Constantinos Koshiaris

The need for randomization in animal trials: an overview of systematic reviews.

Background and Objectives Randomization, allocation concealment, and blind outcome assessment have been shown to reduce bias in human studies. Authors from the Collaborative Approach to Meta Analysis and Review of Animal Data from Experimental Studies (CAMARADES) collaboration recently found that these features protect against bias in animal stroke studies. We extended the scope the work from CAMARADES to include investigations of treatments for any condition. Methods We conducted an overview of systematic reviews. We searched Medline and Embase for systematic reviews of animal studies testing any intervention (against any control) and we included any disease area and outcome. We included reviews comparing randomized versus not randomized (but otherwise controlled), concealed versus unconcealed treatment allocation, or blinded versus unblinded outcome assessment. Results Thirty-one systematic reviews met our inclusion criteria: 20 investigated treatments for experimental stroke, 4 reviews investigated treatments for spinal cord diseases, while 1 review each investigated treatments for bone cancer, intracerebral hemorrhage, glioma, multiple sclerosis, Parkinsons disease, and treatments used in emergency medicine. In our sample 29% of studies reported randomization, 15% of studies reported allocation concealment, and 35% of studies reported blinded outcome assessment. We pooled the results in a meta-analysis, and in our primary analysis found that failure to randomize significantly increased effect sizes, whereas allocation concealment and blinding did not. In our secondary analyses we found that randomization, allocation concealment, and blinding reduced effect sizes, especially where outcomes were subjective. Conclusions Our study demonstrates the need for randomization, allocation concealment, and blind outcome assessment in animal research across a wide range of outcomes and disease areas. Since human studies are often justified based on results from animal studies, our results suggest that unduly biased animal studies should not be allowed to constitute part of the rationale for human trials.

Blood pressure variability and cardiovascular disease: systematic review and meta-analysis

Objective To systematically review studies quantifying the associations of long term (clinic), mid-term (home), and short term (ambulatory) variability in blood pressure, independent of mean blood pressure, with cardiovascular disease events and mortality. Data sources Medline, Embase, Cinahl, and Web of Science, searched to 15 February 2016 for full text articles in English. Eligibility criteria for study selection Prospective cohort studies or clinical trials in adults, except those in patients receiving haemodialysis, where the condition may directly impact blood pressure variability. Standardised hazard ratios were extracted and, if there was little risk of confounding, combined using random effects meta-analysis in main analyses. Outcomes included all cause and cardiovascular disease mortality and cardiovascular disease events. Measures of variability included standard deviation, coefficient of variation, variation independent of mean, and average real variability, but not night dipping or day-night variation. Results 41 papers representing 19 observational cohort studies and 17 clinical trial cohorts, comprising 46 separate analyses were identified. Long term variability in blood pressure was studied in 24 papers, mid-term in four, and short-term in 15 (two studied both long term and short term variability). Results from 23 analyses were excluded from main analyses owing to high risks of confounding. Increased long term variability in systolic blood pressure was associated with risk of all cause mortality (hazard ratio 1.15, 95% confidence interval 1.09 to 1.22), cardiovascular disease mortality (1.18, 1.09 to 1.28), cardiovascular disease events (1.18, 1.07 to 1.30), coronary heart disease (1.10, 1.04 to 1.16), and stroke (1.15, 1.04 to 1.27). Increased mid-term and short term variability in daytime systolic blood pressure were also associated with all cause mortality (1.15, 1.06 to 1.26 and 1.10, 1.04 to 1.16, respectively). Conclusions Long term variability in blood pressure is associated with cardiovascular and mortality outcomes, over and above the effect of mean blood pressure. Associations are similar in magnitude to those of cholesterol measures with cardiovascular disease. Limited data for mid-term and short term variability showed similar associations. Future work should focus on the clinical implications of assessment of variability in blood pressure and avoid the common confounding pitfalls observed to date. Systematic review registration PROSPERO CRD42014015695.

