Exploring the relationship between cultural and structural workforce issues and retention of nurses in general practice: A qualitative study protocol.

AIM(S): The aim of this study is to understand factors that challenge retention and support nurses to stay in general practice. BACKGROUND: One in four general practice nurse positions in England expected to be left unfilled within the next 10 years. Cultural and structural issues associated with working in general practice have been linked with nurses leaving general practice, re-evaluating their professional futures, adjusting work-life balance and bringing forward retirement. This has implications for the future of the general practice nursing workforce and patient care more broadly. DESIGN: Exploratory qualitative interview study funded by the General Nursing Council Trust for England and Wales. University of York ethics approval (Ref: HSRGC/2023/586/A) was gained in September 2023. The study will be conducted between September 2023 and August 2024. METHODS: Qualitative interviews will be conducted with a range of nurses working in, or who have worked in, general practice as well as nurse leaders associated with general practice across England and Wales. Recruitment will be via professional and social media networks and snowballing techniques. We aim to purposively recruit 30-40 participants for maximum variation. Cultural and structural influences which may contribute to retention decisions will be explored. Data will be analysed following framework analysis. DISCUSSION/CONCLUSION: This study will explore how underpinning cultural and structural issues may impact on retention of this highly skilled professional group and identify factors to support retention. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: By exploring factors that support or discourage nurses to remain in general practice, retention strategies can be better planned on order to address the general practice nursing workforce crisis. IMPACT: What problem did the study address? This study will address the retention crisis in nursing in general practice by exploring how cultural and structural issues may impact on retention of this highly skilled professional group and identify factors to support retention. Where and on whom will the research have an impact? From the study findings, recommendations will be developed to inform future policy and practice. Key factors to address attrition will be generated to support employers and policy makers in future primary care workforce planning, as well as supporting nurses, at an individual level, in negotiating their roles in practice. REPORTING METHOD: Standards for Reporting Qualitative Research (O'Brien et al., 2014). PATIENT OR PUBLIC CONTRIBUTION: As this is a workforce study protocol, there is no patient or public contribution.

The well-being of nurses working in general practice during the COVID-19 pandemic: A qualitative study (The GenCo Study).

AIM: Exploration of experiences of nurses working in general practice during the COVID-19 pandemic to evaluate the impact on nurses' professional well-being. DESIGN: An exploratory qualitative study comprised of case studies of three general practice sites in England and a nationwide interview study of nurses working in general practice and nurse leaders. The study was funded by The General Nursing Council for England and Wales Trust. University of York ethics approval (HSRGC/2021/458/I) and Health Research Authority approval was obtained (IRAS: 30353, Protocol number: R23982, Ref 21/HRA/5132, CPMS: 51834). METHODS: Forty participants took part. Case site data consisted of interviews/focus groups and national data consisted of semi-structured interviews. Data collection took place between April and August 2022. Analysis was underpinned by West et al.'s The courage of compassion. Supporting nurses and midwives to deliver high-quality care, The King's fund, 2020 ABC framework of nurses' core work well-being needs. FINDINGS: The majority of participants experienced challenges to their professional well-being contributed to by lack of recognition, feeling undervalued and lack of involvement in higher-level decision-making. Some participants displayed burnout and stress. Structural and cultural issues contributed to this and many experiences pre-dated, but were exacerbated by, the COVID-19 pandemic. CONCLUSIONS: By mapping findings to the ABC framework, we highlight the impact of the COVID-19 pandemic on the well-being of nurses working in general practice and contributing workplace factors. The issues identified have implications for retention and for the future of nursing in general practice. The study highlights how this professional group can be supported in the future. IMPACT: The study contributes to our understanding of the experiences of nurses working in general practice during the COVID-19 pandemic and beyond. Findings have implications for this skilled and experienced workforce, for retention of nurses in general practice, the sustainability of the profession more broadly and care quality and patient safety. REPORTING METHOD: Standards for Reporting Qualitative Research (O'Brien et al. in Journal of the Association of American Medical Colleges, 89(9), 1245-1251, 2014). PATIENT OR PUBLIC CONTRIBUTION: As this was a workforce study there was no patient or public contribution.

Remote and technology-mediated working during the COVID-19 pandemic: A qualitative exploration of the experiences of nurses working in general practice (the GenCo Study).

