OPTIMA, a prospective randomized trial to validate the clinical utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in high clinical risk early breast cancer

Background: Multi-parameter tumor gene expression assays (MPAs) are used to estimate individual patient risk and guide chemotherapy use in hormone-sensitive, HER2-negative early breast cancer. The TAILORx trial supports MPA use in a node-negative population. Evidence for MPA use in postmenopausal node-positive breast cancer has been provided by the RxPONDER trial interim analysis but this relies on the absence of superiority in an analysis where >50% of events were unrelated to breast cancer. There is much uncertainty about MPA use for premenopausal patients. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) (ISRCTN42400492) is a prospective international randomized controlled trial designed to validate MPAs as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Method(s): OPTIMA is a partially blinded study with an adaptive two-stage design. The trial recruits women and men age 40 or older with resected ER-positive, HER2-negative invasive breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment using the Prosigna (PAM50) test. Those with a Prosigna tumor Score (ROR-PT) >60 receive standard management whilst those with a low score (<=60) tumor are treated with endocrine therapy alone. Endocrine therapy for premenopausal women includes ovarian suppression for all participants unless they experience a chemotherapy-induced menopause. Adjuvant abemaciclib is permitted. The trial will be analyzed for (1) non-inferiority of recurrence according to randomization and (2) cost-effectiveness. The key secondary outcome is non-inferiority of recurrence for patients with low ROR-PT score tumors. The efficacy analyses will be performed Per Protocol using Invasive Breast Cancer Free Survival (IBCFS) as the primary outcome measure to limit the risk of a false non-inferiority conclusion. Recruitment of 4500 patients over 8 years will permit demonstration of up to 3% non-inferiority of test-directed treatment with at least 83% power, assuming 5-year IBCFS is 87% with standard management. An integrated qualitative recruitment study addresses challenges to consent and recruitment, building on experience from the feasibility study which found that a multidisciplinary approach is important for recruitment success. OPTIMA is strongly supported by a patient group which has helped design all patient documents and which is represented on the TMG. Result(s): The OPTIMA main trial opened in January 2017 and has continued to recruit throughout the COVID-19 pandemic. Overall recruitment as of 1 July 2022 was 2814 (2593 from UK, 221 from Norway). Patient characteristics are well balanced between the trial arms. Currently 95% of randomized participants are eligible for inclusion in the PP analysis. 66% of the MPA-directed arm participants have been allocated to endocrine therapy only. The test failure rate is < 1%. Conclusion(s): OPTIMA will provide robust unbiased evidence on test-directed chemotherapy safety for both postmenopausal and premenopausal women with 1-3 involved nodes as well as for patients with 4-9 involved nodes and for patients treated with abemaciclib.

Multiple sclerosis and COVID-19: Assessing risk perception, patient behaviors and access to disease-modifying therapies.

BACKGROUND: Following the outbreak of COVID-19, global healthcare systems have had to rapidly adapt. People with multiple sclerosis (pwMS) were required to make decisions about their individual risk and consequent work and social behaviors. This study aimed to evaluate risk perception and patterns of shielding behavior amongst pwMS at the onset of the COVID-19 pandemic and the subsequent impact on patients' employment and access to disease modifying therapies (DMTs). METHODS: Postal surveys were sent to 1690 people within a UK population-based MS cohort during the first wave of the COVID-19 pandemic. Patients were surveyed on: (i) perceived vulnerability to COVID-19; (ii) isolation behavior; (iii) interruption to DMT; (iv) employment status; (v) level of satisfaction with their current working arrangement. RESULTS: Responses were received from 1000 pwMS. Two thirds of patients reported isolating at home during the first wave of the pandemic. This behavior was associated with increased age (p<0.0001), higher disability (p<0.0001) and use of high-efficacy DMTs (p = 0.02). The majority of patients reported feeling vulnerable (82%) with perceived vulnerability associated with higher EDSS (p<0.0001) and receiving a high-efficacy DMT (p = 0.04). Clinician-defined risk was associated with shielding behavior, with those at high-risk more likely to self-isolate/shield (p<0.0001). Patients on high-efficacy DMTs were more likely to have an interruption to their treatment (50%) during the first wave of the pandemic. Most pwMS experienced a change to their working environment, and most were satisfied with the adjustments. CONCLUSION: This study highlights the risk perception, social behavioral practices and changes to treatment experienced by pwMS during the first wave of the COVID-19 pandemic in a large, well-described UK cohort. The results may help inform management of pwMS during future pandemic waves.

