Intention-to-treat. What is the question?

It has become commonplace for Randomized Controlled Trials (RCTs) to be analyzed according to Intention-to-Treat (ITT) principles in which data from all subjects are used regardless of the subjects' adherence to protocol. While ITT analyses can provide useful information in some cases, they do not answer the question that motivates many RCTs, namely, whether the treatments differ in efficacy. ITT tends to reduce information by combining two questions, whether the intervention is effective and whether, as implemented, it has good compliance. Because these questions may be separate there is a risk of misuse. Two examples are presented that demonstrate this potential for abuse: a study on the effectiveness of vitamin E in reducing cardiovascular risk and comparisons of low fat and low carbohydrate diets. In the first case, a treatment that is demonstrably effective is described as without merit. In the second, ITT describes as the same, two diets that actually have different outcomes. These misuses of ITT are not atypical and are not technical problems in statistics but have real consequences for scientific principles and health recommendations. ITT analyses may answer the question of what happens when treatments are recommended but are inappropriate where separate information on adherence and performance is available. It is proposed that results of RCTs, or any experimental study, be reported, not in terms of the analyses that were performed, but rather in terms of the questions that the analyses can answer properly

What is Nutrition & Metabolism?

A new Open Access journal, Nutrition & Metabolism (N&M) will publish articles that integrate nutrition with biochemistry and molecular biology. The open access process is chosen to provide rapid and accessible dissemination of new results and perspectives in a field that is of great current interest. Manuscripts in all areas of nutritional biochemistry will be considered but three areas of particular interest are lipoprotein metabolism, amino acids as metabolic signals, and the effect of macronutrient composition of diet on health. The need for the journal is identified in the epidemic of obesity, diabetes, dyslipidemias and related diseases, and a sudden increase in popular diets, as well as renewed interest in intermediary metabolism

Thermodynamics of weight loss diets

BACKGROUND: It is commonly held that "a calorie is a calorie", i.e. that diets of equal caloric content will result in identical weight change independent of macronutrient composition, and appeal is frequently made to the laws of thermodynamics. We have previously shown that thermodynamics does not support such a view and that diets of different macronutrient content may be expected to induce different changes in body mass. Low carbohydrate diets in particular have claimed a "metabolic advantage" meaning more weight loss than in isocaloric diets of higher carbohydrate content. In this review, for pedagogic clarity, we reframe the theoretical discussion to directly link thermodynamic inefficiency to weight change. The problem in outline: Is metabolic advantage theoretically possible? If so, what biochemical mechanisms might plausibly explain it? Finally, what experimental evidence exists to determine whether it does or does not occur? RESULTS: Reduced thermodynamic efficiency will result in increased weight loss. The laws of thermodynamics are silent on the existence of variable thermodynamic efficiency in metabolic processes. Therefore such variability is permitted and can be related to differences in weight lost. The existence of variable efficiency and metabolic advantage is therefore an empiric question rather than a theoretical one, confirmed by many experimental isocaloric studies, pending a properly performed meta-analysis. Mechanisms are as yet unknown, but plausible mechanisms at the metabolic level are proposed. CONCLUSIONS: Variable thermodynamic efficiency due to dietary manipulation is permitted by physical laws, is supported by much experimental data, and may be reasonably explained by plausible mechanisms

Carbohydrate restriction improves the features of Metabolic Syndrome. Metabolic Syndrome may be defined by the response to carbohydrate restriction

Metabolic Syndrome (MetS) represents a constellation of markers that indicates a predisposition to diabetes, cardiovascular disease and other pathologic states. The definition and treatment are a matter of current debate and there is not general agreement on a precise definition or, to some extent, whether the designation provides more information than the individual components. We consider here five indicators that are central to most definitions and we provide evidence from the literature that these are precisely the symptoms that respond to reduction in dietary carbohydrate (CHO). Carbohydrate restriction is one of several strategies for reducing body mass but even in the absence of weight loss or in comparison with low fat alternatives, CHO restriction is effective at ameliorating high fasting glucose and insulin, high plasma triglycerides (TAG), low HDL and high blood pressure. In addition, low fat, high CHO diets have long been known to raise TAG, lower HDL and, in the absence of weight loss, may worsen glycemic control. Thus, whereas there are numerous strategies for weight loss, a patient with high BMI and high TAG is likely to benefit most from a regimen that reduces CHO intake. Reviewing the literature, benefits of CHO restriction are seen in normal or overweight individuals, in normal patients who meet the criteria for MetS or in patients with frank diabetes. Moreover, in low fat studies that ameliorate LDL and total cholesterol, controls may do better on the symptoms of MetS. On this basis, we feel that MetS is a meaningful, useful phenomenon and may, in fact, be operationally defined as the set of markers that responds to CHO restriction. Insofar as this is an accurate characterization it is likely the result of the effect of dietary CHO on insulin metabolism. Glucose is the major insulin secretagogue and insulin resistance has been tied to the hyperinsulinemic state or the effect of such a state on lipid metabolism. The conclusion is probably not surprising but has not been explicitly stated before. The known effects of CHO-induced hypertriglyceridemia, the HDL-lowering effect of low fat, high CHO interventions and the obvious improvement in glucose and insulin from CHO restriction should have made this evident. In addition, recent studies suggest that a subset of MetS, the ratio of TAG/HDL, is a good marker for insulin resistance and risk of CVD, and this indicator is reliably reduced by CHO restriction and exacerbated by high CHO intake. Inability to make this connection in the past has probably been due to the fact that individual responses have been studied in isolation as well as to the emphasis of traditional therapeutic approaches on low fat rather than low CHO. We emphasize that MetS is not a disease but a collection of markers. Individual physicians must decide whether high LDL, or other risk factors are more important than the features of MetS in any individual case but if MetS is to be considered it should be recognized that reducing CHO will bring improvement. Response of symptoms to CHO restriction might thus provide a new experimental criterion for MetS in the face of on-going controversy about a useful definition. As a guide to future research, the idea that control of insulin metabolism by CHO intake is, to a first approximation, the underlying mechanism in MetS is a testable hypothesis

