SMALL: Open Surgery versus Minimally invasive vacuum-Assisted excision for smaLL screendetected breast cancer - a UK phase III randomised multicentre trial

Background: Mammographic screening programmes reduce breast cancer mortality, but detect many small tumours with favourable biological features which may not progress during a woman's lifetime. Screen-detected cancers are treated with standard surgery and adjuvant therapies, with associated morbidities. There is a need to reduce overtreatment of good prognosis tumours and numerous studies have evaluated the omission of radiotherapy in this context. However, there is little evidence to support surgical de-escalation, although percutaneous minimally invasive treatment approaches have been described. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Method(s): SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screendetected good prognosis cancers. The main eligibility criteria are age >=47 years, unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery;with no axillary surgery in the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are: 1. Noninferiority comparison of the requirement for a second procedure following excision 2. Single arm analysis of local recurrence (LR) at 5 years following VAE Recruitment of 800 patients will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A novel feature of SMALL is the integration of a QuinteT Recruitment Intervention (QRI), which aims to optimise recruitment to the study. Recruitment challenges are identified by analysing recruiter/patient interviews and audiorecordings of trial discussions, and by review of trial screening logs, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Result(s): SMALL opened in December 2019, but recruitment halted in 2020 for 5 months due to COVID-19. At 7st July 2022, 142 patients had been randomised from 26 centres, with a randomisation rate of approximately 45%, and a per site recruitment rate of 0.4-0.5 patients/month, approaching the feasibility recruitment target of 144 patients. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on providing balanced information about treatments, encouraging recruiters to engage with patient preferences, and explaining randomisation). Individual recruiter feedback has commenced, with wider feedback delivered across sites via recruitment training workshops. Conclusion(s): Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes.

"Inside out" - An exceptional intussusception

Introduction: We present the first case of appendiceal intussusception associated with myeloid sarcoma in a young patient. Minimally invasive techniques used along the clinical course are highlighted. Case description: A 2.5-year-old boy was admitted after three weeks of COVID-19 infection with ongoing symptoms of MIS-C. Due to constipation, distended belly and vomiting, US was done which showed ileocolic intussusception. After unsuccessful hydrostatic reduction laparoscopic exploration was performed, where the vermiform appendix was found to be thickened and partially intussuscepted into the coecum. The ileocecal region was exteriorized transumbilically. After manual reduction of the intussusception, a long, thickened, fragile appendix was removed. Histopathology revealed myeloid sarcoma. Bone marrow investigation identified acute myeloid leukemia. During the oncological treatment, laparoscopic cholecystectomy was necessary due to cholecystitis and cholelithiasis. The child recovered uneventfully in terms of surgical complications, with good cosmetic result. Conclusion(s): No similar case in childhood was found in the English literature. Unusual symptoms and radiological findings of intussusception can conceal unexpected disorders. Minimally invasive technique offered advantages in the treatment of the presented patient and can be recommended to treat intussusception or cholelithiasis, if applicable, during an ongoing oncological treatment as well.Copyright © 2023 The Authors

A review of infection prevention and control guidelines for dental offices during the COVID-19 pandemic in mid-2020

