Simplification Strategy Research Articles

State of the Art of Dual Therapy in 2015

Dual therapy refers to combinations of two antiretroviral drugs applied in different clinical settings; they are considered and studied due to possibly reduced drug toxicities. In antiretroviral-naive patients, dual combinations have lower virologic efficacy than standard therapy; the sole efficacious regimen is lamivudine plus lopinavir/ritonavir. Due to a higher possibility of virologic failure, these regimens are generally not allowed in this clinical setting. In antiretroviral-experienced patients, dual regimens are examined in studies with a small sample size, centered on clinical practice, and should be ritonavir-boosted protease inhibitor-based. These combinations have a good virological efficacy; combinations with the integrase inhibitor raltegravir have small sample size and demonstrated efficacy only with etravirine. Virological aspects involving dual therapy should always consider genetic barriers, particularly in simplification strategies, and ritonavir-boosted protease inhibitors are mandatory. As far as immunological aspects are concerned, nucleoside reverse transcriptase inhibitor-sparing regimens have some encouraging data, probably due to the bone marrow toxicity of this class. Combinations with maraviroc were effective in reducing inflammation, but data about immunological recovery are conflicting. The choice of regimen should focus on specific class toxicity since dual regimens are studied in particular for improving safety and tolerability. This review will analyze different dual regimens in the clinical setting, with a peculiar focus on ameliorating toxicities and improving quality of life.

Pronunciation simplification strategies in child language. Experimental study

The aim of this study is to determine the strategies of pronunciation simplification. The sample of the study consisted of 288 Lithuanian children: 96 preschool age children (4;00–4;11), 95 pre-primary school age children (6;00–6;11) and 97 junior primary school age children (8;00–8;11). The data were collected using a non-word repetition task in Lithuanian.The results of the research have shown that Lithuanian children apply universal strategies of pronunciation simplification, mostly substitution and omission; other strategies such as consonant assimilation, metathesis, sound migration to another syllable and sound addition were much less frequent. Also the results show that children possibly apply associations with real Lithuanian words or their derivational forms.The research has demonstrated that the ability to repeat different structure words is related to the rules of Lithuanian phonotactics. Consonant clusters which are typical of Lithuanian words were pronounced accurately, whereas clusters which are rare in Lithuanian words were simplified in their pronunciation. Age was an important factor in the present study: older children repeated non-words more accurately. Older children have a larger lexicon and eventually develop it further; they learn new consonant clusters, which they are capable to pronounce more accurately.

Efavirenz-based simplification after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children in Burkina Faso and C\xf4te d\u2019Ivoire: the MONOD ANRS 12206 non-inferiority randomised trial

BackgroundThe 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years.MethodsThe MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d’Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12–15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test).ResultsBetween May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12–15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), −11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, −13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation.ConclusionsAt the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored.Trial registrationClinicalTrial.gov registry n°NCT01127204, 19 May 2010.

Budget impact analysis of the simplification to atazanavir + ritonavir + lamivudine dual therapy of HIV-positive patients receiving atazanavir-based triple therapies in Italy starting from data of the Atlas-M trial.

BackgroundThis analysis aimed at evaluating the impact of a therapeutic strategy of treatment simplification of atazanavir (ATV)+ ritonavir (r) + lamivudine (3TC) in virologically suppressed patients receiving ATV+r+2 nucleoside reverse transcriptase inhibitors (NRTIs) on the budget of the Italian National Health Service (NHS).MethodsA budget impact model with a 5-year time horizon was developed based on the clinical data of Atlas-M trial at 48 weeks (in terms of percentage of patients experiencing virologic failure and adverse events), from the Italian NHS perspective. A scenario in which the simplification strategy was not considered was compared with three scenarios in which, among a target population of 1,892 patients, different simplification strategies were taken into consideration in terms of percentage of patients simplified on a yearly basis among those eligible for simplification. The costs considered were direct medical costs related to antiretroviral drugs, adverse events management, and monitoring activities.ResultsThe percentage of patients of the target population receiving ATV+r+3TC varies among the scenarios and is between 18.7% and 46.9% in year 1, increasing up to 56.3% and 84.4% in year 5. The antiretroviral treatment simplification strategy considered would lead to lower costs for the Italian NHS in a 5-year time horizon between −28.7 million € and −16.0 million €, with a reduction of costs between −22.1% (−3.6 million €) and −8.8% (−1.4 million €) in year 1 and up to −39.9% (−6.9 million €) and −26.6% (−4.6 million €) in year 5.ConclusionThe therapy simplification for patients receiving ATV+r+2 NRTIs to ATV+r+3TC at a national level would lead to a reduction of direct medical costs over a 5-year period for the Italian NHS.

