Between-centre differences and treatment effects in randomized controlled trials: A case study in traumatic brain injury

BACKGROUND: In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI. METHODS: We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs. RESULTS: In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26). CONCLUSION: Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI

Stenting for symptomatic vertebral artery stenosis: The Vertebral Artery Ischaemia Stenting Trial

$\textbf{Objective:}$ To compare in the Vertebral Artery Ischaemia Stenting Trial (VIST) the risks and benefits of vertebral angioplasty and stenting with best medical treatment (BMT) alone for symptomatic vertebral artery stenosis. $\textbf{Methods:}$ VIST was a prospective, randomized, open-blinded endpoint clinical trial performed in 14 hospitals in the United Kingdom. Participants with symptomatic vertebral stenosis ≥50% were randomly assigned (1:1) to vertebral angioplasty/stenting plus BMT or to BMT alone with randomization stratified by site of stenosis (extracranial vs intracranial). Because of slow recruitment and cessation of funding, recruitment was stopped after 182 participants. Follow-up was a minimum of ≥1 year for each participant. $\textbf{Results:}$ Three patients did not contribute any follow-up data and were excluded, leaving 91 patients in the stent group and 88 in the medical group. Mean follow-up was 3.5 (interquartile range 2.1-4.7) years. Of 61 patients who were stented, stenosis was extracranial in 48 (78.7%) and intracranial in 13 (21.3%). No periprocedural complications occurred with extracranial stenting; 2 strokes occurred during intracranial stenting. The primary endpoint of fatal or nonfatal stroke occurred in 5 patients in the stent group vs 12 in the medical group (hazard ratio 0.40, 95% confidence interval 0.14-1.13, p = 0.08), with an absolute risk reduction of 25 strokes per 1,000 person-years. The hazard ratio for stroke or TIA was 0.50 (p = 0.05). $\textbf{Conclusions:}$ Stenting in extracranial stenosis appears safe with low complication rates. Large phase 3 trials are required to determine whether stenting reduces stroke risk. $\textbf{ISRCTNCOM identifier}$: ISRCTN95212240. $\textbf{Classification of evidence:}$ This study provides Class I evidence that for patients with symptomatic vertebral stenosis, angioplasty with stenting does not reduce the risk of stroke. However, the study lacked the precision to exclude a benefit from stenting.The run in phase with recruitment of the first 100 patients was supported by a grant from the Stroke Association. Recruitment after patient 100 was supported by a grant from the NIHR Health Technology Assessment. Recruitment was supported by the NIHR Clinical Research Network. Hugh S Markus is supported by an NIHR Senior Investigator award and his work is supported by the Cambridge University Hospitals Trust NIHR Comprehensive Biomedical Research Centre. Peter M Rothwell is supported by Wellcome Trust and NIHR Senior Investigator awards and his work is supported by the NIHR Biomedical Research Centre, Oxford

Dissociable effects of 5-HT2C receptor antagonism and genetic inactivation on perseverance and learned non-reward in an egocentric spatial reversal task

Cognitive flexibility can be assessed in reversal learning tests, which are sensitive to modulation of 5-HT2C receptor (5-HT2CR) function. Successful performance in these tests depends on at least two dissociable cognitive mechanisms which may separately dissipate associations of previous positive and negative valence. The first is opposed by perseverance and the second by learned non-reward. The current experiments explored the effect of reducing function of the 5-HT2CR on the cognitive mechanisms underlying egocentric reversal learning in the mouse. Experiment 1 used the 5-HT2CR antagonist SB242084 (0.5 mg/kg) in a between-groups serial design and Experiment 2 used 5-HT2CR KO mice in a repeated measures design. Animals initially learned to discriminate between two egocentric turning directions, only one of which was food rewarded (denoted CS+, CS−), in a T- or Y-maze configuration. This was followed by three conditions; (1) Full reversal, where contingencies reversed; (2) Perseverance, where the previous CS+ became CS− and the previous CS− was replaced by a novel CS+; (3) Learned non-reward, where the previous CS− became CS+ and the previous CS+ was replaced by a novel CS-. SB242084 reduced perseverance, observed as a decrease in trials and incorrect responses to criterion, but increased learned non-reward, observed as an increase in trials to criterion. In contrast, 5-HT2CR KO mice showed increased perseverance. 5-HT2CR KO mice also showed retarded egocentric discrimination learning. Neither manipulation of 5-HT2CR function affected performance in the full reversal test. These results are unlikely to be accounted for by increased novelty attraction, as SB242084 failed to affect performance in an unrewarded novelty task. In conclusion, acute 5-HT2CR antagonism and constitutive loss of the 5-HT2CR have opposing effects on perseverance in egocentric reversal learning in mice. It is likely that this difference reflects the broader impact of 5HT2CR loss on the development and maintenance of cognitive function

