Hôpital Dupuytren

New data on the epidemiology of peripheral artery disease (PAD) are available, and they should be integrated with previous data. We provide an updated, integrated overview of the epidemiology of PAD, a focused literature review was conducted on the epidemiology of PAD. The PAD results were grouped into symptoms, diagnosis, prevalence, and incidence both in the United States and globally, risk factors, progression, coprevalence with other atherosclerotic disease, and association with incident cardiovascular morbidity and mortality. The most common symptom of PAD is intermittent claudication, but noninvasive measures, such as the ankle-brachial index, show that asymptomatic PAD is several times more common in the population than intermittent claudication. PAD prevalence and incidence are both sharply age-related, rising >10% among patients in their 60s and 70s. With aging of the global population, it seems likely that PAD will be increasingly common in the future. Prevalence seems to be higher among men than women for more severe or symptomatic disease. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease, with some differences in the relative importance of factors. Smoking is a particularly strong risk factor for PAD, as is diabetes mellitus, and several newer risk markers have shown independent associations with PAD. PAD is strongly associated with concomitant coronary and cerebrovascular diseases. After adjustment for known cardiovascular disease risk factors, PAD is associated with an increased risk of incident coronary and cerebrovascular disease morbidity and mortality.

International audience

We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.

BACKGROUND: Transcatheter aortic-valve implantation (TAVI) is an emerging intervention for the treatment of high-risk patients with severe aortic stenosis and coexisting illnesses. We report the results of a prospective multicenter study of the French national transcatheter aortic-valve implantation registry, FRANCE 2. METHODS: All TAVIs performed in France, as listed in the FRANCE 2 registry, were prospectively included in the study. The primary end point was death from any cause. RESULTS: A total of 3195 patients were enrolled between January 2010 and October 2011 at 34 centers. The mean (±SD) age was 82.7±7.2 years; 49% of the patients were women. All patients were highly symptomatic and were at high surgical risk for aortic-valve replacement. Edwards SAPIEN and Medtronic CoreValve devices were implanted in 66.9% and 33.1% of patients, respectively. Approaches were either transarterial (transfemoral, 74.6%; subclavian, 5.8%; and other, 1.8%) or transapical (17.8%). The procedural success rate was 96.9%. Rates of death at 30 days and 1 year were 9.7% and 24.0%, respectively. At 1 year, the incidence of stroke was 4.1%, and the incidence of periprosthetic aortic regurgitation was 64.5%. In a multivariate model, a higher logistic risk score on the European System for Cardiac Operative Risk Evaluation (EuroSCORE), New York Heart Association functional class III or IV symptoms, the use of a transapical TAVI approach, and a higher amount of periprosthetic regurgitation were significantly associated with reduced survival. CONCLUSIONS: This prospective registry study reflected real-life TAVI experience in high-risk elderly patients with aortic stenosis, in whom TAVI appeared to be a reasonable option. (Funded by Edwards Lifesciences and Medtronic.).

Churg-Strauss syndrome (CSS) is a systemic vasculitis characterized by the presence of asthma, hypereosinophilia, and necrotizing vasculitis with extravascular eosinophil granulomas. In this retrospective study of 96 patients between 1963 and 1995, we analyzed clinical manifestations, identified prognostic factors, and assessed the long-term outcome. CSS was diagnosed when asthma, hypereosinophilia > 1,500/mm3 or > 10%, and clinical manifestations consistent with systemic vasculitis, with or without histologic evidence, were present. Asthma was the most frequently observed manifestation at presentation, with mononeuritis multiplex the second. Other common manifestations were weight loss, fever, myalgia, skin involvement, paranasal sinusitis, arthralgia, pulmonary infiltrate, and gastrointestinal involvement. Mean eosinophilia at presentation was 7.193 +/- 6.706/mm3; ANCA, present in 20 of 42 (47.6%) patients, predominantly gave the perinuclear labeling pattern. All the patients were treated with corticosteroids alone or in combination with cyclophosphamide or plasma exchanges. Clinical remission was obtained in 91.5%; 22 (25.6%) patients relapsed. Twenty-three patients died during follow-up: 11 of these deaths were directly due to vasculitis. The presence of severe gastrointestinal tract or myocardial involvement was significantly associated with a poor clinical outcome. The long-term prognosis of CSS is good and does not differ from that of polyarteritis nodosa, although most patients need low doses of oral corticosteroids for persistent asthma, even many years after clinical recovery from vasculitis.

