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There is an important need to advance medication development for alcohol use disorder (AUD). BP1.3656B, a highly potent and selective histamine H3 receptor inverse agonist/antagonist, has been developed. Preclinical studies revealed high affinity, good pharmacokinetic profile, good brain penetration, and favorable safety. BP1.3656B reduced alcohol drinking and alcohol-seeking behavior in rodents. Phase I studies revealed good tolerability/pharmacokinetic in humans. Positron emission tomography revealed high brain occupancy in humans. Based on this favorable profile, two trials were conducted in subjects with AUD. In non-treatment seekers, BP1.3656B had no impact on intravenous alcohol self-administration (IV-ASA). A randomized clinical trial testing three doses of BP1.3656B versus placebo in treatment-seekers with AUD showed no reduction of heavy drinking days. Collective results illustrate the challenges inherent to clinical translation of AUD therapies, and reinforce the use of Phase IIa human laboratory paradigms as an important tool to de-risk translation of innovative drug targets for AUD.

The quasigeostrophic and the generalized omega equations are the most widely used methods to reconstruct vertical velocity w from in situ data. As observational networks with much higher spatial and temporal resolutions are being designed, the question arises of identifying the approximations and scales at which an accurate estimation of w through the omega equation can be achieved and what critical scales and observables are needed. In this paper we test different adiabatic omega reconstructions of w over several regions representative of main oceanic regimes of the global ocean in a fully eddy-resolving numerical simulation with a 1/60° horizontal resolution. We find that the best reconstructions are observed in conditions characterized by energetic turbulence and/or weak stratification where near-surface frontal processes are felt deep into the ocean interior. The quasigeostrophic omega equation gives satisfactory results for scales larger than ~10 km horizontally while the improvements using a generalized formulation are substantial only in conditions where frontal turbulent processes are important (providing improvements with satisfactory reconstruction skill down to ~5 km in scale). The main sources of uncertainties that could be identified are related to processes responsible for ocean thermal wind imbalance (TWI), which is particularly difficult to account for (especially in observation-based studies) and to the deep flow that is generally improperly accounted for in omega reconstructions through the bottom boundary condition. Nevertheless, the reconstruction of mesoscale vertical velocities may be sufficient to estimate vertical fluxes of oceanic properties in many cases of practical interest.