3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

Brief of Thirty-Four Law Professors as Amici Curiae in Support of Appellants in Altera Corp. v. Papst Licensing GMBH

Beginning with its 1998 decision in Red Wing Shoe Co. v. Hockerson-Halberstadt, Inc., 148 F.3d 1355, 1360 (Fed. Cir. 1998), the Federal Circuit has embraced a rigid, bright-line rule for the exercise of personal jurisdiction in patent declaratory judgment actions. Specifically, the Federal Circuit has held, based on “policy considerations unique to the patent context,” Avocent Huntsville Corp. v. Aten Int’l Co., 552 F.3d 1324, 1333 (Fed. Cir. 2008), that contacts created through unsuccessful attempts to license a patent can never be sufficient to create specific personal jurisdiction over a patent holder. In contrast to that rigid, patent-specific rule, the Supreme Court has repeatedly emphasized that the analysis of personal jurisdiction “is not susceptible of mechanical application,” Kulko v. Superior Court, 436 U.S. 84, 92 (1978), and has instead required a case-by-case inquiry into the defendant’s contacts with the forum state and considerations of “fair play and substantial justice,” Burger King Corp. v. Rudzewicz, 471 U.S. 462, 485-86 (1985) (internal quotations omitted). Applying the analysis mandated by Supreme Court precedent, it is clear that personal jurisdiction exists in declaratory judgment actions, such as this one, where the patent holder purposefully targeted the forum state by sending demand letters into the state and engaging in in-person meetings in the state with the specific purpose of licensing the patent-in-suit. In addition, important public policy interests support allowing courts to exercise personal jurisdiction over patentees who engage in patent licensing activities targeted at the forum state. The Supreme Court and Congress have consistently emphasized a strong public policy in clearing invalid patents from the marketplace. The Declaratory Judgment Act furthers this policy by allowing accused infringers to obtain a decision on patent validity at a reasonable time and in a reasonable place. The rigid rule established by Red Wing Shoe, however, frustrates the goal of encouraging patent challenges by granting patent holders unilateral control over where a declaratory judgment suit may be filed. For these reasons, the Federal Circuit should sua sponte consider this case en banc to overturn the restrictive jurisdictional rule established by Red Wing Shoe.La

Σ(1385)± resonance production in Pb–Pb collisions at √sNN = 5.02 TeV

Hadronic resonances are used to probe the hadron gas produced in the late stage of heavy-ion collisions since they decay on the same timescale, of the order of 1 to 10 fm/c, as the decoupling time of the system. In the hadron gas, (pseudo)elastic scatterings among the products of resonances that decayed before the kinetic freeze-out and regeneration processes counteract each other, the net effect depending on the resonance lifetime, the duration of the hadronic phase, and the hadronic cross sections at play. In this context, the Σ(1385)± particle is of particular interest as models predict that regeneration dominates over rescattering despite its relatively short lifetime of about 5.5 fm/c. The first measurement of the Σ(1385)± resonance production at midrapidity in Pb-Pb collisions at sNN−−−√=5.02 TeV with the ALICE detector is presented in this Letter. The resonances are reconstructed via their hadronic decay channel, Λπ, as a function of the transverse momentum (pT) and the collision centrality. The results are discussed in comparison with the measured yield of pions and with expectations from the statistical hadronization model as well as commonly employed event generators, including PYTHIA8/Angantyr and EPOS3 coupled to the UrQMD hadronic cascade afterburner. None of the models can describe the data. For Σ(1385)±, a similar behaviour as K∗(892)0 is observed in data unlike the predictions of EPOS3 with afterburner

Measurement of the lifetime and Λ separation energy of 3ΛH

The most precise measurements to date of the 3ΛH lifetime τ and Λ separation energy BΛ are obtained using the data sample of Pb-Pb collisions at √= 5.02 TeV collected by ALICE at the LHC. The 3ΛH is reconsNN structed via its charged two-body mesonic decay channel (3ΛH→ 3He + π− and the charge-conjugate process). The measured values τ=[253±11 (stat.)±6 (syst.)] ps and BΛ=[102±63 (stat.)±67 (syst.)] keV are compatible with predictions from effective field theories and confirm that the 3ΛH structure is consistent with a weakly-bound system

