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Submitting institution
Swansea University / Prifysgol Abertawe
Unit of assessment
3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
Summary impact type
Health
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Predictive risk stratification tools to identify those at highest risk of emergency admission to hospital and thereby reduce the level of those emergency admissions have been widely promoted in UK and international policy. The national rollout of a web-based risk stratification tool (PRISM) for use by general practitioners (GPs) was halted following the results of Swansea University’s study: PRISMATIC. This large-scale trial in the general population (n = >230,000) showed that the introduction of the PRISM software led to unexpected increases in emergency admissions, days spent in hospital and costs, without benefit to quality of life. Close collaboration between Swansea University researchers and policy makers in Wales prevented the implementation of PRISM, which did not have an evidence base of effectiveness and had unintended adverse consequences for patients and the NHS in practice. Non-implementation of PRISM avoided additional emergency admissions (27,690 annually) and hospitalisation days (75,815 annually) for patients in Wales and resulted in cost savings for the NHS (GBP201,000,000 annually).

2. Underpinning research

Although an evidence-based approach is the ideal model for planning and delivering healthcare, barriers exist to using research evidence to implement and evaluate service change. In 2013, Swansea University’s Health Services Research (HSR) group conducted a national email survey of health service commissioners at the most devolved level of decision-making in Wales (Local Health Boards – LHBs) followed by in-depth interviews with representatives of LHBs, purposively selecting five to reflect geographic and economic characteristics. This programme of work included qualitative work to understand barriers and facilitators in implementing policy and research evidence in chronic conditions management at local and regional levels. The research exposed a gap between evidence-based aims of national health policy and how health services are commissioned, implemented, and evaluated at local level (R1).

It was against this background that the Predictive Risk Stratification Model (PRISM) tool was introduced in Wales, designed to allow GP staff to be able to view risk scores for patients across the spectrum of risk of emergency admission to hospital during the following year1. Routine data used to generate scores included inpatient, outpatient and general practice data, alongside a deprivation index. The full PRISM intervention comprised the software, a user friendly handbook, 2 hours of practice-based training, clinical support through two locally appointed GP champions’ and a ‘help desk’ accessible by telephone or email. At the time, there was research evidence on the accuracy of emergency admission risk prediction tools but there was a lack of evidence regarding how well predictive risk tools work in supporting the management of patients. A study was designed by the HSR group to provide information on costs and effects of PRISM; how it was used in practice, barriers and facilitators to its implementation; and its perceived value in supporting the management of patients with and at risk of developing chronic conditions (R2).

From the outset, the research group aimed to understand what might be needed to bring PRISM into effective use by exploring clinician’s and practice managers’ attitudes and expectations about using it. The group conducted 4 focus groups and 10 interviews with a total of 43 primary care doctors and colleagues from 32 general practices. The researchers found that policy imperatives and the pressure of rising demand meant respondents were open to trying out PRISM, despite underlying uncertainty about what difference it could make (R3).

Between 2012 and 2015, the HSR group conducted a randomised trial to evaluate the PRISM intervention (PRISMATIC, ISRCTN55538212). The trial included the outcomes of 230,099 participants registered to 32 general practices in the Swansea area who received the intervention in random clusters over 52 weeks. The approach was innovative in two ways:

  • the use of routine data from the Secure Anonymised Information Linkage (SAIL) databank to compare services delivered to patients (emergency, acute, primary, community and social care) across the spectrum of risk between intervention and control practices. SAIL includes routine Welsh hospital data such as emergency admissions secondary care as well as GP practice data. The linked data approach allowed for the inclusion of routine outcomes for everyone registered for participating general practices without their explicit provision of consent based on a privacy protection methodology developed at Swansea University by Professor Lyons (R4).

  • the use of a progressive cluster randomised stepped wedge trial design, ensuring that all participating practices had the opportunity to implement and use the intervention during the study period. As the trial progressed, the number of intervention practices increased and the number of control practices fell (Fig . 1).

Embedded image

Figure 1 Randomised multiple interrupted time series study design overview (R2)

The trial outcomes were wholly unexpected, with the introduction of PRISM increasing emergency episodes, hospitalisation and costs across, and within, risk levels without clear evidence of benefits to patients, findings that were contrary to the views of practitioners and UK policy (R5, R6).

1 Wales predictive model, final report and technical documentation. D Wennberg, M Siegel, R Stephens - Prepared for NHS Wales, Informing healthcare, 2008 https://www.yumpu.com/en/document/view/32003147/wales\-predictive\-model\-final\-report\-and\-technical\-documentation

3. References to the research

All papers represented are published in peer reviewed journals and have been supported by NIHR and Welsh government. R5 has been submitted to REF2021. PRISMATIC findings were published in both an NIHR Journal Series monograph and BMJ Quality and Safety (R5 and R6). The Editor’s choice article prompted the publication of an editorial and the paper was ranked number 2 in their “Top 10” articles of 2019.

R1. Evans BA, Snooks H , Howson H, Davies M . How hard can it be to include research evidence and evaluation in local health policy implementation? Results from a mixed methods study. Implementation Sci 8, 17 (2013). doi:10.1186/1748-5908-8-17 cited 72 times 17.11.2020 https://implementationscience.biomedcentral.com/articles/10.1186/1748\-5908\-8\-17.

R2. Hutchings HA, Evans BA, Fitzsimmons D, Harrison J, Heaven M, Huxley P, Kingston MR, Lewis L, Phillips CJ, Porter AM, Russell IT, Sewell B, Warm D, Watkins A and Snooks HA. Predictive risk stratification model: a progressive cluster-randomised trial in chronic conditions management (PRISMATIC) research protocol. Trials 14, 301 (2013) doi:10.1186/1745-6215-14-301.

R3. Porter A, Kingston MR , Evans BA, Hutchings H , Whitman S, Snooks H. It could be a 'Golden Goose': a qualitative study of views in primary care on an emergency admission risk prediction tool prior to implementation. BMC Fam Pract. 2016 Jan 6;17:1. doi: 10.1186/s12875-015-0398-3.

R4. Lyons RA , Jones KH, John G, Brooks CJ, Verplancke J-P, Ford DV, Brown G, Leake K. The SAIL databank: linking multiple health and social care datasets. BMC Medical Informatics and Decision Making. 2009;9(1):3  doi: 10.1186/1472-6947-9-3.

R5. Snooks H , Bailey-Jones K, Burge-Jones D, Dale J, Davies J, Evans BA, Farr A, Fitzsimmons D, Heaven M, Howson H, Hutchings H, John G, Kingston M, Lewis L, Phillips C, Porter A, Sewell B, Warm D, Watkins A, Whitman S, Williams V, Russell I. Effects and costs of implementing predictive risk stratification in primary care: a randomised stepped wedge trial BMJ Quality & Safety 2019;28:697-705. doi:10.1136/bmjqs-2018-007976.

R6. Snooks H , Bailey-Jones K, Burge-Jones D, Dale J, Davies J, Evans B, Farr A, Fitzsimmons D, Harrison J, Heaven M, Howson H, Hutchings HA, John G, Mark Kingston, Leo Lewis, Ceri Phillips, Alison Porter, Bernadette Sewell, Daniel Warm, Alan Watkins, Shirley Whitman, Victoria Williams, and Ian T Russell. Predictive risk stratification model: a randomised stepped-wedge trial in primary care (PRISMATIC). Health Serv Deliv Res 2018;6(1). doi:10.3310/hsdr06010.

Grants supporting the underpinning research at Swansea University:

G1 PI: Helen Snooks, Swansea University,” Implementation of the Framework for Research and Evaluation related to the Model of Chronic Conditions Management in Wales” Welsh Government, 2008 – 2012, GBP241,129.

G2 PI: Helen Snooks, Swansea University, “How do people with chronic conditions experience care in Wales?”, Wales Office of R&D (WORD), 2008, GBP13,300.

G3 PI: Helen Snooks, Swansea University, “Chronic Conditions Management Research and Evaluation Advice and support”, Wales Office of R&D (WORD), 2009 – 2012, GBP9,956.

G4 PI: Helen Snooks, Swansea University, “Baseline study of CCM in Wales – supplementary reports” WORD and Caerphilly and Rhondda Cynon Taf Local Health Boards, 2009, GBP10,512.

G5 PI: Helen Snooks, Swansea University “Predictive risk stratification: impact on care for people with or at risk of chronic conditions” 09/1801/1054, NIHR, HSDRP 2010 – 2015, GBP691,101.

G6 PI: Mark Kingston, Swansea University “Emergency Admission Risk Prediction survey” Abertawe Bro Morgannwg University Health Board, 2014 – 2016, GBP11,000.

G7 PI: Mark Kingston, Swansea University “Emergency Admission Risk Prediction Qualitative study” Abertawe Bro Morgannwg University Health Board, 2016 – 2018, GBP7,000.

4. Details of the impact

Tackling the increasing burden of emergency hospital admissions is a major policy goal in the UK and internationally. Ageing populations, the increasing prevalence of chronic diseases and risk-averse practitioner behaviour underlie unmanageable increases in emergency admissions, leading to increased costs, risks associated with inpatient stays and difficulties with patient flow. As part of a move from the inefficient provision of care within ‘silos’ of medical disciplines, such as cardiac, respiratory, or gastrointestinal medicine, stratification of general practice populations by risk of emergency admission has been widely promoted. This new approach allows proactive assessment and care for the whole person, rather than the reactive treatment of patients following crises. Implementation and use of predictive risk stratification in primary care has been incentivised in UK policy through targets and payments. The aim of this policy has been to enable the delivery of targeted interventions for people at high risk of emergency admission to hospital and thus to reduce these admissions, and also reduce pressure on the acute sector.