Reproducibility of the serum lipid response to coffee oil in healthy volunteers

BACKGROUND: Humans and animals show a certain consistency in the response of their serum lipids to fat-modified diets. This may indicate a genetic basis underlying this response. Coffee oil might be used as a model substance to investigate which genes determine differences in the serum lipid response. Before carrying out such studies our objective was to investigate to what extent the effect of coffee oil on serum lipid concentrations is reproducible within subjects. METHODS: The serum lipid response of 32 healthy volunteers was measured twice in separate five-week periods in which coffee oil was administered (69 mg cafestol / day). RESULTS: Total cholesterol levels increased by 24% in period 1 (range:0;52%) and 18% in period 2 (1;48%), LDL cholesterol by 29 % (-9;71%) and 20% (-12;57%), triglycerides by 66% (16;175%) and 58% (-13;202%), and HDL cholesterol did not change significantly: The range of the HDL response was -19;25% in period 1 and -20;33% in period 2. The correlation between the two responses was 0.20 (95%CI -0.16, 0.51) for total cholesterol, 0.16 (95%CI -0.20, 0.48) for LDL, 0.67 (95%CI 0.42, 0.83) for HDL, and 0.77 (95%CI 0.56, 0.88) for triglycerides. CONCLUSIONS: The responses of total and LDL cholesterol to coffee oil were poorly reproducible within subjects. The responses of HDL and triglycerides, however, appeared to be highly reproducible. Therefore, investigating the genetic sources of the variation in the serum-lipid response to coffee oil is more promising for HDL and triglycerides

A Survey of Dog Owners in Remote Northern Australian Indigenous Communities to Inform Rabies Incursion Planning

Australia is underprepared for a rabies incursion due to a lack of information about how a rabies outbreak would spread within the susceptible canine populations and which control strategies would be best to control it. The aim of this study was to collect information to parameterize a recently developed dog rabies spread model as well as use this information to gauge how the community would accept potential control strategies. Such information–together with model outputs–would be used to inform decision makers on the best control strategies and improve Australia’s preparedness against a canine rabies incursion. The parameters this study focussed on were detection time, vaccination rates and dog-culling and dog movement restriction compliance. A cross-sectional survey of 31 dog-owners, using a questionnaire, was undertaken in the five communities of the Northern Peninsular Area (NPA) in northern Australia regarding community dog movements, veterinary visits, reporting systems, perceptions of sick dogs and potential human behaviours during hypothetical rabies outbreaks. It highlighted the significant shortfalls in veterinary care that would need to be vastly improved during an outbreak, who educational programs should be targeted towards and which dog movements should be restricted. The results indicate that men were significantly more likely than women to allow their dogs to roam and to move their dogs. The current low vaccination rate of 12% highlighted the limited veterinary services that would need to be substantially increased to achieve effective rabies control. Participation in mass vaccination was accepted by 100% of the respondents. There was lower acceptance for other possible rabies control strategies with 10–20% of the respondents stating a resistance to both a mass culling program and a ban on dog movements. Consequently, movement bans and mass dog culling would have limited effectiveness as a control strategy in the NPA community. More than half of the respondents said that they would report their sick dogs within a week. This would lead to a much more optimistic rabies detection time than observed in other regions with recent dog rabies outbreaks. Findings from this study can be used to parameterize a recently developed dog rabies spread model as well as to develop informed policies for managing a future rabies incursion, thus improving Australia’s preparedness against a canine rabies incursion. Author Summary Australia is underprepared for a rabies incursion due to limited information about how a rabies outbreak would behave and which control strategies would be best to control it. A disease spread model of rabies has been developed to help policy-makers decide on the best response to a rabies incursion. However, data to inform this model are lacking. Therefore, the aim of this study was to gather information to parameterize the existing rabies spread model and to gauge how the community would accept potential control strategies. A survey of dog-owners, using a questionnaire, was undertaken in five remote, indigenous communities in northern Australia. We found that compared to women, men were more likely to allow their dogs to roam and to move their dogs. The current vaccination rates in these dog populations are low due to limited veterinary services. This would make delivery of vaccine in the event of a rabies incursion potentially challenging. However, compliance of dog owners with mass vaccination campaigns would be high. However, compliance with movement control of dogs might be problematic, as would the mass culling of dogs, although, rabies detection following an incursion could optimistically occur within a week

Nutrient adequacy during weight loss interventions: a randomized study in women comparing the dietary intake in a meal replacement group with a traditional food group

