Comparative replication capacity of raltegravir-resistant strains and antiviral activity of the new-generation integrase inhibitor dolutegravir in human primary macrophages and lymphocytes

To evaluate the replication capacity and phenotypic susceptibility to dolutegravir and raltegravir of wild-type and raltegravir-resistant HIV-1 strains in several cellular systems

Standardized Hepatitis B Virus RNA Quantification in Untreated and Treated Chronic Patients: a Promising Marker of Infection Follow-Up.

The measurement and interpretation of HBV DNA and RNA levels in HBV infected patients treated with antiviral therapy supports the objective of HBV disease management. Here, we quantified circulating HBV RNA through a standardized and sensitive assay in follow-up samples from both naive and treated patients as a marker of infection evolution. HBV DNA (HBV DNA for use in Cobas 6800/8800 Automated Roche Molecular Systems), RNA (Roche HBV RNA Investigational Assay for use in the Cobas 6800/8800; Roche), HBeAg and HBsAg (Elycsys HBsAg chemiluminescence immunoassay by Cobas 8000; Roche), and core-related antigen (Lumipulse G chemiluminescence assay; Fujirebio) levels were measured in cohorts of untreated or nucleos(t)ide treated, HBV-infected subjects in an outpatient hospital setting. HBV DNA levels in untreated people were 3.6 log10 higher than corresponding RNA levels and were stable over 5 years of observation. While only five of 52 treated patients had DNA levels below the lower limit of quantification (10 IU/mL) at the end of follow-up, 13 had HBV RNA levels persistently above this limit, including eight with undetectable DNA. In samples with undetectable core-related antigen we observed a median HBsAg titer 2.7-fold higher than in samples with undetectable RNA (adjusted P = 0.012). Detectable HBV RNA with undetectable HBV DNA was a negative predictor of HBsAg decrease to a level ≤100 IU/mL (P = 0.03). In naive patients the difference between HBV DNA and RNA was higher than previously reported. HBV RNA rapidly decreased during treatment. However, in some cases, it was detectable even after years of effective therapy, being a negative predictor of HBsAg decrease. The investigational RNA assay for use on the Cobas 6800/8800 instruments is a sensitive and standardized method that could be applied in general management of HBV infection. IMPORTANCE This study focused on the quantification of circulating HBV RNA by using a standardized and sensitive assay. Thanks to this system we observed a higher difference between circulating HBV DNA and RNA than previously reported. In treated patients, HBV RNA decreased together with DNA, although some patients presented detectable levels even after years of successful antiviral treatment, suggesting a persistent viral transcription. Of note, the detection of viral RNA when HBV DNA is undetectable was a negative predictor of HBsAg decrease to a level ≤100 IU/mL. This assay could be extremely helpful in HBV patients management to study viral transcription and to identify those treated patients that may achieve sustained viral suppression

A general piecewise multi-state survival model: Application to breast cancer

Multi-state models are considered in the field of survival analysis for modelling illnesses that evolve through several stages over time. Multi-state models can be developed by applying several techniques, such as non-parametric, semi-parametric and stochastic processes, particularly Markov processes. When the development of an illness is being analysed, its progression is tracked periodically. Medical reviews take place at discrete times, and a panel data analysis can be formed. In this paper, a discrete-time piecewise non-homogeneous Markov process is constructed for modelling and analysing a multi-state illness with a general number of states. The model is built, and relevant measures, such as survival function, transition probabilities, mean total times spent in a group of states and the conditional probability of state change, are determined. A likelihood function is built to estimate the parameters and the general number of cut-points included in the model. Time-dependent covariates are introduced, the results are obtained in a matrix algebraic form and the algorithms are shown. The model is applied to analyse the behaviour of breast cancer. A study of the relapse and survival times of 300 breast cancer patients who have undergone mastectomy is developed. The results of this paper are implemented computationally with MATLAB and R.Ministerio de Economía y Competitividad FQM-307European Regional Development Fund (ERDF) MTM2017-88708-PUniversity of Milano-Bicocca 2014-ATE-022

Novel HBsAg mutations correlate with hepatocellular carcinoma, hamper HBsAg secretion and promote cell proliferation in vitro

An impaired HBsAg-secretion can increase HBV oncogenic-properties. Here, we investigate genetic-determinants in HBsAg correlated with HBV-induced hepatocellular carcinoma (HCC), and their impact on HBsAg-secretion and cell-proliferation

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

Dissipative and Non-dissipative Single-Qubit Channels: Dynamics and Geometry

Single-qubit channels are studied under two broad classes: amplitude damping channels and generalized depolarizing channels. A canonical derivation of the Kraus representation of the former, via the Choi isomorphism is presented for the general case of a system's interaction with a squeezed thermal bath. This isomorphism is also used to characterize the difference in the geometry and rank of these channel classes. Under the isomorphism, the degree of decoherence is quantified according to the mixedness or separability of the Choi matrix. Whereas the latter channels form a 3-simplex, the former channels do not form a convex set as seen from an ab initio perspective. Further, where the rank of generalized depolarizing channels can be any positive integer upto 4, that of amplitude damping ones is either 2 or 4. Various channel performance parameters are used to bring out the different influences of temperature and squeezing in dissipative channels. In particular, a noise range is identified where the distinguishability of states improves inspite of increasing decoherence due to environmental squeezing.Comment: 12 pages, 4 figure