From 2008, Professor Helen Snooks led a programme of policy research and evaluation support commissioned by the Welsh Government and established a close working relationship with colleagues responsible for the development and implementation of the Chronic Conditions Management policy in Wales (G1 – G4). This programme of work led to the development of a successful application for research funding led by Snooks, in partnership with the Welsh Government and local NHS collaborators, to evaluate the introduction of predictive risk stratification in primary care in one area of Wales (G5). At the time of the initiation of this evaluation, a national roll out of the PRISM software to all GPs across Wales had been planned for April 2010 but was paused in 2011 pending the PRISMATIC trial outcomes (C1). Media interest was high throughout the study, including a feature on BBC Wales (C2).

The trial findings (R5, R6) showed that the implementation of PRISM was associated with increases in:

  • emergency hospital admissions by 1%,

  • emergency department (ED) attendances by 3%,

  • outpatient visits by 5%,

  • proportion of days with recorded GP activity by 1%,

  • days spent in hospital by 3%.

  • NHS costs per participant of GBP76.00 per year.

The unintended consequences of the PRISM intervention highlighted by the PRISMATIC study were hugely significant in terms of NHS usage and costs.

When the findings were released, the roll out was halted altogether in Wales. In 2020, the Deputy Director of Primary Care in the Welsh Government stated “The trial results indicated that effects were unanticipated and in the opposite direction to those sought. The work concluded that caution needs to be exercised in using predictive risk tools at an individual patient level to support clinical decision making. This is a useful piece of research for consideration in decision making and planning. As a result, the PRISM tool was not rolled out more widely in the Welsh health system” (C3).**

The 2020 follow-up survey results show that the impact of the research in Wales has been high, with only 14% of general practices having access to emergency admission predictive risk tools in Welsh Health Boards compared to over 80% across the UK (C4).

PRISMATIC has had significant impacts on health policy, patient care and NHS costs in Wales. The research findings showed that the introduction of predictive risk stratification in primary care had the opposite of the intended effect, increasing emergency admissions to hospital (primary outcome) and the use of emergency, primary and outpatient services. Extrapolating the study findings to the population of Wales, it is estimated that the non-implementation of PRISM in Wales has avoided approximately 30,000 admissions to hospital and 76,000 hospitalisation days per year, thus avoiding incurred annual costs of GBP2,000,000.

Note: A workshop/seminar had been planned in 2020 to disseminate the findings across the other nations of the UK but it was cancelled due to the COVID-19 pandemic.

5. Sources to corroborate the impact

C1 Letter from the Medical Director, Department for Public Health and Health Professions, NHS Wales, confirming the halt to roll-out of PRISM, Oct 2011.

C2 BBC Wales “Preventing emergencies: Swansea team pioneer trial of new NHS system” Nov 2013.

C3 Confirmation letter from the Deputy Director, Primary Care, Welsh Government on the influence of the PRISMATIC findings on health policy in Wales, 14.2.2020.

C4 Kingston M, Hutchings H, Griffiths R, Porter A, Russell I, Snooks H. Emergency Admission Risk Stratification in UK primary care: national survey of access and use. Peer reviewed article published in British Journal of General Practice 21 September 2020; DOI: 10.3399/bjgp20x712793.

Submitting institution
Swansea University / Prifysgol Abertawe
Unit of assessment
3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
Summary impact type
Political
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Research conducted by Swansea University’s In Vitro Toxicology Group has been pivotal to the development of standardised safety tests that facilitate nanomaterial hazard identification and risk assessment for human health. DNA damage is associated with carcinogenesis; assessing the DNA damaging capacity of a substance is a vital aspect of safety assessment for the protection of human health. Although regulatory safety tests for most chemicals are well defined, they are not appropriate for nanomaterials. This has been a substantial barrier to nanotechnology innovation worldwide, negatively impacting regulators, industry and the consumer public. Research at Swansea University (SU) has enabled current regulatory testing approaches to be re-written and has provided tailored safety testing methods for nanomaterials, ensuring the safe development of the global nanotechnology industry.

2. Underpinning research

Nanotechnology, which encompasses the manipulation of extremely small things (at the level of atoms and molecules), is widely regarded as the next global frontier in science, bringing significant economic and societal benefits through major technological breakthroughs that improve quality of life. The global nanotechnology market (nano-enabled products, nano-intermediates and nanomaterials) currently consists of ca . 3,200 companies with *>*10,000 employees, grossing a global turnover of >USD50,000,000,000 in 2020, with a projected growth to >USD170,000,000,000 by 2025. To maintain industry productivity and achieve this market growth, it is essential to overcome barriers preventing the widespread use and further innovative development of nanotechnologies. Specifically, the potential human safety risks posed by engineered nanomaterial (ENM) exposure are uncertain and there is a lack of a safety testing framework, as the standard methods used for chemical safety assessment are not appropriate for ENMs. Hence, the primary needs of the nanotechnology industry are:

  1. A risk assessment regulatory framework, with effective testing strategies to support safety.

  2. Effective human and environmental hazard detection tools to allow industry to make informed decisions on product viability and design. Effective tools must be rapid, predictive and cost effective.

Modification of the standard safety testing approach to specifically address problems associated with ENM design, has been shown by the In Vitro Toxicology Group to be vital in enabling evaluation of the safety of ENMs to protect human health. Indeed, IVTG-led work in providing hazard testing method adaptations have formed the basis for international regulatory changes. The adaptations described through this research have been recommended in a variety of international regulatory policy documents describing ENM safety testing and are being implemented by industry, regulatory authorities and standardization bodies.

Nano(geno)toxicology research, evaluating the DNA damaging potential of ENMs, was initiated at SU in 2007 by Shareen Doak and Gareth Jenkins who secured major research awards from both MRC (GBP475,000 G1) and EPSRC (GBP1,067,482 G2), resulting in the work published between 2009-2012. This research demonstrated that standard safety testing systems developed to detect chemically induced DNA damage were not appropriate for evaluating ENMs and required revisions to avoid future repetition of the asbestos legacy ( R1, R2).

In 2012, the group published recommendations on how to improve multiple aspects of the methodology underlying standard DNA damage testing systems (the micronucleus assay and Ames test) to tailor them specifically for the evaluation of ENMs ( R3). While the group provided guidance on how to adapt the micronucleus assay to allow robust testing of ENMs, they recommended that the Ames test was not suitable at all and needed to be replaced. Furthermore, the group demonstrated successful use of a modified micronucleus test with biomedically relevant ENMs ( R4). These published recommendations ( R3, R5) have been widely accepted and used to adapt regulatory practice for ENMs in numerous risk assessment policy documents by a variety of international regulatory and standardisation bodies. Further work resulted in the development of newer and even more appropriate tests for evaluating nanosafety, focusing on the generation of novel cellular models for the human lung, skin and liver that better represent the complexities of the human body than traditional techniques ( R6). Martin Clift’s arrival in 2015 facilitated expansion of this work in developing more sophisticated human lung test systems that better predict human health and DNA damage impacts following ENM exposure through inhalation ( G3).

International recognition of this hazard assessment research is reflected by the award in 2018 of a Horizon 2020 (H2020) European Commission funded project “PATROLS” ( G4) valued at EUR12.700,000 PATROLS is coordinated by Doak and consists of 23 partners located in Europe, Canada, the US, Japan and Korea. PATROLS includes representation from key beneficiaries including government, regulatory and industrial bodies.

3. References to the research

) *Names provided in bold indicate authors of this document.

The research from the In Vitro Toxicology Group has led to more than 70 peer-reviewed publications in leading journals in the field, been cited over 1600 times and has led to over GBP32,000,000 in research grant income from the European Commission, research councils and industry.

R1. Singh N, Manshian B, Jenkins GJS, Griffiths S, Williams P, Maffeis TG, Wright CJ, Doak SH (2009). Nanogenotoxicology: the DNA damaging potential of engineered nanomaterials. Biomaterials, 30, 3891-3914.

This seminal paper filled a gap in our current understanding of nanogenotoxicology testing and provided specific recommendations that addressed the substantial limitations in our knowledge within the field, at that time. Its publication led to Doak being invited onto national and international committees concerned with nanomaterial safety, including the Genetic Toxicology Technical Committee (GTTC) of the International Life Sciences Institute (ILSI, USA) and the UK Government Committee on Mutagenicity (COM). This output was a key publication linked to the award of an MRC (GBP475,000.00) grant.

R2. Doak SH, Griffiths SM, Manshian B, Singh N, Williams PM, Brown AP, Jenkins GJS (2009). Confounding experimental considerations in nano(geno)toxicology.  Mutagenesis, 24, 285-293.

This paper provided further recommendations on how the field should move forward, underpinned by new data to highlight where there were experimental design problems specifically associated with nanomaterial physico-chemical behaviour when undertaking hazard assessment tests. This paper, together with R1, resulted in Doak being invited to sit on the GTTC and COM committees. This output was a key publication linked to the award of an MRC (GBP475,000) grant.