AIM: To explore how nurses working in general practice experienced remote and technology-mediated working during the COVID-19 pandemic. DESIGN: Exploratory qualitative study with nursing team members working in general practices in England and national nurse leaders. METHODS: Data were collected between April and August 2022. Forty participants took part in either semi-structured interviews or focus groups. Data were analysed using Framework Analysis informed by the PERCS (Planning and Evaluating Remote Consultation Services) Framework. University of York ethics approval [HSRGC/2021/458/I] and Health Research Authority approval were obtained [IRAS:30353. Protocol number: R23982. Ref 21/HRA/5132. CPMS: 51834]. The study was funded by The General Nursing Council for England and Wales Trust. RESULTS: Participants continued to deliver a significant proportion of patient care in-person. However, remote and technology-mediated care could meet patients' needs and broaden access in some circumstances. When remote and technology-mediated working were used this was often part of a blended model which was expected to continue. This could support some workforce issues, but also increase workload. Participants did not always have access to remote technology and were not involved in decision-making about what was used and how this was implemented. They rarely used video consultations, which were not seen to add value in comparison to telephone consultations. Some participants expressed concern that care had become more transactional than therapeutic and there were potential safety risks. CONCLUSION: The study explored how nurses working in general practice during the COVID-19 pandemic engaged with remote and technology-mediated working. It identifies specific issues of access to technology, workload, hybrid working, disruption to therapeutic relationships, safety risks and lack of involvement in decision-making. Changes were implemented quickly with little strategic input from nurses. There is now an opportunity to reflect and build on what has been learned in relation to remote and technology-mediated working to ensure the future development of safe and effective nursing care in general practice. IMPACT: The paper contributes to understanding of remote and technology-mediated working by nurses working in general practice during the COVID-19 pandemic and indicates to employers and policy makers how this can be supported moving forward. REPORTING METHOD: Standards for Reporting Qualitative Research (O'Brien et al., 2014). PATIENT OR PUBLIC CONTRIBUTION: This was a workforce study so there was no patient or public contribution. IMPLICATIONS FOR THE PROFESSION AND PATIENT CARE: The paper highlights specific issues which have implications for the development of remote, technology-mediated and blended working for nurses in general practice, care quality and patient safety. These require full attention to ensure the future development of safe and effective nursing care in general practice moving forward.

General Practice Nurses' experiences of changing care delivery during COVID-19. Implications for future practice: Qualitative study protocol.

AIM: To explore how General Practice Nurses experience implementing change at pace and scale in delivering care during consecutive waves of the COVID-19 pandemic. To evaluate the impact of changes to general practice nurses' working practices on professional wellbeing. BACKGROUND: In response to the COVID-19 pandemic, general practice rapidly and extensively changed care delivery. There has been little exploration of the experiences of General Practice Nurses and care delivery, job satisfaction, workload, stress and professional support. DESIGN: A qualitative case study design of three to five general practice case sites will explore General Practice Nurses' experiences during the Covid-19 pandemic. The study was funded and approved by the General Nursing Council Trust in June 2021. University ethics approval was gained in July 2021. Health Research Authority approval has been obtained [IRAS:30353. Protocol number: R23982. Ref 21/HRA/5132. CPMS: 51834]. METHODS: Data will consist of focus groups and/or semi-structured interviews with General Practice Nurses, primary healthcare team members and other key informants. Business/strategy and nurse team meetings relating to workforce planning/review will be observed. Documents will be analysed and routinely collected general practice data will provide descriptive contextualisation at each site. The study will be theoretically underpinned by the Non-adoption, Abandonment, Scale-up, Spread and Sustainability Framework and data analysed using framework analysis. DISCUSSION: General Practice Nurses have a unique sphere of knowledge and undertake specific work in primary care. This workforce is challenged by recruitment, retention and retirement issues, leading to the loss of highly experienced and knowledgeable professionals. It is important to explore how working practices brought about by Covid-19 affect General Practice Nurses. IMPACT: This study will explore working practices brought about by the Covid-19 pandemic to inform care delivery, patient care and support General Practice Nursing workforce wellbeing and will highlight and mitigate negative aspects of novel and changing care delivery. Key factors in implementing and supporting future practice and change implementation will be developed. TRIAL REGISTRATION: CPMS: 51834.

Exploring the relationship between nursing identity and advanced nursing practice: An ethnographic study.

