The effect of walking on risk factors for cardiovascular disease: an updated systematic review and meta-analysis of randomised control trials.

OBJECTIVE: To conduct a systematic review and meta-analysis of randomised control trials that examined the effect of walking on risk factors for cardiovascular disease. METHODS: Four electronic databases and reference lists were searched (Jan 1971-June 2012). Two authors identified randomised control trials of interventions ≥ 4 weeks in duration that included at least one group with walking as the only treatment and a no-exercise comparator group. Participants were inactive at baseline. Pooled results were reported as weighted mean treatment effects and 95% confidence intervals using a random effects model. RESULTS: 32 articles reported the effects of walking interventions on cardiovascular disease risk factors. Walking increased aerobic capacity (3.04 mL/kg/min, 95% CI 2.48 to 3.60) and reduced systolic (-3.58 mm Hg, 95% CI -5.19 to -1.97) and diastolic (-1.54 mm Hg, 95% CI -2.83 to -0.26) blood pressure, waist circumference (-1.51 cm, 95% CI -2.34 to -0.68), weight (-1.37 kg, 95% CI -1.75 to -1.00), percentage body fat (-1.22%, 95% CI -1.70 to -0.73) and body mass index (-0.53 kg/m(2), 95% CI -0.72 to -0.35) but failed to alter blood lipids. CONCLUSIONS: Walking interventions improve many risk factors for cardiovascular disease. This underscores the central role of walking in physical activity for health promotion.

Maternal plasma and amniotic fluid cytokines in monochorionic, diamniotic twin pregnancies complicated by twin-to-twin transfusion syndrome.

INTRODUCTION: Cytokine imbalance has been implicated in placental-related pathologies, i.e. recurrent miscarriage and pre-eclampsia. Such conditions are more prevalent in multiple pregnancies. Twin-to-twin transfusion syndrome (TTTS) is associated with asymmetric placental blood flow and intra-cardiac pressures. We hypothesised that cytokine expression may be aberrant in this condition and that fetoscopic laser ablation (FLA) may cause local cytokine release. MATERIAL AND METHODS: A prospective cohort of monochorionic, diamniotic twins with TTTS (n = 23) was studied. Circulating T helper cell type 1 (TH1)/TH2 maternal cytokines and cytokine-related and angiogenic factors were measured in plasma and amniotic fluid before and after FLA by human FASTQuant or ELISA. Basal comparisons were made with uncomplicated monochorionic and dichorionic (DC) twins. RESULTS: Median maternal plasma platelet-derived growth factor-BB was highest in uncomplicated DC twins (p = 0.049), whereas tissue inhibitor of metalloproteinases (TIMP)-1 was highest in TTTS twins (p = 0.003). In TTTS amniotic fluid, interleukin (IL)-6, IL-1ß, tumour necrosis factor-α, IL-10, IL-4, IL-8, interferon-γ, TIMP-1 and intercellular adhesion molecule-1 were significantly higher than maternal plasma concentrations. There were no significant differences in plasma or amniotic fluid cytokines after FLA, with the exception of amniotic fluid keratinocyte growth factor, which was significantly reduced. DISCUSSION: TTTS is associated with minimal changes in cytokine levels when compared to uncomplicated twins, although the majority of cytokine levels were higher in amniotic fluid than maternal blood. It does not appear that FLA evokes a significant change in cytokines.

A randomised controlled trial of a probiotic 'functional food' in the management of irritable bowel syndrome.

