Showing papers by "Pierre-and-Marie-Curie University published in 2008"

Fast unfolding of communities in large networks

Abstract: We propose a simple method to extract the community structure of large networks. Our method is a heuristic method that is based on modularity optimization. It is shown to outperform all other known community detection method in terms of computation time. Moreover, the quality of the communities detected is very good, as measured by the so-called modularity. This is shown first by identifying language communities in a Belgian mobile phone network of 2.6 million customers and by analyzing a web graph of 118 million nodes and more than one billion links. The accuracy of our algorithm is also verified on ad-hoc modular networks. .

Fast unfolding of communities in large networks

Abstract: We propose a simple method to extract the community structure of large networks. Our method is a heuristic method that is based on modularity optimization. It is shown to outperform all other known community detection methods in terms of computation time. Moreover, the quality of the communities detected is very good, as measured by the so-called modularity. This is shown first by identifying language communities in a Belgian mobile phone network of 2 million customers and by analysing a web graph of 118 million nodes and more than one billion links. The accuracy of our algorithm is also verified on ad hoc modular networks.

Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)

Abstract: Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations. In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease. This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work. The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available. Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed. The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.

Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients

Abstract: A decrease in the abundance and biodiversity of intestinal bacteria within the dominant phylum Firmicutes has been observed repeatedly in Crohn disease (CD) patients. In this study, we determined the composition of the mucosa-associated microbiota of CD patients at the time of surgical resection and 6 months later using FISH analysis. We found that a reduction of a major member of Firmicutes, Faecalibacterium prausnitzii, is associated with a higher risk of postoperative recurrence of ileal CD. A lower proportion of F. prausnitzii on resected ileal Crohn mucosa also was associated with endoscopic recurrence at 6 months. To evaluate the immunomodulatory properties of F. prausnitzii we analyzed the anti-inflammatory effects of F. prausnitzii in both in vitro (cellular models) and in vivo [2,4,6-trinitrobenzenesulphonic acid (TNBS)-induced] colitis in mice. In Caco-2 cells transfected with a reporter gene for NF-kappaB activity, F. prausnitzii had no effect on IL-1beta-induced NF-kappaB activity, whereas the supernatant abolished it. In vitro peripheral blood mononuclear cell stimulation by F. prausnitzii led to significantly lower IL-12 and IFN-gamma production levels and higher secretion of IL-10. Oral administration of either live F. prausnitzii or its supernatant markedly reduced the severity of TNBS colitis and tended to correct the dysbiosis associated with TNBS colitis, as demonstrated by real-time quantitative PCR (qPCR) analysis. F. prausnitzii exhibits anti-inflammatory effects on cellular and TNBS colitis models, partly due to secreted metabolites able to block NF-kappaB activation and IL-8 production. These results suggest that counterbalancing dysbiosis using F. prausnitzii as a probiotic is a promising strategy in CD treatment.

The Variational Approach to Fracture

Abstract: 1 Introduction 2 Going variational 2.1 Griffith's theory 2.2 The 1-homogeneous case - A variational equivalence 2.3 Smoothness - The soft belly of Griffith's formulation 2.4 The non 1-homogeneous case - A discrete variational evolution 2.5 Functional framework - A weak variational evolution 2.6 Cohesiveness and the variational evolution 3 Stationarity versus local or global minimality - A comparison 3.1 1d traction 3.1.1 The Griffith case - Soft device 3.1.2 The Griffith case - Hard device 3.1.3 Cohesive case - Soft device 3.1.4 Cohesive case - Hard device 3.2 A tearing experiment 4 Initiation 4.1 Initiation - The Griffith case 4.1.1 Initiation - The Griffith case - Global minimality 4.1.2 Initiation - The Griffith case - Local minimality 4.2 Initiation - The cohesive case 4.2.1 Initiation - The cohesive 1d case - Stationarity 4.2.2 Initiation - The cohesive 3d case - Stationarity 4.2.3 Initiation - The cohesive case - Global minimality 5 Irreversibility 5.1 Irreversibility - The Griffith case - Well-posedness of the variational evolution 5.1.1 Irreversibility - The Griffith case - Discrete evolution 5.1.2 Irreversibility - The Griffith case - Global minimality in the limit 5.1.3 Irreversibility - The Griffith case - Energy balance in the limit 5.1.4 Irreversibility - The Griffith case - The time-continuous evolution 5.2 Irreversibility - The cohesive case 6 Path 7 Griffith vs. Barenblatt 8 Numerics and Griffith 8.1 Numerical approximation of the energy 8.1.1 The first time step 8.1.2 Quasi-static evolution 8.2 Minimization algorithm 8.2.1 The alternate minimization algorithm 8.2.2 The backtracking algorithm 8.3 Numerical experiments 8.3.1 The 1D traction (hard device) 8.3.2 The Tearing experiment 8.3.3 Revisiting the 2D traction experiment on a fiber reinforced matrix 9 Fatigue 9.1 Peeling Evolution 9.2 The limitfatigue law when d tends to 0 9.3 A variational formulation for fatigue 9.3.1 Peeling revisited 9.3.2 Generalization Appendix Glossary References.

