Totality Of Available Evidence Research Articles

Analysis of nurse practitioner practice in US emergency departments: Evidence supporting the educational preparation, credentialing, scope of practice, and outcomes.

The nurse practitioner (NP) role within emergency care has grown in recent years and now there are an estimated 25,000 NPs employed in diverse emergency care settings. Despite this significant growth and expansion of the NP within emergency care areas, challenges exist. In addition to the pervasive confusion regarding the NP role in emergency care, data and statistics detailing characteristics and outcomes of NP practice in emergency care is either lacking or misrepresented. This article explores barriers and provides current and accurate information describing the current educational preparation, credentialing, scope of practice, and outcomes among NPs in US emergency departments. The totality of available evidence reviewed supports safe, timely, efficient, and patient-centered care provided by NPs in emergency care.

Comparative effects of guided vs. potent P2Y12 inhibitor therapy in acute coronary syndrome: a network meta-analysis of 61 898 patients from 15 randomized trials.

Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65-0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96-1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. This study is registered in PROSPERO (CRD42021258603). A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.

The current state of comparative effectiveness research in inflammatory bowel disease

The current state of comparative effectiveness research in inflammatory bowel disease

Bayesian Interpretation of the EXCEL Trial and Other Randomized Clinical Trials of Left Main Coronary Artery Revascularization

Patients with left main coronary artery disease have improved outcomes with coronary revascularization compared with medical therapy, but the choice of optimal revascularization technique is unresolved. To use bayesian methods to analyze the risk differences for patients with left main coronary artery disease randomized to treatment with coronary artery bypass surgery (CABG) compared with those randomized to percutaneous coronary intervention (PCI) in recent randomized clinical trials (RCTs). A systematic review using the PubMed database with the query string "(left main disease) and (PCI or CABG) and (5-year follow-up) and (clinical trial)" identified all RCTs from January 1996 to January 2020 comparing CABG to PCI for treatment of patients with left main coronary artery disease and with 5-year follow-up data. With the use of bayesian methods, the largest and most publicized RCT (EXCEL; Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization; 2019) was reanalyzed (1) as an isolated entity using noninformative priors and (2) in the context of previous knowledge using informative priors derived from similar trials. Published aggregate data were used with assignments from each trial following the original intention-to-treat principle. Combining EXCEL data with varying levels of prior information using Bayes theorem provided final (posterior) probability distributions for primary and secondary outcomes. A composite end point of death, nonfatal myocardial infarction, and stroke was the primary EXCEL outcome and was accordingly the primary outcome for this reanalysis. Secondary analyses were performed for isolated all-cause mortality and for the composite outcome along with repeated revascularization procedures. When EXCEL data were analyzed using the originally stated noninferiority design, the 5-year primary outcome difference reported (2.8%; 95% CI, -0.9% to 6.5%) exceeded the predefined 4.2% noninferiority margin; thus, the null hypothesis of PCI inferiority could not be rejected. By contrast, the present bayesian analysis of the EXCEL primary outcome estimated 95% probability that the 5-year primary outcome difference was increased with PCI compared with CABG and 87% probability that this difference was greater than 1 extra event per 100 patients treated. Bayesian analyses also suggested 99% probability that EXCEL total mortality was increased with PCI and 94% probability that this absolute difference exceeded 1 extra deaths per 100 treated. A systematic review identified 3 other RCTs that studied the same question. The incorporation of this prior knowledge reduced the estimated probability of any excess mortality with PCI to 85%. For the secondary composite end point, which also included repeated revascularizations, there were estimated probabilities of 98% for at least 4 extra events and of 90% for at least 5 extra events per 100 patients treated with PCI. Bayesian analysis assisted in RCT data interpretation and specifically suggested, whether based on EXCEL results alone or on the totality of available evidence, that PCI was associated with inferior long-term results for all events, including mortality, compared with CABG for patients with left main coronary artery disease.

Going Beyond the Guidelines in Individualising the Use of Antihypertensive Drugs in Older Patients.

