Effect of statin therapy in the outcome of bloodstream infections due to Staphylococcus aureus: a prospective cohort study.

INTRODUCTION Statins have pleiotropic effects that could influence the prevention and outcome of some infectious diseases. There is no information about their specific effect on Staphylococcus aureus bacteremia (SAB). METHODS A prospective cohort study including all SAB diagnosed in patients aged ≥18 years admitted to a 950-bed tertiary hospital from March 2008 to January 2011 was performed. The main outcome variable was 14-day mortality, and the secondary outcome variables were 30-day mortality, persistent bacteremia (PB) and presence of severe sepsis or septic shock at diagnosis of SAB. The effect of statin therapy at the onset of SAB was studied by multivariate logistic regression and Cox regression analysis, including a propensity score for statin therapy. RESULTS We included 160 episodes. Thirty-three patients (21.3%) were receiving statins at the onset of SAB. 14-day mortality was 21.3%. After adjustment for age, Charlson index, Pitt score, adequate management, and high risk source, statin therapy had a protective effect on 14-day mortality (adjusted OR = 0.08; 95% CI: 0.01-0.66; p = 0.02), and PB (OR = 0.89; 95% CI: 0.27-1.00; p = 0.05) although the effect was not significant on 30-day mortality (OR = 0.35; 95% CI: 0.10-1.23; p = 0.10) or presentation with severe sepsis or septic shock (adjusted OR = 0.89; CI 95%: 0.27-2.94; p = 0.8). An effect on 30-day mortality could neither be demonstrated on Cox analysis (adjusted HR = 0.5; 95% CI: 0.19-1.29; p = 0.15). CONCLUSIONS Statin treatment in patients with SAB was associated with lower early mortality and PB. Randomized studies are necessary to identify the role of statins in the treatment of patients with SAB.

Role of Age and Sex in the Diagnosis of Early-stage Malignant Melanoma: A Cross-Sectional study.

Age and sex have been identified as predictors of outcome in malignant melanoma (MM). This aim of this multicentre, cross-sectional study was to analyse the role of age and sex as explanatory variables for the diagnosis of thin MM. A total of 2430 patients with MM were recruited. Cases of in situ-T1 MM were more frequent than T2-T4 MM (56.26% vs. 43.74%). Breslow thickness increased throughout decades of life (analysis of variance (ANOVA) p < 0.001), with a weak correlation between Breslow thickness and patient's age (r   = 0.202, p < 0.001). Breslow thickness was significantly less in women (1.79 vs. 2.38 mm, p = 0.0001). Binary logistic regression showed a significant (p < 0.001) odds ratio for age 0-29 years (1.18), and 30-59 years (1.16), and for women (1.09). Age and sex explained 3.64% of the variation observed in Tis-T1 frequency (R2 = 0.0364). Age and sex appear to explain a low percentage of the variation in the early detection of MM.

Patients' and physicians' preferences for type 2 diabetes mellitus treatments in Spain and Portugal: a discrete choice experiment.

