Sean Ewings

Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial

Summary Background Respiratory virus infection is a common cause of hospitalisation in adults. Rapid point-of-care testing (POCT) for respiratory viruses might improve clinical care by reducing unnecessary antibiotic use, shortening length of hospital stay, improving influenza detection and treatment, and rationalising isolation facility use; however, insufficient evidence exists to support its use over standard clinical care. We aimed to assess the effect of routine POCT on a broad range of clinical outcomes including antibiotic use. Methods In this pragmatic, parallel-group, open-label, randomised controlled trial, we enrolled adults (aged ≥18 years) within 24 h of presenting to the emergency department or acute medical unit of a large UK hospital with acute respiratory illness or fever higher than 37·5°C (≤7 days duration), or both, over two winter seasons. Patients were randomly assigned (1:1), via an internet-based allocation sequence with random permuted blocks, to have a molecular POC test for respiratory viruses or routine clinical care. The primary outcome was the proportion of patients who received antibiotics while hospitalised (up to 30 days). Secondary outcomes included duration of antibiotics, proportion of patients receiving single doses or brief courses of antibiotics, length of stay, antiviral use, isolation facility use, and safety. Analysis was by modified intention to treat, excluding patients who declined intervention or were withdrawn for protocol violations. This study is registered with ISRCTN, number 90211642, and has been completed. Findings Between Jan 15, 2015, and April 30, 2015, and between Oct 1, 2015, and April 30, 2016, we enrolled 720 patients (362 assigned to POCT and 358 to routine care). Six patients withdrew or had protocol violations. 301 (84%) of 360 patients in the POCT group received antibiotics compared with 294 (83%) of 354 controls (difference 0·6%, 95% CI −4·9 to 6·0; p=0·84). Mean duration of antibiotics did not differ between groups (7·2 days [SD 5·1] in the POCT group vs 7·7 days [4·9] in the control group; difference −0·4, 95% CI −1·2 to 0·4; p=0·32). 50 (17%) of 301 patients treated with antibiotics in the POCT group received single doses or brief courses of antibiotics (<48 h) compared with 26 (9%) of 294 patients in the control group (difference 7·8%, 95% CI 2·5 to 13·1; p=0·0047; number needed to test=13). Mean length of stay was shorter in the POCT group (5·7 days [SD 6·3]) than in the control group (6·8 days [7·7]; difference −1·1, 95% CI −2·2 to −0·3; p=0·0443). Appropriate antiviral treatment of influenza-positive patients was more common in the POCT group (52 [91%] of 57 patients) than in the control group (24 [65%] of 37 patients; difference 26·4%, 95% CI 9·6 to 43·2; p=0·0026; number needed to test=4). We found no differences in adverse outcomes between the groups (77 [21%] of 360 patients in the POCT group vs 88 [25%] of 354 patients in the control group; −3·5%, −9·7 to 2·7; p=0·29). Interpretation Routine use of molecular POCT for respiratory viruses did not reduce the proportion of patients treated with antibiotics. However, the primary outcome measure failed to capture differences in antibiotic use because many patients were started on antibiotics before the results of POCT could be made available. Although POCT was not associated with a reduction in the duration of antibiotics overall, more patients in the POCT group received single doses or brief courses of antibiotics than did patients in the control group. POCT was also associated with a reduced length of stay and improved influenza detection and antiviral use, and appeared to be safe. Funding University of Southampton.

