One evidence base; three stories: do opioids relieve chronic breathlessness?

The efficacy of low-dose systemic opioids for chronic breathlessness was questioned by the recent Cochrane review by Barnes et al We examined the reasons for this conflicting finding and re-evaluated the efficacy of systemic opioids. Compared with previous meta-analyses, Barnes et al reported a smaller effect and lower precision, but did not account for matched data of crossover trials (11/12 included trials) and added a risk-of-bias criterion (sample size). When re-analysed to account for crossover data, opioids decreased breathlessness (standardised mean differences -0.32; -0.18 to -0.47; I2=44.8%) representing a clinically meaningful reduction of 0.8 points (0-10 numerical rating scale), consistent across meta-analyses.

Psychometric validation of the needs assessment tool: progressive disease in interstitial lung disease.

The inter-rater/test-retest reliability and construct validity of a palliative care needs assessment tool in interstitial lung disease (NAT:PD-ILD) were tested using NAT:PD-ILD-guided video-recorded consultations, and NAT:PD-ILD-guided consultations, and patient and carer-report outcomes (St George's Respiratory Questionnaire (SGRQ)-ILD, Carer Strain Index (CSI)/Carer Support Needs Assessment Tool (CSNAT)). 11/16 items reached at least fair inter-rater agreement; 5 items reached at least moderate test-retest agreement. 4/6 patient constructs demonstrated agreement with SGRQ-I scores (Kendall's tau-b, 0.24-20.36; P<0.05). 4/7 carer constructs agreed with the CSI/CSNAT items (kappa, 0.23-20.53). The NAT:PD-ILD is reliable and valid. Clinical effectiveness and implementation are to be evaluated.

Breathlessness and presentation to the emergency department: a survey and clinical record review.

BACKGROUND: Breathlessness is a frequently occurring symptom of cardiorespiratory conditions and is a common cause of emergency department presentation. The aim of this study was to estimate the prevalence of acute-on-chronic breathlessness as a cause for presentation to the major emergencies area of the emergency department. METHODS: A prospective patient self-report survey and clinical record review of consecutive attendees to the major emergencies area of the emergency department in a single tertiary hospital between 12/5/14 and 29/5/14 was conducted. Eligible patients were clinically stable and had mental capacity to provide data. RESULTS: There were 2,041 presentations during the study period, of whom 1,345 (66%) were eligible. There was a 90% survey response rate (1,212/1,345); 424/1,212 (35%) self-reported breathlessness most days over the past month of whom 245 gave breathlessness as a reason for this presentation. Therefore, the prevalence of acute-on-chronic breathlessness as a reason to present to the major emergencies area was 20.2% (245/1,212, 95% CI 17.9% to 22.5%). During this period there were 4,692 major and minor presentations; breathlessness was therefore a cause of at least 5.2% (245/4,692, 95% CI 4.6 to 5.9%) of all emergency department presentations. CONCLUSIONS: This study found that one in five ambulance presentations to the ED were due to acute-on-chronic breathlessness. Most patients had non-malignant underlying conditions, had experienced considerable breathlessness for an extended period, had discussed breathlessness with their GP and presented out of daytime hours. Others were often involved in their decision to present. This represents clinically significant burden for patients, their family carers and the emergency health services.

Clinical and cost-effectiveness of compression hosiery versus compression bandages in treatment of venous leg ulcers (Venous leg Ulcer Study IV, VenUS IV): a randomised controlled trial.