OBJECTIVE To assess Spanish and Portuguese patients' and physicians' preferences regarding type 2 diabetes mellitus (T2DM) treatments and the monthly willingness to pay (WTP) to gain benefits or avoid side effects. METHODS An observational, multicenter, exploratory study focused on routine clinical practice in Spain and Portugal. Physicians were recruited from multiple hospitals and outpatient clinics, while patients were recruited from eleven centers operating in the public health care system in different autonomous communities in Spain and Portugal. Preferences were measured via a discrete choice experiment by rating multiple T2DM medication attributes. Data were analyzed using the conditional logit model. RESULTS Three-hundred and thirty (n=330) patients (49.7% female; mean age 62.4 [SD: 10.3] years, mean T2DM duration 13.9 [8.2] years, mean body mass index 32.5 [6.8] kg/m(2), 41.8% received oral + injected medication, 40.3% received oral, and 17.6% injected treatments) and 221 physicians from Spain and Portugal (62% female; mean age 41.9 [SD: 10.5] years, 33.5% endocrinologists, 66.5% primary-care doctors) participated. Patients valued avoiding a gain in bodyweight of 3 kg/6 months (WTP: €68.14 [95% confidence interval: 54.55-85.08]) the most, followed by avoiding one hypoglycemic event/month (WTP: €54.80 [23.29-82.26]). Physicians valued avoiding one hypoglycemia/week (WTP: €287.18 [95% confidence interval: 160.31-1,387.21]) the most, followed by avoiding a 3 kg/6 months gain in bodyweight and decreasing cardiovascular risk (WTP: €166.87 [88.63-843.09] and €154.30 [98.13-434.19], respectively). Physicians and patients were willing to pay €125.92 (73.30-622.75) and €24.28 (18.41-30.31), respectively, to avoid a 1% increase in glycated hemoglobin, and €143.30 (73.39-543.62) and €42.74 (23.89-61.77) to avoid nausea. CONCLUSION Both patients and physicians in Spain and Portugal are willing to pay for the health benefits associated with improved diabetes treatment, the most important being to avoid hypoglycemia and gaining weight. Decreased cardiovascular risk and weight reduction became the third most valued attributes for physicians and patients, respectively.

Changes in Body Composition in Anorexia Nervosa: Predictors of Recovery and Treatment Outcome.

The restoration of body composition (BC) parameters is considered to be one of the most important goals in the treatment of patients with anorexia nervosa (AN). However, little is known about differences between AN diagnostic subtypes [restricting (AN-R) and binge/purging (AN-BP)] and weekly changes in BC during refeeding treatment. Therefore, the main objectives of our study were twofold: 1) to assess the changes in BC throughout nutritional treatment in an AN sample and 2) to analyze predictors of BC changes during treatment, as well as predictors of treatment outcome. The whole sample comprised 261 participants [118 adult females with AN (70 AN-R vs. 48 AN-BP), and 143 healthy controls]. BC was measured weekly during 15 weeks of day-hospital treatment using bioelectrical impedance analysis (BIA). Assessment measures also included the Eating Disorders Inventory-2, as well as a number of other clinical indices. Overall, the results showed that AN-R and AN-BP patients statistically differed in all BC measures at admission. However, no significant time×group interaction was found for almost all BC parameters. Significant time×group interactions were only found for basal metabolic rate (p = .041) and body mass index (BMI) (p = .035). Multiple regression models showed that the best predictors of pre-post changes in BC parameters (namely fat-free mass, muscular mass, total body water and BMI) were the baseline values of BC parameters. Stepwise predictive logistic regressions showed that only BMI and age were significantly associated with outcome, but not with the percentage of body fat. In conclusion, these data suggest that although AN patients tended to restore all BC parameters during nutritional treatment, only AN-BP patients obtained the same fat mass values as healthy controls. Put succinctly, the best predictors of changes in BC were baseline BC values, which did not, however, seem to influence treatment outcome.

Psychiatric Status across Body Mass Index in a Mediterranean Spanish Population.

BACKGROUND Mental and body weight disorders are among the major global health challenges, and their comorbidity may play an important role in treatment and prevention of both pathologies. A growing number of studies have examined the relationship between psychiatric status and body weight, but our knowledge is still limited. OBJECTIVE The present study aims to investigate the cross-sectional relationships of psychiatric status and body mass index (BMI) in Málaga, a Mediterranean city in the South of Spain. MATERIALS AND METHODS A total of 563 participants were recruited from those who came to his primary care physician, using a systematic random sampling, non-proportional stratified by BMI categories. Structured clinical interviews were used to assess current Axes-I and II mental disorders according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). BMI was calculated as weight (Kg) divided by square of height in meters (m2). Logistic regression was used to investigate the association between BMI and the presence of any mental disorder. BMI was introduced in the models using restricted cubic splines. RESULTS We found that high BMI values were directly associated with mood and adjustment disorders, and low BMI values were directly associated with avoidant and dependent personality disorders (PDs). We observed an inverse relationship between low BMI values and cluster A PDs. There were not significant relationships between anxiety or substance-related disorders and BMI. CONCLUSION Psychiatric status and BMI are related in a Mediterranean Spanish population. A multidisciplinary approach to both pathologies becomes increasingly more necessary.