BACKGROUND: The Direct Repeat locus of the Mycobacterium tuberculosis complex (MTC) is a member of the CRISPR (Clustered regularly interspaced short palindromic repeats) sequences family. Spoligotyping is the widely used PCR-based reverse-hybridization blotting technique that assays the genetic diversity of this locus and is useful both for clinical laboratory, molecular epidemiology, evolutionary and population genetics. It is easy, robust, cheap, and produces highly diverse portable numerical results, as the result of the combination of (1) Unique Events Polymorphism (UEP) (2) Insertion-Sequence-mediated genetic recombination. Genetic convergence, although rare, was also previously demonstrated. Three previous international spoligotype databases had partly revealed the global and local geographical structures of MTC bacilli populations, however, there was a need for the release of a new, more representative and extended, international spoligotyping database. RESULTS: The fourth international spoligotyping database, SpolDB4, describes 1939 shared-types (STs) representative of a total of 39,295 strains from 122 countries, which are tentatively classified into 62 clades/lineages using a mixed expert-based and bioinformatical approach. The SpolDB4 update adds 26 new potentially phylogeographically-specific MTC genotype families. It provides a clearer picture of the current MTC genomes diversity as well as on the relationships between the genetic attributes investigated (spoligotypes) and the infra-species classification and evolutionary history of the species. Indeed, an independent Naïve-Bayes mixture-model analysis has validated main of the previous supervised SpolDB3 classification results, confirming the usefulness of both supervised and unsupervised models as an approach to understand MTC population structure. Updated results on the epidemiological status of spoligotypes, as well as genetic prevalence maps on six main lineages are also shown. Our results suggests the existence of fine geographical genetic clines within MTC populations, that could mirror the passed and present Homo sapiens sapiens demographical and mycobacterial co-evolutionary history whose structure could be further reconstructed and modelled, thereby providing a large-scale conceptual framework of the global TB Epidemiologic Network. CONCLUSION: Our results broaden the knowledge of the global phylogeography of the MTC complex. SpolDB4 should be a very useful tool to better define the identity of a given MTC clinical isolate, and to better analyze the links between its current spreading and previous evolutionary history. The building and mining of extended MTC polymorphic genetic databases is in progress.

BACKGROUND: Targeted temperature management is recommended for patients after cardiac arrest, but the supporting evidence is of low certainty. METHODS: In an open-label trial with blinded assessment of outcomes, we randomly assigned 1900 adults with coma who had had an out-of-hospital cardiac arrest of presumed cardiac or unknown cause to undergo targeted hypothermia at 33°C, followed by controlled rewarming, or targeted normothermia with early treatment of fever (body temperature, ≥37.8°C). The primary outcome was death from any cause at 6 months. Secondary outcomes included functional outcome at 6 months as assessed with the modified Rankin scale. Prespecified subgroups were defined according to sex, age, initial cardiac rhythm, time to return of spontaneous circulation, and presence or absence of shock on admission. Prespecified adverse events were pneumonia, sepsis, bleeding, arrhythmia resulting in hemodynamic compromise, and skin complications related to the temperature management device. RESULTS: A total of 1850 patients were evaluated for the primary outcome. At 6 months, 465 of 925 patients (50%) in the hypothermia group had died, as compared with 446 of 925 (48%) in the normothermia group (relative risk with hypothermia, 1.04; 95% confidence interval [CI], 0.94 to 1.14; P = 0.37). Of the 1747 patients in whom the functional outcome was assessed, 488 of 881 (55%) in the hypothermia group had moderately severe disability or worse (modified Rankin scale score ≥4), as compared with 479 of 866 (55%) in the normothermia group (relative risk with hypothermia, 1.00; 95% CI, 0.92 to 1.09). Outcomes were consistent in the prespecified subgroups. Arrhythmia resulting in hemodynamic compromise was more common in the hypothermia group than in the normothermia group (24% vs. 17%, P<0.001). The incidence of other adverse events did not differ significantly between the two groups. CONCLUSIONS: In patients with coma after out-of-hospital cardiac arrest, targeted hypothermia did not lead to a lower incidence of death by 6 months than targeted normothermia. (Funded by the Swedish Research Council and others; TTM2 ClinicalTrials.gov number, NCT02908308.).