Effect of increased compulsion on readmission to hospital or disengagement from community services for patients with psychosis: follow-up of a cohort from the OCTET trial

BACKGROUND Community treatment orders (CTOs) have not been shown in randomised trials to reduce readmission to hospital in patients with psychosis, but these trials have been short (11-12 months). We previously investigated the effect of CTOs on readmission rates over 12 months in a randomised trial (OCTET). Here, we present follow-up data for a cohort of individuals recruited to our original trial to examine the long-term effect of CTOs on readmissions and the risk of patients disengaging from mental health services temporarily or enduringly. METHODS For OCTET, an open-label, parallel, randomised controlled trial, we recruited patients aged 18-65 years involuntarily admitted to mental health hospitals in 32 trusts in England, with a diagnosis of psychosis and deemed suitable for CTOs by their clinicians. Between Nov 10, 2008, and Feb 22, 2011, we recruited and randomly assigned 336 eligible patients (1:1) to be discharged on either a CTO (n=167) or to voluntary status via Section 17 leave (control group; n=169). For the analysis presented in this report, we assessed data at 36 months for 330 of these patients. We tested rates of readmission to hospital, time to first readmission, number of readmissions, and duration of readmission in patients assigned to CTO versus those assigned to control, and in all patients with CTO experience at any time in the 36 months versus those without. We also tested whether duration of CTO affected readmission outcomes in patients with CTO experience. We examined discontinuation (≥60 days between clinical contacts) and disengagement from services (no clinical contact for ≥90 days with no return to contact) in the whole cohort. OCTET is registered with isrctn.com, number ISRCTN73110773. FINDINGS We obtained data for 330 patients in the relevant period between Nov 10, 2008 and Feb 22, 2014 (36 months after the last patient was randomly assigned to OCTET). We identified no difference between the randomised groups in the numbers of patients readmitted (100 [61%] of 165 CTOs vs 113 [68%] of 165 controls; relative risk 0·88 [95% CI 0·75-1·03]), number of readmissions (mean 2·4 readmissions [SD 1·91] vs 2·2 [1·43]; incident density ratio [IDR] 0·97 [95% CI 0·76-1·24]), duration of readmissions (median 117·5 days [IQR 63-303] vs 139·5 days [63·0-309·5]; IDR 0·84 [95% CI 0·51-1·38]), or time to first readmission (median 601·0 days [95% CI 387·0-777·0] vs 420·0 days [352·0-548·0]; hazard ratio [HR] 0·81 [95% CI 0·62-1·06]). The CTO experience group had significantly more readmissions than the group without (IDR 1·39 [95% CI 1·07-1·79]) and we noted no significant difference between groups in readmission rates, duration of readmission, or time to first readmission. We did not identify a linear relationship between readmission outcomes and duration of CTO. 19 (6%) patients disengaged from services (12 [7%] of 165 CTOs vs 7 [4%] of 165 controls). Longer duration of compulsion was associated with later disengagement (HR 0·946 [95% CI 0·90-0·99, p=0·023). 187 (57%) experienced no discontinuities, and we noted no significant difference between the CTO and control groups for time to disengagement or number of discontinuities. Levels of discontinuity were associated with compulsion (IDR 0·973 [95% CI 0·96-0·99, p<0·0001]. We identified no effect of baseline characteristics on the associations between compulsion and disengagement. INTERPRETATION We identified no evidence that increased compulsion leads to improved readmission outcomes or to disengagement from services in patients with psychosis over 36 months. The level of persisting clinical follow-up was much higher than expected, irrespective of CTO status, and could partly account for the absence of CTO effect. The findings from our 36-month follow-up support our original findings that CTOs do not provide patient benefits, and the continued high level of their use should be reviewed. FUNDING National Institute for Health Research.

Development of tools to study personal weight control strategies: OxFAB taxonomy

To describe the development of the Oxford Food and Activity Behaviors (OxFAB) taxonomy and questionnaire to explore the cognitive and behavioral strategies used by individuals during weight management attempts.