Compressed sensing and best k-term approximation

Abstract: The typical paradigm for obtaining a compressed version of a discrete signal represented by a vector x ∈ R is to choose an appropriate basis, compute the coefficients of x in this basis, and then retain only the k largest of these with k < N . If we are interested in a bit stream representation, we also need in addition to quantize these k coefficients. Assuming, without loss of generality, that x already represents the coefficients of the signal in the appropriate basis, this means that we pick an approximation to x in the set Σk of k-sparse vectors (1.1) Σk := {x ∈ R : # supp(x) ≤ k}, where supp(x) is the support of x, i.e., the set of i for which xi = 0, and #A is the number of elements in the set A. The best performance that we can achieve by such an approximation process in some given norm ‖ · ‖X of interest is described by the best k-term approximation error

Time Lines of Infection and Disease in Human Influenza: A Review of Volunteer Challenge Studies

Abstract: The dynamics of viral shedding and symptoms following influenza virus infection are key factors when considering epidemic control measures. The authors reviewed published studies describing the course of influenza virus infection in placebo-treated and untreated volunteers challenged with wild-type influenza virus. A total of 56 different studies with 1,280 healthy participants were considered. Viral shedding increased sharply between 0.5 and 1 day after challenge and consistently peaked on day 2. The duration of viral shedding averaged over 375 participants was 4.80 days (95% confidence interval: 4.31, 5.29). The frequency of symptomatic infection was 66.9% (95% confidence interval: 58.3, 74.5). Fever was observed in 37.0% of A/H1N1, 40.6% of A/H3N2 (p = 0.86), and 7.5% of B infections (p = 0.001). The total symptoms scores increased on day 1 and peaked on day 3. Systemic symptoms peaked on day 2. No such data exist for children or elderly subjects, but epidemiologic studies suggest that the natural history might differ. The present analysis confirms prior expert opinion on the duration of viral shedding or the frequency of asymptomatic influenza infection, extends prior knowledge on the dynamics of viral shedding and symptoms, and provides original results on the frequency of respiratory symptoms or fever.

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

Abstract: Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1-/- and Tcrb-/- mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1-/- mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1-/- mice reconstituted with IFN-gamma-deficient splenocytes were not protected. These data indicate that T cell-mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNgamma. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD.

Towards non-blinking colloidal quantum dots.

Abstract: At a single-molecule level, fluorophore emission intensity fluctuates between bright and dark states. These fluctuations, known as blinking, limit the use of fluorophores in single-molecule experiments. The dark-state duration shows a universal heavy-tailed power-law distribution characterized by the occurrence of long non-emissive periods. Here we have synthesized novel CdSe-CdS core-shell quantum dots with thick crystalline shells, 68% of which do not blink when observed individually at 33 Hz for 5 min. We have established a direct correlation between shell thickness and blinking occurrences. Importantly, the statistics of dark periods that appear at high acquisition rates (1 kHz) are not heavy tailed, in striking contrast with previous observations. Blinking statistics are thus not as universal as thought so far. We anticipate that our results will help to better understand the physico-chemistry of single-fluorophore emission and rationalize the design of other fluorophores that do not blink.