AIMS AND OBJECTIVES: To consider the relationship between professional nursing identity and advanced practice by exploring intra-professional relationships between advanced nurse practitioners (ANPs) and nursing colleagues. BACKGROUND: Advanced nursing practice continues to develop internationally. Previous studies suggest advanced practice may lack support within nursing, which may lead to underutilisation, retention and patient safety issues. However, the relationship between the wider nursing profession and advanced practice is poorly understood and the theory that professional identity creates cultural barriers to advanced practice has received little empirical attention. DESIGN: Ethnographic methodology was used. METHODS: Fieldwork methods were participant observation and semi-structured interviews. Participants were ANPs (n = 9) and nursing colleagues (n = 5) across two primary care general practice organisations. Data were analysed thematically using framework analysis, underpinned a priori by professional identity theories. Reporting was guided by COREQ. RESULTS: Three themes were identified which indicated how intra-professional relationships were conducted: Conciliating Nursing, where ANPs took responsibility for developing positive relationships with other nurses; Vertical Discounting, where nursing colleagues were dismissive and undermined ANPs, who themselves behaved similarly towards other nurses; and Lateral Othering, where ANPs undermined other ANPs. Vertical Discounting and Lateral Othering destabilised advanced practice. CONCLUSION: Intra-professional relationships, and the broader nursing profession, shape advanced practice. We theorise this is underpinned by threats to professional identity, while weak professional identity amongst even established advanced practitioners exacerbates lack of support. Highlighting these issues allows space to develop alternative strategies to negotiate intra-professional relationships, informed by professional identity theories, which support rather than inhibit advanced practice. RELEVANCE TO CLINICAL PRACTICE: As advanced practice expands throughout primary and secondary care, and across allied health professions, the impact of professional identity and relationships on health care will likely increase and the importance of strong advanced practice identity will become increasingly relevant.

Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer.

INTRODUCTION: Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. METHODS: Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n=84), gene expression profiling (n=47), matched pre- and post-AI aCGH (n=19 pairs) and Ki67-based AI-response analysis (n=39). RESULTS: Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). CONCLUSIONS: These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response.

Should the dosage of controlled-release oxycodone in advanced cancer be modified on the basis of patient characteristics?

PURPOSE: This study aimed to investigate whether the characteristics of patients with advanced cancer explain the variability in oxycodone clearance, with the potential for this information to determine maintenance dosing. METHODS: Patients (n = 36) with advanced cancer who were receiving delayed-release oxycodone (Oxycontin®) (mean dose, 31.4 mg; range, 5-120 mg) mostly twice daily (mean duration = 80 days; range, 5-651 days) provided venous blood samples (n = 139, median = 3 per patient) drawn from 0.25 to 23.4 h post-dose. Plasma was assayed for oxycodone (mean = 39.4 ng/mL; range, 1-256 ng/mL) by high-performance liquid chromatography with tandem mass spectrometry detection. Pharmacokinetic modeling was performed using nonlinear mixed-effects modeling (NONMEM). RESULTS: A one-compartment model with first-order absorption and elimination best described the data. Typical population values and between-subject variability (coefficient of variation, percent) for oxycodone clearance and the oral absorption rate constant were 73 L/h (31.9 %) and 0.0735 h (133 %), respectively. The volume of distribution was estimated based on literature values for intravenous oxycodone in cancer patients. The inclusion of weight, sex, age, creatinine clearance, and serum albumin concentration did not significantly explain pharmacokinetic variability in clearance or absorption rate constant. The subject with the most elevated liver function test values also had the lowest clearance per kilogram. CONCLUSIONS: Oxycodone clearance was similar to that reported previously for healthy adults. Despite reports that patient characteristics significantly affect oxycodone pharmacokinetics, our results do not support alteration of current prescribing practices for maintenance dosing of Oxycontin® in most patients with advanced cancer. The influence of marked liver dysfunction on oxycodone clearance requires further investigation.

Vitamin D deficiency in patients with malignancy in Brisbane.

PURPOSE: This study aims to investigate the prevalence and factors predictive of vitamin D deficiency in patients with malignancy in Brisbane, Australia (latitude 27° S). METHODS: This is a prospective cross-sectional study measuring serum levels of 25-hydroxyvitamin D (25-OHD) in 100 subjects with non-haematological cancer at least 18 years of age not taking vitamin D supplements attending a day oncology unit and oncology/palliative care inpatient ward in Brisbane, Australia. RESULTS: Thirty-seven per cent of outpatient and 49 % of inpatient subjects respectively were vitamin D deficient. Functional status was predictive of low vitamin D levels. CONCLUSION: There was a high prevalence of vitamin D deficiency in patients with cancer in Brisbane, Australia.

