Simeprevir, daclatasvir and sofosbuvir for hepatitis C virus-infected patients with decompensated liver disease.

Approximately three million individuals in the United States are chronically infected with hepatitis C virus (HCV). Chronic HCV infection may lead to the development of compensated as well as decompensated liver cirrhosis. The Phase II IMPACT study was conducted in HCV genotype 1- or 4-infected cirrhotic patients with portal hypertension or decompensated liver disease and assessed for the first time the combination of the three direct-acting antivirals simeprevir, daclatasvir and sofosbuvir. Treatment-naïve or treatment-experienced adults with Child-Pugh (CP) score <7 (CP A) and evidence of portal hypertension, or CP score 7-9 (CP B), received 12 weeks of simeprevir 150 mg, daclatasvir 60 mg and sofosbuvir 400 mg, once daily. The primary efficacy endpoint was sustained virologic response 12 weeks after end of treatment (SVR12). Pharmacokinetics and safety were also assessed. Overall, 40 patients were enrolled (CP A: 19; CP B: 21). All 40 patients achieved SVR12. At week 8, the mean pharmacokinetic exposure to simeprevir, sofosbuvir, daclatasvir and GS-331007 (sofosbuvir metabolite) was 2.2-, 1.5-, 1.2- and 1.2-fold higher in patients with CP B than CP A, respectively. Grade 1/2 adverse events (AEs) occurred in 26 of 40 (65%) patients. One CP B patient had a Grade 3 AE (gastrointestinal haemorrhage), which was reported as a serious AE but not considered related to study drugs. Treatment for 12 weeks with simeprevir, daclatasvir and sofosbuvir was generally safe and well tolerated, and resulted in 100% of cirrhotic patients with portal hypertension or decompensated liver disease achieving SVR12.

Antimicrobial activity of a new synthetic peptide loaded in polylactic acid or poly(lactic-co-glycolic) acid nanoparticles against Pseudomonas aeruginosa, Escherichia coli O157:H7 and methicillin resistant Staphylococcus aureus (MRSA).

Nanocarrier systems are currently being developed for peptide, protein and gene delivery to protect them in the blood circulation and in the gastrointestinal tract. Polylactic acid (PLA) and poly(lactic-co-glycolic) acid (PLGA) nanoparticles loaded with a new antimicrobial GIBIM-P5S9K peptide were obtained by the double emulsion solvent extraction/evaporation method. PLA- and PLGA-NPs were spherical with sizes between 300 and 400 nm for PLA and 200 and 300 nm for PLGA and <0.3 polydispersity index as determined by dynamic light scattering and scanning electron microscopy), having the zeta potential of >20 mV. The peptide-loading efficiency of PLA-NP and PLGA-NPs was 75% and 55%, respectively. PLA- and PLGA-NPs released around 50% of this peptide over 8 h. In 10% human sera the size of peptide loaded PLA- and PLGA-NPs increased between 25.2% and 39.3%, the PDI changed from 3.2 to 5.1 and the surface charge from -7.15 to 14.6 mV. Both peptide loaded PLA- and PLGA-NPs at 0.5 µM peptide concentration inhibited the growth of Escherichia coli O157:H7 (E. coli O157:H7), methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas. aeruginosa (P. aeruginosa). In contrast, free peptide inhibited at 10 µM but did not inhibit at 0.5 and 1 µM. These PLA- and PLGA-NPs presented <10% hemolysis indicating that they are hemocompatible and promising for delivery and protection system of GIBIM-P5S9K peptide.

Interferon-free, direct-acting antiviral therapy for chronic hepatitis C.

The treatment environment for chronic hepatitis C has undergone a revolution, particularly in genotype 1. Gone are interferon-based therapy and its associated tolerability challenges, inadequate response rates and numerous baseline factors that affect response to therapy. New and emerging treatment regimens employ all-oral combinations of direct-acting antiviral agents, and results of clinical trials suggest that these regimens routinely achieve cure rates >90%, even in patients who failed prior interferon-based triple therapy. In 2015, three all-oral FDA-approved regiments will be available for genotype 1 (sofosbuvir /ledipasvir, sofosbuvir/simeprevir, and paritaprevir/r/ombitasvir/dasabuvir). Furthermore, new treatment combinations appear to be more tolerable and require shorter duration of therapy. We provide an overview of the classes of direct-acting antiviral agents (DAAs), the clinical factors affecting their integration into combination therapies and recent findings from trials of such combination therapies in patients with genotype 1 HCV infection.

Importance of HCV genotype 1 subtypes for drug resistance and response to therapy.