The Loci of Evolution: How Predictable is Genetic Evolution?

Abstract: Is genetic evolution predictable? Evolutionary developmental biologists have argued that, at least for morphological traits, the answer is a resounding yes. Most mutations causing morphological variation are expected to reside in the cis-regulatory, rather than the coding, regions of developmental genes. This “cis-regulatory hypothesis” has recently come under attack. In this review, we first describe and critique the arguments that have been proposed in support of the cis-regulatory hypothesis. We then test the empirical support for the cis-regulatory hypothesis with a comprehensive survey of mutations responsible for phenotypic evolution in multicellular organisms. Cis-regulatory mutations currently represent approximately 22% of 331 identified genetic changes although the number of cis-regulatory changes published annually is rapidly increasing. Above the species level, cis-regulatory mutations altering morphology are more common than coding changes. Also, above the species level cis-regulatory mutations predominate for genes not involved in terminal differentiation. These patterns imply that the simple question “Do coding or cis-regulatory mutations cause more phenotypic evolution?” hides more interesting phenomena. Evolution in different kinds of populations and over different durations may result in selection of different kinds of mutations. Predicting the genetic basis of evolution requires a comprehensive synthesis of molecular developmental biology and population genetics.

Design, Synthesis, and Properties of Inorganic and Hybrid Thin Films Having Periodically Organized Nanoporosity†

Abstract: This review presents an extensive discussion on the major advances in the field of periodically organized mesoporous thin films (POMTFs) obtained via surfactant templated growth of inorganic or hybrid polymers. A large variety of templating agents can be coupled with inorganic polymerization reactions for the design of periodically organized nanostructured hybrid phases that yield POMTFs. The tuning of the interface between the template and the polymerizing phase and the control over chemical and processing conditions are the key parameters in producing tailor-made POMTFs with a high degree of reproducibility. This dynamic coupling between chemical and processing conditions dictates extensive use of complementary ex situ measurements with in situ characterization techniques that follow, in real time, film formation from the molecular precursor solutions to the final stabilized POMTF. Among modern analytical tools, 2D-GISAXS, ellipsoporosimetry, HRTEM, X-ray reflectometry, WAXS, time-resolved infrared spec...

Immune activation and inflammation in HIV-1 infection: causes and consequences.

Abstract: Thorough research on HIV is progressively enabling us to understand the intricate mechanisms that link HIV-1 infection to the onset of immunodeficiency. The infection and depletion of CD4(+) T cells represent the most fundamental events in HIV-1 infection. However, in recent years, the role played by chronic immune activation and inflammation in HIV pathogenesis has become increasingly apparent: quite paradoxically, immune activation levels are directly associated with HIV-1 disease progression. In addition, HIV-1-infected patients present intriguing similarities with individuals of old age: their immune systems are characterized by a loss of regenerative capacity and an accumulation of ageing T cells. In this review, we discuss the potential reasons for the establishment of sustained immune activation and inflammation from the early stages of HIV-1 infection, as well as the long-term consequences of this process on the host immune system and health. A simplified model of HIV pathogenesis is proposed, which links together the three major facets of HIV-1 infection: the massive depletion of CD4(+) T cells, the paradoxical immune activation and the exhaustion of regenerative capacity.

Phenotype and function of human T lymphocyte subsets: Consensus and issues

Abstract: In recent years, a tremendous effort has been devoted to the detailed characterization of the phenotype and function of distinct T cell subpopulations in humans, as well as to their pathway(s) of differentiation and role in immune responses But these studies seem to have generated more questions than definitive answers To clarify issues related to the function and differentiation of T cell subsets, one session of the MASIR 2008 conference was dedicated to this topic Several points of consensus and discord were highlighted in the work presented during this session We provide here an account of these points, including the relative heterogeneity of T cell subpopulations during infections with distinct pathogens, the relationship between phenotypic and functional T cell attributes, and the pathway(s) of T cell differentiation Finally, we discuss the problems which still limit general agreement