Hypertension is commonly diagnosed in older patients, with increasing cardiovascular (CV) risk as systolic blood pressure (BP) increases. Maximising CV risk reduction must be reconciled with minimising the risk of treatment-related harms and burden, especially among frail, multi-morbid and older old patients who have been excluded from most randomised trials. Contemporary clinical guidelines, based on such trials, differ in their recommendations as to threshold levels warranting treatment with antihypertensive drugs (AHDs) and target levels that should be achieved. In optimising AHD prescribing in older patients, we propose the following decision framework: decide therapeutic goals in accordance with patient characteristics and preferences; estimate absolute CV risk; measure and profile BP accurately in ways that account for lability in BP levels and minimise error in BP measurement; determine threshold and target BP levels likely to confer net benefit, taking into account age, co-morbidities, frailty and cognitive function; and consider situations that warrant AHD deprescribing on the basis of potential current or future harm. In applying this framework to older persons, and based on a review of relevant randomised trials and observational studies, individuals most likely to benefit from treating systolic BP to no less than 130mmHg are those of any age who are fit and have high baseline systolic BP (≥160mmHg); high CV risk, i.e. established CV disease or risk of CV events exceeding 20% at 10years; previous stroke or transient ischaemic attack; heart failure; and stage 3-4 chronic kidney disease with proteinuria. Individuals most likely to be harmed from treating BP to target systolic <140mmHg are those who have no CV disease and aged over 80years; moderate to severe frailty, cognitive impairment or functional limitations; labile BP and/or history of orthostatic hypotension, syncope and falls; or life expectancy < 12months. Treatment should never be so intense as to reduce diastolic BP to < 60mmHg in any older person. At a time when guidelines are calling for less conservative management of hypertension in all age groups, we contend that a more temperate approach, such as that offered here and based on the totality of available evidence, may assist in maximising net benefit in older patients.

Using meta-analysis for evidence synthesis: The case of incomplete neutralization in German

Within quantitative phonetics, it is common practice to draw conclusions based on statistical significance alone. Using incomplete neutralization of final devoicing in German as a case study, we illustrate the problems with this approach. If researchers find a significant acoustic difference between voiceless and devoiced obstruents, they conclude that neutralization is incomplete; and if they find no significant difference, they conclude that neutralization is complete. However, such strong claims regarding the existence or absence of an effect based on significant results alone can be misleading. Instead, the totality of available evidence should be brought to bear on the question. Towards this end, we synthesize the evidence from 14 studies on incomplete neutralization in German using a Bayesian random-effects meta-analysis. Our meta-analysis provides evidence in favor of incomplete neutralization. We conclude with some suggestions for improving the quality of future research on phonetic phenomena: ensure that sample sizes allow for high-precision estimates of the effect; avoid the temptation to deploy researcher degrees of freedom when analyzing data; focus on estimates of the parameter of interest and the uncertainty about that parameter; attempt to replicate effects found; and, whenever possible, make both the data and analysis available publicly.

Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfonylureas? Lessons from the TOSCA.IT trial.

Are physicians neglecting the risk of heart failure in diabetic patients who are receiving sulfonylureas? Lessons from the TOSCA.IT trial.

Three arguments for humility

Ramseyan humility is the thesis that we cannot know which properties realize the roles specified by the laws of completed physics. Lewis seems to offer a sceptical argument for this conclusion. Humean fundamental properties can be permuted as to their causal roles and distribution throughout spacetime, yielding alternative possible worlds with the same fundamental structure as actuality, but at which the totality of available evidence is the same. On the assumption that empirical knowledge requires evidence, we cannot know which of these worlds is actual. However, Lewis also appeals to a range of familiar semantic principles when framing his argument, which leads some authors to suppose that he can also plausibly be interpreted as offering a purely semantic argument for humility in addition. In this paper I grant that these arguments are Lewisian, but argue that Lewis is also committed to a theory of mind that licenses a purely metaphysical argument for humility based on the idea that mental properties supervene on fundamental structure. Given that knowing which x is the F requires knowing that a is the F, the supposition that we could come to know which properties actually occupy the fundamental roles entails differences in mental properties between worlds with the same fundamental structure, violating supervenience. Humility follows right away, without any further epistemic or semantic principles. This argument is immune to almost every way of rebutting the sceptical and semantic arguments; conversely, almost every way of rebutting the metaphysical argument tells equally against the others.