Synthesis and Functional Characterization of Novel Sialyl LewisX Mimic-Decorated Liposomes for E-selectin-Mediated Targeting to Inflamed Endothelial Cells.

Sialyl LewisX (sLeX) is a natural ligand of E-selectin that is overexpressed by inflamed and tumor endothelium. Although sLeX is a potential ligand for drug targeting, synthesis of the tetrasaccharide is complicated with many reaction steps. In this study, structurally simplified novel sLeX analogues were designed and linked with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-polyethylene glycol-2000 (DSPE-PEG) for E-selectin-mediated liposomal delivery. The sLeX structural simplification strategies include (1) replacement of the Gal-GlcNAc disaccharide unit with lactose to reduce many initial steps and (2) substitution of neuraminic acid with a negatively charged group, i.e., 3'-sulfo, 3'-carboxymethyl (3'-CM), or 3'-(1-carboxy)ethyl (3'-CE). While all the liposomes developed were similar in particle size and charge, the 3'-CE sLeX mimic liposome demonstrated the highest uptake in inflammatory cytokine-treated human umbilical vein endothelial cells (HUVECs), being even more potent than native sLeX-decorated liposomes. Inhibition studies using antiselectin antibodies revealed that their uptake was mediated primarily by overexpressed E-selectin on inflamed HUVECs. Molecular dynamics simulations were performed to gain mechanistic insight into the E-selectin binding differences among native and mimic sLeX. The terminally branched methyl group of the 3'-CE sLeX mimic oriented and faced the bulk hydrophilic solution during E-selectin binding. Since this state is entropically unfavorable, the 3'-CE sLeX mimic molecule might be pushed toward the binding pocket of E-selectin by a hydrophobic effect, leading to a higher probability of hydrogen-bond formation than native sLeX and the 3'-CM sLeX mimic. This corresponded with the fact that the 3'-CE sLeX mimic liposome exhibited much greater uptake than the 3'-CM sLeX mimic liposome.

Synthesis and biological evaluation of potential inhibitors of the cysteine proteases cruzain and rhodesain designed by molecular simplification

Analogues of 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]indol-4-amine 1, a known cruzain inhibitor, were synthesized using a molecular simplification strategy. Five series of analogues were obtained: indole, pyrimidine, quinoline, aniline and pyrrole derivatives. The activity of the compounds was evaluated against the enzymes cruzain and rhodesain as well as against Trypanosoma cruzi amastigote and trypomastigote forms. The 4-aminoquinoline derivatives showed promising activity against both enzymes, with IC50 values ranging from 15 to 125µM. These derivatives were selective inhibitors for the parasitic proteases, being unable to inhibit mammalian cathepsins B and S. The most active compound against cruzain (compound 5a; IC50=15µM) is considerably more synthetically accessible than 1, while retaining its ligand efficiency. As observed for the original lead, compound 5a was shown to be a competitive enzyme inhibitor. In addition, it was also active against T. cruzi (IC50=67.7µM). Interestingly, the pyrimidine derivative 4b, although inactive in enzymatic assays, was highly active against T. cruzi (IC50=3.1µM) with remarkable selectivity index (SI=128) compared to uninfected fibroblasts. Both 5a and 4b exhibit drug-like physicochemical properties and are predicted to have a favorable ADME profile, therefore having great potential as candidates for lead optimization in the search for new drugs to treat Chagas disease.

Acquisition of English Onset Clusters by Chinese and Korean EFL Learners

This study accounts for the acquisition of English onset /s stop r/, /s stop/ and /stop r/ clusters by Chinese and Korean learners. Participants in this study include 10 low level and 10 high level Mandarin and Korean EFL learners each. The material includes 27 words of target clusters. The results show that Mandarin and Korean speakers tended to make more modification in the more marked tri-consonant clusters than the less marked bi-consonant clusters. In addition, high level subjects performed noticeably better than low level subjects in both groups. Korean and Mandarin speakers’ simplification strategies were different: Mandarin speakers inserted /u/ or /ə/ into the clusters, whereas Korean speakers preferred to replace one of the consonants (often /r/) with another consonant in tri-consonant clusters and /stop r/ clusters. Both Korean speakers and lower English proficiency Mandarin speakers mistakenly aspirated the voiceless stops /p, t, k/ in the onset /s stop/ clusters.

