works.
The research proceeded in two stages. Study I undertook a comparative international review of actual or proposed orphan works legislation, and identified key characteristics of orphan works licensing schemes. Study II investigated the potential effects of such schemes by conducting a simulated rights clearance exercise for six scenarios (establishing licence terms and fees for specific commercial and non-commercial uses), and analysing the resulting dataset for effects of the characteristics identified in Study I.
I. Comparative Review
The comparative review relied on a close scrutiny of actual or proposed legislation and considered government reports, draft bills, publications and other commentaries on the orphan works issue. The countries reviewed included jurisdictions with operational orphan works regulations: Canada, Denmark, Hungary, India, and Japan; as well as provisions at the EU level and in the US (draft legislation and current practice). The purpose of the review was to identify key features of legal regimes with respect to factors such as – (i) categories of works covered; (ii) standards of diligent search; (iii) the mechanism for obtaining permission; (iv) the existence of a register or database of recording suspected orphan works; (v) the role of collecting societies;(vi) tariffs set by category of work; (vii) mechanisms for challenging tariffs; (viii) remedies for reappearing authors and case law, if any, on damages for infringing use.
Findings Study I:
(1) Two distinct approaches appear to be used for governing orphan works in the jurisdictions reviewed. The first may be labelled ‘ex-ante’, and involves rights clearing before a work is used, the second is ‘ex-post’ and typically involves the management of infringement risks by the user.
In the former an applicant is required to engage with an authorising body or collecting society in order to receive a licence to make use of an orphan work. In contrast, the latter involves either the creation of a statutory copyright exception, or a limitation of liability where an applicant makes use of an orphan work after having exerted some effort to identify the potential rightholder (e.g. diligent search, attribution). These regimes provide different levels of protection for authors and users.
The ex-ante approach is exemplified by Canada, Japan and India where a potential user has to discuss terms with a copyright board. In ex-post systems payment is only due in case an author reappears. This approach is exemplified by the US. The analysis shows a strong protection for rightholders, both ex ante and ex post, in India, and Japan; and a relatively lower protection in the US, and to a certain extent Denmark (under the system of Extended Collective Licensing). Canada and Hungary are intermediate cases (e.g. no advertising requirements prior to use, but public listing of granted licences).
(2) While most jurisdictions require a diligent search to be conducted by the applicant there is no uniform standard constituting a diligent search. Across jurisdictions the specifications for diligent search vary considerably. Requirements involving the preventive search of the author range from the weak provisions of Denmark (no search required), Canada (requiring “reasonable effort”), and the US (“reasonable search” required) to the strong provisions of India, Japan, Hungary and the EU (but not France) providing a duty for the user of performing a “diligent search” or “due diligence search” (India) accompanied by some form of record tracking of the steps performed. The EU lists minimum sources for a diligent search in the Annex to the Orphan Works Directive. Advertising requirements (in the national press or equivalent) are provided in Japan and India.
(3) The United States had proposed a “limited liability” approach, under which the use of orphan works is possible after a reasonable search. In the case of an infringement claim orphan users are liable only for a reasonable compensation. Denmark uses an Extended Collective Licensing system, which involves collective negotiation with users (normally for multiple licensing) valid also for non-represented authors. In turn, the EU leaves Member States free to choose their regulatory approach (for example, France has chosen a central licensing system in its forthcoming legislation). All the other countries reviewed implement the central licensing system, with a central public authority granting copyright licences on orphan works.
(4) Prices are set by central authorities in the countries that have a central licensing system, and by collecting societies in Denmark. Interestingly, national central authorities have claimed that although no official negotiation process is provided by law, the price of licences is set on a case by case basis, after considering the individual circumstances of the applicant. Set prices can be challenged mostly in an ordinary court of law in the examined countries, or alternatively before the licensing authority with a quasi-judicial procedure (e.g. Canada). Infringement claims are handled by ordinary courts in all countries (including the US) or by licensing authorities with quasi-judicial procedures (in Hungary). In Denmark, both prices and infringement claims are under the jurisdiction of a special tribunal (the Copyright Licensing Tribunal). The above rules on price, infringement, and legal remedies do not derive from EU law, which leaves these matters to Member States.