Phylogenetic approach reveals that virus genotype largely determines HIV set-point viral load.

HIV virulence, i.e. the time of progression to AIDS, varies greatly among patients. As for other rapidly evolving pathogens of humans, it is difficult to know if this variance is controlled by the genotype of the host or that of the virus because the transmission chain is usually unknown. We apply the phylogenetic comparative approach (PCA) to estimate the heritability of a trait from one infection to the next, which indicates the control of the virus genotype over this trait. The idea is to use viral RNA sequences obtained from patients infected by HIV-1 subtype B to build a phylogeny, which approximately reflects the transmission chain. Heritability is measured statistically as the propensity for patients close in the phylogeny to exhibit similar infection trait values. The approach reveals that up to half of the variance in set-point viral load, a trait associated with virulence, can be heritable. Our estimate is significant and robust to noise in the phylogeny. We also check for the consistency of our approach by showing that a trait related to drug resistance is almost entirely heritable. Finally, we show the importance of taking into account the transmission chain when estimating correlations between infection traits. The fact that HIV virulence is, at least partially, heritable from one infection to the next has clinical and epidemiological implications. The difference between earlier studies and ours comes from the quality of our dataset and from the power of the PCA, which can be applied to large datasets and accounts for within-host evolution. The PCA opens new perspectives for approaches linking clinical data and evolutionary biology because it can be extended to study other traits or other infectious diseases.

Interpretation and use of FRAX in clinical practice.

The introduction of the WHO FRAX® algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. Its use in fracture risk prediction has strengths, but also limitations of which the clinician should be aware and are the focus of this review INTRODUCTION: The International Osteoporosis Foundation (IOF) and the International Society for Clinical Densitometry (ISCD) appointed a joint Task Force to develop resource documents in order to make recommendations on how to improve FRAX and better inform clinicians who use FRAX. The Task Force met in November 2010 for 3 days to discuss these topics which form the focus of this review. METHODS: This study reviews the resource documents and joint position statements of ISCD and IOF. RESULTS: Details on the clinical risk factors currently used in FRAX are provided, and the reasons for the exclusion of others are provided. Recommendations are made for the development of surrogate models where country-specific FRAX models are not available. CONCLUSIONS: The wish list of clinicians for the modulation of FRAX is large, but in many instances, these wishes cannot presently be fulfilled; however, an explanation and understanding of the reasons may be helpful in translating the information provided by FRAX into clinical practice.

Activity-dependent regulation of energy metabolism by astrocytes: an update.

Astrocytes play a critical role in the regulation of brain metabolic responses to activity. One detailed mechanism proposed to describe the role of astrocytes in some of these responses has come to be known as the astrocyte-neuron lactate shuttle hypothesis (ANLSH). Although controversial, the original concept of a coupling mechanism between neuronal activity and glucose utilization that involves an activation of aerobic glycolysis in astrocytes and lactate consumption by neurons provides a heuristically valid framework for experimental studies. In this context, it is necessary to provide a survey of recent developments and data pertaining to this model. Thus, here, we review very recent experimental evidence as well as theoretical arguments strongly supporting the original model and in some cases extending it. Aspects revisited include the existence of glutamate-induced glycolysis in astrocytes in vitro, ex vivo, and in vivo, lactate as a preferential oxidative substrate for neurons, and the notion of net lactate transfer between astrocytes and neurons in vivo. Inclusion of a role for glycogen in the ANLSH is discussed in the light of a possible extension of the astrocyte-neuron lactate shuttle (ANLS) concept rather than as a competing hypothesis. New perspectives offered by the application of this concept include a better understanding of the basis of signals used in functional brain imaging, a role for neuron-glia metabolic interactions in glucose sensing and diabetes, as well as novel strategies to develop therapies against neurodegenerative diseases based upon improving astrocyte-neuron coupled energetics.

