Ability to Work and Employment Rates in Human Immunodeficiency Virus (HIV)-1-Infected Individuals Receiving Combination Antiretroviral Therapy: The Swiss HIV Cohort Study

Background.  Limited data exist on human immunodeficiency virus (HIV)-infected individuals' ability to work after receiving combination antiretroviral therapy (cART). We aimed to investigate predictors of regaining full ability to work at 1 year after starting cART. Methods.  Antiretroviral-naive HIV-infected individuals <60 years who started cART from January 1998 through December 2012 within the framework of the Swiss HIV Cohort Study were analyzed. Inability to work was defined as a medical judgment of the patient's ability to work as 0%. Results.  Of 5800 subjects, 4382 (75.6%) were fully able to work, 471 (8.1%) able to work part time, and 947 (16.3%) were unable to work at baseline. Of the 947 patients unable to work, 439 (46.3%) were able to work either full time or part time at 1 year of treatment. Predictors of recovering full ability to work were non-white ethnicity (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.20-3.54), higher education (OR, 4.03; 95% CI, 2.47-7.48), and achieving HIV-ribonucleic acid <50 copies/mL (OR, 1.83; 95% CI, 1.20-2.80). Older age (OR, 0.55; 95% CI, .42-.72, per 10 years older) and psychiatric disorders (OR, 0.24; 95% CI, .13-.47) were associated with lower odds of ability to work. Recovering full ability to work at 1 year increased from 24.0% in 1998-2001 to 41.2% in 2009-2012, but the employment rates did not increase. Conclusions.  Regaining full ability to work depends primarily on achieving viral suppression, absence of psychiatric comorbidity, and favorable psychosocial factors. The discrepancy between patients' ability to work and employment rates indicates barriers to reintegration of persons infected with HIV.

A vaccine formulation combining rhoptry proteins NcROP40 and NcROP2 improves pup survival in a pregnant mouse model of neosporosis.

Currently there are no effective vaccines for the control of bovine neosporosis. During the last years several subunit vaccines based on immunodominant antigens and other proteins involved in adhesion, invasion and intracellular proliferation of Neospora caninum have been evaluated as targets for vaccine development in experimental mouse infection models. Among them, the rhoptry antigen NcROP2 and the immunodominant NcGRA7 protein have been assessed with varying results. Recent studies have shown that another rhoptry component, NcROP40, and NcNTPase, a putative dense granule antigen, exhibit higher expression levels in tachyzoites of virulent N. caninum isolates, suggesting that these could be potential vaccine candidates to limit the effects of infection. In the present work, the safety and efficacy of these recombinant antigens formulated in Quil-A adjuvant as monovalent vaccines or pair-wise combinations (rNcROP40+rNcROP2 and rNcGRA7+rNcNTPase) were evaluated in a pregnant mouse model of neosporosis. All the vaccine formulations elicited a specific immune response against their respective native proteins after immunization. Mice vaccinated with rNcROP40 and rNcROP2 alone or in combination produced the highest levels of IFN-γ and exhibited low parasite burdens and low IgG antibody levels after the challenge. In addition, most of the vaccine formulations were able to increase the median survival time in the offspring. However, pup survival only ensued in the groups vaccinated with rNcROP40+rNcROP2 (16.2%) and rNcROP2 (6.3%). Interestingly, vertical transmission was not observed in those survivor pups immunized with rNcROP40+rNcROP2, as shown by PCR analyses. These results show a partial protection against N. caninum infection after vaccination with rNcROP40+rNcROP2, suggesting a synergistic effect of the two recombinant rhoptry antigens.

Optimally Combining Censored and Uncensored Datasets

Economists and other social scientists often face situations where they have access to two datasets that they can use but one set of data suffers from censoring or truncation. If the censored sample is much bigger than the uncensored sample, it is common for researchers to use the censored sample alone and attempt to deal with the problem of partial observation in some manner. Alternatively, they simply use only the uncensored sample and ignore the censored one so as to avoid biases. It is rarely the case that researchers use both datasets together, mainly because they lack guidance about how to combine them. In this paper, we develop a tractable semiparametric framework for combining the censored and uncensored datasets so that the resulting estimators are consistent, asymptotically normal, and use all information optimally. When the censored sample, which we refer to as the master sample, is much bigger than the uncensored sample (which we call the refreshment sample), the latter can be thought of as providing identification where it is otherwise absent. In contrast, when the refreshment sample is large and could typically be used alone, our methodology can be interpreted as using information from the censored sample to increase effciency. To illustrate our results in an empirical setting, we show how to estimate the effect of changes in compulsory schooling laws on age at first marriage, a variable that is censored for younger individuals. We also demonstrate how refreshment samples for this application can be created by matching cohort information across census datasets.

