Implementing absolute cardiovascular disease risk assessment into pathology collection services.

BACKGROUND: Pathology services represent an ideal setting to integrate absolute cardiovascular disease (CVD) risk estimation when patients attend for routine cholesterol testing. This study aimed to explore the process of implementing CVD risk estimation into point-of-care service delivery by pathology staff to inform future implementation and sustainability. METHODS: A new service for CVD risk estimation via a self-directed screening station was implemented into 14 pathology service sites across Tasmania, Australia. Before implementation, observations at pathology services (n = 26) and semi-structured interviews were undertaken with 26 pathology staff (88% female, 77% aged 41-60 years) to identify factors that could impact implementation of the service. The process of implementation was then evaluated using participant observations and clinical trial recruitment data. Transcripts and field notes were analysed thematically according to the Medical Research Council Framework and used to develop a programme logic model to understand how the service could be adapted to be successfully integrated into routine workflow at pathology services. RESULTS: Eight key themes were identified during the pre-implementation phase as important factors that could impact upon integration of CVD risk estimation into pathology services. Themes related to factors within the organisation, including available resources, logistics and workflow, as well as having sufficient time to complete the intervention. Additional factors related to the individual motivations of staff, collaborative leadership and patient characteristics. Success of implementation varied among sites, requiring the trialling of different strategies to support uptake of the service and patient recruitment. CONCLUSIONS: Implementing CVD risk estimation into point-of-care pathology services required an understanding of the core implementation components specific to each context, and for implementation strategies to be targeted to the individual and organisational contexts. The generated programme logic model may be useful in guiding future implementation endeavours within these services and aiding the selection of apt implementation strategies. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04896021, registered 19/05/2021, https://clinicaltrials.gov/study/NCT04896021.

How do general practitioners manage patient health literacy differences in cardiovascular disease prevention consultations? An interview study.

OBJECTIVES: Low health literacy is associated with worse health outcomes, including for cardiovascular disease (CVD). However, general practitioners (GPs) have limited support to identify and address patient health literacy needs in CVD prevention consultations. This study explored GPs' experiences of patient health literacy needs during CVD risk assessment and management consultations. METHODS: Semi-structured interviews with 18 GPs in Tasmania, Australia in 2021. A Framework Analysis approach was used to code transcripts to a thematic framework. RESULTS: GPs perceptions on patient health literacy informed three themes: 1. Methods of estimating health literacy; 2. GPs' perceptions about the impact of health literacy on CVD prevention including risk factor knowledge and behaviours; and 3. Strategies for communicating with patients experiencing health literacy challenges. The findings show that while no formal tools were used to assess health literacy in this sample, perceived health literacy can change GPs' communication and prevention strategies. CONCLUSION: The findings raise concerns about the equity of choices made available to patients, based on subjective perceptions of their health literacy level. PRACTICE IMPLICATION: GPs could be better supported to assess and address patient health literacy needs in CVD prevention consultations.

Prehospital early warning scores for adults with suspected sepsis: the PHEWS observational cohort and decision-analytic modelling study.

Background: Guidelines for sepsis recommend treating those at highest risk within 1 hour. The emergency care system can only achieve this if sepsis is recognised and prioritised. Ambulance services can use prehospital early warning scores alongside paramedic diagnostic impression to prioritise patients for treatment or early assessment in the emergency department. Objectives: To determine the accuracy, impact and cost-effectiveness of using early warning scores alongside paramedic diagnostic impression to identify sepsis requiring urgent treatment. Design: Retrospective diagnostic cohort study and decision-analytic modelling of operational consequences and cost-effectiveness. Setting: Two ambulance services and four acute hospitals in England. Participants: Adults transported to hospital by emergency ambulance, excluding episodes with injury, mental health problems, cardiac arrest, direct transfer to specialist services, or no vital signs recorded. Interventions: Twenty-one early warning scores used alongside paramedic diagnostic impression, categorised as sepsis, infection, non-specific presentation, or other specific presentation. Main outcome measures: Proportion of cases prioritised at the four hospitals; diagnostic accuracy for the sepsis-3 definition of sepsis and receiving urgent treatment (primary reference standard); daily number of cases with and without sepsis prioritised at a large and a small hospital; the minimum treatment effect associated with prioritisation at which each strategy would be cost-effective, compared to no prioritisation, assuming willingness to pay £20,000 per quality-adjusted life-year gained. Results: Data from 95,022 episodes involving 71,204 patients across four hospitals showed that most early warning scores operating at their pre-specified thresholds would prioritise more than 10% of cases when applied to non-specific attendances or all attendances. Data from 12,870 episodes at one hospital identified 348 (2.7%) with the primary reference standard. The National Early Warning Score, version 2 (NEWS2), had the highest area under the receiver operating characteristic curve when applied only to patients with a paramedic diagnostic impression of sepsis or infection (0.756, 95% confidence interval 0.729 to 0.783) or sepsis alone (0.655, 95% confidence interval 0.63 to 0.68). None of the strategies provided high sensitivity (> 0.8) with acceptable positive predictive value (> 0.15). NEWS2 provided combinations of sensitivity and specificity that were similar or superior to all other early warning scores. Applying NEWS2 to paramedic diagnostic impression of sepsis or infection with thresholds of > 4, > 6 and > 8 respectively provided sensitivities and positive predictive values (95% confidence interval) of 0.522 (0.469 to 0.574) and 0.216 (0.189 to 0.245), 0.447 (0.395 to 0.499) and 0.274 (0.239 to 0.313), and 0.314 (0.268 to 0.365) and 0.333 (confidence interval 0.284 to 0.386). The mortality relative risk reduction from prioritisation at which each strategy would be cost-effective exceeded 0.975 for all strategies analysed. Limitations: We estimated accuracy using a sample of older patients at one hospital. Reliable evidence was not available to estimate the effectiveness of prioritisation in the decision-analytic modelling. Conclusions: No strategy is ideal but using NEWS2, in patients with a paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. Research is needed to develop better definition, diagnosis and treatments for sepsis. Study registration: This study is registered as Research Registry (reference: researchregistry5268). Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/136/10) and is published in full in Health Technology Assessment; Vol. 28, No. 16. See the NIHR Funding and Awards website for further award information.