SMEs in the face of crisis: The supply chain risk management perspective

COVID-19 has shown how fragile our societies and economies are. Supply chains have particularly been affected. We all had to learn again that the basic supply of some goods is not as crisis-proof as we thought. Moreover, the strong division of labour and the concentration on a few companies in certain areas present considerable weaknesses in the case of a new external crisis such as the pandemic. Small and medium-sized enterprises (SMEs) have been affected by the current pandemic, particularly as they are highly sensitive to external threats. Using data collected between December 2020 and January 2021 through semi-structured interviews conducted with owners and/or managers of SMEs located in six different European countries (i.e., Austria, Estonia, Germany, Greece, Italy, and Portugal), the chapter aims to provide fresh perspectives on how SMEs address supply chain risk management in times of an external and dynamic crisis. © 2021, IGI Global. All rights reserved.

DRIVING IMPROVEMENT in AXIAL SPONDYLOARTHRITIS SERVICES: The USE of QUALITY IMPROVEMENT APPROACHES and TOOLS

Background: Quality Improvement (QI) methods have been used in healthcare since the late 1980s across a wide range of healthcare settings. However, in the UK they have not been applied widely within rheumatology including axial Spon-dyloarthritis (axial SpA). In 2017, the UK healthcare regulator, NICE, produced a national clinical guideline for axial SpA, but there was no mechanism to encourage uptake of its recommendations. The National Axial Spondyloarthritis Society created a programme to use QI approaches to help encourage uptake of the Guidelines and act as a catalyst for wider improvement in axial SpA care. Objectives: To encourage service improvement in axial Spondyloarthritis care through the use of quality improvement theory and methods. Methods: In late 2019 six rheumatology departments were selected to participate in the frst cohort. The programme design was underpinned by: A framework for management grounded in systems theory1 A learning system that brings healthcare organisations together2 A set of tools to develop, test and implement changes: the Model for Improvement3. The teams met four times for training in QI methods, plus team-based online coaching. They had time to develop their projects and networking opportunities to share their data and experiences of implementation. We conducted a qualitative review of the programme in year one. We interviewed 31 programme participants and reviewed programme documentation. Results: The review found that: A proven QI framework provides a strong basis to build improvement A competitive programme helps foster motivation and accountability The programme provides the time to use tools to understand the problem and construct improvement aims Measurement is key to understand improvement and to create a story of change Collaboration and engagement is key within the team and with other stakeholders. The teams have: • Trained community-based physiotherapists, leading to improved rheumatology referrals Implemented an infammatory back pain pathway from primary care Introduced an MRI spine IBP protocol to reduce variation in imaging Established a tertiary referral service which has improved time to diagnosis Implemented mental health interventions for patients and reduced the percentage of patients with abnormal scores Established a pathway for physiotherapy self-referral and reduced Did Not Attend rates Used audit to make the business case for an extended scope practitioner Conclusion: Despite the challenges of posed by the Covid-19 pandemic, a structured QI programme has enabled clinicians to stay engaged and implement projects to reduce diagnostic delay and improve care.

PROCEDURES IN THE LAST WEEK OF LIFE FOR DEATHS IN HOSPITAL (COMPARING PRE- AND MIDCORONAVIRUS- 19 TIME PERIODS)

Background The Gold Standards Framework1 (GSF) was introduced in The Dudley Group NHS Foundation Trust (DGFT) in 2018;to encourage identification of those at the end of life and promote individualised advanced care planning including consideration of procedures in the last days of life. Method Retrospective audit to look at procedures conducted in the last week of life for patients who died at DGFT. Due to the coronavirus-19 pandemic, a period in Autumn 2019 prior to the pandemic and then a second period during the first-wave in Spring 2020 was studied. A list of adult patients who were coded as having a procedure in the last week of their admission, where the discharge method was death (occurring in November 2019 or April 2020) was compiled by the Informatics Team and information collected from notes using a proforma. Results The majority of patients in both the 2019 (64%) and 2020 (69%) audit had lengths of stays of 7 days or less (they died within a week of admission). Over 90% of patients in both groups had blood tests and imaging. Approximately 50% of patients had at least one admission in the 3 months prior to their final admission in the 2019 group, however, this was half (24%) in the 2020 group. Approximately 40% in both groups had been identified as GSF red or amber, however, up to 80% had documentation indicating recognition that in last year of life and evidence of good communication. Conclusions Implementation of the Gold Standards Framework has provided a structure to support identification of patients in the last year of life. In view of the number of admissions prior to the final admission there needs to be continued work to identify patients in a timely manner to support with the development of an individual plan of care.