R3. Doak SH, Manshian B, Jenkins GJS, Singh N (2012). In vitro genotoxicity testing strategy for nanomaterials and the adaptation of current OECD guidelines. Mutation Research, 745, 104-111.

This paper, for the first time in the field, specifically outlined which global regulatory test systems were appropriate for ENM DNA damage testing and the method adaptations needed. The recommendations and guidance provided in this paper have been adopted internationally. The paper underpins the changes to regulatory practice and consequently has been cited in all the sources to corroborate the impact. The paper was also a key output that led to the successful award of the H2020 PATROLS project, which is coordinated by Doak.

R4. Singh N, Jenkins GJS, Nelson BC, Marquis BJ, Maffeis TGG, Brown AP, Williams PM, Wright CJ, Doak SH (2012). The role of iron redox state in the genotoxicity of ultrafine superparamagnetic iron oxide nanoparticles. Biomaterials, 33, 163-170.

Submitted to REF2014, this output contains a significant portion of the data generated through the successfully awarded MRC grant (GBP475,000). The paper demonstrates the application of the genotoxicity testing systems developed through R1-R3. It illustrates how the adapted genotoxicity testing system can be applied to evaluate and understand the DNA damaging potential of ENMs in a robust and reliable manner. The manuscript considers iron oxide nanomaterials destined for biomedical uses as the test material and illustrates how the physico-chemical features of the material strongly influence its safety.

R5. Elespuru RK, Pfuhler S, Aardema M, Chen T, Doak SH, Doherty A, Farabaugh C, Kenny J, Ouedraogo G, Mahadevan B, Moore M, Tanir J, Manjanatha MGM, Stankowski LF (2018) Genotoxicity assessment of nanomaterials: recommendations on best practices, assays and methods. Toxicological Sciences, 164, 391-416.

This seminal paper is the result of Doak’s role in the GTTC committee; it is the first to consider the full suite of regulatory genotoxicity testing methods and the manner in which they can be used to assess nanomaterial safety. It is co-authored by experts from industry, regulators and academics, located across three continents. This paper led to Doak being invited to present the analysis outcomes to several government public health organisations e.g., Public Health England (UK), National Institute for Public Health and the Environment (Netherlands), and in Australia at the Food Standards Australia New Zealand (FSANZ), Therapeutic Goods Administration (TGA) and National Industrial Chemicals Notification and Assessment Scheme (NICNAS).

R6. Wills JW, Hondow N, Thomas AD, Chapman KE, Fish D, Maffeis TG, Penny MW, Brown RA, Jenkins GJS, Brown AP, White PA, Doak SH (2016). Genetic toxicity assessment of engineered nanoparticles using a 3D in vitro skin model (EpiDermTM). Particle Fibre Toxicology, 13, 50.

This paper is a strong example of where the group have developed and adapted novel methods utilising advanced cell culture models to suit nanomaterial hazard assessment. It was a key paper that led to the award of PATROLS and more recently awarded H2020 grants. Additionally, this paper resulted in Doak’s being invited to present this work at the quadrennial International Workshop on Genotoxicity Testing (IWGT), Japan, Nov 2017.

Examples of grant income stemming from research:

G1. MRC - GBP475,000 April 2008-Nov 2011. PI-Doak, CoI Jenkins. Understanding the Genotoxic Potential of Ultra-Fine Superparamagnetic Iron Oxide Nanoparticles.

G2. EPSRC - GBP1,067,482 Oct 2009-Oct 2013. CoI-Doak. Nanoparticle Cytometrics: A Quantitative Analysis of the Toxic Effect of Nanoparticles.

G3. Unilever - GBP90,000 March 2017-Feb 2020. PI-Clift, CoI-Doak. An Advanced Multi-Cellular and Dynamic Flow Model of the Human Alveolar Airway to Study the Impact of Inhaled Particulate.

G4. European Commission H2020: PATROLS – GBP12,700,000 Oct 2017-March 2021. PI-Doak, CoI-Jenkins & Clift (SU are the lead; 24 partners from 14 different countries worldwide).

4. Details of the impact

The work of SU’s In Vitro Toxicology Group has been pivotal in the development of standardised safety tests for nanomaterial hazard identification and risk assessment to protect human health. Beneficiaries include 1) regulators and policymakers who use the research to formulate a nanomaterials regulatory framework (see Fig. 1 for global reach); 2) the nanotechnology industries who need to protect their workforces and develop nano-products that are safe and accepted by society; and 3) the consumer public, with safer nanomaterial enabled products available to them.

Embedded image

Figure 1 Global reach of regulatory policies influenced by Doak's research

Regulatory and Policy Impact

The tailored adaptation of testing approaches for nanomaterial safety evaluation has had global impact. SU led research ( R2, R3, R5) has been widely utilised in international risk assessment policy documents to adapt the DNA damage testing methodology to include appropriate measures for evaluating the safety of nanomaterials. Organisations benefitting from this research include the:

  • Organisation for Economic Co-Operation and Development (OECD) ( C1; 2014),

  • European Chemicals Agency (ECHA) ( C2; 2013-2017),

  • European Food Safety Authority (EFSA) ( C3; 2011-2018),

  • Australian Pesticides & Veterinary Medicines Authority (APVMA) ( C5; 2015).

An international programme to develop the OECD guidance for nanomaterial-specific DNA damage testing methods was initiated in Canada in 2013, involving 16 countries and published in 2014. Doak, an independent expert advisor for the OECD’s Working Party on Manufactured Nanomaterials (WPMN), was the Plenary Speaker and was centrally involved in discussions that led to an open-access OECD report with recommendations on nano-specific DNA damage testing approaches for international regulatory approval processes ( C1). Doak and Jenkins were key contributors to OECD meetings on adaptation of the In Vitro Micronucleus Assay for Testing Nanomaterials in 2014 (France; 14 participating countries) and 2019 (Italy; 10 participating countries). Doak also attended the 2018 WPMN and advised on accelerated use of new methods to support regulatory needs. Doak’s work in relation to other regulatory policy document changes ( C2 ECHA; C3, EFSA; C4, APVMA) has been applied through similar mechanisms to those described above for the OECD.

The Principal Administrator for the OECD in 2017 stated: “ The impact of this work on both global regulatory policy and industrial practice is significant as it will support current regulatory frameworks that underpin the development and implementation of an effective, proportionate and acceptable future regulatory framework for nanosafety, including REACH, medical device and cosmetic regulations. This in turn will enable the nanotechnology industry to advance, promoting responsible economic growth.” (C5)

Doak and Jenkins have participated in several policy-shaping regulatory committees, such as the UK Government Committee on Mutagenicity (COM), serving from 2013-present and 2009-2019 respectively. In 2010 Doak was invited to join both the GTTC and the European Commissions’ Scientific Committee on Consumer Safety (SCCS) Working Group on Nanomaterials in Cosmetics. Through these activities, the group’s research has been applied to facilitate regulatory decision making in nanomaterial safety dossiers produced by:

  • The European Commissions’ SCCS ( C6, C7; 2015-2019).

  • Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) ( C8; 2014).

  • The evaluation of nano-carbon black and nano-enabled medical devices ( C9; 2017).

In 2017, Doak was invited to lead the GTTC Nanomaterials Working Group (alongside a US Food and Drug Administration, FDA, representative) and is a member of the GTTC Steering Team. Her role in these committees has resulted in changes to both attitude and practice in terms of nanomaterial safety regulation.

Industrial and consumer public impact

Industry has benefitted through the provision of robust ENM safety testing methods, increasing the confidence of regulators in approving ENM products. Multinational, national and local SME companies have benefited from the provision of research expertise and guidance. This has enabled companies to be in a position to file nano-related Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) regulatory submissions and is exemplified by the Health & Safety manager of OCSiAl, who stated: “ the knowledge-sharing and guidance provided by Swansea University has allowed us to proceed with the registration of our project under REACH, minimising the costs for compliance with potential regulatory classifications” ( C10). The consumer public also benefit from safer nanomaterial enabled products produced by, for example, Royal Mint, Unilever, Eurometeux, Knauf Insulation, Iron Oxide REACH Consortium, and the Titanium Dioxide Industry Consortium, who have all been provided with both testing guidance and provision of experimental data (2014-2020).

5. Sources to corroborate the impact

C1. OECD document: Genotoxicity of Manufactured Nanomaterials: Report of the OECD Expert Meeting. Series on the Safety of Manufactured Nanomaterials No. 43 ENV/JM/MONO(2014)34; 03-Dec-2014 (p11-13).

C2. ECHA’s Guidance on information requirements and chemical safety assessment: Appendix R7-1 for nanomaterials applicable to Chapter R7a Endpoint specific guidance (May 2017; p62).

C3. EFSA document: Guidance on the risk assessment of the application of nanoscience and nanotechnologies in the food and feed chain. May 2011, and in the subsequent 2018 updated document (p42-43).

C4. Australian Government; Australian Pesticides & Veterinary Medicines Authority. Nanotechnologies for pesticides and veterinary medicines: regulatory considerations (final report), July 2015 (p120).

C5. Testimonial from Principle Administrator for the OECD.

C6. European Commission’s SCCS “Opinion on Carbon Black (nano-form)” (2015; p41,62).

C7. European Commission’s SCCS “Guidance on the Safety Assessment of Nanomaterials in Cosmetics” (2019; p50,53-54).

