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1.
Yearb Med Inform ; 28(1): 232-234, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31419837

RESUMO

OBJECTIVES: To introduce and summarize current research in the field of Public Health and Epidemiology Informatics. METHODS: The 2018 literature concerning public health and epidemiology informatics was searched in PubMed and Web of Science, and the returned references were reviewed by the two section editors to select 15 candidate best papers. These papers were then peer-reviewed by external reviewers to give the editorial team an enlightened selection of the best papers. RESULTS: Among the 805 references retrieved from PubMed and Web of Science, three were finally selected as best papers. All three papers are about surveillance using digital tools. One study is about the surveillance of flu, another about emerging animal infectious diseases and the last one is about foodborne illness. The sources of information are Google news, Twitter, and Yelp restaurant reviews. Machine learning approaches are most often used to detect signals. CONCLUSIONS: Surveillance is a central topic in public health informatics with the growing use of machine learning approaches in regards of the size and complexity of data. The evaluation of the approaches developed remains a serious challenge.

2.
J Hosp Infect ; 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31419468

RESUMO

Pseudomonas aeruginosa remains one of the most common nosocomial pathogens in intensive care units (ICUs). Although exogenous acquisition has been widely documented in outbreaks, its importance is unclear in non-epidemic situations. We aimed to elucidate the role of exogenous origin of P. aeruginosa in ICU patients. We performed a chronological analysis of the acquisition of P. aeruginosa using samples collected in 2009 in DYNAPYO cohort study during which patients and tap water were weekly screened. Molecular relatedness of P. aeruginosa isolates was investigated by pulsed-field gel electrophoresis. Exogenous acquisition was defined as identification of a P. aeruginosa pulsotype previously isolated from another patient or tap water in the ICU. DYNAPYO cohort included 1,808 patients (10,402 samples) and 233 water taps (4,946 samples). Typing of 1,515 isolates from 373 patients and 375 isolates from 81 tap water samples identified 296 pulsotypes. Analysis showed an exogenous acquisition in 170 (45.6%) of 373 patients. The pulsotype identified was previously isolated from another patient and from a tap water sample for 86 and 29 patients respectively. The results differed according to the ICU. The exogenous acquisition of P. aeruginosa could be prevented in a half proportion of patients. The overall findings of this survey supports the need for studies on routes of transmission and risk assessment approach to better define how to control exogenous acquisition in ICUs.

3.
J Virol ; 93(18)2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31243126

RESUMO

The Ebola vaccine based on Ad26.ZEBOV/MVA-BN-Filo prime-boost regimens is being evaluated in multiple clinical trials. The long-term immune response to the vaccine is unknown, including factors associated with the response and variability around the response. We analyzed data from three phase 1 trials performed by the EBOVAC1 Consortium in four countries: the United Kingdom, Kenya, Tanzania, and Uganda. Participants were randomized into four groups based on the interval between prime and boost immunizations (28 or 56 days) and the sequence in which Ad26.ZEBOV and MVA-BN-Filo were administered. Consecutive enzyme-linked immunosorbent assay (ELISA) measurements of the IgG binding antibody concentrations against the Kikwit glycoprotein (GP) were available for 177 participants to assess the humoral immune response up to 1 year postprime. Using a mathematical model for the dynamics of the humoral response, from 7 days after the boost immunization up to 1 year after the prime immunization, we estimated the durability of the antibody response and the influence of different factors on the dynamics of the humoral response. Ordinary differential equations (ODEs) described the dynamics of antibody response and two populations of antibody-secreting cells (ASCs), short-lived (SL) and long-lived (LL). Parameters of the ODEs were estimated using a population approach. We estimated that half of the LL ASCs could persist for at least 5 years. The vaccine regimen significantly affected the SL ASCs and the antibody peak but not the long-term response. The LL ASC compartment dynamics differed significantly by geographic regions analyzed, with a higher long-term antibody persistence in European subjects. These differences could not be explained by the observed differences in cellular immune response.IMPORTANCE With no available licensed vaccines or therapies, the West African Ebola virus disease epidemic of 2014 to 2016 caused 11,310 deaths. Following this outbreak, the development of vaccines has been accelerated. Combining different vector-based vaccines as heterologous regimens could induce a durable immune response, assessed through antibody concentrations. Based on data from phase 1 trials in East Africa and Europe, the dynamics of the humoral immune response from 7 days after the boost immunization onwards were modeled to estimate the durability of the response and understand its variability. Antibody production is maintained by a population of long-lived cells. Estimation suggests that half of these cells can persist for at least 5 years in humans. Differences in prime-boost vaccine regimens affect only the short-term immune response. Geographical differences in long-lived cell dynamics were inferred, with higher long-term antibody concentrations induced in European participants.