A COMPARISON OF PATIENTS WHO DIED IN A DISTRICT GENERAL HOSPITAL BEFORE AND DURING THE FIRSTWAVE OF THE CORONAVIRUS-19 PANDEMIC

Background The ongoing Coronavirus-19 (CV-19) pandemic has had worldwide impact with over 240 million cases globally1 to date. As with most the UK, The Dudley Group NHS Foundation Trust (DGFT) has cared for patients with the virus since Spring 2020 and we reviewed if the types of patients who died (all causes) changed in the pandemic on a local level. Method Retrospective review of adult inpatients who died at DGFT - looking at November 2019 (before CV-19) and April 2020 (early in first-wave). A list of adults who were coded as dying as an inpatient in these two periods was compiled by the Informatics Team and data collected from 45 notes for each month. Results There were 148 adult inpatient deaths in November 2019, which increased 77% to 262 in April 2020. Median ages at death were similar (77 years) but fewer females (27%). 4% were known to Specialist Palliative Care before admission. Average lengths of stay were similar (5-6 days) and approaching end of life was recognised in the majority of cases. In April 2020, there was a decreased number of patients with recent hospital admissions (24%) and a threefold increase in those with an unimpaired functional status (29%). Fewer were admitted from home but more from care homes (18%). 25% of those with CV-19 as cause of death had no documented comorbidities (all aged over 74). Conclusions There appears an increase of inpatient deaths at the start of the Coronavirus-19 pandemic in three main groups: care home residents, those with comorbidities and older people with no comorbidities/unimpaired functioning. Promoting advance care planning with these groups as a priority may be beneficial for future waves - especially wishes for hospital admission and preferred place of care. (Assessment of impacts of the CV-19 vaccination programme on these patient groups could be considered).

Compulsory licensing: an effective tool for securing access to Covid-19 vaccines for developing states?

A significant issue in combatting the Covid-19 pandemic is the need to enhance developing states' access to Covid-19 vaccines. The present paper considers the request for a temporary waiver of intellectual property rights in relation to Covid-19 technologies and treatments submitted to the World Trade Organization and analyses a key argument against the proposed waiver: that the compulsory licensing provisions set out in the TRIPS Agreement are sufficiently flexible to help states get access to vaccines. The compulsory licensing flexibilities set out in TRIPS, including the amendment to TRIPS in Article 31bis, are evaluated, to explore whether compulsory licensing could be an effective tool in helping developing states to access Covid-19 vaccines. Key issues are explored from a human rights perspective to examine whether a rights-based approach to the compulsory licensing provisions could offer further insights as to how the provisions could be more workable, to enhance access to medicines and vaccines for developing states.

The feasibility and advantages of an at-home intravesical therapy service for benign conditions

