Effectiveness of chronic obstructive pulmonary disease-management programs: systematic review and meta-analysis

BACKGROUND: Disease-management programs may enhance the quality of care provided to patients with chronic diseases, such as chronic obstructive pulmonary disease (COPD). The aim of this systematic review was to assess the effectiveness of COPD disease-management programs. METHODS: We conducted a computerized search of MEDLINE, EMBASE, CINAHL, PsychINFO, and the Cochrane Library (CENTRAL) for studies evaluating interventions meeting our operational definition of disease management: patient education, 2 or more different intervention components, 2 or more health care professionals actively involved in patients' care, and intervention lasting 12 months or more. Programs conducted in hospital only and those targeting patients receiving palliative care were excluded. Two reviewers evaluated 12,749 titles and fully reviewed 139 articles; among these, data from 13 studies were included and extracted. Clinical outcomes considered were all-cause mortality, lung function, exercise capacity (walking distance), health-related quality of life, symptoms, COPD exacerbations, and health care use. A meta-analysis of exercise capacity and all-cause mortality was performed using random-effects models. RESULTS: The studies included were 9 randomized controlled trials, 1 controlled trial, and 3 uncontrolled before-after trials. Results indicate that the disease-management programs studied significantly improved exercise capacity (32.2 m, 95% confidence interval [CI], 4.1-60.3), decreased risk of hospitalization, and moderately improved health-related quality of life. All-cause mortality did not differ between groups (pooled odds ratio 0.84, 95% CI, 0.54-1.40). CONCLUSION: COPD disease-management programs modestly improved exercise capacity, health-related quality of life, and hospital admissions, but not all-cause mortality. Future studies should explore the specific elements or characteristics of these programs that bring the greatest benefit.

Prevalence of alcohol-impaired drivers based on random breath tests in a roadside survey

Sobriety checkpoints are not usually randomly located by traffic authorities. As such, information provided by non-random alcohol tests cannot be used to infer the characteristics of the general driving population. In this paper a case study is presented in which the prevalence of alcohol-impaired driving is estimated for the general population of drivers. A stratified probabilistic sample was designed to represent vehicles circulating in non-urban areas of Catalonia (Spain), a region characterized by its complex transportation network and dense traffic around the metropolis of Barcelona. Random breath alcohol concentration tests were performed during spring 2012 on 7,596 drivers. The estimated prevalence of alcohol-impaired drivers was 1.29%, which is roughly a third of the rate obtained in non-random tests. Higher rates were found on weekends (1.90% on Saturdays, 4.29% on Sundays) and especially at night. The rate is higher for men (1.45%) than for women (0.64%) and the percentage of positive outcomes shows an increasing pattern with age. In vehicles with two occupants, the proportion of alcohol-impaired drivers is estimated at 2.62%, but when the driver was alone the rate drops to 0.84%, which might reflect the socialization of drinking habits. The results are compared with outcomes in previous surveys, showing a decreasing trend in the prevalence of alcohol-impaired drivers over time.

Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia.

BACKGROUND: Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established. METHODS: Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A •- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT). RESULTS: Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A •- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A •- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M). CONCLUSIONS: Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.

Acute effects of transmyocardial laser revascularization on left-ventricular function: an haemodynamic and echocardiographic study.

While the lesions produced by transmyocardial laser revascularisation (TMLR) induce scar formation, it is important to determine whether this procedure can be deleterious for the left-ventricular function, which is already impaired by the underlying ischaemic process in some patients. Ten channels were drilled in the left lateral wall of the hearts of ten pigs (mean weight, 61 +/- 8.2kg) with a Holmium:YAG laser. Haemodynamic measurements and echocardiographic assessment of left-ventricular function were performed before the TMLR procedure, 5 and 30 min after, and lastly after 5 min of pacing at a rate increased by 30% of the baseline value. Echocardiographic assessment was in the short axis at the level of the laser channels, and included left-ventricular ejection fraction and segmental wall motility of the lasered area (scale 0-3:0 = normal 1 = hypokinesia, 2 = akinesia, 3 = dyskinesia). Values at 5 and 30 min were compared with baseline values; the difference was considered significant if p < 0.05. Haemodynamical values were stable throughout all the procedures. The ejection fraction showed a slight but significant decrease 5 min after the creation of the channels (60.4 +/- 6.8% vs 54 +/- 7.6%, p=0.02) and recovered at 30min. The segmental motility score of the involved areas increased to 1 after 5 min in five animals, and came back to 0 at 30 min except in one animal. Even with pacing no segmental dysfunction occurred. The reversibility of the segmental hypokinesia induced by TMLR, as well as the absence of pace-induced dysfunction 30 min after the procedure strongly suggest the inocuity of TMLR in this experimental set-up.

