Cost-effectiveness Analysis of Ocrelizumab for the Treatment of Relapsing and Primary Progressive Multiple Sclerosis in Portugal

Objectives: Ocrelizumab demonstrated significant clinical benefit for the treatment of relapsing (RMS) and primary progressive (PPMS) multiple sclerosis (MS), an incurable disease characterized by disability progression. This study evaluated the clinical and economic impact of ocrelizumab relative to current clinical practice, including other disease-modifying therapies (DMT), available in Portugal. Methods: Markov models for MS were adapted to estimate the impact of ocrelizumab across three patient populations: treatment-naïve RMS, previously treated RMS, and PPMS. Health states were defined according to the Expanded Disability Status Scale. For RMS, the model further captured the occurrence of relapses and progression to secondary progressive multiple sclerosis (SPMS). A lifetime time-horizon and Portuguese societal perspective were adopted. Results: For RMS patients, ocrelizumab was estimated to maximize the expected time (years) without progression to SPMS (10.50) relative to natalizumab (10.10), dimethyl fumarate (8.64), teriflunomide (8.39), fingolimod (8.38), interferon β-1a (8.33) and glatiramer acetate (8.18). As the most effective option, with quality-adjusted life year (QALY) gains between 0.3 and 1.2, ocrelizumab was found to be cost-saving relative to natalizumab and fingolimod, and presented incremental cost-effectiveness ratios (ICER) below €16,720/QALY relative to the remaining DMT. For PPMS patients, the ICER of ocrelizumab versus best supportive care was estimated at €78,858/QALY. Conclusions: Ocrelizumab provides important health benefits for RMS and PPMS patients, comparing favourably with other widely used therapies. In RMS, ocrelizumab was revealed to be either cost-saving or have costs-per-QALY likely below commonly accepted cost-effectiveness thresholds. In PPMS, ocrelizumab fills a clear clinical gap in the current clinical practice. Overall, ocrelizumab is expected to provide good value for money in addressing the need of MS patients.info:eu-repo/semantics/publishedVersio

Evaluation of endothelial function and subclinical atherosclerosis in association with hepatitis C virus in HIV-infected patients: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Relationship of hepatitis C virus (HCV) infection with an increased risk of cardiovascular disease (CVD) in HIV-infected patients remains controversial. We evaluated endothelial function and subclinical atherosclerosis in HIV-infected patients with and without HCV.</p> <p>Methods</p> <p>Flow-mediated dilatation (FMD) of the brachial artery and circulating levels of cell adhesion molecules (CAM) were measured in HCV/HIV-coinfected and HIV-monoinfected patients. Subclinical atherosclerosis was assessed by carotid intima-media thickness (cIMT).</p> <p>Results</p> <p>63 (31%) HCV/HIV-coinfected and 138 (69%) HIV-monoinfected patients were included. Median soluble vascular CAM-1 (sVCAM-1) and intercellular CAM-1 (sICAM-1) levels were significantly higher in HIV/HCV-coinfected patients (P < 0.001 for both cases). Median (interquartile range) FMD was 6.21% (2.86-9.62) in HCV/HIV-coinfected and 5.54% (2.13-9.13) in HIV-monoinfected patients (P = 0.37). Adjustment for variables associated with HCV and FMD disclosed similar results. FMD correlated inversely with cIMT and age. Carotid IMT did not differ between HCV/HIV-coinfected and HIV-monoinfected patients in unadjusted (0.61 [0.55-0.65] mm vs 0.60 [0.53-0.72] mm; P = 0.39) or adjusted analyses.</p> <p>Conclusion</p> <p>HCV infection was associated with higher levels of sICAM-1 and sVCAM-1, but no evidence of increased subclinical atherosclerosis was found when endothelial function was evaluated through FMD, or when assessing the cIMT.</p

Biodiversity of Fusarium species in Mexico associated with ear rot in maize, and their identification using a phylogenetic approach

Fusariumproliferatum, F. subglutinans, and F. verticillioides are known causes of ear and kernel rot in maize worldwide. In Mexico, only F. verticillioides and F. subglutinans, have been reported previously as causal agents of this disease. However, Fusarium isolates with different morphological characteristics to the species that are known to cause this disease were obtained in the Highland-Valley region of this country from symptomatic and symptomless ears of native and commercial maize genotypes. Moreover, while the morphological studies were not sufficient to identify the correct taxonomic position at the species level, analyses based in the Internal Transcribed Spacer region and the Nuclear Large Subunit Ribosomal partial sequences allowed for the identification of F. subglutinans, F. solani, and F. verticillioides, as well as four species (F. chlamydosporum, F. napiforme, F. poae, and F. pseudonygamai) that had not previously been reported to be associated with ear rot. In addition, F. napiforme and F. solani were absent from symptomless kernels. Phylogenetic analysis showed genetic changes in F. napiforme, and F. pseudonygamai isolates because they were not true clones, and probably constitute separate sibling species. The results of this study suggest that the biodiversity of Fusarium species involved in ear rot in Mexico is greater than that reported previously in other places in the world. This new knowledge will permit a better understanding of the relationship between all the species involved in ear rot disease and their relationship with maize