Long-chain polyunsaturated fatty acids and the preterm infant: a case study in developmentally sensitive nutrient needs in the United States1–4

The vast majority of infant formulas in the United States contain the long-chain polyunsaturated fatty acids (PUFAs) docosahexaenoic acid (22:6n-3) and arachidonic acid (20:4n-6), which were first permitted by the US Food and Drug Administration in 2001. As a scientific case study, preclinical animal studies of these nutrients definitively influenced the design and interpretation of human clinical studies. Early studies were tied to the availability of test substances, and in hindsight suggest re-evaluation of the essential fatty acid concept in light of the totality of available evidence. Research in the 1950s established the essentiality of n-6 PUFAs for skin integrity; however, widespread recognition of the essentiality of n-3 PUFAs came decades later despite compelling evidence of their significance. Barriers to an understanding of the essentiality of n-3 PUFAs were as follows: 1) their role is in neural function, which is measured only with difficulty compared with skin lesions and growth faltering that are apparent for n-6 PUFAs; 2) the experimental use of vegetable oils as PUFA sources that contain the inefficiently used C18 PUFAs rather than the operative C20 and C22 PUFAs; 3) the shift from reliance on high-quality animal studies to define mechanisms that established the required nutrients in the first part of the 20th century to inherently challenging human studies. Advances in nutrition of premature infants require the best practices and opinions available, taking into account the totality of preclinical and clinical evidence.

Consensus and confusion in molluscan trees: evaluating morphological and molecular phylogenies.

Mollusks are the most morphologically disparate living animal phylum, they have diversified into all habitats, and have a deep fossil record. Monophyly and identity of their eight living classes is undisputed, but relationships between these groups and patterns of their early radiation have remained elusive. Arguments about traditional morphological phylogeny focus on a small number of topological concepts but often without regard to proximity of the individual classes. In contrast, molecular studies have proposed a number of radically different, inherently contradictory, and controversial sister relationships. Here, we assembled a data set of 42 unique published trees describing molluscan interrelationships. We used these data to ask several questions about the state of resolution of molluscan phylogeny compared with a null model of the variation possible in random trees constructed from a monophyletic assemblage of eight terminals. Although 27 different unique trees have been proposed from morphological inference, the majority of these are not statistically different from each other. Within the available molecular topologies, only four studies to date have included the deep sea class Monoplacophora; but 36.4% of all trees are not significantly different. We also present supertrees derived from two data partitions and three methods, including all available molecular molluscan phylogenies, which will form the basis for future hypothesis testing. The supertrees presented here were not constructed to provide yet another hypothesis of molluscan relationships, but rather to algorithmically evaluate the relationships present in the disparate published topologies. Based on the totality of available evidence, certain patterns of relatedness among constituent taxa become clear. The internodal distance is consistently short between a few taxon pairs, particularly supporting the relatedness of Monoplacophora and the chitons, Polyplacophora. Other taxon pairs are rarely or never found in close proximity, such as the vermiform Caudofoveata and Bivalvia. Our results have specific utility for guiding constructive research planning to better test relationships in Mollusca as well as other problematic groups. Taxa with consistently proximate relationships should be the focus of a combined approach in a concerted assessment of potential genetic and anatomical homology, whereas unequivocally distant taxa will make the most constructive choices for exemplar selection in higher level phylogenomic analyses.

How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (IST‐3)

How is more negative evidence being used to support claims of benefit: The curious case of the third international stroke trial (<scp>IST</scp>‐3)

THE UTINKA BURIAL

New Middle Bronze Age fi nds are described originating in the Achinsk-Mariinsk forest-steppe, southwestern Siberia which represents a contact zone between the Okunev and Samus cultures. A burial discovered near Lake Utinka by local inhabitants, northeastern Kemerovo region, was found to contain steatite beads and unusual pendants in the form of a bear and a bird. The subsequent fi eld survey revealed characteristics of the burial construction and fragments of clay vessels. The designs on the vessels suggest that the burial was associated with the Samus culture. However, their manufacturing technology and the features of the steatite beads indicate Okunev affi nities. Based on the totality of available evidence, it is suggested that contact existed between the Samus and Okunev cultures in the Achinsk-Mariinsk forest-steppe area.