Systemic Treatments for Mesothelioma: Standard and Novel

Systemic therapy is the only treatment option for the majority of mesothelioma patients, for whom age, co-morbid medical illnesses, non-epithelial histology, and locally advanced disease often preclude surgery. For many years, chemotherapy had a minimal impact on the natural history of this cancer, engendering considerable nihilism. Countless drugs were evaluated, most of which achieved response rates below 20% and median survival of <1 year. Several factors have hampered the evaluation of systemic regimens in patients with mesothelioma. The disease is uncommon, affecting only about 2500 Americans annually. Thus, most clinical trials are small, and randomized studies are challenging to accrue. There is significant heterogeneity within the patient populations of these small trials, for several reasons. Since all of the staging systems for mesothelioma are surgically based, it is almost impossible to accurately determine the stage of a patient who has not been resected. Patients with very early stage disease may be lumped together with far more advanced patients in the same study. The disease itself is heterogenous, with many different prognostic factors, most notably three pathologic subtypes—epithelial, sarcomatoid, and biphasic—that have different natural histories, and varying responses to treatment. Finally, response assessment is problematic, since pleural-based lesions are difficult to measure accurately and reproducibly. Assessment criteria often vary between trials, making some cross-trial comparisons difficult to interpret. Despite these limitations, in recent years, there has been a surge of optimism regarding systemic treatment of this disease. Several cytotoxic agents have been shown to generate reproducible responses, improve quality of life, or prolong survival in mesothelioma. Drugs with single-agent activity include pemetrexed, raltitrexed, vinorelbine, and vinflunine. The addition of pemetrexed or raltitrexed to cisplatin prolongs survival. The addition of cisplatin to pemetrexed, raltitrexed, gemcitabine, irinotecan, or vinorelbine improves response rate. The combination of pemetrexed plus cisplatin is considered the benchmark front-line regimen for this disease, based on a phase III trial in 456 patients that yielded a response rate of 41% and a median survival of 12.1 months. Vitamin supplementation with folic acid is essential to decrease toxicity, though recent data suggests that there may be an optimum dose of folic acid that should be administered; higher doses may diminish the effectiveness of pemetrexed. There are also several unresolved questions about the duration and timing of treatment with pemetrexed that are the subject of planned clinical trials. It is essential to recognize that the improvements observed with the pemetrexed/cisplatin combination, though real, are still modest. Other active drugs or drug combinations may be more appropriate for specific individuals, and further research is still needed to improve upon these results. Since the majority of mesotheliomas in the United States occur in the elderly, non-cisplatin-containing pemetrexed combinations may be more appropriate for some patients. Now that effective agents have been developed for initial treatment, several classical cytotoxic drugs and many novel agents are being evaluated in the second-line setting. These include drugs targeted against the epidermal growth factor, platelet-derived growth factor, vascular endothelial growth factor, src kinase, histone deacetylase, the proteasome, and mesothelin. Given the progress made in recent years, there is reason to believe that more effective treatments will continue to be developed

The production of nominal and verbal inflection in an agglutinative language: evidence from Hungarian

The contrast between regular and irregular inflectional morphology has been useful in investigating the functional and neural architecture of language. However, most studies have examined the regular/irregular distinction in non-agglutinative Indo-European languages (primarily English) with relatively simple morphology. Additionally, the majority of research has focused on verbal rather than nominal inflectional morphology. The present study attempts to address these gaps by introducing both plural and past tense production tasks in Hungarian, an agglutinative non-Indo-European language with complex morphology. Here we report results on these tasks from healthy Hungarian native-speaking adults, in whom we examine regular and irregular nominal and verbal inflection in a within-subjects design. Regular and irregular nouns and verbs were stem on frequency, word length and phonological structure, and both accuracy and response times were acquired. The results revealed that the regular/irregular contrast yields similar patterns in Hungarian, for both nominal and verbal inflection, as in previous studies of non-agglutinative Indo-European languages: the production of irregular inflected forms was both less accurate and slower than of regular forms, both for plural and past-tense inflection. The results replicate and extend previous findings to an agglutinative language with complex morphology. Together with previous studies, the evidence suggests that the regular/irregular distinction yields a basic behavioral pattern that holds across language families and linguistic typologies. Finally, the study sets the stage for further research examining the neurocognitive substrates of regular and irregular morphology in an agglutinative non-Indo-European language

Phase Ia Clinical Evaluation of the Safety and Immunogenicity of the Plasmodium falciparum Blood-Stage Antigen AMA1 in ChAd63 and MVA Vaccine Vectors

Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question