Nutritional labelling for healthier food or non-alcoholic drink purchasing and consumption.

BACKGROUND: Nutritional labelling is advocated as a means to promote healthier food purchasing and consumption, including lower energy intake. Internationally, many different nutritional labelling schemes have been introduced. There is no consensus on whether such labelling is effective in promoting healthier behaviour. OBJECTIVES: To assess the impact of nutritional labelling for food and non-alcoholic drinks on purchasing and consumption of healthier items. Our secondary objective was to explore possible effect moderators of nutritional labelling on purchasing and consumption. SEARCH METHODS: We searched 13 electronic databases including CENTRAL, MEDLINE and Embase to 26 April 2017. We also handsearched references and citations and sought unpublished studies through websites and trials registries. SELECTION CRITERIA: Eligible studies: were randomised or quasi-randomised controlled trials (RCTs/Q-RCTs), controlled before-and-after studies, or interrupted time series (ITS) studies; compared a labelled product (with information on nutrients or energy) with the same product without a nutritional label; assessed objectively measured purchasing or consumption of foods or non-alcoholic drinks in real-world or laboratory settings. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion and extracted study data. We applied the Cochrane 'Risk of bias' tool and GRADE to assess the quality of evidence. We pooled studies that evaluated similar interventions and outcomes using a random-effects meta-analysis, and we synthesised data from other studies in a narrative summary. MAIN RESULTS: We included 28 studies, comprising 17 RCTs, 5 Q-RCTs and 6 ITS studies. Most (21/28) took place in the USA, and 19 took place in university settings, 14 of which mainly involved university students or staff. Most (20/28) studies assessed the impact of labelling on menus or menu boards, or nutritional labelling placed on, or adjacent to, a range of foods or drinks from which participants could choose. Eight studies provided participants with only one labelled food or drink option (in which labelling was present on a container or packaging, adjacent to the food or on a display board) and measured the amount consumed. The most frequently assessed labelling type was energy (i.e. calorie) information (12/28).Eleven studies assessed the impact of nutritional labelling on purchasing food or drink options in real-world settings, including purchases from vending machines (one cluster-RCT), grocery stores (one ITS), or restaurants, cafeterias or coffee shops (three RCTs, one Q-RCT and five ITS). Findings on vending machines and grocery stores were not interpretable, and were rated as very low quality. A meta-analysis of the three RCTs, all of which assessed energy labelling on menus in restaurants, demonstrated a statistically significant reduction of 47 kcal in energy purchased (MD -46.72 kcal, 95% CI -78.35, -15.10, N = 1877). Assuming an average meal of 600 kcal, energy labelling on menus would reduce energy purchased per meal by 7.8% (95% CI 2.5% to 13.1%). The quality of the evidence for these three studies was rated as low, so our confidence in the effect estimate is limited and may change with further studies. Of the remaining six studies, only two (both ITS studies involving energy labels on menus or menus boards in a coffee shop or cafeteria) were at low risk of bias, and their results support the meta-analysis. The results of the other four studies which were conducted in a restaurant, cafeterias (2 studies) or a coffee shop, were not clearly reported and were at high risk of bias.Seventeen studies assessed the impact of nutritional labels on consumption in artificial settings or scenarios (henceforth referred to as laboratory studies or settings). Of these, eight (all RCTs) assessed the effect of labels on menus or placed on a range of food options. A meta-analysis of these studies did not conclusively demonstrate a reduction in energy consumed during a meal (MD -50 kcal, 95% CI -104.41, 3.88, N = 1705). We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies.Six laboratory studies (four RCTs and two Q-RCTs) assessed the impact of labelling a single food or drink option (such as chocolate, pasta or soft drinks) on energy consumed during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant difference in energy (kcal) consumed (SMD 0.05, 95% CI -0.17 to 0.27, N = 732). However, the confidence intervals were wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence as low, so our confidence in the effect estimate is limited and may change with further studies.There was no evidence that nutritional labelling had the unintended harm of increasing energy purchased or consumed. Indirect evidence came from five laboratory studies that involved mislabelling single nutrient content (i.e. placing low energy or low fat labels on high-energy foods) during a snack or meal. A meta-analysis of these studies did not demonstrate a statistically significant increase in energy (kcal) consumed (SMD 0.19, 95% CI -0.14to 0.51, N = 718). The effect was small and the confidence intervals wide, suggesting uncertainty in the true effect size. We rated the quality of the evidence from these studies as very low, providing very little confidence in the effect estimate. AUTHORS' CONCLUSIONS: Findings from a small body of low-quality evidence suggest that nutritional labelling comprising energy information on menus may reduce energy purchased in restaurants. The evidence assessing the impact on consumption of energy information on menus or on a range of food options in laboratory settings suggests a similar effect to that observed for purchasing, although the evidence is less definite and also of low quality.Accordingly, and in the absence of observed harms, we tentatively suggest that nutritional labelling on menus in restaurants could be used as part of a wider set of measures to tackle obesity. Additional high-quality research in real-world settings is needed to enable more certain conclusions.Further high-quality research is also needed to address the dearth of evidence from grocery stores and vending machines and to assess potential moderators of the intervention effect, including socioeconomic status.

