Framingham risk score and alternatives for prediction of coronary heart disease in older adults.

BACKGROUND: Guidelines for the prevention of coronary heart disease (CHD) recommend use of Framingham-based risk scores that were developed in white middle-aged populations. It remains unclear whether and how CHD risk prediction might be improved among older adults. We aimed to compare the prognostic performance of the Framingham risk score (FRS), directly and after recalibration, with refit functions derived from the present cohort, as well as to assess the utility of adding other routinely available risk parameters to FRS.¦METHODS: Among 2193 black and white older adults (mean age, 73.5 years) without pre-existing cardiovascular disease from the Health ABC cohort, we examined adjudicated CHD events, defined as incident myocardial infarction, CHD death, and hospitalization for angina or coronary revascularization.¦RESULTS: During 8-year follow-up, 351 participants experienced CHD events. The FRS poorly discriminated between persons who experienced CHD events vs. not (C-index: 0.577 in women; 0.583 in men) and underestimated absolute risk prediction by 51% in women and 8% in men. Recalibration of the FRS improved absolute risk prediction, particulary for women. For both genders, refitting these functions substantially improved absolute risk prediction, with similar discrimination to the FRS. Results did not differ between whites and blacks. The addition of lifestyle variables, waist circumference and creatinine did not improve risk prediction beyond risk factors of the FRS.¦CONCLUSIONS: The FRS underestimates CHD risk in older adults, particularly in women, although traditional risk factors remain the best predictors of CHD. Re-estimated risk functions using these factors improve accurate estimation of absolute risk.

Towards a system analysis of the early steps of infectious endocarditis pathogenesis