Pre-existent NRTI and NNRTI resistance impacts on maintenance of virological suppression in HIV-1-infected patients who switch to a tenofovir/emtricitabine/rilpivirine single-tablet regimen.

To evaluate the maintenance of virological suppression (VS) in antiretroviral-treated HIV-1-suppressed patients switching to a tenofovir/emtricitabine/rilpivirine (TDF/FTC/RPV) single-tablet regimen, by considering pre-existent resistance (pRes). pRes was evaluated according to resistance on all previous plasma genotypic resistance tests. Probability and predictors of virological rebound (VR) were evaluated. Three hundred and nine patients were analysed; 5.8% of them showed resistance to both NRTIs and NNRTIs, while 12.6% showed resistance to only one of these drug classes. By 72 weeks, the probability of VR was 11.3%. A higher probability of VR was found in the following groups: (i) patients with NRTI + NNRTI pRes compared with those harbouring NRTI or NNRTI pRes and with those without reverse transcriptase inhibitor pRes (39.2% versus 11.5% versus 9.4%, P < 0.0001); (ii) patients with a virus with full/intermediate resistance to both tenofovir/emtricitabine and rilpivirine compared with those having a virus with full/intermediate resistance to tenofovir/emtricitabine or rilpivirine and those having a virus fully susceptible to TDF/FTC/RPV (36.4% versus 17.8% versus 9.7%, P < 0.001); and (iii) patients with pre-therapy viraemia >500000 copies/mL compared with those with lower viraemia levels (>500 000: 16.0%; 100 000-500 000: 9.3%; <100 000 copies/mL: 4.8%, P = 0.009). pRes and pre-therapy viraemia >500000 copies/mL were independent predictors of VR by multivariable Cox regression. TDF/FTC/RPV as a treatment simplification strategy shows a very high rate of VS maintenance. The presence of pRes to both NRTIs and NNRTIs and a pre-therapy viraemia >500000 copies/mL are associated with an increased risk of VR, highlighting the need for an accurate selection of patients before simplification.

Navigating Institutional Complexity: The Production of Risk Culture in the Financial Sector

AbstractFollowing the financial crisis, financial sector organizations faced increased pressures to reform their ‘risk cultures’. In this paper, we argue that the emergence of regulatory and managerial attention to risk culture is symptomatic of pressures to redefine the fundamental ends of financial institutions and to rebalance the pre‐crisis emphasis on a logic of opportunity and risk‐taking with a logic of precaution and risk control. Based on the analysis of normative practitioner texts and on extended contact with regulators, advisers and corporate actors in the UK financial sector over four years, we show how this initial complexity ofendsis translated into uncertainty and conflict about themeansthrough which risk culture might become an object amenable to intervention. On this basis, we contribute to the growing literature on ‘institutional complexity’ by showing how organizational actors address conflicting pressures aboutbothends and means, and by discussing some key implications of their simplification strategies. Our analysis also contributes to recent studies of ‘means‐ends decoupling’, showing how means, ends and the object of intervention itself – risk culture – co‐evolve as they are reconstructed by organizational actors via their everyday practices.

Factors associated with virological rebound in HIV-infected patients receiving protease inhibitor monotherapy.

The Protease Inhibitor Monotherapy Versus Ongoing Triple Therapy (PIVOT) trial found that protease inhibitor monotherapy as a simplification strategy is well tolerated in terms of drug resistance but less effective than combination therapy in suppressing HIV viral load. We sought to identify factors associated with the risk of viral load rebound in this trial. PIVOT was a randomized controlled trial in HIV-positive adults with suppressed viral load for at least 24 weeks on combination therapy comparing a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy versus ongoing triple therapy. In participants receiving monotherapy, we analysed time to confirmed viral load rebound and its predictors using flexible parametric survival models. Of 290 participants initiating protease inhibitor monotherapy (80% darunavir, 14% lopinavir, and 6% other), 93 developed viral load rebound on monotherapy. The risk of viral load rebound peaked at 9 months after starting monotherapy and then declined to approximately 5 per 100 person-years from 18 months onwards. Independent predictors of viral load rebound were duration of viral load suppression before starting monotherapy (hazard ratio 0.81 per additional year <50 copies/ml; P < 0.001), CD4 cell count (hazard ratio 0.73 per additional 100 cells/μl for CD4 nadir; P = 0.008); ethnicity (hazard ratio 1.87 for nonwhite versus white, P = 0.025) but not the protease inhibitor agent used (P = 0.27). Patients whose viral load was analysed with the Roche TaqMan-2 assay had a 1.87-fold risk for viral load rebound compared with Abbott RealTime assay (P = 0.012). A number of factors can identify patients at low risk of rebound with protease inhibitor monotherapy, and this may help to better target those who may benefit from this management strategy.