Cardiac Function Assessed by Transesophageal Echocardiography During Pectus Excavatum Repair

Background. We assessed end-diastolic right ventricular (RV) dimensions and left ventricular (LV) ejection fraction by use of intraoperative transesophageal echocardiography before and after surgical correction of pectus excavatum in adults. Methods. A prospective study was conducted including 17 patients undergoing surgical correction of pectus excavatum according to the technique of Ravitch-Shamberger between 1999 and 2004. Intraoperative transesophageal echocardiography was performed under general anesthesia before and after surgery to assess end-diastolic RV dimensions and LV ejection fraction. The end-diastolic RV diameter and area were measured in four-chamber and RV inflow-outflow view, and the RV volume was calculated from these data. The LV was assessed by transgastric short-axis view, and its ejection fraction was calculated by use of the Teichholz formula. Results. The end-diastolic RV diameter, area, and volume all significantly increased after surgery (mean values +/- SD, respectively: 2.4 +/- 0.8 cm versus 3.0 +/- 0.9 cm, p < 0.001; 12.5 +/- 5.2 cm(2) versus 18.4 +/- 7.5 cm(2), p < 0.001; and 21.7 +/- 11.7 mL versus 40.8 +/- 23 mL, p < 0.001). The LV ejection fraction also significantly increased after surgery (58.4% +/- 15% versus 66.2% +/- 6%, p < 0.001). Conclusions. Surgical correction of pectus excavatum according to Ravitch-Shamberger technique results in a significant increase in end-diastolic RV dimensions and a significantly increased LV ejection fraction. (Ann Thorac Surg 2010; 89: 240-4) (C) 2010 by The Society of Thoracic Surgeons

Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function.

Protective adaptive immune responses rely on TCR-mediated recognition of Ag-derived peptides presented by self-MHC molecules. However, self-Ag (tumor)-specific TCRs are often of too low affinity to achieve best functionality. To precisely assess the relationship between TCR-peptide-MHC binding parameters and T cell function, we tested a panel of sequence-optimized HLA-A(*)0201/NY-ESO-1(157-165)-specific TCR variants with affinities lying within physiological boundaries to preserve antigenic specificity and avoid cross-reactivity, as well as two outliers (i.e., a very high- and a low-affinity TCR). Primary human CD8 T cells transduced with these TCRs demonstrated robust correlations between binding measurements of TCR affinity and avidity and the biological response of the T cells, such as TCR cell-surface clustering, intracellular signaling, proliferation, and target cell lysis. Strikingly, above a defined TCR-peptide-MHC affinity threshold (K(D) < approximately 5 muM), T cell function could not be further enhanced, revealing a plateau of maximal T cell function, compatible with the notion that multiple TCRs with slightly different affinities participate equally (codominantly) in immune responses. We propose that rational design of improved self-specific TCRs may not need to be optimized beyond a given affinity threshold to achieve both optimal T cell function and avoidance of the unpredictable risk of cross-reactivity.

Influence of reconstruction parameters during filtered backprojection and ordered-subset expectation maximization in the measurement of the left-ventricular volumes and function during gated SPECT.

A crucial method for investigating patients with coronary artery disease (CAD) is the calculation of the left ventricular ejection fraction (LVEF). It is, consequently, imperative to precisely estimate the value of LVEF--a process that can be done with myocardial perfusion scintigraphy. Therefore, the present study aimed to establish and compare the estimation performance of the quantitative parameters of the reconstruction methods filtered backprojection (FBP) and ordered-subset expectation maximization (OSEM). METHODS: A beating-heart phantom with known values of end-diastolic volume, end-systolic volume, and LVEF was used. Quantitative gated SPECT/quantitative perfusion SPECT software was used to obtain these quantitative parameters in a semiautomatic mode. The Butterworth filter was used in FBP, with the cutoff frequencies between 0.2 and 0.8 cycles per pixel combined with the orders of 5, 10, 15, and 20. Sixty-three reconstructions were performed using 2, 4, 6, 8, 10, 12, and 16 OSEM subsets, combined with several iterations: 2, 4, 6, 8, 10, 12, 16, 32, and 64. RESULTS: With FBP, the values of end-diastolic, end-systolic, and the stroke volumes rise as the cutoff frequency increases, whereas the value of LVEF diminishes. This same pattern is verified with the OSEM reconstruction. However, with OSEM there is a more precise estimation of the quantitative parameters, especially with the combinations 2 iterations × 10 subsets and 2 iterations × 12 subsets. CONCLUSION: The OSEM reconstruction presents better estimations of the quantitative parameters than does FBP. This study recommends the use of 2 iterations with 10 or 12 subsets for OSEM and a cutoff frequency of 0.5 cycles per pixel with the orders 5, 10, or 15 for FBP as the best estimations for the left ventricular volumes and ejection fraction quantification in myocardial perfusion scintigraphy.