Raltegravir with Optimized Background Therapy for Resistant HIV-1 Infection

Abstract: Results In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detect ed in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. Conclusions In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Estimating the impact of school closure on influenza transmission from Sentinel data

Abstract: The threat posed by the highly pathogenic H5N1 influenza virus requires public health authorities to prepare for a human pandemic. Although pre-pandemic vaccines and antiviral drugs might significantly reduce illness rates, their stockpiling is too expensive to be practical for many countries. Consequently, alternative control strategies, based on non-pharmaceutical interventions, are a potentially attractive policy option. School closure is the measure most often considered. The high social and economic costs of closing schools for months make it an expensive and therefore controversial policy, and the current absence of quantitative data on the role of schools during influenza epidemics means there is little consensus on the probable effectiveness of school closure in reducing the impact of a pandemic. Here, from the joint analysis of surveillance data and holiday timing in France, we quantify the role of schools in influenza epidemics and predict the effect of school closure during a pandemic. We show that holidays lead to a 20-29% reduction in the rate at which influenza is transmitted to children, but that they have no detectable effect on the contact patterns of adults. Holidays prevent 16-18% of seasonal influenza cases (18-21% in children). By extrapolation, we find that prolonged school closure during a pandemic might reduce the cumulative number of cases by 13-17% (18-23% in children) and peak attack rates by up to 39-45% (47-52% in children). The impact of school closure would be reduced if it proved difficult to maintain low contact rates among children for a prolonged period.

Observation of the suppression of the flux of cosmic rays above 4x10(19) eV

Abstract: The energy spectrum of cosmic rays above 2.5 x 10;{18} eV, derived from 20,000 events recorded at the Pierre Auger Observatory, is described. The spectral index gamma of the particle flux, J proportional, variantE;{-gamma}, at energies between 4 x 10;{18} eV and 4 x 10;{19} eV is 2.69+/-0.02(stat)+/-0.06(syst), steepening to 4.2+/-0.4(stat)+/-0.06(syst) at higher energies. The hypothesis of a single power law is rejected with a significance greater than 6 standard deviations. The data are consistent with the prediction by Greisen and by Zatsepin and Kuz'min.

Facilitated PCI in patients with ST-elevation myocardial infarction.

Abstract: In this international, double-blind, placebo-controlled study, we randomly assigned patients with ST-segment elevation myocardial infarction who presented 6 hours or less after the onset of symptoms to receive combination-facilitated PCI, abciximabfacilitated PCI, or primary PCI. All patients received unfractionated heparin or enoxaparin before PCI and a 12-hour infusion of abciximab after PCI. The primary end point was the composite of death from all causes, ventricular fibrillation occurring more than 48 hours after randomization, cardiogenic shock, and congestive heart failure during the first 90 days after randomization. Results A total of 2452 patients were randomly assigned to a treatment group. Significantly more patients had early ST-segment resolution with combination-facilitated PCI (43.9%) than with abciximab-facilitated PCI (33.1%) or primary PCI (31.0%; P = 0.01 and P = 0.003, respectively). The primary end point occurred in 9.8%, 10.5%, and 10.7% of the patients in the combination-facilitated PCI group, abciximab-facilitated PCI group, and primary-PCI group, respectively (P = 0.55); 90-day mortality rates were 5.2%, 5.5%, and 4.5%, respectively (P = 0.49). Conclusions Neither facilitation of PCI with reteplase plus abciximab nor facilitation with abciximab alone significantly improved the clinical outcomes, as compared with abciximab given at the time of PCI, in patients with ST-segment elevation myocardial infarction. (ClinicalTrials.gov number, NCT00046228.)

On the convergence of the proximal algorithm for nonsmooth functions involving analytic features

Abstract: We study the convergence of the proximal algorithm applied to nonsmooth functions that satisfy the Łjasiewicz inequality around their generalized critical points. Typical examples of functions complying with these conditions are continuous semialgebraic or subanalytic functions. Following Łjasiewicz’s original idea, we prove that any bounded sequence generated by the proximal algorithm converges to some generalized critical point. We also obtain convergence rate results which are related to the flatness of the function by means of Łjasiewicz exponents. Apart from the sharp and elliptic cases which yield finite or geometric convergence, the decay estimates that are derived are of the type O(k −s ), where s ∈ (0, + ∞) depends on the flatness of the function.