Handling macromolecule signals in the quantification of the neurochemical profile.

In vivo localized proton magnetic resonance spectroscopy (1H MRS) became a powerful and unique technique to non-invasively investigate brain metabolism of rodents and humans. The main goal of 1H MRS is the reliable quantification of concentrations of metabolites (neurochemical profile) in a well-defined region of the brain. The availability of very high magnetic field strengths combined with the possibility of acquiring spectra at very short echo time have dramatically increased the number of constituents of the neurochemical profile. The quantification of spectra measured at short echo times is complicated by the presence of macromolecule signals of particular importance at high magnetic fields. An error in the macromolecule estimation can lead to substantial errors in the obtained neurochemical profile. The purpose of the present review is to overview methods of high field 1H MRS with a focus on the metabolite quantification, in particular in handling signals of macromolecules. Three main approaches of handling signals of macromolecules are described, namely mathematical estimation of macromolecules, measurement of macromolecules in vivo, and direct acquisition of the in vivo spectrum without the contribution of macromolecules.

Functional dynamics of PDZ binding domains: a normal-mode analysis.

Postsynaptic density-95/disks large/zonula occludens-1 (PDZ) domains are relatively small (80-120 residues) protein binding modules central in the organization of receptor clusters and in the association of cellular proteins. Their main function is to bind C-terminals of selected proteins that are recognized through specific amino acids in their carboxyl end. Binding is associated with a deformation of the PDZ native structure and is responsible for dynamical changes in regions not in direct contact with the target. We investigate how this deformation is related to the harmonic dynamics of the PDZ structure and show that one low-frequency collective normal mode, characterized by the concerted movements of different secondary structures, is involved in the binding process. Our results suggest that even minimal structural changes are responsible for communication between distant regions of the protein, in agreement with recent NMR experiments. Thus, PDZ domains are a very clear example of how collective normal modes are able to characterize the relation between function and dynamics of proteins, and to provide indications on the precursors of binding/unbinding events.

S-system parameter estimation for noisy metabolic profiles using newton-flow analysis.

Biochemical systems are commonly modelled by systems of ordinary differential equations (ODEs). A particular class of such models called S-systems have recently gained popularity in biochemical system modelling. The parameters of an S-system are usually estimated from time-course profiles. However, finding these estimates is a difficult computational problem. Moreover, although several methods have been recently proposed to solve this problem for ideal profiles, relatively little progress has been reported for noisy profiles. We describe a special feature of a Newton-flow optimisation problem associated with S-system parameter estimation. This enables us to significantly reduce the search space, and also lends itself to parameter estimation for noisy data. We illustrate the applicability of our method by applying it to noisy time-course data synthetically produced from previously published 4- and 30-dimensional S-systems. In addition, we propose an extension of our method that allows the detection of network topologies for small S-systems. We introduce a new method for estimating S-system parameters from time-course profiles. We show that the performance of this method compares favorably with competing methods for ideal profiles, and that it also allows the determination of parameters for noisy profiles.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Social and medical vulnerability factors of emergency department frequent users in a universal health insurance system.