Sepsis is a life-threatening condition in which an abnormal response to infection causes heart, lung or kidney failure. People with sepsis need urgent treatment. They need to be prioritised at the emergency department rather than waiting in the queue. Paramedics attempt to identify people with possible sepsis using an early warning score (based on simple measurements, such as blood pressure and heart rate) alongside their impression of the patient's diagnosis. They can then alert the hospital to assess the patient quickly. However, an inaccurate early warning score might miss cases of sepsis or unnecessarily prioritise people without sepsis. We aimed to measure how accurately early warning scores identified people with sepsis when used alongside paramedic diagnostic impression. We collected data from 71,204 people that two ambulance services transported to four different hospitals in 2019. We recorded paramedic diagnostic impressions and calculated early warning scores for each patient. At one hospital, we linked ambulance records to hospital records and identified who had sepsis. We then calculated the accuracy of using the scores alongside diagnostic impression to diagnose sepsis. Finally, we used modelling to predict how many patients (with and without sepsis) paramedics would prioritise using different strategies based on early warning scores and diagnostic impression. We found that none of the currently available early warning scores were ideal. When they were applied to all patients, they prioritised too many people. When they were only applied to patients whom the paramedics thought had infection, they missed many cases of sepsis. The NEWS2, score, which ambulance services already use, was as good as or better than all the other scores we studied. We found that using the NEWS2, score in people with a paramedic impression of infection could achieve a reasonable balance between prioritising too many patients and avoiding missing patients with sepsis.

Prehospital early warning scores for adults with suspected sepsis: retrospective diagnostic cohort study.

BACKGROUND: Ambulance services need to identify and prioritise patients with sepsis for early hospital assessment. We aimed to determine the accuracy of early warning scores alongside paramedic diagnostic impression to identify sepsis that required urgent treatment. METHODS: We undertook a retrospective diagnostic cohort study involving adult emergency medical cases transported to Sheffield Teaching Hospitals ED by Yorkshire Ambulance Service in 2019. We used routine ambulance service data to calculate 21 early warning scores and categorise paramedic diagnostic impressions as sepsis, infection, non-specific presentation or other presentation. We linked cases to hospital records and identified those meeting the sepsis-3 definition who received urgent hospital treatment for sepsis (reference standard). Analysis determined the accuracy of strategies that combined early warning scores at varying thresholds for positivity with paramedic diagnostic impression. RESULTS: We linked 12 870/24 955 (51.6%) cases and identified 348/12 870 (2.7%) with a positive reference standard. None of the strategies provided sensitivity greater than 0.80 with positive predictive value greater than 0.15. The area under the receiver operating characteristic curve for the National Early Warning Score, version 2 (NEWS2) applied to patients with a diagnostic impression of sepsis or infection was 0.756 (95% CI 0.729, 0.783). No other early warning score provided clearly superior accuracy to NEWS2. Paramedic impression of sepsis or infection had sensitivity of 0.572 (0.519, 0.623) and positive predictive value of 0.156 (0.137, 0.176). NEWS2 thresholds of >4, >6 and >8 applied to patients with a diagnostic impression of sepsis or infection, respectively, provided sensitivities and positive predictive values of 0.522 (0.469, 0.574) and 0.216 (0.189, 0.245), 0.447 (0.395, 0.499) and 0.274 (0.239, 0.313), and 0.314 (0.268, 0.365) and 0.333 (0.284, 0.386). CONCLUSION: No strategy is ideal but using NEWS2 alongside paramedic diagnostic impression of infection or sepsis could identify one-third to half of sepsis cases without prioritising unmanageable numbers. No other score provided clearly superior accuracy to NEWS2. TRIAL REGISTRATION NUMBER: researchregistry5268, https://www.researchregistry.com/browse-the-registry%23home/registrationdetails/5de7bbd97ca5b50015041c33/.