4.
PLoS Pathog ; 15(5): e1007758, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31095640

RESUMO

The low pathogenicity and replicative potential of HIV-2 are still poorly understood. We investigated whether HIV-2 reservoirs might follow the peculiar distribution reported in models of attenuated HIV-1/SIV infections, i.e. limited infection of central-memory CD4 T lymphocytes (TCM). Antiretroviral-naive HIV-2 infected individuals from the ANRS-CO5 (12 non-progressors, 2 progressors) were prospectively included. Peripheral blood mononuclear cells (PBMCs) were sorted into monocytes and resting CD4 T-cell subsets (naive [TN], central- [TCM], transitional- [TTM] and effector-memory [TEM]). Reactivation of HIV-2 was tested in 30-day cultures of CD8-depleted PBMCs. HIV-2 DNA was quantified by real-time PCR. Cell surface markers, co-receptors and restriction factors were analyzed by flow-cytometry and multiplex transcriptomic study. HIV-2 DNA was undetectable in monocytes from all individuals and was quantifiable in TTM from 4 individuals (median: 2.25 log10 copies/106 cells [IQR: 1.99-2.94]) but in TCM from only 1 individual (1.75 log10 copies/106 cells). HIV-2 DNA levels in PBMCs (median: 1.94 log10 copies/106 PBMC [IQR = 1.53-2.13]) positively correlated with those in TTM (r = 0.66, p = 0.01) but not TCM. HIV-2 reactivation was observed in the cells from only 3 individuals. The CCR5 co-receptor was distributed similarly in cell populations from individuals and donors. TCM had a lower expression of CXCR6 transcripts (p = 0.002) than TTM confirmed by FACS analysis, and a higher expression of TRIM5 transcripts (p = 0.004). Thus the low HIV-2 reservoirs differ from HIV-1 reservoirs by the lack of monocytic infection and a limited infection of TCM associated to a lower expression of a potential alternative HIV-2 co-receptor, CXCR6 and a higher expression of a restriction factor, TRIM5. These findings shed new light on the low pathogenicity of HIV-2 infection suggesting mechanisms close to those reported in other models of attenuated HIV/SIV infection models.

5.
Lancet HIV ; 6(5): e334-e340, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31047670

RESUMO

The evaluation of immune-based approaches to achieve an antiretroviral therapy free remission of HIV infection requires proven efficacy through antiretroviral therapy interruption placebo-controlled trials. This approach is not without risk to participants and innovative trial designs need to be developed that minimise the number of participants treated with placebo and ineffective candidates. Multi-arm, multi-stage (MAMS) trial designs can be used in this context to accelerate the development of an immune-based therapeutic agent for HIV cure. Issues related to implementing a MAMS design within the planned EHVA T01 trial are considered here. EHVA T01 is a multicentre, MAMS, double-blind, phase 1 and 2 trial that aims to evaluate the effect of immune interventions on viral control in HIV-1 infected participants following analytic treatment interruption. The application of a MAMS design increases the likelihood that the EHVA T01 trial will identify a successful treatment and minimises the number of participants undergoing analytical treatment interruptions who have been treated with futile agents. The use of a MAMS design is a promising strategy to evaluate complex immune-based approaches aimed at curing HIV-infection, particularly relevant to the pipeline with multiple agents requiring examination.