Smoking cessation and survival in lung, upper aero-digestive tract and bladder cancer: cohort study

Background:The aim was to examine the association between smoking cessation and prognosis in smoking-related cancer as it is unclear that cessation reduces mortality.Methods:In this retrospective cohort study from 1999 to 2013, we assessed the association between cessation during the first year after diagnosis and all-cause and cancer-specific mortality.Results:Of 2882 lung, 757 upper aero-digestive tract (UAT) and 1733 bladder cancer patients 27%, 29% and 21% of lung, UAT and bladder cancer patients quit smoking. In lung cancer patients that quit, all-cause mortality was significantly lower (HR: 0.82 (0.74–0.92), while cancer-specific mortality (HR: 0.89 (0.76–1.04) and death due to index cancer (HR: 0.90 (0.77–1.05) were non-significantly lower. In UAT cancer, all-cause mortality (HR: 0.81 (0.58–1.14), cancer-specific mortality (HR: 0.84 (0.48–1.45), and death due to index cancer (HR: 0.75 (0.42–1.34) were non-significantly lower. There was no evidence of an association between quitting and mortality in bladder cancer. The HRs were 1.02 (0.81–1.30) for all-cause, 1.23 (0.81–1.86) for cancer specific, and 1.25 (0.71–2.20) for death due to index cancer. These showed a non-significantly lower risk in sensitivity analyses.Conclusions:People with lung and possibly UAT cancer who quit smoking have a lower risk of mortality than people who continue smoking.

Early detection of multiple myeloma in primary care using blood tests: a case–control study in primary care

Background Multiple myeloma is a haematological cancer characterised by numerous non-specific symptoms leading to diagnostic delay in a large proportion of patients. Aim To identify which blood tests are useful in suggesting or excluding a diagnosis of myeloma. Design and setting A matched case–control study set in UK primary care using routinely collected data from the Clinical Practice Research Datalink. Method Symptom prevalence and blood tests were analysed up to 5 years before diagnosis in 2703 cases and 12 157 matched controls. Likelihood ratios (LR) were used to classify tests or their combinations as useful rule-in tests (LR+ = ≥5), or rule-out tests (LR− = ≤0.2). Results Raised plasma viscosity (PV) had an LR+ = 2.0, 95% confidence interval [CI] = 1.7 to 2.3; erythrocyte sedimentation rate (ESR) 1.9, 95% CI = 1.7 to 2.0; and C-reactive protein (CRP) 1.2, 95% CI = 1.1 to 1.4. A normal haemoglobin had an LR− = 0.42, 95% CI = 0.39 to 0.45; calcium LR− = 0.81, 95% CI = 0.78 to 0.83; and creatinine LR− = 0.80, 95% CI = 0.77 to 0.83. The test combination with the lowest LR− was all normal haemoglobin with calcium and PV, which had an LR− = 0.06, 95% CI = 0.02 to 0.18, though the LR− for normal haemoglobin and PV together was 0.12 (95% CI = 0.07 to 0.23). Conclusion Plasma viscosity and ESR are better for both ruling in and ruling out the disease compared with C-reactive protein. A combination of a normal ESR or PV and normal haemoglobin is a simple rule-out approach for patients currently being tested in primary care.

whoishRisk – an R package to calculate WHO/ISH cardiovascular risk scores for all epidemiological subregions of the world

The World Health Organisation and International Society of Hypertension (WHO/ISH) cardiovascular disease (CVD) risk assessment charts have been implemented in many low- and middle-income countries as part of the WHO Package of Essential Non-Communicable Disease (PEN) Interventions for Primary Health Care in Low-Resource settings. Evaluation of the WHO/ISH cardiovascular risk charts and their use is a key priority and since they only existed in paper or PDF formats, we developed an R implementation of the charts for all epidemiological subregions of the world. The main strengths of this implementation are that it is built in a free, open-source, coding language with simple syntax, can be downloaded from github as a package (“whoishRisk”), and can be used with a standard computer.

Interarm Difference in Systolic Blood Pressure in Different Ethnic Groups and Relationship to the "White Coat Effect": A Cross-Sectional Study