A model-based economic analysis of the CFHealthHub intervention to support adherence to inhaled medications for people with cystic fibrosis in the UK.

BACKGROUND: Adherence to preventative inhaled therapies in people with cystic fibrosis (CF) is low, resulting in potentially avoidable health losses and the need for costly rescue therapies. OBJECTIVES: To estimate the cost-effectiveness of the CFHealthHub (CFHH) intervention to support adherence to inhaled medications. METHODS: A state transition model was developed to assess the cost-effectiveness of the CFHH intervention versus usual care from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. Costs and health outcomes were discounted at a rate of 3.5 percent per annum. Costs were valued at 2021/22 prices. The model structure includes health states defined by survival status, level of lung function, and transplant history. Treatment effects were modeled by changing the probabilities of transitioning between lung function states and reducing exacerbation rates. Model parameters were informed by the CFHH trial, CF Registry data, routine cost databases, literature, and expert opinion. Deterministic and probabilistic sensitivity analyses were undertaken to assess uncertainty. RESULTS: The CFHH intervention is expected to generate additional health gains and cost savings compared with usual care. Assuming that it is delivered for 10 years, the CFHH intervention is expected to generate 0.17 additional quality-adjusted life years and cost savings of GBP 1,600 (EUR 1,662) per patient. CONCLUSIONS: The CFHH intervention is expected to dominate usual care, irrespective of the duration over which the intervention is delivered. The modeled benefits and cost savings are smaller than initially expected and are sensitive to relative treatment effects on lung function.

Navigating the maze of osteoarthritis treatment: A qualitative study exploring the experience of individuals with osteoarthritis in Tasmania, Australia.

OBJECTIVE: Using a qualitative design this study aimed to (1) explore the experience of people living with osteoarthritis (OA), (2) gain an understanding of their navigation of the health system and, (3) explore their opinions on the role of exercise and joint replacement surgery for the management of OA. METHODS: Purposive sampling was used to recruit 26 participants with knee OA, aged 45 years and over, from Tasmania, Australia. Semi-structured interviews were audio-recorded, transcribed, coded, and thematically analysed to document participant understanding and experience of OA and their opinions on the role of exercise and surgery in managing OA. RESULTS: Of the 26 participants, 80% (n = 21) were female with a mean age of 66 years. The main theme identified was that individuals with knee OA were navigating a maze of OA treatments. Three related subthemes were that participants: (i) perceived their general practitioner did not have an ongoing role in their OA care, (ii) self-directed their management and, (iii) sampled from a 'smorgasbord' of treatment options, including low-value care options. Two other major themes were: the role of exercise for OA management, and surgery as a last resort. CONCLUSION: Our findings suggest that OA patients may not be choosing consistent, high-value care for their OA. This highlights the importance of an evidence-based multi-disciplinary approach to guide patients to self-manage their OA and support their navigation of the health system. Reducing emphasis on the pathway to surgery and streamlining access to conservative management strategies may assist people to receive high-value care.

A descriptive study of samples sizes used in agreement studies published in the PubMed repository.

INTRODUCTION: A sample size justification is required for all studies and should give the minimum number of subjects to be recruited for the study to achieve its primary objective. The aim of this review is to describe sample sizes from agreement studies with continuous or categorical endpoints and different methods of assessing agreement, and to determine whether sample size justification was provided. METHODS: Data were gathered from the PubMed repository with a time interval of 28th September 2018 to 28th September 2020. The search returned 5257 studies of which 82 studies were eligible for final assessment after duplicates and ineligible studies were excluded. RESULTS: We observed a wide range of sample sizes. Forty-six studies (56%) used a continuous outcome measure, 28 (34%) used categorical and eight (10%) used both. Median sample sizes were 50 (IQR 25 to 100) for continuous endpoints and 119 (IQR 50 to 271) for categorical endpoints. Bland-Altman limits of agreement (median sample size 65; IQR 35 to 124) were the most common method of statistical analysis for continuous variables and Kappa coefficients for categorical variables (median sample size 71; IQR 50 to 233). Of the 82 studies assessed, only 27 (33%) gave justification for their sample size. CONCLUSIONS: Despite the importance of a sample size justification, we found that two-thirds of agreement studies did not provide one. We recommend that all agreement studies provide rationale for their sample size even if they do not include a formal sample size calculation.

Correct use and ease-of-use of placebo ELLIPTA dry-powder inhaler in adult patients with chronic obstructive pulmonary disease.