The Effect of Four-Lane to Three-Lane Conversion on the Number of Crashes and Crash Rates in Iowa Roads, June 2005

We analyze crash data collected by the Iowa Department of Transportation using Bayesian methods. The data set includes monthly crash numbers, estimated monthly traffic volumes, site length and other information collected at 30 paired sites in Iowa over more than 20 years during which an intervention experiment was set up. The intervention consisted in transforming 15 undivided road segments from four-lane to three lanes, while an additional 15 segments, thought to be comparable in terms of traffic safety-related characteristics were not converted. The main objective of this work is to find out whether the intervention reduces the number of crashes and the crash rates at the treated sites. We fitted a hierarchical Poisson regression model with a change-point to the number of monthly crashes per mile at each of the sites. Explanatory variables in the model included estimated monthly traffic volume, time, an indicator for intervention reflecting whether the site was a “treatment” or a “control” site, and various interactions. We accounted for seasonal effects in the number of crashes at a site by including smooth trigonometric functions with three different periods to reflect the four seasons of the year. A change-point at the month and year in which the intervention was completed for treated sites was also included. The number of crashes at a site can be thought to follow a Poisson distribution. To estimate the association between crashes and the explanatory variables, we used a log link function and added a random effect to account for overdispersion and for autocorrelation among observations obtained at the same site. We used proper but non-informative priors for all parameters in the model, and carried out all calculations using Markov chain Monte Carlo methods implemented in WinBUGS. We evaluated the effect of the four to three-lane conversion by comparing the expected number of crashes per year per mile during the years preceding the conversion and following the conversion for treatment and control sites. We estimated this difference using the observed traffic volumes at each site and also on a per 100,000,000 vehicles. We also conducted a prospective analysis to forecast the expected number of crashes per mile at each site in the study one year, three years and five years following the four to three-lane conversion. Posterior predictive distributions of the number of crashes, the crash rate and the percent reduction in crashes per mile were obtained for each site for the months of January and June one, three and five years after completion of the intervention. The model appears to fit the data well. We found that in most sites, the intervention was effective and reduced the number of crashes. Overall, and for the observed traffic volumes, the reduction in the expected number of crashes per year and mile at converted sites was 32.3% (31.4% to 33.5% with 95% probability) while at the control sites, the reduction was estimated to be 7.1% (5.7% to 8.2% with 95% probability). When the reduction in the expected number of crashes per year, mile and 100,000,000 AADT was computed, the estimates were 44.3% (43.9% to 44.6%) and 25.5% (24.6% to 26.0%) for converted and control sites, respectively. In both cases, the difference in the percent reduction in the expected number of crashes during the years following the conversion was significantly larger at converted sites than at control sites, even though the number of crashes appears to decline over time at all sites. Results indicate that the reduction in the expected number of sites per mile has a steeper negative slope at converted than at control sites. Consistent with this, the forecasted reduction in the number of crashes per year and mile during the years after completion of the conversion at converted sites is more pronounced than at control sites. Seasonal effects on the number of crashes have been well-documented. In this dataset, we found that, as expected, the expected number of monthly crashes per mile tends to be higher during winter months than during the rest of the year. Perhaps more interestingly, we found that there is an interaction between the four to three-lane conversion and season; the reduction in the number of crashes appears to be more pronounced during months, when the weather is nice than during other times of the year, even though a reduction was estimated for the entire year. Thus, it appears that the four to three-lane conversion, while effective year-round, is particularly effective in reducing the expected number of crashes in nice weather.

A theory of optimal random crackdowns

An incentives based theory of policing is developed which can explain the phenomenon of random “crackdowns,” i.e., intermittent periods of high interdiction/surveillance. For a variety of police objective functions, random crackdowns can be part of the optimal monitoring strategy. We demonstrate support for implications of the crackdown theory using traffic data gathered by the Belgian Police Department and use the model to estimate the deterrence effectof additional resources spent on speeding interdiction.