Lack of Association Between Common Endothelial Nitric Oxide Synthase Gene Haplotypes and Left Ventricular Hypertrophy in Hypertension

The endothelial nitric oxide synthase (NOS3) gene has been implicated in the pathogenesis of hypertension-related left ventricular hypertrophy (LVH). Candidate-gene studies have examined the role of NOS3 variation, but reported results are inconsistent. In this study, we investigated the association of three clinically relevant polymorphisms (promoter T786C, intronic 4a/b, and nonsynonymous G894T) in a case-control sample of 230 ethnically homogeneous (Caucasians) patients with essential hypertension, with (n = 64) and without (n = 166) clinically diagnosed LVH. Haplotype analysis was also performed. In single-marker analyses, no significant associations with LVH were detected by univariate and multivariate regression models. In the haplotype-based association analysis, no common haplotype was associated with the development of LVH. A rare haplotype consisting of the three mutant alleles (C-a-T*) was found to be present only in patients with LVH (3.4%) and not in control hypertensive patients. Despite the biological rationale for the involvement of the NOS3 gene in LVH, no evidence for a major role of common NOS3 haplotypic variation was found. Considering the totality of available evidence, single-gene analyses of the NOS3 gene have not uncovered detectable genetic effects, and pathway-based analyses that examine interactions of multiple loci may be more informative about the complex genetic etiology of LVH.

Comparative effectiveness research and genomic personalized medicine.

What is comparative effectiveness research? Although healthcare expenditures continue to rise rapidly in the USA, clinical measures of the health of the population have fallen behind many other developed countries. As shown in Figure 1, the average US healthcare expenditures have grown more rapidly over the past 30 years than in any other major industrialized country. Cancer treatments constitute a substantial proportion of these escalating costs, with novel biologic agents constituting an ever greater share [1]. Even more distressing is evidence that outcomes achieved from that healthcare spending, including life expectancy, are poor compared with health outcomes in other industrialized nations. (Figure 2) [2]. To address this challenging environment, it is essential to identify important diagnostic and therapeutic questions, and to acquire, evaluate and, where appropriate, synthesize all relevant information related to effectiveness, safety and overall value of comparative diagnostic, treatment and prevention strategies in order to properly inform important clinical and policy decisions. Comparative effectiveness research (CER) attempts to frame the delivery of healthcare by contrasting the benefits and harms of different diagnostic, therapeutic or preventative strategies in typical patients in an effort to define the most effective, safe and efficient interventions. The Institute of Medicine (Washington, DC, USA) defines CER as [3]: “...the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition, or to improve the delivery of care. The purpose of comparative effectiveness research is to assist consumers, clinicians, purchasers and policy-makers to make informed decisions that will improve healthcare at both the individual and population levels.” Fundamental to this definition is the direct comparison of the effectiveness and safety of different interventions in ‘typical’ patients seen in everyday practice. Comparative results from prospective randomized controlled clinical trials (RCTs) or systematic reviews of such trials represent the ‘gold standard’ of CER. Since RCTs may be of poor quality, not available or sometimes even unethical and, at best, based on highly selected patients not representative of the general population, alternative sources of evidence are often utilized to guide the evaluation of new interventions and address the need for patients, clinicians and policy-makers to make critical decisions. The limitations of available evidence from RCTs have led to the exploration of additional sources, which, when applied with the same rigorous attention to study design, conduct, ana lysis and reporting, may provide reasonable, valid and generalizable estimates of comparative effectiveness, safety and costs (Box 1). Such approaches include carefully conducted cohort and population studies, as well as clinical simulations utilizing evidence from RCTs, meta-analyses, cohort and population studies to emulate realistic clinical scenarios reflecting the impact of an intervention on clinical effectiveness, toxicity, quality of life and costs. The ultimate goal of CER is to gather the totality of available evidence to address the comparative effectiveness, toxicity and overall value of established and emerging interventions.

Restrictive Versus Liberal Red Blood Cell Transfusion Strategies for Preterm Infants: A Systematic Review of Randomized Controlled Trials

Background: Many neonatal intensive care units have introduced restrictive transfusion policies for preterm infants. The justification for such an approach is debatable. Objective: To systematically review the evidence from randomized controlled trials (RCTs) on the benefit to risk ratio of lower versus higher red blood cell transfusion thresholds in preterm infants. Methods: Systematic review based on an electronic literature search (09/2007) in PubMed and CENTRAL (Cochrane Library, Issue 3 2007) for RCTs on different transfusion strategies in preterm infants. Results: Seven fully published RCTs including 712 preterm infants with various gestational and postnatal ages were found to be eligible for inclusion in this systematic review. Transfusion thresholds differed between trials, as did the duration of studies, the reported outcomes and the methodological quality. The largest RCT included 451 Extremely-Low-Birth- Weight (ELBW) infants, was of high methodological quality and found no difference in reducing mortality before discharge home or survival with any of either severe retinopathy of prematurity, bronchopulmonary dysplasia or brain injury. Conclusions: Clinical and methodological heterogeneity between studies prevents firm conclusions based on the totality of available evidence. According to the results of the largest RCT, maintaining a higher hemoglobin level in ELBW infants seems to confer little clinical benefit. Keywords: Systematic review, preterm infants, transfusion threshold, restrictive, liberal