BACKGROUND: Inhaler technique errors are common in chronic obstructive pulmonary disease (COPD) treatment, potentially leading to poor disease management. Our pooled analysis approach assessed correct use and ease-of-use of a placebo ELLIPTA dry-powder inhaler (DPI) in patients with COPD. METHODS: Adults with COPD from open-label/non-blinded studies evaluating a placebo ELLIPTA DPI and reporting outcomes of correct use (based on the ELLIPTA DPI patient information leaflet [PIL]) and/or ease-of-use were included. Correct use and ease-of use at study end were primary and secondary endpoints, respectively. Data from patients in the placebo ELLIPTA DPI arm of each study were pooled, and the intent-to-treat (ITT) population was used for all analyses. RESULTS: Four placebo ELLIPTA DPI studies, reporting correct use (n = 4) and ease-of-use (n = 2), were included in the analysis. The ITT population comprised 1232 patients (mean age 66.2 years). For the primary endpoint, 80.1% (n = 975/1217) of patients demonstrated correct use at study end (95% confidence interval [CI]: 77.8%-82.3%). For the secondary endpoint, 95.7% (n = 797/833) of patients rated placebo ELLIPTA DPI use "easy"/"very easy" at study end (95% CI: 94.1%-97.0%). Correct use and "easy"/"very easy" user ratings remained high across younger (40-64 years) and older (≥65 years) age groups. CONCLUSIONS: Across age groups, most patients used the placebo ELLIPTA DPI correctly and rated it "easy"/"very easy" to use. Consistent with the Global Initiative for Chronic Obstructive Lung Disease 2021 report, our findings emphasize that proper training and clear instructions on PILs are important for optimal inhaler use.

Accuracy of emergency medical service telephone triage of need for an ambulance response in suspected COVID-19: an observational cohort study.

OBJECTIVE: To assess accuracy of emergency medical service (EMS) telephone triage in identifying patients who need an EMS response and identify factors which affect triage accuracy. DESIGN: Observational cohort study. SETTING: Emergency telephone triage provided by Yorkshire Ambulance Service (YAS) National Health Service (NHS) Trust. PARTICIPANTS: 12 653 adults who contacted EMS telephone triage services provided by YAS between 2 April 2020 and 29 June 2020 assessed by COVID-19 telephone triage pathways were included. OUTCOME: Accuracy of call handler decision to dispatch an ambulance was assessed in terms of death or need for organ support at 30 days from first contact with the telephone triage service. RESULTS: Callers contacting EMS dispatch services had an 11.1% (1405/12 653) risk of death or needing organ support. In total, 2000/12 653 (16%) of callers did not receive an emergency response and they had a 70/2000 (3.5%) risk of death or organ support. Ambulances were dispatched to 4230 callers (33.4%) who were not conveyed to hospital and did not deteriorate. Multivariable modelling found variables of older age (1 year increase, OR: 1.05, 95% CI: 1.04 to 1.05) and presence of pre-existing respiratory disease (OR: 1.35, 95% CI: 1.13 to 1.60) to be predictors of false positive triage. CONCLUSION: Telephone triage can reduce ambulance responses but, with low specificity. A small but significant proportion of patients who do not receive an initial emergency response deteriorated. Research to improve accuracy of EMS telephone triage is needed and, due to limitations of routinely collected data, this is likely to require prospective data collection.

Composite Outcomes in Clinical Prediction Modeling: Are We Trying to Predict Apples and Oranges?

Composite outcomes are widely used in clinical research. Existing literature has considered the pros and cons of composite outcomes in clinical trials, but their extensive use in clinical prediction has received much less attention. Clinical prediction assists decision-making by directing patients with higher risks of adverse outcomes toward interventions that provide the greatest benefits to those at the greatest risk. In this article, we summarize our existing understanding of the advantages and disadvantages of composite outcomes, consider how these relate to clinical prediction, and highlight the problem of key predictors having markedly different associations with individual components of the composite outcome. We suggest that a "composite outcome fallacy" may occur when a clinical prediction model is based on strong associations between key predictors and one component of a composite outcome (such as mortality) and used to direct patients toward intervention when these predictors actually have an inverse association with a more relevant component of the composite outcome (such as the use of a lifesaving intervention). We propose that clinical prediction scores using composite outcomes should report their accuracy for key components of the composite outcome and examine for inconsistencies among predictor variables.

Accuracy of telephone triage for predicting adverse outcomes in suspected COVID-19: an observational cohort study.

