Carl J. Griffin

OBJECTIVE This trial compared the efficacy and safety of the first oral glucagon-like peptide 1 (GLP-1) receptor agonist, oral semaglutide, as monotherapy with placebo in patients with type 2 diabetes managed by diet and exercise alone. Two estimands addressed two efficacy-related questions: a treatment policy estimand (regardless of trial product discontinuation or rescue medication use) and a trial product estimand (on trial product without rescue medication use) in all randomized patients. RESEARCH DESIGN AND METHODS This was a 26-week, phase 3a, randomized, double-blind, placebo-controlled, parallel-group trial conducted in 93 sites in nine countries. Adults with type 2 diabetes insufficiently controlled with diet and exercise were randomized (1:1:1:1) to once-daily oral semaglutide 3 mg, 7 mg, 14 mg, or placebo. The primary end point was change from baseline to week 26 in HbA1c. The confirmatory secondary end point was change from baseline to week 26 in body weight. RESULTS In the 703 patients randomized (mean age 55 years, 50.8% male, and mean baseline HbA1c 8.0% [64 mmol/mol]), oral semaglutide reduced HbA1c (placebo-adjusted treatment differences at week 26: treatment policy estimand, −0.6% [3 mg], −0.9% [7 mg], and −1.1% [14 mg]; trial product estimand, −0.7% [3 mg], −1.2% [7 mg], and −1.4% [14 mg]; P < 0.001 for all) and body weight (treatment policy, −0.1 kg [3 mg], −0.9 kg [7 mg], and −2.3 kg [14 mg, P < 0.001]; trial product, −0.2 kg [3 mg], −1.0 kg [7 mg, P = 0.01], and −2.6 kg [14 mg, P < 0.001]). Mild-to-moderate transient gastrointestinal events were the most common adverse events with oral semaglutide. Trial product discontinuations occurred in 2.3–7.4% with oral semaglutide and 2.2% with placebo. CONCLUSIONS In patients with type 2 diabetes, oral semaglutide monotherapy demonstrated superior and clinically relevant improvements in HbA1c (all doses) and body weight loss (14 mg dose) versus placebo, with a safety profile consistent with other GLP-1 receptor agonists.

<h3>Objective</h3> To assess the efficacy and safety of lasmiditan in the acute treatment of migraine. <h3>Methods</h3> Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS). <h3>Results</h3> Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0–3.6, <i>p</i>&lt; 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR 2.2, 95% CI 1.6–3.0, <i>p</i>&lt; 0.001). Furthermore, compared with those dosed with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95% CI 1.3–2.1, <i>p</i>&lt; 0.001) and lasmiditan 100 mg (40.9%; OR 1.7, 95% CI, 1.3–2.2, <i>p</i>&lt; 0.001) were free of their MBS at 2 hours after dosing. Adverse events were mostly mild or moderate in intensity. <h3>Conclusions</h3> Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors. <h3>ClinicalTrials.gov identifier</h3> NCT02439320. <h3>Classification of evidence</h3> This study provides Class I evidence that for adult patients with migraine, lasmiditan increases the proportion of subjects who are headache pain free at 2 hours after treating a migraine attack.

Beginning in Kent in the summer of 1830 before spreading throughout the country, the Swing Riots were the most dramatic and widespread rising of the English rural poor. Seeking an end to their immiseration, the protestors destroyed machines, demanded higher wages and more generous poor relief, and even frequently resorted to incendiarism to enforce their modest demands. But occurring against a backdrop of revolutions in continental Europe and a political crisis, Swing to many represented a genuine challenge to the existing ruling order, provoking a bitter and bloody repression. This book offers a new account of this defining moment in British history. It is shown that the protests were more organised, intensive and politically motivated than has hitherto been thought, representing complex statements about the nature of authority, gender and the politics of rural life.

Developing understandings of protest and cultures of resistance has been a central theme of the ‘new’ cultural geography of the 1990s and 2000s. But whilst geographers of the here and now have been highly sensitive to the importance of acts of protest which occur outside of the context of broader social movements, geographers concerned with past protests have tended to focus overwhelmingly upon either understanding the development of social movements or highly specific place‐based studies. Through a focus upon the hitherto ignored practice of ‘tree maiming’, this paper demonstrates not only the value of examining specific protest practices in helping to better understand the complexity of conflict, but also how in periods of acute socio‐economic change the evolving relationship between humans and the non‐human – in this case trees – is a central discourse to the protest practices of the poor. Such attacks often involved complex cultural understandings about the ways in which trees should – and should not – be socially enrolled.