BACKGROUND: Drawbacks exist with the standard treatment (four-layer compression bandages) for venous leg ulcers. We have therefore compared the clinical effectiveness and cost-effectiveness of two-layer compression hosiery with the four-layer bandage for the treatment of such ulcers. METHODS: We undertook this pragmatic, open, randomised controlled trial with two parallel groups in 34 centres in England and Northern Ireland. The centres were community nurse teams or services, family doctor practices, leg ulcer clinics, tissue viability clinics or services, and wound clinics. Participants were aged 18 years or older with a venous leg ulcer and an ankle brachial pressure index of at least 0·8, and were tolerant of high compression. We randomly allocated participants (1:1) to receive two-layer compression hosiery or a four-layer bandage, using a remote randomisation service and prevalidated computer randomisation program. Participants were stratified by ulcer duration and ulcer area with permuted blocks (block sizes four and six). The primary endpoint was time to ulcer healing, with a maximum follow-up of 12 months. Although participants and health-care providers were not masked to treatment allocation, the primary endpoint was measured by masked assessment of photographs. Primary analysis was intention to treat with Cox regression, with adjustment for ulcer area, ulcer duration, physical mobility, and centre. This trial is registered with the ISRCTN register, number ISRCTN49373072. FINDINGS: We randomly allocated 457 participants to the two treatment groups: 230 to two-layer hosiery and 227 to the four-layer bandage, of whom 453 (230 hosiery and 223 bandage) contributed data for analysis. Median time to ulcer healing was 99 days (95% CI 84-126) in the hosiery group and 98 days (85-112) in the bandage group, and the proportion of ulcers healing was much the same in the two groups (70·9% hosiery and 70·4% bandage). More hosiery participants changed their allocated treatment (38·3% hosiery vs 27·0% bandage; p=0·02). 300 participants had 895 adverse events, of which 85 (9·5%) were classed as serious but unrelated to trial treatment. INTERPRETATION: Two-layer compression hosiery is a viable alternative to the four-layer bandage-it is equally as effective at healing venous leg ulcers. However, a higher rate of treatment changes in participants in the hosiery group than in the bandage group suggests that hosiery might not be suitable for all patients. FUNDING: NIHR Health Technology Assessment programme (07/60/26).

Validation of the VEINES-QOL quality of life instrument in venous leg ulcers: repeatability and validity study embedded in a randomised clinical trial.

BACKGROUND: VEINES-QOL/Sym is a disease-specific quality of life instrument for use in venous diseases of the leg. Its relative scoring system precludes comparisons between studies. There were very few venous leg ulcer patients in the validation samples. We report a validation study for venous leg ulcers and develop a scoring system which enables comparison between studies. METHODS: Four hundred fifty-one participants in the VenUS IV trial of the management of venous leg ulcers were asked to complete a VEINES-QOL questionnaire at recruitment, along with SF-12, pain, and other aspects of quality of life. VEINES-QOL was repeated after two weeks and after 4 months. Healing of ulcers was confirmed by blind assessment of digital photographs. Three scoring systems for VEINES-QOL were compared. RESULTS: No floor or ceiling effects were observed for VEINES-QOL items, item-item correlations were weak to moderate, item-score correlations were moderate. Internal reliability was good. The VEINES-Sym subscale was confirmed by factor analysis. Test-retest reliability was satisfactory for the scale scores; individual items showed moderate to good agreement. Relationships with SF-12, pain, and the quality items confirmed construct validity. Participants whose ulcers had healed showed greater mean increase in scores than did those yet to heal, though they continued to report leg problems. An intrinsic scoring method appeared superior to the original relative method. CONCLUSIONS: VEINES-QOL was suitable for use in the study of venous leg ulcers. The intrinsic scoring method should be adopted, to facilitate comparisons between studies. TRIAL REGISTRATION: VenUS IV is registered with the ISRCTN register, number ISRCTN49373072 .

Effect of blending Jersey and Holstein-Friesian milk on Cheddar cheese processing, composition, and quality.