BACKGROUND: Irritable Bowel Syndrome (IBS) is a common condition characterised by pain, distension and altered bowel habit. Evidence suggests functional foods containing probiotics improve gastrointestinal transit, however, data are limited by short follow-up periods and evaluation in selected populations. METHODS: A multi-centre, randomized, double blind, controlled trial to evaluate the effect of a probiotic vs non-probiotic dairy product on symptoms in IBS with a constipation element (IBS-Constipation or IBS-Mixed profile). Set in 13 general practices within central England. Individuals meeting the ROME III criteria for IBS, aged 18-65 completed a pre-study diary. Eligible individuals were randomized to consume dairy 'yoghurt' products which either did or did not contain active probiotics twice daily and to complete a daily diary. Primary outcome was subjective global assessment of symptom relief at week 4. Other outcomes comprised, IBS symptom scores, pain, bloating and flatulence levels, stool frequency, stool consistency, ease of bowel movement and quality of life. RESULTS: 179 were randomized (91 active, 88 placebo). 76 (43 active, 33 placebo) completed the study. No significant between group differences existed at 4 weeks (57% active vs 53% placebo, reported adequate relief (p = 0.71)). By week 8, 46% active vs 68% placebo reported adequate relief (p = 0.03). This was sustained at week 12. CONCLUSIONS: Significant improvements were reported for most outcomes in all trial participants but improvement did not differ by group. This trial does not provide evidence for effectiveness of a probiotic in IBS, in variance with a body of published literature and review conclusions. Differential drop out may however cloud interpretation of data. UK TRIAL REGISTRATION: ISRCTN78863629.

An international longitudinal registry of patients with atrial fibrillation at risk of stroke (GARFIELD): the UK protocol.

BACKGROUND: Atrial fibrillation (AF) is an independent risk factor for stroke and a significant predictor of mortality. Evidence-based guidelines for stroke prevention in AF recommend antithrombotic therapy corresponding to the risk of stroke. In practice, many patients with AF do not receive the appropriate antithrombotic therapy and are left either unprotected or inadequately protected against stroke. The purpose of the Global Anticoagulant Registry in the FIELD (GARFIELD) is to determine the real-life management and outcomes of patients newly diagnosed with non-valvular AF. METHODS/DESIGN: GARFIELD is an observational, international registry of newly diagnosed AF patients with at least one additional investigator-defined risk factor for stroke. The aim is to enrol 55,000 patients at more than 1000 centres in 50 countries worldwide. Enrolment will take place in five independent, sequential, prospective cohorts; the first cohort includes a retrospective validation cohort. Each cohort will be followed up for 2 years. The UK stands to be a significant contributor to GARFIELD, aiming to enrol 4,582 patients, and reflecting the care environment in which patients with AF are managed. The UK protocol will also focus on better understanding the validity of the two main stroke risk scores (CHADS2 and CHA2DS2VASC) and the HAS-BLED bleeding risk score, in the context of a diverse patient population. DISCUSSION: The GARFIELD registry will describe how therapeutic strategies, patient care, and clinical outcomes evolve over time. This study will provide UK-specific comprehensive data that will allow a range of evaluations both at a national level and in relation to global data and contribute to a better understanding of AF management in the UK. TRIAL REGISTRATION: ClinicalTrial.gov: NCT01090362.

Trial Protocol: a randomised controlled trial of extended anticoagulation treatment versus routine anticoagulation treatment for the prevention of recurrent VTE and post thrombotic syndrome in patients being treated for a first episode of unprovoked VTE (The ExACT Study).

BACKGROUND: Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity. The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot. However, the recurrence rate following a deep vein thrombosis remains approximately 10% per annum following treatment cessation irrespective of the duration of anticoagulation therapy. Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence.Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration. It has a cumulative incidence after 2 years of around 25% and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure. METHODS/DESIGN: Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and randomly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis. At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device. In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study. Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life questionnaires. DISCUSSION: The primary aim of the study is to investigate whether extending oral anticoagulation treatment (prior to discontinuing treatment) beyond 3-6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence. The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting. TRIAL REGISTRATION: ISRCTN73819751.

Attentional bias retraining in cigarette smokers attempting smoking cessation (ARTS): study protocol for a double blind randomised controlled trial.