6.
Front Immunol ; 10: 874, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105698

RESUMO

The goal of HIV therapeutic vaccination is to induce HIV-specific immune response able to control HIV replication. We previously reported that vaccination with ex vivo generated Dendritic Cells (DC) loaded with HIV-lipopeptides in HIV-infected patients (n = 19) on antiretroviral therapy (ART) was well-tolerated and immunogenic. Vaccine-elicited HIV-specific T cell responses were associated with improved control of viral replication following antiretroviral interruption (ATI from w24 to w48). We show an inverse relationship between HIV-specific responses (production of IL-2, IL-13, IL-21, IFN-g, CD4 polyfunctionality, i.e., production of at least two cytokines) and the peak of viral load during ATI. Here we have performed an integrative systems vaccinology analysis including: (i) post vaccination (w16) immune responses assessed by cytometry, cytokine secretion, and Interferon-γ ELISPOT assays; (ii) whole blood and cellular gene expression measured during vaccination; and (iii) viral parameters following ATI, with the objective to disentangle the relationships between these markers and to identify vaccine signatures. During vaccination, 69 gene expression modules out of 260 varied significantly including (by order of significance) modules related to inflammation (Chaussabel Modules M3.2, M4.13, M4.6, M5.7, M7.1, M4.2), plasma cells (M4.11) and T cells (M4.1, 4.15). Cellular immune responses were positively correlated to genes belonging to T cell functional modules (M4.1, M4.15) at w16 and negatively correlated to genes belonging to inflammation modules (M7.1, M5.7, M3.2, M4.13, M4.2). More specifically, we show that prolonged increased abundance of inflammatory gene pathways related to toll-like receptor signaling (especially TLR4) are associated with both lower vaccine immune responses and control of viral replication post ATI. Further comparison of DC vaccine gene signatures with previously reported non-HIV vaccine signatures, such as flu and pneumococcal vaccines, revealed common pathways across vaccines. Overall, these results show that too long duration and too high intensity of vaccine inflammatory responses hamper the magnitude of effector responses.

8.
J Virol ; 93(10)2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30814287

RESUMO

HIV controllers (HIC) maintain control of HIV replication without combined antiretroviral treatment (cART). The mechanisms leading to virus control are not fully known. We used gene expression and cellular analyses to compare HIC and HIV-1-infected individuals under cART. In the blood, HIC are characterized by a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T cell activation gene expression. This balance that persists after stimulation of cells with HIV antigens was consistent with functional analyses showing a bias toward a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. Taking advantage of the characterization of HIC based upon their CD8+ T lymphocyte capacity to suppress HIV-infection, we show here that unsupervised analysis of differentially expressed genes fits clearly with this cytotoxic activity, allowing the characterization of a specific signature of HIC. These results reveal significant features of HIC making the bridge between cellular function, gene signatures, and the regulation of inflammation and killing capacity of HIV-specific CD8+ T cells. Moreover, these genetic profiles are consistent through analyses performed from blood to peripheral blood mononuclear cells and T cells. HIC maintain strong HIV-specific immune responses with low levels of inflammation. Our findings may pave the way for new immunotherapeutic approaches leading to strong HIV-1-specific immune responses while minimizing inflammation.IMPORTANCE A small minority of HIV-infected patients, called HIV controllers (HIC), maintains spontaneous control of HIV replication. It is therefore important to identify mechanisms that contribute to the control of HIV replication that may have implications for vaccine design. We observed a low inflammation, a downmodulation of natural killer inhibitory cell signaling, and an upregulation of T-cell activation gene expression in the blood of HIC compared to patients under combined antiretroviral treatment. This profile persists following in vitro stimulation of peripheral blood mononuclear cells with HIV antigens, and was consistent with functional analyses showing a Th1 and cytotoxic T cell response and a lower production of inflammatory cytokines. These results reveal significant features of HIC that maintain strong HIV-specific immune responses with low levels of inflammation. These findings define the immune status of HIC that is probably associated with the control of viral load.