L'endocardite infectieuse (EI) est une maladie potentiellement mortelle qui doit être prévenue dans toute la mesure du possible. Au cours de ces dernières 50 années, les recommandations Américaines et Européennes pour la prophylaxie de PEI proposaient aux patients à risques de prendre un antibiotique, préventif avant de subir une intervention médico-chirurgicale susceptible d'induire une bactériémie transitoire. Cependant, des études épidémiologiques récentes ont montré que la plupart des EI survenaient en dehors de tous actes médico-chirurgicaux, et indépendamment de la prise ou non de prophylaxie antibiotique . L'EI pourrait donc survenir suite à la cumulation de bactériémies spontanées de faibles intensités, associées à des activités de la vie courante telle que le brossage dentaire pour le streptocoques, ou à partir de tissus colonisés ou de cathéters infectés pour les staphylocoques. En conséquence, les recommandations internationales pour la prophylaxie de PEI ont été revues et proposent une diminution drastique de l'utilisation d'antibiotiques. Cependant, le risque d'EI représenté par le cumul de bactériémies de faibles intensités n'a pas été démontré expérimentalement. Nous avons développé un nouveau modèle d'EI expérimentale induite par une inoculation en continu d'une faible quantité de bactéries, simulant le cumul de bactériémies de faibles intensités chez l'homme, et comparé l'infection de Streptococcus gordonii et de Staphylococcus aureus dans ce modèle avec celle du modèle d'IE induite par une bactériémie brève, mais de forte intensité. Nous avons démontré, après injection d'une quantité égale de bactéries, que le nombre de végétations infectées était similaire dans les deux types d'inoculations. Ces résultats expérimentaux ont confirmé l'hypothèse qu'une exposition cumulée à des bactériémies de faibles intensités, en dehors d'une procédure médico-chirurgicale, représentait un risque pour le développement d'une El, comme le suggéraient les études épidémiologiques. En plus, ces résultats ont validé les nouvelles recommandations pour la prophylaxie de l'El, limitant drastiquement l'utilisation d'antibiotiques. Cependant, ces nouvelles recommandations laissent une grande partie (> 90%) de cas potentiels d'EI sans alternatives de préventions, et des nouvelles stratégies prophylactiques doivent être investiguées. Le nouveau modèle d'EI expérimentale représente un modèle réaliste pour étudier des nouvelles mesures prophylactiques potentielles appliquées à des expositions cumulées de bactériémies de faible nombre. Dans un contexte de bactériémies spontanées répétitives, les antibiotiques ne peuvent pas résoudre le problème de la prévention de l'EI. Nous avons donc étudié la une alternative de prévention par l'utilisation d'agents antiplaquettaires. La logique derrière cette approche était basée sur le fait que les plaquettes sont des composants clés dans la formation des végétations cardiaques, et le fait que les bactéries capables d'interagir avec les plaquettes sont plus enclines à induire une El. Les agents antiplaquettaires utilisés ont été l'aspirine (inhibiteur du COX1), la ticlopidine (inhibiteur du P2Y12, le récepteur de l'ADP), et l'eptifibatide et Pabciximab, deux inhibiteurs du GPIIb/IIIa, le récepteur plaquettaire pour le fibrinogène. Les anticoagulants étaient le dabigatran etexilate, inhibant lathrombine et l'acenocumarol, un antagoniste de la vitamine K. L'aspirine, la ticlopidine ou l'eptifibatide seuls n'ont pas permis de prévenir l'infection valvulaire (> 75% animaux infectés). En revanche, la combinaison d'aspirine et de ticlopidine, aussi bien que l'abciximab, ont protégé 45% - 88% des animaux de l'EI par S. gordonii et par S. aureus. L'antithrombotique dabigatran etexilate à protégé 75% des rats contre l'EI par S. aureus, mais pas (< 30% de protection) par S. gordonii. L'acenocoumarol n'a pas eu d'effet sur aucun des deux organismes. En général, ces résultats suggèrent un possible rôle pour les antiplaquettaires et du dabigatran etexilate dans la prophylaxie de l'EI dans un contexte de bactériémies récurrentes de faibles intensités. Cependant, l'effet bénéfique des antiplaquettaires doit être soupesé avec le risque d'hémorragie inhérent à ces molécules, et le fait que les plaquettes jouent un important rôle dans les défenses de l'hôte contre les infections endovasculaires. En plus, le double effet bénéfique du dabigatran etexilate devrait être revu chez les patients porteurs de valves prothétiques, qui ont besoin d'une anticoagulation à vie, et chez lesquels l'EI à S. aureus est associée avec une mortalité de près de 50%. Comme l'approche avec des antiplaquettaires et des antithrombotiques pourrait avoir des limites, une autre stratégie prophylactique pourrait être la vaccination contre des adhésines de surfaces des pathogènes. Chez S. aureus, la protéine de liaison au fibrinogène, ou dumping factor A (ClfA), et la protéine de liaison à la fibronectine (FnbpA) sont des facteurs de virulence nécessaires à l'initiation et l'évolution de PEI. Elles représentent donc des