OBJECTIVE: To assess accuracy of telephone triage in identifying need for emergency care among those with suspected COVID-19 infection and identify factors which affect triage accuracy. DESIGN: Observational cohort study. SETTING: Community telephone triage provided in the UK by Yorkshire Ambulance Service NHS Trust (YAS). PARTICIPANTS: 40 261 adults who contacted National Health Service (NHS) 111 telephone triage services provided by YAS between 18 March 2020 and 29 June 2020 with symptoms indicating COVID-19 infection were linked to Office for National Statistics death registrations and healthcare data collected by NHS Digital. OUTCOME: Accuracy of triage disposition was assessed in terms of death or need for organ support up to 30 days from first contact. RESULTS: Callers had a 3% (1200/40 261) risk of serious adverse outcomes (death or organ support). Telephone triage recommended self-care or non-urgent assessment for 60% (24 335/40 261), with a 1.3% (310/24 335) risk of adverse outcomes. Telephone triage had 74.2% sensitivity (95% CI: 71.6 to 76.6%) and 61.5% specificity (95% CI: 61% to 62%) for the primary outcome. Multivariable analysis suggested respiratory comorbidities may be overappreciated, and diabetes underappreciated as predictors of deterioration. Repeat contact with triage service appears to be an important under-recognised predictor of deterioration with 2 contacts (OR 1.77, 95% CI: 1.14 to 2.75) and 3 or more contacts (OR 4.02, 95% CI: 1.68 to 9.65) associated with false negative triage. CONCLUSION: Patients advised to self-care or receive non-urgent clinical assessment had a small but non-negligible risk of serious clinical deterioration. Repeat contact with telephone services needs recognition as an important predictor of subsequent adverse outcomes.

Prognostic accuracy of triage tools for adults with suspected COVID-19 in a prehospital setting: an observational cohort study.

BACKGROUND: Tools proposed to triage patient acuity in COVID-19 infection have only been validated in hospital populations. We estimated the accuracy of five risk-stratification tools recommended to predict severe illness and compared accuracy to existing clinical decision making in a prehospital setting. METHODS: An observational cohort study using linked ambulance service data for patients attended by Emergency Medical Service (EMS) crews in the Yorkshire and Humber region of England between 26 March 2020 and 25 June 2020 was conducted to assess performance of the Pandemic Respiratory Infection Emergency System Triage (PRIEST) tool, National Early Warning Score (NEWS2), WHO algorithm, CRB-65 and Pandemic Medical Early Warning Score (PMEWS) in patients with suspected COVID-19 infection. The primary outcome was death or need for organ support. RESULTS: Of the 7549 patients in our cohort, 17.6% (95% CI 16.8% to 18.5%) experienced the primary outcome. The NEWS2 (National Early Warning Score, version 2), PMEWS, PRIEST tool and WHO algorithm identified patients at risk of adverse outcomes with a high sensitivity (>0.95) and specificity ranging from 0.3 (NEWS2) to 0.41 (PRIEST tool). The high sensitivity of NEWS2 and PMEWS was achieved by using lower thresholds than previously recommended. On index assessment, 65% of patients were transported to hospital and EMS decision to transfer patients achieved a sensitivity of 0.84 (95% CI 0.83 to 0.85) and specificity of 0.39 (95% CI 0.39 to 0.40). CONCLUSION: Use of NEWS2, PMEWS, PRIEST tool and WHO algorithm could improve sensitivity of EMS triage of patients with suspected COVID-19 infection. Use of the PRIEST tool would improve sensitivity of triage without increasing the number of patients conveyed to hospital.

Self-management intervention to reduce pulmonary exacerbations by supporting treatment adherence in adults with cystic fibrosis: a randomised controlled trial.

INTRODUCTION: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months. METHODS: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months. RESULTS: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred. CONCLUSIONS: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.

Intravenous or oral antibiotic treatment in adults and children with cystic fibrosis and Pseudomonas aeruginosa infection: the TORPEDO-CF RCT.