9.
J Cachexia Sarcopenia Muscle ; 10(2): 287-297, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30829460

RESUMO

BACKGROUND: Older adults with cancer experience negative long-term functional effects of both cancer and treatments. Exercise may minimize their age-related and cancer-related functional decline. METHODS: We conducted a multicentre open-label 12 month randomized clinical trial with two parallel arms including participants aged ≥70 years with lymphoma or carcinoma requiring curative treatment. The study started at the beginning of any phase of cancer treatment (surgery, chemotherapy, or radiotherapy). The usual care group (UCG) received the current national recommendations in physical activity (a guideline without specific counselling). The intervention group (IG) received 1 year phoned physical activity advice individually adapted to physical assessment (twice a month during the first 6 months and then monthly). The primary outcome was the proportion of subjects with a 1 year decreased short physical performance battery (SPPB) score of 1 point or more. Physical, cognitive, and clinical secondary outcomes were also investigated. RESULTS: We allocated 301 participants (age 76.7 ± 5.0, female 60.6%) to each group. At baseline, the median SPPB was 10/12 in both groups. Breast was the most frequent tumour site (35.7%). After 1 year, 14.0% of participants in the UCG and 18.7% in the IG had a decrease in SPPB score of 1 point or more (P = 0.772). At 2 years, there was no difference in SPPB, gait speed, International Physical Activity Questionnaire score, and verbal fluency. Subgroup analyses after 2 years showed a decline in SPPB for 29.8% of UCG and 5.0% of IG breast cancer participants (P = 0.006), in 21.7% of UCG and 6.2% of IG female participants (P = 0.019), and in 24.5% of UCG and 11.1% of IG normal nutritional status participants (P = 0.009). Falls, hospitalization, institutionalization, and death rates were similar in both groups. CONCLUSIONS: Personalized phoned physical activity advice had not reduced functional decline at 1 year but provided preliminary evidence that may prevent physical performance decline at 2 years in older adults with breast cancer.

10.
J Clin Invest ; 129(5): 1960-1971, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30843873

RESUMO

BACKGROUND: Systems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes. METHODS: This randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1. RESULTS: TIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21. CONCLUSION: This study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.

11.
J Acquir Immune Defic Syndr ; 80(3): 292-300, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30531492

RESUMO

BACKGROUND: An increasing number of HIV-positive individuals now start antiretroviral therapy (ART) with high CD4 cell counts. We investigated whether this makes restoration of CD4 and CD8 cell counts and the CD4:CD8 ratio during virologically suppressive ART to median levels seen in HIV-uninfected individuals more likely and whether restoration depends on gender, age, and other individual characteristics. METHODS: We determined median and quartile reference values for CD4 and CD8 cell counts and their ratio using cross-sectional data from 2309 HIV-negative individuals. We used longitudinal measurements of 60,997 HIV-positive individuals from the Antiretroviral Therapy Cohort Collaboration in linear mixed-effects models. RESULTS: When baseline CD4 cell counts were higher, higher long-term CD4 cell counts and CD4:CD8 ratios were reached. Highest long-term CD4 cell counts were observed in middle-aged individuals. During the first 2 years, median CD8 cell counts converged toward median reference values. However, changes were small thereafter and long-term CD8 cell count levels were higher than median reference values. Median 8-year CD8 cell counts were higher when ART was started with <250 CD4 cells/mm. Median CD4:CD8 trajectories did not reach median reference values, even when ART was started at 500 cells/mm. DISCUSSION: Starting ART with a CD4 cell count of ≥500 cells/mm makes reaching median reference CD4 cell counts more likely. However, median CD4:CD8 ratio trajectories remained below the median levels of HIV-negative individuals because of persisting high CD8 cell counts. To what extent these subnormal immunological responses affect specific clinical endpoints requires further investigation.