C8. European Commission’s SCENIHR: Guidance on the Determination of Potential Health Effects of Nanomaterials Used in Medical Devices. 2015 (p32,37).

C9. ISO/TR 10993-22:2017(en) Biological evaluation of medical devices-Part 22: Guidance on nanomaterials, 2017 ( https://www.iso.org/standard/65918.html).

C10. Testimonial from Health & Safety Lead Manager, OCSiAl.

Submitting institution
Swansea University / Prifysgol Abertawe
Unit of assessment
3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
Summary impact type
Societal
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Research evidence generated by Swansea University, including the creation, curation and analysis of the first suicide-information database for Wales, has shaped the development of a multi-stranded national approach to prevent suicide and self-harm. Swansea research has:

  • Driven national policy changes at government level

  • Prompted additional investment in prevention resources such as an additional GBP500,000/year to support national and regional approaches to preventing suicide and self-harm and dissemination of guidance to all school in Wales of self-harm guidance.

  • Positively influenced media coverage of suicide and self-harm with researchers working with UK government agencies, Samaritans, BBC, ITV and Channel 4.

  • Informed new evidence-based suicide prevention guidance for schools, social care and health services.

  • Influenced revised guidelines for firearms licensing, prescription of anti-depressants and bridge design. These guidelines to reduce access to the means of suicide have also been shared UK-wide,

  • Been adopted internationally, Canada.

2. Underpinning research

Globally, 800,000 people take their own lives each year; in Wales and across the UK, the numbers of suicides each year are approximately 350 and 6000, respectively. Suicide is a tragedy for all concerned and a cause of distress for many people, including family, friends, colleagues, professionals and the community at large. In 2008, the issue of suicide came to prominence in Wales due to an apparent cluster of suicides in young people in the Bridgend area of South Wales. The sensationalism of the extensive national and international newspaper coverage provoked controversy over the size, initiation, maintenance, and cessation of this cluster, culminating in the local police holding a press conference in February 2008 to hold the media to account.

To establish the true extent of the problem amid the sensationalised accounts, in 2013, Professors John and Lloyd aimed to determine whether a statistically definable cluster had occurred and were the first and only research team to do so. By analysing mortality data over 10 years across Wales (a population of 3.2 million), the researchers used novel temporo-spatial statistical analysis to produce evidence of the existence of a suicide cluster among 15- to 35-year-olds around the time of the media attention. However, this apparent cluster was smaller, shorter in duration and predominately later than the phenomenon that was widely reported (R1, G1). The team examined the quality and sensationalism of media articles on suicide in Bridgend for six months before and after the defined cluster (June 26, 2007, to September 16, 2008) using, a tool based on guidance of the responsible reporting of suicide they had developed and published previously (R2). In all, 577 newspaper articles were identified, almost half displayed a high level of poor-quality and sensationalist reporting during the timescale of the suicide cluster. Notably, there was extensive republishing of photos from previous deaths, nearly half of the reports referred to earlier suicides (meaning that each suicide was repeatedly reported in the press) and approximately one in seven articles mentioned the method of suicide in the headline, which contravened reporting guidance (R2). The research highlighted the necessity for improved knowledge of the characteristics of those who die by suicide, the risk factors for suicide and patterns of healthcare contacts to better identify and support those at risk of taking their own lives.

Building on their work using routinely collected data relating to suicide clusters, funded by Health and Care Research Wales, the research group at Swansea developed and established a new database , Suicide Information Database-Wales (SID-Cymru), in 2014 (R3). The largest database of its kind and an important resource in facilitating research on suicide, it accesses and links information on prior health, the nature of previous contacts with services, and wider social circumstances for all those who die by suicide (whether known or unknown to mental health services) within the population of Wales using anonymised routinely collected electronic data in healthcare (primary, emergency department and secondary) and social datasets from the Secure Anonymised Information Linkage (SAIL) Databank (http://www.saildatabank.co.uk\) (R4, G6). The architects of the SAIL databank (Professors Lyons and Ford) were involved in the curation of the data and the associations with SID Cymru. This database was the first to allow access to linked routinely collected electronic data about all persons in Wales over 10 years of age who were recorded to have died by suicide, enabling “big data” analysis of suicide antecedents and service use (R4). Professor John led the analysis of data from primary care providers, hospitals, emergency departments and schools along with evidence synthesis to explore key risk factors for suicide identified in SID-Cymru– such as depression, alcohol and self-harm with a focus on young people (R5, R6, R7).

3. References to the research

All papers represented below are published in peer reviewed journals. All have been supported by NISCHR funding ( R1 and R2, R3, R7), MQ/ADP ( R4) and HCRW ( R6). R1 was submitted to REF2014. R2 is cited in NICE policy. R4 is cited by the UK government on 21 Mar 2013 in the Independent Caldicott review, information governance in the health and care system. R6 is cited by World Happiness Report (APO) and UK government’s Research into Platforms’ Operating Models and Management of Online Harms.

R1. Jones P, Gunnell D, Platt S, Scourfield J, Lloyd K, Huxley P, Kamran B, John A, Wells C, Dennis M. (2013). Identifying probable suicide clusters in Wales using national mortality data. PLoS ONE 8(8): e71713. doi: 10.1371/journal.pone.0071713.

R2. John A, Hawton K, Gunnell D, Lloyd K, Scourfield J, Jones P, Luce A, Marchant A, Platt S, Price S, Dennis M. (2017). Newspaper reporting on a cluster of suicides in the UK crisis: A study of article characteristics using PRINTQUAL. Crisis 38(1):17-25. doi: 10.1027/0227-5910/a000410.

R3. John A, Dennis M, Kosnes L, Gunnell DG, Scourfield J, Ford DV, Lloyd KR. (2014). Suicide Information Database-Cymru: A protocol for a population-based, routinely collected data linkage study to explore risks and patterns of healthcare contact prior to suicide to identify opportunities for intervention. BMJ Open 4(11). doi: 10.1136/bmjopen-2014-006780.

R4. Lyons RA, Jones KH, John G, Brooks C, Verplancke J-P, Ford D et al. (2009). The SAIL databank: Linking multiple health and social care datasets. BMC Med Inform Decis Mak 9:3. doi:10.1186/1472-6947-9-3.

R5. Marchant A, Turner S, Lloyd B, Peters P, Williams D, Lloyd K, Lyons R, John A. (2019). Self-harm presentation across healthcare settings by sex in young people: An e-cohort study using routinely collected linked healthcare data in Wales, UK. Arch Dis in Childhood 105(4).  doi: 10.1136/archdischild-2019-317248.

R6. John A, Glendenning AC, Marchant A, Montgomery P, Stewart A, Wood S, Lloyd K, Hawton K. (2018). Self-harm, suicidal behaviours, and cyberbullying in children and young people: Systematic review. Journal of Medical Internet Research 20(4): e129. doi:  10.2196/jmir.9044

R7. John A, Marchant A, Fone D, McGregor J, Dennis M, Tan J, & Lloyd, K. (2016). Recent trends in primary-care antidepressant prescribing to children and young people: An e-cohort study. Psychological Medicine 46(16):1-13. doi: 10.1017/S0033291716002099.

Grants supporting the underpinning research at Swansea University:

G1. NISCHR (Reference SC09/06), £196,000, PI A John.

G2. NISCHR (Reference RFS-12-25), £236,104, Jan 2012-Dec 2015, PI A John.

G3. HCRW (Reference SC-14-11), £66,000, Oct 2014- Mar 2019, PI A John.

G4. MQ: Transforming Mental Health (Reference MQBF/3 ADP), £799,961 , Apr 2018- Mar 2021, PI A John.

G5. Wolfson Foundation (Reference JHR-1261) £10,000, PI A John.

G6. SAIL Databank Farr Institute of Health Informatics Research. The Farr Institute is supported by a consortium of ten UK research organizations: Arthritis Research UK, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Engineering and Physical Sciences Research Council, the Medical Research Council, the National Institute of Health Research, the National Institute for Social Care and Health Research (Welsh Government) and the Chief Scientist Office (Scottish Government Health Directorates). MRC Grant No: MR/K006525/1.

4. Details of the impact

Driving policy change

The work of the Swansea group in the design, development and use of SID-Cymru (R3) represents the first use of anonymised, routinely generated real-life data on the population of Wales. Data from SID-Cymru directed the Welsh Government’s suicide prevention strategy for Wales (2015-2020), ‘Talk to Me 2’, launched in June 2015 . The then Minister for Health and Social Services thanked Professor John in the strategy foreword “for her leadership of the National Advisory Group, and its work to develop Talk to Me 2. I commend the strategy and action plan and anticipate further improvements in the months and years to come” (C1). In December 2018, the National Assembly for Wales published a report on Suicide prevention in Wales (C2). In the report Professor John is quoted extensively, advocating training, resource accessibility, self-harm tracking to improve data collection (R5), the importance of doing more in schools to address suicide and self-harm (R6), raising awareness in journalism (R1, R2), and the need for specific funding for suicide prevention.

