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Plant Physiol Biochem ; 195: 238-246, 2023 Feb.
Article in English | MEDLINE | ID: mdl-36645928


Strawberry (Fragaria × ananassa Duch.) production is a major aspect of the agricultural economy in Turkey's Mediterranean region, offering high rates of employment and farm revenue. The effects of treatment of the exogenous amino acid on yield, quality, and physiological diversity for strawberry production was analyzed considering the economic aspects. To achieve this, 4 different irrigation regimes (IR (irrigation) 125, IR100, IR75, IR50) with proline treatment was tested. The total berry yield, photosynthesis and leaf water potential (LWP) significantly decreased as irrigation application rates declined. The IR125 treatment with proline (PIR125) produced the highest overall berry production. The use of proline significantly increased berry production by 23%. Exogenous proline generated 3.5 kg/1 m3 greater yields than control in terms of irrigation water use efficiency (IWUE). Under the IR50 conditions, the treatment of proline yielded a 32% higher than the control. Moreover, proline significantly increased fruit soluble solids content (SSC) by 6.4%. The production system achieves the highest cost-benefit ratio (CBR) under PIR125 whereas the lowest cost-benefit ratio under IR50. When each scenario was considered at individually, it was evident that the more water used the more efficient high tunnel strawberry production. The fact that proline generated an increase in CBR in all four irrigation regimes proves this amino acid's economic effectiveness. As a result, PIR125 is recommended for the highest efficiency and CBR in Mediterranean environment. However, it has been discovered that using proline to alleviate this problem in areas where water is limited could be quite helpful.

Fragaria , Fragaria/metabolism , Proline/metabolism , Cost-Benefit Analysis , Agriculture/methods , Fruit/metabolism , Water/metabolism , Agricultural Irrigation
Beijing Da Xue Xue Bao Yi Xue Ban ; 54(5): 863-873, 2022 Oct 18.
Article in Chinese | MEDLINE | ID: mdl-36241229


OBJECTIVE: To explore the role of the microbiota in drug naïve first-onset schizophrenia patients and to seek evidence from multidimensional longitudinal analyses of the intestinal microbiome and clinical phenotype with antipsychotic drugs (APDs) therapy. METHODS: In this study, 28 drug naïve first onset schizophrenia patients and age-, gender- and education-matched 29 healthy controls were included, and the patients were treated with APDs. We collected fecal and serum samples at baseline and after 6 weeks of treatment to identify the different microbiota strains and analyse their correlation with clinical symptoms and serum metabolites. The 16S rRNA genes of the gut microbiota were sequenced, and the diversity and relative abundance at the phylum and genus levels were analyzsed in detail. The PANSS score, BMI changed value, and serum metabolome were included in the data analyses. RESULTS: A multiomics study found a potential connection among the clinical phenotype, microbiota and metabolome. The species diversity analyses revealed that the alpha diversity index (chao1, ACE, and goods_coverage) in the schizophrenia APDs group was significantly lower than that in the control group, and the schizophrenia group had clear demarcation from the control group. The microbiota composition analysis results showed that the relative abundance of the genera of Bacteroides, Streptococcus, Romboutsia, and Eubacterium ruminantium group significantly changed after APDs treatment in the schizophrenia patients. These strains could reflect the APDs treatment effect. More genera had differences between the patient and control groups. The LEfSe analysis showed that Prevotella_9 and Bacteroides were enriched in schizophrenia, while Blautia, Dialister, and Roseburia were enriched in the control group. The correlation analysis between microbiota and clinical symptoms showed that Bifidobacterium in schizophrenia was positively correlated with the PANSS reduction rate of the general psychopathology scale. The BMI changed value was positively correlated with the alteration of Clostridium_sensu_stricto_1 during treatment and the baseline abundance of Bacteroides. Moreover, metabolomic data analysis revealed a significant correlation between specific genera and metabolites, such as L-methionine, L-proline, homovanillic acid, N-acetylserotonin, and vitamin B6. CONCLUSION: Our study found some microbiota features in schizophrenia patients and healthy controls, and several strains were correlated with APDs effects. Furthermore, the multiomics analysis implies the intermediate role of microbiota between antipsychotic effects and serum metabolites and provides new evidence to interpret the difference from multiple levels in the pathogenesis and pharmacological mechanism of schizophrenia.