BACKGROUND: People with cystic fibrosis are susceptible to pulmonary infection with Pseudomonas aeruginosa. This may become chronic and lead to increased mortality and morbidity. If treatment is commenced promptly, infection may be eradicated through prolonged antibiotic treatment. OBJECTIVE: To compare the clinical effectiveness, cost-effectiveness and safety of two eradication regimens. DESIGN: This was a Phase IV, multicentre, parallel-group, randomised controlled trial. SETTING: Seventy UK and two Italian cystic fibrosis centres. PARTICIPANTS: Participants were individuals with cystic fibrosis aged > 28 days old who had never had a P. aeruginosa infection or who had been infection free for 1 year. INTERVENTIONS: Fourteen days of intravenous ceftazidime and tobramycin or 3 months of oral ciprofloxacin. Inhaled colistimethate sodium was included in both regimens over 3 months. Consenting patients were randomly allocated to either treatment arm in a 1 : 1 ratio using simple block randomisation with random variable block length. MAIN OUTCOME MEASURES: The primary outcome was eradication of P. aeruginosa at 3 months and remaining free of infection to 15 months. Secondary outcomes included time to reoccurrence, spirometry, anthropometrics, pulmonary exacerbations and hospitalisations. Primary analysis used intention to treat (powered for superiority). Safety analysis included patients who had received at least one dose of any of the study drugs. Cost-effectiveness analysis explored the cost per successful eradication and the cost per quality-adjusted life-year. RESULTS: Between 5 October 2010 and 27 January 2017, 286 patients were randomised: 137 patients to intravenous antibiotics and 149 patients to oral antibiotics. The numbers of participants achieving the primary outcome were 55 out of 125 (44%) in the intravenous group and 68 out of 130 (52%) in the oral group. Participants randomised to the intravenous group were less likely to achieve the primary outcome; although the difference between groups was not statistically significant, the clinically important difference that the trial aimed to detect was not contained within the confidence interval (relative risk 0.84, 95% confidence interval 0.65 to 1.09; p = 0.184). Significantly fewer patients in the intravenous group (40/129, 31%) than in the oral group (61/136, 44.9%) were hospitalised in the 12 months following eradication treatment (relative risk 0.69, 95% confidence interval 0.5 to 0.95; p = 0.02). There were no clinically important differences in other secondary outcomes. There were 32 serious adverse events in 24 participants [intravenous: 10/126 (7.9%); oral: 14/146 (9.6%)]. Oral therapy led to reductions in costs compared with intravenous therapy (-£5938.50, 95% confidence interval -£7190.30 to -£4686.70). Intravenous therapy usually necessitated hospital admission, which accounted for a large part of this cost. LIMITATIONS: Only 15 out of the 286 participants recruited were adults - partly because of the smaller number of adult centres participating in the trial. The possibility that the trial participants may be different from the rest of the cystic fibrosis population and may have had a better clinical status, and so be more likely to agree to the uncertainty of trial participation, cannot be ruled out. CONCLUSIONS: Intravenous antibiotics did not achieve sustained eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. Although there were fewer hospitalisations in the intravenous group during follow-up, this confers no advantage over the oral therapy group, as intravenous eradication frequently requires hospitalisation. These results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis. FUTURE WORK: Future research studies should combine long-term follow-up with regimens to reduce reoccurrence after eradication. TRIAL REGISTRATION: Current Controlled Trials ISRCTN02734162 and EudraCT 2009-012575-10. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 65. See the NIHR Journals Library website for further project information.

Cystic fibrosis is a genetic condition that affects mucous glands, causing sticky mucus in the lungs and digestive system. People with cystic fibrosis are prone to lung infection with a bacterium called Pseudomonas aeruginosa, which can lead to serious long-term complications and death. It is possible to eradicate P. aeruginosa if antibiotics are started promptly and taken for several months. The Trial of Optimal TheRapy for Pseudomonas EraDicatiOn in Cystic Fibrosis (TORPEDO-CF) was designed to find out if intravenous ceftazidime and tobramycin were better at eradicating P. aeruginosa than oral ciprofloxacin. A total of 286 children, young people and adults with cystic fibrosis joined the study from 70 UK and two Italian centres. Approximately half of the participants received treatment with intravenous antibiotics and half with oral antibiotics. All participants received inhaled colistin for 3 months and were followed up for a minimum of 15 months. We studied whether or not either treatment eradicated P. aeruginosa, and if reinfection happened during follow-up. We also collected data on lung function, other chest infections and hospital admissions, and examined whether or not one treatment was more cost-effective than the other. In total, 15 adults joined TORPEDO-CF, so the study population may not totally match the wider cystic fibrosis population; however, in TORPEDO-CF, we found that intravenous antibiotics did not achieve persistent eradication of P. aeruginosa in a greater proportion of cystic fibrosis patients. We also found that oral antibiotics were more cost-effective than intravenous antibiotics. The intravenous antibiotics group had fewer hospital admissions during follow-up, but, as they were usually admitted for their initial treatment, this was not considered an advantage over the oral antibiotics group. The TORPEDO-CF results do not support the use of intravenous antibiotics to eradicate P. aeruginosa in cystic fibrosis and, when the findings of this trial are applied in routine clinical practice in the NHS, patients will most likely receive oral treatment as an outpatient, avoiding the need for hospital admission.

Prognostic accuracy of emergency department triage tools for adults with suspected COVID-19: the PRIEST observational cohort study.

