A model to predict cardiovascular events in patients with newly diagnosed Wegener's granulomatosis and microscopic polyangiitis

Objective To create a prognostic tool to quantify the 5-year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease. Methods We reviewed CV outcomes during the long-term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort. Results Seventy-four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11–1.90), diastolic hypertension (OR 1.97, 95% CI 0.98–3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20–0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80). Conclusion Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83751/1/20433_ftp.pd

Rapid reduction versus abrupt quitting for smokers who want to stop soon: a randomised controlled non-inferiority trial

Background: The standard way to stop smoking is to stop abruptly on a quit day with no prior reduction in consumption of cigarettes. Many smokers feel that reduction is natural and if reduction programmes were offered, many more might take up treatment. Few trials of reduction versus abrupt cessation have been completed. Most are small, do not use pharmacotherapy, and do not meet the standards necessary to obtain a marketing authorisation for a pharmacotherapy.\ud Design/Methods: We will conduct a non-inferiority andomised trial of rapid reduction versus standard abrupt cessation among smokers who want to stop smoking. In the reduction arm,participants will be advised to reduce smoking consumption by half in the first week and to 25% of baseline in the second, leading up to a quit day at which participants will stop smoking completely.This will be assisted by nicotine patches and an acute form of nicotine replacement therapy. In the abrupt arm participants will use nicotine patches only, whilst smoking as normal, for two weeks prior to a quit day, at which they will also stop smoking completely. Smokers in either arm will have standard withdrawal orientated behavioural support programme with a combination of nicotine patches and acute nicotine replacement therapy post-cessation.\ud Outcomes/Follow-up: The primary outcome of interest will be prolonged abstinence from smoking, with secondary trial outcomes of point prevalence, urges to smoke and withdrawal\ud symptoms. Follow up will take place at 4 weeks, 8 weeks and 6 months post-quit day

Could the clinical interpretability of subgroups detected using clustering methods be improved by using a novel two-stage approach?

Background: Recognition of homogeneous subgroups of patients can usefully improve prediction of their outcomes and the targeting of treatment. There are a number of research approaches that have been used to recognise homogeneity in such subgroups and to test their implications. One approach is to use statistical clustering techniques, such as Cluster Analysis or Latent Class Analysis, to detect latent relationships between patient characteristics. Influential patient characteristics can come from diverse domains of health, such as pain, activity limitation, physical impairment, social role participation, psychological factors, biomarkers and imaging. However, such 'whole person' research may result in data-driven subgroups that are complex, difficult to interpret and challenging to recognise clinically. This paper describes a novel approach to applying statistical clustering techniques that may improve the clinical interpretability of derived subgroups and reduce sample size requirements. Methods: This approach involves clustering in two sequential stages. The first stage involves clustering within health domains and therefore requires creating as many clustering models as there are health domains in the available data. This first stage produces scoring patterns within each domain. The second stage involves clustering using the scoring patterns from each health domain (from the first stage) to identify subgroups across all domains. We illustrate this using chest pain data from the baseline presentation of 580 patients. Results: The new two-stage clustering resulted in two subgroups that approximated the classic textbook descriptions of musculoskeletal chest pain and atypical angina chest pain. The traditional single-stage clustering resulted in five clusters that were also clinically recognisable but displayed less distinct differences. Conclusions: In this paper, a new approach to using clustering techniques to identify clinically useful subgroups of patients is suggested. Research designs, statistical methods and outcome metrics suitable for performing that testing are also described. This approach has potential benefits but requires broad testing, in multiple patient samples, to determine its clinical value. The usefulness of the approach is likely to be context-specific, depending on the characteristics of the available data and the research question being asked of it

Plasma proteins predict conversion to dementia from prodromal disease.

PublishedJournal ArticleMulticenter StudyResearch Support, Non-U.S. Gov'tBACKGROUND: The study aimed to validate previously discovered plasma biomarkers associated with AD, using a design based on imaging measures as surrogate for disease severity and assess their prognostic value in predicting conversion to dementia. METHODS: Three multicenter cohorts of cognitively healthy elderly, mild cognitive impairment (MCI), and AD participants with standardized clinical assessments and structural neuroimaging measures were used. Twenty-six candidate proteins were quantified in 1148 subjects using multiplex (xMAP) assays. RESULTS: Sixteen proteins correlated with disease severity and cognitive decline. Strongest associations were in the MCI group with a panel of 10 proteins predicting progression to AD (accuracy 87%, sensitivity 85%, and specificity 88%). CONCLUSIONS: We have identified 10 plasma proteins strongly associated with disease severity and disease progression. Such markers may be useful for patient selection for clinical trials and assessment of patients with predisease subjective memory complaints.Medical Research Council (MRC)Alzheimer’s Research UKThe National Institute for Health Research (NIHR) Biomedical Research CentreBiomedical Research Unit for DementiaAddNeuroMed through the EU FP6 programInnovative Medicines Initiative Joint Undertaking under an EMIF grantEuropean Union’s Seventh Framework Programme (FP7/2007-2013

Future therapeutic targets in rheumatoid arthritis?

