Shahrul Mt-Isa

Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.

CONTEXT Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. OBJECTIVE To investigate association of genetic loci with CRP levels and risk of coronary heart disease. DESIGN, SETTING, AND PARTICIPANTS We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls. MAIN OUTCOME MEASURE Risk of coronary heart disease. RESULTS Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease. CONCLUSION The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

Effects of targeted delivery of propionate to the human colon on appetite regulation, body weight maintenance and adiposity in overweight adults.

Objective The colonic microbiota ferment dietary fibres, producing short chain fatty acids. Recent evidence suggests that the short chain fatty acid propionate may play an important role in appetite regulation. We hypothesised that colonic delivery of propionate would increase peptide YY (PYY) and glucagon like peptide-1 (GLP-1) secretion in humans, and reduce energy intake and weight gain in overweight adults. Design To investigate whether propionate promotes PYY and GLP-1 secretion, a primary cultured human colonic cell model was developed. To deliver propionate specifically to the colon, we developed a novel inulin-propionate ester. An acute randomised, controlled cross-over study was used to assess the effects of this inulin-propionate ester on energy intake and plasma PYY and GLP-1 concentrations. The long-term effects of inulin-propionate ester on weight gain were subsequently assessed in a randomised, controlled 24-week study involving 60 overweight adults. Results Propionate significantly stimulated the release of PYY and GLP-1 from human colonic cells. Acute ingestion of 10 g inulin-propionate ester significantly increased postprandial plasma PYY and GLP-1 and reduced energy intake. Over 24 weeks, 10 g/day inulin-propionate ester supplementation significantly reduced weight gain, intra-abdominal adipose tissue distribution, intrahepatocellular lipid content and prevented the deterioration in insulin sensitivity observed in the inulin-control group. Conclusions These data demonstrate for the first time that increasing colonic propionate prevents weight gain in overweight adult humans. Trial registration number NCT00750438.

Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study

Objective To determine whether older patients with chronic knee pain should be advised to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs). Design Randomised controlled trial and patient preference study. Setting 26 general practices. Participants People aged ≥50 with knee pain: 282 in randomised trial and 303 in preference study. Interventions Advice to use topical or oral ibuprofen. Primary outcome measures WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, major and minor adverse effects. Results Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval −2 to 6); in the preference study, it was one point (−4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference −17% to −2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 µmol/l to 6.5 µmol/l); and more participants changed treatments because of adverse effects (16% v 1%, −16% to −5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness. Conclusions Advice to use oral or topical preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs. Trial registration ISRCTN 79353052.

Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation

Background Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. Aim To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. Methods A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. Results Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31). Discussion We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.

Emergency department treatments and physiotherapy for acute whiplash: a pragmatic, two-step, randomised controlled trial

BACKGROUND Little is known about the effectiveness of treatments for acute whiplash injury. We aimed to estimate whether training of staff in emergency departments to provide active management consultations was more effective than usual consultations (Step 1) and to estimate whether a physiotherapy package was more effective than one additional physiotherapy advice session in patients with persisting symptoms (Step 2). METHODS Step 1 was a pragmatic, cluster randomised trial of 12 NHS Trust hospitals including 15 emergency departments who treated patients with acute whiplash associated disorder of grades I-III. The hospitals were randomised by clusters to either active management or usual care consultations. In Step 2, we used a nested individually randomised trial. Patients were randomly assigned to receive either a package of up to six physiotherapy sessions or a single advice session. Randomisation in Step 2 was stratified by centre. Investigator-masked outcomes were obtained at 4, 8, and 12 months. Masking of clinicians and patients was not possible in all steps of the trial. The primary outcome was the Neck Disability Index (NDI). Analysis was intention to treat, and included an economic evaluation. The study is registered ISRCTN33302125. FINDINGS Recruitment ran from Dec 5, 2005 to Nov 30, 2007. Follow-up was completed on Dec 19, 2008. In Step 1, 12 NHS Trusts were randomised, and 3851 of 6952 eligible patients agreed to participate (1598 patients were assigned to usual care and 2253 patients were assigned to active management). 2704 (70%) of 3851 patients provided data at 12 months. NDI score did not differ between active management and usual care consultations (difference at 12 months 0·5, 95% CI -1·5 to 2·5). In Step 2, 599 patients were randomly assigned to receive either advice (299 patients) or a physiotherapy package (300 patients). 479 (80%) patients provided data at 12 months. The physiotherapy package at 4 months showed a modest benefit compared to advice (NDI difference -3·7, -6·1 to -1·3), but not at 8 or 12 months. Active management consultations and the physiotherapy package were more expensive than usual care and single advice session. No treatment-related serious adverse events or deaths were noted. INTERPRETATION Provision of active management consultation did not show additional benefit. A package of physiotherapy gave a modest acceleration to early recovery of persisting symptoms but was not cost effective from a UK NHS perspective. Usual consultations in emergency departments and a single physiotherapy advice session for persistent symptoms are recommended. FUNDING NIHR Health Technology Assessment programme.

Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis

Objective To investigate the overall probability of error in preparing and administering intravenous medicines; to identify at which stage of the process an error is most likely to occur; and to determine the impact of error correction on the error probability. Design Systematic review and random-effects Bayesian conditional independence modelling. Methods Medline and EMBASE were searched for studies on intravenous medicines. The error rates of each stage were extracted. These, expert estimates, and error rates from generic tasks, were used in a Bayesian conditional independence model to find error ‘hot-spots.’ The main outcome measure was the probability of at least one error occurring during intravenous therapy. Results Nine published studies were identified for inclusion in the systematic review and meta-analysis. The overall probability of making at least one error in intravenous therapy was 0.73 (95% credible interval (CrI) 0.54 to 0.90). If error-checking was introduced at each stage of the process, the overall rate fell to 0.22 (95% CrI 0.14 to 0.31). Errors were most likely in the reconstitution step. Removing the reconstitution step by providing preprepared injections would reduce the overall error rate to 0.17 (95% CrI 0.09 to 0.27). Conclusions Intravenous therapy is complex and error-prone. Error-checking at each stage could reduce the error probability. The use of preprepared injections may help by eliminating errors in the reconstitution of drug and diluent. However, it will be important to ensure that benefits are not outweighed by practical disadvantages such as an increase in selection errors.

Balancing benefit and risk of medicines: a systematic review and classification of available methodologies.

The need for formal and structured approaches for benefit–risk assessment of medicines is increasing, as is the complexity of the scientific questions addressed before making decisions on the benefit–risk balance of medicines. We systematically collected, appraised and classified available benefit–risk methodologies to facilitate and inform their future use.

Associations of plasma fibrinogen and factor VII clotting activity with coronary heart disease and stroke: prospective cohort study from the screening phase of the Thrombosis Prevention Trial

Summary.  Background: As with ‘conventional’ risk factors such as cholesterol and smoking, there is a need for large, long‐term prospective studies on hemostatic factors. Objectives: To investigate the prospective relationship of fibrinogen and factor VII clotting activity (FVIIc) with risk of coronary heart disease (CHD) and stroke in a study with a large number of outcomes over a period of 15 years. Patients/methods: A cohort of 22 715 men aged 45–69 years was screened for participation in the Thrombosis Prevention Trial. Men were followed up for fatal and non‐fatal CHD and stroke events. There were 1515 CHD events (933 CHD deaths) and 391 strokes (180 stroke deaths). Hazard ratios (HRs) and 95% confidence intervals are expressed per standardized increase in log fibrinogen and log FVIIc, adjusting for age, trial treatment group, conventional CHD risk factors and regression dilution bias. Results: Hazard ratios for fibrinogen were 1.52 (1.37–1.70) for all CHD events, and 1.36 (1.09–1.69) for all strokes. Exclusion of events within the first 10 years showed a persistent association between CHD and fibrinogen, with an adjusted HR of 1.93 (1.42–2.64). The HRs for FVIIc, adjusting for age and trial treatment, were 1.07 (1.01–1.12) for all CHD events and 1.07 (0.97–1.20) for all strokes, and the fully adjusted HRs were, respectively, 0.97 (0.84–1.05) and 1.07 (0.85–1.33). Conclusions: The persisting association between fibrinogen and CHD beyond 10 years may imply a causal effect. There is a small effect of FVIIc on CHD, after adjustment for age and trial treatment, but no association independent of other risk factors.

