Cost-effectiveness analysis of the first-line EGFR-TKIs in patients with advanced EGFR-mutated non-small-cell lung cancer.

AIM: To evaluate the cost-effectiveness of first-line treatments, such as erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib, for patients diagnosed with stage IIIB/IV NSCLC harboring EGFR mutations. MATERIALS & METHODS: A partitioned survival model was developed to estimate quality-adjusted life-year (QALY) and incremental cost-effectiveness ratio (ICER) from the perspective of the Spanish National Health System. Two Bayesian NMAs were performed independently, by using the polynomial fraction method to fit Kaplan-Meier curves for overall survival and progression-free survival. Deterministic and probabilistic sensitivity analyses were performed to evaluate the uncertainty. RESULTS: The ICER was calculated for the four first-line treatments by comparing them with gefitinib, and the ratios obtained were as follows: €166,416/QALY for osimertinib, €183,682/QALY for dacomitinib, €167,554/QALY for afatinib, €36,196/QALY for erlotinib. It was seen that patients who received osimertinib presented higher QALYs (0.49), followed by dacomitinib (0.33), afatinib (0.32), erlotinib (0.31), and gefitinib (0.28). CONCLUSIONS: Gefitinib is the most cost-effective treatment. In terms of QALYs gained, Osimertinib was more effective than all other TKIs. Nevertheless, with a Spanish threshold of €24,000/QALY, the reduction in the acquisition cost of osimertinib will have to be greater than 70%, to obtain a cost-effectiveness alternative.

Interferon-free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review.

Treatment of hepatitis C virus (HCV) infection with genotype 3 remains a challenge. The HCV elimination rate with direct-acting antivirals (DAAs) is lower than the values reported for other HCV genotypes. In addition, genotype 3-infected patients have a higher risk of disease progression and hepatocellular carcinoma. The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon-free regimens. A literature search was conducted in the PubMed/Medline, Embase and Web of Science electronic databases. Trials enrolling patients with chronic hepatitis C infection treated with DAAs with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcome was sustained virological response (SVR). In total, 323 references were identified, and 29 met the inclusion criteria: 18 general clinical trials, three general observational studies, three studies in patients with decompensated liver cirrhosis and four studies in HIV-HCV-coinfected patients. Overall, 4068 genotype 3 patients were included. As compared with sofosbuvir and ribavirin for 24 weeks, sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks provided higher SVR rates, particularly in patients with cirrhosis. Treatment of patients with decompensated cirrhosis remains a great challenge. Sofosbuvir/ledipasvir+ribavirin for 12 weeks were associated with an SVR of 85% in these patients. In summary, treatment of HCV genotype 3 patients is improving rapidly, and this population may no longer be considered a difficult-to-treat subgroup in the near future.

Recyclability assessment of nano-reinforced plastic packaging.

Packaging is expected to become the leading application for nano-composites by 2020 due to the great advantages on mechanical and active properties achieved with these substances. As novel materials, and although there are some current applications in the market, there is still unknown areas under development. One key issue to be addressed is to know more about the implications of the nano-composite packaging materials once they become waste. The present study evaluates the extrusion process of four nanomaterials (Layered silicate modified nanoclay (Nanoclay1), Calcium Carbonate (CaCO3), Silver (Ag) and Zinc Oxide (ZnO) as part of different virgin polymer matrices of polyethylene (PE), Polypropylene (PP) and Polyethyleneterephtalate (PET). Thus, the following film plastic materials: (PE-Nanoclay1, PE-CaCO3, PP-Ag, PET-ZnO, PET-Ag, PET-Nanoclay1) have been processed considering different recycling scenarios. Results on recyclability show that for PE and PP, in general terms and except for some minor variations in yellowness index, tensile modulus, tensile strength and tear strength (PE with Nanoclay1, PP with Ag), the introduction of nanomaterial in the recycling streams for plastic films does not affect the final recycled plastic material in terms of mechanical properties and material quality compared to conventional recycled plastic. Regarding PET, results show that the increasing addition of nanomaterial into the recycled PET matrix (especially PET-Ag) could influence important properties of the recycled material, due to a slight degradation of the polymer, such as increasing pinholes, degradation fumes and elongation at break. Moreover, it should be noted that colour deviations were visible in most of the samples (PE, PP and PET) in levels higher than 0.3 units (limit perceivable by the human eye). The acceptance of these changes in the properties of recycled PE, PP and PET will depend on the specific applications considered (e.g. packaging applications are more strict in material quality that urban furniture or construction products).

Role of bacillus thuringiensis toxin domains in toxicity and receptor binding in the diamondback moth

The toxic fragment of Bacillus thuringiensis crystal proteins consists of three distinct structural domains. There is evidence that domain I is involved in pore formation and that domain II is involved in receptor binding and specificity. It has been found that, in some cases, domain III is also important in determining specificity. Furthermore, involvement of domain III in binding has also been reported recently. To investigate the role of toxin domains in the diamondback moth (Plutella xylostella), we used hybrid toxins with domain III substitutions among Cry1C, Cry1E, and Cry1Ab. Neither Cry1E nor G27 (a hybrid with domains I and II from Cry1E and domain III from Cry1C) was toxic, whereas Cry1C and F26 (the reciprocal hybrid) were equally toxic. H04 (a hybrid with domains I and II from Cry1Ab and domain III from Cry1C) showed toxicity that was of a similar level as that of Cry1Ab and significantly higher than that of Cry1C. Binding assays with 125I-Cry1C showed that Cry1C and F26 competed for the same binding sites on midgut membrane vesicles, whereas Cry1E, G27, and H04 did not bind to these sites. Our results show that, in contrast to findings in other insects for the toxins and hybrids used here, toxin specificity as well as specificity of binding to membrane vesicles in the diamondback moth is mediated by domain II (and/or I) and not by domain III.