12.
BMC Med Res Methodol ; 18(1): 159, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30514234

RESUMO

BACKGROUND: Biological assays for the quantification of markers may suffer from a lack of sensitivity and thus from an analytical detection limit. This is the case of human immunodeficiency virus (HIV) viral load. Below this threshold the exact value is unknown and values are consequently left-censored. Statistical methods have been proposed to deal with left-censoring but few are adapted in the context of high-dimensional data. METHODS: We propose to reverse the Buckley-James least squares algorithm to handle left-censored data enhanced with a Lasso regularization to accommodate high-dimensional predictors. We present a Lasso-regularized Buckley-James least squares method with both non-parametric imputation using Kaplan-Meier and parametric imputation based on the Gaussian distribution, which is typically assumed for HIV viral load data after logarithmic transformation. Cross-validation for parameter-tuning is based on an appropriate loss function that takes into account the different contributions of censored and uncensored observations. We specify how these techniques can be easily implemented using available R packages. The Lasso-regularized Buckley-James least square method was compared to simple imputation strategies to predict the response to antiretroviral therapy measured by HIV viral load according to the HIV genotypic mutations. We used a dataset composed of several clinical trials and cohorts from the Forum for Collaborative HIV Research (HIV Med. 2008;7:27-40). The proposed methods were also assessed on simulated data mimicking the observed data. RESULTS: Approaches accounting for left-censoring outperformed simple imputation methods in a high-dimensional setting. The Gaussian Buckley-James method with cross-validation based on the appropriate loss function showed the lowest prediction error on simulated data and, using real data, the most valid results according to the current literature on HIV mutations. CONCLUSIONS: The proposed approach deals with high-dimensional predictors and left-censored outcomes and has shown its interest for predicting HIV viral load according to HIV mutations.

13.
PLoS One ; 13(11): e0207794, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30500852

RESUMO

HIV-1 infection can be controlled by anti-retroviral drug therapy, but this is a lifetime treatment and the virus remains latent and rapidly rebounds if therapy is stopped. HIV-1-infected individuals under this drug regimen have increased rates of cancers, cardiovascular diseases, and autoimmunity due to compromised immunity. A therapeutic vaccine boosting cellular immunity against HIV-1 is therefore desirable and, possibly combined with other immune modulating agents, could obviate the need for long-term drug therapies. An approach to elicit strong T cell-based immunity is to direct virus protein antigens specifically to dendritic cells (DCs), which are the key cell type for controlling immune responses. For eliciting therapeutic cellular immunity in HIV-1-infected individuals, we developed vaccines comprised of five T cell epitope-rich regions of HIV-1 Gag, Nef, and Pol (HIV5pep) fused to monoclonal antibodies that bind either, the antigen presenting cell activating receptor CD40, or the endocytic dendritic cell immunoreceptor DCIR. The study aimed to demonstrate vaccine safety, establish efficacy for broad T cell responses in both primed and naïve settings, and identify one candidate vaccine for human therapeutic development. The vaccines were administered to Rhesus macaques by intradermal injection with poly-ICLC adjuvant. The animals were either i) naïve or, ii) previously primed with modified vaccinia Ankara vector (MVA) encoding HIV-1 Gag, Pol, and Nef (MVA GagPolNef). In the MVA-primed groups, both DC-targeting vaccinations boosted HIV5pep-specific blood CD4+ T cells producing multiple cytokines, but did not affect the MVA-elicited CD8+ T cell responses. In the naive groups, both DC-targeting vaccines elicited antigen-specific polyfunctional CD4+ and CD8+ T cell responses to multiple epitopes and these responses were unchanged by a subsequent MVA GagPolNef boost. In both settings, the T cell responses elicited via the CD40-targeting vaccine were more robust and were detectable in all the animals, favoring further development of the CD40-targeting vaccine for therapeutic vaccination of HIV-1-infected individuals.