The Dynamics of Photosynthesis

Abstract: Despite recent elucidation of the three-dimensional structure of major photosynthetic complexes, our understanding of light energy conversion in plant chloroplasts and microalgae under physiological conditions requires exploring the dynamics of photosynthesis. The photosynthetic apparatus is a flexible molecular machine that can acclimate to metabolic and light fluctuations in a matter of seconds and minutes. On a longer time scale, changes in environmental cues trigger acclimation responses that elicit intracellular signaling between the nucleo-cytosol and chloroplast resulting in modification of the biogenesis of the photosynthetic machinery. Here we attempt to integrate well-established knowledge on the functional flexibility of light-harvesting and electron transfer processes, which has greatly benefited from genetic approaches, with data derived from the wealth of recent transcriptomic and proteomic studies of acclimation responses in photosynthetic eukaroytes.

A Systematic Review of Randomized Trials Evaluating Regional Techniques for Postthoracotomy Analgesia

Abstract: BACKGROUND:Thoracotomy induces severe postoperative pain and impairment of pulmonary function, and therefore regional analgesia has been intensively studied in this procedure. Thoracic epidural analgesia is commonly considered the “gold standard” in this setting; however, evaluation of the evidence is needed to assess the comparative benefits of alternative techniques, guide clinical practice and identify areas requiring further research. METHODS:In this systematic review of randomized trials we evaluated thoracic epidural, paravertebral, intrathecal, intercostal, and interpleural analgesic techniques, compared to each other and to systemic opioid analgesia, in adult thoracotomy. Postoperative pain, analgesic use, and complications were analyzed. RESULTS:Continuous paravertebral block was as effective as thoracic epidural analgesia with local anesthetic (LA) but was associated with a reduced incidence of hypotension. Paravertebral block reduced the incidence of pulmonary complications compared with systemic analgesia, whereas thoracic epidural analgesia did not. Thoracic epidural analgesia was superior to intrathecal and intercostal techniques, although these were superior to systemic analgesia; interpleural analgesia was inadequate. CONCLUSIONS:Either thoracic epidural analgesia with LA plus opioid or continuous paravertebral block with LA can be recommended. Where these techniques are not possible, or are contraindicated, intrathecal opioid or intercostal nerve block are recommended despite insufficient duration of analgesia, which requires the use of supplementary systemic analgesia. Quantitative meta-analyses were limited by heterogeneity in study design, and subject numbers were small. Further well designed studies are required to investigate the optimum components of the epidural solution and to rigorously evaluate the risks/benefits of continuous infusion paravertebral and intercostal techniques compared with thoracic epidural analgesia. (Anesth Analg 2008;107:1026‐40)

Outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation for refractory cardiogenic shock*

Abstract: Objective:To assess the outcomes and long-term quality-of-life of patients supported by extracorporeal membrane oxygenation (ECMO) for refractory cardiogenic shock.Design, Setting, and Patients:Refractory cardiogenic shock is almost always lethal without emergency circulatory support, e.g., ECMO. EC

The Algebraic and Geometric Theory of Quadratic Forms

Abstract: Introduction Classical theory of symmetric bilinear forms and quadratic forms: Bilinear forms Quadratic forms Forms over rational function fields Function fields of quadrics Bilinear and quadratic forms and algebraic extensions $u$-invariants Applications of the Milnor conjecture On the norm residue homomorphism of degree two Algebraic cycles: Homology and cohomology Chow groups Steenrod operations Category of Chow motives Quadratic forms and algebraic cycles: Cycles on powers of quadrics The Izhboldin dimension Application of Steenrod operations The variety of maximal totally isotropic subspaces Motives of quadrics Appendices Bibliography Notation Terminology.

Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection.

Abstract: Background We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. Methods We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. Results Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. Conclusions When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)