Dimerization of Hepatitis E Virus Capsid Protein E2s Domain Is Essential for Virus–Host Interaction

Hepatitis E virus (HEV), a non-enveloped, positive-stranded RNA virus, is transmitted in a faecal-oral manner, and causes acute liver diseases in humans. The HEV capsid is made up of capsomeres consisting of homodimers of a single structural capsid protein forming the virus shell. These dimers are believed to protrude from the viral surface and to interact with host cells to initiate infection. To date, no structural information is available for any of the HEV proteins. Here, we report for the first time the crystal structure of the HEV capsid protein domain E2s, a protruding domain, together with functional studies to illustrate that this domain forms a tight homodimer and that this dimerization is essential for HEV–host interactions. In addition, we also show that the neutralizing antibody recognition site of HEV is located on the E2s domain. Our study will aid in the development of vaccines and, subsequently, specific inhibitors for HEV

Three-Dimensional Characterization of the Vascular Bed in Bone Metastasis of the Rat by Microcomputed Tomography (MicroCT)

BackgroundAngiogenesis contributes to proliferation and metastatic dissemination of cancer cells. Anatomy of blood vessels in tumors has been characterized with 2D techniques (histology or angiography). They are not fully representative of the trajectories of vessels throughout the tissues and are not adapted to analyze changes occurring inside the bone marrow cavities. Methodology/Principal Findings We have characterized the vasculature of bone metastases in 3D at different times of evolution of the disease. Metastases were induced in the femur of Wistar rats by a local injection of Walker 256/B cells. Microfil®, (a silicone-based polymer) was injected at euthanasia in the aorta 12, 19 and 26 days after injection of tumor cells. Undecalcified bones (containing the radio opaque vascular casts) were analyzed by microCT, and a first 3D model was reconstructed. Bones were then decalcified and reanalyzed by microCT; a second model (comprising only the vessels) was obtained and overimposed on the former, thus providing a clear visualization of vessel trajectories in the invaded metaphysic allowing quantitative evaluation of the vascular volume and vessel diameter. Histological analysis of the marrow was possible on the decalcified specimens. Walker 256/B cells induced a marked osteolysis with cortical perforations. The metaphysis of invaded bones became progressively hypervascular. New vessels replaced the major central medullar artery coming from the diaphyseal shaft. They sprouted from the periosteum and extended into the metastatic area. The newly formed vessels were irregular in diameter, tortuous with a disorganized architecture. A quantitative analysis of vascular volume indicated that neoangiogenesis increased with the development of the tumor with the appearance of vessels with a larger diameter. Conclusion This new method evidenced the tumor angiogenesis in 3D at different development times of the metastasis growth. Bone and the vascular bed can be identified by a double reconstruction and allowed a quantitative evaluation of angiogenesis upon time

SH3 Domain-Mediated Recruitment of Host Cell Amphiphysins by Alphavirus nsP3 Promotes Viral RNA Replication

Among the four non-structural proteins of alphaviruses the function of nsP3 is the least well understood. NsP3 is a component of the viral replication complex, and composed of a conserved aminoterminal macro domain implicated in viral RNA synthesis, and a poorly conserved carboxyterminal region. Despite the lack of overall homology we noted a carboxyterminal proline-rich sequence motif shared by many alphaviral nsP3 proteins, and found it to serve as a preferred target site for the Src-homology 3 (SH3) domains of amphiphysin-1 and -2. Nsp3 proteins of Semliki Forest (SFV), Sindbis (SINV), and Chikungunya viruses all showed avid and SH3-dependent binding to amphiphysins. Upon alphavirus infection the intracellular distribution of amphiphysin was dramatically altered and colocalized with nsP3. Mutations in nsP3 disrupting the amphiphysin SH3 binding motif as well as RNAi-mediated silencing of amphiphysin-2 expression resulted in impaired viral RNA replication in HeLa cells infected with SINV or SFV. Infection of Balb/c mice with SFV carrying an SH3 binding-defective nsP3 was associated with significantly decreased mortality. These data establish SH3 domain-mediated binding of nsP3 with amphiphysin as an important host cell interaction promoting alphavirus replication

