A practical approach to the guideline-directed pharmacological treatment of heart failure with reduced ejection fraction

Over the last 15–20 years, remarkable developments of heart failure (HF) pharmacotherapies have been achieved. However, HF remains a global healthcare challenge with more than 64 million patients worldwide. Optimization of guideline-directed chronic HF medical therapy is highly recommended with every patient visit to improve outcomes in patients with HF with reduced ejection fraction. However, the majority of patients in real-world settings are treated with doses that are lower than those with proven efficacy in clinical trials, which might be due to concerns of adverse effects and inertia of physicians. Likewise, a significant proportion of patients still do not receive all drug classes that could improve their prognosis. The recent European Society of Cardiology guidelines do not provide detailed recommendations on how these drug classes should be implemented in the treatment of inpatients to allow for both safety and a high likelihood of efficacy. We therefore propose a practical approach algorithm to support physicians to treat HF patients in their daily practice

Learning Stackelberg Equilibria and Applications to Economic Design Games

We study the use of reinforcement learning to learn the optimal leader's strategy in Stackelberg games. Learning a leader's strategy has an innate stationarity problem -- when optimizing the leader's strategy, the followers' strategies might shift. To circumvent this problem, we model the followers via no-regret dynamics to converge to a Bayesian Coarse-Correlated Equilibrium (B-CCE) of the game induced by the leader. We then embed the followers' no-regret dynamics in the leader's learning environment, which allows us to formulate our learning problem as a standard POMDP. We prove that the optimal policy of this POMDP achieves the same utility as the optimal leader's strategy in our Stackelberg game. We solve this POMDP using actor-critic methods, where the critic is given access to the joint information of all the agents. Finally, we show that our methods are able to learn optimal leader strategies in a variety of settings of increasing complexity, including indirect mechanisms where the leader's strategy is setting up the mechanism's rules

Long-Range PSU(2,2|4) Bethe Ansaetze for Gauge Theory and Strings

We generalize various existing higher-loop Bethe ansaetze for simple sectors of the integrable long-range dynamic spin chain describing planar N=4 Super Yang-Mills Theory to the full psu(2,2|4) symmetry and, asymptotically, to arbitrary loop order. We perform a large number of tests of our conjectured equations, such as internal consistency, comparison to direct three-loop diagonalization and expected thermodynamic behavior. In the special case of the su(1|2) subsector, corresponding to a long-range t-J model, we are able to derive, up to three loops, the S-matrix and the associated nested Bethe ansatz from the gauge theory dilatation operator. We conjecture novel all-order S-matrices for the su(1|2) and su(1,1|2) subsectors, and show that they satisfy the Yang-Baxter equation. Throughout the paper, we muse about the idea that quantum string theory on AdS_5xS^5 is also described by a psu(2,2|4) spin chain. We propose asymptotic all-order Bethe equations for this putative "string chain", which differ in a systematic fashion from the gauge theory equations.Comment: 67 pages, In Honor of Hans Bethe, v2: references added, typos fixed, sign conventions improved, v3: published versio

Comparative effectiveness of levetiracetam, valproate and carbamazepine among elderly patients with newly diagnosed epilepsy: subgroup analysis of the randomized, unblinded KOMET study

BACKGROUND: Few clinical trials have evaluated the efficacy and tolerability of antiepileptic drugs (AEDs) as initial monotherapy for elderly patients. METHODS: This post-hoc subgroup analysis of data from an unblinded, randomized, 52-week superiority study (KOMET) compared the effectiveness of levetiracetam (LEV) with extended-release sodium valproate (VPA-ER) and controlled-release carbamazepine (CBZ-CR) as monotherapy in patients aged 60 years with newly diagnosed epilepsy. The physician chose VPA or CBZ as preferred standard treatment; patients were randomized to standard AEDs or LEV. The primary endpoint was time to treatment withdrawal. Results are exploratory, since KOMET was not powered for a subgroup analysis by age. RESULTS: Patients (n = 308) were randomized to LEV (n = 48) or VPA-ER (n = 53) in the VPE-ER stratum or to LEV (n = 104) or CBZ-CR (n = 103) in the CBZ-CR stratum. Mean age was 69.6 years, range 60.2-89.9 years (intention-to-treat population n = 307). Time to treatment withdrawal hazard ratio [HR] (95 % confidence interval [CI]) for LEV vs. standard AEDs was 0.44 (0.28-0.67); LEV vs. VPA-ER: 0.46 (0.16-1.33); LEV vs. CBZ-CR: 0.45 (0.28-0.72). Twelve-month withdrawal rates were: LEV vs. standard AEDs, 20.4 vs. 38.7 %; LEV vs. VPA-ER, 10.4 vs. 23.1 %; LEV vs. CBZ-CR, 25.0 vs. 46.6 %. Time to first seizure was similar between LEV and standard AEDs (HR: 0.92, 95 % CI: 0.63-1.35), LEV and VPA-ER (0.77, 0.38-1.56), and LEV and CBZ-CR (1.02, 0.64-1.63). Adverse events were reported by 76.2, 67.3, and 82.5 % of patients for LEV, VPA-ER, and CBZ-CR, respectively. Discontinuation rates due to AEs were 11.3, 10.2, and 35.0 % for LEV, VPA-ER, and CBZ-CR, respectively.CONCLUSIONS: Time to treatment withdrawal was longer with LEV compared with standard AEDs. This finding was driven primarly by the result in the CBZ-CR stratum, which in turn was likely due to the more favorable tolerability profile of LEV. Results of this post-hoc analysis suggest that LEV(VLID)195291