The assessment of Ki-67 as a prognostic marker in neuroendocrine tumours: a systematic review and meta-analysis

Introduction Gastroenteropancreatic neuroendocrine tumours (GEP NETs) are classified according to tumour mitotic count or Ki-67 labelling index (LI). Aim(s) To systematically review articles reporting the prognosis of patients by Ki-67 LI and thereby improve the ability of clinicians to prognosticate for their patients. Method 265 abstracts were identified relating Ki-67 and survival. After exclusion criteria were applied, 22 articles remained. Articles were excluded if they described non-human specimens, were non-English language, published prior to 2000, reported non-GEP NETs, reported subgroups selected by treatment modality or included <20 cases. Random-effects meta-analysis was used to combine studies to estimate survival proportions. Results Authors used varied methods in which to present 5-year survival, with often limited survival information. This reduced the number of studies that could be included in the meta-analysis. 5-year survival for patients with grade 1 and 2 GEP NETs were estimated to be 89% (95% CI 85% to 92%, m=12 studies, n=977 participants) and 70% (95% CI 62% to 79%, m=9, n=726), respectively. Using an alternative grade 1/2 boundary of 5%, 5-year survival rates for Ki-67≤5% and 5–20% were estimated as 89% (95% CI 84% to 94%, m=7, n=654) and 51% (95% CI 44% to 59%, m=4, n=183), respectively. For Ki-67>20%, 5-year survival was estimated to be 25% (95% CI 12% to 38%, m=10, n=208). Conclusions Standardisation of grade boundaries has allowed us to combine data from multiple studies and amass a body of evidence linking Ki-67 and survival.

A Bayesian network for modelling blood glucose concentration and exercise in type 1 diabetes

This article presents a new statistical approach to analysing the effects of everyday physical activity on blood glucose concentration in people with type 1 diabetes. A physiologically based model of blood glucose dynamics is developed to cope with frequently sampled data on food, insulin and habitual physical activity; the model is then converted to a Bayesian network to account for measurement error and variability in the physiological processes. A simulation study is conducted to determine the feasibility of using Markov chain Monte Carlo methods for simultaneous estimation of all model parameters and prediction of blood glucose concentration. Although there are problems with parameter identification in a minority of cases, most parameters can be estimated without bias. Predictive performance is unaffected by parameter misspecification and is insensitive to misleading prior distributions. This article highlights important practical and theoretical issues not previously addressed in the quest for an artificial pancreas as treatment for type 1 diabetes. The proposed methods represent a new paradigm for analysis of deterministic mathematical models of blood glucose concentration.

Anterior Thigh Tissue Thickness Measured Using Ultrasound Imaging in Older Recreational Female Golfers and Sedentary Controls

Physical activity is vital for the prevention of sarcopenia and frailty. The training effects of recreational golf on muscle function in older people are unknown. The present study examined quadriceps muscle and subcutaneous fat thickness in 66 older females. Thirty-one golfers (mean age 69.1 years, standard deviation ±3.4) were compared with 35 less active non-golfers (73.4 ± 4.2 years). Images of the dominant anterior thigh were obtained using real-time B-mode ultrasound imaging. Thickness of muscle (rectus femoris, vastus intermedius, and intermuscular fascia) and subcutaneous tissue (fat and perimuscular fascia) was measured, and percentage contributions calculated. Muscle thickness was significantly greater (p < 0.001) in golfers (mean 2.78 cm ± 0.73 cm) than non-golfers (2.18 cm ± 0.55 cm). Mean percentage contribution of muscle and non-contractile tissue was 64% ± 9% and 36% ± 9%, respectively, in golfers, compared to 58% ± 8% and 42% ± 8% in non-golfers (p = 0.013). Multiple linear regression analysis, controlling for age and BMI, showed that golfers still had higher total anterior thigh thickness (regression parameter for non-golfers B = −0.984, p = 0.004) and higher muscle thickness (B = −0.619, p = 0.002). This study indicates an association between recreational golf and greater relative thigh muscle thickness and lower subcutaneous fat than in less active controls. Training effects need to be examined in prospective controlled trials in males and females in different age groups.