The Sequential Organ Failure Assessment or SOFA score was developed to assess the acute morbidity of critical illness at a population level and has been widely validated as a tool for this purpose across a range of healthcare settings and environments.In recent years, the SOFA score has become extensively used in a range of other applications. A change in the SOFA score of 2 or more is now a defining characteristic of the sepsis syndrome, and the European Medicines Agency has accepted that a change in the SOFA score is an acceptable surrogate marker of efficacy in exploratory trials of novel therapeutic agents in sepsis. The requirement to detect modest serial changes in a patients' SOFA score therefore means that increased clarity on how the score should be assessed in different circumstances is required.This review explores the development of the SOFA score, its applications and the challenges associated with measurement. In addition, it proposes guidance designed to facilitate the consistent and valid assessment of the score in multicentre sepsis trials involving novel therapeutic agents or interventions.ConclusionThe SOFA score is an increasingly important tool in defining both the clinical condition of the individual patient and the response to therapies in the context of clinical trials. Standardisation between different assessors in widespread centres is key to detecting response to treatment if the SOFA score is to be used as an outcome in sepsis clinical trials.

BACKGROUND: In November 2001, the Food and Drug Administration (FDA) approved drotrecogin alfa (activated) (DrotAA) for adults who had severe sepsis and a high risk of death. The FDA required a study to evaluate the efficacy of DrotAA for adults who had severe sepsis and a low risk of death. METHODS: We randomly assigned adult patients with severe sepsis and a low risk of death (defined by an Acute Physiology and Chronic Health Evaluation [APACHE II] score <25 or single-organ failure) to receive an intravenous infusion of placebo or DrotAA (24 microg per kilogram of body weight per hour) for 96 hours in a double-blind, placebo-controlled, multicenter trial. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. In-hospital mortality within 90 days after the start of the infusion was measured, and safety information was collected. RESULTS: Enrollment in the trial was terminated early because of a low likelihood of meeting the prospectively defined objective of demonstrating a significant reduction in the 28-day mortality rate with the use of DrotAA. The study enrolled 2640 patients and collected data on 2613 (1297 in the placebo group and 1316 in the DrotAA group) at the 28-day follow-up. There were no statistically significant differences between the placebo group and the DrotAA group in 28-day mortality (17.0 percent in the placebo group vs. 18.5 percent in the DrotAA group; P=0.34; relative risk, 1.08; 95 percent confidence interval, 0.92 to 1.28) or in in-hospital mortality (20.5 percent vs. 20.6 percent; P=0.98; relative risk, 1.00; 95 percent confidence interval, 0.86 to 1.16). The rate of serious bleeding was greater in the DrotAA group than in the placebo group during both the infusion (2.4 percent vs. 1.2 percent, P=0.02) and the 28-day study period (3.9 percent vs. 2.2 percent, P=0.01). CONCLUSIONS: The absence of a beneficial treatment effect, coupled with an increased incidence of serious bleeding complications, indicates that DrotAA should not be used in patients with severe sepsis who are at low risk for death, such as those with single-organ failure or an APACHE II score less than 25.

AIMS: This European Association Cardiovascular Imaging (EACVI) Expert Consensus document aims at defining the main quantitative information on cardiac structure and function that needs to be included in standard echocardiographic report following recent ASE/EACVI chamber quantification, diastolic function, and heart valve disease recommendations. The document focuses on general reporting and specific pathological conditions such as heart failure, coronary artery and valvular heart disease, cardiomyopathies, and systemic diseases. METHODS AND RESULTS: Demographic data (age, body surface area, blood pressure, and heart rhythm and rate), type (vendor and model) of ultrasound system used and image quality need to be reported. In addition, measurements should be normalized for body size. Reference normal values, derived by ASE/EACVI recommendations, shall always be reported to differentiate normal from pathological conditions. This Expert Consensus document suggests avoiding the surveillance of specific variable using different ultrasound techniques (e.g. in echo labs with high expertise in left ventricular ejection fraction by 3D and not by 2D echocardiography). The report should be also tailored in relation with different cardiac pathologies, quality of images, and needs of the caregivers. CONCLUSION: The conclusion should be concise reflecting the status of left ventricular structure and function, the presence of left atrial and/or aortic dilation, right ventricular dysfunction, and pulmonary hypertension, leading to an objective communication with the patient health caregiver. Variation over time should be considered carefully, taking always into account the consistency of the parameters used for comparison.

IMPORTANCE: Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE: To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS: We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS: Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES: The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS: Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE: Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00334828.