Factors Associated with Findings of Published Trials of Drug–Drug Comparisons: Why Some Statins Appear More Efficacious than Others

BackgroundPublished pharmaceutical industry–sponsored trials are more likely than non-industry-sponsored trials to report results and conclusions that favor drug over placebo. Little is known about potential biases in drug–drug comparisons. This study examined associations between research funding source, study design characteristics aimed at reducing bias, and other factors that potentially influence results and conclusions in randomized controlled trials (RCTs) of statin–drug comparisons.Methods and FindingsThis is a cross-sectional study of 192 published RCTs comparing a statin drug to another statin drug or non-statin drug. Data on concealment of allocation, selection bias, blinding, sample size, disclosed funding source, financial ties of authors, results for primary outcomes, and author conclusions were extracted by two coders (weighted kappa 0.80 to 0.97). Univariate and multivariate logistic regression identified associations between independent variables and favorable results and conclusions. Of the RCTs, 50% (95/192) were funded by industry, and 37% (70/192) did not disclose any funding source. Looking at the totality of available evidence, we found that almost all studies (98%, 189/192) used only surrogate outcome measures. Moreover, study design weaknesses common to published statin–drug comparisons included inadequate blinding, lack of concealment of allocation, poor follow-up, and lack of intention-to-treat analyses. In multivariate analysis of the full sample, trials with adequate blinding were less likely to report results favoring the test drug, and sample size was associated with favorable conclusions when controlling for other factors. In multivariate analysis of industry-funded RCTs, funding from the test drug company was associated with results (odds ratio = 20.16 [95% confidence interval 4.37–92.98], p < 0.001) and conclusions (odds ratio = 34.55 [95% confidence interval 7.09–168.4], p < 0.001) that favor the test drug when controlling for other factors. Studies with adequate blinding were less likely to report statistically significant results favoring the test drug.ConclusionsRCTs of head-to-head comparisons of statins with other drugs are more likely to report results and conclusions favoring the sponsor's product compared to the comparator drug. This bias in drug–drug comparison trials should be considered when making decisions regarding drug choice.

The totality of available evidence shows the race IQ gap still remains.