OBJECTIVES: The objectives were to identify the social and medical factors associated with emergency department (ED) frequent use and to determine if frequent users were more likely to have a combination of these factors in a universal health insurance system. METHODS: This was a retrospective chart review case-control study comparing randomized samples of frequent users and nonfrequent users at the Lausanne University Hospital, Switzerland. The authors defined frequent users as patients with four or more ED visits within the previous 12 months. Adult patients who visited the ED between April 2008 and March 2009 (study period) were included, and patients leaving the ED without medical discharge were excluded. For each patient, the first ED electronic record within the study period was considered for data extraction. Along with basic demographics, variables of interest included social (employment or housing status) and medical (ED primary diagnosis) characteristics. Significant social and medical factors were used to construct a logistic regression model, to determine factors associated with frequent ED use. In addition, comparison of the combination of social and medical factors was examined. RESULTS: A total of 359 of 1,591 frequent and 360 of 34,263 nonfrequent users were selected. Frequent users accounted for less than a 20th of all ED patients (4.4%), but for 12.1% of all visits (5,813 of 48,117), with a maximum of 73 ED visits. No difference in terms of age or sex occurred, but more frequent users had a nationality other than Swiss or European (n = 117 [32.6%] vs. n = 83 [23.1%], p = 0.003). Adjusted multivariate analysis showed that social and specific medical vulnerability factors most increased the risk of frequent ED use: being under guardianship (adjusted odds ratio [OR] = 15.8; 95% confidence interval [CI] = 1.7 to 147.3), living closer to the ED (adjusted OR = 4.6; 95% CI = 2.8 to 7.6), being uninsured (adjusted OR = 2.5; 95% CI = 1.1 to 5.8), being unemployed or dependent on government welfare (adjusted OR = 2.1; 95% CI = 1.3 to 3.4), the number of psychiatric hospitalizations (adjusted OR = 4.6; 95% CI = 1.5 to 14.1), and the use of five or more clinical departments over 12 months (adjusted OR = 4.5; 95% CI = 2.5 to 8.1). Having two of four social factors increased the odds of frequent ED use (adjusted = OR 5.4; 95% CI = 2.9 to 9.9), and similar results were found for medical factors (adjusted OR = 7.9; 95% CI = 4.6 to 13.4). A combination of social and medical factors was markedly associated with ED frequent use, as frequent users were 10 times more likely to have three of them (on a total of eight factors; 95% CI = 5.1 to 19.6). CONCLUSIONS: Frequent users accounted for a moderate proportion of visits at the Lausanne ED. Social and medical vulnerability factors were associated with frequent ED use. In addition, frequent users were more likely to have both social and medical vulnerabilities than were other patients. Case management strategies might address the vulnerability factors of frequent users to prevent inequities in health care and related costs.

FRAX® International Task Force of the 2010 Joint International Society for Clinical Densitometry & International Osteoporosis Foundation Position Development Conference.

Osteoporosis is a serious worldwide epidemic. FRAX® is a web-based tool developed by the Sheffield WHO Collaborating Center team, that integrates clinical risk factors and femoral neck BMD and calculates the 10 year fracture probability in order to help health care professionals identify patients who need treatment. However, only 31 countries have a FRAX® calculator. In the absence of a FRAX® model for a particular country, it has been suggested to use a surrogate country for which the epidemiology of osteoporosis most closely approximates the index country. More specific recommendations for clinicians in these countries are not available. In North America, concerns have also been raised regarding the assumptions used to construct the US ethnic specific FRAX® calculators with respect to the correction factors applied to derive fracture probabilities in Blacks, Asians and Hispanics in comparison to Whites. In addition, questions were raised about calculating fracture risk in other ethnic groups e.g., Native Americans and First Canadians. The International Society for Clinical Densitometry (ISCD) in conjunction with the International Osteoporosis Foundation (IOF) assembled an international panel of experts that ultimately developed joint Official Positions of the ISCD and IOF advising clinicians regarding FRAX® usage. As part of the process, the charge of the FRAX® International Task Force was to review and synthesize data regarding geographic and race/ethnic variability in hip fractures, non-hip osteoporotic fractures, and make recommendations about the use of FRAX® in ethnic groups and countries without a FRAX® calculator. This synthesis was presented to the expert panel and constitutes the data on which the subsequent Official Positions are predicated. A summary of the International Task Force composition and charge is presented here.