Changes in diet, cardiovascular risk factors and modelled cardiovascular risk following diagnosis of diabetes: 1-year results from the ADDITION-Cambridge trial cohort.

AIMS: To describe change in self-reported diet and plasma vitamin C, and to examine associations between change in diet and cardiovascular disease risk factors and modelled 10-year cardiovascular disease risk in the year following diagnosis of Type 2 diabetes. METHODS: Eight hundred and sixty-seven individuals with screen-detected diabetes underwent assessment of self-reported diet, plasma vitamin C, cardiovascular disease risk factors and modelled cardiovascular disease risk at baseline and 1 year (n = 736) in the ADDITION-Cambridge trial. Multivariable linear regression was used to quantify the association between change in diet and cardiovascular disease risk at 1 year, adjusting for change in physical activity and cardio-protective medication. RESULTS: Participants reported significant reductions in energy, fat and sodium intake, and increases in fruit, vegetable and fibre intake over 1 year. The reduction in energy was equivalent to an average-sized chocolate bar; the increase in fruit was equal to one plum per day. There was a small increase in plasma vitamin C levels. Increases in fruit intake and plasma vitamin C were associated with small reductions in anthropometric and metabolic risk factors. Increased vegetable intake was associated with an increase in BMI and waist circumference. Reductions in fat, energy and sodium intake were associated with reduction in HbA1c , waist circumference and total cholesterol/modelled cardiovascular disease risk, respectively. CONCLUSIONS: Improvements in dietary behaviour in this screen-detected population were associated with small reductions in cardiovascular disease risk, independently of change in cardio-protective medication and physical activity. Dietary change may have a role to play in the reduction of cardiovascular disease risk following diagnosis of diabetes.

Is community treatment best? a randomised trial comparing delivery of cancer treatment in the hospital, home and GP surgery.

BACKGROUND: Care closer to home is being explored as a means of improving patient experience as well as efficiency in terms of cost savings. Evidence that community cancer services improve care quality and/or generate cost savings is currently limited. A randomised study was undertaken to compare delivery of cancer treatment in the hospital with two different community settings. METHODS: Ninety-seven patients being offered outpatient-based cancer treatment were randomised to treatment delivered in a hospital day unit, at the patient's home or in local general practice (GP) surgeries. The primary outcome was patient-perceived benefits, using the emotional function domain of the EORTC quality of life (QOL) QLQC30 questionnaire evaluated after 12 weeks. Secondary outcomes included additional QOL measures, patient satisfaction, safety and health economics. RESULTS: There was no statistically significant QOL difference between treatment in the combined community locations relative to hospital (difference of -7.2, 95% confidence interval: -19·5 to +5·2, P=0.25). There was a significant difference between the two community locations in favour of home (+15·2, 1·3 to 29·1, P=0.033). Hospital anxiety and depression scale scores were consistent with the primary outcome measure. There was no evidence that community treatment compromised patient safety and no significant difference between treatment arms in terms of overall costs or Quality Adjusted Life Year. Seventy-eight percent of patients expressed satisfaction with their treatment whatever their location, whereas 57% of patients preferred future treatment to continue at the hospital, 81% at GP surgeries and 90% at home. Although initial pre-trial interviews revealed concerns among health-care professionals and some patients regarding community treatment, opinions were largely more favourable in post-trial interviews. INTERPRETATION: Patient QOL favours delivering cancer treatment in the home rather than GP surgeries. Nevertheless, both community settings were acceptable to and preferred by patients compared with hospital, were safe, with no detrimental impact on overall health-care costs.

Changes in physical activity and modelled cardiovascular risk following diagnosis of diabetes: 1-year results from the ADDITION-Cambridge trial cohort.