Background: The COVID-19 pandemic was a challenge for all dental professionals who had to rapidly update infection prevention and control (IPAC) guidelines and protocols due to increased risk of SARS-CoV-2 transmission during common aerosol-generating procedures (AGPs), and a lack of consensus on how best to mitigate the risk of transmission in a dental office. Thus, the purpose of this descriptive study was to compare the variance in IPAC guidelines for dental offices that emerged, and to assess practice consistency from early to mid-2020. Methods: A comprehensive literature search was conducted from May 26 to July 8, 2020 for IPAC documentation specific to the dental office during the COVID-19 pandemic. Documents that met the inclusion criteria were independently reviewed. Data was extracted using a framework based on the following IPAC domains: pre-appointment, waiting room, personal protective equipment (PPE) selection, treatment room, and post-dismissal. Results: A total of 67 IPAC documents specific to dental offices were reviewed in this study. Included documents originated from 22 dental associations, 17 peer-reviewed articles, 13 dental regulators, 11 government bodies, two public health units, and two dental corporations. There was a great degree of variance with IPAC guidelines from the pre-appointment stage, during treatment, and post-treatment. Recommendations that emerged with some level of consistency involved pre-screening patients for COVID-19 symptoms (97%), staggering appointments (84%), social distancing, minimizing occupants in the waiting room, wearing a face shield over protective eyewear for AGPs (92%), and preprocedural rinses (84%). There was less consistency with recommendations for consolidating multiple appointments (36%), waiting room ventilation (46%), N95 masks (47%) versus FFP2/FFP3 masks (30%) use for AGPs, fit-testing respirators (37%), enclosing open operatories for AGPs (28%), prioritizing minimally invasive procedures (30%), and using third-party laundry companies (32%). Conclusions: The risk of SARS-CoV-2 transmission, lack of consensus on mode of spread, and need for rapid action resulted in a significant variation in most downstream IPAC interventions in the hierarchy of controls, including choice of PPE, treatment room, and post-dismissal domains. Upstream interventions, including pre-appointment and waiting room domains, were relatively consistent in practices in early to mid-2020.

Finding an Answer for an Adolescent with Back Pain

Case report - Introduction: This is the case of an adolescent referred to rheumatology following 5 years of back pain. After years of trying a number of treatments without much success, the cause was found to be a previously undiagnosed urological pathology. The case highlights awareness of non-rheumatological causes and incidental findings which can redirect a patient towards more appropriate treatment and reduce the potential for long-term adverse health issues and anxiety. Case report - Case description: B was referred age 16 to rheumatology with a 5-year history of lower back pain. She had previously seen paediatricians with symptoms initially attributed to constipation due to intermittent straining and hard stool. However, constipation remedies had not relieved the pain which progressed gradually to a more persistent dull ache with impact on daily activities. Various analgesics (including paracetamol and non-steroidal anti-inflammatories), exercises and acupuncture had not helped. There was no history of recurrent urinary tract infections or symptom correlation with fluid intake, menstruation or bowel habit. No inflammatory features or connective tissue disease symptoms were noted and family history was unremarkable Clinical examination was normal apart from mild tenderness in the lumbar region. Rheumatoid factor was borderline positive (15 iu/mL) with the rest of blood tests normal including renal function, inflammatory markers (CRP, ESR), anti CCP and ANA. She had minimal microscopic haematuria without proteinuria. MRI spine in 2015 was normal. In view of her young age and symptoms affecting daily activities, STIR sequence spinal MRI was requested. This excluded any new or old inflammatory changes but incidentally identified a dilated left pelvi-calyceal system. Renal ultrasound confirmed a grossly hydronephrotic left kidney with hydroureter and minimal renal tissue suggesting longstanding obstruction. No calculi were seen. The patient was referred to urologists. Further investigations (including MRI abdomen) confirmed similar findings and a distal ureteric stricture. A MAG 3 renogram showed a normal right kidney but only 12% functioning of the left kidney. Urologists have advised surgery (removal of left kidney and ureter) which may relieve symptoms or a conservative non-surgical approach (continue analgesia, physiotherapy and monitoring). The patient and her family are relieved to have a possible cause identified and are considering the surgical option due to ongoing flank discomfort. Case report - Discussion: This was an interesting finding of hydroureter and hydronephrosis causing longstanding back pain presenting to rheumatologists. Until completion of the spondyloarthropathy protocol MRI (STIR images), aetiology had been unclear. Hydronephrosis and hydroureter has no specific age or racial predilection. Signs and symptoms may depend on whether obstruction is acute/chronic. Chronic cases may be asymptomatic or present as a dull discomfort (like this case). Some cases may only present in adulthood with pain precipitated by fluid intake. Blood tests may show impaired kidney function. Post-mortem studies suggest 50% of people have at least one renal abnormality (e.g., renal cysts, duplex ureters) with autopsy series incidence of hydronephrosis reported as 3.1%. Causes include anatomical abnormalities such as vesico-ureteric reflux, urethral strictures (usually present in childhood), calculi, benign prostatic hyperplasia, or intrapelvic neoplasms, pregnancy and infections (e.g., TB). Sudden onset unilateral renomegaly was reported in one case of primary Sjogren's with lymphocytic interstitial nephritis and positive Sjogren's autoantibodies. Our patient has no clinical or serological evidence of connective tissue disease. Minor pelvi-calyceal distension can occur as a normal finding in wellhydrated patients and pregnancy. However, significant hydronephrosis requires assessment to determine cause as it may affect long term renal function. Imaging via computed tomography, ultrasound and urograms can help guide further management. In this case the preceding cause and duration of pathology is unknown. Sterile, giant hydronephrosis treatment options include observation and ureteric stent or nephrostomy in patients unfit for surgery. Nephrectomy is advised for pain and recurrent infection in a non-functioning kidney. Complications may include bowel perforation, vascular injury and urine leakage. Both open and minimally invasive procedures have good reported outcomes. The COVID-19 pandemic and exams have affected timing of any elective procedures and the patient understands surgery may or may not offer complete symptom resolution. Case report - Key learning points: . Non-inflammatory causes of back pain should always be considered in cases of persistent back pain, particularly in young people to ascertain if there is a treatable cause . Hydronephrosis cases can be asymptomatic or present with vague, intermittent, non-specific abdominal symptoms with normal physical examination with or without haematuria. This can cause diagnostic uncertainty and delay referral to urology and appropriate renal investigations . Assessment of renal function (including MAG 3 renogram) is important to guide further management . Surgical interventions (pyeloplasty/nephrectomy) may ease symptoms long term but there is no guarantee of a successful outcome and operative risks need to be considered too . Left undiagnosed, potentially this patient could have had further disruption to daily activities and both physical and mental well being.