Influencing resource allocation for suicide prevention

In response to the aforementioned ‘Everybody’s Business’ report in 2018 (C3), and as part of its subsequent recommendations in the implementation of the ‘Talk to me 2’ strategy, the Welsh Government pledged an additional GBP500,000 a year specifically to support national and regional approaches to preventing suicide and self-harm (C4). The then Health Minister said **: “ we will target the additional investment we are making towards actions that can help prevent and reduce suicidal behaviours, as well as providing appropriate support to communities to address this complex issue. As a society, we all need to work together to prevent suicide. Friends, families, organisations, and communities all have a part to play.”

In 2016 Professors John and Lloyd conducted research to re-evaluate the quality of prescribing for depression (a key risk factor for suicide) in young people (R7). This research identified a significant gap in young people’s mental health research. The potential to bring together billions of pieces of data (including administrative health, social and education data, to psychological and clinical data) on to one platform, enabled by the SAIL Databank, has attracted a further investment of over GBP12,000,000.

Supporting the media in the responsible reporting and portrayal of suicide and suicidal behaviour

Professor John’s research on media reporting preceding and during the Bridgend suicide cluster (R1, R2), brought her to the attention of the Samaritans. As a result of this research, she attended meetings with Welsh journalists to discuss the principles of responsible reporting. She also worked with the Samaritans Wales office to translate their media guidelines into Welsh and for their formal adoption in Wales (C4). This collaboration has also led her to consult on numerous television programmes. As a result of her input, the depictions of suicide in BBC, ITV and Channel 4 soap opera storylines (Casualty, Coronation Street and Hollyoaks) were changed, including the avoidance of details relating to methods used and the construction of storylines. As attested by the executive lead of Samaritans’ Media Advice Service, “Given the millions of viewers for these programmes it is vitally important to address issues that are likely to affect vulnerable individuals (such as details of methods) and promote protective behaviours (stories of help-seeking or recovery). Irresponsible depictions can have an immense reach across the population, as seen in recent studies published in relation to the Netflix youth drama “13 Reasons Why” where a suicide death was depicted graphically and is associated with increases in imitative suicidal behaviour. Prof John worked with us with producers, writers and actors on the shows with a number of meetings held on sets across the UK. Her input and expertise were extremely useful and ensured that these programmes were aired with appropriately informed consultation. The Coronation street storyline in particular was changed in a number of ways as a result of the input from Samaritans with Prof John” (C4).

Professor John was also part of a team that created the Public Health England national guidance on the identification and prevention of suicide clusters, which referenced the work on suicide clusters (R1), media reporting (R2) and cyberbullying (R6). The guidance is used extensively across the UK by local public health teams in managing suspected suicide clusters (C5).

Providing practical guidance for schools and youth services

Professor John’s research was instrumental in the recommendation for and development of Welsh Government guidance on early intervention and the safe management of self-harm and suicidal thoughts in young people. In a research engagement seminar presenting findings from R5, R6 and R7, attended by stakeholders from across government, education, health and social services, which prompted teachers’ requests for practical advice on how to help. This seminar resulted in a recommendation for guidance on managing self-harm for those working with young people, which was reiterated in ‘Mind over Matter’, a 2018 report on the step change needed in emotional and mental health support for children and young people in Wales (C6). In September 2019, the Welsh government launched school guidance on “Responding to issues of self-harm and thoughts of suicide in young people”, issuing hard copies to all 1,569 schools in Wales ( C7). The guidance is used by school staff and governors, youth-services workers, social workers, health professionals, and voluntary organisations working with children and is now available in hard copy and online.

Reducing access to the means of suicide

Analysis of data from SID-Cymru (R3) identified several factors relevant to the deaths, from socio-demographic and educational factors to access to lethal means of suicide (antidepressants and firearms). This analysis informed the Public Health Wales “Thematic review of deaths of children and young people through probable suicide, 2006-2012” (C8). This audit combined with their Cochrane reviews of means restriction for the prevention of suicide has led to changes in the guidance for bridge design in Wales. Architects of the Pont Menai Suspension Bridge discussed suicide prevention aspects with Professor John, “ As a result considerations for suicide prevention (parapet height etc) were incorporated into the design of the bridge which will have long term impact and save lives” (C9). Additionally, Swansea research informed changes in antidepressant prescribing guidance that was circulated to all GP practices in Wales in 2015; this guidance highlighted that “ doctors are reminded that when prescribing for depressive illness in children and adolescents only fluoxetine has been shown to be effective and when initiated should be carefully monitored in line with current guidance (see current BNF for advice, which is replicated on the reverse of this letter). Use of other medication to treat depressive illness should be initiated by a specialist and only when ongoing monitoring has been put in place” (C10). Swansea research also underpinned the publication of new guidance on firearms licensing law, New guidance on firearms licensing law published in October 2014, incorporates the recommendation about safe storage of firearms including inspection by police of storage arrangements. (C11). As a result of this program of work on means restriction, Professors John and Lloyd were invited to be co-directors of the Cochrane Suicide and Self Harm Satellite.

International Reach

The success of SID-Cymru has led to similar systems being adopted internationally. For example, Swansea have collaborated with the Public Health Agency in Canada to support the development of a similar system there (C12).

5. Sources to corroborate the impact

C1. Talk to me 2: Suicide and Self Harm Prevention Strategy for Wales 2015-2020, (See p.5), https://bit.ly/3aNhpHJ.

C2. Everybody’s Business: A report on suicide prevention in Wales, December 2018. (See paragraphs 25, 93, 129, 139, 209, 227, 273, 281) https://bit.ly/3bB6BM7

C3 Press release from Welsh Government, 20 February 2019 (PDF).

C4 Testimonial from Executive Lead, Samaritans Media Advice Service, December 2020.

C5 Identifying and responding to suicide clusters: A practical resource published by Public Health England, September 2019 https://bit.ly/2ZKp3fF.

C6 Mind Over Matter – A report on the step change needed in emotional and mental health support for children and young people in Wales, National Assembly for Wales Children, Young People and Education Committee April 2018

C7 Responding to issues of self-harm and thoughts of suicide in young people Guidance for teachers, professionals, volunteers and youth services. Welsh Government, Sept 2019 https://bit.ly/3kj6icI.

C8 Thematic review of deaths of children and young people through suicide, 2013-2017 Publisher: Public Health Wales NHS Trust, 2019.

C9 Testimonial from WG lead, Structures Manager- Transport, Welsh Government, 18 Dec 2020.

C10 Welsh Health Circular, Prescribing for children and young people in relation to antidepressants, October 2015.

C11 Child Death Review Programme, Annual Report, July 2015. P.30, https://phw.nhs.wales/services-and-teams/child-death-review/child-death-review-publications/child-death-review-programme-annual-report-july-2015/

C12 Thibodeau et al, Individual, programmatic and systemic indicators of the quality of mental health care using a large health administrative database: an avenue for preventing suicide mortality, Health Promotion and Chronic Disease Prevention in Canada, Research, Policy and Practice Vol 38, No 7/8, July/August 2018, doi.org/10.24095/hpcdp.38.7/8.04.

Submitting institution
Swansea University / Prifysgol Abertawe
Unit of assessment
3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
Summary impact type
Health
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Research by the Griffiths-Wang group at Swansea University has changed the way in which many sterols, including steroids and other cholesterol-like molecules, can be analysed. Owing to the nature of their structure, the diversity of occurrence in nature and the tendency of cholesterol to dominate in abundance, analysis of sterols has historically proved challenging. The Griffiths-Wang group have overcome these challenges by developing a novel “enzyme-assisted derivatisation for sterol analysis” (EADSA) technology, opening up new approaches to patient management for health care professionals worldwide. The monitoring of sterol metabolites has proven invaluable for disease diagnosis and prognosis and in monitoring the response to therapy for patients with rare inborn errors of metabolism, including lysosomal acid lipase deficiency (LALD), cholesterol 25-hydroxylase (CH25H) deficiency, spastic paraplegia type 5 (SPG5), Smith-Lemli-Opitz syndrome (SLOS) and acyl-CoA oxidase 2 (ACOX2) deficiency.

2. Underpinning research

Inborn errors of metabolism (IEM) provoke a broad spectrum of clinical presentations, from mild to lethal forms, and are mostly incurable but very often treatable. Although detection and diagnosis are key, the biochemical profile is needed for effective patient management. Since 2007, Swansea University’s Griffiths-Wang group has investigated the biochemistry of cholesterol biosynthesis and metabolism and how it is implicated in disease. Cholesterol metabolites, including hormonal steroids and bile acids, have been analysed by mass spectrometry (MS) for several decades. One class of cholesterol metabolite called oxysterols is of particular clinical and pharmaceutical interest, as they can act as ligands to, or modulators of, nuclear receptors, G protein-coupled receptors (GPCRs) and N-methyl-D-aspartate receptors (NMDARs), and their abundances in body fluids can reflect underlying biochemical errors and ultimately disease. Oxysterols are difficult molecules to characterise as they are ‘invisible’ to most methodologies due to the absence of a strong chromophore or easily ionised functional group.

In 2008 the Griffiths-Wang group was the first to describe a method to investigate the oxysterol content of human plasma using high-performance liquid chromatography−mass spectrometry (HPLC−MS) that incorporated “enzyme-assisted derivatisation” and high-resolution MS. The methodology was shown to be straightforward, specific, highly sensitive and could be performed on an “omic” format (R1). The methodology opened a previously closed “window” into the combined metabolomic analysis of sterols, oxysterols, and steroid hormones. The technology was patented and formed the basis of the Swansea University spinout company Cholestenix Ltd (incorporated in November 2013), with a mission to deliver new innovative treatments and biomarkers for devastating neurodegenerative diseases. Using this method, Griffiths & Wang discovered novel ligands to nuclear receptors and to the Class F GPCR Smoothened (R6, R7).