AIMS: To describe change in physical activity over 1 year and associations with change in cardiovascular disease risk factors in a population with screen-detected Type 2 diabetes. METHODS: Eight hundred and sixty-seven individuals with screen-detected diabetes underwent measurement of self-reported physical activity, cardiovascular disease risk factors and modelled cardiovascular disease risk at baseline and 1 year (n = 736) in the ADDITION-Cambridge trial. Multiple linear regression was used to quantify the association between change in different physical activity domains and cardiovascular disease risk factors at 1 year. RESULTS: There was no change in self-reported physical activity over 12 months. Even relatively large changes in physical activity were associated with relatively small changes in cardiovascular disease risk factors after allowing for changes in self-reported medication and diet. For every 30 metabolic equivalent-h increase in recreational activity (equivalent to 10 h/brisk walking/week), there was an average reduction of 0.1% in HbA(1c) in men (95% CI -0.15 to -0.01, P = 0.021) and an average reduction of 2 mmHg in systolic blood pressure in women (95% CI -4.0 to -0.05, P = 0.045). CONCLUSIONS: Few associations were observed between change in different physical activity domains and cardiovascular disease risk factors in this trial cohort. Cardiovascular disease risk reduction appeared to be driven largely by factors other than changes in self-reported physical activity in the first year following diagnosis.

Predictors of anxiety and depression among people attending diabetes screening: a prospective cohort study embedded in the ADDITION (Cambridge) randomized control trial.

OBJECTIVE: This study aimed to identify factors predicting anxiety and depression among people who attend primary care-based diabetes screening. DESIGN: A prospective cohort study embedded in the ADDITION (Cambridge) randomized control trial. METHODS: Participants (N= 3,240) at risk of diabetes were identified from 10 primary care practices and invited to a stepwise screening programme as part of the ADDITION (Cambridge) trial. Main outcome measures were anxiety and depression at 12 months post-screening assessed using the Hospital Anxiety and Depression Scale (HADS). RESULTS: Hierarchical linear regressions showed that demographic, clinical, and psychological variables collectively accounted for 52% of the variance in HADS anxiety scores and 53% of the variance in HADS depression scores 12 months after diabetes screening. Screening outcome (positive or negative for diabetes) was not related to differences in anxiety or depression at 12 months. Higher number of self-reported (diabetes) symptoms after first attendance was associated with higher anxiety and depression at 12-month follow-up, after controlling for anxiety and depression after first attendance. CONCLUSION: Participants in a diabetes screening programme showed low scores on anxiety and depression scales after first appointment and 1 year later. Diagnosis of diabetes was shown to have a limited psychological impact and may be less important than symptom perception in determining emotional outcomes after participation in diabetes screening.

Can informed choice invitations lead to inequities in intentions to make lifestyle changes among participants in a primary care diabetes screening programme? Evidence from a randomized trial.

OBJECTIVE: To test whether information about benefits and harms of screening for type 2 diabetes increases intentions to make lifestyle changes amongst attenders, predominantly among the socially advantaged and those with a strong future time orientation. STUDY DESIGN: Planned subgroup analysis of attenders for screening participating in a randomized controlled trial of an informed choice invitation vs a standard invitation to attend for type 2 diabetes screening. METHODS: Potentially eligible participants were identified from practice registers using routine data which were used to calculate risk scores for diabetes for all aged 40-69 years without known type 2 diabetes and area deprivation based on post code. In total, 1272 individuals in the top 25% risk category were randomized to receive one of two invitations to attend their practices for screening: an informed choice invitation or a standard invitation. The subsequent attenders completed self-report measures of future time orientation and deprivation immediately before undergoing a screening test. RESULTS: Individual-level deprivation demonstrated a significant moderator effect [F (4,635) = 4.32, P = 0.002]: individuals who were high in deprivation had lower intentions to engage in lifestyle change following receipt of the informed choice invitation. However, intentions were not patterned by deprivation when it was assessed at the area-level using the Index of Multiple Deprivation 2007. The hypothesized moderating effect of future time orientation on invitation type was also supported [F(14,613) = 2.46, P = 0.002): individuals low in future time orientation had markedly lower intentions to engage in lifestyle change following receipt of an informed choice invitation compared with a standard invitation for screening. CONCLUSION: Efforts to enhance informed choice where the implications of diagnosis are a requirement for lifestyle change may require that the immediate benefits are communicated, and efforts to address the apparent barriers to diabetes self-care are made, if the potential for inequity is to be avoided.

Who attends a UK diabetes screening programme? Findings from the ADDITION-Cambridge study.