The treatment for patients infected with hepatitis C virus (HCV) genotype 1 has undergone major changes with the availability of direct-acting antivirals. Triple therapy, containing telaprevir or boceprevir, first-wave NS3 protease inhibitors, in combination with peginterferon and ribavirin, improved rates of sustained virologic response compared with peginterferon and ribavirin alone in patients with HCV genotype 1. However, the development of drug-resistant variants is a concern. In patients treated with telaprevir or boceprevir, different patterns of resistance are observed for the two major HCV genotype 1 subtypes, 1a and 1b. Genotype 1b is associated with a lower rate of resistant variant selection and better response to triple therapy compared with genotype 1a. Similar subtype-specific patterns have been observed for investigational direct-acting antivirals, including second-wave NS3 protease inhibitors, NS5A inhibitors and non-nucleoside NS5B inhibitors. This review explores resistance to approved and investigational direct-acting antivirals for the treatment of HCV, focusing on the differences between genotype 1a and genotype 1b. Finally, given the importance of HCV genotype 1 subtype on resistance and treatment outcomes, clinicians must also be aware of the tests currently available for genotype subtyping and their limitations.

A simple and inexpensive point-of-care test for hepatitis B surface antigen detection: serological and molecular evaluation.

Early identification of chronic hepatitis B is important for optimal disease management and prevention of transmission. Cost and lack of access to commercial hepatitis B surface antigen (HBsAg) immunoassays can compromise the effectiveness of HBV screening in resource-limited settings and among marginalized populations. High-quality point-of-care (POC) testing may improve HBV diagnosis in these situations. Currently available POC HBsAg assays are often limited in sensitivity. We evaluated the NanoSign(®) HBs POC chromatographic immunoassay for its ability to detect HBsAg of different genotypes and with substitutions in the 'a' determinant. Thirty-seven serum samples from patients with HBV infection, covering HBV genotypes A-G, were assessed for HBsAg titre with the Roche Elecsys HBsAg II quantification assay and with the POC assay. The POC assay reliably detected HBsAg at a concentration of at least 50 IU/mL for all genotypes, and at lower concentrations for some genotypes. Eight samples with substitutions in the HBV 'a' determinant were reliably detected after a 1/100 dilution. The POC strips were used to screen serum samples from 297 individuals at risk for HBV in local clinical settings (health fairs and outreach events) in parallel with commercial laboratory HBsAg testing (Quest Diagnostics EIA). POC testing was 73.7% sensitive and 97.8% specific for detection of HBsAg. Although the POC test demonstrated high sensitivity over a range of genotypes, false negatives were frequent in a clinical setting. Nevertheless, the POC assay offers advantages for testing in both developed and resource-limited countries due to its low cost (0.50$) and immediately available results.

[Role of plasma procalcitonin in the diagnosis of ventilator-associated pneumonia: systematic review and metaanalysis]. / Papel de la procalcitonina plasmática en el diagnóstico de la neumonía asociada a ventilación mecánica: revisión sistemática y metaanálisis.

OBJECTIVE: To determine the role of plasma procalcitonin (PCT) levels in diagnosing ventilator-associated pneumonia. DESIGN: A systematic review of publications prospectively assessing the diagnostic role of PCT in ventilator-associated pneumonia was carried out. The search was performed using Medline, Embase, the Cochrane Collaboration and MEDION, with reviewing of the references of retrieved articles. We extracted data that allowed the calculation of sensitivity, specificity, likelihood ratios and diagnostic odds ratio. Intervention Metaregression was performed to determine whether exposure to previous antibiotic treatment, the time to occurrence of ventilator-associated pneumonia and the type of patients had an impact upon the diagnostic performance of procalcitonin. RESULTS: Seven studies were considered (373 patients, 434 episodes). We found no publication bias or threshold effect. High plasma PCT levels were associated to an increased risk of suffering ventilator-associated pneumonia (OR: 8.39; 95% CI: 5.4-12.6). The pooled data on sensitivity, specificity, positive and negative likelihood ratio, and diagnostic odds ratio found were 76% (69-82), 79% (74-84), 4.35 (2.48-7.62), 0.26 (0.15-0.46) and 17.9 (10.1-31.7), respectively. Diagnostic yield was modified by prior exposure to antibiotics (rDOR 0.11, 0.02-0.069), but not by the type of critically ill patient or the time to occurrence of ventilator-associated pneumonia. CONCLUSIONS: Our results suggest that PCT provides additional information on the risk of VAP. Inclusion of PCT in diagnostic algorithms could improve their effectiveness.

Distribution and accumulation of Cd, Cu, Hg, Pb and Zn in the surface sediments of El Tobari Lagoon, central-East Gulf of California: An ecosystem associated with agriculture and aquaculture activities.

The purpose of this research is to provide a comprehensive assessment of the concentration levels and spatial variability of cadmium (Cd), copper (Cu), mercury (Hg), lead (Pb) and zinc (Zn) in El Tobari Lagoon in surface sediments during two seasons for several geochemical variables that could explain the observed heavy metal variability. Seventy-two surface sediments samples were collected in 12 different sites of the El Tobari Lagoon. Sediment samples were dried and subjected to acid extraction using a microwave system and five metals (Cd, Cu, Hg, Pb and Zn) were measured using atomic adsorption spectrometry. A certificate sediment material and blanks were used as quality control purposes. The enrichment factor (EF) and the index of geoaccumulation (Igeo) were calculated as index of metals contamination for the sediments, using aluminum as the conservative element. The five metals examined in sediments from El Tobari Lagoon exhibited a linear correlation with Al as result of the large specific surface areas of these sediment components and the chemical affinities between them. The metals contents in sites of the El Tobari Lagoon were variable, and Cd, Cu and Hg presented a seasonal behavior. The enrichment factor and index of geoaccumulation analysis indicated that Cd and Hg exhibited a certain extent (EF for Cd ranged from 4.10 to 10.29; EF for Hg ranged from 2.77 to 12.89) of anthropogenic pollution, while Cu showed sporadic (EF ranged from 0.43 to 2.54) anthropogenic contamination. The highest concentrations of Cd, Cu and Hg were found in the sites that regularly received discharge effluents from agriculture and aquaculture.

