Explainable Machine Learning Analysis of Right Heart Failure After Left Ventricular Assist Device Implantation.

Right heart failure (RHF) remains a common and serious complication after durable left ventricular assist device (LVAD) implantation. We used explainable machine learning (ML) methods to derive novel insights into preimplant patient factors associated with RHF. Continuous-flow LVAD implantations from 2008 to 2017 in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) were included. A total of 186 preimplant patient factors were analyzed and the primary outcome was 30 days of severe RHF. A boosted decision tree ML algorithm and an explainable ML method were applied to identify the most important factors associated with RHF, nonlinear relationships and interactions, and risk inflection points. Out of 19,595 patients, 19.1% developed severe RHF at 30 days. Thirty top predictors of RHF were identified with the top five being INTERMACS profile, Model for End-stage Liver Disease score, the number of inotropic infusions, hemoglobin, and race. Many top factors exhibited nonlinear relationships with key risk inflection points such as INTERMACS profile between 2 and 3, right atrial pressure of 15 mmHg, pulmonary artery pressure index of 3, and prealbumin of 23 mg/dl. Finally, the most important variable interactions involved INTERMACS profile and the number of inotropes. These insights could help formulate patient optimization strategies prior to LVAD implantation.

Antiparallel EmrE exports drugs by exchanging between asymmetric structures.

Small multidrug resistance transporters provide an ideal system to study the minimal requirements for active transport. EmrE is one such transporter in Escherichia coli. It exports a broad class of polyaromatic cation substrates, thus conferring resistance to drug compounds matching this chemical description. However, a great deal of controversy has surrounded the topology of the EmrE homodimer. Here we show that asymmetric antiparallel EmrE exchanges between inward- and outward-facing states that are identical except that they have opposite orientation in the membrane. We quantitatively measure the global conformational exchange between these two states for substrate-bound EmrE in bicelles using solution NMR dynamics experiments. Förster resonance energy transfer reveals that the monomers within each dimer are antiparallel, and paramagnetic relaxation enhancement NMR experiments demonstrate differential water accessibility of the two monomers within each dimer. Our experiments reveal a 'dynamic symmetry' that reconciles the asymmetric EmrE structure with the functional symmetry of residues in the active site.