AIMS: One of the factors influencing the cost-effectiveness of population screening for Type 2 diabetes may be uptake. We examined attendance and practice- and individual-level factors influencing uptake at each stage of a diabetes screening programme in general practice. METHODS: A stepwise screening programme was undertaken among 135, 825 people aged 40-69 years without known diabetes in 49 general practices in East England. The programme included a score based on routinely available data (age, sex, body mass index and prescribed medication) to identify those at high risk, who were offered random capillary blood glucose (RBG) and glycosylated haemoglobin tests. Those screening positive were offered fasting capillary blood glucose (FBG) and confirmatory oral glucose tolerance tests (OGTT). RESULTS: There were 33 539 high-risk individuals invited for a RBG screening test; 24 654 (74%) attended. Ninety-four per cent attended the follow-up FBG test and 82% the diagnostic OGTT. Seventy per cent of individuals completed the screening programme. Practices with higher general practitioner staff complements and those located in more deprived areas had lower uptake for RBG and FBG tests. Male sex and a higher body mass index were associated with lower attendance for RBG testing. Older age, prescription of antihypertensive medication and a higher risk score were associated with higher attendance for FBG and RBG tests. CONCLUSIONS: High attendance rates can be achieved by targeted stepwise screening of individuals assessed as high risk by data routinely available in general practice. Different strategies may be required to increase initial attendance, ensure completion of the screening programme, and reduce the risk that screening increases health inequalities.

Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours.

BACKGROUND: There are high expectations regarding the potential for the communication of DNA-based disease risk estimates to motivate behaviour change. OBJECTIVES: To assess the effects of communicating DNA-based disease risk estimates on risk-reducing behaviours and motivation to undertake such behaviours. SEARCH STRATEGY: We searched the following databases using keywords and medical subject headings: Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4 2010), MEDLINE (1950 to April 2010), EMBASE (1980 to April 2010), PsycINFO (1985 to April 2010) using OVID SP, and CINAHL (EBSCO) (1982 to April 2010). We also searched reference lists, conducted forward citation searches of potentially eligible articles and contacted authors of relevant studies for suggestions. There were no language restrictions. Unpublished or in press articles were eligible for inclusion. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials involving adults (aged 18 years and over) in which one group received actual (clinical studies) or imagined (analogue studies) personalised DNA-based disease risk estimates for diseases for which the risk could plausibly be reduced by behavioural change. Eligible studies had to include a primary outcome measure of risk-reducing behaviour or motivation (e.g. intention) to alter such behaviour. DATA COLLECTION AND ANALYSIS: Two review authors searched for studies and independently extracted data. We assessed risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions. For continuous outcome measures, we report effect sizes as standardised mean differences (SMDs). For dichotomous outcome measures, we report effect sizes as odds ratios (ORs). We obtained pooled effect sizes with 95% confidence intervals (CIs) using the random effects model applied on the scale of standardised differences and log odds ratios. MAIN RESULTS: We examined 5384 abstracts and identified 21 studies as potentially eligible. Following a full text analysis, we included 14 papers reporting results of 7 clinical studies (2 papers report on the same trial) and 6 analogue studies.Of the seven clinical studies, five assessed smoking cessation. Meta-analyses revealed no statistically significant effects on either short-term (less than 6 months) smoking cessation (OR 1.35, 95% CI 0.76 to 2.39, P = 0.31, n = 3 studies) or cessation after six months (OR 1.07, 95% CI 0.64 to 1.78, P = 0.80, n = 4 studies). Two clinical studies assessed diet and found effects that significantly favoured DNA-based risk estimates (OR 2.24, 95% CI 1.17 to 4.27, P = 0.01). No statistically significant effects were found in the two studies assessing physical activity (OR 1.03, 95% CI 0.59 to 1.80, P = 0.92) or the one study assessing medication or vitamin use aimed at reducing disease risks (OR 1.26, 95% CI 0.58 to 2.72, P = 0.56). For the six non-clinical analogue studies, meta-analysis revealed a statistically significant effect of DNA-based risk on intention to change behaviour (SMD 0.16, 95% CI 0.04 to 0.29, P = 0.01).There was no evidence that communicating DNA-based disease risk estimates had any unintended adverse effects. Two studies that assessed fear arousal immediately after the presentation of risk information did, however, report greater fear arousal in the DNA-based disease risk estimate groups compared to comparison groups.The quality of included studies was generally poor. None of the clinical or analogue studies were considered to have a low risk of bias, due to either a lack of clarity in reporting, or where details were reported, evidence of a failure to sufficiently safeguard against the risk of bias. AUTHORS' CONCLUSIONS: Mindful of the weak evidence based on a small number of studies of limited quality, the results of this review suggest that communicating DNA-based disease risk estimates has little or no effect on smoking and physical activity. It may have a small effect on self-reported diet and on intentions to change behaviour. Claims that receiving DNA-based test results motivates people to change their behaviour are not supported by evidence. Larger and better-quality RCTs are needed.