Investigation of K+K− interactions via femtoscopy in Pb-Pb collisions at √sNN = 2.76 TeV at the CERN Large Hadron Collider

Femtoscopic correlations of non-identical charged kaons (K+K−) are studied in Pb−Pb collisions at a center-of-mass energy per nucleon−nucleon collision sNN−−−√=2.76 TeV by ALICE at the LHC. One-dimensional K+K− correlation functions are analyzed in three centrality classes and eight intervals of particle-pair transverse momentum. The Lednický and Luboshitz interaction model used in the K+K− analysis includes the final-state Coulomb interactions between kaons and the final-state interaction through a0(980) and f0(980) resonances. The mass of f0(980) and coupling were extracted from the fit to K+K− correlation functions using the femtoscopic technique for the first time. The measured mass and width of the f0(980) resonance are consistent with other published measurements. The height of the ϕ(1020) meson peak present in the K+K− correlation function rapidly decreases with increasing source radius, qualitatively in agreement with an inverse volume dependence. A phenomenological fit to this trend suggests that the ϕ(1020) meson yield is dominated by particles produced directly from the hadronization of the system. The small fraction subsequently produced by FSI could not be precisely quantified with data presented in this paper and will be assessed in future work

Two-particle transverse momentum correlations in pp and p-Pb collisions at energies available at the CERN Large Hadron Collider

Two-particle transverse momentum differential correlators, recently measured in Pb-Pb collisions at LHC energies, provide an additional tool to gain insights into particle production mechanisms and infer transport properties, such as the ratio of shear viscosity to entropy density, of the medium created in Pb-Pb collisions. The longitudinal long-range correlations and the large azimuthal anisotropy measured at low transverse momenta in small collision systems, namely pp and p-Pb, at LHC energies resemble manifestations of collective behaviour. This suggests that locally equilibrated matter may be produced in these small collision systems, similar to what is observed in Pb-Pb collisions. In this work, the same two-particle transverse momentum differential correlators are exploited in pp and p-Pb collisions at s√=7 TeV and sNN−−−√=5.02 TeV, respectively, to seek evidence for viscous effects. Specifically, the strength and shape of the correlators are studied as a function of the produced particle multiplicity to identify evidence for longitudinal broadening that might reveal the presence of viscous effects in these smaller systems. The measured correlators and their evolution from pp and p-Pb to Pb-Pb collisions are additionally compared to predictions from Monte Carlo event generators, and the potential presence of viscous effects is discussed

Observation of flow angle and flow magnitude fluctuations in Pb-Pb collisions at sNN\sqrt{s_{\rm NN}} = 5.02 TeV at the LHC

This Letter reports on the first measurements of transverse momentum dependent flow angle Ψn and flow magnitude vn fluctuations determined using new four-particle correlators. The measurements are performed for various centralities in Pb–Pb collisions at a center-of-mass energy per nucleon pair of sNN = 5.02 TeV with ALICE at the CERN Large Hadron Collider. Both flow angle and flow magnitude fluctuations are observed in the presented centrality ranges and are strongest in the most central collisions and for a transverse momentum pT>2GeV/c. Comparison with theoretical models, including iEBE-VISHNU, MUSIC, and AMPT, show that the measurements exhibit unique sensitivities to the initial state of heavy-ion collisions.This Letter reports on the first measurements of transverse momentum dependent flow angle $\Psi_n$ and flow magnitude $v_n$ fluctuations, determined using new four-particle correlators. The measurements are performed for various centralities in Pb-Pb collisions at a centre-of-mass energy per nucleon pair of $\sqrt{s_{\rm NN}}$ = 5.02 TeV with ALICE at the CERN Large Hadron Collider. Both flow angle and flow magnitude fluctuations are observed in the presented centrality ranges and are strongest in the most central collisions and for a transverse momentum $p_{\rm T}>2$ GeV/$c$. Comparison with theoretical models, including iEBE-VISHNU, MUSIC, and AMPT, show that the measurements exhibit unique sensitivities to the initial state of heavy-ion collisions