Confronting the devastating 'Twindemic': Drug overdose deaths and the COVID-19

The last 25 years have seen a dramatic increase in drug overdose related deaths in both the industrialized and developing countries. Hundreds of thousands of people die every year. This human tragedy has recently been complicated by the COVID-19 epidemic, sidelining the minimal effort that was being implemented. As a global community, the governments, medical institutions, NGOs and the general public need to focus on this devastating human tragedy before more lives are lost senselessly, and unnecessarily. Increased public awareness about new approaches to manage the already afflicted ones including targeted, minimally invasive procedures is required. In addition, the focus needs to be on aggressive research and development of innovative and safer medications and newer modalities for those suffering from chronic pain. This paper offers a perspective, context and a vision for future. Copyright © 2022 Faculty of Anaesthesia, Pain and Intensive Care, AFMS. All rights reserved.

Environmental and Nasal Pathogen Surveillance in Seattle Area Homeless Shelters

Background. The need for community surveillance of respiratory viruses in high-risk settings such as homeless shelters has been underscored by the COVID-19 pandemic. Here, we show that sampling high-touch surfaces is a low-cost, minimally intensive means of community respiratory virus surveillance. Methods. Environmental samples were collected weekly from adult and family homeless shelters in King County, WA from November 2019 - April 2020. At times when residents were present, a 10cm2 area of selected high-touch surfaces were swabbed and bioaerosol samples were collected in high-traffic areas. Surfaces included entrance and restroom doorknobs, counters, and surfaces unique to each shelter. Study staff collected mid-turbinate swabs from shelter resident participants aged > 3 months with symptoms of acute respiratory illness (ARI). All samples were tested by RT-PCR for 27 viruses. From January 1, 2020 onward, samples were also tested for SARS-CoV-2. Results. A total of 788 environmental swabs, 1509 nasal swabs, and 98 bioaerosol samples from 6 adult and 3 family shelters were tested. Adenovirus (109 positive swabs, 13.8% of tested swabs), rhinovirus (107, 13.6%) and human bocavirus (62, 7.9%) were the most frequently detected viruses in surface swabs. Rhinovirus (160, 10.6%), human coronaviruses (79, 5.24%) and influenza B (43, 2.85%) were the most detected in nasal swabs. All viruses detected in nasal swabs were found in surface swabs. Of 9 surfaces, exterior bathroom doorknobs were the physical location with the highest number of pathogens detected. SARS-CoV-2 was first detected in surface swabs on 3/20/20, and in nasal swabs on 3/10/20. Bioaerosol samples detected virus in a low percentage of samples relative to surface and nasal swabs. Table 1 Count and period prevalence of environmental viral detection by shelter type, November 18, 2019 - April 10, 2020. (Figure Presented) Conclusion. Respiratory viruses detected through environmental sampling in homeless shelters were similar to the viruses detected from ARI episodes in study participants. Environmental surface sampling presents a plausible, minimally invasive method of surveillance for both endemic and emerging respiratory pathogens, as evidenced by the detection of SARS-CoV-2 during the early stages of the pandemic. Further research could focus on sampling public locations for broader community surveillance and culturing viruses found on these surfaces.