Comparative bioaccumulation of trace metals using six filter feeder organisms in a coastal lagoon ecosystem (of the central-east Gulf of California).

The Tobari Lagoon, located in the central-east coast of the Gulf of California, receives effluents from the Yaqui Valley, one of the most extensive agricultural areas of México. The Tobari Lagoon also receives effluents from nearby shrimp farms and untreated municipal sewage. Surface sediment samples and six different species of filter feeders (Crassostrea corteziensis, Crassostrea gigas, Chione gnidia, Anadara tuberculosa, Chione fluctifraga, and Fistulobalanus dentivarians) were collected during the dry and the rainy seasons and analyzed to determine concentrations of cadmium (Cd), copper (Cu), mercury (Hg), lead (Pb), and zinc (Zn). Seasonal variations in metal concentrations in sediment were evident, especially for Cd, Cu, Hg, and Zn. The total and bioavailable concentrations of the five metals are not elevated in comparison to other areas around the world. The percentages of bioavailable respect to total concentrations of the metals varied from 0.6 % in Hg to 50.2 % for Cu. In the organisms, Hg showed the lowest concentrations (ranged from 0.22 to 0.65 µg/g) while Zn showed the highest (ranged from 36.6 to 1,702 µg/g). Linear correlations between the levels of Cu, Pb, and Zn in the soft tissues of C. fluctifraga and C. gnidia, and A. tuberculosa and C. gnidia were found. Seasonal and interspecies variations in the metal levels in filter feeders were found; F. dentivarians, C. corteziensis, and C. gigas exhibited the highest levels, could be used as biomonitors of metals contamination in this area.

Survey of treatment recommendations for elderly patients with glioblastoma.

INTRODUCTION: Glioblastoma, which is the most commonly diagnosed primary CNS neoplasm, is more frequent in individuals aged 65 years or more. Our purpose is to identify how glioblastoma diagnosed in elderly population is treated by Spanish oncologists. MATERIAL AND METHODS: A survey was emailed to all members of Spanish Group for Neuro-oncology Research (GEINO). RESULTS: Twenty-six neuro-oncologists from 26 hospitals completed the survey. The answers were different depending on the age, performance status, and MGMT methylation status. Patients between 65 and 70 years of age are mainly treated with Stupp treatment. For patients between ages of 70 and 80 years, 46.2% made recommendations for Perry regimen, for both methylated and non-methylated patients. For patients older than 80  years, monotherapy treatment is considered more frequently. In cases of non-MGMT promoter methylation, systemic therapy with temozolomide is still recommended in many hospitals. CONCLUSION: Our research demonstrates there is no uniform approach to the management of elderly patients with glioblastoma among academic neuro-oncologists.

Baseline of Susceptibility to the Cry1F Protein in Mexican Populations of Fall Armyworm.

The fall armyworm, Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae), is currently the most important maize pest in Mexico. Its control is mainly based on the use of conventional insecticides. Additionally, Bt-maize expressing Cry1F protein represents an alternative to control this pest. We estimated the baseline susceptibility in Mexican populations of S. frugiperda to Cry1F protein. Twenty-eight geographical populations were field collected from Baja California Sur, Chihuahua, Coahuila, Durango, Sinaloa, Sonora, and Tamaulipas states. The F1 neonate larvae of each population were subjected to diet-overlay bioassay. After 7 d of Cry1F exposure, the percent mortality and the percent growth inhibition with respect to the untreated control were recorded (S-LAB). The LC50 ranged from 14.4 (6.3-24.0) (Cajeme 1, Sonora) to 161.8 ng/cm2 (92.0-320) (Ahumada 2, Chihuahua), while the LC95 was between 207.1 (145-363) (Obregón, Sonora) and 1,217 ng/cm2 (510.8-7,390.0) (Río Bravo 2, Tamaulipas). The sensitivity ratios at 50% mortality, (LC50 field/LC50 S-Lab) and 95% mortality were ≤6.45 and ≤5.05-fold, respectively. The 50% growth inhibition (GI50) ranged from 2.8 (0.008-9.3) (Obregón, Sonora) to 42.4 ng/cm2 (3.6-147.0) (Cajeme 1, Sonora). The GI95 was between 75.4 (San Luis Río Colorado, Sonora) to 1,198 ng/cm2 (Cajeme 1, Sonora). The relative inhibition at 50% of the growth, (RI50 = GI50 field /GI50 S-LAB) was ≤3.5 and at 95% (RI95) was ≤1.91-fold. These results indicated susceptibility to Cry1F protein in the evaluated populations of S. frugiperda.