245 research outputs found
Reliability of the CARE rule and the HEART score to rule out an acute coronary syndrome in non-traumatic chest pain patients
In patients consulting in the Emergency Department for chest pain, a HEART score β€ 3 has been shown to rule out an acute coronary syndrome (ACS) with a low risk of major adverse cardiac event (MACE) occurrence. A negative CARE rule (β€ 1) that stands for the first four elements of the HEART score may have similar rule-out reliability without troponin assay requirement. We aim to prospectively assess the performance of the CARE rule and of the HEART score to predict MACE in a chest pain population. Prospective two-center non-interventional study. Patients admitted to the ED for non-traumatic chest pain were included, and followed-up at 6Β weeks. The main study endpoint was the 6-week rate of MACE (myocardial infarction, coronary angioplasty, coronary bypass, and sudden unexplained death). 641 patients were included, of whom 9.5% presented a MACE at 6Β weeks. The CARE rule was negative for 31.2% of patients, and none presented a MACE during follow-up [0, 95% confidence interval: (0.0β1.9)]. The HEART score was β€ 3 for 63.0% of patients, and none presented a MACE during follow-up [0% (0.0β0.9)]. With an incidence below 2% in the negative group, the CARE rule seemed able to safely rule out a MACE without any biological test for one-third of patients with chest pain and the HEART score for another third with a single troponin assay
A very low geno2pheno false positive rate is associated with poor viro-immunological response in drug-naΓ―ve patients starting a first-line HAART.
Background: We previously found that a very low geno2pheno false positive rate (FPR β€2%) defines a viral population
associated with low CD4 cell count and the highest amount of X4-quasispecies. In this study, we aimed at evaluating
whether FPR β€2% might impact on the viro-immunological response in HIV-1 infected patients starting a first-line HAART.
Methods: The analysis was performed on 305 HIV-1 B subtype infected drug-naΔ±Β¨ve patients who started their first-line
HAART. Baseline FPR (%) values were stratified according to the following ranges: β€2; 2β5; 5β10; 10β20; 20β60; >60. The impact of genotypically-inferred tropism on the time to achieve immunological reconstitution (a CD4 cell count gain from HAART initiation β₯150 cells/mm3) and on the time to achieve virological success (the first HIV-RNA measurement <50 copies/mL from HAART initiation) was evaluated by survival analyses.
Results: Overall, at therapy start, 27% of patients had FPR β€10 (6%, FPR β€2; 7%, FPR 2β5; 14%, FPR 5β10). By 12 months of therapy the rate of immunological reconstitution was overall 75.5%, and it was significantly lower for FPR β€2 (54.1%) in comparison to other FPR ranks (78.8%, FPR 2β5; 77.5%, FPR 5β10; 71.7%, FPR 10β20; 81.8%, FPR 20β60; 75.1%, FPR >60; p = 0.008). The overall proportion of patients achieving virological success was 95.5% by 12 months of therapy. Multivariable Cox analyses showed that patients having pre-HAART FPR β€2% had a significant lower relative adjusted hazard [95% C.I.] both to achieve immunological reconstitution (0.37 [0.20β0.71], p = 0.003) and to achieve virological success (0.50 [0.26β0.94], p = 0.031) than those with pre-HAART FPR >60%.
Conclusions: Beyond the genotypically-inferred tropism determination, FPR β€2% predicts both a poor immunological
reconstitution and a lower virological response in drug-naΔ±Β¨ve patients who started their first-line therapy. This parameter
could be useful to identify patients potentially with less chance of achieving adequate immunological reconstitution and
virological undetectability
Boolean Dynamics with Random Couplings
This paper reviews a class of generic dissipative dynamical systems called
N-K models. In these models, the dynamics of N elements, defined as Boolean
variables, develop step by step, clocked by a discrete time variable. Each of
the N Boolean elements at a given time is given a value which depends upon K
elements in the previous time step.
We review the work of many authors on the behavior of the models, looking
particularly at the structure and lengths of their cycles, the sizes of their
basins of attraction, and the flow of information through the systems. In the
limit of infinite N, there is a phase transition between a chaotic and an
ordered phase, with a critical phase in between.
We argue that the behavior of this system depends significantly on the
topology of the network connections. If the elements are placed upon a lattice
with dimension d, the system shows correlations related to the standard
percolation or directed percolation phase transition on such a lattice. On the
other hand, a very different behavior is seen in the Kauffman net in which all
spins are equally likely to be coupled to a given spin. In this situation,
coupling loops are mostly suppressed, and the behavior of the system is much
more like that of a mean field theory.
We also describe possible applications of the models to, for example, genetic
networks, cell differentiation, evolution, democracy in social systems and
neural networks.Comment: 69 pages, 16 figures, Submitted to Springer Applied Mathematical
Sciences Serie
Low unspliced cell-associated HIV RNA in early treated adolescents living with HIV on long suppressive ART
Introduction: Initiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population.
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Methods: Forty adolescents perinatally infected with HIV on suppressive ART for >5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested.
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Results: CA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-Ξ± was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study.