Why does low dose morphine augment fentanyl analgesia?

Opioids dominate the field of pain management because of their ability to provide analgesia in many medical circumstances. However, side effects including respiratory depression, constipation, tolerance, physical dependence, and the risk of addiction limit their clinical utility. Fear of these side effects results in the under-treatment of acute pain. For many years, research has focused on ways to improve the therapeutic index (the ratio of desirable analgesic effects to undesirable side effects) of opioids. One strategy, combining opioid agonists that bind to different opioid receptor types, may prove successful.^ We discovered that subcutaneous co-administration of a moderately analgesic dose of the mu-opioid receptor (MOR) selective agonist fentanyl (20μg/kg) with subanalgesic doses of the less MOR-specific agonist morphine (100ng/kg-100μg/kg), augmented acute fentanyl analgesia in rats. Parallel [35S]GTPγS binding studies using naïve rat substantia gelatinosa membrane treated with fentanyl (4μM) and morphine (1nM-1pM) demonstrated a 2-fold increase in total G-protein activation. This correlation between morphine-induced augmentation of fentanyl analgesia and G-protein activation led to our proposal that interactions between MORs and DORs underlie opioid-induced augmentation. We discovered that morphine-induced augmentation of fentanyl analgesia and G-protein activity was mediated by DORs. Adding the DOR-selective antagonist naltrindole (200ng/kg, 40nM) at doses that did not alter the analgesic or G-protein activation of fentanyl, blocked increases in analgesia and G-protein activation induced by fentanyl/morphine combinations. Equivalent doses of the MOR-selective antagonist cyprodime (20ng/kg, 4nM) did not block augmentation. Substitution of the DOR-selective agonist SNC80 for morphine yielded similar results, further supporting our conclusion that interactions between MORs and DORs are responsible for morphine-induced augmentation of fentanyl analgesia and G-protein activation. Confocal microscopy of rat substantia gelatinosa showed that changes in the rate of opioid receptor internalization did not account for these effects.^ In conclusion, fentanyl analgesia augmentation by subanalgesic morphine is mediated by increased G-protein activation resulting from functional interactions between MORs and DORs, not changes in MOR internalization. Additional animal and clinical studies are needed to determine whether side effect incidence changes following opioid co-administration. If side effect incidence decreases or remains unchanged, these findings could have important implications for clinical pain treatment. ^

A hybrid method in combining treatment effects from matched and unmatched studies

In the biomedical studies, the general data structures have been the matched (paired) and unmatched designs. Recently, many researchers are interested in Meta-Analysis to obtain a better understanding from several clinical data of a medical treatment. The hybrid design, which is combined two data structures, may create the fundamental question for statistical methods and the challenges for statistical inferences. The applied methods are depending on the underlying distribution. If the outcomes are normally distributed, we would use the classic paired and two independent sample T-tests on the matched and unmatched cases. If not, we can apply Wilcoxon signed rank and rank sum test on each case. ^ To assess an overall treatment effect on a hybrid design, we can apply the inverse variance weight method used in Meta-Analysis. On the nonparametric case, we can use a test statistic which is combined on two Wilcoxon test statistics. However, these two test statistics are not in same scale. We propose the Hybrid Test Statistic based on the Hodges-Lehmann estimates of the treatment effects, which are medians in the same scale.^ To compare the proposed method, we use the classic meta-analysis T-test statistic on the combined the estimates of the treatment effects from two T-test statistics. Theoretically, the efficiency of two unbiased estimators of a parameter is the ratio of their variances. With the concept of Asymptotic Relative Efficiency (ARE) developed by Pitman, we show ARE of the hybrid test statistic relative to classic meta-analysis T-test statistic using the Hodges-Lemann estimators associated with two test statistics.^ From several simulation studies, we calculate the empirical type I error rate and power of the test statistics. The proposed statistic would provide effective tool to evaluate and understand the treatment effect in various public health studies as well as clinical trials.^