ESR1 is co-expressed with closely adjacent uncharacterised genes spanning a breast cancer susceptibility locus at 6q25.1.

Approximately 80% of human breast carcinomas present as oestrogen receptor α-positive (ER+ve) disease, and ER status is a critical factor in treatment decision-making. Recently, single nucleotide polymorphisms (SNPs) in the region immediately upstream of the ER gene (ESR1) on 6q25.1 have been associated with breast cancer risk. Our investigation of factors associated with the level of expression of ESR1 in ER+ve tumours has revealed unexpected associations between genes in this region and ESR1 expression that are important to consider in studies of the genetic causes of breast cancer risk. RNA from tumour biopsies taken from 104 postmenopausal women before and after 2 weeks treatment with an aromatase (oestrogen synthase) inhibitor was analyzed on Illumina 48K microarrays. Multiple-testing corrected Spearman correlation revealed that three previously uncharacterized open reading frames (ORFs) located immediately upstream of ESR1, C6ORF96, C6ORF97, and C6ORF211 were highly correlated with ESR1 (Rs =  0.67, 0.64, and 0.55 respectively, FDR<1 × 10(-7)). Publicly available datasets confirmed this relationship in other groups of ER+ve tumours. DNA copy number changes did not account for the correlations. The correlations were maintained in cultured cells. An ERα antagonist did not affect the ORFs' expression or their correlation with ESR1, suggesting their transcriptional co-activation is not directly mediated by ERα. siRNA inhibition of C6ORF211 suppressed proliferation in MCF7 cells, and C6ORF211 positively correlated with a proliferation metagene in tumours. In contrast, C6ORF97 expression correlated negatively with the metagene and predicted for improved disease-free survival in a tamoxifen-treated published dataset, independently of ESR1. Our observations suggest that some of the biological effects previously attributed to ER could be mediated and/or modified by these co-expressed genes. The co-expression and function of these genes may be important influences on the recently identified relationship between SNPs in this region and breast cancer risk.

Co-occurring Usher syndrome Type 1 and Renal Failure.

PURPOSE: To describe a patient with a rare co-occurrence of Usher syndrome type 1C (USH1C) and renal disease, suspected to be secondary to Alport syndrome. METHOD: Case report and literature review of cases with Usher syndrome and renal failure. Clinical examination, color fundus photography, visual field tests, electroretinography and whole exome sequencing were used to diagnose and document the patient's clinical presentation. RESULTS: An 18-year-old female with known history of congenital hearing loss and chronic renal failure, presents with progressive night and peripheral visual impairment suspicious for an inherited retinal disease. Visual field testing, fundus exam and electroretinography findings supported the diagnosis of Usher syndrome. Whole exome sequencing (WES) identified a novel homozygous frameshift variant (c.238del) in USH1C. WES also identified a homozygous COL4A3 variant of unknown significance, which may be responsible for concomitant Alport syndrome. CONCLUSION: By presenting this rare case of co-occurring Usher syndrome Type 1 and renal failure, we highlight the importance of conducting further investigations that could reveal an additional underlying etiology when these entities are present.

Co-designing a personalised care plan for patients with rectal cancer: reflections and practical learnings.

BACKGROUND: Consumer involvement is considered an essential component of contemporary cancer research, with a movement towards participatory methods, to the benefit of consumers and researchers. Overall, in-depth research on participant experiences and perceptions of their co-designer role-and how these may (or may not) change during a co-design project-is limited. The purpose of this paper was to synthesise the reflective accounts of consumers, project staff, and a researcher who partnered on a project to develop a personalised care plan template, with the aim of generating guidance for others looking to partner with consumers in health and medical research. Here, our team of researchers, project staff, and consumers reflect on the experience of working together using Gibbs' Reflective Cycle, which was completed by team members with responses then undergoing inductive data analysis. RESULTS: Reflections are categorised under three core themes: (1) setting up the group and building relationships (2) measuring the value of consumer involvement, and (3) potential challenges for consumer involvement. Through reflection on our experiences of co-design, our team developed and identified practical strategies that contributed to the success of our partnership. These include setting expectations as a group; having experienced consumers on the team; having regular, pre-scheduled meetings that run to time; and working to overcome challenges identified by the group such as power imbalances, time commitment, and lack of diversity. CONCLUSION: These practical reflections on creating a safe and supportive environment in which genuine consumer involvement can take place could inform other institutions and researchers looking to work meaningfully with consumers in research.