BACKGROUND: Smokers attend preferentially to cigarettes and other smoking-related cues in the environment, in what is known as an attentional bias. There is evidence that attentional bias may contribute to craving and failure to stop smoking. Attentional retraining procedures have been used in laboratory studies to train smokers to reduce attentional bias, although these procedures have not been applied in smoking cessation programmes. This trial will examine the efficacy of multiple sessions of attentional retraining on attentional bias, craving, and abstinence in smokers attempting cessation. METHODS/DESIGN: This is a double-blind randomised controlled trial. Adult smokers attending a 7-session weekly stop smoking clinic will be randomised to either a modified visual probe task with attentional retraining or placebo training. Training will start 1 week prior to quit day and be given weekly for 5 sessions. Both groups will receive 21 mg transdermal nicotine patches for 8-12 weeks and withdrawal-orientated behavioural support for 7 sessions. Primary outcome measures are the change in attentional bias reaction time and urge to smoke on the Mood and Physical Symptoms Scale at 4 weeks post-quit. Secondary outcome measures include differences in withdrawal, time to first lapse and prolonged abstinence at 4 weeks post-quit, which will be biochemically validated at each clinic visit. Follow-up will take place at 8 weeks, 3 months and 6 months post-quit. DISCUSSION: This is the first randomised controlled trial of attentional retraining in smokers attempting cessation. This trial could provide proof of principle for a treatment aimed at a fundamental cause of addiction. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN54375405.

Iodine status of UK schoolgirls: a cross-sectional survey.

BACKGROUND: Iodine deficiency is the most common cause of preventable mental impairment worldwide. It is defined by WHO as mild if the population median urinary iodine excretion is 50-99 µg/L, moderate if 20-49 µg/L, and severe if less than 20 µg/L. No contemporary data are available for the UK, which has no programme of food or salt iodination. We aimed to assess the current iodine status of the UK population. METHODS: In this cross-sectional survey, we systematically assessed iodine status in schoolgirls aged 14-15 years attending secondary school in nine UK centres. Urinary iodine concentrations and tap water iodine concentrations were measured in June-July, 2009, and November-December, 2009. Ethnic origin, postcode, and a validated diet questionnaire assessing sources of iodine were recorded. FINDINGS: 810 participants provided 737 urine samples. Data for dietary habits and iodine status were available for 664 participants. Median urinary iodine excretion was 80·1 µg/L (IQR 56·9-109·0). Urinary iodine measurements indicative of mild iodine deficiency were present in 51% (n=379) of participants, moderate deficiency in 16% (n=120), and severe deficiency in 1% (n=8). Prevalence of iodine deficiency was highest in Belfast (85%, n=135). Tap water iodine concentrations were low or undetectable and were not positively associated with urinary iodine concentrations. Multivariable general linear model analysis confirmed independent associations between low urinary iodine excretion and sampling in summer (p<0·0001), UK geographical location (p<0·0001), low intake of milk (p=0·03), and high intake of eggs (p=0·02). INTERPRETATION: Our findings suggest that the UK is iodine deficient. Since developing fetuses are the most susceptible to adverse effects of iodine deficiency and even mild perturbations of maternal and fetal thyroid function have an effect on neurodevelopment, these findings are of potential major public health importance. This study has drawn attention to an urgent need for a comprehensive investigation of UK iodine status and implementation of evidence-based recommendations for iodine supplementation. FUNDING: Clinical Endocrinology Trust.

Comparison of postdischarge physiotherapy versus usual care following primary total knee arthroplasty for osteoarthritis: an exploratory pilot randomized clinical trial.