cibles potentielles pour le développement de vaccins contre cette infection. Récemment, des nombreuses publications ont décrit que la bactérie Lactococcus lactis pouvait être utilisée comme vecteur pour la diffusion d'antigènes bactériens in vivo, et que cette approche pourrait être une stratégie de vaccination contre les infections bactériennes. Nous avons exploré l'effet de l'immunisation par des recombinant de L. lactis exprimant le ClfA, la FnbpA, ou le ClfA ensemble avec et une forme tronquée de la FnbpA (Fnbp, comprenant seulement le domaine de liaison à la fibronectine mais sans le domaine A de liaison au fibrinogène [L. lactis ClfA/Fnbp]), dans la prophylaxie de PIE expérimentale à S. aureus. L. lactis ClfA a été utilisés comme agent d'immunisation contre la souche S. aureus Newman (qui a particularité de n'exprimer que le ClfA, mais pas la FnbpA). L. lactis ClfA, L. lactis FnbpA, et L. lactis ClfA/Fnbp, ont été utilisé comme agents d'immunisation contre une souche isolée d'une IE, S. aureus P8 (exprimant ClfA et FnbpA). L'immunisation avec L. lactis ClfA a généré des anticorps anti-ClfA fonctionnels, capables de bloquer la liaison de S. aureus Newman au fibrinogène in vitro et protéger 13/19 (69%) animaux d'une El due à S. aureus Newman (P < 0.05 comparée aux contrôles). L'immunisation avec L. lactis ClfA, L. lactis FnbpA, ou L. lactis ClfA/Fnbp, a généré des anticorps contre chacun de ces antigènes. Cependant, ils n'ont pas permis de bloquer l'adhésion de S. aureus P8 au fibrinogène et à la fibronectine in vitro. De plus, l'immunisation avec L. lactis ClfA ou L. lactis FnbpA s'est avérée inefficace in vivo (< 10% d'animaux protégés d'une El) et l'immunisation avec L. lactis ClfA/Fnbp a fourni une protection limitée de l'EI (8/23 animaux protégés; P < 0.05 comparée aux contrôles) après inoculation avec S. aureus P8. Dans l'ensemble, ces résultats indiquent que L. lactis est un système efficace pour la présentation d'antigènes in vivo et potentiellement utile pour la prévention de PEI à S. aureus. Cependant, le répertoire de protéines de surface de S. aureus capable d'évoquer une panoplie d'anticorps efficace reste à déterminer.. En résumé, notre étude a démontré expérimentalement, pour la première fois, qu'une bactériémie répétée de faible intensité, simulant la bactériémie ayant lieu, par exemple, lors des activités de la vie quotidienne, est induire un taux d'EI expérimentale similaire à celle induite par une bactériémie de haute intensité suite à une intervention médicale. Dans ce contexte, où l'utilisation d'antibiotiques est pas raisonnable, nous avons aussi montré que d'autres mesures prophylactiques, comme l'utilisation d'agents antiplaquettaires ou antithrombotiques, ou la vaccination utilisant L. lactis comme vecteur d'antigènes bactériens, sont des alternatives prometteuses qui méritent d'être étudiées plus avant. Thesis Summary Infective endocarditis (IE) is a life-threatening disease that should be prevented whenever possible. Over the last 50 years, guidelines for IE prophylaxis proposed the use of antibiotics in patients undergoing dental or medico-surgical procedures that might induce high, but transient bacteremia. However, recent epidemiological studies indicate that IE occurs independently of medico-surgical procedures and the fact that patients had taken antibiotic prophylaxis or not, i.e., by cumulative exposure to random low-grade bacteremia, associated with daily activities (e.g. tooth brushing) in the case of oral streptococci, or with a colonized site or infected device in the case of staphylococci. Accordingly, the most recent American and European guidelines for IE prophylaxis were revisited and updated to drastically restrain antibiotic use. Nevertheless, the relative risk of IE represented by such cumulative low-grade bacteremia had never been demonstrated experimentally. We developed a new model of experimental IE due to continuous inoculation of low-grade bacteremia, mimicking repeated low-grade bacteremia in humans, and compared the infectivity of Streptococcus gordonii and Staphylococcus aureus in this model to that in the model producing brief, high-level bacteremia. We demonstrated that, after injection of identical bacterial numbers, the rate of infected vegetations was similar in both types of challenge. These experimental results support the hypothesis that cumulative exposure to low-grade bacteremia, outside the context of procedure-related bacteremia, represents a genuine risk of IE, as suggested by human epidemiological studies. In addition, they validate the newer guidelines for IE prophylaxis, which drastic limit the procedures in which antibiotic prophylaxis is indicated. Nevertheless, these refreshed guidelines leave the vast majority (> 90%) of potential IE cases without alternative propositions of prevention, and novel strategies must be considered to propose effective alternative and "global" measures to prevent IE initiation. The more realistic experimental model of IE induced by low-grade bacteremia provides an accurate experimental