Low carbohydrate diets in family practice: what can we learn from an internet-based support group

The Active Low-Carber Forums (ALCF) is an on-line support group started in 2000 which currently has more than 86,000 members. Data collected from posts to the forum and from an on-line survey were used to determine the behavior and attitudes of people on low carbohydrate diets. Members were asked to complete a voluntary 27-item questionnaire over the internet. Our major findings are as follows: survey respondents, like the membership at large, were mostly women and mostly significantly overweight, a significant number intending to and, in many cases, succeeding at losing more than 100 lbs. The great majority of members of ALCF identify themselves as following the Atkins diet or some variation of it. Although individual posts on the forum and in the narrative part of our survey are critical of professional help, we found that more than half of respondents saw a physician before or during dieting and, of those who did, about half received support from the physician. Another 28 % found the physician initially neutral but supportive after positive results were produced. Using the same criteria as the National Weight Registry (without follow-up) – 30 lbs or more lost and maintained for more than one year – it was found that more than 1400 people had successfully used low carb methods. In terms of food consumed, the perception of more than half of respondents were that they ate less than before the diet and whereas high protein, high fat sources replaced carbohydrate to some extent, the major change indicated by survey-takers is a large increase in green vegetables and a large decrease in fruit intake. Government or health agencies were not sources of information for dieters in this group and a collection of narrative comments indicates a high level of satisfaction, indeed enthusiasm for low carbohydrate dieting. The results provide both a tabulation of the perceived behavior of a significant number of dieters using low carbohydrate strategies as well as a collection of narratives that provide a human perspective on what it is like to be on such a diet. An important conclusion for the family physician is that it becomes possible to identify a diet that is used by many people where the primary principle is replacement of starch and sugar-containing foods with non-starchy vegetables, with little addition of fat or protein. Used by many people who identify themselves as being on the Atkins diet, such a strategy provides the advantages of carbohydrate-restricted diets but is less iconoclastic than the popular perception and therefore more acceptable to traditional nutritionists. It is reasonable for family practitioners to turn this observation into a recommendation for patients for weight control and other health problems

Interrelations of platelet aggregation and secretion.

A B S T R A C T The mechanism of stimulus-response coupling in human platelets was investigated with a new instrument that simultaneously monitors aggregation and secretion in the same sample of plateletrich plasma. When platelets were stimulated by high concentrations of ADP, secretion began only after aggregation was almost complete. With lower concentrations of ADP or with epinephrine, biphasic aggregation was observed, and secretion began simultaneously with, or slightly after, the second phase of aggregation. When platelets were stimulated with high concentrations of y-thrombin or A23187, secretion and aggregation began essentially together. With very low concentrations of y-thrombin or A23187, biphasic aggregation was observed with secretion paralleling the second phase. At every concentration of collagen, secretion and aggregation appeared to be parallel events. Under every condition where the beginning of secretion lagged behind aggregation, secretion was dependent upon aggregation and was inhibited by indomethacin; this is referred to as aggregation-mediated platelet activation. When secretion began at the same time as aggregation, it also occurred in the absence of aggregation and was not blocked by indomethacin; this is referred to as directly induced platelet activation. These observations are -consistent with a simple model of platelet stimulusresponse coupling that includes two mechanisms for activation; aggregation-mediated activation is inhibited by indomethacin, while direct activation does not depend upon aggregation and is not inhibited by indomethacin. Secretion and second wave aggregation appear to be parallel events, with little evidence for second wave aggregation being a consequence of secretion as usually described