Author contributions In an academic-industry partnership, SomaLogic, Inc. and the academic collaborators worked together on study design, interpretation of the data and preparation of the manuscript. S.A.W., P.G. and N.W. were responsible for designing, writing and final editing of the manuscript and responses to reviewer comments. In addition to all authors being generally involved in the program, specific contributions were as follows: M.K. and M.J.S. were accountable for the data from the Whitehall II study and advised on the study design for the CV and diabetes models. C.L. and N.W. were accountable for the data from the Fenland study and advising on diabetes risk and behavioral models. C.B. and M.A.S. were accountable for the data from the Heritage Family study. C.J. was accountable for the data from the HUNT3 study. R.O. was accountable for the data from the Covance study.

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Objective To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel.Design Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria.

U ntrained people with type 2 diabetes have been shown to have a re d u c e d VO 2 m a x c o m p a red with nondiabetic people, even in the absence of card i o v a scular disease (1). In addition, it has been re p o rted that VO 2 kinetics are impaired in women with type 2 diabetes (2). The causes of the exercise impairment are unknown, and thus the physiological and clinical significance of these findings warrants further study.VO 2 m a x is the classic measure of overall c a rd i o re s p i r a t o ry fitness and describes the highest oxygen uptake obtainable by an individual for a given form of exerc i s e despite increased eff o rt and increased work rate. In contrast, VO 2 kinetics measure the e fficiency of the card i o re s p i r a t o ry re s p o n s e to an imposed work demand. Specific a l l y, VO 2 kinetics describe the rate at which the c a rd i o re s p i r a t o ry system is able to deliver oxygen to skeletal muscle and the rate at which oxygen is consumed by skeletal muscle at the beginning of exercise. VO 2 k i n e t i c s a re measured during repeated submaximal constant-load exercise bouts. The rise to steady state is described by a time constant, .is determined by fitting an exponential c u rve to VO 2 kinetics data ( Fig. 1). A slowed is a marker of impaired oxygen delivery and/or extraction. It takes longer for an individual with a slowed to reach steady state.Although the exercise impairments in diabetes have been described, the eff e c t s of e x e rcise training on VO 2 kinetics in untrained women with diabetes and the baseline impairments discussed above are not well described. Although many studies have examined the metabolic effects of e x e rcise training in subjects with diabetes (3-5), fewer investigators have studied the e ffects of exercise training on card i o v a s c ular parameters such as VO 2 m a x in subjects with diabetes (3,4). In addition, the impact of exercise training on VO 2 kinetics in subjects with type 2 diabetes has not been well characterized. It appears that the exerc i s e e ff o rt expended by people with diabetes may be greater for a given workload (even at very low workloads) than for nondiabetic patients (2). Studying the card i o v a scular response to exercise training in diabetes may provide insight into tre a tment recommendations, such as optimal e x e rcise prescriptions, for this common disease with a significantly increased risk of c a rdiovascular morbidity and mort a l i t y.We hypothesized that VO 2 m a x and VO 2 kinetics would improve with exercise training in women with type 2 diabetes. To A b b re v i a t i o n s : A N O VA, analysis of variance; ECG, electro c a rdiogram; FFM, fat-free mass; FSH, folliclestimulating hormone; LOPAR, Low Level Physical Activity Recall Questionnaire; LV, left ventricular; MET, metabolic equivalent; RER, re s p i r a t o ry exchange ratio. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. O B J E C T I V E-Women with uncomplicated t...

mmma Previous studies on cycling cadence have focused on the economy of the cadence. in search of the optimal pedal cadence. The purpose of this study was to determine the hemodynarnic changes associated with varylng pedal cadence at a constant workload. It was hypothesized that increased pedal cadence would enhance the skeletal muscle pump, resulting in elevation of cardiac output. Seven cycllsts were enlisted to cycle at 200 watts at pedal cadences of 70.90 and 110 rpm (random order). Oxygen uptake. heart rate. stroke volume, cardiac output. blood pressure. and vascular resistance were determined. As has been previously shown, oxygen uptake increased with increased cadence (70. 90. 110 rpm) at this workload. Heart rate. stroke volume. cardiac output and blood pressure were increased. and vascular resistance decreased, with increased cadence. Cardiac output increased (34 %)in excessof theincrease in oxygen uptake (15 %) as shown by the decrease (-14.5 %) in the arterial-venous oxygen difference occurring with increasing cadence. Apparently, even though the workload was constant, the increase in pedal cadence resulted in a more effective skeletal-muscle pump which increased muscle blood flow and venous return. It is not known if this might contribute to the natural selection of higher cadences by cycling athletes. even though there is reduced economy.a Key words: Pedal frequency, cardiac output, skeletal-muscle pump, cycling economy, cardiovascular l ntrod udion The cadence used by cyclists has been investigated as to the most efficient or economic pedal frequency required for performance (3.7.12.18,19,24). A non-linear reltionship appean to exist between oxygen uptake and pedal cadence (3). In general, investigations have indicated that oxygen uptake increases at pedal cadences both below and above an "optimum" pedal cadence during a constant workload (3,24). This "optimum" pedal cadence increases linearly with increasingworkInt.