Abstract BACKGROUND Interarm differences (IADs) ≥10 mm Hg in systolic blood pressure (BP) are associated with greater incidence of cardiovascular disease. The effect of ethnicity and the white coat effect (WCE) on significant systolic IADs (ssIADs) are not well understood. METHODS Differences in BP by ethnicity for different methods of BP measurement were examined in 770 people (300 White British, 241 South Asian, 229 African-Caribbean). Repeated clinic measurements were obtained simultaneously in the right and left arm using 2 BPTru monitors and comparisons made between the first reading, mean of second and third and mean of second to sixth readings for patients with, and without known hypertension. All patients had ambulatory BP monitoring (ABPM). WCE was defined as systolic clinic BP ≥10 mm Hg higher than daytime ABPM. RESULTS No significant differences were seen in the prevalence of ssIAD between ethnicities whichever combinations of BP measurement were used and regardless of hypertensive status. ssIADs fell between the 1st measurement (161, 22%), 2nd/3rd (113, 16%), and 2nd–6th (78, 11%) (1st vs. 2nd/3rd and 2nd–6th, P < 0.001). Hypertensives with a WCE were more likely to have ssIADs on 1st, (odds ratio [OR] 1.73 (95% confidence interval 1.04–2.86); 2nd/3rd, (OR 3.05 (1.68–5.53); and 2nd–6th measurements, (OR 2.58 (1.22–5.44). Nonhypertensive participants with a WCE were more likely to have a ssIAD on their first measurement (OR 3.82 (1.77 to −8.25) only. CONCLUSIONS ssIAD prevalence does not vary with ethnicity regardless of hypertensive status but is affected by the number of readings, suggesting the influence of WCE. Multiple readings should be used to confirm ssIADs.

Physician Support of Smoking Cessation After Diagnosis of Lung, Bladder, or Upper Aerodigestive Tract Cancer

PURPOSE Smoking cessation after a diagnosis of lung, bladder, and upper aerodigestive tract cancer appears to improve survival, and support to quit would improve cessation. The aims of this study were to assess how often general practitioners provide active smoking cessation support for these patients and whether physician behavior is influenced by incentive payments. METHODS Using electronic primary care records from the UK Clinical Practice Research Datalink, 12,393 patients with incident cases of cancer diagnosed between 1999 and 2013 were matched 1 to 1 to patients with incident cases of coronary heart disease (CHD) diagnosed during the same time. We assessed differences in the proportion for whom physicians updated smoking status, advised quitting, and prescribed cessation medications, as well as the proportion of patients who stopped smoking within a year of diagnosis. We further examined whether any differences arose because the physicians were offered incentives to address smoking in patients with CHD and not cancer. RESULTS At diagnosis, 32.0% of patients with cancer and 18.2% of patients with CHD smoked tobacco. Patients with cancer were less likely than patients with CHD to have their general practitioners update smoking status (OR = 0.18; 95% CI, 0.17–0.19), advise quitting (OR = 0.38; 95% CI, 0.36–0.40), or prescribe medication (OR = 0.67; 95% CI, 0.63–0.73), and they were less likely to have stopped smoking (OR = 0.76; 95% CI, 0.69–0.84). One year later 61.7% of patients with cancer and 55.4% with CHD who were smoking at diagnosis were still smoking. Introducing incentive payments was associated with more frequent interventions, but not for patients with CHD specifically. CONCLUSIONS General practitioners were less likely to support smoking cessation in patients with cancer than with CHD, and patients with cancer were less likely to stop smoking. This finding is not due to the difference in incentive payments.

Opportunities for earlier diagnosis of type 1 diabetes in children: A case-control study using routinely collected primary care records.

BACKGROUND The epidemiology of type 1 diabetes mellitus (T1DM) suggests diagnostic delays may contribute to children developing diabetic ketoacidosis at diagnosis. We sought to quantify opportunities for earlier diagnosis of T1DM in primary care. METHODS A matched case-control study of children (0-16 years) presenting to UK primary care, examining routinely collected primary care consultation types and National Institute for Health and Care Excellence (NICE) warning signs in the 13 weeks before diagnosis. RESULTS Our primary analysis included 1920 new T1DM cases and 7680 controls. In the week prior to diagnosis more cases than controls had medical record entries (663, 34.5% vs 1014, 13.6%, odds ratio 3.46, 95% CI 3.07-3.89; p<0.0001) and the incidence rate of face-to-face consultations was higher in cases (mean 0.32 vs 0.11, incidence rate ratio 2.90, 2.61-3.21; p<0.0001). The preceding week entries were found in 330 cases and 943 controls (17.2% vs 12.3%, OR 1.49, 1.3-1.7, p<0.0001), but face-to-face consultations were no different (IRR 1.08 (0.9-1.29, p=0.42)). INTERPRETATION There may be opportunities to reduce time to diagnosis for up to one third of cases, by up to two weeks. Diagnostic opportunities might be maximised by measures that improve access to primary care, and public awareness of T1DM.