Consumer involvement in cancer research can inform the initial setting of research priorities, and then the design and conduct of research, with a view to optimising research impact. As part of a project to develop a personalised care plan for patients with newly diagnosed rectal cancer, our team of medical oncologists and project staff partnered with a group of consumers from project initiation. Here, we reflect on our experiences, including the benefits and challenges associated with consumer involvement. Positive aspects of the partnership between consumers, project staff, and the researcher included the establishment of a cohesive team, which substantially improved the study design, conduct, and study outcomes. This experience increased the enthusiasm of the project staff and researcher for consumer engagement in future research. Things that negatively impacted the team included the loss of consumers due to cancer-related health issues. A lack of diversity in the consumer group was recognised as a limitation of the breadth of the consumer voice throughout the project. Upon reflection, there were many important learnings regarding meeting preparation, structure, and team culture that we discuss here, looking to provide practical guidance on optimising consumer involvement.

Cardiopulmonary exercise variables and their association with postoperative morbidity and mortality after major oesophagogastric cancer surgery-a multicentre observational study.

Background: Outcomes after oesophagogastric cancer surgery remain poor. Cardiopulmonary exercise testing (CPET) used for risk stratification before oesophagogastric cancer surgery is based on conflicting evidence. This study explores the relationship between CPET and postoperative outcomes, specifically for patients undergoing neoadjuvant treatment. Methods: Patients undergoing oesophagogastric cancer resection and CPET (pre- or post-neoadjuvant treatment, or both) were retrospectively enrolled into a multicentre pooled cohort study. Oxygen uptake at peak exercise (VO2 peak) was compared with 1-yr postoperative survival. Secondary analyses explored relationships between patient characteristics, tumour pathology characteristics, CPET variables (absolute, relative to weight, ideal body weight, and body surface area), and postoperative outcomes (morbidity, 1-yr and 3-yr survival) were assessed using logistic regression analyses. Results: Seven UK centres recruited 611 patients completing a 3-yr postoperative follow-up period. Oesophagectomy was undertaken in 475 patients (78%). Major complications occurred in 25%, with 18% 1-yr and 43% 3-yr mortality. No association between VO2 peak or other selected CPET variables and 1-yr survival was observed in the overall cohort. In the overall cohort, the anaerobic threshold relative to ideal body weight was associated with 3-yr survival (P=0.013). Tumour characteristics (ypT/ypN/tumour regression/lymphovascular invasion/resection margin; P<0.001) and Clavien-Dindo ≥3a (P<0.001) were associated with 1-yr and 3-yr survival. On subgroup analyses, pre-neoadjuvant treatment CPET; anaerobic threshold (absolute; P=0.024, relative to ideal body weight; P=0.001, body surface area; P=0.009) and VE/VCO2 at anaerobic threshold (P=0.026) were associated with 3-yr survival. No other CPET variables (pre- or post-neoadjuvant treatment) were associated with survival. Conclusions: VO2 peak was not associated with 1-yr survival after oesophagogastric cancer resection. Tumour characteristics and major complications were associated with survival; however, only some selected pre-neoadjuvant treatment CPET variables were associated with 3-yr survival. CPET in this cohort of patients demonstrates limited outcome predictive precision. Clinical trial registration: NCT03637647.

Cardiorespiratory fitness predicts mortality and hospital length of stay after major elective surgery in older people.