Antipsychotic Agents , Feces , Microbiota , Schizophrenia , Humans , Homovanillic Acid , Metabolomics/methods , Methionine , Proline , RNA, Ribosomal, 16S/genetics , Vitamin B 6
World J Microbiol Biotechnol ; 38(12): 247, 2022 Oct 27.
Article in English | MEDLINE | ID: mdl-36289148


This study aimed to select endophytic fungi to produce L-asparaginase and partially optimising the production of the enzyme using cacti as substrate. Seventeen endophytes were assessed for intracellular enzymatic potential in modified Czapek Dox's medium using L-proline as an inducer. The best producer was evaluated for intracellular and extracellular enzymatic activity in modified Czapek Dox's medium using flours of Opuntia ficus-indica and Nopalea cochenillifera as substrate. The biomass and L-asparaginase production profile was analysed and the best conditions for enzyme production were verified using factorial design. Penicillium decaturense URM 7966, Diaporthe ueckerae URM 8321, and Colletotrichum annellatum URM 8538 produced 0.76 U g- 1, 0.87 U g- 1, and 0.74 U g- 1 L-asparaginase, respectively. Diaporthe ueckerae URM 8321 produced only intracellular L-asparaginase, using flours of N. cochenillifera (0.72 U g- 1) and O. ficus-indica (0.90 U g- 1) and the last was selected for the next steps. The ideal time for biomass and L-asparaginase production was 120 h. The best conditions for enzyme production (1.67 U g- 1) were initial pH 4.0, inoculum concentration 1% and cacti flour concentration 0.2%; where was observed an increase of 46.11% in compared to the initial production. Opuntia ficus-indica flour is indicated as an alternative low-cost substrate for the production of L-asparaginase by the endophytic fungus D. ueckerae URM 8321.

Asparaginase , Cactaceae , Fungi , Proline
Appl Microbiol Biotechnol ; 106(19-20): 6455-6469, 2022 Oct.
Article in English | MEDLINE | ID: mdl-36069926


Solanum viarum serves as a raw material for the steroidal drug industry due to its alkaloid and glycoalkaloid content. Elicitation is well-known for measuring the increase in the yield of bioactive compounds in in vitro cultures. The current study was performed for the accumulation of metabolites viz. solasodine, solanidine, and α-solanine in S. viarum culture using microbial-based elicitors added in 1%, 3%, 5%, and 7% on 25th and 35th day of culture period and harvested on 45th and 50th days of culture cycle. The treatment of 3% Trichoderma reesei and Bacillus tequilensis culture filtrate (CF) significantly increased biomass, alkaloids/glycoalkaloid content, and yield in S. viarum. T. reesei was found to be the best treatment for enhanced growth (GI = 11.65) and glycoalkaloid yield (2.54 mg DW plant-1) after the 50th day of the culture cycle when added on the 25th day. The abundance of gene transcripts involved in the biosynthesis of alkaloids/glycoalkaloids, revealed by quantitative real-time PCR expression analysis correlates with the accumulation of their respective metabolites in elicited plants. Biochemical analysis shows that elicited plants inhibited oxidative damage caused by reactive oxygen species by activating enzymes (superoxide dismutase and ascorbate peroxidase) as well as non-enzymatic antioxidant mechanisms (alkaloids, total phenols, total flavonoids, carotenoids, and proline). The findings of this study clearly demonstrate that the application of T. reesei and B. tequilensis CF at a specific dose and time significantly improve biomass as well as upregulates the metabolite biosynthetic pathway in an important medicinal plant- S. viarum. KEY POINTS: • Biotic elicitors stimulated the alkaloids/glycoalkaloid content in S. viarum plant cultures. • T. reesei was found to be most efficient for enhancing the growth and alkaloids content. • Elicited plants activate ROS based-defense mechanism to overcome oxidative damage.

Alkaloids , Solanum , Alkaloids/chemistry , Antioxidants , Ascorbate Peroxidases , Carotenoids , Flavonoids , Phenols , Proline , Reactive Oxygen Species , Solanum/chemistry , Solanum/genetics , Superoxide Dismutase
Nature ; 603(7899): 25-27, 2022 03.
Article in English | MEDLINE | ID: mdl-35233098

