Melanie L. Bell

The effect of a probiotic milk product on plasma cholesterol: a meta-analysis of short-term intervention studies

Introduction: Certain fermented dairy milk products may have beneficial effects on plasma cholesterol levels. However, a number of studies have produced conflicting results as to whether dietary supplementation by a probiotic dairy product containing the bacteria culture Causido® reduces plasma cholesterol.Objective: To conduct a meta-analysis of intervention studies to evaluate the effect of the Causido® culture on plasma total cholesterol and low-density lipoprotein (LDL)-cholesterol.The probiotic milk product: The yoghurt product Gaio® is fermented with Causido®, composed of one strain of Enterococcus faecium (human species) with the proposed cholesterol-lowering effect, and two strains of Streptococcus thermophilus.Study inclusion and data extraction: Six studies were identified from a literature search and from the yoghurt producer. All studies met the inclusion criteria. Summary data for plasma concentrations of total cholesterol and LDL-cholesterol were extracted from the original publications or by personal request to the authors. Data from 4–8 weeks of treatment duration was used.Statistical analysis: We performed a traditional meta-analysis where mean differences between intervention and control of the pre–post changes in total cholesterol and LDL-cholesterol were calculated, as well as 95% confidence intervals (CIs).Results: In the six studies included in the meta-analysis, the Gaio® interventions produced changes in total cholesterol above those of the control groups ranging from −0.02 to −1.02 mmol/l and in LDL-cholesterol ranging from −0.02 to −1.15 mmol/l. After inclusion of an open-label study, the meta-analysis of the double-blind studies showed that Gaio® as compared to the control group changed total cholesterol by −0.22 mmol/l (95% CI: −0.35 to −0.08, P<0.01) and LDL-cholesterol by −0.20 mmol/l (95% CI: −0.33 to −0.06, P<0.005). The outcome was essentially the same if all studies were included.Conclusions: The present meta-analysis of controlled short-term intervention studies shows that the fermented yoghurt product produced a 4% decrease in total cholesterol and a 5% decrease in LDL-cholesterol when the open-label study is excluded. To demonstrate sustained effects on blood lipids, long-term studies are required.Sponsorship: MD Foods A/S, Denmark. European Journal of Clinical Nutrition (2000) 54, 856–860

Resistant starch consumption promotes lipid oxidation

BackgroundAlthough the effects of resistant starch (RS) on postprandial glycemia and insulinemia have been extensively studied, little is known about the impact of RS on fat metabolism. This study examines the relationship between the RS content of a meal and postprandial/post-absorbative fat oxidation.Results12 subjects consumed meals containing 0%, 2.7%, 5.4%, and 10.7% RS (as a percentage of total carbohydrate). Blood samples were taken and analyzed for glucose, insulin, triacylglycerol (TAG) and free fatty acid (FFA) concentrations. Respiratory quotient was measured hourly. The 0%, 5.4%, and 10.7% meals contained 50 μCi [1-14C]-triolein with breath samples collected hourly following the meal, and gluteal fat biopsies obtained at 0 and 24 h. RS, regardless of dose, had no effect on fasting or postprandial insulin, glucose, FFA or TAG concentration, nor on meal fat storage. However, data from indirect calorimetry and oxidation of [1-14C]-triolein to 14CO2 showed that addition of 5.4% RS to the diet significantly increased fat oxidation. In fact, postprandial oxidation of [1-14C]-triolein was 23% greater with the 5.4% RS meal than the 0% meal (p = 0.0062).ConclusionsThese data indicate that replacement of 5.4% of total dietary carbohydrate with RS significantly increased post-prandial lipid oxidation and therefore could decrease fat accumulation in the long-term.

Disruption of sonic hedgehog signaling alters growth and patterning of lingual taste papillae.

Taste buds on the anterior part of the tongue develop in conjunction with epithelial-mesenchymal specializations in the form of gustatory (taste) papillae. Sonic hedgehog (Shh) and Bone Morphogenetic Protein 4 (BMP4) are expressed in developing taste papillae, but the roles of these signaling molecules in specification of taste bud progenitors and in papillary morphogenesis are unclear. We show here that BMP4 is not expressed in the early tongue, but is precisely coexpressed with Shh in papillary placodes, which serve as a signaling center for both gustatory and papillary development. To elucidate the role of Shh, we used an in vitro model of mouse fungiform papillary development to determine the effects of two functional inhibitors of Shh signaling: anti-Shh (5E1) antibody and cyclopamine. Cultured E11.5 tongue explants express Shh and BMP4(LacZ) in a pattern similar to that of intact embryos, localizing to developing papillary placodes after 2 days in culture. Tongues cultured with 5E1 antibody continue to express these genes in papillary patterns but develop more papillae that are larger and closer together than in controls. Tongues cultured with cyclopamine have a dose-dependent expansion of Shh and BMP4(LacZ) expression domains. Both antibody-treated and cyclopamine-treated tongue explants also are smaller than controls. Taken together, these results suggest that, although Shh is not involved in the initial specification of papillary placodes, Shh does play two key roles during pmcry development: (1) as a morphogen that directs cells toward a nonpapillary fate, and (2) as a mitogen, causing expansion of the interplacodal epithelium and underlying mesenchyme.