Effects of fishery protection on biometry and genetic structure of two target sea cucumber species from the Mediterranean Sea

Sea cucumber fisheries are now occurring in most of the tropical areas of the world, having expanded from its origin in the central Indo-Pacific. Due to the overexploitation of these resources and the increasing demand from Asian countries, new target species from Mediterranean Sea and northeastern Atlantic Ocean are being caught. The fishery effects on biometry and genetic structure of two target species (Holothuria polii and H. tubulosa) from Turkey, were assessed. The heaviest and largest individuals of H. polii were found into the non-fishery area of Kusadasi, also showing the highest genetic diversity. Similar pattern was detected in H. tubulosa, but only the weight was significantly higher in the protected area. However, the observed differences on the fishery effects between species, could be explained considering the different percentage of catches (80% for H. polii and 20% for H. tubulosa)

Two common nonsynonymous paraoxonase 1 (PON1) gene polymorphisms and brain astrocytoma and meningioma

<p>Abstract</p> <p>Background</p> <p>Human serum paraoxonase 1 (PON1) plays a major role in the metabolism of several organophosphorus compounds. The enzyme is encoded by the polymorphic gene <it>PON1</it>, located on chromosome 7q21.3. Aiming to identify genetic variations related to the risk of developing brain tumors, we investigated the putative association between common nonsynonymous <it>PON1 </it>polymorphisms and the risk of developing astrocytoma and meningioma.</p> <p>Methods</p> <p>Seventy one consecutive patients with brain tumors (43 with astrocytoma grade II/III and 28 with meningioma) with ages ranging 21 to 76 years, and 220 healthy controls subjects were analyzed for the frequency of the nonsynonymous <it>PON1 </it>genotypes L55M rs854560 and Q192R rs662. All participants were adult Caucasian individuals recruited in the central area of Spain.</p> <p>Results</p> <p>The frequencies of the <it>PON1 </it>genotypes and allelic variants of the polymorphisms <it>PON1 </it>L55M and <it>PON1 </it>Q192R did not differ significantly between patients with astrocytoma and meningioma and controls. The minor allele frequencies were as follows: <it>PON1 </it>55L, 0.398, 0.328 and 0.286 for patients with astrocytoma, meningioma and control individuals, respectively; <it>PON1 </it>192R, 0.341, 0.362 and 0.302 for patients with astrocytoma, meningioma and control individuals, respectively. Correction for age, gender, or education, made no difference in odds ratios and the <it>p </it>values remained non-significant. Haplotype association analyses did not identify any significant association with the risk of developing astrocytoma or meningioma.</p> <p>Conclusions</p> <p>Common nonsynonymous <it>PON1 </it>polymorphisms are not related with the risk of developing astrocytoma and meningioma.</p

A Dynamic Landscape for Antibody Binding Modulates Antibody-Mediated Neutralization of West Nile Virus

Neutralizing antibodies are a significant component of the host's protective response against flavivirus infection. Neutralization of flaviviruses occurs when individual virions are engaged by antibodies with a stoichiometry that exceeds a required threshold. From this “multiple-hit” perspective, the neutralizing activity of antibodies is governed by the affinity with which it binds its epitope and the number of times this determinant is displayed on the surface of the virion. In this study, we investigated time-dependent changes in the fate of West Nile virus (WNV) decorated with antibody in solution. Experiments with the well-characterized neutralizing monoclonal antibody (MAb) E16 revealed a significant increase in neutralization activity over time that could not be explained by the kinetics of antibody binding, virion aggregation, or the action of complement. Additional kinetic experiments using the fusion-loop specific MAb E53, which has limited neutralizing activity because it recognizes a relatively inaccessible epitope on mature virions, identified a role of virus “breathing” in regulating neutralization activity. Remarkably, MAb E53 neutralized mature WNV in a time- and temperature-dependent manner. This phenomenon was confirmed in studies with a large panel of MAbs specific for epitopes in each domain of the WNV envelope protein, with sera from recipients of a live attenuated WNV vaccine, and in experiments with dengue virus. Given enough time, significant inhibition of infection was observed even for antibodies with very limited, or no neutralizing activity in standard neutralization assays. Together, our data suggests that the structural dynamics of flaviviruses impacts antibody-mediated neutralization via exposure of otherwise inaccessible epitopes, allowing for antibodies to dock on the virion with a stoichiometry sufficient for neutralization