Antiviral Agents/therapeutic use , Clinical Trials as Topic , Drug Repositioning , Host-Pathogen Interactions/drug effects , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/economics , Antibodies, Neutralizing/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , COVID-19/economics , COVID-19/immunology , COVID-19/mortality , COVID-19/virology , COVID-19 Vaccines , Cytidine/analogs & derivatives , Cytidine/therapeutic use , Depsipeptides/pharmacology , Depsipeptides/therapeutic use , Dexamethasone/administration & dosage , Dexamethasone/therapeutic use , Drug Combinations , Drug Synergism , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Hospitalization , Humans , Hydroxylamines/therapeutic use , Internationality , Lactams/therapeutic use , Leucine/therapeutic use , Mice , National Institutes of Health (U.S.)/organization & administration , Nitriles/therapeutic use , Peptide Elongation Factor 1/antagonists & inhibitors , Peptides, Cyclic/pharmacology , Peptides, Cyclic/therapeutic use , Proline/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , RNA-Dependent RNA Polymerase/antagonists & inhibitors
Nature ; 601(7894): 496, 2022 01.
Article in English | MEDLINE | ID: mdl-35064230

Antiviral Agents/therapeutic use , COVID-19/virology , Drug Development/trends , Drug Resistance, Viral , Research Personnel , SARS-CoV-2/drug effects , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Administration, Oral , Alanine/administration & dosage , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/supply & distribution , COVID-19/mortality , COVID-19/prevention & control , COVID-19 Vaccines/supply & distribution , Cytidine/administration & dosage , Cytidine/analogs & derivatives , Cytidine/pharmacology , Cytidine/therapeutic use , Drug Approval , Drug Combinations , Drug Resistance, Viral/drug effects , Drug Resistance, Viral/genetics , Drug Therapy, Combination , Hospitalization/statistics & numerical data , Humans , Hydroxylamines/administration & dosage , Hydroxylamines/pharmacology , Hydroxylamines/therapeutic use , Lactams/administration & dosage , Lactams/pharmacology , Lactams/therapeutic use , Leucine/administration & dosage , Leucine/pharmacology , Leucine/therapeutic use , Medication Adherence , Molecular Targeted Therapy , Mutagenesis , Nitriles/administration & dosage , Nitriles/pharmacology , Nitriles/therapeutic use , Proline/administration & dosage , Proline/pharmacology , Proline/therapeutic use , Public-Private Sector Partnerships/economics , Ritonavir/administration & dosage , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/enzymology , SARS-CoV-2/genetics
Gastroenterol Hepatol ; 45(5): 342-349, 2022 May.
Article in English, Spanish | MEDLINE | ID: mdl-34129903


BACKGROUND AND OBJECTIVE: The emergence of highly tolerable, effective, and shorter duration direct-acting antivirals (DAAs) regimens offers the opportunity to simplify hepatitis C virus management but medical costs are unknown. Thus, we aimed to determine the direct medical costs associated with a combo-simplified strategy (one-step diagnosis and low monitoring) to manage HCV infection within an 8-week glecaprevir/pibrentasvir (GLE/PIB) regimen in clinical practice in Spain. PATIENTS AND METHODS: Healthcare resources and clinical data were collected retrospectively from medical charts of 101 eligible patients at 11 hospitals. Participants were adult, treatment naïve subjects with HCV infection without cirrhosis in whom a combo-simplified strategy with GLE/PIB for 8 weeks were programmed between Apr-2018 and Nov-2018. RESULTS: The GLE/PIB effectiveness was 100% (CI95%: 96.2-100%) in the mITT population and 94.1% (CI95%: 87.5-97.8%) in the ITT population. Three subjects discontinued the combo-simplified strategy prematurely, none of them due to safety reasons. Five subjects reported 8 adverse events, all of mild-moderate intensity. Combo-simplified strategy mean direct costs were 754.35±103.60€ compared to 1689.42€ and 2007.89€ of a theoretical 12-week treatment with 4 or 5 monitoring visits, respectively; and 1370.95€ and 1689.42€ of a theoretical 8-week with 3 or 4 monitoring visits, respectively. Only 4.9% of the subjects used unexpected health care resources. CONCLUSIONS: 8-week treatment with GLE/PIB combined with a combo simplified strategy in real-life offers substantial cost savings without affecting the effectiveness and safety compared to traditional approaches.