OBJECTIVE: To evaluate a pilot trial of a postdischarge physiotherapy intervention to improve patient function versus usual physiotherapy in patients undergoing total knee arthroplasty aiming to assess: recruitment rate, feasibility and acceptability of the intervention and control, suitability of outcomes, retention and adverse events and to inform sample size calculation for a definitive trial. DESIGN: Exploratory pilot randomized controlled trial using independent assessment. SETTING: Mixed urban and rural, UK. PARTICIPANTS: Patients undergoing primary, elective unilateral knee arthroplasty for osteoarthritis. INTERVENTION: Two additional home physiotherapy visits of functional weight-bearing exercises, functional task-specific training versus treatment as usual. MAIN OUTCOME: Oxford Knee Score at 12 months. SECONDARY OUTCOMES: completion rates, adverse events, Knee Injury and Osteoarthritis Outcome Score, leg extensor power, timed 10-m walk, timed sit-to-stand, resource use diaries. Assessments completed at baseline (pre-operatively), 3, 6 and 12 months. RESULTS: Of 181 eligible participants 107 (59.1%) were randomized over 13 months, one participant withdrew, no adverse events. Intervention group n = 56 (mean age 67.8), control group n = 51 (mean age 70.8). The difference in mean change of Oxford Knee Scores between groups (intervention--control) at 12 months was 0.2 (95% confidence interval (CI) -3.8, 4.2), P = 0.94. Patient diaries revealed non-trial additional physiotherapy requires improved measurement. CONCLUSIONS: Successful recruitment and retention rates were achieved. The intervention appeared feasible and acceptable but may be suboptimal in intensity given recent research. A sample size of 1271 participants would be required for a fully powered randomized controlled trial using the main outcome. However new outcomes, potentially of greater validity and responsiveness, require consideration.

The relationship between serum TSH and free T4 in older people.

The frequency distribution of serum thyroid stimulating hormone (TSH) shows a skewed pattern that may change with age. The set point of the hypothalamic-pituitary-thyroid axis for an individual is thought to be genetically determined and has been described as a log-linear relationship of serum TSH to free thyroxine (T4); however, the validity of this hypothesis has yet to be established in older people. The aim of the study was to describe the relationship between serum TSH and free T4 in older people and define factors influencing this relationship. We conducted a cross-sectional, observational study of thyroid function in a community population of older subjects over 65 years of age. The relationship between serum TSH and free T4 was not linear as previously described, but is best described as a fourth-order polynomial. Both gender and smoking status affected the relationship. This suggests that more complex modelling is required when investigating the hypothalamic-pituitary-thyroid axis.

Orangutans employ unique strategies to control branch flexibility.

Orangutans are the largest habitually arboreal mammal. For them, as for all arboreal mammals, access to the abundant fruits and narrowest gaps found among the thin peripheral branches of tree crowns poses considerable safety risks and energetic demands. Most arboreal primates use flexed-limb postures to minimize problems caused by branch compliance and instability. Here, we show that Sumatran orangutans employ unique locomotor strategies to control compliance and allow access to the terminal branch niche for feeding and gap crossing. We calculated a "stiffness score," which is a measure of the flexibility of the supports on which orangutans moved. We found that certain locomotor behaviors clearly are associated with the most compliant supports; these behaviors appear to lack regular limb sequences, which serves to avoid the risk of resonance in branch sway caused by high-frequency, patterned gait. Balance and increased stability are achieved through long contact times between multiple limbs and supports and a combination of pronograde (horizontal) and orthograde (vertical) body postures, used both above branches and in suspension underneath them. Overall, adult females seem to be the most conservative in their travel, selecting more solid and secure supports than males and adolescents. These results have implications for understanding locomotor diversity in fossil and extant apes and for orangutan conservation and reintroduction programs.

Telemonitoring and self-management in the control of hypertension (TASMINH2): a randomised controlled trial.

