Cost-effectiveness of sofosbuvir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.

UNLABELLED: We assessed the cost-effectiveness of sofosbuvir (SOF)-based triple therapy (TT) compared with boceprevir (BOC)- and telaprevir (TVR)-based TT in untreated genotype 1 (G1) chronic hepatitis C (CHC) patients discriminated according to IL28B genotype, severity of liver fibrosis, and G1 subtype. The available published literature provided the data source. The target population was made up of untreated Caucasian patients, aged 50 years, with G1CHC and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euros at 2013 value), life-years gained (LYG), quality-adjusted life year (QALY), and incremental cost-effectiveness ratio (ICER). Cost of SOF was assumed to be € 3,500 per week, i.e., the price generating a willingness-to-pay threshold of € 25,000 per LYG compared with TVR in the entire population of untreated G1 patients. The robustness of the results was evaluated by one-way deterministic and multivariate probabilistic sensitivity analyses. SOF was cost-effective compared with BOC in all strategies with the exception of cirrhosis and IL28B CC patients. In comparison with TVR-based strategies, SOF was cost-effective in IL28B CT/TT (ICER per LYG € 22,229) and G1a (€ 19,359) patients, not cost-effective in IL28B CC (€45,330), fibrosis F0-F3 (€ 26,444), and in cirrhosis (€ 34,906) patients, and dominated in G1b patients. The models were sensitive to SOF prices and to likelihood of sustained virological response. CONCLUSION: In untreated G1 CHC patients, SOF-based TT may be a cost-effective alternative to first-generation protease inhibitors depending on pricing. The cost-effectiveness of SOF improved in IL28B CT/TT and G1a patients. SOF was dominated by TVR in G1b patients even if, in clinical practice, this issue could be counterbalanced by the good tolerability profile of SOF and by the shorter treatment duration.

HLA and killer cell immunoglobulin-like receptors influence the natural course of CMV infection.

BACKGROUND: Natural killer (NK) cells provide a major defense against cytomegalovirus (CMV) infection through the interaction of their surface receptors, including the activating and inhibitory killer immunoglobulin-like receptors (KIRs), and human leukocyte antigens (HLA) class I molecules. This study assessed whether the KIR and HLA repertoire may influence the risk of developing symptomatic or asymptomatic disease after primary CMV infection in the immunocompetent host. METHODS: Sixty immunocompetent patients with primary symptomatic CMV infection were genotyped for KIR and their HLA ligands, along with 60 subjects with a previous asymptomatic infection as controls. RESULTS: The frequency of the homozygous A haplotype (only KIR2DS4 as activating KIR) was higher in symptomatic patients than controls (30% vs 12%, respectively; odds ratio [OR] = 3.24; P = .01). By logistic regression, the risk of developing symptomatic disease was associated with the homozygous A haplotype and the HLABw4(T) allele. Combining the 2 independent variables, we found that 37 out of 60 (62%) symptomatic patients but only 18 out of 60 (30%) of controls possessed the homozygous A haplotype or the HLABw4(T) allele with a highly significant OR (OR = 3.75, P < .0005). CONCLUSIONS: Immunocompetent subjects carrying the homozygous A haplotype or the HLABw4(T) allele are at higher risk of developing symptomatic disease after primary CMV infection.

Totally laparoscopic liver resections for primary and metastatic cancer in the elderly: safety, feasibility and short-term outcomes.

BACKGROUND: Standard oncologic liver resections performed on elderly patients (≥70 years old) have been shown to be safe and effective. The aim of this study was to analyze operative and oncologic short-term outcomes of totally laparoscopic liver resections (TLLR) performed on elderly patients for malignancies. METHODS: We performed a retrospective statistical analysis of prospectively recorded data of TLLR performed from October 2008 to February 2012 by a single hepato-pancreato-biliary (HPB) surgeon. Patients were divided into two groups according to age (<70 vs. ≥ 70 years old) and perioperative outcomes were compared. RESULT: A total of 60 TLLR for malignancies were identified of which 25 patients (42 %) were aged ≥ 70 years (Group A) and 35 (58 %) were aged <70 years (Group B). There was no difference in operative time (170 vs. 180 min, p = 0.267), median blood loss (200 vs. 250 ml, p = 0.183), number and time of Pringle maneuver (p = 0.563 and p = 0.180), blood transfusion rate (4 vs. 17 %, p = 0.222), conversion rate (4 vs. 9 %, p = 0.443), morbidity rate (12 vs. 20 %, p = 0.797), and perioperative mortality rate (0 vs. 3 %, p = 0.688). An R0 resection was achieved in 92 (Group A) versus 83 % (Group B) (p = 0.265). At a median follow-up of 18 months, 12 % of patients in Group A experienced a disease recurrence with a related mortality rate similar to that of Group B (8 vs. 12 %, p = 0.375). CONCLUSION: This retrospective comparative study shows that TLLR performed on elderly for liver neoplasm are feasible and safe and lead to short-term outcomes similar to those of younger patients.

Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison.

BACKGROUND: Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. OBJECTIVE: We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. METHODS: An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. RESULTS: The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16). CONCLUSIONS: Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen.

Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: The benefit of sublingual immunotherapy (SLIT) with grass allergens for seasonal allergic rhinitis has been extensively studied, but data on efficacy are still equivocal. OBJECTIVE: To assess the effectiveness of SLIT with grass allergens in the reduction of symptoms and medication in patients with seasonal allergic rhinitis to grass pollen. METHODS: Computerized bibliographic searches of MEDLINE (1995-2010) were supplemented by hand searches of reference lists. Studies were included if they were double-blind randomized controlled trials (RCTs) comparing SLIT to placebo and if they included patients with history of allergy to grass pollen treated with natural grass pollen extracts. Nineteen RCTs with 2971 patients were analyzed. The outcomes assessed were symptom and medication scores. RESULTS: Using a random-effects model, SLIT with grass allergens significantly reduces both symptoms (standardized mean difference, -0.32; 95% CI, -0.44 to -0.21) and medication use (standardized mean difference, -0.33; 95% CI, -0.50 to -0.16) compared with placebo. The treatment is more efficacious in adults than in children. Prolonging duration of preseasonal treatment for more than 12 weeks improves the treatment efficacy. CONCLUSION: This meta-analysis found that SLIT with grass allergens is effective in patients with seasonal allergic rhinitis compared with placebo. The benefit is clinically modest, and criteria are needed to identify patients most likely to benefit from SLIT.

Association between the interleukin-1beta polymorphisms and Alzheimer's disease: a systematic review and meta-analysis.

The pro-inflammatory cytokine interleukin(IL)-1beta is a main component in inflammatory pathways and is overexpressed in the brain of Alzheimer's disease (AD) patients. Several studies report associations between IL-1beta polymorphisms and AD, but findings from different studies are controversial. Our aim was to verify the correlation between the single nucleotide polymorphisms (SNPs) of the IL-1beta, at sites -511 and +3953, and AD by meta-analysis. Computerized bibliographic searches of PUBMED and AlzGene database (http://www.alzgene.org) were supplemented with manual searches of reference lists. There is evidence for association between IL-1beta +3953 SNP and AD, with an OR=1.60 (95% C.I.: 1.16-2.22; Z=2.83 p=0.005) for TT genotype. No significant difference in genotype distribution of the IL-1beta -511 SNP in AD was obtained, but high between-study heterogeneity was found. To reduce heterogeneity, subgroup analyses were performed using, as stratifying variables, characteristics of the population under study (age, gender, type of AD diagnosis, Mini Mental State Examination of the controls) and characteristics related to the study design (statistical power of individual studies). The frequency of the IL-1beta -511 TT genotype resulted significantly higher than other genotypes only when the Caucasian studies with the highest statistical power were included in the subgroup analysis (OR=1.32; 95% C.I.: 1.03-1.69; p=0.03), with no evidence of between-study heterogeneity. Our data support an association between the TT genotype of IL-1beta +3953 SNP and AD, and suggest a possible association of the -511 TT genotype. Unreplicability of the results seems to be due mainly to the lack of statistical power of the individual studies.

The effect of allergen immunotherapy in the onset of new sensitizations: a meta-analysis.

BACKGROUND: Although the preventive efficacy of allergen immunotherapy (AIT) in the onset of new allergen sensitizations has been asserted by many reviews, position papers, and consensus conferences, the evidence available is from only 3 studies. The objective of this work was a systematic review to evaluate the preventive efficacy of AIT in the onset of new allergen sensitizations. The end-point was the risk difference (RD) in the onset of new allergen sensitizations between patients treated with AIT and pharmacotherapy. METHODS: Computerized bibliographic searches of MEDLINE, EMBASE, and the Cochrane Library (until November 30th, 2016) were done. Random-effects and fixed-effects model meta-analyses were performed. Randomized controlled trials or observational studies comparing children treated with AIT with house dust mite (HDM) to subjects who did not receive AIT, with a long-term observation period (at least 3 years including treatment and follow-up) have been included. RESULTS: Eight studies totaling 721 children (390 treated with AIT and 331 with pharmacotherapy) met the inclusion criteria. The risk of bias was high. Low evidence supports the conclusion that AIT prevents the onset of new allergen sensitizations, with 3 of 8 studies reporting a reduction in the onset of new sensitizations in patients treated with AIT vs pharmacotherapy. Our meta-analysis found no difference between AIT and pharmacotherapy, with high heterogeneity (RD, -0.10; 95% confidence interval [CI], -0.31 to 0.11; p = 0.32; I2 = 91.4%). CONCLUSION: The data of this systematic review do not support a preventive effect in the onset of new allergen sensitizations, in children treated with AIT in comparison with those treated with pharmacotherapy.

Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis.

IMPORTANCE: Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. OBJECTIVE: To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. DATA SOURCES: Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. STUDY SELECTION: Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. DATA EXTRACTION AND SYNTHESIS: Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. MAIN OUTCOMES AND MEASURES: The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. RESULTS: Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, -0.28; 95% CI, -0.37 to -0.19; P < .001) and in the medication score (SMD, -0.24; 95% CI, -0.31 to -0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. CONCLUSIONS AND RELEVANCE: Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.

Nitrogen uptake and nitrogen fertilizer recovery in old and modern wheat genotypes grown in the presence or absence of interspecific competition.

Choosing genotypes with a high capacity for taking up nitrogen (N) from the soil and the ability to efficiently compete with weeds for this nutrient is essential to increasing the sustainability of cropping systems that are less dependent on auxiliary inputs. This research aimed to verify whether differences exist in N uptake and N fertilizer recovery capacity among wheat genotypes and, if so, whether these differences are related to a different competitive ability against weeds of wheat genotypes. To this end, 12 genotypes, varying widely in morphological traits and year of release, were grown in the presence or absence of interspecific competition (using Avena sativa L. as a surrogate weed). Isotopic tracer (15)N was used to measure the fertilizer N uptake efficiencies of the wheat genotypes and weed. A field experiment, a split-plot design with four replications, was conducted during two consecutive growing seasons in a typical Mediterranean environment. In the absence of interspecific competition, few differences in either total N uptake (range: 98-112 kg N ha(-1)) or the (15)N fertilizer recovery fraction (range: 30.0-36.7%) were observed among the wheat genotypes. The presence of competition, compared to competitor-free conditions, resulted in reductions in grain yield (49%), total N uptake (29%), and an (15)N fertilizer recovery fraction (32%) that were on average markedly higher in modern varieties than in old ones. Both biomass and grain reductions were strongly related to the biomass of the competitor (correlation coefficients > 0.95), which ranged from 135 to 573 g m(-2). Variations in both grain and biomass yield due to interspecific competition were significantly correlated with percentage of soil cover and leaf area at tillering, plant height at heading, and total N uptake, thus highlighting that the ability to take up N from the soil played a certain role in determining the different competitive abilities against weed of the genotypes.

Personalized cost-effectiveness of boceprevir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.

BACKGROUND: We assessed the cost-effectiveness of boceprevir-based triple therapy compared to peginterferon alpha and ribavirin dual therapy in untreated patients with genotype 1 chronic hepatitis C; patients were discriminated according to the combination of baseline plus on-treatment predictors of boceprevir-based triple therapy. METHODS: Cost-effectiveness analysis performed according to data from the available published literature. The target population was composed of untreated Caucasian patients, aged 50 years, with genotype 1 chronic hepatitis C, and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro, at 2013 value), life-years gained, quality-adjusted life year, and incremental cost-effectiveness ratio. The robustness of the results was evaluated by multivariable probabilistic sensitivity analyses. RESULTS: According to the baseline predictors of sustained virological response (genotype 1b, low viral load, fibrosis F0-F3, and body mass index) and the 1Log drop of HCV-RNA after the dual therapy lead-in period, boceprevir was cost-effective in different patient profiles. CONCLUSIONS: In untreated genotype 1b chronic hepatitis C patients, the cost-effectiveness of boceprevir-based triple therapy widely ranges according to different profiles of sustained virological response predictors, allowing optimization and personalization of triple therapy.

An aggregate AQI: Comparing different standardizations and introducing a variability index.

Many studies demonstrate a strong relationship between air pollution and respiratory and cardiovascular diseases. For this reason, assessing air pollution, and conveying information about its possible adverse health effects, may encourage population and policy makers to reduce those activities increasing pollution levels. In this paper a relative index of variability, to be associated with the aggregate Air Quality Index (AQI) among pollutants proposed by Ruggieri and Plaia (2011), is developed in order to better investigate air pollution conditions for the whole area of a city/region. The most widely-used and up to date pollution indices, based mainly on AQI computed by the US Environmental Protection Agency (EPA) and often defined by the value of the pollutant with the highest (opportunely standardized) concentration on a given day, aim at warning the people for short term health impact. An aggregate AQI, taking into account the combined effects of all the considered pollutants, gives emphasis to possible chronic health effects and long term damages on environment caused by air pollution. The proposed index of variability adds precious information to the aggregate AQI, as it allows one to know whether the value assumed by the AQI is influenced by one or more pollutants. The two indices are jointly used on simulated data, considering different possible scenarios. Applications to real air pollution data are also reported. Before applying the two indices, the effects of different standardizations on data are evaluated from a theoretical point of view.