The effect of Jersey milk use solely or at different inclusion rates in Holstein-Friesian milk on Cheddar cheese production was investigated. Cheese was produced every month over a year using nonstandardized milk consisting of 0, 25, 50, 75, and 100% Jersey milk in Holstein-Friesian milk in a 100-L vat. Actual, theoretical, and moisture-adjusted yield increased linearly with percentage of Jersey milk. This was also associated with increased fat and protein recoveries and lower yield of whey. The composition of whey was also affected by the percentage of Jersey milk, with lower whey protein and higher whey lactose and solids. Cutting time was lower when Jersey milk was used, but the cutting to milling time was higher because of slower acidity development. Hence, overall cheesemaking time was not affected by the use of Jersey milk. Using Jersey milk increased cheese fat content in autumn, winter, and spring and decreased cheese moisture in spring and summer. Cheese protein, salt, and pH levels were not affected. Cheese was analyzed for texture and color, and it was professionally graded at 3 and 8mo. The effect of Jersey on cheese sensory quality was an increase in cheese yellowness during summer and a higher total grading score at 3mo in winter; no other difference in cheese quality was found. The study indicates that using Jersey milk is a valid method of improving Cheddar cheese yield.

Short communication: Estimation of the financial benefit of using Jersey milk at different inclusion rates for Cheddar cheese production using partial budgeting.

Partial budgeting was used to estimate the net benefit of blending Jersey milk in Holstein-Friesian milk for Cheddar cheese production. Jersey milk increases Cheddar cheese yield. However, the cost of Jersey milk is also higher; thus, determining the balance of profitability is necessary, including consideration of seasonal effects. Input variables were based on a pilot plant experiment run from 2012 to 2013 and industry milk and cheese prices during this period. When Jersey milk was used at an increasing rate with Holstein-Friesian milk (25, 50, 75, and 100% Jersey milk), it resulted in an increase of average net profit of 3.41, 6.44, 8.57, and 11.18 pence per kilogram of milk, respectively, and this additional profit was constant throughout the year. Sensitivity analysis showed that the most influential input on additional profit was cheese yield, whereas cheese price and milk price had a small effect. The minimum increase in yield, which was necessary for the use of Jersey milk to be profitable, was 2.63, 7.28, 9.95, and 12.37% at 25, 50, 75, and 100% Jersey milk, respectively. Including Jersey milk did not affect the quantity of whey butter and powder produced. Although further research is needed to ascertain the amount of additional profit that would be found on a commercial scale, the results indicate that using Jersey milk for Cheddar cheese making would lead to an improvement in profit for the cheese makers, especially at higher inclusion rates.

Self-referrals to a doctors' mental health service over 10 years.

BACKGROUND: The adverse impact on doctors' health of constant organizational change in healthcare is well established. AIMS: To investigate the change in self-referral rates to a doctors' mental health service, and associated morbidity over a decade. METHODS: All doctors attending a doctors' mental health service between 1 January 2002 and 31 December 2011 were asked to complete the Clinical Outcomes in Routine Evaluation questionnaire and Maslach burnout inventory as part of routine assessment before treatment. Univariate analysis of variance was used to test for statistically significant differences between severity scores in different years. RESULTS: Between 1 January 2002 and 31 December 2011, 1062 doctors attended the service; 852 (80%) completed both questionnaires and 64 (6%) completed one of them. The overall response rate was 86% (916/1062). Referrals increased >4-fold, from 44 in 2002 to 185 in 2011. Sixty-one per cent scored above the threshold for psychological distress and 59% for burnout. There were no significant changes in morbidity over time. CONCLUSIONS: Increasing numbers of doctors sought help from the doctors' mental health support service. More than half scored above the thresholds for burnout and psychological distress and these proportions were consistent over 10 years. Doctors may be more willing to seek help than a decade ago. Further research is needed to confirm the underlying reasons for this. More resource is needed to meet the increase in demand.

Opioids for chronic refractory breathlessness: patient predictors of beneficial response.