Body Fluid Degradomics and Characterization of Basic N-Terminome.

Rapid improvements in instrumentation and data analysis make mass spectrometry-based proteomics the method of choice for global characterization of proteomes and discovery of protein-based biomarkers. On the contrary to tissue biopsies, body fluids-e.g., blood, wound fluid, urine, and saliva-are noninvasive and easy to collect and process. However, they are very complex and present high dynamic ranges of protein concentrations, rendering direct shotgun proteomics analysis as inefficient for identification of low-abundance proteins in these specimens. Sample prefractionation, immunoaffinity depletion of highly abundant proteins, and enrichment of posttranslational modifications (PTM) are common strategies for proteome simplification of body fluids. Combinatorial peptide ligand libraries (CPLL) relatively deplete high-abundance proteins by binding equimolar amounts of protein species in the sample and provide an elegant species-independent alternative to immunoaffinity-based approaches. By cleaving target proteins, proteases catalyze an irreversible PTM, whereby uncontrolled proteolysis is associated with many diseases. Thus, proteolytic events represent powerful indicators for disease progression and their specific identification in body fluids holds great promises for establishment of novel biomarkers. Quantitative N-terminal enrichment strategies, such as terminal amine isotopic labeling of substrates (TAILS) detect protease-generated neo-N-termini with high specificity and increase coverage of low-abundance proteins by inherent proteome simplification. In this chapter, we describe a protocol that combines the CPLL technology with iTRAQ-based TAILS to systematically characterize the basic N-terminome of body fluid proteomes and its alterations in disease conditions that we have successfully applied to explore the wound fluid degradome at multiple time points after skin injury.

Abacavir + dolutegravir + lamivudine for the treatment of HIV

ABSTRACTIntroduction: Since the last revision of both European and American guidelines (EACS and DHHS), new data from clinical trials and cohort studies, as well as experience in clinical practice, have prompted significant changes to the list of recommended/preferred options for the treatment of HIV infected patients, highlighted the role of INSTI-based regimens. Dolutegravir (DTG) in combination with abacavir/lamivudine (ABC/3TC) is one of these preferred regimens in multiple clinical scenarios, including treatment-naive and treatment-experienced patients.Areas covered: In this article we describe the coformulation of ABC/3TC/DTG in a fixed-dose combination (FDC) approved in September 2014 for the treatment of HIV infection. We focused our research on the efficacy and safety data resulting from phase 2 and 3 clinical study, particularly on the results of both SPRING (1 and 2) and SINGLE studies.Expert opinion: Triple combination therapy with ABC/3TC/DTG should be considered among the initial options for treatment-naive patients, being effective, well tolerated, with a high genetic barrier to resistance along with a convenient once-daily administration.In treatment-experienced patients the single-tablet regimen (STR) based on ABC/3TC/DTG could be used as simplification strategy in subjects with sustained viral suppression, as the high genetic barrier of DTG should ensure a safe switch from both NNRTI or PI based regimens.

Simplification of the unified gas kinetic scheme.

The unified gas kinetic scheme (UGKS) is an asymptotic preserving (AP) scheme for kinetic equations. It is superior for transition flow simulation and has been validated in the past years. However, compared to the well-known discrete ordinate method (DOM), which is a classical numerical method solving the kinetic equations, the UGKS needs more computational resources. In this study, we propose a simplification of the unified gas kinetic scheme. It allows almost identical numerical cost as the DOM, but predicts numerical results as accurate as the UGKS. In the simplified scheme, the numerical flux for the velocity distribution function and the numerical flux for the macroscopic conservative quantities are evaluated separately. The equilibrium part of the UGKS flux is calculated by analytical solution instead of the numerical quadrature in velocity space. The simplification is equivalent to a flux hybridization of the gas kinetic scheme for the Navier-Stokes (NS) equations and the conventional discrete ordinate method. Several simplification strategies are tested, through which we can identify the key ingredient of the Navier-Stokes asymptotic preserving property. Numerical tests show that, as long as the collision effect is built into the macroscopic numerical flux, the numerical scheme is Navier-Stokes asymptotic preserving, regardless the accuracy of the microscopic numerical flux for the velocity distribution function.

