La résistance bactérienne aux antibiotiques.

50 years ago, the introduction of penicillin, followed by many other antibacterial agents, represented an often underestimated medical revolution. Indeed, until that time, bacterial infections were the prime cause of mortality, especially in children and elderly patients. The discovery of numerous new substances and their development on an industrial scale gave us the illusion that bacterial infections were all but vanquished. However, the widespread and sometimes uncontrolled use of these agents has led to the selection of bacteria resistant to practically all available antibiotics. Bacteria utilize three main resistance strategies: (1) modification of their permeability, (2) modification of target, and (3) modification of the antibiotic. Bacteria modify their permeability either by becoming impermeable to antibiotics, or by actively excreting the drug accumulated in the cell. As an alternative, they can modify the structure of the antibiotic's molecular target--usually an essential metabolic enzyme of the bacterium--and thus escape the drug's toxic effect. Lastly, they can produce enzymes capable of modifying and directly inactivating antibiotics. In addition, bacteria have evolved extremely efficient genetic transfer systems capable of exchanging and accumulating resistance genes. Some pathogens, such as methicillin-resistant Staphylococcus aureus and multiresistant Mycobacterium tuberculosis, have become resistant to almost all available antibiotics and there are only one or two substances still active against such organisms. Antibiotics are very precious drugs which must be administered to patients who need them. On the other hand, the development of resistance must be kept under control by a better comprehension of its mechanisms and modes of transmission and by abiding by the fundamental rules of anti-infectious chemotherapy, i.e.: (1) choose the most efficient antibiotic according to clinical and local epidemiological data, (2) target the bacteria according to the microbiological data at hand, and (3) administer the antibiotic in an adequate dose which will leave the pathogen no chance to develop resistance.

Effects of selection and drift on G matrix evolution in a heterogeneous environment: a multivariate Qst-Fst Test with the freshwater snail Galba truncatula.

Unraveling the effect of selection vs. drift on the evolution of quantitative traits is commonly achieved by one of two methods. Either one contrasts population differentiation estimates for genetic markers and quantitative traits (the Q(st)-F(st) contrast) or multivariate methods are used to study the covariance between sets of traits. In particular, many studies have focused on the genetic variance-covariance matrix (the G matrix). However, both drift and selection can cause changes in G. To understand their joint effects, we recently combined the two methods into a single test (accompanying article by Martin et al.), which we apply here to a network of 16 natural populations of the freshwater snail Galba truncatula. Using this new neutrality test, extended to hierarchical population structures, we studied the multivariate equivalent of the Q(st)-F(st) contrast for several life-history traits of G. truncatula. We found strong evidence of selection acting on multivariate phenotypes. Selection was homogeneous among populations within each habitat and heterogeneous between habitats. We found that the G matrices were relatively stable within each habitat, with proportionality between the among-populations (D) and the within-populations (G) covariance matrices. The effect of habitat heterogeneity is to break this proportionality because of selection for habitat-dependent optima. Individual-based simulations mimicking our empirical system confirmed that these patterns are expected under the selective regime inferred. We show that homogenizing selection can mimic some effect of drift on the G matrix (G and D almost proportional), but that incorporating information from molecular markers (multivariate Q(st)-F(st)) allows disentangling the two effects.

PFO closure vs. medical therapy in cryptogenic stroke or transient ischemic attack: A systematic review and meta-analysis.