Aitchison Geometry for Probability and Likelihood as a new approach to mathematical statistics

The Aitchison vector space structure for the simplex is generalized to a Hilbert space structure A2(P) for distributions and likelihoods on arbitrary spaces. Centralnotations of statistics, such as Information or Likelihood, can be identified in the algebraical structure of A2(P) and their corresponding notions in compositional data analysis, such as Aitchison distance or centered log ratio transform.In this way very elaborated aspects of mathematical statistics can be understoodeasily in the light of a simple vector space structure and of compositional data analysis. E.g. combination of statistical information such as Bayesian updating,combination of likelihood and robust M-estimation functions are simple additions/perturbations in A2(Pprior). Weighting observations corresponds to a weightedaddition of the corresponding evidence.Likelihood based statistics for general exponential families turns out to have aparticularly easy interpretation in terms of A2(P). Regular exponential families formfinite dimensional linear subspaces of A2(P) and they correspond to finite dimensionalsubspaces formed by their posterior in the dual information space A2(Pprior).The Aitchison norm can identified with mean Fisher information. The closing constant itself is identified with a generalization of the cummulant function and shown to be Kullback Leiblers directed information. Fisher information is the local geometry of the manifold induced by the A2(P) derivative of the Kullback Leibler information and the space A2(P) can therefore be seen as the tangential geometry of statistical inference at the distribution P.The discussion of A2(P) valued random variables, such as estimation functionsor likelihoods, give a further interpretation of Fisher information as the expected squared norm of evidence and a scale free understanding of unbiased reasoning

Up-regulation of the levels of expression and function of a constitutively active mutant of the hamster alpha1B-adrenoceptor by ligands that act as inverse agonists.

The alpha1-adrenergic agonist phenylephrine stimulated phospholipase D (PLD) activity in Rat 1 fibroblasts transfected to express either the wild-type hamster alpha1B-adrenoceptor or a constitutively active mutant (CAM) form of this receptor. The EC50 for agonist stimulation of PLD activity was substantially lower at the CAM receptor than at the wild-type receptor as previously noted for phenylephrine stimulation of phosphoinositidase C activity. Sustained treatment of cells expressing the CAM alpha1B-adrenoceptor with phentolamine resulted in a marked up-regulation in levels of this receptor with half-maximal effects produced within 24 h and with an EC50 of approx. 40 nM. Such an up-regulation could be produced with a range of other ligands generally viewed as alpha1-adrenoceptor antagonists but equivalent treatment of cells expressing the wild-type alpha1B-adrenoceptor was unable to mimic these effects. After sustained treatment of the CAM alpha1B-adrenoceptor expressing cells with phentolamine, basal PLD activity was increased and phenylephrine was now able to stimulate PLD activity to greater levels than in vehicle-treated CAM alpha1B-adrenoceptor-expressing cells. The EC50 for phenylephrine stimulation of PLD activity was not altered, however, by phentolamine pretreatment and the associated up-regulation of the receptor. After phentolamine-induced up-regulation of basal PLD activity, a range of alpha1-antagonists were shown to possess the characteristics of inverse agonists of the CAM alpha1B-adrenoceptor as they were able to substantially decrease the elevated basal PLD activity.

IL-28A (IFN-λ2) modulates lung DC function to promote Th1 immune skewing and suppress allergic airway disease.

IL-28 (IFN-λ) cytokines exhibit potent antiviral and antitumor function but their full spectrum of activities remains largely unknown. Recently, IL-28 cytokine family members were found to be profoundly down-regulated in allergic asthma. We now reveal a novel role of IL-28 cytokines in inducing type 1 immunity and protection from allergic airway disease. Treatment of wild-type mice with recombinant or adenovirally expressed IL-28A ameliorated allergic airway disease, suppressed Th2 and Th17 responses and induced IFN-γ. Moreover, abrogation of endogenous IL-28 cytokine function in IL-28Rα(-/-) mice exacerbated allergic airway inflammation by augmenting Th2 and Th17 responses, and IgE levels. Central to IL-28A immunoregulatory activity was its capacity to modulate lung CD11c(+) dendritic cell (DC) function to down-regulate OX40L, up-regulate IL-12p70 and promote Th1 differentiation. Consistently, IL-28A-mediated protection was absent in IFN-γ(-/-) mice or after IL-12 neutralization and could be adoptively transferred by IL-28A-treated CD11c(+) cells. These data demonstrate a critical role of IL-28 cytokines in controlling T cell responses in vivo through the modulation of lung CD11c(+) DC function in experimental allergic asthma. →See accompanying Closeup by Michael R Edwards and Sebastian L Johnston http://dx.doi.org/10.1002/emmm.201100143.