Adjusted treatment COMPArisons between guSelkumab and uStekinumab for treatment of moderate-to-severe plaque psoriasis: the COMPASS analysis.

BACKGROUND: Guselkumab is an interleukin-23 inhibitor indicated for the treatment of moderate-to-severe plaque psoriasis in adults. Guselkumab has demonstrated additional benefit in patients with early inadequate response to ustekinumab. Long-term efficacy comparisons of guselkumab and ustekinumab are currently lacking among ustekinumab-naive patients. OBJECTIVES: To assess the relative efficacy of guselkumab and ustekinumab for maintenance therapy of moderate-to-severe plaque psoriasis, using individual patient data (IPD) from randomized controlled trials. METHODS: IPD for guselkumab from the VOYAGE 1 and 2 trials were pooled and compared with IPD for ustekinumab from the NAVIGATE trial. Multivariable logistic regression analyses compared guselkumab 100 mg and ustekinumab 45 mg or 90 mg for the achievement and maintenance of Psoriasis Area and Severity Index (PASI) 90, 75 and 100 responses up to 40 weeks. The regression models accounted for a range of clinically relevant covariates (e.g. age, sex, psoriasis duration). Relative efficacy was expressed using odds ratios (ORs) and predicted probability of treatment response associated with each intervention. RESULTS: Patients receiving guselkumab had significantly higher probabilities of achieving a PASI 90 response than patients receiving ustekinumab, at both week 16 [70·4% vs. 46·0%, OR 2·79, 95% confidence interval (CI) 2·22-3·45] and week 40 (74·2% vs. 54·5%, OR 2·40, 95% CI 1·89-3·13]. Guselkumab was also associated with a significantly increased likelihood of achieving both PASI 75 and PASI 100 responses at weeks 16 and 40, compared with ustekinumab. CONCLUSIONS: Adjusted analyses leveraging IPD demonstrate that guselkumab has a significantly higher probability of achieving and maintaining PASI treatment responses through week 40 than ustekinumab does.

CERES-Maize model for simulating genotype-by-environment interaction of maize and its stability in the dry and wet savannas of Nigeria.

When properly calibrated and evaluated, dynamic crop simulation models can provide insights into the different components of genotype by environment interactions (GEIs). Modelled outputs could be used to complement data from multi-environment trials. Field experiments were conducted in the rainy and dry seasons of 2015 and 2016 across four locations in maize growing regions of Northern Nigeria using 16 maize varieties planted under near-optimal conditions of moisture and soil nitrogen. The CERES-Maize model was calibrated using data from three locations and two seasons (rainy and dry) and evaluated using data from one location and two seasons all in 2015. Observed data from the four locations and two seasons in 2016 was used to create eight different environments. Two profile pits were dug in each location and were used separately in the simulations for each environment to provide replicated data for stability analysis in a combined ANOVA. The effects of the environment, genotype and GEI were highly significant (p = 0.001) for both observed and simulated grain yields. The environment explained 67 % and 64 % of the variations in observed and simulated grain yields respectively. The variance component of GEI (13 % for observed and 15 % for simulated) were lower but still considerable when compared to that of genotypes (19 % for observed and 21 % for simulated). From the stability analysis of the observed and simulated grain yields using six different stability models, three models (ASV, Ecovalence, and Sigma) ranked Ife Hybrid as the most stable variety. The slope of the regression (bi) model ranked Sammaz 11 as the most stable variety, while the Shukla model ranked Sammaz 28 as the most stable variety. Long-term seasonal analysis with the CERES-Maize model revealed that early and intermediate maturing varieties produce high yields in both wet and dry savannas, early and extra-early varieties produce high yields only in the dry savannas, while late maturing varieties produce high yields only in the wet savannas. When properly calibrated and evaluated, the CERES-Maize model can be used to generate data for GEI and stability studies of maize genotype in the absence of observed field data.

All-fiber bidirectional optical parametric oscillator for precision sensing.

We present the design and operation of an all-fiber, synchronously pumped, bidirectional optical parametric oscillator (OPO) for precision sensing applications. The fiber-based OPO (FOPO) generates two frequency combs with identical repetition rates but different carrier offset frequencies. A narrow beatnote was observed with full-width at half-maximum (FWHM) linewidth of <10 Hz when the two frequency combs were overlapped on a photodetector. The all-fiber design removes the need for free-space alignment and adjustment. In addition, an external delay line to overlap the two pulse trains in time on the detector is not needed since our unique design provides automatic delay compensation. We expect the novel FOPO to find important applications in precision measurements including rotation sensing with ultra-large sensing area and sensitivity.