Introduction & Objectives: Intravesical instillations of GAG-layer replacement are utilised in a number of benign bladder conditions and are traditionally delivered in an outpatient setting. Our unit was considering the feasibility of an at-home service when the COVID-19 pandemic resulted in the sudden cancellation of non-essential services. This provided impetus to rapidly change service delivery so this effective therapy could continue to be available. Here we outline the implementation of an at-home intravesical therapy service & report on early patient satisfaction outcomes. Materials & Methods: The product was chosen based on local use and practical advantages. Collaboration with the company ensured optimal planning and initiation. Review of regulations & cost-effective analysis led to dispensation via a community pharmacy after appropriate tuition. Patients were identified via the unit's intravesical treatment database. Inclusion criteria were the willingness to learn intermittent catheterisation, to have the medication administered at home, and to conduct telephone review. Tuition was delivered by qualified urology nurses in a single 30-60 minute session, utilising video and diagrams. Patients that were shielding were instructed by community bladder nurses. PROMS data were collected via a unit-designed questionnaire. Clinical outcome data were collected from follow-up notes. Results: Between March 2020 and January 2021, 65 patients (mean age 50 years) commenced at-home therapy. 22 (88%) were female. The first patient was instructed 11 days after compulsory cessation of outpatient instillations. Efficacy was 65%-83% across different indications (bladder pain, recurrent UTIs, chemical cystitis, radiation cystitis & ketamine bladder). 25 patients returned the PROMS questionnaire. 20 had previously had outpatient nurse-delivered instillations, 5 were treatment naive. 20 performed self-catheterisation, 1 used the adapter, 4 received assistance from a relative/carer. Whilst some patients reported difficulty with catheter insertion, medicine instillation and/or UTI following administration, 72% completed the course at home. 11/20 experiencing both service models preferred at-home administration;9/20 preferred the hospital option. Positive feedback for at-home treatment included convenience, time saved, and privacy. Concerns were centred on technical aspects. Overall satisfaction was reported as very good, good or satisfactory by 18 (72%), and was linked to ability to continue treatment. Savings in our unit per treatment course or treatment year ranged between £180 & £470, dependent on the number of overall treatments. Conclusions: This study shows radical service change can be implemented quickly, safely and effectively. Careful patient selection and tuition enables cost-savings, freeing of outpatient space and improved patient satisfaction. We encourage other institutions to consider commencement of an at-home instillation service.

INHERITING A DESIGN BUILD PROJECT: LESSONS LEARNED FROM THE 2021 STUDENT STEEL BRIDGE COMPETITION

Each year the American Institute of Steel Construction (AISC) runs the Student Steel Bridge Competition (SSBC). A competition which challenges teams to design and build a small-scale steel bridge with a large set of requirements and scoring criteria. The United States Military Academy (USMA) takes part each year but the 2020 SSBC was cancelled due to the COVID-19 pandemic. The cancellation resulted in the 2021 USMA Steel Bridge Team inheriting the 2020 team's design and some of their fabrication. Inheriting the bridge forced the designers and team managers to make decisions on how to best posture the team for success with limited knowledge of the design and fabrication. Which raised the question of what engineering management (EM) tools are the most valuable when inheriting an engineering project. As commercial projects vary in length, and do not always maintain the same team throughout the project life cycle, aspiring project managers must be prepared to inherit partially completed projects. Treating the 2021 SSBC as a case study, the USMA Steel Bridge Team's systems engineers collected data, recorded observations, and took surveys to figure out which EM techniques were the most useful to the team. The team determined that the most important techniques were to develop an in-depth risk assessment, detailed scheduling, and monitoring and controlling. These tools of management were useful because they could be easily tailored to an ongoing project. © American Society for Engineering Management, 2021

Determining the appropriate use of Technology Enabled Care Services (TECS) to manage upper-limb trauma injuries during the COVID-19 pandemic: A multicentre retrospective observational study.

BACKGROUND: The COVID-19 pandemic created a unique opportunity to explore the use of Technology Enabled Care Services (TECS), which remains novel for many service providers. This study assesses the factors that affect adaptation to remote monitoring of patients after upper-limb trauma injury. A standardised risk-stratified screening tool is further developed here to support clinical staff in both the determination of appropriate use of TECS and the optimisation of patient care. OBJECTIVES: 1: To explore the patient and injury factors that determine the appropriate use of TECS for patients with upper-limb injury. 2: To use these findings to refine a standardised screening tool for the appropriate choice of follow-up format. METHODS: A retrospective review of patient management was undertaken across three NHS upper-limb trauma units during the first UK COVID-19 lockdown. Data were collected, and themes were analysed across a number of predetermined categories. This was underpinned by a review of contemporary policy guidance and literature. RESULTS: A total of 85% of patients were offered an appropriate format of follow-up; this was defined by the ability to achieve desired patient-clinician goals and lack of complications. Key factors in determining appropriate follow-up included extent of injury, mental health considerations, and the need for face-to-face (F2F) assessment and treatment. CONCLUSION: Study findings demonstrate consistency between units in the factors determining the appropriate use of TECS. The refined screening tool provides a risk-stratified, standardised approach to the choice of follow-up format, F2F or TECS. It is hoped that this will support future clinical decision-making processes to ensure optimal patient care.