Hepatitis C, Chronic , Hepatitis C , Adult , Aminoisobutyric Acids , Antiviral Agents/adverse effects , Benzimidazoles , Cyclopropanes , Genotype , Hepacivirus , Hepatitis C/drug therapy , Hepatitis C, Chronic/drug therapy , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Proline/therapeutic use , Pyrrolidines , Quinoxalines , Retrospective Studies , Sulfonamides
Ann Palliat Med ; 10(10): 10313-10326, 2021 10.
Article in English | MEDLINE | ID: mdl-34670381


BACKGROUND: Hepatitis C virus (HCV) infection is an important health threat in China to which direct acting antivirals (DAAs) are very effective. In 2019, another novel DAA glecaprevir/pibrentasvir (GLE/PIB) was officially approved. Knowledge of its cost-effectiveness would be informative for clinical decision-making but has not been evaluated. This study aims to evaluate the cost-effectiveness of GLE/PIB to inform policy-making on drug reimbursement and HCV eradication. METHODS: Markov models were developed from the payers' perspective and simulated the lifetime experience of adult patients chronically infected with HCV genotype 1 or genotype 2. Two regimens, GLE/PIB and pegylated interferon (pegIFN) plus ribavirin (RBV), were compared in cost and quality adjusted life years (QALY) with both outcomes being discounted to 2020 values. The incremental cost-effectiveness ratio (ICER) was computed to reflect the incremental benefit of GLE/PIB versus pegIFN + RBV. The robustness of the model outcomes was examined using deterministic and probabilistic sensitivity analysis (PSA) to identify influential parameters and to assess the probability of GLE/PIB being cost-effective. The GDP per capita in China in 2019 ($10,275) was used as the threshold for cost-effectiveness. RESULTS: For the entire target population, GLE/PIB was the dominant regimen attaining a cost-saving of $255 and 1.17 more QALYs relative to pegIFN + RBV. The finding was more pronounced for HCV genotype 1 infection by saving $1,656 and creating 1.37 more QALYs. At the $10,275 threshold, the probability of GLE/PIB being cost-effective was 99.32% overall and 99.85% for HCV genotype 1 infection. The age of starting DAA treatment, price of pegIFN + RBV, cost of cirrhosis treatment and duration of the GLE/PIB regimen were the five most influential factors. For the patients with HCV genotype 2 infection, the ICER of GLE/PIB was $12,914/QALY with 95% confidence interval of $4,047/QALY to $37,640/QALY. The GLE/PIB regimen statistically cannot be ruled out as a cost-effective option for HCV genotype 2 infection. CONCLUSIONS: GLE/PIB is a cost-effective strategy to treat chronic HCV genotype 1 and HCV genotype 2 infection in China. This regimen should be initiated at a younger age to maximize its value. To achieve national eradication, it may be timely to consider replacing pegIFN + RBV with DAAs, such as GLE/PIB, as the first-line treatment.

Antiviral Agents , Hepatitis C, Chronic , Adult , Aminoisobutyric Acids , Antiviral Agents/therapeutic use , Benzimidazoles , China , Cost-Benefit Analysis , Cyclopropanes , Drug Therapy, Combination , Genotype , Hepatitis C, Chronic/drug therapy , Humans , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines , Sulfonamides
Proc Natl Acad Sci U S A ; 117(48): 30610-30618, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33184174


Peptide binding to major histocompatibility complexes (MHCs) is a central component of the immune system, and understanding the mechanism behind stable peptide-MHC binding will aid the development of immunotherapies. While MHC binding is mostly influenced by the identity of the so-called anchor positions of the peptide, secondary interactions from nonanchor positions are known to play a role in complex stability. However, current MHC-binding prediction methods lack an analysis of the major conformational states and might underestimate the impact of secondary interactions. In this work, we present an atomically detailed analysis of peptide-MHC binding that can reveal the contributions of any interaction toward stability. We propose a simulation framework that uses both umbrella sampling and adaptive sampling to generate a Markov state model (MSM) for a coronavirus-derived peptide (QFKDNVILL), bound to one of the most prevalent MHC receptors in humans (HLA-A24:02). While our model reaffirms the importance of the anchor positions of the peptide in establishing stable interactions, our model also reveals the underestimated importance of position 4 (p4), a nonanchor position. We confirmed our results by simulating the impact of specific peptide mutations and validated these predictions through competitive binding assays. By comparing the MSM of the wild-type system with those of the D4A and D4P mutations, our modeling reveals stark differences in unbinding pathways. The analysis presented here can be applied to any peptide-MHC complex of interest with a structural model as input, representing an important step toward comprehensive modeling of the MHC class I pathway.

