Three pigeons were exposed to second-order schedules in which responding under a fixed-interval (FI) component schedule was reinforced according to a variable-interval (VI) schedule of food ...reinforcement. Completion of each component resulted in either (1) brief presentation of a stimulus present during reinforcement (paired brief stimulus), (2) brief presentation of a stimulus not present during reinforcement (nonpaired brief stimulus), or (3) no stimulus presentation (tandem schedule). Under the two nonpaired brief stimulus conditions, either a change in keylight color or onset of houselight illumination was used as the brief stimulus. Similar patterns of keypecking occurred under tandem and nonpaired keylight brief-stimulus presentations, whereas nonpaired houselight brief-stimulus presentations generated positively accelerated within-component keypeck patterning for two pigeons. When the same keylight brief stimulus was paired with food, positively accelerated patterns of keypecking were obtained for all pigeons. Differences in the effects of nonpaired brief-stimulus presentations on second-order schedule performance suggest that component schedule patterning under nonpaired brief-stimulus procedures is a function of the particular type of stimulus used (i.e., houselight versus keylight). These results suggest that (1) brief houselight illumination may function as a sensory reinforcer, and (2) a briefly presented food-paired stimulus can function as an effective conditioned reinforcer.
•Pigeon’s keypecking was maintained under second order brief-stimulus schedules of food presentation -VI 360 s (40 s).•Brief stimuli were nonpaired houselight or keylight illumination. Subsequently, keylight illumination was paired with food.•The paired keylight produced greater component pausing and patterning compared to performance when the keylight was unpaired.•When the houselight was the unpaired stimulus patterning and local response rates were the greatest for two of three pigeons.•Houselight illumination may be a sensory reinforcer and pairing a stimulus with food may form a conditioned reinforcer.
The generalized matching law or Law of Allocation proposed by Baum (2018a, 2018b) potentially provides a broad conceptual framework within which to understand the allocation of time among activities. ...In its simplest form, the law incorporates power-function induction of activities by variables such as rate and amount of delivered inducers. Whether these variables affect allocation independently of one another is a central issue, because independence of the variables would allow simple multiplication of power functions and would make quantitative prediction simple too. The present experiment used a titration procedure to test the independence of rate and amount of food in determining pigeons’ allocation of pecking between two keys. Amount ratio was varied within sessions to engender different peck ratios. Rate ratio was varied across two series of conditions. The results conformed to the predictions of the simple version of the Law of Allocation by strongly supporting independence of rate and amount. The Law of Allocation may have broad application for understanding activities in natural settings and everyday life.
•Matching theory raises the question whether rate and amount of a reinforcer are independent.•Experiments have produced mixed results, but generally favor rate-amount independence.•In a titration procedure, specific levels of outcome variables are achieved by varying input variables.•Rate-amount independence was tested with pigeons in a titration procedure.•Rate-amount independence was confirmed.
AbstractThe ability to accurately forecast a project’s final duration and cost is essential to successful project management. The technique of earned value management (EVM) is considered to provide ...an effective methodology for obtaining such forecasts; however, this has not yet been adequately tested on empirical data. Therefore, the accuracy of the most commonly used EVM time and cost forecasting methods is evaluated on a diverse and qualitative database consisting of 51 real-life projects. As most projects originate from the construction industry, an explicit focus on these construction projects is provided. Moreover, the desired real forecasting outcomes based on the actual project progress data are also supported by a Monte Carlo simulation study. It is demonstrated that highly accurate time and cost forecasts can be obtained by applying the EVM methodology. Furthermore, the best performing forecasting methods for the projects in the considered database are identified, also taking into account timeliness and the influence of the project network structure.
