Impact case study database

Figure 1. Summary of the impact. Image under (i) is a family from Seattle Children’s Hospital craniofacial routine clinic, (ii) shows the CLAPA Leaver’s Pack, (iii) is from ReSurge International ( https://www.flickr.com/photos/interplast/119428083).

(i) Adoption of the framework by all 16 cleft teams in the UK to improve patient care and service delivery The core set of measures for psychological adjustment developed by Stock in conjunction with key stakeholders ( R1, R3, R4, G1, G2, S1, S2) have been implemented by all 16 UK Cleft Teams to assess all 5-year-olds. The Cleft Teams use these data, alongside the National Minimum Audit protocol, to provide key psychological evidence for intervention ( S1). Furthermore, Stock’s research has led to the formal assessment of the psychological wellbeing of parents across all NHS teams for the first time ( R4, S1).

Clinics at Alderhey and the Royal Manchester Children’s Hospital, for example, have adopted the framework and measures, replacing an existing screening protocol that lacked in relevant areas of psychosocial concerns. Stock and Rumsey’s framework:

‘is now used at the 5-year clinic alongside the nationally agreed minimum audit protocol…to more fully screen their psychosocial needs and to *identify those at risk.*’ ( S2).

The Chair of the Cleft Psychology Clinical Excellence Network (2013-2019) and Consultant Clinical Psychologist highlighted that Stock’s research also provided the foundation for service change for adult patients. The Chair reported, ‘ when an adult returns to the cleft service, rather than being referred straight to a surgeon or a dentist, many cleft teams will [now] schedule a psychology consultation’ ( S3).

(ii) New UK charity services for adults with cleft The UK charity for CL/P (CLAPA) originally focused on services aimed at children, families and young people, with minimal support provided for adults. Stock’s research ( R3, R4, R6) highlighted the psychological distress and on-going support needs of adults with CL/P. Additionally, her research provided a strong evidence base that led CLAPA to secure funding to provide services directed to previously unmet need. As a result, CLAPA established a full-time Adult Services Manager post in 2017 to develop a programme of adult services and put in place one-to-one peer support (accessed by 73 people, as of March 2019) and expand online services ( S4, S5). The Adult Services Manager reported that they had developed multi-modal resources including videos and podcasts (959 views and 1456 plays, respectively, as of October 2020) ( S5). Furthermore, young adults transitioning from routine care are now supported with a UK-wide ‘Leaver’s Pack’ (distributed since January 2020) to address their common queries and concerns and provide information on how to access services going forward. Adults using the services reported that they felt more confident visiting the GP or dentist and understood more about cleft treatment options ( S5). A service user with CL/P stated that the new support CLAPA provides, ‘ helped us to build a community and get adults the help they need’ ( S6).

(iii) Global adaptation of the framework for patient benefit Rumsey and Stock adapted their intervention framework for use worldwide by applying a three-tiered approach. Tier 1 facilitates teams in countries with minimal resources to explore patient-centred outcomes, while Tier 3 allows teams from the best resourced countries to comprehensively assess patient-centred outcomes, audit practice and share data worldwide. Furthermore, in 2017 Rumsey and Stock trained 468 health professionals from 15 disciplines in 26 countries in how to identify and address psychological issues in their patients using the tiered measures and intervention framework ( S7).

The former Chief Co-ordinator of the Cleft and Craniofacial Centre, Sri Ramachandra University, India, which treats over 1000 young people each year, said that ‘ the tiered measures … are helping to promote patient-centred care in developing countries especially’ ( S7). She further stated that the training provided by Rumsey and Stock in 2017 ‘ has made a positive difference to the way [attendees] work, focusing more on [the] patients’ perspective in making treatment decisions’ ( S7).

Stock’s framework and measures have also influenced both prenatal services and adult-led services in The Netherlands ( S8). The Amsterdam University Cleft Team now includes counselling in prenatal consultations to help communicate the diagnosis appropriately and provide support to parents ( S8). A Professor of the Amsterdam University Cleft Team, who is the current President of the European Cleft Palate Craniofacial Association, reported that Stock’s research ‘ has improved the way parents received information about the cleft once it was diagnosed during the 20-week ultrasound’ ( G2, S8).