These practice guidelines on the management of arterial hypertension are a concise summary of the more extensive ones prepared by the Task Force jointly appointed by the European Society of Hypertension and the European Society of Cardiology. These guidelines have been prepared on the basis of the best available evidence on all issues deserving recommendations; their role must be educational and not prescriptive or coercive for the management of individual subjects who may differ widely in their personal, medical and cultural characteristics. The members of the Task Force have participated independently in the preparation of these guidelines, drawing on their academic and clinical experience and by objective examination and interpretation of all available literature. A disclosure of their potential conflict of interest is reported on the websites of the ESH and the ESC.

Interferon-alpha (IFN-alpha) is a nonleukemogenic treatment of polycythemia vera (PV) able to induce cytogenetic remissions. Its use is limited by toxicity, leading to treatment discontinuation in approximately 20% of patients. We completed a phase 2 multicenter study of pegylated IFN-alpha-2a in 40 PV patients. Objectives included evaluation of efficacy, safety, and monitoring of residual disease using JAK2V617F quantification (%V617F). Median follow-up was 31.4 months. At 12 months, all 37 evaluable patients had hematologic response, including 94.6% complete responses (CRs). Only 3 patients (8%) had stopped treatment. After the first year, 35 patients remained in hematologic CR, including 5 who had stopped pegylated IFN-alpha-2a. Sequential samples for %V617F monitoring, available in 29 patients, showed %V617F decrease in 26 (89.6%). Median %V617F decreased from 45% before pegylated IFN-alpha-2a to 22.5%, 17.5%, 5%, and 3% after 12, 18, 24, and 36 months, respectively. Molecular CR (JAK2V617F undetectable) was achieved in 7 patients, lasting from 6(+) to 18(+) months, and persisted after pegylated IFN-alpha-2a discontinuation in 5. No vascular event was recorded. These results show that pegylated IFN-alpha-2a yields high rates of hematologic and molecular response in PV with limited toxicity, and could even eliminate the JAK2 mutated clone in selected cases. Available at www.clinicaltrials.gov as #NCT00241241.

Prosthetic heart valve (PHV) dysfunction is rare but potentially life-threatening. Although often challenging, establishing the exact cause of PHV dysfunction is essential to determine the appropriate treatment strategy. In clinical practice, a comprehensive approach that integrates several parameters of valve morphology and function assessed with 2D/3D transthoracic and transoesophageal echocardiography is a key to appropriately detect and quantitate PHV dysfunction. Cinefluoroscopy, multidetector computed tomography, cardiac magnetic resonance imaging, and to a lesser extent, nuclear imaging are complementary tools for the diagnosis and management of PHV complications. The present document provides recommendations for the use of multimodality imaging in the assessment of PHVs.

BACKGROUND AND STUDY AIM: Polyp miss rates during colonoscopy have been calculated in a few tandem or back-to-back colonoscopy studies. Our objective was to assess the adenoma miss rate while limiting technique or operator expertise biases, i. e. by performing a large multicenter study, with same-day back-to-back video colonoscopy, done by two different operators in randomized order and blinded to the other examination. PATIENTS AND METHODS: 294 patients at 11 centers were included. Among the 286 analyzable tandem colonoscopies, miss rates were calculated in both a lesion- and patient-based analysis. Each of these rates was determined for polyps overall, for adenomas, and then for lesions larger than 5 mm, and for advanced adenomas. Univariate and logistic regression analysis were performed to define independent variables associated with missed polyps or adenomas. RESULTS: The miss rates for polyps, adenomas, polyps > or = 5 mm, adenomas > or = 5 mm, and advanced adenomas were, respectively, 28 %, 20 %, 12 %, 9 % and 11 %. None of the masses with a carcinomatous (n = 3) or carcinoid component (n = 1) was missed. The specific lesion miss rates for patients with polyps and adenomas were respectively 36 % and 26 % but the corresponding rates were 23 % and 9.4 % when calculated for all 286 patients. The diameter (1-mm increments) and number of polyps (> or = 3) were independently associated with a lower polyp miss rate, whereas sessile or flat shape and left location were significantly associated with a higher miss rate. Adequacy of cleansing, presence of diverticula, and duration of withdrawal for the first procedure were not associated with adenoma miss rate. CONCLUSIONS: We confirm a significant miss rate for polyps or adenoma during colonoscopy. Detection of flat polyps is an issue that must be focused on to improve the quality of colonoscopy.

