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• The responses of the NDVI to climatic factors were spatiotemporal heterogeneous. • Karst NDVI in southwest China was predicted based on multiple factors. • The model performance regarding NDVI at the spatial scales was relatively good. • The 1 km resolution NDVI data were suitable for predicting karst vegetation. Karst vegetation (KV) is one of the most important indicators for maintaining the surface energy balance in southwestern China. The spatial pattern of KV is mainly affected by climate, human activities, and environmental factors. The relationships between the KV and these factors are complex and nonlinear. Most previous studies on the nonlinear relationship characteristics and regional regularity were not comprehensive. In this study, the correlation and the time-lagged response of KV to climatic factors were investigated using Pearson correlation analysis, and a nonlinear model of the relationships between the karst normalized difference vegetation index (NDVI) and multiple factors was built based on a back propagation neural network optimized using the beetle antennae search algorithm (BAS-BP), and then, the karst NDVI was predicted. The results showed that (1) in most karst regions, the seasonal NDVI was mainly influenced by temperature, but the autumn NDVI was mainly affected by precipitation. The correlation between the interannual variation in the NDVI and the interannual variation in the precipitation was higher than the correlation between the interannual variation in the NDVI and the interannual variation in temperature. The NDVI and the other climatic factors were not strongly correlated. The NDVI responded to the climatic factors with different time-lagged intervals in different spatiotemporal scales. (2) At multiple spatial scales, the mean correlation coefficient (R) and means squared error (MSE) values of the vegetation prediction in the different geomorphic areas were 0.6565 and 0.0072, respectively. The maximum R was up to 0.9059. In different lithology areas, the mean values of R and MSE were 0.6898 and 0.0072, respectively. The maximum R value was 0.9142. (3) The prediction model of the interannual variation in the NDVI was trained, and it was then tested for the validation period. The R values ranged from 0.5299 to 0.7744, with an average of 0.6606. In contrast to the prediction results on different spatial scales, the model's performance regarding the interannual variation in the NDVI was relatively poor. (4) The mean R values were 0.6708, 0.5575, and 0.5468 and the mean MSE values were 0.0067, 0.0084, and 0.0114 for the 1 km, 250 m, and 8 km NDVI resolution predictions, respectively. The obtained results showed that the model's performance regarding the NDVI prediction was better at a spatial resolution of 1 km than at spatial resolutions of 250 m and 8 km. [ABSTRACT FROM AUTHOR]

Background: Calcitonin gene-related peptide (CGRP) is a validated target for the treatment of episodic migraine. Here we assess the safety, tolerability, and efficacy of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of high-frequency episodic migraine.Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had migraine headaches 8-14 days per month. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1; stratified by sex and use of concomitant preventive drugs) after a 28 day run-in period to three 28 day treatment cycles of subcutaneous 225 mg TEV-48125, 675 mg TEV-48125, or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Patients reported headache information daily using an electronic diary. Primary endpoints were change from baseline in migraine days during the third treatment cycle (weeks 9-12) and safety and tolerability. The secondary endpoint was change relative to baseline in headache-days during weeks 9-12. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered at ClinicalTrials.gov, number NCT02025556.Findings: Between Jan 8, 2014, and Oct 15, 2014, we enrolled 297 participants: 104 were randomly assigned to receive placebo, 95 to receive 225 mg TEV-48125, and 96 to receive 675 mg TEV-48125. The least square mean (LSM) change in number of migraine-days from baseline to weeks 9-12 was -3.46 days (SD 5.40) in the placebo group, -6.27 days (5.38) in the 225 mg dose group, and -6.09 days (5.22) in the 675 mg dose group. The LSM difference in the reduction of migraine-days between the placebo and 225 mg dose groups was -2.81 days (95% CI -4.07 to -1.55; p<0.0001), whereas the difference between the placebo and 675 mg dose group was -2.64 days (-3.90 to -1.38; p<0.0001). LSM differences in the reduction of headache-days were -2.63 days (-3.91 to -1.34; p<0.0001) between the placebo group and 225 mg dose group and -2.58 days (-3.87 to 1.30; p <0.0001) between the placebo group and the 675 mg dose group. Adverse events occurred in 58 (56%) patients in the placebo group, 44 (46%) patients in the 225 mg dose group, and 57 (59%) patients in the 675 mg dose group; moderate or severe adverse events were reported for 29 (27%) patients, 24 (25%) patients, and 26 (27%) patients, respectively.Interpretation: TEV-48125, at doses of 225 mg and 675 mg given once every 28 days for 12 weeks, was safe, well tolerated, and effective as a preventive treatment of high-frequency episodic migraine, thus supporting advancement of the clinical development programme to phase 3 clinical trials.Funding: Teva Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Benefits of calcitonin-gene related peptide (CGRP) inhibition have not been established in chronic migraine. Here we assess the safety, tolerability, and efficacy of two doses of TEV-48125, a monoclonal anti-CGRP antibody, in the preventive treatment of chronic migraine.Methods: In this multicentre, randomised, double-blind, double-dummy, placebo-controlled, parallel-group phase 2b study, we enrolled men and women (aged 18-65 years) from 62 sites in the USA who had chronic migraine. Using a randomisation list generated by a central computerised system and an interactive web response system, we randomly assigned patients (1:1:1, stratified by sex and use of concomitant preventive drugs) to three 28-day treatment cycles of subcutaneous TEV-48125 675/225 mg (675 mg in the first treatment cycle and 225 mg in the second and third treatment cycles), TEV-48125 900 mg (900 mg in all three treatment cycles), or placebo. Investigators, patients, and the funder were blinded to treatment allocation. Daily headache information was captured using an electronic diary. Primary endpoints were change from baseline in the number of headache-hours during the third treatment cycle (weeks 9-12) and safety and tolerability during the study. Secondary endpoint was change in the number of moderate or severe headache-days in weeks 9-12 relative to baseline. Efficacy endpoints were analysed for the intention-to-treat population. Safety and tolerability were analysed using descriptive statistics. This trial is registered with ClinicalTrials.gov, number, NCT02021773.Findings: Between Jan 8, 2014, and Aug 27, 2014, we enrolled 264 participants: 89 were randomly assigned to receive placebo, 88 to receive 675/225 mg TEV-48125, and 87 to receive 900 mg TEV-48125. The mean change from baseline in number of headache-hours during weeks 9-12 was -59.84 h (SD 80.38) in the 675/225 mg group and -67.51 h (79.37) in the 900 mg group, compared with -37.10 h (79.44) in the placebo group. The least square mean difference in the reduction of headache-hours between the placebo and 675/225 mg dose groups was -22.74 h (95% CI -44.28 to -1.21; p=0.0386), whereas the difference between placebo and 900 mg dose groups was -30.41 h (-51.88 to -8.95; p=0.0057). Adverse events were reported by 36 (40%) patients in the placebo group, 47 (53%) patients in the 675/225 mg dose group, and 41 (47%) patients in the 900 mg dose group, whereas treatment-related adverse events were recorded in 15 (17%) patients, 25 (29%) patients, and 28 (32%) patients, respectively. The most common adverse events were mild injection-site pain and pruritus. Four (1%) patients had serious non-treatment-related adverse events (one patient in the placebo group, one patient in the 675/225 mg group, and two patients in the 900 mg group); no treatment-related adverse events were serious and there were no relevant changes in blood pressure or other vital signs.Interpretation: TEV-48125 given by subcutaneous injection every 28 days seems to be tolerable and effective, thus supporting the further development of TEV-48125 for the preventive treatment of chronic migraine in a phase 3 trial.Funding: Teva Pharmaceuticals. [ABSTRACT FROM AUTHOR]