OBJECTIVE: This study aimed to define the relationship between cardiorespiratory fitness and age in the context of postsurgery mortality and morbidity in older people. BACKGROUND: Postsurgery mortality and morbidity increase with age. Cardiorespiratory fitness also declines with age, and the independent and linked associations between cardiorespiratory fitness and age on postsurgical mortality and morbidity remain to be determined. METHODS: An unselected consecutive group of 389 adults with a mean age of 66 years (range 26-86 years) underwent cardiorespiratory exercise testing before major hepatobiliary surgery at a single center. Mortality and critical care unit and hospital lengths of stay were collected from patient records. Primary outcomes were in-hospital all-cause mortality after surgery and hospital and critical care lengths of stay. RESULTS: Anaerobic threshold was the most significant independent predictor for postoperative mortality (P = 0.003; ß = -0.657 and odds ratio = 0.52) in 18 of 389 (4.6%) patients who died during their in-hospital stay. Age was not a significant predictor in this model. Older people with normal cardiorespiratory fitness spent the same number of days in the hospital or critical care unit as younger people with similar cardiorespiratory fitness (13 vs 12; P = 0.08 and 1 vs 1; P = 0.103). Patients older than 75 years with low cardiorespiratory fitness spent a median of 11 days longer in hospital (23 vs 12; P < 0.0001) and 2 days longer in critical care (2.9 vs 0.9; P < 0.0001) when compared with patients with adequate cardiorespiratory fitness. CONCLUSIONS: Cardiorespiratory fitness is an independent predictor of mortality and length of hospital stay and provides significantly more accurate prognostic information than age alone. Clinicians should consider both the prognostic value of cardiorespiratory testing and techniques to preserve cardiorespiratory function before elective surgery in older people.

Examining the Peer-Reviewed Published Literature Regarding Low Back Pain in Rowing: A Scoping Review.

Background: Low back pain (LBP) is highly prevalent in the rowing population. The body of existing research variously investigates risk factors, prevention, and treatment methods. Purpose: The purpose of this scoping review was to explore the breadth and depth of the LBP literature in rowing and to identify areas for future research. Study Design: Scoping review. Methods: PubMed, Ebsco and ScienceDirect were searched from inception to November 1, 2020. Only published, peer-reviewed, primary, and secondary data pertaining to LBP in rowing were included for this study. Arksey and O'Malley's framework for guided data synthesis was used. Reporting quality of a subsection of the data was assessed using the STROBE tool. Results: Following the removal of duplicates and abstract screening, a set of 78 studies were included and divided into the following categories: epidemiology, biomechanics, biopsychosocial, and miscellaneous. The incidence and prevalence of LBP in rowers were well mapped. The biomechanical literature covered a wide range of investigations with limited cohesion. Significant risk factors for LBP in rowers included back pain history and prolonged ergometer use. Conclusion: A lack of consistent definitions within the studies caused fragmentation of the literature. There was good evidence for prolonged ergometer use and history of LBP to constitute risk factors and this may assist future LBP preventative action. Methodological issues such as small sample size and barriers to injury reporting increased heterogeneity and decreased data quality. Further exploration is required to determine the mechanism of LBP in rowers through research with larger samples.

Expensive Drugs for Rare Diseases in Canada: Time for Action Everywhere and by Everyone.

Expensive drugs for rare diseases pose unique economic, evidentiary and ethical challenges, and these will continue to escalate unless steps are taken urgently to address these challenges. We propose concrete actions that all stakeholders (federal and provincial/territorial governments, patients, healthcare providers, the public and drug manufacturers) could take now as a first step toward enhancing sustainability in the use of innovative (albeit expensive) therapies within our publicly funded healthcare system.

Expensive Drugs for Rare Diseases in Canada: What Value and at What Cost?

There has been explosive growth in the market for expensive drugs for rare diseases (EDRDs). Traditional standards of evidence are not achievable for rare diseases, so lower standards are applied. The price of these drugs is extremely high. This combination of lower standards and higher prices make EDRDs attractive to manufacturers. Legislation designed to incentivize drug development for rare diseases contains loopholes that drive prices up worldwide. Canada compounds those problems with a complex network of agencies that impede communication between those providing market authorization and those purchasing drugs. Drug pricing is not related to metrics like investment or value, but rather willingness to pay. Without high-quality evidence to assess value, we inadvertently prioritize patients with rare diseases over those with common diseases, creating conflict among ethical principles such as social utility, justice and the rule of rescue. Lack of transparency over what is being funded and for whom makes it hard to mitigate challenges through effective policy development. We review the evidentiary, economic and ethical issues around EDRDs and ways to move forward, including enhanced transparency and the development of high-quality evidence to ensure that we do not pay for drugs that do not work.

Implementation of pharmacogenetic testing in oncology: DPYD-guided dosing to prevent fluoropyrimidine toxicity in British Columbia.

Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.

Is saliva a valid substitute for plasma in pharmacokinetic studies of oxycodone and its metabolites in patients with cancer?