Ambulatory blood pressure measurements are related to albumin excretion and are predictive for risk of microalbuminuria in young people with type 1 diabetes.

AIMS/HYPOTHESIS: The relationship between BP and microalbuminuria in young people with type 1 diabetes is not completely clear. As microalbuminuria is preceded by a gradual rise in albumin excretion within the normal range, we hypothesised that ambulatory BP (ABP) may be closely related to albumin excretion and progression to microalbuminuria. METHODS: ABP monitoring (ABPM) was performed in 509 young people with type 1 diabetes (age median [range]: 15.7 [10.7-22.6] years) followed with annual assessments of three early morning urinary albumin:creatinine ratios (ACRs) and HbA(1c). Systolic BP (SBP) and diastolic BP (DBP) and the nocturnal fall in BP were analysed in relation to ACR. RESULTS: All ABPM variables were significantly related to baseline log(10) ACR (p < 0.001). After the ABPM evaluation, 287 patients were followed for a median of 2.2 (1.0-5.5) years. ABP at baseline was independently related to mean ACR during follow-up. Nineteen initially normoalbuminuric patients developed microalbuminuria after 2.0 (0.2-4.0) years and their baseline daytime DBP was higher than in normoalbuminuric patients (p < 0.001). After adjusting for baseline ACR and HbA(1c), there was an 11% increased risk of microalbuminuria for each 1 mmHg increase in daytime DBP. Forty-eight per cent of patients were non-dippers for SBP and 60% for DBP; however, ACR was not different between dippers and non-dippers and there were no differences in the nocturnal fall in BP between normoalbuminuric and future microalbuminuric patients. CONCLUSIONS/INTERPRETATION: In this cohort of young people with type 1 diabetes, ABP was significantly related to ACR, and daytime DBP was independently associated with progression to microalbuminuria. Increasing albumin excretion, even in the normal range, may be associated with parallel rises in BP.

How much might cardiovascular disease risk be reduced by intensive therapy in people with screen-detected diabetes?

AIMS: To assess the cardiovascular disease (CVD) risk of people with screen-detected Type 2 diabetes and to estimate the risk reduction achievable through early intensive pharmacological intervention. METHODS: In ADDITION-Cambridge, diabetic patients were identified among people aged 40-69 years through a stepwise screening procedure including a risk score, random and fasting capillary blood glucose, HbA(1c) and oral glucose tolerance test. In those without prior macrovascular disease, 10-year CVD risk was computed using UK Prospective Diabetes Study (UKPDS) and Framingham engines. The absolute risk reduction achievable and its plausible range were predicted using relative risk reductions for individual therapies from published trials and sensitivity analysis. RESULTS: Of the 867 individuals with undiagnosed diabetes, 19% had pre-existing CVD, 97% were overweight or obese, 86% had hypertension, 75% had dyslipidaemia, 20% had microalbuminuria and 18% were smokers. Of those with hypertension, 35% were not prescribed drugs and 42% were suboptimally treated. Of participants with dyslipidaemia, 68% were not prescribed medications and 22% were poorly controlled. Median 10-year CVD risk was 34.0%[interquartile range (IQR) 26.2-44.6] in men and 21.5% (IQR 15.7-28.7) in women using the UKPDS engine; 38.6% (IQR 27.8-53.0) in men and 24.6% (IQR 17.2-32.9) in women using Framingham equations. In the most conservative scenario (no additive effect of therapies), the absolute risk reduction achievable through multifactorial therapy ranged from 4.9 to 9.5% (UKPDS) and from 5.4 to 10.5% (Framingham). The corresponding ranges of numbers needed to treat were 11-20 and 10-19. CONCLUSIONS: People with screen-detected diabetes have an adverse cardiovascular risk profile, which is potentially modifiable through application of existing treatment recommendations.

Severity of obesity and management of hypertension, hypercholesterolaemia and smoking in primary care: population-based cohort study.