Practical and statistical issues in missing data for longitudinal patient-reported outcomes.

Patient-reported outcomes are increasingly used in health research, including randomized controlled trials and observational studies. However, the validity of results in longitudinal studies can crucially hinge on the handling of missing data. This paper considers the issues of missing data at each stage of research. Practical strategies for minimizing missingness through careful study design and conduct are given. Statistical approaches that are commonly used, but should be avoided, are discussed, including how these methods can yield biased and misleading results. Methods that are valid for data which are missing at random are outlined, including maximum likelihood methods, multiple imputation and extensions to generalized estimating equations: weighted generalized estimating equations, generalized estimating equations with multiple imputation, and doubly robust generalized estimating equations. Finally, we discuss the importance of sensitivity analyses, including the role of missing not at random models, such as pattern mixture, selection, and shared parameter models. We demonstrate many of these concepts with data from a randomized controlled clinical trial on renal cancer patients, and show that the results are dependent on missingness assumptions and the statistical approach.

Differential dropout and bias in randomised controlled trials: when it matters and when it may not

Dropout in randomised controlled trials is common and threatens the validity of results, as completers may differ from people who drop out. Differing dropout rates between treatment arms is sometimes called differential dropout or attrition. Although differential dropout can bias results, it does not always do so. Similarly, equal dropout may or may not lead to biased results. Depending on the type of missingness and the analysis used, one can get a biased estimate of the treatment effect with equal dropout rates and an unbiased estimate with unequal dropout rates. We reinforce this point with data from a randomised controlled trial in patients with renal cancer and a simulation study.

Short-Term Triglyceride Lowering With Fenofibrate Improves Vasodilator Function in Subjects With Hypertriglyceridemia

Objective—The objective of this study was to investigate the effects of lowering plasma triglycerides (TGs) on endothelial function and gain insight into the role played by free fatty acids (FFAs) in hypertriglyceridemia-associated vascular dysfunction. Methods and Results—Eleven hypertriglyceridemic subjects without coronary artery disease, diabetes, elevated low-density lipoprotein cholesterol, tobacco use, or hypertension were studied using a randomized, double-blinded, crossover design (fenofibrate and placebo, 14 days). After each regimen, forearm blood flow was assessed by plethysmography in response to arterial acetylcholine, nitroprusside, and verapamil infusion. Hourly plasma TGs, FFA, glucose, and insulin were measured during a 24-hour feeding cycle to characterize the metabolic environment. Changes in plasma FFA after intravenous heparin were used to estimate typical FFA accumulation in the luminal endothelial microenvironment. Fenofibrate lowered plasma TG (P <0.001), total cholesterol (P <0.01), and apolipoprotein B (P <0.01) without altering high-density lipoprotein or low-density lipoprotein cholesterol concentrations. Forearm blood flow in response to acetylcholine (P <0.0001), nitroprusside (P <0.001), and verapamil (P <0.0001) improved after fenofibrate. Fenofibrate lowered 24-hour (P <0.0001) and post-heparin (P <0.001) TG and tended to lower 24-hour (P =0.054) and post-heparin (P =0.028) FFA. Conclusions—Vascular smooth muscle function significantly improves after lowering plasma TG without changes in confounding lipoproteins or insulin resistance. The data raise additional questions regarding the role of FFA in hypertriglyceridemia-associated vascular dysfunction.