BACKGROUND: The WHO and National Institute for Health and Care Excellence recommend various triage tools to assist decision-making for patients with suspected COVID-19. We aimed to compare the accuracy of triage tools for predicting severe illness in adults presenting to the ED with suspected COVID-19. METHODS: We undertook a mixed prospective and retrospective observational cohort study in 70 EDs across the UK. We collected data from people attending with suspected COVID-19 and used presenting data to determine the results of assessment with the WHO algorithm, National Early Warning Score version 2 (NEWS2), CURB-65, CRB-65, Pandemic Modified Early Warning Score (PMEWS) and the swine flu adult hospital pathway (SFAHP). We used 30-day outcome data (death or receipt of respiratory, cardiovascular or renal support) to determine prognostic accuracy for adverse outcome. RESULTS: We analysed data from 20 891 adults, of whom 4611 (22.1%) died or received organ support (primary outcome), with 2058 (9.9%) receiving organ support and 2553 (12.2%) dying without organ support (secondary outcomes). C-statistics for the primary outcome were: CURB-65 0.75; CRB-65 0.70; PMEWS 0.77; NEWS2 (score) 0.77; NEWS2 (rule) 0.69; SFAHP (6-point rule) 0.70; SFAHP (7-point rule) 0.68; WHO algorithm 0.61. All triage tools showed worse prediction for receipt of organ support and better prediction for death without organ support. At the recommended threshold, PMEWS and the WHO criteria showed good sensitivity (0.97 and 0.95, respectively) at the expense of specificity (0.30 and 0.27, respectively). The NEWS2 score showed similar sensitivity (0.96) and specificity (0.28) when a lower threshold than recommended was used. CONCLUSION: CURB-65, PMEWS and the NEWS2 score provide good but not excellent prediction for adverse outcome in suspected COVID-19, and predicted death without organ support better than receipt of organ support. PMEWS, the WHO criteria and NEWS2 (using a lower threshold than usually recommended) provide good sensitivity at the expense of specificity. TRIAL REGISTRATION NUMBER: ISRCTN56149622.

Do not attempt cardiopulmonary resuscitation (DNACPR) decisions in people admitted with suspected COVID-19: Secondary analysis of the PRIEST observational cohort study.

AIMS: We aimed to describe the characteristics and outcomes of adults admitted to hospital with suspected COVID-19 according to their DNACPR decisions, and identify factors associated with DNACPR decisions. METHODS: We undertook a secondary analysis of 13,977 adults admitted to hospital with suspected COVID-19 and included in the Pandemic Respiratory Infection Emergency System Triage (PRIEST) study. We recorded presenting characteristics and outcomes (death or organ support) up to 30 days. We categorised patients as early DNACPR (before or on the day of admission) or late/no DNACPR (no DNACPR or occurring after the day of admission). We undertook descriptive analysis comparing these groups and multivariable analysis to identify independent predictors of early DNACPR. RESULTS: We excluded 1249 with missing DNACPR data, and identified 3929/12748 (31%) with an early DNACPR decision. They had higher mortality (40.7% v 13.1%) and lower use of any organ support (11.6% v 15.7%), but received a range of organ support interventions, with some being used at rates comparable to those with late or no DNACPR (e.g. non-invasive ventilation 4.4% v 3.5%). On multivariable analysis, older age (p < 0.001), active malignancy (p < 0.001), chronic lung disease (p < 0.001), limited performance status (p < 0.001), and abnormal physiological variables were associated with increased recording of early DNACPR. Asian ethnicity was associated with reduced recording of early DNACPR (p = 0.001). CONCLUSIONS: Early DNACPR decisions were associated with recognised predictors of adverse outcome, and were inversely associated with Asian ethnicity. Most people with an early DNACPR decision survived to 30 days and many received potentially life-saving interventions. REGISTRATION: ISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533.

Derivation and validation of a clinical severity score for acutely ill adults with suspected COVID-19: The PRIEST observational cohort study.

OBJECTIVES: We aimed to derive and validate a triage tool, based on clinical assessment alone, for predicting adverse outcome in acutely ill adults with suspected COVID-19 infection. METHODS: We undertook a mixed prospective and retrospective observational cohort study in 70 emergency departments across the United Kingdom (UK). We collected presenting data from 22445 people attending with suspected COVID-19 between 26 March 2020 and 28 May 2020. The primary outcome was death or organ support (respiratory, cardiovascular, or renal) by record review at 30 days. We split the cohort into derivation and validation sets, developed a clinical score based on the coefficients from multivariable analysis using the derivation set, and the estimated discriminant performance using the validation set. RESULTS: We analysed 11773 derivation and 9118 validation cases. Multivariable analysis identified that age, sex, respiratory rate, systolic blood pressure, oxygen saturation/inspired oxygen ratio, performance status, consciousness, history of renal impairment, and respiratory distress were retained in analyses restricted to the ten or fewer predictors. We used findings from multivariable analysis and clinical judgement to develop a score based on the NEWS2 score, age, sex, and performance status. This had a c-statistic of 0.80 (95% confidence interval 0.79-0.81) in the validation cohort and predicted adverse outcome with sensitivity 0.98 (0.97-0.98) and specificity 0.34 (0.34-0.35) for scores above four points. CONCLUSION: A clinical score based on NEWS2, age, sex, and performance status predicts adverse outcome with good discrimination in adults with suspected COVID-19 and can be used to support decision-making in emergency care. REGISTRATION: ISRCTN registry, ISRCTN28342533, http://www.isrctn.com/ISRCTN28342533.

Onabotulinum toxin-A versus extended release tolterodine in the management of idiopathic overactive bladder in children: A pilot randomised controlled trial (OVERT trial).