Stock’s framework has also been applied in the care of patients with other craniofacial conditions. The Associate Professor of Paediatrics at the Seattle Children’s Hospital and University of Washington School of Medicine drew on Stock’s work from 2014, which provided an evidence base for practice ( S9). Expected psychological outcomes are now discussed for the first time with new families with young infants diagnosed with Craniofacial Microsomia ( G5- G6, S9).

Figure 1. Impact of the interventions

Adoption of the ESCAPE-pain intervention into evidence-based guidelinesWalsh’s research ( R1- R3) provided compelling evidence for ESCAPE-pain (knee) clinical efficacy, cost-effectiveness, acceptability to patients and the beneficial impact on the wider healthcare system in the long-term. This led to the inclusion of ESCAPE-pain (knee) in the NICE guidelines (CG177) for lower limb OA in 2014 ( S1, p143-145). The NHS has recognised the patient benefits of ESCAPE-pain (knee&hip), naming it in their Long-Term Plan to redesign patient services ( S2). The NHS will expand availability of the online version of ESCAPE-pain (knee&hip) to improve access to planned care ( S2, p73).

Patient benefit and cost savings to the NHS ESCAPE-pain (knee) ( R3) was one of only seven interventions for musculoskeletal conditions identified by Public Health England (PHE) in 2017 as producing significant savings for the NHS. PHE reported that each GBP1 spent on ESCAPE-pain (knee) led to a GBP5.20 return on investment, and estimated the net savings per patient at GBP1,309.78 ( S3, p24). The Academic Health Science Networks (AHSNs), led by South London in partnership with Versus Arthritis, drove the implementation of ESCAPE-pain (knee&hip) across the UK ( S4), delivering it in approximately 300 locations between 2017-2019, with approximately 20,000 participants receiving the intervention ( S5). Based on PHE’s estimated net saving per person, the intervention has saved the NHS approximately GBP26,200,000.

ESCAPE-pain (knee&hip) ( R4, R5) interventions were included in the NIHR ‘ Moving Forward’ review on ‘ *Important current and impactful musculoskeletal (MSK) research.*’ The review was published in 2018 for NHS Clinical Commissioning Groups, local authorities and Sustainability and Transformation Partnerships to support implementation of best practice in MSK services ( S6, p2). ESCAPE-pain (knee&hip) has become an integral part of the NHS care pathway for people with MSK conditions ( S6, p12). The ‘Moving Forward’ review states ‘ It saves money for the NHS as it reduces GP consultations, medical referrals and investigations like X-rays and MRI scans. In addition, participants take fewer pain killers’ ( S6, p26). In recognition of the innovation, ESCAPE-pain (knee&hip) was awarded the MSK Care Initiative of the Year in the Health Service Value Awards 2020 ( S5).

In the West of England AHSN, ESCAPE-pain (knee&hip) was made available in two formats. The first was free of charge to patients, delivered in healthcare or council settings by physiotherapists. The second format was delivered at a small charge to patients by exercise professionals in leisure centres ( S7). The training of non-healthcare professionals in leisure centres and community facilities formed part of early developmental work by Walsh in her Arthritis UK Career Development Fellowship ( S8). As of November 2019, the Health Innovation Network (AHSN South London) has trained almost 400 fitness instructors to become ESCAPE-pain (knee&hip) programme facilitators, who are in turn delivering the intervention in multiple non-NHS sites across the UK, benefiting over 4,000 people ( S9). Evaluation of leisure centre-based provision in the West of England demonstrated improvements in patients’ self-management skills and reduced GP visits post-intervention, reducing pressure on healthcare staff and services ( S10, p48).