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Conclusions: Low CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation
Attraction Basins as Gauges of Robustness against Boundary Conditions in Biological Complex Systems
One fundamental concept in the context of biological systems on which researches have flourished in the past decade is that of the apparent robustness of these systems, i.e., their ability to resist to perturbations or constraints induced by external or boundary elements such as electromagnetic fields acting on neural networks, micro-RNAs acting on genetic networks and even hormone flows acting both on neural and genetic networks. Recent studies have shown the importance of addressing the question of the environmental robustness of biological networks such as neural and genetic networks. In some cases, external regulatory elements can be given a relevant formal representation by assimilating them to or modeling them by boundary conditions. This article presents a generic mathematical approach to understand the influence of boundary elements on the dynamics of regulation networks, considering their attraction basins as gauges of their robustness. The application of this method on a real genetic regulation network will point out a mathematical explanation of a biological phenomenon which has only been observed experimentally until now, namely the necessity of the presence of gibberellin for the flower of the plant Arabidopsis thaliana to develop normally
A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma
Previous results suggest that GEM affects 5-fluorouracil (5-FU) metabolism and pharmacokinetics in cancer patients, while combined with oxaliplatin, levo-folinic acid, and 5-FU (GOLF regimen), at doses achievable in cancer patients, determines high cytotoxic and proapoptotic antitumour activity in colon cancer cells in vitro. On these bases we designed a phase IβII clinical trial testing the GOLF
regimen in patients with metastatic colorectal carcinoma, who had received at least a prior line of chemotherapy. In total, 29 patients (20 males and nine females) enrolled in the study received every 2 weeks, gemcitabine (patients #1β3 received 600 mgm2; patients # 4β6 received 850 mgm2; while patients # 7β29 received 1000 mgm2) on the day 1, levo-folinic acid (100 mgm2) on the days
1 and 2; 5-fluorouracil (400 mgm2) in bolus injection, followed by a 22-h continuous infusion (800 mgm2) on the days 1 and 2, and oxaliplatin (85 mgm2), 6 h after the 5-FU bolus on day 2. The most frequent side effect was grade IβII haematological toxicity. In total, 28 patients were evaluable for response: three achieved a complete response, nine a partial response, 10 had a stable disease,
and six progressed. The average time to progression and overall survival of the patients was, respectively, 7.26 and 22 months. Our GOLF combination is well tolerated and seems promising for the treatment of advanced colorectal cancer
Different Chitin Synthase Genes Are Required for Various Developmental and Plant Infection Processes in the Rice Blast Fungus Magnaporthe oryzae
Chitin is a major component of fungal cell wall and is synthesized by chitin synthases (Chs). Plant pathogenic fungi normally have multiple chitin synthase genes. To determine their roles in development and pathogenesis, we functionally characterized all seven CHS genes in Magnaporthe oryzae. Three of them, CHS1, CHS6, and CHS7, were found to be important for plant infection. While the chs6 mutant was non-pathogenic, the chs1 and chs7 mutants were significantly reduced in virulence. CHS1 plays a specific role in conidiogenesis, an essential step for natural infection cycle. Most of chs1 conidia had no septum and spore tip mucilage. The chs6 mutant was reduced in hyphal growth and conidiation. It failed to penetrate and grow invasively in plant cells. The two MMD-containing chitin synthase genes, CHS5 and CHS6, have a similar expression pattern. Although deletion of CHS5 had no detectable phenotype, the chs5 chs6 double mutant had more severe defects than the chs6 mutant, indicating that they may have overlapping functions in maintaining polarized growth in vegetative and invasive hyphae. Unlike the other CHS genes, CHS7 has a unique function in appressorium formation. Although it was blocked in appressorium formation by germ tubes on artificial hydrophobic surfaces, the chs7 mutant still produced melanized appressoria by hyphal tips or on plant surfaces, indicating that chitin synthase genes have distinct impacts on appressorium formation by hyphal tip and germ tube. The chs7 mutant also was defective in appressorium penetration and invasive growth. Overall, our results indicate that individual CHS genes play diverse roles in hyphal growth, conidiogenesis, appressorium development, and pathogenesis in M. oryzae, and provided potential new leads in the control of this devastating pathogen by targeting specific chitin synthases
Polymorphism in Gag Gene Cleavage Sites of HIV-1 Non-B Subtype and Virological Outcome of a First-Line Lopinavir/Ritonavir Single Drug Regimen
Virological failure on a boosted-protease inhibitor (PI/r) first-line triple combination is usually not associated with the detection of resistance mutations in the protease gene. Thus, other resistance pathways are being investigated. First-line PI/r monotherapy is the best model to investigate in vivo if the presence of mutations in the cleavage sites (CS) of gag gene prior to any antiretroviral treatment might influence PI/r efficacy. 83 patients were assigned to initiate antiretroviral treatment with first-line lopinavir/r monotherapy in the randomised Monark trial. We compared baseline sequence of gag CS between patients harbouring B or non-B HIV-1 subtype, and between those who achieved viral suppression and those who experienced virological failure while on LPV/r monotherapy up to Week 96. Baseline sequence of gag CS was available for 82/83 isolates; 81/82 carried at least one substitution in gag CS compared to HXB2 sequence. At baseline, non-B subtype isolates were significantly more likely to harbour mutations in gag CS than B subtype isolates (p<0.0001). Twenty-three patients experienced virological failure while on lopinavir/r monotherapy. The presence of more than two substitutions in p2/NC site at baseline significantly predicted virological failure (pβ=β0.0479), non-B subtype isolates being more likely to harbour more than two substitutions in this specific site. In conclusion, gag cleavage site was highly polymorphic in antiretroviral-naive patients harbouring a non-B HIV-1 strain. We show that pre-therapy mutations in gag cleavage site sequence were significantly associated with the virological outcome of a first-line LPV/r single drug regimen in the Monark trial
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