In 2008, Griffiths, Wang and colleagues published a proof-of-concept study in a clinical setting that demonstrated the use of “enzyme-assisted derivatisation for sterol analysis” (EADSA) to detect inborn errors of metabolism. The method was used effectively in the 100% correct diagnosis of Smith-Lemli-Opitz syndrome using amniotic fluid. SLOS is a rare autosomal recessive disease where severe cases present with profound intellectual disability and major physical abnormalities (R2).

In 2013-14, the efficacy of the technology in diagnosing disease in a clinical setting was further proven when EADSA was used to analyse the plasma of a young patient who presented with jaundice. The data confirmed the patient to be suffering from oxysterol 7α-hydroxylase deficiency, a very rare autosomal recessive disease which presents with liver disease in infants, and which can lead to hereditary spastic paraplegia type 5 (SPG5), a type of motor neuron disease, in adults. The technology was crucially used to monitor the response to therapy and subsequently demonstrated the improved biochemical phenotype of the patient when successfully treated with chenodeoxycholic acid (CDCA) (R3).

The group developed the technology further with the introduction of isotope-coded derivatisation reagents, allowing the multiplexed analysis of samples with the detection of sterols, including steroids and bile acids with either a hydroxy or ketone function by HPLC-MS, a key aspect of the Swansea technology. The ultimate method allows the quantitative measurement of the widest range of cholesterol precursors and metabolites, in terms of exact molecular structures, in a single analysis ( R4, R5). The EADSA method was exploited to identify novel oxysterols in plasma from patients suffering from cerebrotendinous xanthomatosis (CTX, a rare autosomal recessive neurometabolic disease leading to progressive spastic-ataxic gait disorder and cognitive decline due to abnormal bile acid and cholesterol metabolism), SPG5 and SLOS (R4, R7), and then to identify unusual intermediate metabolites in patients diagnosed with a number of different lysosomal storage disorders, to define the biochemical phenotypes of those disorders (R5).

The derivatization technology described in these papers was patented by Swansea University and licensed to global chemical suppliers (Avanti Polar Lipids Inc. and Cayman Chemical Company).

Furthermore, SU-led research on motor neuron disorders (including SPG5, CTX and amyotrophic lateral sclerosis) using cerebrospinal fluid (CSF) and plasma from patients showed that specific cholesterol-derived acids selectively regulate the balance between survival and death of motor neurons, revealing therapeutic potential towards this devastating group of diseases (R6).

3. References to the research

All papers represented below are published in peer reviewed journals. All have been supported by BBSRC funding and represent collaborative work either with clinical or industrial partners. R1 is cited in 5x patents technologies, R6 is cited in 1x patent (linked patents: WO2014132052A2. EP3044192B1, WO2017037465A1. WO2018007803A1, US9851368B2). R1 and R2 were submitted to REF2014.

R1. Discovering Oxysterols in Plasma: A Window on the Metabolome. Griffiths WJ, …, Wang Y. J. Proteome Res. 2008 Aug; 7(8): 3602-3612; PMCID: PMC2567817; DOI: 10.1021/pr8001639.

R2. Potential of Sterol Analysis by Liquid Chromatography–Tandem Mass Spectrometry for the Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome. Griffiths WJ, Wang Y, …, Shackleton C. Clin Chem. 2008 Aug; 54 (8): 1317-1324; PMCID: PMC2533047; DOI: 10.1373/clinchem.2007.100644.

R3. Liver disease in infancy caused by oxysterol 7 α-hydroxylase deficiency: successful treatment with chenodeoxycholic acid. Dai D, …, Wang Y, Griffiths WJ, Clayton PT. J Inherit Metab Dis. 2014 Sep; 37(5): 851-61; PMID: 24658845. DOI: 10.1007/s10545-014-9695-6.

R4. Quantitative charge-tags for sterol and oxysterol analysis. Crick PJ, …, Wang Y, Griffiths WJ. Clin Chem. 2015 Feb; 61(2): 400-11; PMID: 25512642. DOI: 10.1373/clinchem.2014.231332.

R5. Identification of unusual oxysterols and bile acids with 7-oxo or 3β,5α,6β-trihydroxy functions in human plasma by charge-tagging mass spectrometry with multistage fragmentation. Griffiths WJ, …, Wang Y. J Lipid Res. 2018 Jun; 59(6): 1058-1070; PMCID: PMC5983402; DOI: 10.1194/jlr.D083246.

R6. Cholestenoic acids regulate motor neuron survival via liver X receptors. Theofilopoulos S, Griffiths WJ, …, Wang Y. J Clin Invest. 2014 Nov; 124(11): 4829-42; PMCID: PMC4347238; DOI: 10.1172/JCI68506.

R7. Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates. Abdel-Khalik J, …, **Griffiths WJ, Wang Y. J Steroid Biochem Mol Biol. 2021 Feb; 206:105794. PMCID: PMC7816163; DOI: 10.1016/j.jsbmb.2020.105794. Epub 2020 Nov 24.

Grants supporting the underpinning research at Swansea University:

G1. GlaxoSmithKline, GBP50,000, Dec 2007–Nov 2010.

G2. BBSRC (BB/C515771/2), GBP42,226, May 2008–Sept 2009 PI Griffiths.

G3. BBSRC (BB/K019112/1), GBP652,377, July 2013–Aug 2016 PI Ghazal, CoI Griffiths.

G4. BBSRC (BB/I001735/1), GBP326,463, Sept 2011–Aug 2014 PI Griffiths, CoI Wang.

G5. BBSRC (BB/L001942/1), GBP382,198, Jan 2014–April 2017 PI Wang, CoI Griffiths.

G6. BBSRC (BB/N015932/1), GBP460,386, Oct 2016–Oct 2019 PI Griffiths CoI Wang.

4. Details of the impact

The difference between incidence and detection of inborn errors of metabolism is dependent on the ability of the clinician to first suspect a rare disease and secondly confirm both the phenotype and genotype. For the patients and families of those suffering with rare conditions, a diagnosis means an opportunity for early treatment e.g., by CDCA in the case of CTX and oxysterol 7α-hydroxylase deficiency, and an end to the uncertainty and lack of information around treatment measures and outcomes, opening avenues for connection with support groups. Many inborn errors of metabolism do not yet have a specific therapy, so for the clinician a confirmed phenotype allows potential treatments to be tried and tested.

The EADSA technology has been used to identify key sterol metabolites and bile acid precursors in patient samples. The unique technology and expertise of Griffiths and Wang, which they offered without charge, has helped to confirm biochemical phenotypes of, and improve the selection of treatments for and the management of 70 patients with a range of rare inborn errors of cholesterol metabolism across Europe, Asia and the U.S ( Table 1).

Table 1 The number of individual patients per disease benefitting from biochemical diagnosis from the Griffiths-Wang group, 2014-2020. The prevalence, where known, is included for context of the rarity of each condition (data from OMIM).

Disease Prevalence/100,000 (confirmed cases) Patients
Spastic Paraplegia Type 5 (SPG5) Unknown 13
SPG5 (under therapy with CDCA) - 1
Acyl-CoA Oxidase 2 (ACOX2) Deficiency Unknown 3
ACOX2 Deficiency (under therapy with CDCA) - 13
Lysosomal Acid Lipase Deficiency (LALD) - Wolman <1 /100,000 2
Niemann Pick Type B (NPB) 0.4 /100,000 3
Niemann Pick Type C (NPC) 1 /100,000 11
Smith-Lemli-Opitz Syndrome (SLOS) 3.7 /100,000 10
Cerebrotendinous xanthomatosis (CTX) 1 – 0.2 /100,000 14
Lathosterolosis Unknown 1
NSDHL Deficiency (CHILD) Unknown 1
Cholesterol 25-hydroxylase (CH25H) Deficiency Unknown 3
CH25H Deficiency (following transplantation) - 3
Total no. patients worldwide benefitting from the research. 70

These patients can now be more confidently diagnosed and better treated, and their disease is better managed through the application of this novel patented technology. Specific examples of the impact the research has had within disease states are presented below:

SPG5

SPG5 is a rare condition with unknown prevalence that is caused by mutations in the CYP7B1 gene, which controls the production of the enzyme oxysterol 7α-hydroxylase, a key enzyme in steroid metabolism in the brain. A deficiency in this enzyme leads to a wide range of signs and symptoms, most notably neurodegeneration and movement problems. In infants, the deficiency may present with liver disease, in which case it is referred to as oxysterol 7α-hydroxylase deficiency.

In 2016 Professors Griffiths and Wang “greatly assisted in characterizing the biochemical phenotype (sterol profile) of a Cypriot patient with spastic paraplegia, in particular a patient with novel, bi-allelic CYP7B1 mutations causing SPGA5A”. This was the first Cypriot patient identified with this condition [C1].

In Athens, the Griffiths-Wang laboratory was instrumental between 2016 and 2017 in the successful treatment of a 22-year-old patient with SPG5. The laboratory measured sterols in monthly blood and urine samples over a period of 18 months to track the patient’s response to treatment with chenodeoxycholic acid (CDCA). The clinicians confirmed that “the procedure performed helped considerably in the treatment of the patient and the biochemical profile in response to CDCA treatment” [C2].