(5) In Canada, Japan, India, Denmark and France an upfront payment is normally required byte applicant in exchange for using orphan works. In Canada, payment is upfront in approximately two-thirds of cases, whilst it is contingent on the rightholder reappearing in the remaining third. See De Beer and Bouchard (2010). In Hungary the amount is identified but may not be deposited (for non-profit licensees). It will be paid directly to the rightholder, in the event that he or she reappears. In the US, no payment is made until a court decision is issued, following an infringement claim.
Particular roles are envisaged for collecting societies in Denmark, in which they handle the whole system, Hungary, where collecting societies retain unclaimed revenues after five years from expiry of licence, and Canada, where collecting societies are consulted during tariff setting, and hold collected fees (to be used as they see fit).
(6) In the US, in Hungary, and France a voluntary public online register for suspected orphan works is established. The EU is establishing a register at the Office for Harmonization in the Internal Market (OHIM). In Japan, some institutions have their own register of orphan works. No register is envisaged in India, Canada or Denmark (prior to the Orphan Works Directive). However details of all licences granted are available on-line in Canada.
II. Rights Clearance Simulation
The “Rights Clearance Exercise” reported in Study II is a combination of various methods. In a first step a simulation approach is employed to collect a unique dataset on actual or potential licence fees for orphan works. Representatives of rights clearance authorities from countries covered in the comparative legal review (Canada, Denmark, France, Hungary, India, Japan, supplemented by some US data) were asked to provide a licence fee for each of six scenarios that are likely to occur in reality (from creating a small online resource to mass digitisation projects).
The identification of the various scenarios was the outcome of a rigorous methodological procedure. The six identified scenarios were:
Historical geographic maps for a video game for mobile phones (up to 50 maps
A vintage postcard collection for web publication and eventual sale of prints (up to50 cards)
National folk tune recordings for multimedia/teaching (DVD) (up to 50)
Re-issuing a 1960/70s TV series as part of a digital on-demand service (one series)
Mass digitisation of photographs (archives) by a public non-profit institution, with possible sale of prints (above 100,000 items)
Mass digitisation of books by a private for-profit institution, with possible sale of books (above 100,000 items)
Two rates for each scenario were sought, for commercial and non-commercial use. In a second step the dataset is subjected to various analytical techniques, including a regression approach and a comparison of collective licensing systems against others through the computation of effect sizes.
Findings Study II:
(1) There does not appear to be a standard price for licensing orphan works. In fact tariffs vary widely. For example, to clear 50 items from a folk tune archive for commercial use will cost the equivalent of £188 per year in Canada, and (under reasonable assumptions) £9,312 per year in France. In fact, the only consistent finding appears to be that in almost all cases commercial licence fees tend to exceed non-commercial ones.
(2) Licences were not available for all scenarios. Re-issuing orphaned broadcasts seems particularly problematic, with no licence offered in any of the countries investigated.
(3) There is no systematic recognition of what may constitute an appropriate duration for licences. Licences were very variable from country to country, ranging from a monthly to a five-year licence, without the provision of a permanent licence.
(4) We find high tariffs that discourage mass digitisation projects. Per item fees initially appearing very low and thus sustainable turn out to render mass-digitisation unviable for public and non-profit institutions when scaled up under reasonable assumptions. Mass digitisation projects involving 100,000 items may incur annual licensing fees exceeding £1 million per year.
(5) The average level of fees imposed on a potential user of an orphan work is similar in collective and individual licensing regimes. This is an interesting finding because it mitigates arguments that one of the regimes will lead to higher fees. The operating costs involved in running an orphan works scheme appear therefore an important factor when choosing between individual and collective approaches.
(6) A limited liability system seems to have advantages for archives and other non-profit institutions exposed to orphan works, enabling those organisations to share their stock of orphaned artefacts with the public. In contrast, the up-front rights clearing seems to provide more appropriate incentives for commercial uses of orphaned artefacts, guaranteeing that a reappearing rightholder will be compensated for the exploitation of any work.