We have previously shown that a thickened cell wall is responsible for the vancomycin resistance of vancomycin-resistant Staphylococcus aureus (VRSA) (equivalent to vancomycin-intermediate S. aureus and glycopeptide-intermediate S. aureus) strain Mu50 (L. Cui, H. Murakami, K. Kuwahara-Arai, H. Hanaki, and K. Hiramatsu, Antimicrob. Agents Chemother. 44:2276-2285, 2000). However, the mechanism of vancomycin resistance in other VRSA strains remained unclear. In this study, 16 clinical VRSA strains from seven countries were subjected to serial daily passage in drug-free medium. After 10 to 84 days of passage in the nonselective medium, passage-derived strains with decreased MICs of vancomycin (MIC, <4 mg/liter) were obtained. However, all of the passage-derived strains except one (15 of 16) still possessed subpopulations that were resistant to vancomycin as judged by population analysis, and vancomycin-resistant mutant strains were selected from the passage-derived strains by one-step vancomycin selection with a frequency of 4.25 x 10(-6) to 1.64 x 10(-3). The data indicated that vancomycin-resistant cells are frequently generated from the passage-derived strains even after vancomycin selective pressure is lifted. Cell wall thicknesses and MICs of glycopeptides (vancomycin and teicoplanin) and beta-lactams (imipenem and oxacillin) were determined for a total of 48 strains, including 15 sets of three strains: the clinical VRSA strain, the passage-derived strain, and the vancomycin-resistant mutant strain obtained from the passage-derived strain. No simple correlation between glycopeptide and beta-lactam MICs was seen, while significant correlations between MICs of vancomycin and teicoplanin (r = 0.679; P < 0.001) and between MICs of imipenem and oxacillin (r = 0.787; P < 0.001) were recognized. Moreover, all of the VRSA strains had significantly thickened cell walls, which became thinner with the loss of vancomycin resistance during drug-free passages and again became thick in the resistant mutant strains. The data showed that cell wall thickness had high correlation with the MICs of the two glycopeptides (correlation coefficients, 0.908 for vancomycin and 0.655 for teicoplanin) but not with those of the beta-lactam antibiotics tested. These results together with coupled changes of cell wall thickness and vancomycin MICs in 16 isogenic sets of strains indicate that thickening of the cell wall is a common phenotype of clinical VRSA strains and may be a phenotypic determinant for vancomycin resistance in S. aureus.

BACKGROUND: Common variable immunodeficiency is characterized by recurrent infections and defective immunoglobulin production. METHODS: The DEFI French national study prospectively enrolled adult patients with primary hypogammaglobulinemia. Clinical events before inclusion were retrospectively analyzed at that time. RESULTS: From April 2004 through April 2007, 341 patients were enrolled, 252 of whom had received a diagnosis of common variable immunodeficiency; of those, 110 were male, 142 were female, and 228 were white. The median age at first symptoms was 19 years. The median age at common variable immunodeficiency diagnosis was 33.9 years. The median delay for diagnosis was 15.6 years for the 138 patients with initial symptoms before 1990 and 2.9 years for the 114 patients with initial symptoms from 1990 to the time of the study. The most frequent initial symptoms were upper respiratory tract infections: bronchitis (in 38% of patients), sinusitis (36%), pneumonia (31%), and/or bronchiectasis (14%). Overall, 240 patients had respiratory symptoms. Pneumonia was reported in 147 patients; Streptococcus pneumoniae and Haemophilus influenzae were documented in 46 and 17 cases, respectively. Recurrent or chronic diarrhea was reported in 118 patients. Giardia (35 cases), Salmonella (19), and Campylobacter (19) infections were more frequent in patients with undetectable serum immunoglobulin A (P<.001). Sixteen patients developed opportunistic infections. Persistent infections and requirement for antibiotics despite immunoglobulin substitution correlated with severe defect of memory switched B cells (P=.003) but not with immunoglobulin G trough levels (P=.55). CONCLUSION: Although reduced within the past decade, the delay of diagnosis of common variable immunodeficiency remains unacceptable. Recurrence of upper respiratory tract infection or pneumonia should lead to systematic evaluation of serum immunoglobulin.