The advent of tau-targeted positron emission tomography tracers such as flortaucipir (18F-AV-1451, also known as 18F-T807) have made it possible to investigate the sequence of development of tau and ...amyloid-β in relationship to age, and to the development of cognitive impairment due to Alzheimer's disease. In this study, flortaucipir tau and florbetapir amyloid positron emission tomography were obtained for 217 subjects including 16 young and 58 older cognitively normal subjects, 95 subjects with mild cognitive impairment (Mini-Mental State Examination 24-30) and 48 subjects with clinically-defined possible or probable Alzheimer's disease (Mini-Mental State Examination >10). Images were evaluated visually and quantitatively by regional and voxel-based cortical to cerebellar standard uptake value ratios. For amyloid positron emission tomography positive (Aβ+) subjects, flortaucipir neocortical standard uptake value ratio was significantly higher with more advanced clinical stage (Alzheimer's disease > mild cognitive impairment > older cognitively normal) and was significantly elevated for Aβ+ mild cognitive impairment and Alzheimer's disease subjects relative to the respective Aβ- subjects. In contrast, florbetapir Aβ- older cognitively normal subjects showed an increase in flortaucipir standard uptake value ratios in mesial temporal lobe regions (amygdala, hippocampus/choroid plexus region of interest) compared to younger cognitively normal subjects, but no increased standard uptake value ratios in neocortical regions. Analysis of covariance with planned contrasts showed no differences in regional or composite posterior neocortical flortaucipir standard uptake value ratio as a function of diagnostic group among Aβ- older cognitively normal or clinically diagnosed Alzheimer's disease or mild cognitive impairment subjects. The pattern of flortaucipir distribution among Aβ+ subjects was reminiscent of the cross-sectional distribution of tau reported in post-mortem pathology studies, in that the most commonly affected regions were the inferior and lateral temporal lobes, the same regions where the first signs of increased retention appeared in Aβ+ cognitively normal subjects. However, there was large variability in extent/density of flortaucipir tau binding among Aβ+ subjects. Although high neocortical flortaucipir retention was consistently associated with an Aβ+ florbetapir positron emission tomography scan, not all Aβ+ subjects had elevated flortaucipir standard uptake value ratios. Finally, within the Aβ+ group, increasing levels of flortaucipir tau binding were associated with increased cognitive impairment, as assessed by Mini-Mental State Examination and Alzheimer's Disease Assessment Scale. These results suggest development of tau beyond the mesial temporal lobe is associated with, and may be dependent on, amyloid accumulation. Further, the results are consistent with the hypothesis that cortical tau is associated with cognitive impairment.
Determining how to optimize a scientific and efficient farmland nitrogen (N) fertilizer schedule by combining existing technology is currently a hot topic. Maize is one of the major crops in China, ...and enhancing the yield of maize is conducive to ensuring China's food security. In this study, the central region of Jilin Province was adopted as the research object, and a three-year (2014–2016) field experiment was performed. The data from 2014 were used to calibrate the DSSAT model, and the data from 2015 were used for validation. After calibration and validation, the DSSAT model and a genetic algorithm (GA) were used to optimize the N fertilizer schedule of maize under 20 years (1973–1992) of meteorological data for Changchun. The experimental data from 2016 were used to validate the results of the optimized N fertilizer schedule. As revealed from the results, the DSSAT model effectively simulated the growth and development of maize under drip irrigation and rain-fed methods in Changchun. The model was first calibrated based on the crop yield, phenological phases and soil moisture and N content data, and good agreement was achieved between the simulated and measured data in both the calibration and validation periods. In the calibration and validation periods, the normalized root mean square error (nRMSE) for grain yield was 1.45% and 1.61%, respectively. The total amount in the new N fertilizer schedule is 198 kg/ha, which is slightly higher than that in the traditional schedule (187.5 kg/ha), and the yield of maize in the proposed N fertilizer schedule was upregulated by 7–9% compared with the conventional N fertilization schedule in the experimental results for 2016. Through an analysis of economic benefits, drip irrigation is better than the rain-fed method, and the optimized N fertilization schedule will make the economic benefits more significant (8.4%–12.4% increase). Additionally, this method is easier to combine with remote sensing and weather forecasting, forming a real-time method of field management optimization schedule decision-making.
●The combination of DSSAT model and genetic algorithm.●The optimal fertilization schedule under full drip irrigation in Northeast China.●Contribute to the real time irrigation and fertilizer schedule.
In a trial of galcanezumab, an antibody to calcitonin gene–related peptide, for the treatment of cluster headache, a subcutaneous dose reduced the mean weekly frequency of cluster attacks from 17.8 ...to 9.1, as compared with 17.3 to 12.1 in the placebo group. Injection-site reactions occurred in 8% of the patients receiving galcanezumab.