Handling missing data in RCTs; a review of the top medical journals

BackgroundMissing outcome data is a threat to the validity of treatment effect estimates in randomized controlled trials. We aimed to evaluate the extent, handling, and sensitivity analysis of missing data and intention-to-treat (ITT) analysis of randomized controlled trials (RCTs) in top tier medical journals, and compare our findings with previous reviews related to missing data and ITT in RCTs.MethodsReview of RCTs published between July and December 2013 in the BMJ, JAMA, Lancet, and New England Journal of Medicine, excluding cluster randomized trials and trials whose primary outcome was survival.ResultsOf the 77 identified eligible articles, 73 (95%) reported some missing outcome data. The median percentage of participants with a missing outcome was 9% (range 0 – 70%). The most commonly used method to handle missing data in the primary analysis was complete case analysis (33, 45%), while 20 (27%) performed simple imputation, 15 (19%) used model based methods, and 6 (8%) used multiple imputation. 27 (35%) trials with missing data reported a sensitivity analysis. However, most did not alter the assumptions of missing data from the primary analysis. Reports of ITT or modified ITT were found in 52 (85%) trials, with 21 (40%) of them including all randomized participants. A comparison to a review of trials reported in 2001 showed that missing data rates and approaches are similar, but the use of the term ITT has increased, as has the report of sensitivity analysis.ConclusionsMissing outcome data continues to be a common problem in RCTs. Definitions of the ITT approach remain inconsistent across trials. A large gap is apparent between statistical methods research related to missing data and use of these methods in application settings, including RCTs in top medical journals.

Effects of indomethacin and celecoxib on renal function in athletes

INTRODUCTION Strenuous exercise induces a marked reduction in renal hemodynamics. Prostaglandins (PG) play an important role in maintaining renal integrity in the face of hemodynamic changes. Inhibition of cyclooxygenase (COX) and thus PG formation can further compromise renal perfusion. The role of selective COX-2 inhibition on renal hemodynamics during exercise has not been investigated. METHODS Twelve healthy males (22-47 yr) took part in a randomized placebo controlled study investigating the effects of nonselective COX inhibition (indomethacin) and COX-2 selective inhibition (celecoxib) on renal hemodynamics during exercise. Renal blood flow (RBF), glomerular filtration rate (GFR), and free water clearance were measured using standard clearance techniques. Each experimental session was performed at least a week apart. The medications were taken for 36 h before study with the last dose at 0700 h on the day of study. Following baseline studies, each participant exercised for 30 min at 80% of their maximal aerobic power. Renal function was monitored for 2 h post-recovery. RESULTS RBF and GFR fell by 40% after exercise with no significant difference between placebo, indomethacin, or celecoxib. Indomethacin (-2.43 +/- 0.95 mL x min(-1), P < 0.007) and celecoxib (-3.88 +/- 0.94 mL x min(-1), P < 0.0001) significantly reduced free water clearance compared with placebo during recovery. CONCLUSION This study has confirmed that selective and nonselective COX inhibition can induce significant inhibition of free water clearance, indicating that these acute changes are regulated predominantly via COX-2. Acute cerebral edema with hyponatremia has been reported after major endurance sporting events. Identifiable risk factors include excessive hydration and use of NSAID. Impaired free water clearance during exercise potentiated by COX inhibition provides a pathophysiological explanation for these observations.

Effect Sizes for 2×2 Contingency Tables

Sample size calculations are an important part of research to balance the use of resources and to avoid undue harm to participants. Effect sizes are an integral part of these calculations and meaningful values are often unknown to the researcher. General recommendations for effect sizes have been proposed for several commonly used statistical procedures. For the analysis of tables, recommendations have been given for the correlation coefficient for binary data; however, it is well known that suffers from poor statistical properties. The odds ratio is not problematic, although recommendations based on objective reasoning do not exist. This paper proposes odds ratio recommendations that are anchored to for fixed marginal probabilities. It will further be demonstrated that the marginal assumptions can be relaxed resulting in more general results.

Improving decision making about clinical trial participation – a randomised controlled trial of a decision aid for women considering participation in the IBIS-II breast cancer prevention trial

Background:Decision aids may improve informed consent in clinical trial recruitment, but have not been evaluated in this context. This study investigated whether decision aids (DAs) can reduce decisional difficulties among women considering participation in the International Breast Cancer Intervention Study-II (IBIS-II) trial.Methods:The IBIS-II trial investigated breast cancer prevention with anastrazole in two cohorts: women with increased risk (Prevention), and women treated for ductal carcinoma in situ (DCIS). Australia, New Zealand and United Kingdom participants were randomised to receive a DA (DA group) or standard trial consent materials (control group). Questionnaires were completed after deciding about participation in IBIS-II (post decision) and 3 months later (follow-up).Results:Data from 112 Prevention and 34 DCIS participants were analysed post decision (73 DA; 73 control); 95 Prevention and 24 DCIS participants were analysed at follow-up (58 DA; 61 control). There was no effect on the primary outcome of decisional conflict. The DCIS–DA group had higher knowledge post decision, and the Prevention-DA group had lower decisional regret at follow-up.Conclusions:This was the first study to evaluate a DA in the clinical trial setting. The results suggest DAs can potentially increase knowledge and reduce decisional regret about clinical trial participation.