Safety and efficacy of REZUM for the treatment of BPH in an Australian cohort

Introduction & Objectives: Minimally invasive transurethral therapies for benign prostatic hypertension are becoming increasingly common in Europe and America. They may be performed under local anaesthetic and provide a good alternative to invasive procedures in a COVID era. REZUM, a minimally invasive transurethral water-vapor therapy, has been shown to be a safe and effective treatment for BPH, especially where preserved sexual function is a priority. Although short-term clinical outcomes are promising, long-term data from robust studies is lacking. In Australia, there are few providers of REZUM, which utilises steam injections to reduce prostatic tissue. This study aims to investigate the safety and efficacy of REZUM in an Australian cohort. Methods: A clinical audit was conducted of 50 patients who underwent REZUM to treat symptoms of BPH over a 12-month period. Procedures were performed under general anaesthetic. Demographics, comorbidities, sexual function, prostate volume, PSA, voiding flow rate, post-void residual volume and International Prostate Symptom Score were extracted from medical records, in addition to patient's reasons for seeking minimally invasive treatment. Corresponding post-operative data was collected. Descriptive statistics of the cohort were obtained using Stata 16.0. Paired t-test was used to identify if there was a significant difference between IPSS scores pre- and postprocedure Results: Patients accessing treatment ranged from 48 to 84 years (mean 64.6). Median prostate volume was 55mL (inter-quartile range 45-78mls) and mean International Prostate Symptom Score (IPSS) was 20.3. 28% of the cohort cited concern for ejaculatory function, either from medication side effects or TURP, as their primary reason for seeking minimally invasive treatment. A further 25% of the cohort was additionally concerned about other side effects from medications and/or TURP or had experienced medication failure. The mean follow up period was 6 months (range 6-weeks-26 months). 69% of men were satisfied with their symptom improvement at the time of review, with the expectation of ongoing improvement in men who had attended a 6-week post-operative review only. Postprocedure mean IPSS was 7.9 (range 2-33). Mean reduction in IPSS score post-procedure was 12.7 points (p<0.001). 3 men experienced complications (retention, infection, bulbar stricture). Conclusions: REZUM provides a safe alternative to traditional invasive prostatic treatments. It may be performed under local anaesthetic, providing an effective alternative in a COVID era. Men concerned about medications, more invasive treatments and ejaculatory dysfunction are increasingly seeking relief from this minimally invasive option and experiencing good outcomes including significant symptom improvement sustained over medium-term follow up.