<p>Abstract</p> <p>Background</p> <p>Safe and effective weight control strategies are needed to stem the current obesity epidemic. The objective of this one-year study was to document and compare the macronutrient and micronutrient levels in the foods chosen by women following two different weight reduction interventions.</p> <p>Methods</p> <p>Ninety-six generally healthy overweight or obese women (ages 25–50 years; BMI 25–35 kg/m²) were randomized into a Traditional Food group (TFG) or a Meal Replacement Group (MRG) incorporating 1–2 meal replacement drinks or bars per day. Both groups had an energy-restricted goal of 5400 kJ/day. Dietary intake data was obtained using 3-Day Food records kept by the subjects at baseline, 6 months and one-year. For more uniform comparisons between groups, each diet intervention consisted of 18 small group sessions led by the same Registered Dietitian.</p> <p>Results</p> <p>Weight loss for the 73% (n = 70) completing this one-year study was not significantly different between the groups, but was significantly different (p ≤ .05) within each group with a mean (± standard deviation) weight loss of -6.1 ± 6.7 kg (TFG, n = 35) vs -5.0 ± 4.9 kg (MRG, n = 35). Both groups had macronutrient (Carbohydrate:Protein:Fat) ratios that were within the ranges recommended (50:19:31, TFG vs 55:16:29, MRG). Their reported reduced energy intake was similar (5729 ± 1424 kJ, TFG vs 5993 ± 2016 kJ, MRG). There was an improved dietary intake pattern in both groups as indicated by decreased intake of saturated fat (≤ 10%), cholesterol (<200 mg/day), and sodium (< 2400 mg/day), with increased total servings/day of fruits and vegetables (4.0 ± 2.2, TFG vs 4.6 ± 3.2, MRG). However, the TFG had a significantly lower dietary intake of several vitamins and minerals compared to the MRG and was at greater risk for inadequate intake.</p> <p>Conclusion</p> <p>In this one-year university-based intervention, both dietitian-led groups successfully lost weight while improving overall dietary adequacy. The group incorporating fortified meal replacements tended to have a more adequate essential nutrient intake compared to the group following a more traditional food group diet. This study supports the need to incorporate fortified foods and/or dietary supplements while following an energy-restricted diet for weight loss.</p

Effects of a carbohydrate-restricted diet on emerging plasma markers for cardiovascular disease

BACKGROUND: Increasing evidence supports carbohydrate restricted diets (CRD) for weight loss and improvement in traditional markers for cardiovascular disease (CVD); less is known regarding emerging CVD risk factors. We previously reported that a weight loss intervention based on a CRD (% carbohydrate:fat:protein = 13:60:27) led to a mean weight loss of 7.5 kg and a 20% reduction of abdominal fat in 29 overweight men. This group showed reduction in plasma LDL-cholesterol and triglycerides and elevations in HDL-cholesterol as well as reductions in large and medium VLDL particles and increases in LDL particle size. In this study we report on the effect of this intervention with and without fiber supplementation on plasma homocysteine, lipoprotein (a) [Lp(a)], C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). METHODS: Twenty nine overweight men [body mass index (BMI) 25–35 kg/m(2)] aged 20–69 years consumed an ad libitum CRD (% carbohydrate:fat:protein = 13:60:27) including a standard multivitamin every other day for 12 wk. Subjects were matched by age and BMI and randomly assigned to consume 3 g/d of either a soluble fiber supplement (n = 14) or placebo (n = 15). RESULTS: There were no group or interaction (fiber × time) main effects, but significant time effects were observed for several variables. Energy intake was spontaneously reduced (-30.5%). This was accompanied by an increase in protein intake (96.2 ± 29.8 g/d to 107.3 ± 29.7 g/d) and methionine intake (2.25 ± 0.7 g/d, to 2.71 ± 0.78 g/d; P < 0.001). Trans fatty acid intake was significantly reduced (-38.6%) while dietary folate was unchanged, as was plasma homocysteine. Bodyweight (-7.5 ± 2.5 kg) was reduced as was plasma Lp(a) (-11.3%). Changes in plasma Lp(a) correlated with reductions in LDL-cholesterol (r = .436, P < 0.05) and fat loss (r = .385, P < 0,05). At wk 12, both CRP (-8.1%) and TNF-α (-9.3%) were reduced (P < 0.05) independently of weight loss. IL-6 concentrations were unchanged. CONCLUSION: A diet based on restricting carbohydrates leads to spontaneous caloric reduction and subsequent improvement in emerging markers of CVD in overweight/obese men who are otherwise healthy

Polymorphisms in the SAA1/2 Gene Are Associated with Carotid Intima Media Thickness in Healthy Han Chinese Subjects: The Cardiovascular Risk Survey