Giono, Translator or Reader of Moby-Dick?

The article discusses the interaction between reading and translating, in the case of the first unabridged translation of Moby-Dick into French by Jean Giono, Lucien Jacques and Joan Smith, published by Gallimard in 1941. After a brief survey of the status of that translation—an important cultural landmark in France—the paper examines what the paratext (Giono’s diary, notes and letters) and the typescripts reveal about a seemingly paradoxical situation: Giono’s keen reading of Moby-Dick on the one hand and the simplification and clarification strategies adopted in the translation on the other hand. A selection of stylistic analyses illustrates both the choices made by the translators and the part played by each participant in the project. It appears that Giono did not necessarily misread Moby-Dick, underestimating its scope and significance. Instead, after reading the novel, he grew indifferent to its translation and concentrated his energy on his own writing in which he re-invested his reading experience. As to the other co-translators, Joan Smith provided a word-for-word translation of the text that made no attempt at interpreting the text, while Lucien Jacques strove to re-write Smith’s literal first draft, in spite of his difficult position as a non-reader (albeit an enthusiastic one) of Moby-Dick.

An Analysis of Simplification Strategies in a Reading Textbook of Japanese as a Foreign Language

Reading is one of the bases of second language learning, and it can be most effective when the linguistic difficulty of the text matches the reader's level of language proficiency. The present paper reviews previous research on the readability and simplification of Japanese texts, and presents an analysis of a collection of simplified texts for learners of Japanese as a foreign language. The simplified texts are compared to their original versions to uncover different strategies used to make the texts more accessible to learners. The list of strategies thus obtained can serve as useful guidelines for assessing, selecting, and devising texts for learners of Japanese as a foreign language.

Induction of apoptosis in Ehrlich ascites tumour cells via p53 activation by a novel small-molecule MDM2 inhibitor - LQFM030.

The activation of the p53 pathway through the inhibition of MDM2 has been proposed as a novel therapeutic strategy against tumours. A series of cis-imidazoline analogues, termed nutlins, were reported to displace the recombinant p53 protein from its complex with MDM2 by binding to MDM2 in the p53 pocket, and exhibited an antitumour activity both in vitro and in vivo. Thus, the purpose of this study was to evaluate the antitumour properties of LQFM030 (2), a nutlin analogue created by employing the strategy of molecular simplification. LQFM030 (2) cytotoxicity was evaluated in Ehrlich ascites tumour (EAT) cells, p53 wild type, by the trypan blue exclusion test, and the mechanisms involved in EAT cell death were investigated by light and fluorescence microscopy, flow cytometry, real-time PCR and Western blotting. Our results demonstrate that LQFM030 has dose-dependent antiproliferative activity and cytotoxic activity on EAT cells, induces the accumulation of p53 protein and promotes cell cycle arrest and apoptosis. p53 gene transcription was unaffected by LQFM030 (2); however, MDM2 mRNA increased and MDM2 protein decreased. These results suggest that the small-molecule p53 activator LQFM030 (2) has the potential for further development as a novel cancer therapeutic agent.

Efficacy and safety of contemporary dual-drug antiretroviral regimens as first-line treatment or as a simplification strategy: a systematic review and meta-analysis

Some guidelines recommended two-drug antiretroviral therapies as alternative regimens to triple therapy in selected patients with the aim of reducing drug burden and toxicity and preserving future treatment options. We aimed to assess the efficacy and safety of dual-therapy versus triple therapy as first-line treatment or in treatment simplification. For this systematic review and meta-analysis, we searched Medline, Embase (via OVID), the Cochrane Trial Registry, and major conference proceedings for randomised trials published between Jan 1, 2008, and Dec 31, 2015. We included studies comparing dual-therapy (from two independent classes) antiretroviral regimens as a first-line or a switch strategy (in virologically suppressed individuals) with standard triple-drug regimens. Our primary outcome was the risk of virological failure (non-completion=failure) at the 48 week timepoint. We did a random-effect meta-analysis to pool the relative risk (RR) or odds ratio (OR) for each of the outcomes. For the primary outcome, we included 21 studies (11 first-line and ten switch studies), providing data for 4821 individuals (2478 in dual-therapy groups and 2343 in control groups). Overall, the RR of failure with dual-therapy compared with triple-therapy (control) groups was 1·14 (95% CI 0·91-1·43). In first-line studies, the RR of failure for dual-therapy versus control groups was 1·17 (0·94-1·47; I(2)=51%), which reduced to 1·05 (0·86-1·28; I(2)=26%) on exclusion of maraviroc-containing studies. In switch studies, the RR of failure for dual-therapy versus control groups was 1·21 (0·72-2·02; I(2)=67%), which reduced to 1·13 (0·64-1·99; I(2)=61%) after exclusion of maraviroc-containing studies. In patients with a baseline viral load of more than 100 000 copies per mL, RR of failure for dual-therapy versus control groups was 1·24 (1·03-1·49), which reduced to 1·18 (0·94-1·47) on excluding maraviroc-containing studies. We recorded the ORs for dual-therapy versus control groups for serious adverse events (1·16 [0·92-1·48]), adverse events (0·82 [0·52-1·28]), and mutations (2·11 [1·32-3·36]). Dual therapy, especially with regimens excluding maraviroc, could be safe and efficacious, particularly in patients with baseline viral loads of less than 100 000 copies per mL. However, dual therapy seems to have a greater risk of selecting resistance mutations compared with standard triple therapy. None.