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by persistent joint inflammation. Without adequate treatment, patients with RA will develop joint deformity and progressive functional impairment. With the implementation of treat-to-target strategies and availability of biologic therapies, the outcomes for patients with RA have significantly improved. However, the unmet need in the treatment of RA remains high as some patients do not respond sufficiently to the currently available agents, remission is not always achieved and refractory disease is not uncommon. With better understanding of the pathophysiology of RA, new therapeutic approaches are emerging. Apart from more selective Janus kinase inhibition, there is a great interest in the granulocyte macrophage-colony stimulating factor pathway, Bruton's tyrosine kinase pathway, phosphoinositide-3-kinase pathway, neural stimulation and dendritic cell-based therapeutics. In this review, we will discuss the therapeutic potential of these novel approaches

Nonequilibrium thermodynamics and energy efficiency in weight loss diets

Carbohydrate restriction as a strategy for control of obesity is based on two effects: a behavioral effect, spontaneous reduction in caloric intake and a metabolic effect, an apparent reduction in energy efficiency, greater weight loss per calorie consumed. Variable energy efficiency is established in many contexts (hormonal imbalance, weight regain and knock-out experiments in animal models), but in the area of the effect of macronutrient composition on weight loss, controversy remains. Resistance to the idea comes from a perception that variable weight loss on isocaloric diets would somehow violate the laws of thermodynamics, that is, only caloric intake is important ("a calorie is a calorie"). Previous explanations of how the phenomenon occurs, based on equilibrium thermodynamics, emphasized the inefficiencies introduced by substrate cycling and requirements for increased gluconeogenesis. Living systems, however, are maintained far from equilibrium, and metabolism is controlled by the regulation of the rates of enzymatic reactions. The principles of nonequilibrium thermodynamics which emphasize kinetic fluxes as well as thermodynamic forces should therefore also be considered

Nutrition education: a questionnaire for assessment and teaching

It is generally recognized that there is a need for improved teaching of nutrition in medical schools and for increased education of the general population. A questionnaire, derived in part from a study of physician knowledge, was administered to first year medical students in order to assess their knowledge of various aspects of nutrition and metabolism, and as a teaching tool to transmit information about the subject. The performance of first year students was consistent with a generally educated population but there were surprising deficits in some fundamental areas of nutrition. Results of the questionnaire are informative about student knowledge, and immediate reinforcement from a questionnaire may provide a useful teaching tool. In addition, some of the subject matter can serve as a springboard for discussion of critical issues in nutrition such as obesity and markers for cardiovascular disease. A major barrier to improved teaching of nutrition is the lack of agreement on some of these critical issues and there are apparent inconsistencies in recommendations of government and health agencies. It seems reasonable that improved teaching should address the lack of knowledge of nutrition, rather than knowledge of official guidelines. Student awareness of factual information should be the primary goal

Costs of Reproduction and Terminal Investment by Females in a Semelparous Marsupial

Evolutionary explanations for life history diversity are based on the idea of costs of reproduction, particularly on the concept of a trade-off between age-specific reproduction and parental survival, and between expenditure on current and future offspring. Such trade-offs are often difficult to detect in population studies of wild mammals. Terminal investment theory predicts that reproductive effort by older parents should increase, because individual offspring become more valuable to parents as the conflict between current versus potential future offspring declines with age. In order to demonstrate this phenomenon in females, there must be an increase in maternal expenditure on offspring with age, imposing a fitness cost on the mother. Clear evidence of both the expenditure and fitness cost components has rarely been found. In this study, we quantify costs of reproduction throughout the lifespan of female antechinuses. Antechinuses are nocturnal, insectivorous, forest-dwelling small (20–40 g) marsupials, which nest in tree hollows. They have a single synchronized mating season of around three weeks, which occurs on predictable dates each year in a population. Females produce only one litter per year. Unlike almost all other mammals, all males, and in the smaller species, most females are semelparous. We show that increased allocation to current reproduction reduces maternal survival, and that offspring growth and survival in the first breeding season is traded-off with performance of the second litter in iteroparous females. In iteroparous females, increased allocation to second litters is associated with severe weight loss in late lactation and post-lactation death of mothers, but increased offspring growth in late lactation and survival to weaning. These findings are consistent with terminal investment. Iteroparity did not increase lifetime reproductive success, indicating that terminal investment in the first breeding season at the expense of maternal survival (i.e. semelparity) is likely to be advantageous for females

Physiogenomic analysis of weight loss induced by dietary carbohydrate restriction

BACKGROUND: Diets that restrict carbohydrate (CHO) have proven to be a successful dietary treatment of obesity for many people, but the degree of weight loss varies across individuals. The extent to which genetic factors associate with the magnitude of weight loss induced by CHO restriction is unknown. We examined associations among polymorphisms in candidate genes and weight loss in order to understand the physiological factors influencing body weight responses to CHO restriction. METHODS: We screened for genetic associations with weight loss in 86 healthy adults who were instructed to restrict CHO to a level that induced a small level of ketosis (CHO ~10% of total energy). A total of 27 single nucleotide polymorphisms (SNPs) were selected from 15 candidate genes involved in fat digestion/metabolism, intracellular glucose metabolism, lipoprotein remodeling, and appetite regulation. Multiple linear regression was used to rank the SNPs according to probability of association, and the most significant associations were analyzed in greater detail. RESULTS: Mean weight loss was 6.4 kg. SNPs in the gastric lipase (LIPF), hepatic glycogen synthase (GYS2), cholesteryl ester transfer protein (CETP) and galanin (GAL) genes were significantly associated with weight loss. CONCLUSION: A strong association between weight loss induced by dietary CHO restriction and variability in genes regulating fat digestion, hepatic glucose metabolism, intravascular lipoprotein remodeling, and appetite were detected. These discoveries could provide clues to important physiologic adaptations underlying the body mass response to CHO restriction