Chronic refractory breathlessness is common and distressing in advanced disease. Despite level I evidence to support the use of opioids for this symptom, not all patients benefit. This study aimed to discover which patient characteristics predict those most likely to gain improvement in breathlessness. This is an international, multicentre, retrospective analysis of 213 individual pooled datasets from four clinical trials of an opioid for chronic refractory breathlessness. "Response to opioid" was defined as 1) an absolute value of ≥ 10 mm improvement on the visual analogue scale (VAS) and 2) a relative value of ≥ 10% improvement from baseline VAS. We investigated baseline predictors using logistic regression. In the final model, higher baseline breathlessness intensity scores strongly predicted absolute and relative response (p<0.001). Younger age also predicted relative response (p = 0.025); functional status and dominant cause of breathlessness did not. Some evidence supported the descriptor "not enough air", but was not statistically significant (p = 0.052). A therapeutic trial of opioids is appropriate, irrespective of the cause of the breathlessness or functional status. Younger people or those with worse breathlessness are more likely to benefit. Opioids have a role in the management of chronic refractory breathlessness, but net benefit for individuals must be optimised.

Minimally clinically important difference in chronic breathlessness: every little helps.

OBJECTIVES: The aim of the study was to determine the minimally clinically important difference (MCID) for breathlessness due to chronic heart failure (CHF). BACKGROUND: The measurement of breathlessness is difficult because it is subjective and multifactorial. Statistically significant changes in assessment may not be clinically meaningful. This is the first determination of MCID in chronic breathlessness in CHF using patient-rated data. METHODS: Measurements were made as part of a randomized, controlled, crossover trial of morphine, oxycodone, or placebo for breathlessness in CHF. Breathlessness intensity was assessed at baseline and at the end of each intervention (day 4) using 11-point numerical rating scales (NRS), modified Borg (mBorg) scales, and global impression of change (GC) in breathlessness at day 4. From these data, the change in NRS or mBorg associated with a 1-point change in GC was calculated. RESULTS: Thirty-five patients completed all study interventions, resulting in 105 data sets. We defined MCID as a 1-point change in GC. Regression analysis found that the MCID, including 95% CIs, equaled change in average NRS breathlessness per 24 hours of 0.5 to 2.0 U (P < .001), change in worst NRS breathlessness per 24 hours of 0.4 to 2.9 (P < .001), change in average mBorg score of 0.2 to 2.0 (P < .001), and change in worst mBorg score as between 0.3 and 1.9 (P < .001). Corresponding effect size calculations lay within the 95% CIs for the regression analysis for each measure. CONCLUSIONS: A 1-point change in NRS or mBorg score is a reasonable estimate of the MCID in average daily chronic breathlessness in CHF.

Agreed statistics: measurement method comparison.

Statistical Methods for Assessing Agreement between Two Methods of Clinical Measurement. By J. Martin Bland, Douglas G. Altman. Lancet 1986; 1(8476):307-10. Abstract reprinted with permission of Elsevier, copyright 1986. In clinical measurement comparison of a new measurement technique with an established one is often needed to see whether they agree sufficiently for the new to replace the old. Such investigations are often analyzed inappropriately, notably by using correlation coefficients. The use of correlation is misleading. An alternative approach, based on graphical techniques and simple calculations, is described, together with the relation between this analysis and the assessment of repeatability.

A systematic review of the performance of instruments designed to measure the dimensions of pressure ulcers.

The objective was to undertake a systematic review of the performance of wound measurement instruments used for patients with pressure ulcers. Studies of any design, evaluating methods for estimating wound diameter, depth, surface area, or volume in patients with pressure ulcers were included. Eligible evaluations had to report intra- or inter-rater reliability, accuracy, agreement, or feasibility of methods. Electronic databases and other sources were accessed for study identification. Included studies were critically appraised using a modified checklist for diagnostic test evaluations. Twelve studies were included. Most had methodological problems and/or used inappropriate statistical methods. Reliable methods for measuring pressure ulcer surface area may include: grid tracings from photographs combined with whole plus partial square count; a portable digital pad; and stereophotogrammetry combined with computerized image analysis. The agreement between photographic tracing and direct transparency tracing may be satisfactory (both methods being combined with computerized planimetry). No definitive conclusions could be reached about studies of diameter or depth; this means that there is little evidence to underpin recommendations in clinical guidelines. Evaluations of volume measurement were of poor quality, and there were few data on feasibility. Further primary research is needed to evaluate methods of wound measurement used in clinical practice.