BACKGROUND/OBJECTIVES: This study aims to assess whether patent foramen ovale (PFO) closure is superior to medical therapy in preventing recurrence of cryptogenic ischemic stroke or transient ischemic attack (TIA). METHODS: We searched PubMed for randomized trials which compared PFO closure with medical therapy in cryptogenic stroke/TIA using the items: "stroke or cerebrovascular accident or TIA" and "patent foramen ovale or paradoxical embolism" and "trial or study". RESULTS: Among 650 potentially eligible articles, 3 were included including 2303 patients. There was no statistically significant difference between PFO-closure and medical therapy in ischemic stroke recurrence (1.91% vs. 2.94% respectively, OR: 0.64, 95%CI: 0.37-1.10), TIA (2.08% vs. 2.42% respectively, OR: 0.87, 95%CI: 0.50-1.51) and death (0.60% vs. 0.86% respectively, OR: 0.71, 95%CI: 0.28-1.82). In subgroup analysis, there was significant reduction of ischemic strokes in the AMPLATZER PFO Occluder arm vs. medical therapy (1.4% vs. 3.04% respectively, OR: 0.46, 95%CI: 0.21-0.98, relative-risk-reduction: 53.2%, absolute-risk-reduction: 1.6%, number-needed-to-treat: 61.8) but not in the STARFlex device (2.7% vs. 2.8% with medical therapy, OR: 0.93, 95%CI: 0.45-2.11). Compared to medical therapy, the number of patients with new-onset atrial fibrillation (AF) was similar in the AMPLATZER PFO Occluder arm (0.72% vs. 1.28% respectively, OR: 1.81, 95%CI: 0.60-5.42) but higher in the STARFlex device (0.64% vs. 5.14% respectively, OR: 8.30, 95%CI: 2.47-27.84). CONCLUSIONS: This meta-analysis does not support PFO closure for secondary prevention with unselected devices in cryptogenic stroke/TIA. In subgroup analysis, selected closure devices may be superior to medical therapy without increasing the risk of new-onset AF, however. This observation should be confirmed in further trials using inclusion criteria for patients with high likelihood of PFO-related stroke recurrence.

Training medical students to conduct motivational interviewing: a randomized controlled trial.

OBJECTIVE: To examine the effectiveness of motivational interviewing (MI) training among medical students. METHODS: All students (n=131) (year 5) at Lausanne Medical School, Switzerland were randomized into an experimental or a control group. After a training in basic communication skills (control condition), an 8-h MI training was completed by 84.8% students in the exprimental group. One week later, students in both groups were invited to meet with two standardized patients. MI skills were coded by blinded research assistants using the Motivational Interviewing Treatment Integrity 3.0. RESULTS: Superior MI performance was shown for trained versus control students, as demonstrated by higher scores for "Empathy" [p<0.001] and "MI Spirit" [p<0.001]. Scores were similar between groups for "Direction", indicating that students in both groups invited the patient to talk about behavior change. Behavior counts assessment demonstrated better performance in MI in trained versus untrained students regarding occurences of MI-adherent behavior [p<0.001], MI non-adherent behavior [p<0.001], Closed questions [p<0.001], Open questions [p=0.001], simple reflections [p=0.03], and Complex reflections [p<0.001]. Occurrences were similar between groups regarding "Giving information". CONCLUSION: An 8-h training workshop was associated with improved MI performance. PRACTICE IMPLICATIONS: These findings lend support for the implementation of MI training in medical schools.

Wound infection after excision and primary midline closure for pilonidal disease: risk factor analysis to improve patient selection.

BACKGROUND: Excision and primary midline closure for pilonidal disease (PD) is a simple procedure; however, it is frequently complicated by infection and prolonged healing. The aim of this study was to analyze risk factors for surgical site infection (SSI) in this context. METHODS: All consecutive patients undergoing excision and primary closure for PD from January 2002 through October 2008 were retrospectively assessed. The end points were SSI, as defined by the Center for Disease Control, and time to healing. Univariable and multivariable risk factor analyses were performed. RESULTS: One hundred thirty-one patients were included [97 men (74%), median age = 24 (range 15-66) years]. SSI occurred in 41 (31%) patients. Median time to healing was 20 days (range 12-76) in patients without SSI and 62 days (range 20-176) in patients with SSI (P < 0.0001). In univariable and multivariable analyses, smoking [OR = 2.6 (95% CI 1.02, 6.8), P = 0.046] and lack of antibiotic prophylaxis [OR = 5.6 (95% CI 2.5, 14.3), P = 0.001] were significant predictors for SSI. Adjusted for SSI, age over 25 was a significant predictor of prolonged healing. CONCLUSION: This study suggests that the rate of SSI after excision and primary closure of PD is higher in smokers and could be reduced by antibiotic prophylaxis. SSI significantly prolongs healing time, particularly in patients over 25 years.