Design, synthesis and cellular and molecular pharmacology of 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401): A novel non-cross-resistant anthracycline antibiotic with the intrinsic ability to circumvent P -glycoprotein-mediated drug resistance

We designed and synthesized a novel daunorubicin (DNR) analogue that effectively circumvents P-glycoprotein (P-gp)-mediated drug resistance. The fully protected carbohydrate intermediate 1,2-dibromoacosamine was prepared from acosamine and effectively coupled to daunomycinone in high yield. Deprotection under alkaline conditions yielded 2$\sp\prime$-bromo-4$\sp\prime$-epidaunorubicin (WP401). The in vitro cytotoxicity and cellular and molecular pharmacology of WP401 were compared with those of DNR in a panel of wild-type cell lines (KB-3-1, P388S, and HL60S) and their multidrug-resistant (MDR) counterparts (KB-V1, P388/DOX, and HL60/DOX). Fluorescent spectrophotometry, flow cytometry, and confocal laser scanning microscopy were used to measure intracellular accumulation, retention, and subcellular distribution of these agents. All MDR cell lines exhibited reduced DNR uptake that was restored, upon incubation with either verapamil (VER) or cyclosporin A (CSA), to the level found in sensitive cell lines. In contrast, the uptake of WP401 was essentially the same in the absence or presence of VER or CSA in all tested cell lines. The in vitro cytotoxicity of WP401 was similar to that of DNR in the sensitive cell lines but significantly higher in resistant cell lines (resistance index (RI) of 2-6 for WP401 vs 75-85 for DNR). To ascertain whether drug-mediated cytotoxicity and retention were accompanied by DNA strand breaks, DNA single- and double-strand breaks were assessed by alkaline elution. High levels of such breaks were obtained using 0.1-2 $\mu$g/mL of WP401 in both sensitive and resistant cells. In contrast, DNR caused strand breaks only in sensitive cells and not much in resistant cells. We also compared drug-induced DNA fragmentation similar to that induced by DNR. However, in P-gp-positive cells, WP401 induced 2- to 5-fold more DNA fragmentation than DNR. This increased DNA strand breakage by WP401 was correlated with its increased uptake and cytotoxicity in these cell lines. Overall these results indicate that WP401 is more cytotoxic than DNR in MDR cells and that this phenomenon might be related to the reduced basicity of the amino group and increased lipophilicity of WP401. ^

Probability inundation map for a scenario combining storm surge and sea-level rise

Coastal managers require reliable spatial data on the extent and timing of potential coastal inundation, particularly in a changing climate. Most sea level rise (SLR) vulnerability assessments are undertaken using the easily implemented bathtub approach, where areas adjacent to the sea and below a given elevation are mapped using a deterministic line dividing potentially inundated from dry areas. This method only requires elevation data usually in the form of a digital elevation model (DEM). However, inherent errors in the DEM and spatial analysis of the bathtub model propagate into the inundation mapping. The aim of this study was to assess the impacts of spatially variable and spatially correlated elevation errors in high-spatial resolution DEMs for mapping coastal inundation. Elevation errors were best modelled using regression-kriging. This geostatistical model takes the spatial correlation in elevation errors into account, which has a significant impact on analyses that include spatial interactions, such as inundation modelling. The spatial variability of elevation errors was partially explained by land cover and terrain variables. Elevation errors were simulated using sequential Gaussian simulation, a Monte Carlo probabilistic approach. 1,000 error simulations were added to the original DEM and reclassified using a hydrologically correct bathtub method. The probability of inundation to a scenario combining a 1 in 100 year storm event over a 1 m SLR was calculated by counting the proportion of times from the 1,000 simulations that a location was inundated. This probabilistic approach can be used in a risk-aversive decision making process by planning for scenarios with different probabilities of occurrence. For example, results showed that when considering a 1% probability exceedance, the inundated area was approximately 11% larger than mapped using the deterministic bathtub approach. The probabilistic approach provides visually intuitive maps that convey uncertainties inherent to spatial data and analysis.

