Causes of extinction of vertebrates during the Holocene of mainland Australia: arrival of the dingo, or human impact?

The arrival of the dingo in mainland Australia is believed to have caused the extinction of three native vertebrates: the thylacine, the Tasmanian devil and the Tasmanian native hen. The dingo is implicated in these extinctions because, while these three species disappeared during the late Holocene of mainland Australia in the presence of the dingo, they persisted in Tasmania in its absence. Moreover, the dingo might plausibly have competed with the thylacine and devil, and preyed on the native hen. However, another variable is similarly correlated with these extinctions: there is evidence for an increase in the human population on the mainland that gathered pace about 4000 years ago and was associated with innovations in hunting technology and more intensive use of resources. These changes may have combined to put increased hunting pressure on large vertebrates, and to reduce population size of many species that were hunted by people on the mainland. We suggest that these changes, which were quite dramatic on mainland Australia but were muted or absent in Tasmania, could have led to the mainland extinctions of the thylacine, devil and hen

Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis DUAL-1 and DUAL-2 Randomized Clinical Trials

IMPORTANCE Digital ulcers in patients with systemic sclerosis are associated with pain and poor quality of life. Endothelin-1 promotes vasculopathy in systemic sclerosis after macitentan, an endothelin-1 blocker. OBJECTIVE To evaluate the efficacy of macitentan in reducing the number of new digital ulcers in patients with systemic sclerosis. DESIGN, SETTING, AND PARTICIPANTS Two international, randomized, double-blind, placebo-controlled trials (DUAL-1, DUAL-2) were conducted between January 2012 and February 2014. Participants were patients with systemic sclerosis and active digital ulcers at baseline. Target enrollment for each study was 285 patients. INTERVENTIONS Patients were randomized (1: 1: 1) to receive oral doses of 3 mg of macitentan, 10mg of macitentan, or placebo once daily and stratified according to number of digital ulcers at baseline (3). MAIN OUTCOMES AND MEASURES The primary outcome for each trial was the cumulative number of new digital ulcers from baseline to week 16. Treatment effect was expressed as the ratio between treatment groups. RESULTS In DUAL-1, among 289 randomized patients (mean age 51.2 years; 85.8% women), 226 completed the study. The adjusted mean number of new digital ulcers per patient over 16 weeks was 0.94 in the 3-mg macitentan group (n = 95) and 1.08 in the 10-mg macitentan group (n = 97) compared with 0.85 in the placebo group (n = 97) (absolute difference, 0.09 [95% CI, -0.37 to 0.54] for 3mg of macitentan vs placebo and 0.23 [-0.27 to 0.72] for 10mg of macitentan vs placebo). Among 265 patients randomized in DUAL-2 (mean age 49.6 years; 81.9% women), 216 completed the study. In DUAL-2, the adjusted mean number of new digital ulcers was 1.44 in the 3-mg macitentan group (n = 88) and 1.46 in the 10-mg macitentan group (n = 88) compared with 1.21 in the placebo group (n = 89) (absolute difference, 0.23 [95% CI, -0.35 to 0.82] for 3mg of macitentan vs placebo and 0.25 [95% CI, -0.34 to 0.84] for 10mg of macitentan vs placebo). Adverse events more frequently associated with macitentan than with placebo were headache, peripheral edema, skin ulcer, anemia, upper respiratory tract infection, diarrhea, and nasopharyngitis. CONCLUSIONS AND RELEVANCE Among patients with systemic sclerosis and active ischemic digital ulcers, treatment with macitentan did not reduce new digital ulcers over 16 weeks. These results do not support the use of macitentan for the treatment of digital ulcers in this patient population