Pharmacokinetics, adverse effects and tolerability of a novel analogue of human pancreatic polypeptide, PP 1420

AIMS The objectives of this phase 1 study were to confirm the tolerability of single ascending subcutaneous doses of PP 1420 in healthy subjects, to assess its adverse effects and to investigate the drugs pharmacokinetics and dose proportionality. METHODS This was a double-blind, placebo-controlled, randomized study. There were three dosing periods. Each subject (n= 12) was randomized to receive one dose of placebo and two ascending doses of PP 1420, given as a subcutaneous injection. Blood samples were taken over 24 h to assess pharmacokinetics. Standard safety and laboratory data were collected. The primary endpoint was the tolerability of PP 1420. The secondary endpoint was exposure to PP 1420 as assessed by C(max) and AUC(0,∞). RESULTS PP 1420 was well tolerated by all subjects with no serious adverse effects. Following single subcutaneous doses of PP 1420 at 2, 4 and 8 mg to male subjects, C(max) was reached at a median t(max) of approximately 1 h post dose (range 0.32-2.00 h). Thereafter, plasma concentrations of PP 1420 declined with geometric mean apparent terminal elimination t(1/2) ranging from 2.42-2.61 h (range 1.64-3.95 h) across all dose levels. CONCLUSIONS Subcutaneous PP 1420 was well tolerated in healthy human subjects at single doses between 2-8 mg, with no tolerability issues arising. Where observed, adverse events were not serious, and there was no evidence of a dose-relationship to frequency of adverse events. The results therefore support the conduct of clinical trials to investigate efficacy, tolerability and pharmacokinetics during repeated dosing.

Does a monetary incentive improve the response to a postal questionnaire in a randomised controlled trial? The MINT incentive study

BackgroundSending a monetary incentive with postal questionnaires has been found to improve the proportion of responders, in research in non-healthcare settings. However, there is little research on use of incentives to improve follow-up rates in clinical trials, and existing studies are inconclusive. We conducted a randomised trial among participants in the Managing Injuries of the Neck Trial (MINT) to investigate the effects on the proportion of questionnaires returned and overall non-response of sending a £5 gift voucher with a follow-up questionnaire.MethodsParticipants in MINT were randomised to receive either: (a) a £5 gift voucher (incentive group) or (b) no gift voucher (no incentive group), with their 4 month or 8 month follow-up questionnaire. We recorded, for each group, the number of questionnaires returned, the number returned without any chasing from the study office, the overall number of non-responders (after all chasing efforts by the study office), and the costs of following up each group.Results2144 participants were randomised, 1070 to the incentive group and 1074 to the no incentive group. The proportion of questionnaires returned (RR 1.10 (95% CI 1.05, 1.16)) and the proportion returned without chasing (RR 1.14 (95% CI 1.05, 1.24) were higher in the incentive group, and the overall non-response rate was lower (RR 0.68 (95% CI 0.53, 0.87)). Adjustment for injury severity and hospital of recruitment to MINT made no difference to these results, and there were no differences in results between the 4-month and 8-month follow up questionnaires. Analysis of costs suggested a cost of £67.29 per additional questionnaire returned.ConclusionMonetary incentives may be an effective way to increase the proportion of postal questionnaires returned and minimise loss to follow-up in clinical trials.Trial registration numberISRCTN61305297