Design, Synthesis, and Evaluation of Linker-Duocarmycin Payloads: Toward Selection of HER2-Targeting Antibody-Drug Conjugate SYD985.

Antibody-drug conjugates (ADCs) that are currently on the market or in clinical trials are predominantly based on two drug classes: auristatins and maytansinoids. Both are tubulin binders and block the cell in its progression through mitosis. We set out to develop a new class of linker-drugs based on duocarmycins, potent DNA-alkylating agents that are composed of a DNA-alkylating and a DNA-binding moiety and that bind into the minor groove of DNA. Linker-drugs were evaluated as ADCs by conjugation to the anti-HER2 antibody trastuzumab via reduced interchain disulfides. Duocarmycin 3b, bearing an imidazo[1,2-a]pyridine-based DNA-binding unit, was selected as the drug moiety, notably because of its rapid degradation in plasma. The drug was incorporated into the linker-drugs in its inactive prodrug form, seco-duocarmycin 3a. Linker attachment to the hydroxyl group in the DNA-alkylating moiety was favored over linking to the DNA-binding moiety, as the first approach gave more consistent results for in vitro cytotoxicity and generated ADCs with excellent human plasma stability. Linker-drug 2 was eventually selected based on the properties of the corresponding trastuzumab conjugate, SYD983, which had an average drug-to-antibody ratio (DAR) of about 2. SYD983 showed subnanomolar potencies against multiple human cancer cell lines, was highly efficacious in a BT-474 xenograft model, and had a long half-life in cynomolgus monkeys, in line with high stability in monkey and human plasma. Studies comparing ADCs with a different average DAR showed that a higher average DAR leads to increased efficacy but also to somewhat less favorable physicochemical and toxicological properties. Fractionation of SYD983 with hydrophobic interaction chromatography resulted in SYD985, consisting of about 95% DAR2 and DAR4 species in an approximate 2:1 ratio and having an average DAR of about 2.8. SYD985 combines several favorable properties from the unfractionated ADCs with an improved homogeneity. It was selected for further development and recently entered clinical Phase I evaluation.

Mapping FACT-P to EQ-5D in a large cross-sectional study of metastatic castration-resistant prostate cancer patients.

PURPOSE: To construct a model to predict preference-adjusted EuroQol 5D (EQ-5D) health utilities for patients with metastatic castrate-resistant prostate cancer (mCRPC) using the disease-specific health-related quality of life (HRQoL) measure, functional assessment of cancer therapy-prostate (FACT-P). METHODS: HRQoL data were collected from patients with mCRPC who were enrolled in an observational study conducted in 47 centers across six European Union countries. Utility values were generated using a UK-specific EQ-5D value set. The predictive validity of the five FACT-P subscales, patient demographics, comorbidities and prior chemotherapy was tested using ordinary least squares (OLS), median, Gamma and Tobit multivariate regression models. RESULTS: FACT-P and EQ-5D questionnaires were completed by 602 (86 %) patients. Mean age [standard deviation (SD)] was 72.1 (7.9) years, mean time from diagnosis (SD) was 5.4 (4.4) years, and mean time since failure of androgen deprivation therapy (SD) was 1.0 (1.6) years. At study inclusion, 39 % of patients were chemotherapy-naïve, 37 % were undergoing chemotherapy, and 24 % were post-chemotherapy. Mean FACT-P and EQ-5D utility values were 104 and 0.66, respectively. OLS regression was the best-performing model, explaining 61.2 % of the observed EQ-5D variation. All FACT-P subscales were significantly predictive; the physical and functional well-being subscales had the highest explanatory value (coefficient 0.023 and 0.001, respectively, p < 0.0001). The other variables did not add additional explanatory value. CONCLUSIONS: The algorithm developed enables translation of cancer-specific HRQoL measures to preference-adjusted health status in patients with mCRPC. The function may be useful in calculating EQ-5D scores when EQ-5D data have not been gathered directly.

The cost of treatment failure: resource use and costs incurred by hepatitis C virus genotype 1-infected patients who do or do not achieve sustained virological response to therapy.