Pre-Pandemic Sentinel Lymph Node Biopsy In Vulvar Cancer: 4-Year Single Centre Audit

Introduction and aims of the study: In early vulvar cancer, lymph node status is the most important prognostic factor. Sentinel lymph node biopsy (SLNB) is the minimally invasive procedure that lead to the most significant reduction in the classical high morbidity associated with the sistematic inguinal-femoral lymphadenectomy. Besides quality control, the aim of this study is to document the overall experience around SLNB at this referral Centre before the Covid pandemic, in order to monitor and possibly prevent future related changes. Methods: Retrospective analysis of patient files in cases where SLNB was performed as part of the treatment for vulvar cancer at the authors’ Department, from January, 2016 to December, 2019. A single surgeon performed the SLNB with the combined technique (technetium and patent blue). Data collected included demographics, pathology, accuracy, surgery and perioperative results, feasibility and survival. Results: 18 patients with vulvar squamous cell cancer were enrolled in the study. Median age was 68 years, average BMI 27.5kg/m2, 61.1% were married and Charlson score ≥5 was 55.6%. Primary site was labia majora in 44.4% and mid-line was affected in 27.8%. FIGO stage IB in 72.2% of cases, mean tumour diameter was 20.2 (7-39)mm. SLNB was bilateral in 27.8%, 1 out of 38 nodes removed was positive and average number of nodes per patient was 2.1. Mean hospital stay was 13.2 days, blood loss 72ml and no surgical complications. There was a single case of groin recurrence in 45.1 months mean follow-up time and 2 cases of non-related deaths. 33.3% and 5.6% patients had short and long-term postoperative complications, respectively, mostly infectious. Conclusions: SLNB is a reliable and safe minimally invasive technique that should be performed by experienced gynaecological oncologists in well-equipped and multidisciplinary Centres. The Covid pandemic is believed to be causing severe difficulties in the management of patients with vulvar cancer, from diagnosis to follow-up and treatment of recurrences. This study allows a future comparison with positive results at this Centre, possibly reflecting other similar scenarios in Europe.

Impact of Enhanced Recovery After Surgery Implementation and COVID-19 on Hysterectomy Outcomes at a Public Hospital

INTRODUCTION: Immediately prior to the COVID-19 pandemic, our public hospital implemented an enhanced recovery after surgery (ERAS) protocol. The purpose of this study was to evaluate ERAS outcomes for hysterectomy patients at our public hospital, given concerns about barriers to care in our underserved population. METHODS: A retrospective analysis was performed comparing outcomes (percent of outpatient cases, length of stay, perioperative opioids, percent of emergency department [ED] return) for hysterectomy patients for pre- and post-intervention periods (January to June in 2019 and 2021). Outcomes were compared using the Fisher exact test or t-test. RESULTS: A total of 192 preintervention and 120 post-intervention hysterectomy cases were analyzed. The majority of patients were Hispanic/Latinx in both groups (82% vs. 76%;P=.25). There was no significant change in the percentage of minimally-invasive procedures (71% vs 72%;P=1.0). The percentage of outpatient hysterectomies increased from 0% to 53% (P<.0001), and the mean length of stay (LOS) decreased from 1.6 days to 0.9 days (P<.0001). Peri-operative mean morphine milligram equivalents (MME) decreased from 78 to 54 (P≤.02). Mean post anesthesia care unit stay increased from 186 to 229 minutes (P<.01). There was no significant increase in returns to the ED <30 days (10% vs 13%;P=.36) or mean number of opioid pills prescribed (13 vs 13;P=.21). CONCLUSION: ERAS implementation for hysterectomy patients at a public hospital decreased LOS and peri-operative opioids without significantly increasing ED returns. The COVID-19 pandemic likely helped to expedite the adoption of outpatient management, which was feasible and safe in our underserved patient population.

Adaptation and development of IR services in response to the COVID-19 pandemic: preliminary results of a focused survey

Purpose: The cyclic nature of active and recovery phases of the COVID-19 pandemic, has demanded fast adaptations and preparation for health care workers world-wide. We aimed to assess how interventional radiologists are handling the pandemic during active and recovery phases with regard to work and team structures, as well as mental health and how the pandemic could have increased the awareness of minimally-invasive therapies as alternatives to postponements of non-urgent procedures. Material and methods: 7125 CIRSE members were invited to participate. For this interim report, responses were collected between 23 November 2021 and 17 December 2021. Results: 114 responses were obtained for this preliminary report, of which 102 were complete. 94% (n=99) of respondents were interventional radiology specialists. Most respondents reported having established a routine to handle different waves of the pandemic (89.5%;n=102). Compared to active phases, fewer respondents indicated at least one pandemic-associated measure in their department during recovery phases (46%-71% vs 13%). 56% reported an increase in ambulatory care patients either during active and/or recovery phases. 54% reported more referrals during active and/or recovery phases. 25% reported increased hours at the hospital during recovery phases, 52% indicated increased sick leave, care leave, quarantine, and burn-out of team members and only 39% reported to get enough time to rest during recovery phases. Conclusion: While the COVID-19 pandemic is continuing to burden IR departments and the mental health of IRs, more than half of respondents reported an increase in referrals for minimally-invasive therapies and ambulatory care.