Obesity and obesity-associated cardiovascular risk are increasing worldwide. This study aimed to determine how different levels of obesity are associated with the management of smoking, hypertension and hypercholesterolaemia in primary care. We conducted a cohort study of adults aged 30-100 years in England, sampled from the primary care electronic health records in the Clinical Practice Research Datalink. Prevalence, treatment and control were estimated for each risk factor by body mass index (BMI) category. Adjusted odds ratios (AOR) were estimated, allowing for age, gender, comorbidity and socioeconomic status, with normal weight as reference category. Data were analysed for 247,653 patients including 153,308 (62%) with BMI recorded, of whom 46,149 (30%) were obese. Participants were classified into simple (29,257), severe (11,059) and morbid obesity (5833) categories. Smoking declined with the increasing BMI category, but smoking cessation treatment increased. Age-standardised hypertension prevalence was twice as high in morbid obesity (men 78.6%; women 66.0%) compared with normal weight (men 37.3%; women 29.4%). Hypertension treatment was more frequent (AOR 1.75, 1.59-1.92) but hypertension control less frequent (AOR 0.63, 0.59-0.69) in morbid obesity, with similar findings for severe obesity. Hypercholesterolaemia was more frequent in morbid obesity (men 48.2%; women 36.3%) than normal weight (men 25.0%; women 20.0%). Lipid lowering therapy was more frequent in morbid obesity (AOR 1.83, 1.61-2.07) as was cholesterol control (AOR 1.19, 1.06-1.34). Increasing obesity category is associated with elevated risks from hypertension and hypercholesterolaemia. Inadequate hypertension control in obesity emerges as an important target for future interventions.

A randomized clinical trial comparing fixed vs pro-re-nata dosing of Ozurdex in refractory diabetic macular oedema (OZDRY study).

OBJECTIVE: To compare the clinical effectiveness and safety of 5-monthly fixed dosing vs pro-re-nata (PRN) Ozurdex treatment in patients with refractory diabetic macular oedema (DMO). DESIGN: Prospective, multicentre, randomized active-controlled non-inferiority clinical trial. PARTICIPANTS: Participants were 100 patients who attended Medical Retina Clinics for management of centre-involving refractory DMO. INTERVENTIONS: Participants were randomized 1 : 1 to either 5-monthly fixed dosing or optical coherence tomography (OCT)-guided PRN regimen of Ozurdex therapy for DMO. Data were collected on best-corrected visual acuity (BCVA), patient-reported outcome measures (PROM), macular thickness and morphology, diabetic retinopathy status, number of injections and adverse events from baseline for a period of 12 months.Main outcome measuresThe primary outcome was the difference between arms in change in BCVA from baseline to 12 months. The prespecified non-inferiority margin was five ETDRS letters. Key secondary outcomes included change in PROM scores, change in macular thickness, change in retinopathy and macular morphology, and safety profile. RESULTS: The mean change in BCVA was +1.48 (SD 14.8) in the fixed arm vs -0.17 (SD 13.1) in the PRN arm, with adjusted effect estimate +0.97, 90% confidence interval (-4.01, +5.95), P=0.02 (per protocol analysis). The conclusions of the ITT analysis were primarily supportive, -0.34 (-5.49, 4.81) P=0.07, but sensitive to an alternative assumption on missing data, +0.28 (-4.72, 5.27) P=0.04. CONCLUSIONS: The mean change in BCVA with 5-monthly fixed dosing of Ozurdex was non-inferior to OCT-guided PRN Ozurdex therapy for refractory DMO based on a per protocol analysis.

Improvement in mood and fatigue after dehydroepiandrosterone replacement in Addison's disease in a randomized, double blind trial.

Dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) are adrenal precursors of steroid biosynthesis and centrally acting neurosteroids. Glucocorticoid and mineralocorticoid deficiencies in Addison's disease require life-long hormone replacement, but the associated failure of DHEA synthesis is not corrected. We conducted a randomized, double blind study in which 39 patients with Addison's disease received either 50 mg oral DHEA daily for 12 weeks, followed by a 4-week washout period, then 12 weeks of placebo, or vice versa. After DHEA treatment, levels of DHEAS and Delta(4)-androstenedione rose from subnormal to within the adult physiological range. Total testosterone increased from subnormal to low normal with a fall in serum sex hormone-binding globulin in females, but with no change in either parameter in males. In both sexes, psychological assessment showed significant enhancement of self-esteem with a tendency for improved overall well-being. Mood and fatigue also improved significantly, with benefit being evident in the evenings. No effects on cognitive or sexual function, body composition, lipids, or bone mineral density were observed. Our results indicate that DHEA replacement corrects this steroid deficiency effectively and improves some aspects of psychological function. Beneficial effects in males, independent of circulating testosterone levels, suggest that it may act directly on the central nervous system rather than by augmenting peripheral androgen biosynthesis. These positive effects, in the absence of significant adverse events, suggest a role for DHEA replacement therapy in the treatment of Addison's disease.

Randomized trial to evaluate the clinical benefits of serum alpha-glutathione S-transferase concentration monitoring after liver transplantation.