BACKGROUND: Control of blood pressure is a key component of cardiovascular disease prevention, but is difficult to achieve and until recently has been the sole preserve of health professionals. This study assessed whether self-management by people with poorly controlled hypertension resulted in better blood pressure control compared with usual care. METHODS: This randomised controlled trial was undertaken in 24 general practices in the UK. Patients aged 35-85 years were eligible for enrolment if they had blood pressure more than 140/90 mm Hg despite antihypertensive treatment and were willing to self-manage their hypertension. Participants were randomly assigned in a 1:1 ratio to self-management, consisting of self-monitoring of blood pressure and self-titration of antihypertensive drugs, combined with telemonitoring of home blood pressure measurements or to usual care. Randomisation was done by use of a central web-based system and was stratified by general practice with minimisation for sex, baseline systolic blood pressure, and presence or absence of diabetes or chronic kidney disease. Neither participants nor investigators were masked to group assignment. The primary endpoint was change in mean systolic blood pressure between baseline and each follow-up point (6 months and 12 months). All randomised patients who attended follow-up visits at 6 months and 12 months and had complete data for the primary outcome were included in the analysis, without imputation for missing data. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN17585681. FINDINGS: 527 participants were randomly assigned to self-management (n=263) or control (n=264), of whom 480 (91%; self-management, n=234; control, n=246) were included in the primary analysis. Mean systolic blood pressure decreased by 12.9 mm Hg (95% CI 10.4-15.5) from baseline to 6 months in the self-management group and by 9.2 mm Hg (6.7-11.8) in the control group (difference between groups 3.7 mm Hg, 0.8-6.6; p=0.013). From baseline to 12 months, systolic blood pressure decreased by 17.6 mm Hg (14.9-20.3) in the self-management group and by 12.2 mm Hg (9.5-14.9) in the control group (difference between groups 5.4 mm Hg, 2.4-8.5; p=0.0004). Frequency of most side-effects did not differ between groups, apart from leg swelling (self-management, 74 patients [32%]; control, 55 patients [22%]; p=0.022). INTERPRETATION: Self-management of hypertension in combination with telemonitoring of blood pressure measurements represents an important new addition to control of hypertension in primary care. FUNDING: Department of Health Policy Research Programme, National Coordinating Centre for Research Capacity Development, and Midlands Research Practices Consortium.

Does self-management of oral anticoagulation therapy improve quality of life and anxiety?

BACKGROUND: Research related to service requirements for anticoagulation management has focussed on clinical and health economic outcomes and paid little attention to the impact of treatment and service delivery on patients' quality of life. This was the first large UK study to evaluate the effect of patient self-management (PSM) of oral anticoagulation on treatment-related quality of life (TRQoL) and anxiety in comparison with routine care (RC) and to explore the effect of level of therapeutic control on TRQoL and anxiety across and within each model of care. METHODS: A quantitative survey, set in primary care in the West Midlands. The subjects were 517 randomized controlled trial participants, 242 receiving PSM and 275 RC. Postal questionnaires at baseline and 12 months comprised the State Trait Anxiety Inventory and a treatment-specific measure of positive (satisfaction and self-efficacy) and negative aspects (daily hassles, strained social network and psychological distress) of TRQoL. Change in anxiety and TRQoL scores were compared between PSM and RC. Subgroup analysis was based upon level of therapeutic control (high, medium and low). RESULTS: Overall, 83% (n = 202) PSM and 55% (n = 161) RC patients contributed data. Anxiety scores were similar in both groups. PSM demonstrated greater improvement in self-efficacy than RC across the study period. A statistically significant between-group difference (PSM versus RC) in the self-efficacy also existed in subgroups with medium and high levels of therapeutic control. CONCLUSIONS: PSM is not associated with increased anxiety and has a positive effect upon some aspects of TRQoL compared to RC.

Comparison of two ophthalmoscopes for direct ophthalmoscopy.