14.
PLoS One ; 13(11): e0208037, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30481204

RESUMO

MOTIVATION: The recent revolution in new sequencing technologies, as a part of the continuous process of adopting new innovative protocols has strongly impacted the interpretation of relations between phenotype and genotype. Thus, understanding the resulting gene sets has become a bottleneck that needs to be addressed. Automatic methods have been proposed to facilitate the interpretation of gene sets. While statistical functional enrichment analyses are currently well known, they tend to focus on well-known genes and to ignore new information from less-studied genes. To address such issues, applying semantic similarity measures is logical if the knowledge source used to annotate the gene sets is hierarchically structured. In this work, we propose a new method for analyzing the impact of different semantic similarity measures on gene set annotations. RESULTS: We evaluated the impact of each measure by taking into consideration the two following features that correspond to relevant criteria for a "good" synthetic gene set annotation: (i) the number of annotation terms has to be drastically reduced and the representative terms must be retained while annotating the gene set, and (ii) the number of genes described by the selected terms should be as large as possible. Thus, we analyzed nine semantic similarity measures to identify the best possible compromise between both features while maintaining a sufficient level of details. Using Gene Ontology to annotate the gene sets, we obtained better results with node-based measures that use the terms' characteristics than with measures based on edges that link the terms. The annotation of the gene sets achieved with the node-based measures did not exhibit major differences regardless of the characteristics of terms used.

15.
AIDS ; 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30325777

RESUMO

OBJECTIVES: This study aimed to determine the timing and level of HIV rebound in blood and seminal plasma and to characterize the HIV rebounding populations after antiretroviral treatment interruption (ATI) in HIV-1-infected participants enrolled in a therapeutic vaccine trial. DESIGN: A twelve-week (W) ATI period was proposed at W36 to patients enrolled in the VRI02/ANRS149-LIGHT trial. Paired blood and semen samples were collected before (W32 or W36) and during ATI (W38, W40, W42, W44 and W48). METHODS: HIV-RNA and HIV-DNA were quantified sequentially from blood and semen samples. Ultradeep sequencing (UDS, Roche/454) of partial env HIV-DNA/RNA (C2V3) was performed in both compatments. RESULTS: HIV-RNA rebounded in blood plasma and seminal plasma of all ten participants after ATI (median peak of 5.12 log10 cp/ml [range: 4.61-6.35] and 4.26 log10 cp/ml [3.20-4.67], respectively). HIV-RNA rebound was detected in blood plasma as soon as W38 in 8/10 patients, and in seminal plasma between W38 and W40 in 8/10 patients. Phylogenetic approaches showed intermingled HIV-RNA populations from plasma and semen during ATI, suggesting a lack of viral compartmentalization between blood and semen. CONCLUSION: Our data demonstrate rapid and high HIV rebound in semen after ATI, raising concerns about high risk of HIV sexual transmission during HIV cure trials.

16.
Cytometry A ; 93(11): 1132-1140, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30277649

RESUMO

Flow cytometry is a powerful technology that allows the high-throughput quantification of dozens of surface and intracellular proteins at the single-cell level. It has become the most widely used technology for immunophenotyping of cells over the past three decades. Due to the increasing complexity of cytometry experiments (more cells and more markers), traditional manual flow cytometry data analysis has become untenable due to its subjectivity and time-consuming nature. We present a new unsupervised algorithm called "cytometree" to perform automated population identification (aka gating) in flow cytometry. cytometree is based on the construction of a binary tree, the nodes of which are subpopulations of cells. At each node, the marker distributions are modeled by mixtures of normal distributions. Node splitting is done according to a model selection procedure based on a normalized difference of Akaike information criteria between two competing models. Post-processing of the tree structure and derived populations allows us to complete the annotation of the populations. The algorithm is shown to perform better than the state-of-the-art unsupervised algorithms previously proposed on panels introduced by the Flow Cytometry: Critical Assessment of Population Identification Methods project. The algorithm is also applied to a T-cell panel proposed by the Human Immunology Project Consortium (HIPC) program; it also outperforms the best unsupervised open-source available algorithm while requiring the shortest computation time. © 2018 International Society for Advancement of Cytometry.