Chronic hepatitis C virus (HCV) infection places a considerable economic burden on health services. Cost-effectiveness analyses of antiviral treatment for patients with chronic HCV infection are dependent on assumptions about cost reductions following sustained virological response (SVR) to therapy. This study quantified the medium-term difference in health resource usage and costs depending on treatment outcome. Retrospective chart review of patients with HCV genotype 1 infection who had received at least 2 months pegylated interferon and ribavirin therapy, with known treatment outcome was conducted. Disease status was categorized as chronic hepatitis, cirrhosis or decompensated liver disease. Health resource use was documented for each patient in each disease state. Unit costs were from the NHS 'Payment by Results' database and the British National Formulary. One hundred and ninety three patients (108 SVR, 85 non-SVR) with mean follow-up of 3.5 (SVR) and 4.9 (non-SVR) years were enrolled. No SVR patient progressed to a more severe liver disease state. Annual transition rates for non-SVR patients were 7.4% (chronic hepatitis to cirrhosis) and 4.9% (cirrhosis to decompensated liver disease). By extrapolation of modelled data over a 5-year post-treatment period, failure of patients with chronic hepatitis to achieve SVR was associated with a 13-fold increase (roughly £2300) in costs, whilst for patients who were retreated, the increase was 56-fold, equating to more than £10 000. Achievement of an SVR has significant effects on health service usage and costs. This work provides real-life data for future cost-effectiveness analyses related to the treatment for chronic HCV infection.

Hydroxypropyl-ß-cyclodextrin impacts renal and systemic hemodynamics in the anesthetized dog.

Hydroxypropyl-ß-cyclodextrin (HPßCD) is a complexation agent used to enhance drug solubilization and formulation stability. Although its toxicity is well characterized, its cardiovascular effects are less known. To investigate them, HPßCD was infused intravenously over 10 min in anesthetized dogs (10-40% (w/v, i.e. 200-800 mg/kg) in non-denervated animals and at 40% in denervated animals). HPßCD increased renal arteriolar resistance and decreased renal blood flow at all doses, almost immediately after infusion start, more drastically in females. A less pronounced increase in total peripheral resistance occurred in females only due to sex difference in sympathetic tone. Pulmonary hemodynamic parameters remained unaffected, suggesting that the renal effect was rather selective. As a consequence of the increased systemic blood pressure, heart rate decreased in normal animals without direct effect on cardiac conductance. This effect was abolished in denervated animals. This suggests that autonomous nervous feedback loops are functional in normal animals and that HPßCD has no direct chronotropic effect. In conclusion, systemic and renal hemodynamic changes should be considered as potential background effects at 200-400 mg/kg. At higher doses (800 mg/kg), changes are more pronounced and could mask/exacerbate hemodynamic response of drug candidate; such doses should be avoided in nonclinical safety studies.

Soil nutrients and crop yield response to conservation-effective management practices in the sub-humid highlands agro-ecologies of Kenya.

Crop productivity in most smallholder farming systems in Sub-Saharan Africa experience low use of soil amendment resources, low and erratic rainfall, frequent dry spells, and droughts. Rain-fed agriculture has a high crop yield potential if rainfall and soil nutrient input resources are utilized effectively. Thus, in 2011, we set up an on-farm experiment in Meru South (sub-humid) and Mbeere South (marginal sub-humid) sub-counties in upper Eastern Kenya to assess conservation-effective management (CEM) practices effects on maize (Zea Mays L.) yields response and soil nutrients. The CEM practices were; tied ridging (TR), mulching (MC), and minimum tillage (MT), with conventional tillage (CT) as a control. There were frequent dry spells and droughts during the experimental period. The experiment ran for four seasons, from the long rains season of 2011 (LR11), short rains seasons of 2011 (SR11), long rains season of 2012 (LR12), short rains 2012 (SR12), and long rains season of 2013 (LR13). In Meru South, TR and MT treatments had significantly higher phosphorus content (100% and 66%, respectively) than the control. Also, in the same site, Cu and Zn were high in MT than in CT treatments. In the Mbeere South site, the aboveground biomass yield was significantly higher in TR treatment (by 71%) than CT during SR11, while in LR12 season, it significantly increased by 72% and 46% under MC and TR treatments, respectively, than the control. The TR treatment had significantly higher aboveground biomass than the control (84% and 115%) in the SR12 and LR13 seasons. In Meru South, MC treatment had significantly higher aboveground biomass, which was significantly higher, by 39%, during the SR11 season and 46% in TR treatment in SR12 season than the control. This study highlighted tied ridging as the best-fit practice for enhancing maize crop aboveground biomass production in rain-fed farming systems of marginal lands and sub-humid regions receiving unreliable rainfall. Further, we recommend longer-term experimentation to explore CEM effects on soil nutrients.