BACKGROUND: Nonrheumatic valvular diseases are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease Study 2017, mortality, prevalence, and disability-adjusted life-years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease, and other nonrheumatic valvular diseases were estimated for 195 countries and territories from 1990 to 2017. METHODS: Vital registration data, epidemiologic survey data, and administrative hospital data were used to estimate disease burden using the Global Burden of Disease Study modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimate disease for all countries, because data on nonrheumatic valvular diseases are extremely limited for some regions of the world, such as Sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for both sexes and each 5-year age group, location, and year from 1990 to 2017. RESULTS: Globally, CAVD and degenerative mitral valve disease caused 102 700 (95% uncertainty interval [UI], 82 700-107 900) and 35 700 (95% UI, 30 500-42 500) deaths, and 12.6 million (95% UI, 11.4 million-13.8 million) and 18.1 million (95% UI, 17.6 million-18.6 million) prevalent cases existed in 2017, respectively. A total of 2.5 million (95% UI, 2.3 million-2.8 million) DALYs were estimated as caused by nonrheumatic valvular diseases globally, representing 0.10% (95% UI, 0.09%-0.11%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and degenerative mitral valve disease between 1990 and 2017 by 101% (95% UI, 79%-117%) and 35% (95% UI, 23%-47%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries. CONCLUSIONS: These global and national estimates demonstrate that CAVD and degenerative mitral valve disease are important causes of disease burden among older adults. Efforts to clarify modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.

In 2007, a consortium of European experts on tacrolimus (TAC) met to discuss the most recent advances in the drug/dose optimization of TAC taking into account specific clinical situations and the analytical methods currently available and drew some recommendations and guidelines to help clinicians with the practical use of the drug. Pharmacokinetic, pharmacodynamic, and more recently pharmacogenetic approaches aid physicians to individualize long-term therapies as TAC demonstrates a high degree of both between- and within-individual variability, which may result in an increased risk of therapeutic failure if all patients are administered a uniform dose. TAC has undoubtedly benefited from therapeutic drug monitoring, but interpretation of the blood concentration is confounded by the relative differences between the assays. Single time points, limited sampling strategies, and area under concentration-time curve have all been considered to determine the most appropriate sampling procedure that correlates with efficacy. Therapeutic trough TAC concentration ranges have changed since the initial introduction of the drug, while still maintaining adequate immunosuppression and avoiding drug-related adverse effects. Pharmacodynamic markers have also been considered advantageous to the clinician, which may better reflect efficacy and safety, taking into account the between-individual variability rather than whole blood concentrations. The choice of method, differences between methods, and potential pitfalls of the method should all be considered when determining TAC concentrations. The recommendations of this consensus meeting regarding the analytical methods include the following: encourage the development and promote the use of analytical methods displaying a lower limit of quantification (1 ng/mL), perform careful validation when implementing a new analytical assay, participate in external proficiency testing programs, promote the use of certified material as calibrators in high-performance liquid chromatography with mass spectrometric detection methods, and take account of the assay and intermethod bias when comparing clinical trial outcomes. It is also important to consider that TAC concentrations may also be influenced by other factors such as specific pharmacokinetic characteristics associated with the population, drug interactions, pharmacogenetics, adverse events that may alter TAC concentrations, and any change in the oral formulation that may result in pharmacokinetic changes. This meeting emphasized the importance of obtaining multicenter prospective trials to assess the efficacy of alternative strategies to TAC trough concentrations whether it is other single time points or area under the concentration-time curve Bayesian estimation using limited sampling strategies and to select, standardize, and validate routine biomarkers of TAC pharmacodynamics.

Gilard, Martine; Eltchaninoff, Hélène; Iung,, Bernard; Donzeau-Gouge, Patrick; Chevreul, Karine; Fajadet, Jean; Leprince, Pascal; Leguerrier, Alain; Lievre, Michel; Prat, Alain; Teiger, Emmanuel; Lefevre, Thierry; Himbert, Dominique; Tchetche, Didier; Carrié, Didier; Albat, Bernard; Cribier, Alain; Rioufol, Gilles; Sudre, Arnaud; Blanchard, Didier; Collet, Frederic; Dos Santos, Pierre; Meneveau, Nicolas; Tirouvanziam, Ashok; Caussin, Christophe; Guyon, Philippe; Boschat, Jacques; Le Breton, Herve; Collart, Frederic; Houel, Remi; Delpine, Stephane; Souteyrand, Geraud; Favereau, Xavier; Ohlmann, Patrick; Doisy, Vincent; Grollier, Gilles; Gommeaux, Antoine; Claudel, Jean-Philippe; Bourlon, Francois; Bertrand, Bernard; Van Belle, Eric; Laskar, Marc for the France 2 (French Aortic National Corevalve and Edwards) Investigators Author Information