setting to study new preventive measures applying to cumulative exposure to low bacterial numbers. Since in a context of spontaneous low-grade bacteremia antibiotics are unlikely to solve the problem of IE prevention, we addressed the role of antiplatelet and anticoagulant agents for the prophylaxis of experimental IE induced by S. gordonii and S. aureus. The logic of this approach was based on the fact that platelets are key players in vegetation formation and vegetation enlargement, and on the fact that bacteria capable of interacting with platelets are more prone to induce IE. Antiplatelet agents included the COX1 inhibitor aspirin, the inhibitor of the ADP receptor P2Y12 ticlopidine, and two inhibitors of the platelet fibrinogen receptor GPIIb/IIIa, eptifibatide and abciximab. Anticoagulants included the thrombin inhibitor dabigatran etexilate and the vitamin K antagonist acenocoumarol. Aspirin, ticlopidine or eptifibatide alone failed to prevent aortic infection (> 75% infected animals). In contrast, the combination of aspirin with ticlopidine, as well as abciximab, protected 45% to 88% of animals against IE due to S. gordonii and S. aureus. The antithrombin dabigatran etexilate protected 75% of rats against IE due to S. aureus, but failed (< 30% protection) against S. gordonii. Acenocoumarol had no effect against any bacteria. Overall, these results suggest a possible role for antiplatelet agents and dabigatran etexilate in the prophylaxis of IE in humans in a context of recurrent low- grade bacteremia. However, the potential beneficial effect of antiplatelet agents should be balanced against the risk of bleeding and the fact that platelets play an important role in the host defenses against intravascular infections. In addition, the potential dual benefit of dabigatran etexilate might be revisited in patients with prosthetic valves, who require life-long anticoagulation and in whom S. aureus IE is associated with high mortality rate. Because the antiplatelet and anticoagulant approach might be limited in the context of S. aureus bacteremia, other prophylactic strategies for the prevention of S. aureus IE, like vaccination with anti-adhesion proteins was tested. The S. aureus surface proteins fibrinogen-binding protein clumping-factor A (ClfA) and the fibronectin-binding protein A (FnbpA) are critical virulence factors for the initiation and development of IE. Thus, they represent key targets for vaccine development against this disease. Recently, numerous reports have described that the harmless bacteria Lactococcus lactis can be used as a bacterial vector for the efficient delivery of antigens in vivo, and that this approach is a promising vaccination strategy against bacterial infections. We therefore explored the immunization capacity of non- living recombinant L. lactis ClfA, L. lactis FnbpA, or L. lactis expressing ClfA together with Fnbp (a truncated form of FnbpA with only the fibronectin-binding domain but lacking the fibrinogen-binding domain A [L. lactis ClfA/Fnbp]), to protect against S. aureus experimental IE. L. lactis ClfA was used as immunization agent against the laboratory strain S. aureus Newman (expressing ClfA, but lacking FnbpA). L. lactis ClfA, L. lactis FnbpA, as well as L. lactis ClfA/Fnbp, were used as immunization agents against the endocarditis isolate S. aureus P8 (expressing both ClfA and FnbpA). Immunization with L. lactis ClfA produced anti-ClfA functional antibodies, which were able to block the binding of S. aureus Newman to fibrinogen in vitro and protect 13/19 (69%) animals from IE due to S. aureus Newman (P < 0.05 compared to controls). Immunization with L. lactis ClfA, L. lactis FnbpA or L. lactis ClfA/Fnbp, produced antibodies against each antigen. However, they were not sufficient to block S. aureus P8 binding to fibrinogen and fibronectin in vitro. Moreover, immunization with L. lactis ClfA or L. lactis FnbpA was ineffective (< 10% protected animals) and immunization with L. lactis ClfA/Fnbp conferred limited protection from IE (8/23 protected animals; P < 0.05 compared to controls) after challenge with S. aureus P8. Together, these results indicate that L. lactis is an efficient delivering antigen system potentially useful for preventing S. aureus IE. They also demonstrate that expressing multiple antigens in L. lactis, yet to be elucidated, will be necessary to prevent IE due to clinical S. aureus strains fully equipped with virulence determinants. In summary, our study has demonstrated experimentally, for the first time, the hypothesis that low-grade bacteremia, mimicking bacteremia occurring outside of a clinical intervention, is equally prone to induce experimental IE as high-grade bacteremia following medico-surgical procedures. In this context, where the use of antibiotics for the prophylaxis of IE is limited, we showed that other prophylactic measures, like the use of antiplatelets, anticoagulants, or vaccination employing L. lactis as delivery vector of bacterial antigens, are reasonable alternatives that warrant to be further investigated.

Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts.

BACKGROUND: American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. METHODS AND RESULTS: We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. CONCLUSION: Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.

O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.

Alpha-dystroglycan (alpha-DG) is a cell-surface glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains and certain arenaviruses. Receptor binding is thought to be mediated by a posttranslational modification, and defective binding with laminin underlies a subclass of congenital muscular dystrophy. Using mass spectrometry- and nuclear magnetic resonance (NMR)-based structural analyses, we identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. We demonstrated that patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the like-acetylglucosaminyltransferase (LARGE) protein. These findings expand our understanding of the mechanisms that underlie congenital muscular dystrophy.

A positive interaction between inhibitors of protein synthesis and cefepime in the fight against methicillin-resistant Staphylococcus aureus.

Quinupristin-dalfopristin (Q-D) synergizes with cefepime for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). Here, we studied whether the synergism was restricted to MRSA and if it extended to non-beta-lactam cell wall inhibitors or to other inhibitors of protein synthesis. Three MRSA and two methicillin-susceptible S. aureus (MSSA) strains were tested, including an isogenic pair of mecA (-)/mecA (+) S. aureus Newman. The drug interactions were determined by fractional inhibitory concentration (FIC) indices and population analysis profiles. The antibacterial drugs that we used included beta-lactam (cefepime) and non-beta-lactam cell wall inhibitors (D-cycloserine, fosfomycin, vancomycin, teicoplanin), inhibitors of protein synthesis (Q-D, erythromycin, chloramphenicol, tetracycline, linezolid, fusidic acid), and polynucleotide inhibitors (cotrimoxazole, ciprofloxacin). The addition of each protein inhibitor to cefepime was synergistic (FIC ≤ 0.5) or additive (FIC > 0.5 but < 1) against MRSA, but mostly indifferent against MSSA (FIC ≥ 1 but ≤ 4). This segregation was not observed after adding cotrimoxazole or ciprofloxacin to cefepime. Population analysis profiles were performed on plates in the presence of increasing concentrations of the cell wall inhibitors plus 0.25 × minimum inhibitory concentration (MIC) of Q-D. Cefepime combined with Q-D was synergistic against MRSA, but D-cycloserine and glycopeptides were not. Thus, the synergism was specific to beta-lactam antibiotics. Moreover, the synergism was not lost against fem mutants, indicating that it acted at another level. The restriction of the beneficial effect to MRSA suggests that the functionality of penicillin-binding protein 2A (PBP2A) was affected, either directly or indirectly. Further studies are necessary in order to provide a mechanism for this positive interaction.

Epidemiology of incident heart failure in a contemporary elderly cohort: the health, aging, and body composition study.

BACKGROUND: The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described. METHODS: We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF. RESULTS: During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P < .001). CONCLUSIONS: Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts.