International adaptation and adoption of the interventionsThe Health Authority of Hong Kong translated and culturally adapted the ESCAPE-pain (knee&hip) and FASA interventions ( S11) for delivery to the Hong Kong Chinese population. Known locally as the Integrated Self-Management and Exercise Programme (ISEP), the intervention was implemented into the knee OA care pathway in three large hospitals within the Health Authority in 2018. To facilitate implementation, Walsh was invited by the Health Authority to deliver three days’ training to 50 physiotherapists ( S11). As of October 2020, 1,162 patients with knee OA have received the intervention, and have demonstrated clinically significant improvements in pain, function, quality of life and ability to self-manage. The ISEP intervention was recommended by the physiotherapy unit to the Hong Kong Health Authority for wider implementation across the Territory and was piloted in two further centres in 2019 ( S11).

International online resource during COVID-19As a response to the COVID-19 situation, provision of the online version of ESCAPE-pain (knee&hip) has become a priority. The Joint Effort Initiative Implementation Group endorsed by Osteoarthritis Research Society International (OARSI), developed an online repository for healthcare professionals worldwide seeking to access and signpost patients with OA to remote, high-quality programmes that do not require face-to-face contact ( S12). ESCAPE-pain features prominently in this repository providing programmes for knee, hip and chronic low back pain ( S12, p4).

Figure 1. Summary of impact on A) monitoring of toxic antibiotics streptomycin and colistin and B) safe drug development. Processes are shown before and after McCalley’s research.

**Improving patient safety through laboratory tests to monitor toxic antibiotics (2013-2020; figure 1A)**Multi-drug resistant (MDR) bacterial infection is a growing issue in Europe and the UK as the region is seeing the highest rate of incidence of MDR-tuberculosis ( S1, S2). Outbreaks can lead to thousands of MDR infections across the UK annually ( S1). There are few, highly toxic, drug options for the treatment of MDR infections. Drug testing, developed by McCalley ( R6) and conducted at the Antimicrobial Reference Laboratory (ARL) allows clinicians to monitor levels of toxic drugs in samples of patient blood, optimising efficacy against the pathogens and minimising the toxicity risk ( S1).

McCalley and his team worked with ARL to develop tests for the drugs streptomycin and colistin ( S3). Streptomycin treats tuberculosis but has a narrow therapeutic window – too little is ineffective while too much causes permanent hearing and balance loss (figure 1A); and it can only be used safely if monitored ( S1). Before McCalley’s work with ARL, streptomycin could only be tested at a US laboratory, making turnaround times impractical for UK and EU patients and preventing safe use of this important drug ( S3). Drawing on his research into the mechanisms underlying HPLC separation ( R1), McCalley developed the sole commercial test for streptomycin in Europe now used by ARL. The lead Consultant in Infection and Professor of Antimicrobial Therapeutics at North Bristol NHS Trust, said ‘ without this new assay [test], we would struggle to use streptomycin safely’ ( S1). As the only European-based lab with these capabilities, ARL ‘ has seen a significant year-on-year growth in use of the service’ ( S3).

Previously, tests for colistin, which is used to treat sepsis, could not differentiate between the active and non-active form of the drug (figure 1A), leading to over-estimations of the active form and under-dosing of patients ( S1). Under-dosing with colistin in the first days of hospitalisation leads to poor efficacy, while over-dosing can permanently damage renal function ( S3). The new liquid chromatography mass spectrometry (LC-MS) test developed by UWE ‘ far out-performed the bioassay [test] used previously due to improved specificity for the active form’ said the then Head of the ARL ( S3). It is comparable to tests used internationally, allowing ‘ clinical staff to optimise patient prescribing in the context of published evidence” said the Consultant in Infection and Professor of Antimicrobial Therapeutics ( S1). The Consultant added:

‘ with this improved LC-MS test, we can now use colistin more effectively and more safely in last resort situations’ and ‘ in my opinion monitoring of colistin by LC-MS is essential to its use, and is leading to better outcomes for sepsis patients suffering multi-drug resistant infection’ ( S1).

This is particularly significant given that rates of colistin use are rising in acute care (66% increase since 2016-2017) ( S4).