On the higher-order Kerr effect in femtosecond filaments.

A recent experiment probing the electronic nonlinearity in the femtosecond filament indicated that the optical Kerr effect not only saturates but even changes its sign at high intensities and thus switches from self-focusing to a strongly defocusing regime. Here we examine, through simulations and experiment, some implications of such a behavior. We perform comparative simulations based on the standard model on one hand and on a model implementing the intensity-dependent Kerr effect on the other. Comparison with an experiment provides a strong indication that of these two Kerr-effect models the standard model is better in capturing the observed length of the filament. However, neither of the models can reproduce length and filament radius. Possible implications are discussed.

Long-term outcomes in patients with schizophrenia treated with risperidone long-acting injection or oral antipsychotics in Spain: results from the electronic Schizophrenia Treatment Adherence Registry (e-STAR).

BACKGROUND: The electronic Schizophrenia Treatment Adherence Registry (e-STAR) is a prospective, observational study of patients with schizophrenia designed to evaluate long-term treatment outcomes in routine clinical practice. METHODS: Parameters were assessed at baseline and at 3 month intervals for 2 years in patients initiated on risperidone long-acting injection (RLAI) (n=1345) or a new oral antipsychotic (AP) (n=277; 35.7% and 36.5% on risperidone and olanzapine, respectively) in Spain. Hospitalization prior to therapy was assessed by a retrospective chart review. RESULTS: At 24 months, treatment retention (81.8% for RLAI versus 63.4% for oral APs, p<0.0001) and reduction in Clinical Global Impression Severity scores (-1.14 for RLAI versus -0.94 for APs, p=0.0165) were significantly higher with RLAI. Compared to the pre-switch period, RLAI patients had greater reductions in the number (reduction of 0.37 stays per patient versus 0.2, p<0.05) and days (18.74 versus 13.02, p<0.01) of hospitalizations at 24 months than oral AP patients. CONCLUSIONS: This 2 year, prospective, observational study showed that, compared to oral antipsychotics, RLAI was associated with better treatment retention, greater improvement in clinical symptoms and functioning, and greater reduction in hospital stays and days in hospital in patients with schizophrenia. Improved treatment adherence, increased efficacy and reduced hospitalization with RLAI offer the opportunity of substantial therapeutic improvement in schizophrenia.

Options for calibrating CERES-maize genotype specific parameters under data-scarce environments.

Most crop simulation models require the use of Genotype Specific Parameters (GSPs) which provide the Genotype component of G×E×M interactions. Estimation of GSPs is the most difficult aspect of most modelling exercises because it requires expensive and time-consuming field experiments. GSPs could also be estimated using multi-year and multi locational data from breeder evaluation experiments. This research was set up with the following objectives: i) to determine GSPs of 10 newly released maize varieties for the Nigerian Savannas using data from both calibration experiments and by using existing data from breeder varietal evaluation trials; ii) to compare the accuracy of the GSPs generated using experimental and breeder data; and iii) to evaluate CERES-Maize model to simulate grain and tissue nitrogen contents. For experimental evaluation, 8 different experiments were conducted during the rainy and dry seasons of 2016 across the Nigerian Savanna. Breeder evaluation data were also collected for 2 years and 7 locations. The calibrated GSPs were evaluated using data from a 4-year experiment conducted under varying nitrogen rates (0, 60 and 120kg N ha-1). For the model calibration using experimental data, calculated model efficiency (EF) values ranged between 0.88-0.94 and coefficient of determination (d-index) between 0.93-0.98. Calibration of time-series data produced nRMSE below 7% while all prediction deviations were below 10% of the mean. For breeder experiments, EF (0.58-0.88) and d-index (0.56-0.86) ranges were lower. Prediction deviations were below 17% of the means for all measured variables. Model evaluation using both experimental and breeder trials resulted in good agreement (low RMSE, high EF and d-index values) between observed and simulated grain yields, and tissue and grain nitrogen contents. It is concluded that higher calibration accuracy of CERES-Maize model is achieved from detailed experiments. If unavailable, data from breeder experimental trials collected from many locations and planting dates can be used with lower but acceptable accuracy.

Clinical effectiveness and resource utilization of paliperidone ER for schizophrenia: Pharmacoepidemiologic International Longitudinal Antipsychotic Registry (PILAR).