Major Histocompatibility Complex , Markov Chains , Models, Molecular , Peptides/metabolism , Alanine/genetics , Binding, Competitive , Computer Simulation , DNA Mutational Analysis , Mutation/genetics , Proline/metabolism , Protein Binding
Gastroenterol Clin North Am ; 49(2): 253-277, 2020 06.
Article in English | MEDLINE | ID: mdl-32389362


The World Health Organization has called for the elimination of hepatitis C virus (HCV) as a public health threat by 2030. Highly effective direct-acting antiviral agents provide the therapeutic tools required for elimination. In the absence of a vaccine, HCV elimination will require enhanced primary prevention and an increase in the proportions of people diagnosed and treated. Given that globally only 20% of people with chronic HCV are diagnosed, and around 5% have initiated HCV treatment, the task ahead is enormous. But, global public health needs optimism, and countries currently on track for HCV elimination provide a pathway forward.

Antiviral Agents/administration & dosage , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/prevention & control , 2-Naphthylamine , Anilides/administration & dosage , Antiviral Agents/economics , Benzofurans/administration & dosage , Carbamates/administration & dosage , Drug Therapy, Combination , Global Health , Health Care Costs , Hepatitis C, Chronic/diagnosis , Hepatitis C, Chronic/economics , Humans , Imidazoles/administration & dosage , Proline , Pyrrolidines , Sofosbuvir/administration & dosage , Sulfonamides/administration & dosage , Uracil/administration & dosage , Uracil/analogs & derivatives , Valine/analogs & derivatives , World Health Organization
Cad Saude Publica ; 36(2): e00036619, 2020.
Article in English | MEDLINE | ID: mdl-32022174


Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study that involved the inclusion of PIs in a clinical protocol. The analysis was part of a real-life study that included patients infected with hepatitis C virus genotype 1 treated in a tertiary university hospital in Brazil. Triple therapies (TT) with ribavirin (RBV), peginterferon α-2a (Peg-INF α-2a) and BOC or TVR were compared to dual therapy with RBV and Peg-INF α-2a. Sensitivity analysis of the cost-effectiveness ratio indicated an 88.2% chance of TTs presenting a higher cost per cure. The incremental cost-effectiveness ratios (ICER) exceeded the Brazilian gross domestic product (GDP) per capita by three times in all proposed scenarios. The sensitivity of ICER showed an 88.4% chance of TT not being cost-effective. The impact of PI incorporation was negative and the conduct about this could have been different if a previous cost-effectiveness analysis had been conducted.

Antiviral Agents/therapeutic use , Cost-Benefit Analysis , Hepatitis C, Chronic/drug therapy , Antiviral Agents/economics , Brazil , Drug Therapy, Combination , Genotype , Hepacivirus , Hepatitis C, Chronic/economics , Humans , Interferon alpha-2 , Interferon-alpha , Oligopeptides , Polyethylene Glycols , Proline/analogs & derivatives , Quality-Adjusted Life Years , Recombinant Proteins , Ribavirin
Value Health Reg Issues ; 21: 164-171, 2020 May.
Article in English | MEDLINE | ID: mdl-31978690


OBJECTIVES: The combination of pegylated-interferon and ribavirin (PegIFN+RBV) is currently the gold standard in treating chronic hepatitis C virus (HCV) patients in Malaysia and is reimbursed by the Malaysian authorities. This analysis evaluated the cost-effectiveness (CE) of the ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin (OBT/PTV/r+DSB±RBV) regimen as compared with the PegIFN+RBV or no treatment in chronic HCV Genotype 1 (GT1) treatment-naïve and treatment-experienced cirrhotic and noncirrhotic patients in Malaysia. METHODS: A Markov model based on previously published CE models of HCV was adapted for the Malaysian public healthcare payer perspective, based on good modeling practices. Treatment attributes included efficacy, regimen duration, and EQ-5D treatment-related health utility. Transitional probabilities and health state health utilities were derived from previous studies. Costs were derived from Malaysian data sources. Costs and outcomes were discounted at 3.0% per year. Deterministic and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainties around key variables. RESULTS: Based on the analysis, patients treated with the OBT/PTV/r+DSB±RBV showed less frequent progression to compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and liver-related deaths when compared with standard care (ie, PegIFN+RBV or no treatment). At a price of MYR 1846/day, the OBT/PTV/r+DSB±RBV regimen is cost-effective over PegIFN+RBV and yields better outcomes in terms of life-years (LYs) gained and quality-adjusted life-years (QALYs) at a higher cost, which is still well below the implied willingness to pay threshold of MYR 384 503/QALY. CONCLUSION: The OBT/PTV/r+DSB±RBV regimen is cost-effective for treatment naïve, treatment experienced, cirrhotic, and noncirrhotic GT1 chronic HCV patients in Malaysia.