Acupuncture for irritable bowel syndrome: primary care based pragmatic randomised controlled trial.

BACKGROUND: Acupuncture is used by patients as a treatment for irritable bowel syndrome (IBS) but the evidence on effectiveness is limited. The purpose of the study was to evaluate the effectiveness of acupuncture for irritable bowel syndrome in primary care when provided as an adjunct to usual care. DESIGN: A two-arm pragmatic randomised controlled trial. SETTING: Primary care in the United Kingdom. PATIENTS: 233 patients had irritable bowel syndrome with average duration of 13 years and score of at least 100 on the IBS Symptom Severity Score (SSS). INTERVENTIONS: 116 patients were offered 10 weekly individualised acupuncture sessions plus usual care, 117 patients continued with usual care alone. MEASUREMENTS: Primary outcome was the IBS SSS at three months, with outcome data collected every three months to 12 months. RESULTS: There was a statistically significant difference between groups at three months favouring acupuncture with a reduction in IBS Symptom Severity Score of -27.43 (95% CI: -48.66 to -6.21, p=0.012). The number needed to treat for successful treatment (≥50 point reduction in the IBS SSS) was six (95% CI: 3 to 17), based on 49% success in the acupuncture group vs. 31% in the control group, a difference between groups of 18% (95% CI: 6% to 31%). This benefit largely persisted at 6, 9 and 12 months. CONCLUSIONS: Acupuncture for irritable bowel syndrome provided an additional benefit over usual care alone. The magnitude of the effect was sustained over the longer term. Acupuncture should be considered as a treatment option to be offered in primary care alongside other evidenced based treatments. TRIAL REGISTRATION: Current Controlled Trials ISRCTN08827905.

Homeopathy for mental fatigue: lessons from a randomized, triple blind, placebo-controlled cross-over clinical trial.

BACKGROUND: Difficulty in controlling attention can lead to mental fatigue in the healthy population. We identified one trial reporting a benefit in patients' attention using a homeopathic formula preparation. One component of the preparation was potassium phosphate, widely available off the shelf as Kali phos 6x for cognitive problems. The aim of this exploratory trial was to assess the effectiveness of Kali phos 6x for attention problems associated with mental fatigue. METHODS: We recruited student and staff volunteers (University of York) with self-reported mental fatigue, excluding any using homeopathy or prescribed stimulants, or with a diagnosis of chronic fatigue syndrome. In a triple blind, cross-over, placebo-controlled clinical trial, 86 volunteers were randomized to receive Kali phos 6x or identical placebo 10 minutes before taking a psychological test of attention (Stroop Colour-Word Test). One week later they were crossed over and took the other preparation before repeating the test. RESULTS: We found no evidence of a treatment effect in a comparison of Kali phos 6x with placebo (Kali phos minus placebo = -1.1 (95% CI -3.0 to 0.9, P = 0.3) Stroop score units, Cohen effect size = -0.17) even when allowing for a weak period effect with accuracy scores in the second period being higher than those in the first (P = 0.05). We observed a ceiling effect in the Stroop test which undermined our ability to interpret this result. CONCLUSIONS: Kali phos 6x was not found to be effective in reducing mental fatigue. A ceiling effect in our primary outcome measure meant that we could not rule out a type II error. Thorough piloting of an adequate outcome measure could have led to an unequivocal result. CURRENT CONTROLLED TRIALS: ISRCTN16521161.

Seasonal Patterns of Phytoplankton Taxon Richness in Lakes: Effects of Temperature, Turnover and Abundance.