Between 2013 and 2014 in collaboration with clinicians at Great Ormond Street Hospital and UCL Institute of Child Heath, who were treating a young patient presenting with liver disease, and suffering from oxysterol 7α-hydroxylase deficiency, the Swansea group monitored the biochemical response to treatment with CDCA. The therapy was successful. [C3].

ACOX2 Deficiency

ACOX2 deficiency is an exceptionally rare disease with less than five cases reported world-wide, it arises from mutations in the ACOX2 gene coding a peroxisomal enzyme involved in the sidechain shortening of bile acid precursors, a necessary step in the biosynthesis of primary bile acids. ACOX2 deficiency is an autosomal recessive disorder presenting to differing extents with cholestatic liver disease and neurologic dysfunction in infants and children.

In 2018, Griffiths and Wang used their EADSA technology to define the biochemical phenotype of Turkish patients suspected to have ACOX2 deficiency and “ for the first time, a previously unknown syndrome caused by recessive Acyl CoA Oxidase 2 deficiency has been identified with the great help of Professor William J. Griffiths from Swansea University Medical School in UK. Prof. Griffiths and his laboratory have greatly contributed to both the diagnosis and follow-up of the new disease by performing urine, serum and plasma bile acid analysis” [C4].

Lysosomal Acid Lipase Deficiency (LALD, Wolmans) Cholesterol 25-Hydroxylase Deficiency and Other Sterol-Related Disorders.

Caused by mutations in the LIPA gene, LALDs are rare inherited disorders about which little is known of the signs, symptoms, and progression. Wolmans disease is a LALD characterised by a complete absence of the LIPA protein. LALDs result in problems with lipid metabolism and the accumulation of harmful amounts of lipids in cells and tissues throughout the body, which subsequently causes liver disease.

In 2017 in collaboration with the Genomic Medicines team at St Mary’s Hospital in Manchester, the first ever patients with a double deletion of LIPA and of the adjacent gene CH25H, coding the enzyme cholesterol 25-hydroxylase, were identified using EADSA. Professors Griffiths and Wang were the first to biochemically confirm the enzyme deficiency in these children, and they have continued to “ look in detail at their sterolomic and oxysterol profiles of the LALD (and double deletion) patients before and after treatment with both Enzyme Replacement Therapy and Hemopoietic Stem Cell transplantation. This is proving a critical part in assessing the benefits of treatment” [C5]. Work with the team in Manchester has extended beyond LALDs and currently includes other rare lysosomal disorders Niemann-Pick type B and C diseases. Niemann-Pick disease can affect the brain, nerves, liver, spleen, bone marrow and lungs. There is no cure, but treatments are being developed. People with these conditions experience progressive loss of function of nerves, the brain and other organs. Other inborn errors of cholesterol metabolism being studied include, cerebrotendinous xanthomatosis (CTX), NSDHL deficiency and lathosterolosis. Less than five cases of lathosterolosis have been reported world-wide, the disorder is characterised by facial dysmorphism, congenital anomalies, failure to thrive, developmental delay and liver disease, there are treatments but no cure.

SLOS

SLOS is a severe autosomal recessive disorder resulting from defects in a cholesterol-synthesising enzyme that lead to a build-up of the cholesterol precursor 7-dehydrocholesterol in tissues and blood plasma. SLOS affects an estimated 1 in 20,000 to 60,000 newborns. Mildly affected individuals may have only minor physical abnormalities with learning and behavioural problems, but severe cases can be life-threatening and involve profound intellectual disability and major physical abnormalities, and there is no cure. Despite this, it is important for parents to have a diagnosis for their child and for clinicians to initiate treatments. Professors Griffiths and Wang have discovered a novel bile acid biosynthesis pathway in SLOS which may be responsible for the dysmorphology observed in this disease [R7]. Regarding these discoveries, collaborators at the Great Ormond Street Institute of Child Health stated “ Laboratories such as mine that can pick up unusual metabolites in children with significant disease really value the ability of Bill’s lab to identify the abnormal compound(s) we have detected[C6].

Our EADSA methodology has also been used to diagnose SLOS at Hong Kong Queen Mary Hospital, where the medical technologist stated, “ I can successfully detect 7‐DHC in MS and I am so excited now!”, confirming that elevated 7-DHC provides a diagnosis of SLOS [C7].

The definitive diagnosis and monitoring of response to therapy provide peace of mind and hope to parents of those with IEM and allow clinicians to search for ever better therapies.

5. Sources to corroborate the impact

C1 Testimonial from Senior Consultant in Clinical Genetics at The Cyprus Institute of Neurology and Genetics Cypriot, Aug 2020.

C2 Testimonial from The Rare Diseases Clinic, Athens Medical Centre, supporting work carried out between Mar 2016 and Aug 2017.

C3 Communications with Professorial Research Associate, UCL Great Ormond Street Institute of Child Health.

C4 Testimonial from Division of Paediatric Gastroenterology, Faculty of Medicine, Gazi University, Ankara, Turkey, Dec 2020.

C5 Testimonial from Medical Director, Consultant in Paediatric Inherited Metabolic Disease, NIHR Manchester Children’s Clinical Research Facility, Oct 2020.

C6 Testimonial from Professorial Research Associate, UCL Great Ormond Street Institute of Child Health, Sept 2020.

C7 Communication with medical technologist, Queen Mary Hospital, Hong Kong.

Submitting institution
Swansea University / Prifysgol Abertawe
Unit of assessment
3 - Allied Health Professions, Dentistry, Nursing and Pharmacy
Summary impact type
Technological
Is this case study continued from a case study submitted in 2014?
No

1. Summary of the impact

Against a background of growing antibiotic resistance, environmental sustainability considerations and tighter registration regulations to combat safety concerns, novel antifungal discovery and development has necessarily had to adapt and adopt screening strategies to identify appropriate candidates. Exploiting the differences between fungal and host Cytochrome P450 (CYPs) enzymes, researchers at Swansea university have developed a suite of CYPs, used to understand selectivity for the fungal CYP51 enzyme over the human homolog to assist in the design of the next generation of azole antifungals for agriculture as well as the clinic. This research has been integral to the discovery and development of BASF’s blockbuster broad spectrum fungicide Mefentrifluconazole (Revysol®), currently being used to successfully increase global crop yields for forty crops in over sixty countries worldwide., The technology has also supported the extension of the exclusive use period for Prothioconazole and had clinical impacts in supporting the development of a new antifungal, Oteseconazole, for recurrent vulvovaginal candidiasis (RVVC), a debilitating condition that affects an estimated 138 million women annually.

2. Underpinning research

Azole antifungals, also known as DMI (14-alpha demethylase inhibitors), are widely used in both agriculture (to control plant diseases and preserve yield and quality of crops) and in the clinic (as therapy for the treatment of invasive fungal infections and for anti-estrogen therapy for breast cancer). Azoles work by inhibiting the Cytochrome P450 (CYP) dependent enzyme lanosterol 14-α-demethylase (CYP51), which converts lanosterol to ergosterol, the main sterol in the fungal cell membrane. Depletion of ergosterol damages the cell membrane resulting in cell death1. However, azole inhibition of P450 cytochromes is not always specific to fungal CYP51 and inhibition of human CYPs that contribute to drug metabolism can cause drug-drug interactions, and interactions with human CYPs involved in primary metabolic pathways (e.g., cholesterol biosynthesis) need to be considered. The Swansea P450 research group are focussed on determining the differences that exist between fungal and host cells which may be exploited to combat fungal infection without harming the host.

Previous experimental studies on the specificities of azoles with respect to human and fungal enzymes had relied upon the expression of recombinant proteins, assaying their activities in reconstituted systems and determining the 50% inhibitory concentrations (IC50) of drugs. Functional CYP51 was extremely difficult and time consuming to express, purify, and reconstitute with a highly lipophilic substrate and reductase partner. In 2008 the group produced a strain of Saccharomyces cerevisiae containing human CYP51 (huCYP51) targeted to replace the native S. cerevisiae CYP51 (ScCYP51) at the chromosomal locus and under the control of the yeast CYP51 promoter and used it to test the specificity of azoles (R1). Importantly, the method they described allowed for rapid, high-throughput and reproducible direct side-by-side comparisons of the specificities for new drugs. Their unique suite of azole binding tools was expanded in 2011 to include successful expression of Mycosphaerella graminicola CYP51 (MgCYP51) in E.coli (R2), enabling spectrophotometric analysis using the purified 62-kDa MgCYP51 protein and the first description of an observed selectivity for the market leading Prothioconazole to MgCYP51 from classical azole fungicides. In 2013, this observation was demonstrated to be the result of a chemical breakdown of the product to fungicidal Prothioconazole-desthio (R3). In 2015, the group went further and characterised the M.graminocola cytochrome P450 reductase (MgCPR)/MgCYP51 redox supporting the conclusion that prothioconazole is a profungicide (R4). These represented important developments in fungicide design, producing a functional method to evaluate the effects of agricultural azole fungicides and established the group as international experts within the field, attracting industrial interest as evidenced by 24 linked patents (R2) held by Agrosciences industry leaders including BASF SE and BAYER CROPSCIENCE.