Cost-Benefit Analysis/methods , Genotype , Hepatitis C/drug therapy , 2-Naphthylamine , Anilides/economics , Anilides/therapeutic use , Antiviral Agents/economics , Antiviral Agents/therapeutic use , Carbamates/economics , Carbamates/therapeutic use , Cost-Benefit Analysis/statistics & numerical data , Cyclopropanes/economics , Cyclopropanes/therapeutic use , Hepatitis C/epidemiology , Humans , Lactams, Macrocyclic/economics , Lactams, Macrocyclic/therapeutic use , Malaysia/epidemiology , Proline/analogs & derivatives , Proline/economics , Proline/therapeutic use , Ribavirin/economics , Ribavirin/therapeutic use , Ritonavir/economics , Ritonavir/therapeutic use , Sulfonamides/economics , Sulfonamides/therapeutic use , Treatment Outcome , Uracil/analogs & derivatives , Uracil/economics , Uracil/therapeutic use , Valine
Adv Ther ; 37(1): 457-476, 2020 01.
Article in English | MEDLINE | ID: mdl-31808054


INTRODUCTION: The objective of the study was to evaluate the cost-effectiveness of glecaprevir/pibrentasvir versus other direct-acting antivirals (DAAs) for treating chronic hepatitis C virus (HCV) infections in Japan. METHODS: We developed a health state transition model to capture the natural history of HCV. A cost-effectiveness analysis of DAAs from the perspective of a public healthcare payer in Japan with a lifetime horizon over annual cycles was performed. Treatment attributes, baseline demographics, transition probabilities, health-state utilities, and costs data were extracted from publications. Costs and outcomes were discounted at 2% per annum. In the base case we focused on genotype 1 (GT1) treatment-naïve patients without cirrhosis. The scenario analysis examined a pan-genotype treatment in GT1-3 (i.e., portfolio), treatment-naïve, and treatment-experienced patients. The portfolio cost-effectiveness of DAAs was derived by calculating a weighted average of patient segments defined by treatment history, cirrhosis status, and genotype. RESULTS: The base case results indicated that glecaprevir/pibrentasvir was dominant (i.e., generating higher quality-adjusted life years [QALYs] and lower lifetime costs) compared to all other DAAs. The predicted lifetime risk of hepatocellular carcinoma was 3.66% for glecaprevir/pibrentasvir and sofosbuvir/ledipasvir, 4.99% for elbasvir/grazoprevir, and 5.27% for daclatasvir/asunaprevir/beclabuvir. In scenario analysis the glecaprevir/pibrentasvir (GLE/PIB) portfolio dominated the sofosbuvir (SOF)-based portfolio (namely sofosbuvir/ledipasvir in GT1-2 and sofosbuvir + ribavirin in GT3). The base case probabilistic sensitivity analysis (PSA) showed that glecaprevir/pibrentasvir was cost-effective in 93.4% of the simulations for a willingness-to-pay/QALY range of Japanese yen (JPY) 1.6-20 million. The PSA for the portfolio scenario indicated that the GLE/PIB portfolio was cost-effective in 100% of simulations until the willingness-to-pay/QALY reached JPY 5.2 million; this proportion decreased to 69.4% at a willingness-to-pay/QALY of JPY 20 million. Results were also robust in deterministic sensitivity analyses. CONCLUSION: In GT1 treatment-naïve non-cirrhotic patients GLE/PIB was a cost-effective strategy compared to other DAAs. When a pan-genotypic framework was used, the GLE/PIB portfolio dominated the SOF-based portfolio.