BACKGROUND: Idiopathic Overactive Bladder is the most common cause of urinary incontinence in children. Anticholinergic medications are successful in only 20% of those with daily wetting so there is a real need to find a more effective treatment for this condition. Onabotulinum toxin A injections are often used as a treatment but there have been no randomised controlled trials investigating effectiveness in children. OBJECTIVE: To provide information that would inform the design and conduct of a definitive trial comparing onabotulinum toxin A with extended-release tolterodine for the management of therapy resistant idiopathic overactive bladder in children. Specific objectives were to assess rates of eligibility, recruitment, acceptability of randomisation, loss to follow-up, acceptability of urodynamic assessment and obtain primary outcome data for sample size estimation. STUDY DESIGN: Single-centre, parallel, two-arm, open-label pilot randomised controlled trial. Eligible patients (aged 7-16 years) were recruited at Royal Manchester Children's Hospital and randomised (1:1) using a web-based system. TRIAL REGISTRATION: EudraCT 2014-001068-36; Funding: UK NIHR Research for Patient Benefit Programme. RESULTS: 98 patients were assessed for eligibility, 85 (87%) were eligible for screening, parents of 62 (73%) provided consent, 46 (74%) remained eligible and were randomised (onabotulinum = 22, tolterodine = 24). All participants commenced allocated treatment. Two patients withdrew from follow-up. All participants underwent urodynamic assessment at baseline and 35 (76%) additionally at week 6. The mean (standard deviation) number of wetting episodes per day at week 6 was 1.4 (1.7) in the onabotulinum group and 1.6 (1.0) in the tolterodine group. There was one serious adverse event (probably related to the drug) and 22 non-serious adverse events reported by 8 participants in the onabotulinum group (36%). There were 23 non-serious adverse events reported by 9 participants in the tolterodine group (38%). DISCUSSION: Recruitment was challenging but eligibility and consent rates were high as were retention rates. Treatment compliance in the botox group was high but it was difficult to measure in the tolterodine group. Treatment switching was also an issue. CONCLUSIONS: Recruitment to a definitive trial was demonstrated to be feasible if a large number of centres are involved, though further consideration is required regarding trial design.

Perinatal outcomes of fetal intra-abdominal umbilical vein varix: a multicenter cohort study.

OBJECTIVES: To investigate the perinatal outcomes of fetuses with antenatal diagnoses of intra-abdominal umbilical vein varix (UVV). METHODS: A multicenter retrospective study was conducted in four countries on fetuses diagnosed with intra-abdominal UVV between 2012 and 2019. Collected data included gestational age (GA), UVV maximum diameter at diagnosis and delivery, associated anatomical and chromosomal anomalies, birth weight, and neonatal outcomes. RESULTS: Twenty fetuses were identified, of which 20% had associated chromosomal and/or anatomical abnormalities, most resulting in poor outcomes (either intrauterine fetal death or pregnancy termination). Mean maternal age was 34.1 ± 7.0 years, UVV was diagnosed at 26.5 ± 4.5 weeks of GA on average with a maximum diameter of 12.0 ± 4.0 mm. Mean GA at delivery was 35.4 ± 5.6 weeks. Survival rate was 85%. CONCLUSION: Our study shows a satisfactory outcome when intra-abdominal UVV is an isolated finding, with minimal obstetrical and perinatal consequences. The prognosis is worse when UVV is associated with other anomalies.

Understanding the management of osteoarthritis: A qualitative study of GPs and orthopaedic surgeons in Tasmania, Australia.

Objective: Using a qualitative design this study aimed to 1) explore the attitudes towards and understanding of osteoarthritis (OA) held by Tasmanian general practitioners (GPs) and orthopaedic surgeons, 2) gain a deeper understanding of conservative and surgical management and 3) identify key barriers and challenges. Design: Purposive sampling was used to recruit 17 â€‹GPs and 10 surgeons from Tasmania, Australia. Semi-structured interviews were audio-recorded, transcribed, coded, and thematically analysed to document understanding of OA, management and treatment decision making. Results: GPs and surgeons had a shared understanding of the cause and management of OA which aligned well with evidence-based best practice. Most GPs acknowledged that severity of disease on an X-Ray does not correlate well with symptoms, although some GPs reported always using imaging to support their diagnosis. Conservative management was highly supported by all interviewees, focussing on exercise and/or physiotherapy. Key treatment barriers included managing poor patient understanding of OA, unrealistic expectations for treatment, lack of patient motivation and scepticism towards exercise, and cost and accessibility of conservative treatment options. Surgery was considered a suitable option when conservative management options had been exhausted. Conclusion: This study uniquely interviewed GPs and surgeons from the same population, capturing two crucial areas of OA management. Some key barriers to treatment were identified and options for improving treatment include creating opportunities for increased patient education about OA, enhanced accessibility to OA conservative management programs along with improved reimbursement models supporting conservative management as first-line OA treatment.