Together, the findings from both studies indicate the need for a more structured and consistent approach in governing orphan works that is reflected in the pricing and duration of licences, and in the costs of running any licensing system
A gazetteer and summary of French pottery imported into Scotland c. 1150 to c. 1650 a ceramic contribution to Scotland's economic history Ceramic Resource Disc 3
No full textThe proposal for a series of published inventories, by countries, of all the imported medieval and post medieval pottery recovered from excavations and field walking in Scotland, was advanced on the final day of the Medieval Pottery Research Group’s conference held in Edinburgh in May 2001. Taking on the roll of creating a gazetteer and catalogue of French pottery in Scotland, it was the authors aim to build on the pioneering work of John Hurst and other medieval ceramicists and in the process make a contribution to the ongoing research on identifiable medieval and post-medieval ceramics traded around the North and Irish Sea
Estimating demographic parameters for capture-recapture data in the presence of multiple mark types
No full textIn mark-recapture studies, various techniques can be used to uniquely identify individual animals, such as ringing, tagging or photo-identification using natural markings. In some long-term studies more than one type of marking procedure may be implemented during the study period. In these circumstances, ignoring the different mark types can produce biased survival estimates since the assumption that the different mark types are equally catchable (homogeneous capture probability across mark types) may be incorrect.We implement an integrated approach where we simultaneously analyse data obtained using three different marking techniques, assuming that animals can be cross-classified across the different mark types. We discriminate between competing models using the AIC statistic. This technique also allows us to estimate both relative mark-loss probabilities and relative recapture efficiency rates for the different marking methods.We initially perform a simulation study to explore the different biases that can be introduced if we assume a homogeneous recapture probability over mark type, before applying the method to a real dataset. We make use of data obtained from an intensive long-term observational study of UK female grey seals (Halichoerus grypus) at a single breeding colony, where three different methods are used to identify individuals within a single study: branding, tagging and photo-identification based on seal coat pattern or pelage.Peer reviewe
Broad Immunomodulatory Effects of the Dipeptidyl-peptidase-1 Inhibitor Brensocatib in Bronchiectasis:Data from the Phase 2, Double-Blind, Placebo-controlled WILLOW Trial
No full textRATIONALE: In the WILLOW trial, the Dipeptidyl peptidase-1 inhibitor brensocatib reduced neutrophil serine protease (NSP) activity and prolonged time to first exacerbation in patients with bronchiectasis.OBJECTIVES: We hypothesized that, by reducing NSPs, brensocatib would affect antimicrobial peptides, mucins, and cytokines throughout the inflammatory cascade.METHODS: The WILLOW trial was a phase 2 randomized trial of brensocatib (10mg and 25mg) versus placebo. Sputum was collected at baseline, week 4, week 24 (end of treatment) and week 28 (4 weeks post-treatment). The antimicrobial peptides secretory leukoproteinase inhibitor (SLPI) and α-defensin-3 were measured by ELISA, mucin-5AC (MUC5AC) by liquid chromatography mass spectrometry, myeloperoxidase by immunoassay and 45 inflammatory cytokines by Olink ® Target 48 assay. The relationship between these markers and sputum neutrophil elastase was validated using the EMBARC-BRIDGE bronchiectasis cohort. MEASUREMENTS AND MAIN RESULTS: Of 82 patients randomized to 10mg brensocatib, 87 to 25mg brensocatib, and 87 to placebo, 71, 71 and 73 with sputum available for at least two time points were included. SLPI and α-defensin-3 increased significantly with brensocatib compared to placebo at both week 4 and week 24. MUC5AC reduced in response to treatment. Sub-analysis showed this was primarily among patients with high baseline neutrophil elastase. Myeloperoxidase did not change. 15 cytokines and chemokines increased significantly compared to placebo at week 4 or 28. CXCL10, CCL8, CCL7, CCL3 and IL-6 increased at both doses at both timepoints. In the EMBARC-BRIDGE cohort neutrophil elastase correlated inversely with SLPI, CCL13, IL7, CCL11, CXCL10, CCL8, CCL7, all markers increased by brensocatib.CONCLUSIONS: Brensocatib exerts broad anti-inflammatory effects beyond its known effects on serine proteases. Clinical trial registration available at www.CLINICALTRIALS: gov, ID: NCT03218917.</p