Summary Background Cetuximab and bevacizumab have both been shown to improve outcomes in patients with metastatic colorectal cancer when added to chemotherapy regimens; however, their comparative ...effectiveness when partnered with first-line fluorouracil, folinic acid, and irinotecan (FOLFIRI) is unknown. We aimed to compare these agents in patients with KRAS (exon 2) codon 12/13 wild-type metastatic colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we recruited patients aged 18–75 years with stage IV, histologically confirmed colorectal cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, an estimated life expectancy of greater than 3 months, and adequate organ function, from centres in Germany and Austria. Patients were centrally randomised by fax (1:1) to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab (using permuted blocks of randomly varying size), stratified according to ECOG performance status, number of metastatic sites, white blood cell count, and alkaline phosphatase concentration. The primary endpoint was objective response analysed by intention to treat. The study has completed recruitment, but follow-up of participants is ongoing. The trial is registered with ClinicalTrials.gov , number NCT00433927. Findings Between Jan 23, 2007, and Sept 19, 2012, 592 patients with KRAS exon 2 wild-type tumours were randomly assigned and received treatment (297 in the FOLFIRI plus cetuximab group and 295 in the FOLFIRI plus bevacizumab group). 184 (62·0%, 95% CI 56·2–67·5) patients in the cetuximab group achieved an objective response compared with 171 (58·0%, 52·1–63·7) in the bevacizumab group (odds ratio 1·18, 95% CI 0·85–1·64; p=0·18). Median progression-free survival was 10·0 months (95% CI 8·8–10·8) in the cetuximab group and 10·3 months (9·8–11·3) in the bevacizumab group (hazard ratio HR 1·06, 95% CI 0·88–1·26; p=0·55); however, median overall survival was 28·7 months (95% CI 24·0–36·6) in the cetuximab group compared with 25·0 months (22·7–27·6) in the bevacizumab group (HR 0·77, 95% CI 0·62–0·96; p=0·017). Safety profiles were consistent with the known side-effects of the study drugs. The most common grade 3 or worse adverse events in both treatment groups were haematotoxicity (73 25% of 297 patients in the cetuximab group vs 62 21% of 295 patients in the bevacizumab group), skin reactions (77 26% vs six 2%), and diarrhoea (34 11% vs 40 14%). Interpretation Although the proportion of patients who achieved an objective response did not significantly differ between the FOLFIRI plus cetuximab and FOLFIRI plus bevacizumab groups, the association with longer overall survival suggests that FOLFIRI plus cetuximab could be the preferred first-line regimen for patients with KRAS exon 2 wild-type metastatic colorectal cancer. Funding Merck KGaA.
Summary Background Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a ...human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. Methods In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01752634. Findings Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 54% patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p<0·0001), 150 mg (51 51% patients; 6·52, 3·25–13·08; p<0·0001), and 75 mg (29 29% patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 15% patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four 4%, eight 8%, ten 10%, and seven 7% with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six 6%, four 4%, six 6%, and eight 8%, respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Interpretation Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder. Funding Novartis.
Biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis, otherwise known as ankylosing spondylitis, when conventional therapies are not ...effective. We report efficacy and safety data on ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A), in patients with radiographic axial spondyloarthritis who have not previously been treated with bDMARDs.
In this phase 3, randomised, double-blind, placebo-controlled superiority study of ixekizumab, adult patients with inadequate response or intolerance to non-steroidal anti-inflammatory drugs, an established diagnosis of radiographic axial spondyloarthritis, radiographic sacroiliitis centrally defined by modified New York criteria, and at least one spondyloarthritis feature according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, were recruited from 84 sites (12 countries) in Europe, Asia, and North America. By use of a computer-generated random sequence, patients were randomly assigned (1:1:1:1) to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference group), or placebo. The primary objective was to compare the proportion of patients achieving an ASAS40 response, a composite measure of clinical improvement in axial spondyloarthritis, at week 16 for both ixekizumab treatment groups versus the placebo group. The adalimumab reference group was included as an in-study active reference for comparison with placebo to provide additional context to interpretation of the ixekizumab study results.
Between June 20, 2016, and Aug 22, 2017, 341 patients were randomly assigned to either the placebo group (n=87), adalimumab group (n=90), ixekizumab Q2W (n=83), or ixekizumab Q4W (n=81). At week 16, compared with placebo (16 18% of 87), more patients achieved ASAS40 with ixekizumab Q2W (43 52% of 83; p<0·0001), ixekizumab Q4W (39 48% of 81; p<0·0001), and adalimumab (32 36% of 90; p=0·0053). One serious infection occurred in each of the ixekizumab Q2W (1%), ixekizumab Q4W (1%), and adalimumab (1%) groups; none were reported with placebo. One (1%) Candida infection occurred in the adalimumab group and one (1%) patient receiving ixekizumab Q2W was adjudicated as having probable Crohn's disease. No treatment-emergent opportunistic infections, malignancies, or deaths occurred.
Each dosing regimen of ixekizumab was superior to placebo for improving radiographic axial spondyloarthritis signs and symptoms in patients not previously treated with bDMARDs; the safety profile was consistent with previous indications of ixekizumab.
Eli Lilly and Company
Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary ...analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up.
ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479.
706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 0·34–0·51; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 19% of 278 patients had upper respiratory tract infections; 42 15% had bronchitis, 34 12% had viral upper respiratory tract infections), cough (34 12%), and diarrhoea (28 10%).
D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns.
Janssen Research & Development.
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