The laboratory tests McCalley developed provide the basis for a monitoring service helping clinicians and improving patient care throughout Europe by administering safely toxic (streptomycin and colistin) and last-resort (colistin) antibiotics targeted at MDR infections. ARL is the largest provider of antimicrobial Therapeutic Drug Monitoring in the UK and over 240 laboratories using this service across the UK and Europe. ARL tests 10-15 colistin and 5-10 streptomycin samples per week at GBP120 per sample ( S3), resulting in revenue of approximately GBP125,000 per year.

**Safe drug development at GlaxoSmithKline (GSK): reducing cost and improving speed (2013-2020; figure 1B)**Approval and launch of a new medicine from drug discovery takes on average 9.5-15 years ( S5). Drug discovery starts with screening of between 5,000-10,000 compounds out of which typically only 5 make it to Phase 1 clinical trials. GSK Pharmaceutical core annual R&D investment was GBP2,500,000,000 in 2014, 29% of this spent on early-stage research (drug discovery). The strategic aim of GSK was to improve the proportion of high-quality early drug candidates that progress to clinical development, and to reduce the time and cost involved ( S5).

Collaboration with McCalley enabled GSK to apply HILIC as one of the HPLC procedures used to solve pharmaceutical separation problems in early stage research in identifying impurities in the active pharmaceutical ingredient as well as the preparative separation of pure product from cruder mixtures (figure 1B). McCalley’s work showed that HILIC could be used as an analytical process, and also scaled up to allow larger quantities of material to be purified ( S6, R2- 6). With a shorter, more effective screening process, and simpler scale-up for purification than previously, GSK have reduced their turnaround times and the number of screening rounds required to find optimum analysis conditions. The Head of UK Purification at GSK said their use of McCalley’s methods have led to:

‘approximately a 50% reduction in the running costs of finding suitable separations for scale-up’ and that they ‘speed up the processes required to discover new active chemical entities’ ( S6, R3, R4).

McCalley also demonstrated that HPLC CAD could replace GSK’s previous method for assessing the solubility of new molecules ( R2). GSK adopted the CAD system as the universal detector for drug solubility measurements, which now produces data for hundreds of compounds per week. The Head of UK Purification describes the performance as ‘ an order of magnitude increase on our previous capacity’. In contrast to its predecessor, the CAD system is ‘ robust and easy to operate, allowing quantification of structurally diverse compounds, most importantly in a high throughput fashion’ ( S6, R2). The data from the CAD system allows GSK chemists to rank candidate drugs and identify issues at early stages of development, described as ‘ reducing attrition rates and speeding up the process toward candidate [drug] selection with obvious attendant cost savings’ ( S6).

Figure 1: Summary of the research and its impact. UWE’s Malodour Research environment (see Section 2) includes: 1. Clinical Trial capability; 2. VOC detection using gold standard SIFT-MS; 3. flat-bed in vitro biofilm model and 4. qualified organoleptic breath assessment. (i-v) Impacts resulted from the research (details are provided below).

(i) Development and launch of a novel oral care technology In collaboration with Philips Research Laboratories, Saad developed superior halitosis products ( R5, G8). A Senior Scientist at Phillips stated that Saad’s research showed ‘a direct relationship between bacterial numbers and strength of odour’, critical in determining ‘to what extent tongue bacteria count had to be reduced in order to achieve sustained clean breath’ ( S1). Philips invested in feasibility studies, prototype development and clinical studies with UWE, allowing Philips ‘ to further iterate the technology’ and to devise various technologies including ‘customised bristles under sonic motion to remove bacteria from deep within the tongue structure’ ( S1). The assistance from UWE meant that ‘ TongueCare+ was developed and launched in record 3 years from initial idea to market launch’ ( S1). ‘ TongueCare+ was initially launched in 2016 in Europe and USA before global rollout [and at the time] … first year sales were projected to exceed 25M Euros’. ‘ TongueCare+ is currently retailed by major global retailers such as Amazon, Walmart and Boots’ ( S1). Further impacts were ‘ the creation of a new sub-category of breath odour for Philips Oral Health Care’ and enabling ‘new marketing strategies and technology functions’ ( S1).