OBJECTIVE: To document prescribing patterns in clinical practice and assess long-term outcomes related to initiation of paliperidone ER and other oral antipsychotics among patients with schizophrenia in a naturalistic setting. RESEARCH DESIGN AND METHODS: An international, non-interventional, naturalistic study of adult patients (≥18 years) with schizophrenia. Patients were assigned to the relevant treatment group (paliperidone ER or 'all other oral antipsychotics') after switching to, or initiating, oral antipsychotic treatment. Retrospective 12 month data collection was followed by 12 month prospective data collection, with 3-monthly assessments. The primary endpoint was time to all-cause discontinuation of new medication. Secondary endpoints included Clinical Global Impression-Severity (CGI-S) score, Clinical Global Impression-Schizophrenia (CGI-SCH) score, Personal and Social Performance (PSP) score, health-related quality of life (HR-QoL) and quality of sleep, evaluation of healthcare resource utilization and patient's treatment satisfaction. RESULTS: A total of 4051 patients were included in the intent-to-treat (ITT) analysis set. All-cause study discontinuation rates were comparable between the paliperidone ER group (16.8%) and the 'all other oral antipsychotics' group (15.5%). There was no difference in the time to discontinuation of newly initiated antipsychotic treatments between paliperidone ER and 'all other oral antipsychotics' groups. Paliperidone ER was associated with greater improvements from baseline to endpoint in both the PSP scale score (+14.2 vs +13.1, p = 0.041) and the physical component of quality of life (SF-12 Physical scores; +3.9 vs +2.9, p = 0.003) compared to 'all other oral antipsychotics'. Improvements in mean CGI-S score, CGI-SCH score, HR-QoL, quality of sleep and daytime drowsiness, as well as patients' treatment satisfaction were comparable between treatment groups. The incidence of adverse events was comparable between groups. CONCLUSIONS: This study provides valuable data on the prescribing habits and treatment outcomes associated with use of paliperidone ER in everyday clinical practice, and supports previous findings of the favorable functional improvement and treatment satisfaction associated with paliperidone ER. CLINICAL TRIAL REGISTRATION: NCT00696813; R076477SCH4015 (Register of German Association of Research-based Pharmaceutical Companies [VFA] http://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb).

Efficacy of telaprevir and boceprevir in treatment-naïve and treatment-experienced genotype 1 chronic hepatitis C patients: an indirect comparison using Bayesian network meta-analysis.

BACKGROUND AND AIMS: To indirectly compare the efficacy of telaprevir (TVR) and boceprevir (BOC) combined with peginterferon/ribavirin α-2a/2b (PR) in achieving sustained viral response (SVR) in treatment-naïve and treatment-experienced patients with genotype 1 chronic hepatitis C virus (HCV) infection. METHODS: A systematic literature review was conducted to identify randomized controlled trials reporting the efficacy of PR-based treatment in genotype 1 chronic HCV patients. A Bayesian network meta-analysis was performed on the endpoint of SVR, assuming fixed study effects. For treatment-experienced patients, only previous relapsers and partial responders were included, as no results in prior null responders were available for boceprevir. RESULTS: Eleven publications were included. In treatment-naïve patients, the odds ratios (OR) (posterior median [95% credible interval]) for telaprevir (12 weeks + response guided treatment [RGT] 24/48 weeks PR) and boceprevir (24 weeks + RGT 28/48 weeks PR) versus PR were respectively 3.80 (2.78-5.22) and 2.99 (2.23-4.01). The OR for telaprevir versus boceprevir was 1.42 (0.89-2.25), with a probability for telaprevir being more effective (P[OR > 1]) of 0.93. In treatment-experienced patients, the OR of telaprevir (12 weeks + 48 weeks PR) and boceprevir (32 weeks + RGT 36/48 weeks PR) versus PR were respectively 13.11 (7.30-24.43) and 5.36 (2.90-10.30). The OR for telaprevir versus boceprevir was 2.45 (1.02-5.80), with telaprevir having a probability of 0.98 of being more effective. LIMITATIONS: The main limitation of this study is the low number of trials included in the analysis, especially for the treatment-experienced patient population, which only allowed random-effect models to be explored. We tried to identify potential biases due to study heterogeneity. CONCLUSIONS: In the absence of direct comparative head-to-head studies between telaprevir and boceprevir for the treatment of chronic HCV genotype 1 patients, an indirect comparison based on Bayesian network meta-analysis suggests better efficacy for telaprevir than boceprevir in both treatment-naïve and treatment-experienced patients.