BACKGROUND: Serum amyloid A protein (SAA) is not only an inflammatory factor, but also an apolipoprotein that can replace apolipoprotein A1 (apoA1) as the major apolipoprotein of high-density lipoprotein (HDL), which has been linked to atherosclerosis. However, the relationship between genetic polymorphisms of SAA and the intima-media thickness (IMT) of the common carotid artery in healthy subjects remains unclear. We investigated the role of SAA1 and SAA2 gene polymorphisms with IMT in a cohort of healthy subjects participating in the Cardiovascular Risk Survey (CRS) study. METHODOLOGY/PRINCIPAL FINDINGS: Anthropometric and B-mode ultrasound of the carotid IMT were measured in 1914 subjects (849 men; 1065 women) recruited from seven cities in Xinjiang province, (western China). Four SNPs (rs12218, rs2229338, rs1059559, and rs2468844) were genotyped by use of the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The SNP rs12218 was associated with carotid IMT by analyses of a dominate model (P<0.001) and additive model (P = 0.003), and the difference remained significant after multivariate adjustment (P = 0.008, P<0.001, respectively). This relationship was also observed in rs2468844 after multivariate adjustment by recessive model analysis (P = 0.011) but this was not observed in rs2229338 and rs1059559 before and after multivariate adjustment. These associations were not modified by serum HDL concentration. Furthermore, there were significant interactions between rs2468844 and rs12218 (interaction P<0.001) and rs2229338 (interaction P = 0.001) on carotid IMT. CONCLUSION/SIGNIFICANCE: Both rs12218 of the SAA1 gene and rs2468844 of SAA2 gene are associated with carotid IMT in healthy Han Chinese subjects

Changes in weight loss, body composition and cardiovascular disease risk after altering macronutrient distributions during a regular exercise program in obese women

<p>Abstract</p> <p>Background</p> <p>This study's purpose investigated the impact of different macronutrient distributions and varying caloric intakes along with regular exercise for metabolic and physiological changes related to weight loss.</p> <p>Methods</p> <p>One hundred forty-one sedentary, obese women (38.7 ± 8.0 yrs, 163.3 ± 6.9 cm, 93.2 ± 16.5 kg, 35.0 ± 6.2 kg•m^-2, 44.8 ± 4.2% fat) were randomized to either no diet + no exercise control group (CON) a no diet + exercise control (ND), or one of four diet + exercise groups (high-energy diet [HED], very low carbohydrate, high protein diet [VLCHP], low carbohydrate, moderate protein diet [LCMP] and high carbohydrate, low protein [HCLP]) in addition to beginning a 3x•week^-1supervised resistance training program. After 0, 1, 10 and 14 weeks, all participants completed testing sessions which included anthropometric, body composition, energy expenditure, fasting blood samples, aerobic and muscular fitness assessments. Data were analyzed using repeated measures ANOVA with an alpha of 0.05 with LSD post-hoc analysis when appropriate.</p> <p>Results</p> <p>All dieting groups exhibited adequate compliance to their prescribed diet regimen as energy and macronutrient amounts and distributions were close to prescribed amounts. Those groups that followed a diet and exercise program reported significantly greater anthropometric (waist circumference and body mass) and body composition via DXA (fat mass and % fat) changes. Caloric restriction initially reduced energy expenditure, but successfully returned to baseline values after 10 weeks of dieting and exercising. Significant fitness improvements (aerobic capacity and maximal strength) occurred in all exercising groups. No significant changes occurred in lipid panel constituents, but serum insulin and HOMA-IR values decreased in the VLCHP group. Significant reductions in serum leptin occurred in all caloric restriction + exercise groups after 14 weeks, which were unchanged in other non-diet/non-exercise groups.</p> <p>Conclusions</p> <p>Overall and over the entire test period, all diet groups which restricted their caloric intake and exercised experienced similar responses to each other. Regular exercise and modest caloric restriction successfully promoted anthropometric and body composition improvements along with various markers of muscular fitness. Significant increases in relative energy expenditure and reductions in circulating leptin were found in response to all exercise and diet groups. Macronutrient distribution may impact circulating levels of insulin and overall ability to improve strength levels in obese women who follow regular exercise.</p

Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults

Background: T-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. Methods: We conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46 years and 24 subjects aged 50 years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18 months. Findings: Both vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The foldincrease and peak immune responses after a single MVA-NP + M1 vaccination was significantly higher compared to ChAdOx1 NP + M1. In a mixed regression model, T-cell responses over 18 months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP + M1. Interpretation: A two dose heterologous vaccination regimen of MVA/ChAdOx1 NP + M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly crossreactive protection against influenza