SMALL-Open surgery versus minimally invasive vacuum-assisted excision for small screen detected breast cancer: A phase 3 randomised trial

Background:. Mammographic screening programmes have been shown to reduce breast cancer mortality. However, they detect many small tumours with favourable biological features which may not progress during a woman's lifetime. These are treated with standard surgery and adjuvant therapies, which have associated morbidities. Thus, there is a need to reduce overtreatment of good prognosis tumours found by screening. Minimally invasive treatment approaches have been described but there is no prospective randomised evidence to support their routine use. Vacuum-assisted excision (VAE) is in widespread use for management of benign lesions and lesions of uncertain malignant potential. SMALL (ISRCTN 12240119) is designed to determine the feasibility of using this approach for treatment of small invasive tumours detected within the UK NHS Breast Screening Programme (BSP). Methods:. SMALL is a phase III multicentre randomised trial comparing standard surgery with VAE for screen-detected good prognosis breast cancers. The main eligibility criteria are age ≥47 years, screen-detected unifocal grade 1 tumours with maximum diameter 15mm, which are strongly ER/PR+ve and HER2-ve, with negative clinical/radiological axillary staging. Patients are randomised 2:1 in favour of VAE or surgery;with no axillary surgery in S the VAE arm. Completeness of excision is assessed radiologically, and if excision is incomplete, patients undergo open surgery. Adjuvant radiotherapy and endocrine therapy are mandated in the VAE arm but may be omitted following surgery. Co-primary end-points are:1.Non-inferiority comparison of the requirement for a second procedure following excision2.Single arm analysis of local recurrence (LR) at 5 years following VAE. Recruitment of 800 patients over 4 years will permit demonstration of 10% non-inferiority of VAE for requirement of a second procedure. This ensures sufficient patients for single arm analysis of LR rates, where expected LR free survival is 99% at 5 years, with an undesirable survival probability after VAE of 97%. To ensure that the trial as a whole only has 5% alpha, the significance level for each co-primary outcome is set at 2.5% with 90% power. The Data Monitoring Committee will monitor LR events to ensure these do not exceed 3% per year. Secondary outcome measures include time to ipsilateral recurrence, overall survival, complications, quality of life and health economic analysis. A QuinteT Recruitment Intervention (QRI) is integrated throughout SMALL to optimise recruitment and informed consent. Recruitment challenges are identified by analysing recruiter/patient interviews and audio-recordings of trial discussions, and by review of screening, eligibility and recruitment data and study documentation. Solutions to address these are developed collaboratively, including individual/group recruiter feedback and recruitment tips documents. Results:. SMALL opened in December 2019, but recruitment halted in 2020 due to suspension of the NHS BSP for 5 months due to COVID-19. As of 1st July 2021, 55 patients had been approached in 10 centres, with 33 patients randomised (randomisation rate 60%). A further 23 centres are in set-up, with 8 suspended due to the pandemic. Drawing from preliminary QRI findings and insights from patient representatives, a recruitment tips document has been circulated (on introducing and discussing SMALL, providing balanced information. on treatment options and explaining randomisation). individual recruiter feedback has commenced, with wider feedback planned shortly. Conclusion:. Despite pandemic-related challenges, SMALL has an excellent recruitment rate to date and is expected to have a global impact on treatment of breast cancer within mammographic screening programmes. SMALL is funded by the UK NIHR HTA programme, award 17/42/32.