Selection of patients with germline MLH1 mutated Lynch syndrome by determination of MLH1 methylation and BRAF mutation.

Lynch syndrome is one of the most common hereditary colorectal cancer (CRC) syndrome and is caused by germline mutations of MLH1, MSH2 and more rarely MSH6, PMS2, MLH3 genes. Whereas the absence of MSH2 protein is predictive of Lynch syndrome, it is not the case for the absence of MLH1 protein. The purpose of this study was to develop a sensitive and cost effective algorithm to select Lynch syndrome cases among patients with MLH1 immunohistochemical silencing. Eleven sporadic CRC and 16 Lynch syndrome cases with MLH1 protein abnormalities were selected. The BRAF c.1799T> A mutation (p.Val600Glu) was analyzed by direct sequencing after PCR amplification of exon 15. Methylation of MLH1 promoter was determined by Methylation-Sensitive Single-Strand Conformation Analysis. In patients with Lynch syndrome, there was no BRAF mutation and only one case showed MLH1 methylation (6%). In sporadic CRC, all cases were MLH1 methylated (100%) and 8 out of 11 cases carried the above BRAF mutation (73%) whereas only 3 cases were BRAF wild type (27%). We propose the following algorithm: (1) no further molecular analysis should be performed for CRC exhibiting MLH1 methylation and BRAF mutation, and these cases should be considered as sporadic CRC; (2) CRC with unmethylated MLH1 and negative for BRAF mutation should be considered as Lynch syndrome; and (3) only a small fraction of CRC with MLH1 promoter methylation but negative for BRAF mutation should be true Lynch syndrome patients. These potentially Lynch syndrome patients should be offered genetic counselling before searching for MLH1 gene mutations.

Pervasive positive selection on duplicated and nonduplicated vertebrate protein coding genes.

A stringent branch-site codon model was used to detect positive selection in vertebrate evolution. We show that the test is robust to the large evolutionary distances involved. Positive selection was detected in 77% of 884 genes studied. Most positive selection concerns a few sites on a single branch of the phylogenetic tree: Between 0.9% and 4.7% of sites are affected by positive selection depending on the branches. No functional category was overrepresented among genes under positive selection. Surprisingly, whole genome duplication had no effect on the prevalence of positive selection, whether the fish-specific genome duplication or the two rounds at the origin of vertebrates. Thus positive selection has not been limited to a few gene classes, or to specific evolutionary events such as duplication, but has been pervasive during vertebrate evolution.

Trends of pre-hospital emergency medical services activity over 10 years : a population-based registry analysis

BACKGROUND: The number of requests to pre-hospital emergency medical services (PEMS) has increased in Europe over the last 20 years, but epidemiology of PEMS interventions has little be investigated. The aim of this analysis was to describe time trends of PEMS activity in a region of western Switzerland. METHODS: Use of data routinely and prospectively collected for PEMS intervention in the Canton of Vaud, Switzerland, from 2001 to 2010. This Swiss Canton comprises approximately 10% of the whole Swiss population. RESULTS: We observed a 40% increase in the number of requests to PEMS between 2001 and 2010. The overall rate of requests was 35/1000 inhabitants for ambulance services and 10/1000 for medical interventions (SMUR), with the highest rate among people aged ≥ 80. Most frequent reasons for the intervention were related to medical problems, predominantly unconsciousness, chest pain respiratory distress, or cardiac arrest, whereas severe trauma interventions decreased over time. Overall, 89% were alive after 48 h. The survival rate after 48 h increased regularly for cardiac arrest or myocardial infarction. CONCLUSION: Routine prospective data collection of prehospital emergency interventions and monitoring of activity was feasible over time. The results we found add to the understanding of determinants of PEMS use and need to be considered to plan use of emergency health services in the near future. More comprehensive analysis of the quality of services and patient safety supported by indicators are also required, which might help to develop prehospital emergency services and new processes of care.