PURPOSE: Little is known about the pharmacokinetics (PKs) of oxycodone in patients with advanced cancer. There is considerable reluctance to subject these patients to non-essential tests including repeated venipuncture that has been necessary in PK studies to date. We investigated the possibility of using saliva sampling as a simple non-invasive test to investigate opioid PKs. METHODS: Patients with malignant disease receiving oral sustained release (SR) oxycodone at any dose were asked to provide saliva samples at the same time as blood samples. Samples were not taken within 6 h of a dose of immediate release oxycodone. Plasma and saliva oxycodone and metabolite concentrations were measured using HPLC coupled with tandem mass spectrometric detection. RESULTS: One hundred and thirty-nine paired plasma/saliva samples were collected from 43 cancer patients who had been taking SR oxycodone for more than 5 days at doses ranging from 10 to 600 mg/day (median 40 mg/day). Plasma concentrations of oxycodone and noroxycodone ranged from 1.0 to 256.0 and 0.9-269.4 µg/L, respectively. Salivary concentrations of oxycodone (range 0.93-3,620, mean 336 µg/L) were much higher than plasma concentrations (mean 38.2 µg/L). There was a poor correlation between concentrations of both oxycodone and noroxycodone in plasma and saliva over a range of times following dosing (r (2) = 0.4641 and 0.3891, respectively). No correlation was shown between salivary pH and oxycodone or noroxycodone concentrations. The majority of patients questioned chose saliva sampling over plasma sampling as the preferred method. CONCLUSION: High levels of both oxycodone and its major metabolite are present in saliva, but this does not provide a valid substitute for plasma when monitoring oxycodone levels for PK studies or therapeutic monitoring.

Preoperative optimization: rationale and process: is it economic sense?

PURPOSE OF REVIEW: The development of preoperative clinics and the increasing importance of the anaesthetist in the management of surgical risk have expanded the concept of preoperative optimization. This review will focus on the rationale and process for cost-effective preoperative optimization. RECENT FINDINGS: Postoperative morbidity, rather than mortality, is the most important surgical outcome in economic terms. Since preoperative comorbidity, in association with surgical complexity, is more predictive of hospital costs than the subsequent treatment of postoperative complications per se, preoperative optimization represents an appropriate economic target. Process management, including guidelines to reduce unnecessary investigations and specialist referrals and enhancing perioperative recovery, makes economical sense in the majority of patients who undergo noncardiac surgery with few complications. Preoperative optimization of a minority of high-risk surgical patients is also important given limited critical care resource. However, the evidence for specific optimization strategies in this latter group continues to evolve and requires further clarification in well designed trials. SUMMARY: The requirement for appropriate methods of risk stratification of surgical patients targeted at the reduction of postoperative morbidity, underpins the development of cost-effective preoperative optimization. Specific process-based and clinical measures may then be applied to the development of individualized perioperative care packages.

Perspectives of GPs working in or alongside emergency departments in England: qualitative findings from the GPs and Emergency Departments Study.

BACKGROUND: Around 43% of emergency department (ED) attendances can be managed in general practice. Strategies to address this include directing appropriate patients to GPs working in or alongside EDs (GPED). Views of GPs choosing to work in GPED roles may inform planning and implementation of GPED services as well as wider general practice provision. AIM: To explore the experiences and motivations of GPs choosing to work in GPED services in England, and to identify factors that may support or hinder GPs working in GPED roles. DESIGN AND SETTING: Thematic analysis of 42 semi-structured interviews of GPs working in 10 GPED case sites across England. METHOD: Qualitative GP interviews from a mixed-methods study of GPs in GPED roles were thematically analysed in relation to research aims. RESULTS: Four themes were generated: the 'pull' of a portfolio career; the 'push' of disillusionment with general practice; professional reciprocity; sustainability of GPED services and core general practice. Flexible, favourable working conditions, collaboration, and professional development made GPED an attractive workplace, often as part of a portfolio career or after retiring from core general practice. Working in GPED services was largely driven by disillusionment with core general practice. Both GPED and core general practice were thought to benefit from GPED GPs' skills. There were concerns about GPED sustainability and destabilisation of core general practice. CONCLUSION: GPED may extend the clinical careers of experienced GPs and support recruitment and retention of more recently qualified GPs. Despite some benefits, GPED may destabilise core general practice and increase pressure on both environments.