17.
Stat Med ; 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30259533

RESUMO

In human immunodeficiency virus-infected patients, antiretroviral therapy suppresses the viral replication, which is followed in most patients by a restoration of CD4+ T cells pool. For patients who fail to do so, repeated injections of exogenous interleukin 7 (IL7) are experimented. The IL7 is a cytokine that is involved in the T cell homeostasis and the INSPIRE study has shown that injections of IL7 induced a proliferation of CD4+ T cells. Phase I/II INSPIRE 2 and 3 studies have evaluated a protocol in which a first cycle of three IL7 injections is followed by a new cycle at each visit when the patient has less than 550 CD4 cells/µL. Restoration of the CD4 concentration has been demonstrated, but the long-term best adaptive protocol is yet to be determined. A mechanistic model of the evolution of CD4 after IL7 injections has been developed, which is based on a system of ordinary differential equations and includes random effects. Based on the estimation of this model, we use a Bayesian approach to forecast the dynamics of CD4 in new patients. We propose four prediction-based adaptive protocols of injections to minimize the time spent under 500 CD4 cells/µL for each patient, without increasing the number of injections received too much. We show that our protocols significantly reduce the time spent under 500 CD4 over a period of two years, without increasing the number of injections. These protocols have the potential to increase the efficiency of this therapy.

19.
Bull Math Biol ; 80(9): 2349-2377, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30073567

RESUMO

Immune interventions consisting in repeated injections are broadly used as they are thought to improve the quantity and the quality of the immune response. However, they also raise several questions that remain unanswered, in particular the number of injections to make or the delay to respect between different injections to achieve this goal. Practical and financial considerations add constraints to these questions, especially in the framework of human studies. We specifically focus here on the use of interleukin-7 (IL-7) injections in HIV-infected patients under antiretroviral treatment, but still unable to restore normal levels of [Formula: see text] T lymphocytes. Clinical trials have already shown that repeated cycles of injections of IL-7 could help maintaining [Formula: see text] T lymphocytes levels over the limit of 500 cells/[Formula: see text]L, by affecting proliferation and survival of [Formula: see text] T cells. We then aim at answering the question: how to maintain a patients level of [Formula: see text] T lymphocytes by using a minimum number of injections (i.e., optimizing the strategy of injections)? Based on mechanistic models that were previously developed for the dynamics of [Formula: see text] T lymphocytes in this context, we model the process by a piecewise deterministic Markov model. We then address the question by using some recently established theory on impulse control problem in order to develop a numerical tool determining the optimal strategy. Results are obtained on a reduced model, as a proof of concept: the method allows to define an optimal strategy for a given patient. This method could be applied to optimize injections schedules in clinical trials.

20.
Yearb Med Inform ; 27(1): 207-210, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30157525

RESUMO

OBJECTIVES: To introduce and summarize current research in the field of Public Health and Epidemiology Informatics. METHODS: The 2017 literature concerning public health and epidemiology informatics was searched in PubMed and Web of Science, and the returned references were reviewed by the two section editors to select 14 candidate best papers. These papers were then peer-reviewed by external reviewers to provide the editorial team with an enlightened vision to select the best papers. RESULTS: Among the 843 references retrieved from PubMed and Web of Science, two were finally selected as best papers. The first one analyzes the relationship between the disease, social/mass media, and public emotions to understand public overreaction (leading to a noticeable reduction of social and economic activities) in the context of a nation-wide outbreak of Middle East Respiratory Syndrome (MERS) in Korea in 2015. The second paper concerns a new methodology to de-identify patient notes in electronic health records based on artificial neural networks that outperformed existing methods. CONCLUSIONS: Surveillance is still a productive topic in public health informatics but other very important topics in Public Health are appearing. For example, the use of artificial intelligence approaches is increasing.


Assuntos
Inteligência Artificial , Informática em Saúde Pública , Anonimização de Dados , Epidemiologia , Aprendizado de Máquina , Redes Neurais (Computação) , Saúde Pública
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