Antiviral Agents/economics , Benzimidazoles/economics , Fluorenes/economics , Hepatitis C, Chronic/drug therapy , Hepatitis C, Chronic/economics , Quinoxalines/economics , Sulfonamides/economics , Uridine Monophosphate/analogs & derivatives , Adult , Aminoisobutyric Acids , Antiviral Agents/therapeutic use , Benzimidazoles/therapeutic use , Cost-Benefit Analysis , Cyclopropanes , Drug Therapy, Combination , Female , Fluorenes/therapeutic use , Humans , Japan , Lactams, Macrocyclic , Leucine/analogs & derivatives , Proline/analogs & derivatives , Pyrrolidines , Quinoxalines/therapeutic use , Ribavirin/economics , Sofosbuvir/economics , Sulfonamides/therapeutic use , Uridine Monophosphate/economics , Uridine Monophosphate/therapeutic use
Food Chem ; 302: 125342, 2020 Jan 01.
Article in English | MEDLINE | ID: mdl-31416002


Cereal crops are the rich source of nutritional components that play an important role in micronutrient malnutrition. Biofortification is one of the most successful approaches to enhance the level of micronutrients, mainly targeted in bread wheat. Bread wheat is one of main sources of calories and proteins in the developing countries. In the present study, 50 bread wheat genotypes characterized for the zinc and iron content, the most important micronutrients. On the basis of the results, the nineteen genotypes were selected and evaluated for biochemical as well as quality parameters. The protein content, gluten quantity and quality found to be reduced in high zinc containing genotypes, whereas the total soluble sugars, total carotenoids, proline and grain hardness found to be in positive relation with high micronutrient content. These results could be useful to generate bread wheat varieties rich in micronutrients as well as better nutritional and quality traits.

Biofortification , Bread , Micronutrients/metabolism , Triticum/chemistry , Triticum/genetics , Carotenoids/analysis , Food Quality , Genotype , Iron/analysis , Iron/metabolism , Micronutrients/genetics , Proline/analysis , Proline/metabolism , Seeds/chemistry , Sugars/analysis , Zinc/analysis , Zinc/metabolism
Cad. Saúde Pública (Online) ; 36(2): e00036619, 2020. graf
Article in English | LILACS | ID: biblio-1055632


Abstract: Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study that involved the inclusion of PIs in a clinical protocol. The analysis was part of a real-life study that included patients infected with hepatitis C virus genotype 1 treated in a tertiary university hospital in Brazil. Triple therapies (TT) with ribavirin (RBV), peginterferon α-2a (Peg-INF α-2a) and BOC or TVR were compared to dual therapy with RBV and Peg-INF α-2a. Sensitivity analysis of the cost-effectiveness ratio indicated an 88.2% chance of TTs presenting a higher cost per cure. The incremental cost-effectiveness ratios (ICER) exceeded the Brazilian gross domestic product (GDP) per capita by three times in all proposed scenarios. The sensitivity of ICER showed an 88.4% chance of TT not being cost-effective. The impact of PI incorporation was negative and the conduct about this could have been different if a previous cost-effectiveness analysis had been conducted.

Resumo: A análise de custo-efetividade tem sido essencial para a tomada de decisões em saúde. Diversos países utilizam esse tipo de análise como síntese das evidências para incorporar as tecnologias em saúde. Os inibidores de protease (IPs) boceprevir (BOC) e telaprevir (TVR) são indicados para o tratamento da hepatite C crônica e foram incorporados nas diretrizes internacionais. Os ensaios clínicos pré-marketing demonstraram taxas mais altas de resposta virológica sustentada em relação às terapias anteriores, mas a incorporação dos IPs gerou um impacto financeiro significativo. O estudo teve como objetivo discutir a relevância da análise de custo-efetividade, através de um estudo que envolveu a inclusão de IPs em um protocolo clínico. A análise fez parte de um estudo de vida real que incluiu pacientes com infecção pelo vírus da hepatite C, genótipo 1, tratados em um hospital universitário terciário no Brasil. As terapias triplas (TTs) com ribavirina (RBV), peg-interferon α-2a (Peg-INF α-2a) e BOC ou TVR foram comparadas às terapias duplas com RBV e Peg-INF α-2a. A análise de sensibilidade da custo-efetividade indicou odds de 88,2% de TTs apresentarem custo mais elevado por paciente curado. Em todos os cenários propostos, as razões de custo-efetividade incremental (ICERs) superaram em três vezes o produto interno bruto (PIB) per capita brasileiro. A sensibilidade da ICER mostrou probabilidade de 88,4% das TTs não serem custo-efetivas. O impacto da incorporação dos IPs foi negativo, e a conduta teria sido diferente se tivesse sido realizada uma análise prévia de custo-efetividade.