Inflammatory and mucociliary dysfunction based endotypes across the spectrum of chronic airways diseases
No full textIntroduction: There is substantial overlap between COPD, asthma, bronchiectasis(BE) and cystic fibrosis(CF) and each is characterised by inflammation and mucociliary dysfunction.Hypothesis: Biology, rather than disease labels, may stratify patients into therapeutically relevant subtypes.Methods: Patients were categorized by primary disease and clinical characteristics, spontaneous sputum was collected and inflammatory characteristics (neutrophil elastase(NE) and 19 cytokines) and sputum properties (DNA content, mucins, rheology, dry weight) measured. K-means clustering was performed and parameters compared between and within disease groups. Smokers without respiratory disease were used as controls.Results: The study included patients with asthma(76), COPD(91), BE(54), CF(24) and controls(26). 10 cytokines, NE, dry weight, mucins and multiple sputum parameters were different between disease groups and healthy controls (p<0.05). K means clustering identified 2 clusters defined by neutrophilic (N) or eosinophilic (E) inflammation. The E cluster was associated with lower dry weight, DNA content and higher mucins, particularly MUC5B. The rheology parameters G’ and G* were significantly higher in the E group while Tan(delta) was higher in the N group (p<0.05 all comparisons). Both clusters were present in all disease groups with more neutrophilic inflammation in CF and BE (42% of COPD patients and 46% of asthma patients were neutrophilic vs 78% of BE and 87% of CF,p<0.0001).Conclusion: Airways diseases have heterogenous inflammatory and mucus parameters. Assessment based on disease labels may be aided by endotyping using inflammatory and mucociliary clearance parameters
Inflammatory and mucociliary dysfunction based endotypes across the spectrum of chronic airway diseases
No full textBackground: There is substantial overlap between features of COPD, asthma, bronchiectasis, and cystic fibrosis (CF). Each is characterized by inflammation and mucociliary dysfunction. Research Question: Is there a relationship between inflammation and mucociliary clearance in chronic respiratory conditions, and can biology, rather than disease labels, stratify patients into therapeutically relevant subtypes? Study Design and Methods: Patients were categorized according to primary disease and clinical characteristics recorded. Spontaneous sputum was collected, and inflammatory markers (neutrophil elastase and 18 cytokines), sputum properties (DNA content, mucins, rheology, dry weight), and microbiome (long-read 16S sequencing) were measured. K-means clustering was performed and parameters compared between and within disease groups. Control participants were individuals who had formerly smoked but were without respiratory disease. Results: The study included patients with asthma (n = 76), COPD (n = 91), bronchiectasis (n = 54), CF (n = 24), and control participants (n = 26). Nine cytokines (interferon-γ, IL-4, IL-5, eotaxin, eotaxin-3, thymus and activation regulated chemokine, granulocyte colony-stimulating factor, fractalkine, IL-22), neutrophil elastase, dry weight, mucins, and sputum rheology parameters were significantly different between disease groups and control participants (P < .05). K-means clustering identified 2 clusters defined by neutrophilic or T helper 2 (Th2) inflammation. The Th2 cluster was associated with lower sputum dry weight and DNA content and higher mucin-5B. Rheological parameters G′, G′′, and G∗ were significantly higher in the Th2 group, whereas the tangent of the loss angle δ was higher in the neutrophilic group, indicating a higher viscous to elastic ratio (P < .05 all comparisons). The neutrophilic cluster was associated with decreased alpha diversity (P = .04) and increased presence of Proteobacteria in their sputum microbiome compared with the Th2 cluster (P = .01). More neutrophilic inflammation was present in CF and bronchiectasis (42% of patients with COPD and 46% of patients with asthma were neutrophilic vs 78% of bronchiectasis and 87% of CF (P < .0001). Both clusters were present in all disease groups. Interpretation: Our results indicate that airway diseases have heterogeneous mucus properties. Patients were shown to cluster according to inflammatory endotype rather than disease label. Assessment based on disease labels may be aided by endotyping using inflammatory and mucociliary clearance biomarkers.</p