In a previous study (Rushton & Jensen, 2005), we examined 10 categories of technical research and concluded that the mean Black-White IQ difference in the United States is about 80% heritable. We reviewed evidence that (a) the distribution of IQ scores around the world shows averages of 106 for East Asians, 100 for Whites, 85 for U.S. Blacks, and 70 for sub-Saharan Africans; (b) race differences are most pronounced on the more g-loaded subtests (g being the general factor of mental ability); (c) race differences are most pronounced on the subtests whose scores show the most heritability; and (d) racial differences in brain size parallel the IQ differences. We also reviewed corroborating studies of (e) racial admixture, (f) trans-racial adoption, (g) regression to different racial means, (h) 60 related life-history traits, (i) human origins, and (j) the inadequacy of environmental explanations of the racial IQ difference. (In Africa, the 30-point difference is likely only 50% heritable because environmental factors such as malnutrition and disease have so much more impact than they do elsewhere in the world; Lynn, 2006.) Dickens and Flynn (2006, this issue) challenge our hypothesis. They claim that ‘‘no one can really trace the Black-White IQ gap in the United States back to its origins’’ (p. 913) and that in the United States, Blacks have gained ‘‘4 to 7 IQ points on non-Hispanic Whites between 1972 and 2002’’ (p. 913). But to maintain that ‘‘no one can really trace the . . . gap back to its origins,’’ Dickens and Flynn had to sidestep our citation of Shuey’s (1966) review of the literature, which shows that BlackWhite IQ differences in the United States have remained at 15 to 18 points, or 1.1 standard deviations, for nearly a century. For example, she found 23,596 Black draftees in World War I (1917) had an IQ of 83 (vs. 100 for Whites), with a Black overlap of the White mean of 13%. For recent data, we cited the meta-analysis by Roth, Bevier, Bobko, Switzer, and Tyler (2001), which also shows a mean difference of 1.1 standard deviations (range of 0.38 to 1.46 standard deviations, depending on the test’s g loading), based on 6,246,729 individuals from military, corporate, and higher-education samples. Roth et al. found any narrowing of the gap was ‘‘either small, potentially a function of sampling error . . . or nonexistent for highly g loaded instruments’’ (p. 323, italics added). To claim a 4to 7-point gain for Blacks, Dickens and Flynn chose three independent tests showing medium gains (the Wechsler, Stanford-Binet, and Armed Forces Qualification tests) and relegated to their Appendix B four or more tests showing lesser gains. They excluded the Wonderlic Personnel Test, which they acknowledge showed a gain of only 2.4 points for Blacks between 1970 and 2001. (Dickens and Flynn suggest that more ‘‘high quality’’ Whites than Blacks had taken the test.) They excluded the Kaufman Assessment Battery for Children (K-ABC), which Murray (2005) described as showing a loss of 1 IQ point for Blacks between 1983 and 2004. (Dickens and Flynn say the data contained an inflated standard deviation.) They excluded the very g-loaded Woodcock-Johnson test, which Murray (2005; whom they cite) described as showing the conventional gap of 1.05 standard deviations for the third (2001) standardization sample. (Dickens and Flynn say the Blacks were an unrepresentative ‘‘subsubsample.’’) They also excluded the Differential Ability Scale, which in Lynn’s (1996) analysis (which they cite) showed a maximum gain of 1.83 IQ points for Blacks between 1972 and 1986. (Dickens and Flynn say the sample lacked ‘‘quality.’’) To be compelling, however, researchers must take the totality of available evidence into account (Gottfredson, 2005). Even the tests Dickens and Flynn did analyze do not support their conclusion. The alleged gain of 4 to 7 points is from a ‘‘projected’’ trend line based on a small IQ rise per year multiplied by more years than are in the data using unclear procedures (see the additional appendix in the Web site they refer to). Simple arithmetic applied to the data in their Table A1 shows a mean gain for Blacks of only 3.44 IQ points, from 86.44 to 89.88 Address correspondence to J. Philippe Rushton, Department of Psychology, University of Western Ontario, London, Ontario N6A 5C2, Canada, e-mail: rushton@uwo.ca. PSYCHOLOGICAL SCIENCE

Comment on: Evans JM, Ogston SA, Emslie-Smith A, Morris A (2006) Risk of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulfonylureas and metformin. Diabetologia 49:930–936

To the Editor: The recent paper by Evans et al. [1] on the risk of adverse cardiovascular outcomes in patients with type 2 diabetes treated with sulfonylureas or metformin is of great interest to us. The authors cited a study by our group [2], as having ‘re-ignited’ this long-standing debate. We found the similarity in risk estimates between the two studies striking, with both reporting a 40% lower mortality for metformin users compared to sulfonylurea users. This was particularly reassuring for us, as we did not have access to clinical data in the administrative databases we used [2]. Though Evans et al. did not include it in their cited literature, we also reported a follow-up analysis that evaluated non-fatal events defined by cardiovascular-related hospitalisations [3]. Interestingly, the results from Evans et al. were again very similar to ours, despite the lack of clinical data, with the risk of cardiovascular hospitalisation not increased for sulfonylurea users, suggesting similar baseline risk. An increased risk of hospitalisation was observed by Evans et al. for their Combination 2 (sulfonylurea first, metformin added) cohort, although, to our reading, it appears that their monotherapy and combination therapy cohorts were not entirely mutually exclusive (i.e. subjects in the Combination 1 and 2 cohorts also contributed time to the respective monotherapy cohorts), confounding their analyses with respect to duration and severity of diabetes. Evans et al. suggest that these results support the hypothesis that metformin is cardioprotective, as did Sasali and Leahy [4] in an editorial accompanying our original paper. We question this conclusion, as it remains difficult to fully discern the causal relationship from this series of observational studies. We do recognise that an accumulation of evidence from observational studies can support inferences of causality. To that end, we recently conducted a dose–response relationship analysis within our study cohorts, and observed that increased exposure to sulfonylureas (based on either dosing or adherence) was associated with increased overall and cardiovascular-related mortality [5]. The relationship was particularly evident for the firstgeneration sulfonylureas, chlorpropamide and tolbutamide, but also apparent for glyburide. In contrast, we observed no difference in mortality associated with higher or lower doses of metformin. These results, along with a potential pathophysiological mechanism of impaired myocardial ischaemic preconditioning, prompted D. S. Bell in an accompanying editorial [6] to suggest that it is indeed sulfonylureas that are cardiotoxic. Regardless of the pathophysiological explanation, we believe that the totality of available evidence, from trials [7] and observational studies [1–3, 5], strongly supports the use of metformin as first-line therapy in type 2 diabetes. In the absence of randomised trial evidence of clinical benefit, J. A. Johnson (*) :D. T. Eurich : S. R. Majumdar Faculty of Medicine and Dentistry, University of Alberta, 1200-10405 Jasper Avenue, Edmonton, AB T5J 3N4, Canada e-mail: jeff.johnson@ualberta.ca