BACKGROUND: An increase in serum alpha-glutathione S-transferase concentration (GST) has been shown to be a more sensitive and specific marker of hepatocellular damage than equivalent increases in transaminase activities. A randomized clinical trial of 60 liver transplants in 49 patients was carried out to assess the clinical benefits of GST monitoring as a supplementary test to routine liver function tests during the first 3 postoperative months after liver transplantation. METHODS: Mortality and morbidity were compared in graft recipients who had their GST reported daily to the ward (reporting group) and graft recipients who did not. RESULTS: The 3-month survival rate was significantly greater in the reporting group (P=0.033) and the risk of graft loss was halved (relative hazard ratio=0.50; P=0.29). The reporting group also had significantly more patients who spent less than 3 weeks in the hospital throughout the follow-up period (P=0.036). In addition, the reporting group experienced a lower frequency of biopsies per graft (P=0.038), less severe rejection (P=0.015), and a lower incidence of infection episodes per graft (P=0.03). GST increased by >50% above the upper limit of the reference range at a median of 1 day before the equivalent change in alanine transaminase in association with allograft rejection in the combined groups (95% confidence interval=1 to 2 days) but was lower on the day of diagnosis of rejection in the reporting group (P=0.02). This is compatible with the earlier diagnosis of rejection in the reporting group. CONCLUSIONS: We conclude that the monitoring of GST may improve patient care, reducing both mortality and morbidity.

Irritable bowel syndrome: is the search for lactose intolerance justified?

OBJECTIVES: To determine if confirmation of hypolactasia offers any benefit to the dietary treatment of patients with irritable bowel syndrome (IBS). METHODS: One hundred and twenty-two consecutive IBS patients (37 male, 85 female) were given lactose hydrogen breath tests (LHBT). Those with positive LHBT followed a low lactose diet for 3 weeks. Those improving on the diet were given double-blind, placebo-controlled challenges (DBPCC) with 5 g, 10 g and 15 g of lactose and a placebo, to confirm lactose intolerance. Those who did not respond to the low lactose diet followed either an exclusion or low fibre diet. Symptoms scores were kept prior to the LHBT, 8 h post-LHBT and daily whilst following any dietary change. Patients with negative LHBT returned to clinic and subsequent dietary interventions were recorded. RESULTS: LHBT was positive in 33/122 (27%) IBS patients. Syrr otom scores prior to LHBT were not significantly different between the two groups, but after LHBT the symptoms in the positive group were significantly worse. Twenty-three patients followed a low-lactose diet of which only nine (39%) improved. Six who did not improve followed an exclusion diet, three improved and all were intolerant of milk. Three tried a low fibre diet with two improving. DBPCC were inconclusive. In the negative LHBT group 35 agreed to try a diet and 24 improved (69%). Eight were intolerant of cow's milk. CONCLUSIONS: Use of a low lactose diet was disappointing in IBS patients with lactose malabsorption. Food intolerance was demonstrated in IBS patients with positive or negative LHBT and milk was identified as a problem in both groups. DBPCC were inconclusive. There appears to be little advantage in trying to separate patients who malabsorb lactose from others with IBS.

An analysis of referral patterns for dizziness in the primary care setting.

BACKGROUND: The majority of balance disorders are non life-threatening and symptoms will resolve spontaneously. However, some patients require further investigation and many disorders may benefit from specialist treatment it is unclear whether appropriate identification and referral of this group of patients presently occurs. AIM: To review the management of patients with symptoms of dizziness within primary care. METHOD: A retrospective review of the management of 503 patients who visited their general practitioner (GP) complaining of dizziness between August 1993 and July 1995. Management was then compared with local criteria. RESULTS: On average, 2.2% of patients per year at the practices studied consulted their GP about dizziness, amounting to 0.7% of all consultations. The most common GP diagnosis was of an ear, nose, and throat (ENT) disorder (33.8%). Similarly, many of the 16% referred were directed to ENT (36%) specialists. The proportion of patients referred was significantly higher in those seeing their GP at least twice, those with symptoms lasting a year or more, or where there were additional symptoms associated with the dizziness, indicative of a cardiac, ENT, or neurological disorder. Compared with the local criteria, 17% of management decisions were deemed inappropriate. The major failing was not referring appropriate patients. This group comprised patients with chronic, non-urgent symptoms, and were significantly older than those appropriately referred. CONCLUSION: Patients with chronic symptoms of dizziness, particularly the elderly, are under-referred for specialist consultation and, therefore, do not have access to appropriate treatment regimes. This suggests a need for further training of GPs and evaluation of therapeutic needs of elderly dizzy patients.

A tool to measure radiotherapy complexity and workload: derivation from the basic treatment equivalent (BTE) concept.