Promoting Help-Seeking in Response to Symptoms amongst Primary Care Patients at High Risk of Lung Cancer: A Mixed Method Study

Background Lung cancer symptoms are vague and difficult to detect. Interventions are needed to promote early diagnosis, however health services are already pressurised. This study explored symptomology and help-seeking behaviours of primary care patients at ‘high-risk’ of lung cancer (≥50 years old, recent smoking history), to inform targeted interventions. Methods Mixed method study with patients at eight general practitioner (GP) practices across south England. Study incorporated: postal symptom questionnaire; clinical records review of participant consultation behaviour 12 months pre- and post-questionnaire; qualitative participant interviews (n = 38) with a purposive sample. Results A small, clinically relevant group (n = 61/908, 6.7%) of primary care patients was identified who, despite reporting potential symptoms of lung cancer in questionnaires, had not consulted a GP ≥12 months. Of nine symptoms associated with lung cancer, 53.4% (629/1172) of total respondents reported ≥1, and 35% (411/1172) reported ≥2. Most participants (77.3%, n = 686/908) had comorbid conditions; 47.8%, (n = 414/908) associated with chest and respiratory symptoms. Participant consulting behaviour significantly increased in the 3-month period following questionnaire completion compared with the previous 3-month period (p = .002), indicating questionnaires impacted upon consulting behaviour. Symptomatic non-consulters were predominantly younger, employed, with higher multiple deprivation scores than their GP practice mean. Of symptomatic non-consulters, 30% (18/61) consulted ≤1 month post-questionnaire, with comorbidities subsequently diagnosed for five participants. Interviews (n = 39) indicated three overarching differences between the views of consulting and non-consulting participants: concern over wasting their own as well as GP time; high tolerance threshold for symptoms; a greater tendency to self-manage symptoms. Conclusions This first study to examine symptoms and consulting behaviour amongst a primary care population at ‘high- risk’ of lung cancer, found symptomatic patients who rarely consult GPs, might respond to a targeted symptom elicitation intervention. Such GP-based interventions may promote early diagnosis of lung cancer or other comorbidities, without burdening already pressurised services.

Time spent in rehabilitation and effect on measures of activity after stroke

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To establish if greater time spent in rehabilitation results in greater improvement in measures of activity than less time spent in rehabilitation. To assess the effect of total time spent (in minutes) in rehabilitation on activity/activity limitations following stroke. To assess the effect of rehabilitation schedule on activity/activity limitations following stroke in terms of: average minutes of rehabilitation provided per week; average frequency of rehabilitation provided per week; total duration of rehabilitation. average minutes of rehabilitation provided per week; average frequency of rehabilitation provided per week; total duration of rehabilitation.

Impact of turnaround time on outcome with point-of-care testing for respiratory viruses: a post hoc analysis from a randomised controlled trial

Respiratory viruses are detected in around 40–50% of adults hospitalised with acute respiratory illness (ARI) [1, 2]. Routine laboratory PCR testing for respiratory viruses generally takes several hours to several days to generate results for clinicians and so cannot be used to inform decision making in real time. Decisions about hospitalisation, antibiotics, antivirals and side room isolation therefore need to be made presumptively and reviewed when results are available. Newer rapid molecular test platforms are accurate, easy to use, and generate a result in 1 h or less, making them potentially deployable for point-of-care testing (POCT) in clinical areas [3]. Recently, we reported on a large pragmatic randomised controlled trial (ResPOC) [4] which evaluated the impact of POCT (using the FilmArray Respiratory Panel (BioFire Diagnostics, Salt Lake City, UT, USA) which tests for a comprehensive range of viruses) in adults presenting to hospital with ARI. The study showed that POCT was associated with reductions in hospital length of stay overall and reductions in antibiotics use in patients with exacerbation of airways disease. Although this evidence would suggest that rapid molecular testing needs to be performed within clinical areas for these improved clinical outcomes, it has been suggested that rapid molecular test platforms used within centralised laboratories might also be associated with these clinical benefits, although the turnaround times (TATs) are likely to be much longer. In this follow-on study we evaluate the impact of POCT TAT on clinical outcomes with a view to determining how rapid molecular testing for respiratory viruses should be best implemented in clinical practice. As very rapid turnaround times lead to better outcomes, virus diagnostics should be performed at the point-of-care http://ow.ly/eD6p30koZGg

Comment on: Is high-intensity interval training more effective on improving cardiometabolic risk and aerobic capacity than other forms of exercise in overweight and obese youth? A meta-analysis.