Attitude stabilization of a flexible spacecraft under actuator complete failure

This paper considers the attitude and angular velocity stabilization problem of a class of flexible spacecraft under actuator complete failure. Firstly a new model simplification strategy is put forward to weaken the coupling effects. Then an adaptive observer-based estimation method is proposed to estimate the uncertainty of flexibility, based on which a feedback fault-tolerant control scheme is further developed which guarantees the system stability and asymptotic attitude converging properties. The simulation results illustrate the efficiency of the theoretical results.

Coping with Volume and Variety in Temporal Event Sequences: Strategies for Sharpening Analytic Focus.

The growing volume and variety of data presents both opportunities and challenges for visual analytics. Addressing these challenges is needed for big data to provide valuable insights and novel solutions for business, security, social media, and healthcare. In the case of temporal event sequence analytics it is the number of events in the data and variety of temporal sequence patterns that challenges users of visual analytic tools. This paper describes 15 strategies for sharpening analytic focus that analysts can use to reduce the data volume and pattern variety. Four groups of strategies are proposed: (1) extraction strategies, (2) temporal folding, (3) pattern simplification strategies, and (4) iterative strategies. For each strategy, we provide examples of the use and impact of this strategy on volume and/or variety. Examples are selected from 20 case studies gathered from either our own work, the literature, or based on email interviews with individuals who conducted the analyses and developers who observed analysts using the tools. Finally, we discuss how these strategies might be combined and report on the feedback from 10 senior event sequence analysts.

Effectiveness of Ritonavir-Boosted Protease Inhibitor Monotherapy in Clinical Practice Even with Previous Virological Failures to Protease Inhibitor-Based Regimens.

Background and ObjectiveSignificant controversy still exists about ritonavir-boosted protease inhibitor monotherapy (mtPI/rtv) as a simplification strategy that is used up to now to treat patients that have not experienced previous virological failure (VF) while on protease inhibitor (PI) -based regimens. We have evaluated the effectiveness of two mtPI/rtv regimens in an actual clinical practice setting, including patients that had experienced previous VF with PI-based regimens.MethodsThis retrospective study analyzed 1060 HIV-infected patients with undetectable viremia that were switched to lopinavir/ritonavir or darunavir/ritonavir monotherapy. In cases in which the patient had previously experienced VF while on a PI-based regimen, the lack of major HIV protease resistance mutations to lopinavir or darunavir, respectively, was mandatory. The primary endpoint of this study was the percentage of participants with virological suppression after 96 weeks according to intention-to-treat analysis (non-complete/missing = failure).ResultsA total of 1060 patients were analyzed, including 205 with previous VF while on PI-based regimens, 90 of whom were on complex therapies due to extensive resistance. The rates of treatment effectiveness (intention-to-treat analysis) and virological efficacy (on-treatment analysis) at week 96 were 79.3% (CI95, 76.8−81.8) and 91.5% (CI95, 89.6–93.4), respectively. No relationships were found between VF and earlier VF while on PI-based regimens, the presence of major or minor protease resistance mutations, the previous time on viral suppression, CD4+ T-cell nadir, and HCV-coinfection. Genotypic resistance tests were available in 49 out of the 74 patients with VFs and only four patients presented new major protease resistance mutations.ConclusionSwitching to mtPI/rtv achieves sustained virological control in most patients, even in those with previous VF on PI-based regimens as long as no major resistance mutations are present for the administered drug.