BACKGROUND: To measure the ease of use and performance of the Optyse lens-free ophthalmoscope compared with the standard Keeler pocket ophthalmoscope, and to assess its suitability as an inexpensive ophthalmoscope for medical students. DESIGN: Randomized cross-over study. PARTICIPANTS: Twenty second-year medical students, 10 as ophthalmoscopists ('observers') and 10 as 'patients'. METHODS: Students used both ophthalmoscopes to examine the optic disc in each eye of 10 'patients'. They were randomized as to the order in which they were used. A Consultant ophthalmologist was used as the gold standard. MAIN OUTCOME MEASURES: Main outcome measures were accuracy in estimating vertical cup:disc ratio (VCDR), ease of use (EOU) for each examination, and overall ease of use (OEOU). RESULTS: Of 400 attempted eye examinations, sufficient visualization was achieved in 220 cases to allow a VCDR estimation: 107/200 VCDR estimates with the Optyse and 113/200 with the Keeler. Accuracy of VCDR estimates was better with the Optyse by the equivalent of 0.05 VCDR (P = 0.002). There was no significant difference in EOU or OEOU between the two ophthalmoscopes. EOU for 400 examinations: median (IQR) of 6 (3-8) for Optyse versus 6 (3-8) for Keeler (P = 0.648). OEOU for 20 scores: median (IQR) of 6.5 (2-9) for Optyse versus 5.5 (3-8) for Keeler (P = 0.21). CONCLUSION: Medical students found the Optyse and Keeler pocket ophthalmoscopes to be of similar ease of use and performed slightly better with the Optyse when estimating VCDR. The lens-free Optyse ophthalmoscope is a reasonable alternative to the standard Keeler pocket ophthalmoscope.

Inverted BMI rather than BMI is a better proxy for percentage of body fat.

BACKGROUND: Percentage of body fat (BF%) is a known risk factor for a range of healthcare problems but is difficult to measure. An easy to measure proxy is the weight/height(2) ratio known as the Body Mass Index (BMI kg/m(2)). However, BMI does have some inherent weaknesses which are readily overcome by its inverse iBMI (1000/BMI, cm(2)/kg). METHODS: The association between BF% and both BMI and iBMI together with their distributional properties was explored using previously published data from healthy (n = 2993) and diseased populations (n = 298). RESULTS: BMI is skewed whereas iBMI is symmetrical and so is better approximated by the normal distribution. The relationship between BF% and BMI is curved, but that of iBMI and BF% is linear and thus iBMI explains more of the variation in BF% than BMI. For example a unit increase in BMI for a group of thin women represents an increase of 2.3% in BF, but for obese women this represents only a 0.3% increase in BF-a 7-fold difference. The curvature stems from body mass being the numerator in BMI but the denominator in BF% resulting in a form of hyperbolic curve which is not the case with iBMI. Furthermore, BMI and iBMI have different relationships (interaction) with BF% for men and women, but these differences are less marked with iBMI. CONCLUSIONS: Overall, these characteristics of iBMI favour its use over BMI, especially in statistical models.

Comparison of imputation methods for handling missing covariate data when fitting a Cox proportional hazards model: a resampling study.

BACKGROUND: The appropriate handling of missing covariate data in prognostic modelling studies is yet to be conclusively determined. A resampling study was performed to investigate the effects of different missing data methods on the performance of a prognostic model. METHODS: Observed data for 1000 cases were sampled with replacement from a large complete dataset of 7507 patients to obtain 500 replications. Five levels of missingness (ranging from 5% to 75%) were imposed on three covariates using a missing at random (MAR) mechanism. Five missing data methods were applied; a) complete case analysis (CC) b) single imputation using regression switching with predictive mean matching (SI), c) multiple imputation using regression switching imputation, d) multiple imputation using regression switching with predictive mean matching (MICE-PMM) and e) multiple imputation using flexible additive imputation models. A Cox proportional hazards model was fitted to each dataset and estimates for the regression coefficients and model performance measures obtained. RESULTS: CC produced biased regression coefficient estimates and inflated standard errors (SEs) with 25% or more missingness. The underestimated SE after SI resulted in poor coverage with 25% or more missingness. Of the MI approaches investigated, MI using MICE-PMM produced the least biased estimates and better model performance measures. However, this MI approach still produced biased regression coefficient estimates with 75% missingness. CONCLUSIONS: Very few differences were seen between the results from all missing data approaches with 5% missingness. However, performing MI using MICE-PMM may be the preferred missing data approach for handling between 10% and 50% MAR missingness.