Radiotherapy workload is poorly represented by simple parameters of patients, fractions or fields treated because these do not contain any measure of treatment complexity. However, complexity is increasing and there is an urgent need to quantify this. We have evaluated the basic treatment equivalent (BTE) model as a measure of radiotherapy workload and complexity. Radiotherapy treatment times, from the patient entering to exiting the treatment room maze, were measured for 1298 treatment sessions on 269 patients. The data were used to assess the original model and derive three new models for predicting treatment duration. The most complicated, the 'Addenbrooke's complex model', contained two additional predictor variables, including 'site/technique', in a linear additive form. Before the study, the department used a standard treatment appointment time of 10 minutes. However, 50% of the measured treatments took longer than 10 minutes, (mean 10.9). Summed over the working day, this discrepancy indicates that a standard 10-minute appointment is a poor basis for scheduling radiotherapy. The original BTE model was effective in predicting treatment times, although this was improved by refinement of the model. The Addenbrooke's complex model correctly predicted 70% of treatment times to within 2 minutes (55% for the original BTE model), 80% to within 2.5 minutes and 95% to within 4.7 minutes. The percentage of the variation in observed times accounted for by the model is 59.4%. The models can represent radiotherapy complexity, can improve scheduling on linear accelerators, and are likely to be applicable to other departments. They are thus tools to assess the impact of changes in complexity from new techniques, trial protocols (e.g. the Medical Research Council prostate radiotherapy trial RTO1), and possible time saving from advanced technology such as multileaf collimators (MLCs) or automated machine set-up. The replacement of manually-lifted shielding blocks by MLCs should save 1.1-1.5 minutes for a three- or four-field pelvic plan (i.e. 12%-13%). The models could also be used to aid planning for future linear accelerator provision and for costing radiotherapy treatment.

Residual postoperative tumour volume predicts outcome after high-dose radiotherapy for chordoma and chondrosarcoma of the skull base and spine.

AIMS: High-dose radiotherapy after surgical debulking is the treatment of choice for chordomas and chondrosarcomas. This study reviewed our outcomes, in relation to residual tumour volume and radiation dose, in order to inform our future practice. PATIENTS AND METHODS: Nineteen patients referred to the Neuro-Oncology Unit at Addenbrooke's Hospital (Cambridge, UK) between 1996 and 2009 and treated with photon radiotherapy were reviewed. Seventeen of the 19 were treated with curative intent. The median follow-up was 53 months. The tumours in the study had a mean gross tumour volume (GTV) of 17.2 cm(3) (median 10.5 cm(3)) and a range of 0-76.3 cm(3). The median dose was 65Gy in 39 fractions. RESULTS: The 5 year cause-specific survival for radically treated patients with chordomas was 92% and the 5 year local control rate was 83%. The 5 year cause-specific survival and local control rates with chondrosarcomas were both 100%. A planning target volume (PTV) below 90 cm(3) is predictive of local control, but volumes above this are not. The GTV seems to be a better predictor of outcome: among the 17 of 19 patients treated curatively, a GTV threshold of 30 cm(3) distinguished local failures from the 15 patients with local control, with sensitivity to detect local control of 100% (95% confidence interval 78-100%), specificity 100% (95% confidence interval 16-100%) and positive predictive value 100% (95% confidence interval 78-100%). CONCLUSIONS: Our results show a high level of efficacy for fractionated photon radiotherapy after surgery, in keeping with other series. In addition, we found that although surgical debulking is essential, a small residual tumour volume may still be controlled with high-dose photon radiotherapy. This information may be relevant during neurosurgical planning, possibly allowing a reduction in risk of serious neurological deficits. This should encourage the further development of sophisticated photon radiotherapy, for patients unsuitable for proton therapy.

Trials in primary care: statistical issues in the design, conduct and evaluation of complex interventions.

Trials carried out in primary care typically involve complex interventions that require considerable planning if they are to be implemented successfully. The role of the statistician in promoting both robust study design and appropriate statistical analysis is an important contribution to a multi-disciplinary primary care research group. Issues in the design of complex interventions have been addressed in the Medical Research Council's new guidance document and over the past 7 years by the Royal Statistical Society's Primary Health Care Study Group. With the aim of raising the profile of statistics and building research capability in this area, particularly with respect to methodological issues, the study group meetings have covered a wide range of topics that have been of interest to statisticians and non-statisticians alike. The aim of this article is to provide an overview of the statistical issues that have arisen over the years related to the design and evaluation of trials in primary care, to provide useful examples and references for further study and ultimately to promote good practice in the conduct of complex interventions carried out in primary care and other health care settings. Throughout we have given particular emphasis to statistical issues related to the design of cluster randomised trials.