**(ii) Development of a reformulated oral care product with new evidence-based claims Colgate-Palmolive reformulated their best-selling toothpaste, Colgate Total®, which ‘ represents approximately $1bn of annual revenue for the company’ ( S2, S3). This included replacing the active ingredient triclosan (where regulatory scrutiny risked business and reputation) with Dual Zinc plus Arginine ( S3) as antimicrobial and odour-neutralising agents ( R6, G9). Saad’s research provided the ‘evidence-based claims for the product’ ( S2). Additionally, for such an established product, Saad’s research allowed Colgate-Palmolive to make new claims namely ‘ the Dual Zinc plus Arginine dentrifice in Colgate-Total® can provide short-term (twelve hours) and long-term (one month) improvements in breath quality from a single use’ ( R6, S2). UWE’s Malodour Research environment (figure 1) allowed Colgate-Palmolive ‘ to capture and analyse new dimensions in oral malodour’ such as previously uncharacterised volatile compounds. The reformulated toothpaste was ‘re-launched in January 2019’ ( S2, S3).

**(iii) Repurposing an existing device for the healthcare market resulting in time and cost savings ** Saad tested a prototype electronic nose NeOse^TM Pro invented by the technology company Aryballe and funded by CEMAG Care. NeOse^TM Pro, the bio-optic smell sensor, was targeted at detecting environmental fumes, such as smoke. Saad’s research showed that the core technology in NeOse^TM Pro conformed to both the SIFT-MS and the organoleptic score providing ‘a sound underpinning validation of the NeOse^TM Pro in the field of halitosis’ ( S4). ‘ Saad made recommendations to improve the early prototypes … to reliably test VOC compounds’ and ‘directed the development of key accessories’ ( S5). The core technology was given a new casing including a newly developed mouthpiece for collecting VOCs. Consequently, Aryballe filed a patent application in France with Saad as a named inventor in 2020 ( S6). The Chief Scientific Officer of CEMAG stated that Saad’s work demonstrated ‘the first published use for the technology in the field of healthcare’ that can be used ‘ to measure the full spectrum of compounds in halitosis’ ( S4). Saad’s work quickly resulted in proof-of-concept data and ‘ led to a saving of around one year in the pipeline of this technology’ ( S4). Subsequently, Saad and Varadi set up new collaborations between Colgate-Palmolive and CEMAG-Aryballe ( G9, G10) providing credibility and validation for the device ( S5) and ‘accelerating the route to market in this field’ with consequent cost savings ( S5).

(iv) Improving patient diagnosis, classification and treatmentSaad’s research ( R1, R5, R6, G1) underpinned UWE’s ‘Odour Judge Assessment’ continuous professional development (CPD) programme. Twelve participants (dentists, physicians, hygienists, microbiologists, maxillofacial surgeons) attended each of the six programmes (2004-2013) from the USA, Netherlands, France, Italy, Germany, Sweden, Norway, Iceland, Poland, Hungary and UK. A participant periodontologist and Associate Professor at the Dental Faculty of Strasbourg, is now ‘ able to differentiate [between] the different gases’ leading to discrimination ‘ between physical … and psychiatric conditions’ and ‘coming to a definitive diagnosis’ in a halitosis clinic providing a service for patients across France ( S7). Another participant, dentist and Associate Professor of Medical Technologies at the University of Cagliari, stated that he can now ‘ assess oral malodour prior to dental implantation’ to prevent implant failure ( S8). He now offers in his referral clinic a service for patients with ‘delusional halitosis’ with appropriate interventions ( S8). Additionally, he included a new topic on ‘ microflora of the tongue and oral malodour’ in the dental curriculum at his University ( S8). One dentist involved in Saad’s clinical trials, used Saad’s research to recommend interventions and oral care products to patients that were ‘ successful in alleviating malodour’ and ‘educating patients about tongue cleaning has made a huge difference’ in his practice and has been shared with six partner clinics in London ( S9). He also highlighted that the knowledge he gained from Saad’s research is ‘ improving the quality of life for our patients’ ( S9).