Species richness is a key ecological characteristic that influences numerous ecosystem functions. Here we analyse the patterns and possible causes of phytoplankton taxon richness in seasonal datasets from twenty contrasting lakes in the English Lake District over six years and near-weekly datasets over 33 years from Windermere. Taxon richness was lowest in winter and highest in summer or autumn in all of the lakes. Observed richness was very similar to richness estimated from coverage and sampling effort, implying that it closely reflected true seasonal patterns. Summer populations were dominated by Chlorophyta and functional groups X1, F, N and P (sensu Reynolds). In Windermere, weekly taxon richness was strongly positively correlated with surface water temperature, as was the number of functional groups and the number of taxa per functional group. Turnover in richness of taxa and functional groups were positively correlated and both were related to surface temperature. This suggests that high taxon richness in summer is linked to higher water temperature, promoting a turnover in richness of taxa and functional groups in these lakes. However, since the number of taxa per unit concentration of chlorophyll a decreased with increasing concentration of chlorophyll a, competition might occur when abundance is high.

Economic evaluation of a randomized controlled trial of ultrasound therapy for hard-to-heal venous leg ulcers.

BACKGROUND: A pragmatic, multicentre randomized controlled trial (VenUS III) was conducted to determine whether low-dose ultrasound therapy increased the healing rate of hard-to-heal leg ulcers. This study was a cost-effectiveness analysis of the trial data. METHODS: Cost-effectiveness and cost-utility analyses were conducted alongside the VenUS III trial, in which patients were randomly allocated to either ultrasound treatment administered weekly for 12 weeks along with standard care, or standard care alone. The time horizon was 12 months and based on the UK National Health Service (NHS) perspective. RESULTS: The base-case analysis showed that ultrasound therapy added to standard care was likely to be more costly and provide no extra benefit over standard care alone. Individuals who received ultrasound treatment plus standard care took a mean of 14.7 (95 per cent confidence interval - 32.7 to 56.8) days longer to heal, had 0.009 (-0.042 to 0.024) fewer quality-adjusted life years and had higher treatment costs by £ 197.88 (-35.19 to 420.32). Based on these point estimates, ultrasound therapy plus standard care for leg ulcers was dominated by standard care alone. The analysis of uncertainty showed that this treatment strategy is unlikely to be cost-effective. CONCLUSION: Ultrasound treatment was not cost-effective for hard-to-heal leg ulcers and should not be recommended for adoption in the NHS.

Behavioural activation delivered by the non-specialist: phase II randomised controlled trial.

BACKGROUND: Behavioural activation appears as effective as cognitive-behaviour therapy (CBT) in the treatment of depression. If equally effective, then behavioural activation may be the preferred treatment option because it may be suitable for delivery by therapists with less training. This is the first randomised controlled trial to look at this possibility. AIMS: To examine whether generic mental health workers can deliver effective behavioural activation as a step-three high-intensity intervention. METHOD: A randomised controlled trial (ISRCTN27045243) comparing behavioural activation (n=24) with treatment as usual (n=23) in primary care. RESULTS: Intention-to-treat analyses indicated a difference in favour of behavioural activation of -15.79 (95% CI -24.55 to -7.02) on the Beck Depression Inventory-II and Work and Social Adjustment Scale (mean difference -11.12, 95% CI -17.53 to -4.70). CONCLUSIONS: Effective behavioural activation appears suitable for delivery by generic mental health professionals without previous experience as therapists. Large-scale trial comparisons with an active comparator (CBT) are needed.

New records of the ectoparasitic flagellate Colpodella gonderi on non-Colpoda ciliates.

Colpodella gonderi is the only ectoparasitic flagellate of ciliated protozoa described thus far. This investigation reveals new records of C. gonderi retrieved from soil samples in southern Scotland, UK. Of fourteen ciliates species identified in one single occasion, three of them, Colpoda steinii, Pseudoplatyophrya nana and Grossglockneria acuta, were infested with the parasite. These results provide further evidence that C. gonderi is not host-specific of the ciliate genus Colpoda.