DIET AND HEART DISEASE: The Role of Fat, Alcohol, and Antioxidants

Overwhelming evidence indicates that the Western diet plays a major role in atherogenesis. Clinicians are only now beginning to tease out the precise components of the diet that are harmful or beneficial. With respect to fat intake, it remains unclear whether it is the amount or type of fat that promotes atherosclerotic disease. There appears to be a consistent positive association of cholesterol, saturated fat, and possibly trans-fatty acid intake and atherosclerotic disease. Although there is general agreement that reducing intake of these dietary components would be beneficial, controversy remains on what should replace these harmful fats. Some researchers advocate massive reductions in total fat consumption with replacement with carbohydrates for everyone, whereas others recommend a Mediterranean-style diet, which replaces saturated animal fats with vegetable fats. Very low-fat diets have been shown to lower the chance of a heart attack among those with severe coronary artery disease, but for the majority of Americans who do not have obvious artery disease, there is no convincing evidence that a very low-fat diet is optimal. There may be other adverse health effects of this Asian diet, such as increased rates of hemorrhagic stroke. Further research is required to refine thinking on the optimal composition of fats in diet. The effects of alcohol consumption on chronic diseases are complex. The strength and consistency of the observational and experimental evidence strongly suggests a causal link between light to moderate alcoholic beverage consumption and reduced risks of CHD. These reductions in risk of CHD appear to be mediated largely by raising HDL cholesterol levels, although additional mechanisms remain possible and do not appear to be beverage specific. Maximal benefit in terms of CHD appears to be at the level of one drink per day. From a public policy standpoint, whether the benefits for CHD persist at heavy drinking levels or are attenuated is moot because clear harm of heavy drinking in terms of overall mortality outweighs any benefits in the reduction of heart disease. Although the association of alcohol and CHD is likely to be causal, any individual or public health recommendations must consider the complexity of alcohol's metabolic, physiologic, and psychological effects. With alcohol, the differences between daily intake of small to moderate and large quantities may be the difference between preventing and causing disease. A discussion of alcohol intake should be a part of routine preventive counseling. Given the complex nature of alcohol disease relationships, alcohol consumption should not be viewed as a primary preventive strategy; also, it should not necessarily be viewed as an unhealthy behavior. Based on the totality of available evidence, antioxidants represent a possible but as yet unproven means to reduce risks of cardiovascular disease. Although it remains unclear whether supplementation of diet with antioxidant vitamins will reduce risks of atherosclerotic disease, most researchers agree that consumption of fruits and vegetables is an important part of a healthy diet. The U.S. Department of Agriculture recommends two to four servings of fruit and three to five servings of vegetables per day.

Mood Disorders and Cholesterol-Lowering Drugs

Cross-sectional studies and case reports have raised concern about associations between low or lowered cholesterol levels and adverse mental phenomena such as violence and depression. This link has been hypothesised to be due to altered CNS serotonin (5-hydroxytryptamine; 5-HT) metabolism. However, in epidemiological studies, the link between low cholesterol levels and depression (if at all observed) is probably due to confounding factors. Furthermore, recent data from placebo-controlled studies using effective cholesterol-lowering drugs, such as HMG-CoA reductase inhibitors (statins), have not shown adverse mental effects to be associated with these drugs. The totality of available evidence does not indicate that a clinically relevant link exists between drug-induced reductions in cholesterol levels and mood disorders.