Cost-effectiveness of opportunistic versus organised mammography screening in Switzerland

BACKGROUND: Various centralised mammography screening programmes have shown to reduce breast cancer mortality at reasonable costs. However, mammography screening is not necessarily cost-effective in every situation. Opportunistic screening, the predominant screening modality in several European countries, may under certain circumstances be a cost-effective alternative. In this study, we compared the cost-effectiveness of both screening modalities in Switzerland. METHODS: Using micro-simulation modelling, we predicted the effects and costs of biennial mammography screening for 50-69 years old women between 1999 and 2020, in the Swiss female population aged 30-70 in 1999. A sensitivity analysis on the test sensitivity of opportunistic screening was performed. RESULTS: Organised mammography screening with an 80% participation rate yielded a breast cancer mortality reduction of 13%. Twenty years after the start of screening, the predicted annual breast cancer mortality was 25% lower than in a situation without screening. The 3% discounted cost-effectiveness ratio of organised mammography screening was euro11,512 per life year gained. Opportunistic screening with a similar participation rate was comparably effective, but at twice the costs: euro22,671-24,707 per life year gained. This was mainly related to the high costs of opportunistic mammography and frequent use of imaging diagnostics in combination with an opportunistic mammogram. CONCLUSION: Although data on the performance of opportunistic screening are limited, both opportunistic and organised mammography screening seem effective in reducing breast cancer mortality in Switzerland. However, for opportunistic screening to become equally cost-effective as organised screening, costs and use of additional diagnostics should be reduced.

Parent perceived quality of life is age-dependent in children with food allergy.

Food allergy in children significantly affects their quality of life. Its impact can be analyzed by quality of life questionnaires. The aim of our study was to validate the French version of disease-specific questionnaires and to evaluate the quality of life in children with IgE-mediated food allergy. Two validated food allergy-specific questionnaires for quality of life, the parent's and children's forms (FAQLQ-PF and FAQLQ-CF), were translated from English to French and submitted to children with food allergy and their parents. Questionnaires were analyzed in terms of emotional impact, food anxiety, and social and food limitations. NCT 01480427. Sixty-two parents of children aged 0-12 yrs answered the FAQLQ-PF, and 32 children aged 8-12 yrs the FAQLQ-CF. Construct validity of both questionnaires was assessed by correlation between the FAQLQs and FAIM (r = 0.85 and 0.84, respectively). Both FAQLQs had good internal consistency (Cronbach's α = 0.748 and 0.67, respectively). Young children (0-3 yrs old) showed better quality of life scores than older children (FAQLQ-PF global score: p = 0.02). Worse scores were also shown among children with previous severe systemic reactions (FAQLQ-PF global score: p = 0.039), the ones with an allergic mother (FAQLQ-PF global score: p = 0.002), or allergic siblings (FAQLQ-PF emotional impact score: p = 0.034), the ones with multiple food allergy (more than 1 food) (FAQLQ-PF anxiety score: p = 0.04) and among the girls (FAQLQ-CF global score: p = 0.031). Older children, the ones with severe systemic reactions, or with mothers or siblings also affected by allergies, as well as girls, and children with multiple food allergies show worse quality of life scores.

How are "teaching the teachers" courses in evidence based medicine evaluated? A systematic review.

BACKGROUND: Teaching of evidence-based medicine (EBM) has become widespread in medical education. Teaching the teachers (TTT) courses address the increased teaching demand and the need to improve effectiveness of EBM teaching. We conducted a systematic review of assessment tools for EBM TTT courses.To summarise and appraise existing assessment methods for teaching the teachers courses in EBM by a systematic review. METHODS: We searched PubMed, BioMed, EmBase, Cochrane and Eric databases without language restrictions and included articles that assessed its participants. Study selection and data extraction were conducted independently by two reviewers. RESULTS: Of 1230 potentially relevant studies, five papers met the selection criteria. There were no specific assessment tools for evaluating effectiveness of EBM TTT courses. Some of the material available might be useful in initiating the development of such an assessment tool. CONCLUSION: There is a need for the development of educationally sound assessment tools for teaching the teachers courses in EBM, without which it would be impossible to ascertain if such courses have the desired effect.

Markers of atherosclerosis and inflammation for prediction of coronary heart disease in older adults.