Integrative model for binding of Bacillus thuringiensis toxins in susceptible and resistant larvae of the diamondback moth (Plutella xylostella).

Insecticidal crystal proteins from Bacillus thuringiensis in sprays and transgenic crops are extremely useful for environmentally sound pest management, but their long-term efficacy is threatened by evolution of resistance by target pests. The diamondback moth (Plutella xylostella) is the first insect to evolve resistance to B. thuringiensis in open-field populations. The only known mechanism of resistance to B. thuringiensis in the diamondback moth is reduced binding of toxin to midgut binding sites. In the present work we analyzed competitive binding of B. thuringiensis toxins Cry1Aa, Cry1Ab, Cry1Ac, and Cry1F to brush border membrane vesicles from larval midguts in a susceptible strain and in resistant strains from the Philippines, Hawaii, and Pennsylvania. Based on the results, we propose a model for binding of B. thuringiensis crystal proteins in susceptible larvae with two binding sites for Cry1Aa, one of which is shared with Cry1Ab, Cry1Ac, and Cry1F. Our results show that the common binding site is altered in each of the three resistant strains. In the strain from the Philippines, the alteration reduced binding of Cry1Ab but did not affect binding of the other crystal proteins. In the resistant strains from Hawaii and Pennsylvania, the alteration affected binding of Cry1Aa, Cry1Ab, Cry1Ac, and Cry1F. Previously reported evidence that a single mutation can confer resistance to Cry1Ab, Cry1Ac, and Cry1F corresponds to expectations based on the binding model. However, the following two other observations do not: the mutation in the Philippines strain affected binding of only Cry1Ab, and one mutation was sufficient for resistance to Cry1Aa. The imperfect correspondence between the model and observations suggests that reduced binding is not the only mechanism of resistance in the diamondback moth and that some, but not all, patterns of resistance and cross-resistance can be predicted correctly from the results of competitive binding analyses of susceptible strains.

Global variation in the genetic and biochemical basis of diamondback moth resistance to Bacillus thuringiensis.

Insecticidal proteins from the soil bacterium Bacillus thuringiensis (Bt) are becoming a cornerstone of ecologically sound pest management. However, if pests quickly adapt, the benefits of environmentally benign Bt toxins in sprays and genetically engineered crops will be short-lived. The diamondback moth (Plutella xylostella) is the first insect to evolve resistance to Bt in open-field populations. Here we report that populations from Hawaii and Pennsylvania share a genetic locus at which a recessive mutation associated with reduced toxin binding confers extremely high resistance to four Bt toxins. In contrast, resistance in a population from the Philippines shows multilocus control, a narrower spectrum, and for some Bt toxins, inheritance that is not recessive and not associated with reduced binding. The observed variation in the genetic and biochemical basis of resistance to Bt, which is unlike patterns documented for some synthetic insecticides, profoundly affects the choice of strategies for combating resistance.

Bacillus thuringiensis crystal proteins CRY1Ab and CRY1Fa share a high affinity binding site in Plutella xylostella (L.).

The future success of Bacillus thuringiensis based insecticides depends in part on our ability to prevent insects from developing resistance against their insecticidal crystal proteins. Two recent papers indicated cross-resistance between Cry1A proteins and Cry1Fa in two different insect species (Tabashnik et al., 1994, Appl. Environ. Microbiol. 60, 4627-4629; Gould et al., 1995, J. Econ. Entomol. 88, 1545-1559). Brush border membrane vesicles were prepared from Plutella xylostella and used in binding assays with 125I-labeled trypsin-activated crystal proteins. Competition experiments showed that Cry1Fa competed with Cry1Ab for a same binding site, though the latter still bound to a different minor binding site with apparently the same affinity. Cry1Ca did not compete for Cry1Ab binding sites nor Cry1Fa for Cry1Ca binding sites. Based on these results, a modification of the receptor shared by Cry1Ab and Cry1Fa might confer multiple resistance to Cry1A and Cry1Fa proteins.

[Evaluation of a surveillance program in occupational health in a catchment area of the Valencia community]. / Evaluación de un programa de vigilancia en salud laboral en un área de salud de la Comunidad Valenciana.

BACKGROUND: The poor development of systems of occupational surveillance in Spain is an important obstacle for implementing effective occupational health programmes. The objective of this study is to evaluate the utility and feasibility of an occupational health surveillance system in a Health Area, using the available public sanitary resources, between 1991 and 1993. METHODS: The surveillance system is based on the identification of Sentinel Health Events (Rutstein and cols.) from registers or by notification, obtaining additional information through the procedure of interview. Distribution of cases by condition, level of response to the interviews, and distribution of cases according to its source of information are analysed. The evaluation is made on the following criteria: required elements, utility, representativeness, choice between sensibility and specificity, and limitations. RESULTS: 314 sentinel health events were identified, from which, in 33 cases, occupational exposure to causal agents was confirmed. The occupational diseases notified from compensation systems were 31. 3 cases of interstitial pneumonia were identified, that allowed the detection of an outbreak in textile workers. CONCLUSIONS: The implementation of systems of occupational surveillance, in the actual spanish sanitary context, should take into account the following aspects: organizational flexibility, efficiency, and orientation towards intervention.