Resumen: El análisis de coste-efectividad ha sido esencial para la toma de decisiones en salud. Diversos países utilizan este tipo de análisis como síntesis de evidencias para incorporar tecnologías en salud. Los inhibidores de proteasa (IPs) boceprevir (BOC) y telaprevir (TVR) se indican para el tratamiento de la hepatitis C crónica y fueron incorporados en directrices internacionales. Los ensayos clínicos pre-marketing demostraron tasas más altas de respuesta virológica sostenida, respecto a las terapias anteriores, pero la incorporación de los IPs generó un impacto financiero significativo. El objetivo del estudio fue discutir la relevancia del análisis de coste-efectividad, a través de un estudio que implicó la inclusión de IPs en un protocolo clínico. El análisis formó parte de un estudio de vida real que incluyó a pacientes con infección por el virus de la hepatitis C, genotipo 1, tratados en un hospital universitario terciario en Brasil. Las terapias triples (TTs) con ribavirina (RBV), peg-interferon α-2a (Peg-INF α-2a) y BOC o TVR se compararon con las terapias dobles con RBV y Peg-INF α-2a. El análisis de sensibilidad del coste-efectividad indicó odds de 88,2% de que las TTs presentaran un coste más elevado por paciente curado. En todos los escenarios propuestos, las razones de coste-efectividad incremental (ICERs) superaron tres veces el producto interno bruto (PIB) per cápita brasileño. La sensibilidad de la ICER mostró una probabilidad de que un 88,4% de las TTs no eran costo-efectivas. El impacto de la incorporación de los IPs fue negativo, y el resultado habría sido diferente si se hubiese realizado un análisis previo de coste-efectividad.

Humans , Antiviral Agents/therapeutic use , Cost-Benefit Analysis , Hepatitis C, Chronic/drug therapy , Oligopeptides , Antiviral Agents/economics , Polyethylene Glycols , Ribavirin , Recombinant Proteins , Brazil , Proline/analogs & derivatives , Interferon-alpha , Hepacivirus , Quality-Adjusted Life Years , Hepatitis C, Chronic/economics , Drug Therapy, Combination , Interferon alpha-2 , Genotype
Am J Clin Nutr ; 110(5): 1108-1118, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31504116


BACKGROUND: Recently, a group of betainized compounds have been suggested to play a role in health effects in relation to a whole-grain-rich diet. OBJECTIVES: The aims of this study were to develop a quantitative mass spectrometric method for selected betainized compounds in human plasma, and to investigate their association with nutrient intake and measures of metabolic health in participants of the SYSDIET study. METHODS: The SYSDIET study was a controlled randomized intervention including individuals with metabolic syndrome, where the healthy Nordic diet (HND) group increased intakes of whole grains, canola oil, berries, and fish, whereas the control diet (CD) group consumed low-fiber cereal products, milk fat, and restricted amounts of fish and berries. A quantitative LC combined with triple quadrupole MS method for betainized compounds was developed and applied to fasting plasma samples from baseline (week 0) and the end of the intervention (week 18 or 24). Concentrations of betainized compounds were correlated with intakes of selected nutrients and fiber and measures of metabolic health. RESULTS: Pipecolic acid betaine (PAB) concentrations were significantly higher in the HND group than in the CD group (P = 0.00032) at the end of the intervention and correlated directly (P < 0.0001) with intakes of dietary fiber (r = 0.376) and a biomarker related to whole-grain rye intake, namely the ratio of alkylresorcinol C17:0 to C21:0 (r = 0.442). PAB was associated inversely with fasting plasma insulin consistently at the beginning and at the end of the intervention (P < 0.001, r = -0.300; P < 0.01, r = -0.250, respectively), as well as IL-1 receptor antagonist (P < 0.01, r = -0.232 at the beginning; P < 0.01, r = -0.236 at the end) and serum LDL/HDL cholesterol (P < 0.01, r = -0.239 at the beginning; P < 0.01, r = -0.241 at the end). CONCLUSIONS: Among adults with the metabolic syndrome, PAB plasma concentrations were associated with fasting insulin, inflammation, and lipids and were significantly increased with adoption of the HND. Further studies are needed to clarify the biological functions of betainized compounds. This trial was registered at as NCT00992641.

Betaine/blood , Diet , Dietary Fiber/administration & dosage , Metabolic Syndrome/blood , Whole Grains , Adult , Aged , Biomarkers , Female , Humans , Male , Mass Spectrometry , Middle Aged , Pipecolic Acids/blood , Proline/analogs & derivatives , Proline/blood