Predicting Hemodynamic Changes During Intra-Aortic Balloon Pump Support With a Longitudinal Evaluation.

The use of intra-aortic balloon pump (IABP) has decreased in recent years due to negative outcome studies in cardiogenic shock complicating acute myocardial infarction, despite its favorable adverse-event profile. Acute hemodynamic response studies have identified potential super-responders with immediate improvements in cardiac index (CI) in heart failure patients. This single-center retrospective study aimed to predict CI and mean arterial pressure (MAP) changes throughout the entire duration of IABP support. The study analyzed 336 patients who received IABP between 2016 and 2022. Linear mixed-effect regression models were used to predict CI and MAP improvement during IABP support. The results showed that CI and MAP increases during the first days of support, and changes during IABP support varied with time and were associated with baseline parameters. Longitudinal CI change was associated with body surface area, baseline CI, baseline pulmonary artery pulsatility index, baseline need for pressors, and diabetes. Longitudinal MAP change was associated with baseline MAP, baseline heart rate, need for pressors, or inotropes. The study recommends considering these parameters when deciding if IABP is the most appropriate form of support for a specific patient. Further prospective studies are needed to validate the findings.

Probe Confined Dynamic Mapping for G Protein-Coupled Receptor Allosteric Site Prediction.

Targeting G protein-coupled receptors (GPCRs) through allosteric sites offers advantages over orthosteric sites in identifying drugs with increased selectivity and potentially reduced side effects. In this study, we developed a probe confined dynamic mapping protocol that allows the prediction of allosteric sites at both the GPCR extracellular and intracellular sides, as well as at the receptor-lipid interface. The applied harmonic wall potential enhanced sampling of probe molecules in a selected area of a GPCR while preventing membrane distortion in molecular dynamics simulations. The specific probes derived from GPCR allosteric ligand structures performed better in allosteric site mapping compared to commonly used cosolvents. The M2 muscarinic, ß2 adrenergic, and P2Y1 purinergic receptors were selected for the protocol's retrospective validation. The protocol was next validated prospectively to locate the binding site of [5-fluoro-4-(hydroxymethyl)-2-methoxyphenyl]-(4-fluoro-1H-indol-1-yl)methanone at the D2 dopamine receptor, and subsequent mutagenesis confirmed the prediction. The protocol provides fast and efficient prediction of key amino acid residues surrounding allosteric sites in membrane proteins and facilitates the structure-based design of allosteric modulators.

Autotaxin Activity Predicts 30-Day Mortality in Sepsis Patients and Correlates With Platelet Count and Vascular Dysfunction.

OBJECTIVES: We investigated whether platelet count associated with biomarkers of endothelial function, and additionally sought to identify novel predictors of outcomes in a cohort of patients with severe sepsis at a quaternary care academic medical center. DESIGN: Prospective, observational cohort. PATIENTS: Eighty-six sepsis patients admitted into intensive care units were prospectively enrolled into an on-site sepsis registry and biobank. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Platelet count, mean platelet volume, platelet mass, plasma angiopoietin-1 and angiopoietin-2, syndecan-1, platelet factor 4, sCD40L concentrations, and plasma autotaxin activity were determined for each patient at enrollment. Patient mortality was recorded up to 30 days following hospital discharge. Platelet count and plasma sCD40L was significantly lower in patients who did not survive up to 30 days following hospital discharge. Angiopoietin-2 and the angiopoietin-2/1 ratio were significantly higher in patients who did not survive up to 30 days following discharge. Furthermore, plasma autotaxin activity was significantly higher in patients who did not survive up to 30 days. Interestingly, autotaxin activity correlated with platelet count and the ratio of angiopoietin-2/1 across our population. CONCLUSIONS: Platelet count, the ratio of angiopoietin-2/1, and autotaxin activity all predicted 30-day mortality. Autotaxin activity within the plasma correlates with both platelet counts and vascular dysfunction biomarkers across both survivors and non-survivors indicating a possible involvement of autotaxin within sepsis.