We commend the efforts of García-Hermoso and colleagues (1), whose recent meta-analysis concluded that highintensity interval training (HIIT) is more effective for improving systolic blood pressure (SBP) and maximal oxygen uptake (V̇O2max) than other forms of exercise in overweight and obese youth. However, while this is a timely article, we feel that the conclusions need to be contextualized with regards to important methodological constraints. Considering that this meta-analysis may shape health practitioner practice and public health policy, we strongly feel that these limitations should be addressed. The methodological constraints include the following: (i) limited number of trials – only five trials reported SBP, and only six reported V ̇O2max. Further, the authors admit that the quality of included trials was generally poor. (ii) Poorly characterized outcomes – for example, the six trials that reported V ̇O2max used a variety of measures, including differing exercise modalities and use of submaximal V ̇O2max estimation. (iii) Shifting baseline – the authors do not use a true control group, instead comparing the HIIT intervention to ‘other exercise’. The ‘other exercise’ groups vary widely in terms of exercise prescribed, with some ‘control’ groups arguably prescribed elements of HIIT, making it difficult to discern the true effect (and directionality) of HIIT prescription. Further, HIIT is loosely defined and dependent upon a seemingly infinite number of combinations of differing factors, including exercise modality, number of repetitions, work interval intensity and duration, among others. (iv) Inappropriate subgroup analysis – the authors do attempt to compensate for the lack of a true control group through sub-group analysis, comparing HIIT to different types of comparison exercise groups. However, only three trials were included in the V ̇O2max subgroup analysis. (v) Poor adherence to PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines (2) – for example, simple summary data should be reported for each intervention and control group to enable the reader to infer directionality. Further, additional analyses are poorly described; the meta-regression is poorly rationalized and difficult to interpret. The limitations of this study are alluded to but not explored. (vi) Poor participant inclusion criteria – inclusion of pre-adolescent and postadolescent children. A 6-year-old child will demonstrate a very different physiological response to exercise compared with a 17-year-old youth, largely due to age-dependent metabolic and musculoskeletal differences (3). Further, the authors reported that the weighted mean difference for SBP was 3.67mmHg, which is a greater relative change in a 6-year-old child with an expected resting SBP of ~96mmHg, compared with a 17-year-old adolescent with an expected resting SBP of ~118mmHg (4). Arguably more important than the methodological constraints is the lack of adequate consideration for clinical inference, implementation science and importance to public health. With regard to clinical inference, the weighted mean difference was 1.92mLkg min 1 for V ̇O2max and 3.67mmHg for SBP, both of which are within respective measurement error (5,6). As such, it is difficult to discern the clinical importance of such small changes. In terms of implementation and public health, HIIT may overcome the time barrier to exercise adherence, but there are a number of additional considerations that need to be addressed. Queries such as, but not limited to: should HIIT be tailored to the age and gender of the child? Will this form of exercise prescription put obese children at increased risk for musculoskeletal injury? Should some form of priming period precede the implementation of HIIT, i.e., should HIIT be employed following a period of strength training, which has been shown to improve cardiorespiratory fitness and psychological wellness in obese children, and is well-tolerated? (7,8) Will this form of exercise be enjoyable and sustainable? With regards to the last point, the authors cite one of our previous studies (9) as support for HIIT being more enjoyable compared to other forms of exercise. However, our previous study investigated a high intensity games intervention, not HIIT per se, and we did not compare the games intervention to other forms of exercise (9). Lastly, what kinds of physical resources and obesity reviews doi: 10.1111/obr.12451