Ocean acidification alters the material properties of Mytilus edulis shells

Ocean acidification (OA) and the resultant changing carbonate saturation states is threatening the formation of calcium carbonate shells and exoskeletons of marine organisms. The production of biominerals in such organisms relies on the availability of carbonate and the ability of the organism to biomineralize in changing environments. To understand how biomineralizers will respond to OA the common blue mussel, Mytilus edulis, was cultured at projected levels of pCO2 (380, 550, 750, 1000 µatm) and increased temperatures (ambient, ambient plus 2°C). Nanoindentation (a single mussel shell) and microhardness testing were used to assess the material properties of the shells. Young's modulus (E), hardness (H) and toughness (KIC) were measured in mussel shells grown in multiple stressor conditions. OA caused mussels to produce shell calcite that is stiffer (higher modulus of elasticity) and harder than shells grown in control conditions. The outer shell (calcite) is more brittle in OA conditions while the inner shell (aragonite) is softer and less stiff in shells grown under OA conditions. Combining increasing ocean pCO2 and temperatures as projected for future global ocean appears to reduce the impact of increasing pCO2 on the material properties of the mussel shell. OA may cause changes in shell material properties that could prove problematic under predation scenarios for the mussels; however, this may be partially mitigated by increasing temperature.

Assessment of the effects of ozone exposure and plant competition on the reproductive ability of three therophytic clover species from Iberian pastures

Ozone (O3) phytototoxicity has been reported on a wide range of crops and wild Central European plantspecies, however no information has been provided regarding the sensitivity of plantspecies from dehesa Mediterranean therophytic grasslands in spite of their great plantspecies richness and the high O3 levels that are recorded in this area. A study was carried out in open-top chambers (OTCs) to assess the effects of O3 and competition on the reproductiveability of threecloverspecies: Trifolium cherleri, Trifolium subterraneum and Trifolium striatum. A phytometer approach was followed, therefore plants of these species were grown in mesoscosms composed of monocultures of four plants of each species, of threeplants of each species competing against a Briza maxima individual or of a single plant of each cloverspecies competing with threeB. maximaplants. Three O3 treatments were adopted: charcoal filtered air (CFA), non-filtered air (NFA) and non-filtered air supplemented with 40 nl l−1 of O3 (NFA+). The different mesocosms were exposed to the different O3 treatments for 45 days and then they remained in the open. Ozoneexposure caused reductions in the flower biomass of the threecloverspecies assessed. In the case of T. cherleri and T. subterraneum this effect was found following their exposure to the different O3 treatments during their vegetative period. An attenuation of these effects was found when the plants remained in the open. Ozone-induced detrimental effects on the seed output of T. striatum were also observed. The flower biomass of the cloverplants grown in monocultures was greater than when competing with one or threeB. maxima individuals. An increased flower biomass was found in the CFA monoculture mesocosms of T. cherleri when compared with the remaining mesocosms, once the plants were exposed in the open for 60 days. The implications of these effects on the performance of dehesa acid grasslands and for the definition of O3 critical levels is discussed

MIRACLE at Ad-Hoc CLEF 2005: Merging and Combining Without Using a Single Approach

This paper presents the 2005 Miracle’s team approach to the Ad-Hoc Information Retrieval tasks. The goal for the experiments this year was twofold: to continue testing the effect of combination approaches on information retrieval tasks, and improving our basic processing and indexing tools, adapting them to new languages with strange encoding schemes. The starting point was a set of basic components: stemming, transforming, filtering, proper nouns extraction, paragraph extraction, and pseudo-relevance feedback. Some of these basic components were used in different combinations and order of application for document indexing and for query processing. Second-order combinations were also tested, by averaging or selective combination of the documents retrieved by different approaches for a particular query. In the multilingual track, we concentrated our work on the merging process of the results of monolingual runs to get the overall multilingual result, relying on available translations. In both cross-lingual tracks, we have used available translation resources, and in some cases we have used a combination approach.

Multi-agent Architecture for Heterogeneous Reasoning under Uncertainty Combining MSBN and Ontologies in Distributed Network Diagnosis

This article proposes a MAS architecture for network diagnosis under uncertainty. Network diagnosis is divided into two inference processes: hypothesis generation and hypothesis confirmation. The first process is distributed among several agents based on a MSBN, while the second one is carried out by agents using semantic reasoning. A diagnosis ontology has been defined in order to combine both inference processes. To drive the deliberation process, dynamic data about the influence of observations are taken during diagnosis process. In order to achieve quick and reliable diagnoses, this influence is used to choose the best action to perform. This approach has been evaluated in a P2P video streaming scenario. Computational and time improvements are highlight as conclusions.