Leadership reflections a year on from the rapid roll-out of virtual clinics due to COVID-19: A commentary

COVID-19 changed the way we delivered care to our patients at our Hospital. Prior to the pandemic, no patient facing video clinics and only a small number of telephone clinics were held. In this paper, we share our experience of rapidly implementing virtual clinics (VCs) due to COVID-19. This commentary is based on focused discussions between hospital leaders and provides a reflective account and commentary on leadership lessons learnt from our experience of deploying VCs. We outline success factors (being able to capitalise on existing strategy, having time and space to establish VCs, using an agreed improvement framework, empowering a diverse and expert implementation team with a flat hierarchy, using efficient decision pathways, communication and staff willingness to change), technical challenges (patient capability and skills to use technology, patient connectivity and platform capacity) and considerations for the future (sustaining new ways of working, platform selection, integration, business continuity and commissioning considerations, barriers regarding capability and communication, effectiveness and clinical outcomes). Finally, we provide an overview of the leadership lessons from this project and identify key areas of focus for delivering successful change projects in future (the vision, allocation of resources, methodology selection and managing the skills gap). © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Comparing an operation tomonitoring, with or without endocrine therapy (COMET): Aprospective randomized trial for low-risk DCIS (AFT-25)

Background: Approximately 50,000 women in the U.S. are diagnosed with ductal carcinoma in situ (DCIS)annually. Without treatment, it is estimated that 20-30% of DCIS will lead to invasive breast cancer. Currently, morethan 97% of women undergo surgery, with many also undergoing radiation. An alternative to surgery for low-riskDCIS is active monitoring (AM), an approach in which regularly scheduled mammography and physical exams areused to monitor breast changes and determine if, or when, surgery is needed. Trial design: COMET, a multicenterphase III prospective randomized trial, opened in the U.S. in June 2017 (clinicaltrials.gov reference: NCT02926911).The hypothesis is that management of low-risk DCIS using an AM approach does not yield inferior invasive breastcancer and/or quality of life outcomes compared to surgery. Eligibility criteria: Patients with a new diagnosis of unilateral, bilateral, unifocal, multifocal, or multicentric DCIS, or atypia verging on DCIS are eligible. Patients mustbe ≥40 years of age, have no contraindication for surgery, and pathologic confirmation of grade I/II DCIS. DCIS mustbe ER and/or PR≥ 10% and HER2-negative without invasion, diagnosed within 120 days of registration. Breasttissue, blood and imaging are collected at trial entry and if invasive cancer subsequently occurs, and are stored incentral repositories. Specific aims: The primary aim is to assess whether the 2-yr ipsilateral invasive breast cancerrate for AM is non-inferior to surgery. Secondary aims include comparison of 2-, 5-, and 10-yr mastectomy rate, contralateral invasive breast cancer rate, overall survival and invasive breast cancer-specific survival, as well as 5-and 10-yr ipsilateral invasive breast cancer rate between groups. Patient reported outcomes (PRO) using validatedtools are critical secondary endpoints, and will enable comparison of health-related quality of life and psychosocialoutcomes between surgery and AM groups at prespecified time points over a period of 5 years. Statisticalmethods: An accrual goal of 1200 was estimated using a 2-group test of noninferiority of proportions, with the 2-yrinvasive breast cancer rate in the surgery group assumed to be 0.10, including accounting for upstaging. Theprojected drop-out rate is 25%, for a total of 900 patients treated per allocation arm. The non-inferiority boundarywas set at 0.05. Based on a 1-sided un-pooled z-test, with alpha=0.05, a sample size of n=446 per group will have80% power to detect the specified noninferiority margin. Intention-to-treat analysis of the 2-yr invasive breast cancerrate will be conducted using all patients as randomized, and will be completed using Kaplan-Meier estimates,stratified by group, combined with Greenwood's confidence interval. Several sensitivity analyses (per protocol, as-treated, and instrumental variable) are also planned to account for loss of follow-up, rejection of randomizationallocation and withdrawals. Present and target accrual: Trial accrual as of 7/1/20 is 540 randomized patients from84 activated Alliance for Clinical Trials in Oncology sites. Despite logistical challenges posed by the COVID-19crisis, patients continue to be recruited to the COMET trial. Over 80% of patients have sample sets/images stored inthe tissue and image repositories. This trial will provide definitive clinical, quality of life and biomarker evidenceregarding the trade-offs of surgery vs AM in patients with low-risk DCIS.