Although both inflammatory and atherosclerosis markers have been associated with coronary heart disease (CHD) risk, data directly comparing their predictive value are limited. The authors compared the value of 2 atherosclerosis markers (ankle-arm index (AAI) and aortic pulse wave velocity (aPWV)) and 3 inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)) in predicting CHD events. Among 2,191 adults aged 70-79 years at baseline (1997-1998) from the Health, Aging, and Body Composition Study cohort, the authors examined adjudicated incident myocardial infarction or CHD death ("hard" events) and "hard" events plus hospitalization for angina or coronary revascularization (total CHD events). During 8 years of follow-up between 1997-1998 and June 2007, 351 participants developed total CHD events (197 "hard" events). IL-6 (highest quartile vs. lowest: hazard ratio = 1.82, 95% confidence interval: 1.33, 2.49; P-trend < 0.001) and AAI (AAI </= 0.9 vs. AAI 1.01-1.30: hazard ratio = 1.57, 95% confidence interval: 1.14, 2.18) predicted CHD events above traditional risk factors and modestly improved global measures of predictive accuracy. CRP, TNF-alpha, and aPWV had weaker associations. IL-6 and AAI accurately reclassified 6.6% and 3.3% of participants, respectively (P's </= 0.05). Results were similar for "hard" CHD, with higher reclassification rates for AAI. IL-6 and AAI are associated with future CHD events beyond traditional risk factors and modestly improve risk prediction in older adults.

VARIABILITY OF PHENOTYPIC, PROTEOMIC AND TRANSCRIPTOMIC EXPRESSION OF STAPHYLOCOCCUS AUREUS SURFACE ADHESINS

Staphylococcus aureus is a highly successful pathogen responsible of a wide variety of diseases, from minor skin infection to life-threatening sepsis or infective endocarditis, as well as food poisoning and toxic shock syndrome. This heterogeneity of infections and the ability of S. aureus to develop antibiotic-resistance to virtually any available drugs reflect its extraordinary capacity to adapt and survive in a great variety of environments. The pathogenesis of S. aureus infection involves a wide range of cell wall-associated adhesins and extracellular toxins that promote host colonization and invasion. In addition, S. aureus is extremely well equipped with regulatory systems that sense environmental conditions and respond by fine tuning the expression of metabolic and virulence determinants. Surface adhesins referred to MSCRAMMs - for Microbial Surface Component Recognizing Adherence Matrix Molecules - mediate binding to the host extracellular matrix or serum components, including fibrinogen, fibronectin, collagen and elastin, and promote tissue colonization and invasion. Major MSCRAMMs include a family of surface-attached proteins covalently bound to the cell wall peptidoglycan via a conserved LPXTG motif. Genomic analyses indicate that S. aureus contain up to 22 LPXTG surface proteins, which could potentially act individually or in synergy to promote infection. In the first part of this study we determined the range of adherence phenotypes to fibrinogen and fibronectin among 30 carriage isolates of S. aureus and compared it to the adherence phenotypes of 30 infective endocarditis and 30 blood culture isolates. Overall there were great variations in in vitro adherence, but no differences were observed between carriage and infection strains. We further determined the relation between in vitro adherence and in vivo infectivity in a rat model of experimental endocarditis, using 4 isolates that displayed either extremely low or high adherence phenotypes. Unexpectedly, no differences were observed between the in vivo infectivity of isolates that were poorly and highly adherent in vitro. We concluded that the natural variability of in vitro adherence to fibrinogen and fibronectin did not correlate with in vivo infectivity, and thus that pathogenic differences between various strains might only be expressed in in vivo conditions, but not in vitro. Therefore, considering the importance of adhesins expression for infection, direct measurement of those adhesins present on the bacterial surface were made by proteomic approach. 5 In the second series of experiments we assessed the physical presence of the LPXTG species at the staphylococcal surface, as measured at various time points during growth in different culture media. S. aureus Newman was grown in either tryptic soy broth (TSB) or in Roswell Park Memorial Institute (RPMI) culture medium, and samples were removed from early exponential growth phase to late stationary phase. Experiments were performed with mutants in the global accessory-gene regulator (agr), surface protein A (Spa) and clumping factor A (ClfA). Peptides of surface proteins were recovered by "trypsin-shaving" of live bacteria, and semi-quantitative proteomic analysis was performed by tandem liquid-chromatography and mass-spectrometry (LC-MS). We also determined in parallel the mRNA expression by microarrays analysis, as well as the phenotypic adherence of the bacteria to fibrinogen in vitro. The surface proteome was highly complex and contained numerous proteins theoretically not belonging to the bacterial envelope, including ribosomal proteins and metabolic enzymes. Sixteen of the 21 known LPXTG species were detected, but were differentially expressed. As expected, 9 known agr-regulated proteins (e.g. including Spa, FnBPA, ClfA, IsdA, IsdB, SasH, SasD, SasG and FmtB) increased up to the late exponential growth phase, and were abrogated in agr-negative mutants. However, only Spa and SasH modified their proteomic and mRNA profiles in parallel in the parent and its agr negative mutant, while all other LPXTG proteins modified their proteomic profiles independently of their mRNA. Moreover, ClfA became highly transcribed and active in in vitro fibrinogen adherence tests during late growth (24h), whereas it remained poorly detected by proteomics. Differential expression was also detected in iron-rich TSB versus iron-poor RPMI. Proteins from the iron-regulated surface determinant (isd) system, including IsdA, IsdB and IsdH were barely expressed in iron-rich TSB, whereas they increased their expression by >10 time in iron-poor RPMI. We conclude that semi-quantitative proteomic analysis of specific protein species is feasible in S. aureus and that proteomic, transcriptomic and adherence phenotypes demonstrated differential profiles in S. aureus. Furthermore, peptide signatures released by trypsin shaving suggested differential protein domain exposures in various environments, which might be relevant for antiadhesins vaccines. A comprehensive understanding of the S. aureus physiology should integrate all these approaches.

Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study.

OBJECTIVES: The purpose of this study was to evaluate the association between inflammation and heart failure (HF) risk in older adults. BACKGROUND: Inflammation is associated with HF risk factors and also directly affects myocardial function. METHODS: The association of baseline serum concentrations of interleukin (IL)-6, tumor necrosis factor-alpha, and C-reactive protein (CRP) with incident HF was assessed with Cox models among 2,610 older persons without prevalent HF enrolled in the Health ABC (Health, Aging, and Body Composition) study (age 73.6 +/- 2.9 years; 48.3% men; 59.6% white). RESULTS: During follow-up (median 9.4 years), HF developed in 311 (11.9%) participants. In models controlling for clinical characteristics, ankle-arm index, and incident coronary heart disease, doubling of IL-6, tumor necrosis factor-alpha, and CRP concentrations was associated with 29% (95% confidence interval: 13% to 47%; p < 0.001), 46% (95% confidence interval: 17% to 84%; p = 0.001), and 9% (95% confidence interval: -1% to 24%; p = 0.087) increase in HF risk, respectively. In models including all 3 markers, IL-6, and tumor necrosis factor-alpha, but not CRP, remained significant. These associations were similar across sex and race and persisted in models accounting for death as a competing event. Post-HF ejection fraction was available in 239 (76.8%) cases; inflammatory markers had stronger association with HF with preserved ejection fraction. Repeat IL-6 and CRP determinations at 1-year follow-up did not provide incremental information. Addition of IL-6 to the clinical Health ABC HF model improved model discrimination (C index from 0.717 to 0.734; p = 0.001) and fit (decreased Bayes information criterion by 17.8; p < 0.001). CONCLUSIONS: Inflammatory markers are associated with HF risk among older adults and may improve HF risk stratification.