Comparison of techniques for handling missing covariate data within prognostic modelling studies: a simulation study.

BACKGROUND: There is no consensus on the most appropriate approach to handle missing covariate data within prognostic modelling studies. Therefore a simulation study was performed to assess the effects of different missing data techniques on the performance of a prognostic model. METHODS: Datasets were generated to resemble the skewed distributions seen in a motivating breast cancer example. Multivariate missing data were imposed on four covariates using four different mechanisms; missing completely at random (MCAR), missing at random (MAR), missing not at random (MNAR) and a combination of all three mechanisms. Five amounts of incomplete cases from 5% to 75% were considered. Complete case analysis (CC), single imputation (SI) and five multiple imputation (MI) techniques available within the R statistical software were investigated: a) data augmentation (DA) approach assuming a multivariate normal distribution, b) DA assuming a general location model, c) regression switching imputation, d) regression switching with predictive mean matching (MICE-PMM) and e) flexible additive imputation models. A Cox proportional hazards model was fitted and appropriate estimates for the regression coefficients and model performance measures were obtained. RESULTS: Performing a CC analysis produced unbiased regression estimates, but inflated standard errors, which affected the significance of the covariates in the model with 25% or more missingness. Using SI, underestimated the variability; resulting in poor coverage even with 10% missingness. Of the MI approaches, applying MICE-PMM produced, in general, the least biased estimates and better coverage for the incomplete covariates and better model performance for all mechanisms. However, this MI approach still produced biased regression coefficient estimates for the incomplete skewed continuous covariates when 50% or more cases had missing data imposed with a MCAR, MAR or combined mechanism. When the missingness depended on the incomplete covariates, i.e. MNAR, estimates were biased with more than 10% incomplete cases for all MI approaches. CONCLUSION: The results from this simulation study suggest that performing MICE-PMM may be the preferred MI approach provided that less than 50% of the cases have missing data and the missing data are not MNAR.

Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia.

The measurement of immunoglobulin serum free light chains (sFLC) has prognostic significance in plasma cell dyscrasias but its role in chronic lymphocytic leukaemia (CLL) is unknown. This retrospective study from three UK hospitals analysed sFLC in 181 untreated/pre-treatment CLL patients and 78 treated CLL patients, with samples taken later in their disease. An abnormal sFLC ratio was significantly associated with poor overall survival for the 181 untreated/pre-treatment patients (P = 0.0001) and for all patients (P = 0.002), irrespective of cause of death. Using multivariate analysis (n = 194), four independent prognostic variables for overall survival were identified namely Zap-70 (P = 0.0001), beta2M (P = 0.01), IGHV mutation status (P = 0.017) and an abnormal sFLC ratio (P = 0.024). For CLL patients with unmutated IGHV genes, elevated kappa/lambda ratios were adversely prognostic. For patients with mutated IGHV genes, reduced kappa/lambda ratios were adversely prognostic and associated with the poor prognostic IGHV3-21, IGHV3-48 and IGHV3-53 subgroups, suggesting an abnormal sFLC ratio may reflect biological subgroups within CLL. Abnormal sFLC ratios need to be studied prospectively in CLL patients and the biological rationale for their abnormality investigated.

Combining estimates of interest in prognostic modelling studies after multiple imputation: current practice and guidelines.