On the Structure of Infrared Singularities of Gauge-Theory Amplitudes

A closed formula is obtained for the infrared singularities of dimensionally regularized, massless gauge-theory scattering amplitudes with an arbitrary number of legs and loops. It follows from an all-order conjecture for the anomalous-dimension matrix of n-jet operators in soft-collinear effective theory. We show that the form of this anomalous dimension is severely constrained by soft-collinear factorization, non-abelian exponentiation, and the behavior of amplitudes in collinear limits. Using a diagrammatic analysis, we demonstrate that these constraints imply that to three-loop order the anomalous dimension involves only two-parton correlations, with the possible exception of a single color structure multiplying a function of conformal cross ratios depending on the momenta of four external partons, which would have to vanish in all two-particle collinear limits. We argue that such a function does not appear at three-loop order, and that the same is true in higher orders. Our formula predicts Casimir scaling of the cusp anomalous dimension to all orders in perturbation theory, and we explicitly check that the constraints exclude the appearance of higher Casimir invariants at four loops. Using known results for the quark and gluon form factors, we derive the three-loop coefficients of the 1/epsilon^n pole terms (with n=1,...,6) for an arbitrary n-parton scattering amplitude in massless QCD. This generalizes Catani's two-loop formula proposed in 1998.Comment: 46 pages, 9 figures; v2: improved treatment of collinear limits, references added; v3: improved discussion of non-abelian exponentiation, references updated; v4: typo in eq. (17) fixed, references updated; v5: additional term in (17

Integrability and Transcendentality

We derive the two-loop Bethe ansatz for the sl(2) twist operator sector of N=4 gauge theory directly from the field theory. We then analyze a recently proposed perturbative asymptotic all-loop Bethe ansatz in the limit of large spacetime spin at large but finite twist, and find a novel all-loop scaling function. This function obeys the Kotikov-Lipatov transcendentality principle and does not depend on the twist. Under the assumption that one may extrapolate back to leading twist, our result yields an all-loop prediction for the large-spin anomalous dimensions of twist-two operators. The latter also appears as an undetermined function in a recent conjecture of Bern, Dixon and Smirnov for the all-loop structure of the maximally helicity violating (MHV) n-point gluon amplitudes of N=4 gauge theory. This potentially establishes a direct link between the worldsheet and the spacetime S-matrix approach. A further assumption for the validity of our prediction is that perturbative BMN (Berenstein-Maldacena-Nastase) scaling does not break down at four loops, or beyond. We also discuss how the result gets modified if BMN scaling does break down. Finally, we show that our result qualitatively agrees at strong coupling with a prediction of string theory.Comment: 45 pages LaTeX, 3 postscript figures. v2: Chapter on BMN scaling and transcendentality added. v3: version accepted for publication in JSTA

A Generalized Scaling Function for AdS/CFT

We study a refined large spin limit for twist operators in the sl(2) sector of AdS/CFT. We derive a novel non-perturbative equation for the generalized two-parameter scaling function associated to this limit, and analyze it at weak coupling. It is expected to smoothly interpolate between weakly coupled gauge theory and string theory at strong coupling.Comment: 27 pages, no figures; v2: references added and typos fixe

Planar N=4 Gauge Theory and the Hubbard Model

Recently it was established that a certain integrable long-range spin chain describes the dilatation operator of N=4 gauge theory in the su(2) sector to at least three-loop order, while exhibiting BMN scaling to all orders in perturbation theory. Here we identify this spin chain as an approximation to an integrable short-ranged model of strongly correlated electrons: The Hubbard model.Comment: 35 pages, 2 figures; v2: typos and references fixed, published versio

The Factorized S-Matrix of CFT/AdS

We argue that the recently discovered integrability in the large-N CFT/AdS system is equivalent to diffractionless scattering of the corresponding hidden elementary excitations. This suggests that, perhaps, the key tool for finding the spectrum of this system is neither the gauge theory's dilatation operator nor the string sigma model's quantum Hamiltonian, but instead the respective factorized S-matrix. To illustrate the idea, we focus on the closed fermionic su(1|1) sector of the N=4 gauge theory. We introduce a new technique, the perturbative asymptotic Bethe ansatz, and use it to extract this sector's three-loop S-matrix from Beisert's involved algebraic work on the three-loop su(2|3) sector. We then show that the current knowledge about semiclassical and near-plane-wave quantum strings in the su(2), su(1|1) and sl(2) sectors of AdS_5 x S^5 is fully consistent with the existence of a factorized S-matrix. Analyzing the available information, we find an intriguing relation between the three associated S-matrices. Assuming that the relation also holds in gauge theory, we derive the three-loop S-matrix of the sl(2) sector even though this sector's dilatation operator is not yet known beyond one loop. The resulting Bethe ansatz reproduces the three-loop anomalous dimensions of twist-two operators recently conjectured by Kotikov, Lipatov, Onishchenko and Velizhanin, whose work is based on a highly complex QCD computation of Moch, Vermaseren and Vogt.Comment: 38 pages, LaTeX, JHEP3.cl