Previous comparisons of activity had not included agricultural azoles and pure CYP51 forms but had relied instead on microsomal fractions. In 2013, the group expressed Candida albicans CYP51 (CaCYP51) and the full-length form and a solubilized form of Homo sapiens CYP51 (HsCYP51) in Escherichia coli, purifying all three to homogeneity. They performed detailed azole binding studies using UV-visible spectroscopy under oxidative conditions and using therapeutic azole antifungal drugs and agricultural azole. In addition, 50% inhibitory concentration (IC50) determinations for each azole were made using a CYP51 reconstitution assay system. The potential inhibitory action against CaCYP51 and the undesired side effect of inhibiting HsCYP51 were assessed, and the relative selectivity of each compound for the fungal enzyme was determined. The group subsequently described the worrying lack of selectivity of some agricultural fungicides that could impact human steroid production (R5).

In 2011, the US company Viamet Pharmaceuticals commissioned the Swansea P450 group to establish the modes of action for their lead antifungal compounds. The group used their purified recombinant CaCYP51 and HsCYP51 to measure the binding and inhibition properties of the candidate molecule VT-1161, and compare them against established treatments (clotrimazole, fluconazole, itraconazole, and voriconazole). These studies demonstrated potent inhibition of Candida albicans CYP51 and culture growth without inhibition of human CYP51, indicating a >2,000-fold selectivity, and supporting the potential utility of their candidate molecules in the treatment of Candida infections (R6).

1https://www.drugs.com/drug\-class/azole\-antifungals.html

3. References to the research

All outputs represented below are published in peer reviewed journals. All have been supported by either EU Framework 6 or BBSRC/DEFRA funding. R2 is referenced in 24 patents in Europe, US and World IP organizations. R1and R5 were submitted to REF2014, R6 has been submitted to REF2021.

R1. Parker JE, Merkamm M, Manning NJ, Pompon D, Kelly SL, Kelly DE. (2008) Differential azole antifungal efficacies contrasted using a Saccharomyces cerevisiae strain humanized for sterol 14 alpha-demethylase at the homologous locus. Antimicrob Agents Chemother. 52, 3597-3603. DOI:10.1128/AAC.00517-08.

R2. Parker JE, Warrilow AG, Cools HJ, Martel CM, Nes WD, Fraaije BA, Lucas JA, Kelly DE, Kelly SL. (2011) Mechanism of binding of prothioconazole to Mycosphaerella graminicola CYP51 differs from that of other azole antifungals. Appl Environ Microbiol. 77(4):1460-5. DOI: 10.1128/AEM.01332-10.

R3. Parker JE, Warrilow AG, Cools HJ, Fraaije BA, Lucas JA, Rigdova K, Griffiths WJ, Kelly DE, Kelly SL. (2013) Prothioconazole and prothioconazole-desthio activities against Candida albicans sterol 14-α-demethylase. Appl Environ Microbiol. 79(5):1639-45. DOI: 10.1128/AEM.03246-12.

R4. Price CL, Warrilow AGS, Parker JE, Mullins JGL, Nes WD, Kelly DE, Kelly SL. (2015) Novel substrate specificity and temperature sensitive activity of Mycosphaerella graminicola CYP51 (MgCYP51) supported by the native NADPH cytochrome P450 reductase (CPR). Appl Environ Microb. 81:3379-3386 DOI: 10.1128/AEM.03965-14.

R5. Warrilow AG, Parker JE, Kelly DE, Kelly SL. (2013) Azole affinity of sterol 14 alpha-demethylase (CYP51) enzymes from Candida albicans and Homo sapiens. Antimicrob Agents Chemother. 57(3), 1352-1360. DOI: 10.1128/AAC.02067-12.

R6. Warrilow AG, Hull CM, Parker JE, Garvey EP, Hoekstra WJ, Moore WR, Schotzinger RJ, Kelly DE, Kelly SL. (2014) The clinical candidate VT-1161 is a highly potent inhibitor of Candida albicans CYP51 but fails to bind the human enzyme. Antimicrob Agents Chemother. 58(12):7121-7. DOI: 10.1128/AAC.03707-14.

Supporting Grants:

G1. STEROLTALK: Functional genomics of complex regulatory networks from yeast to human: crosstalk of sterol homeostasis and drug metabolism; EU Framework 6; 2005-2008; S&D Kelly PIs: EUR2,000,000.

G2. EURESFUN (EUropeanReistanceFUNgal): EU Framework 6; 2005-2008; S Kelly PI; EUR2.755,000.

G3. Antifungal resistance via CYP51 mutation. BBSRC Govt partner award with DEFRA; S&D Kelly; 2008-2011; GBP650,000.

4. Details of the impact

The breakthrough technology developed by researchers at Swansea University’s P450 group (R1-R6) has enabled selectivity testing for azole development by both AgroSciences and Pharmaceutical industries, leading to the discovery and development of new antifungals for both the field and the clinic.

Impact on agrichemical product development

Mefentrifluconazole (Revysol®)

The P450 Group’s major advance in CYP expression and purification technology allowed BASF to establish a high-throughput in-vitro screening system enabling them to test synthesised compounds on target fungal enzymes. BASF used the system to steer new product profiles from more than 4000 triazole molecules (C1). This system aimed to identify candidates with both high fungicidal activity and minimal likelihood of adverse side effects thought to arise from aromatase inhibition. This high-throughput program identified Revysol® as a result, the UK now has the first new azole to be registered as a fungicide for 15 years, with wide-reaching impacts (see Table 1). The impact the research had on product selection and development was acknowledged by the BASF principal scientist (C2): “Your expertise, technology and purified proteins turned out to be breakthrough technology. They have a high impact on this program and are a major contribution to success.”. The success of the selection strategy has been illustrated for Revysol by the absence of off-target toxicity that would indicate an endocrine disrupting potential (C3).

The global fungicides market was valued at USD13,601,000,000 in 20191, highlighting the importance of crop-protection but there is increasing pressure on the AgroSciences industry to maintain a pipeline of novel candidates. Emerging global challenges such as antibiotic resistance, sustainability and tighter regulations have led industry leaders to incorporate selectivity assays early in the development process. Revysol ® represents the first and only isopropanol azole of its kind in the market, providing fast-acting and long-lasting disease control for a broad range of crops and disease combinations.

Table 1 The impacts of Revysol®, an exemplar of the advantages of using selectivity assays early in the development process.

Impact type Benefit
Regulatory Revysol® was selected and designed to meet the highest level of regulatory standards, see Fig. 1 for global reach of registration as of October 2020 (C4).
Health Revysol® reduces the risk of human endocrine disruption, as attested by EU registration (C5).

Embedded image

Figure 1 Global registration status for Revysol® as of October 2020 (C4)

Impact on other fungicides and antifungal compounds.

Prothioconazole (Proline®)

In 2014 Bayer submitted a petition to the United States Environmental Protection Agency (EPA) for a three-year extension of the exclusive use period for their product Prothioconazole (C6). Prothioconazole (Proline®) is a triazolinthione fungicide for the control of disease in winter and spring wheat, Durum wheat, winter rye, winter and spring barley, winter and spring oats and for disease control in winter oilseed rape. In their petition the research output, R4, was central to their claim that *“substrate binding studies have indicated that Prothioconazole has a different binding site on the CYP51 enzyme compared with other DMI which may explain why it has retained performance where others are weak or ineffective due to a shift in resistance. As a result, Prothioconazole helps reduce further resistant strain selection to the weakening DMI class by offering a more efficacious rotational treatment within the full spray program.*” The petition was granted by the EPA on April 15, 2015 (C7).

Oteseconazole (VT-1161)

Currently in Phase 3 clinical studies (see Fig. 2), the clinical candidate VT-1161 is an orally available inhibitor of fungal CYP51 that has shown high potency and selectivity. The molecule VT-1161 was shown to be highly selective for fungal CYP51 (R6) and is therefore likely to avoid the side effects that limit the use of current antifungals, including fluconazole and terbinafine, which are often prescribed for acute episodes of vulvovaginal candidiasis and onychomycosis, respectively. (C8).

Embedded image

Figure 2 Clinical Trial Status of VT-1161 as of December 2020 (Mycovia Pharmaceuticals: RVVC: NCT02267382; NCT03562156; NCT03561701. Onychomycosis NCT02267356),

5. Sources to corroborate the impact

C1. CCPB proteins used in screening for Revysol® https://www.youtube.com/watch?v=ZA2_P6VVJSU

C2. Testimonial from Principal Scientist, BASF SE, Dec 2020.

C3. Tesh et al. Innovative selection approach for a new antifungal agent mefentrifluconazole (Revysol®) and the impact upon its toxicity profile. Regul Toxicol Pharmacol. 2019 Aug;106:152-168. doi: 10.1016/j.yrtph.2019.04.009.

C4. Data taken from BASF website (https://agriculture.basf.com/global/en/innovations\-for\-agriculture/innovation\-at\-a\-glance.html\).

C5. EU grants approval for BASF's mefentr.ifluconazole, 04/03/19.

C6. Prothioconazole petition 3year extension, submitted by Bayer CropScience Jan 2014. Page 10.

C7. Review of Justification for Extension of Exclusive Use Period for Prothioconazole, EPA, May 2015.

C8. Mycovia Pharmaceuticals Pipeline for VT-1161, https://www.mycovia.com/pipeline

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