BACKGROUND: Multiple imputation (MI) provides an effective approach to handle missing covariate data within prognostic modelling studies, as it can properly account for the missing data uncertainty. The multiply imputed datasets are each analysed using standard prognostic modelling techniques to obtain the estimates of interest. The estimates from each imputed dataset are then combined into one overall estimate and variance, incorporating both the within and between imputation variability. Rubin's rules for combining these multiply imputed estimates are based on asymptotic theory. The resulting combined estimates may be more accurate if the posterior distribution of the population parameter of interest is better approximated by the normal distribution. However, the normality assumption may not be appropriate for all the parameters of interest when analysing prognostic modelling studies, such as predicted survival probabilities and model performance measures. METHODS: Guidelines for combining the estimates of interest when analysing prognostic modelling studies are provided. A literature review is performed to identify current practice for combining such estimates in prognostic modelling studies. RESULTS: Methods for combining all reported estimates after MI were not well reported in the current literature. Rubin's rules without applying any transformations were the standard approach used, when any method was stated. CONCLUSION: The proposed simple guidelines for combining estimates after MI may lead to a wider and more appropriate use of MI in future prognostic modelling studies.

Investigation of dopamine receptors in susceptibility to behavioural and psychological symptoms in Alzheimer's disease.

OBJECTIVE: Alzheimer's disease (AD) patients commonly suffer from behavioural and psychological symptoms of dementia (BPSD). A genetic component to the development of BPSD in AD has been supported. Polymorphisms within dopamine receptors DRD1, DRD2, DRD3 and DRD4 have previously been investigated in a few interesting studies that are reviewed here and extended using our patient cohort. METHODS: Our large cohort of 395 probable AD patients had longitudinal information on the BPSD (Neuropsychiatric Inventory), which was used to dichotomise patients into whether they had ever suffered from a given symptom within the study period, or not. These measures were related to the DRD1 (A-48G), DRD2 (ser311cys; C-ins/del), DRD3 (ser9gly) and DRD4 (VNTR) genotype and allele frequencies. RESULTS: Associations were revealed between DRD3 and elation, and between DRD4 with agitation/aggression and with depression; however, these findings do not remain significant after correction for multiple testing. No associations were found with the other genetic variants and these symptoms and no associations were observed between any of the polymorphic variants examined and delusions, hallucinations, psychosis and aberrant motor behaviour. CONCLUSION: Our data, in combination with a review of the literature, reveal a potential role for the VNTR variant of DRD4 in the development of depression in AD patients. The findings presented here need to be replicated in large, well characterised longitudinal cohorts.

Protocol for a randomised controlled trial of telemonitoring and self-management in the control of hypertension: telemonitoring and self-management in hypertension. [ISRCTN17585681].

BACKGROUND: Controlling blood pressure with drugs is a key aspect of cardiovascular disease prevention, but until recently has been the sole preserve of health professionals. Self-management of hypertension is an under researched area in which potential benefits for both patients and professionals are great. METHODS AND DESIGN: The telemonitoring and self-management in hypertension trial (TASMINH2) will be a primary care based randomised controlled trial with embedded economic and qualitative analyses in order to evaluate the costs and effects of increasing patient involvement in blood pressure management, specifically with respect to home monitoring and self titration of antihypertensive medication compared to usual care. Provision of remote monitoring results to participating practices will ensure that practice staff are able to engage with self management and provide assistance where required. 478 patients will be recruited from general practices in the West Midlands, which is sufficient to detect clinically significant differences in systolic blood pressure between self-management and usual care of 5 mmHg with 90% power. Patients will be excluded if they demonstrate an inability to self monitor, their blood pressure is below 140/90 or above 200/100, they are on three or more antihypertensive medications, have a terminal disease or their blood pressure is not managed by their general practitioner. The primary end point is change in mean systolic blood pressure (mmHg) between baseline and each follow up point (6 months and 12 months). Secondary outcomes will include change in mean diastolic blood pressure, costs, adverse events, health behaviours, illness perceptions, beliefs about medication, medication compliance and anxiety. Modelling will evaluate the impact of costs and effects on a system wide basis. The qualitative analysis will draw upon the views of users, informal carers and professionals regarding the acceptability of self-management and prerequisites for future widespread implementation should the trial show this approach to be efficacious. DISCUSSION: The TASMINH2 trial will provide important new evidence regarding the costs and effects of self monitoring with telemonitoring in a representative primary care hypertensive population.