Target Temperature Management Effect on the Clinical Outcome of Patients with Out-of-Hospital Cardiac Arrest Treated with Extracorporeal Cardiopulmonary Resuscitation: A Nationwide Observational Study.

This study aimed to investigate whether targeted temperature management (TTM) could enhance outcomes in patients with out-of-hospital cardiac arrest (OHCA) treated with extracorporeal cardiopulmonary resuscitation (ECPR) for refractory cardiac arrest. Using a nationwide OHCA registry, adult patients with witnessed OHCA of presumed cardiac origin who underwent ECPR at the emergency department between 2008 and 2021 were included. We examined the effect of ECPR with TTM on survival and neurological outcomes at hospital discharge using propensity score matching and multivariable logistic regression compared with patients treated with ECPR without TTM. Odds ratios and 95% confidence intervals were determined. A total of 399 ECPR cases were analyzed among 380,239 patients with OHCA. Of these, 330 underwent ECPR without TTM and 69 with TTM. After propensity score matching, 69 matched pairs of patients were included in the analysis. No significant differences in survival and good neurological outcomes between the two groups were observed. In the multivariable logistic regression, no significant differences were observed in survival and neurological outcomes between ECPR with and without TTM. Among the patients who underwent ECPR after OHCA, ECPR with TTM did not improve outcomes compared with ECPR without TTM.

Discovery of 3-Phenyl Indazole-Based Novel Chemokine-like Receptor 1 Antagonists for the Treatment of Psoriasis.

Chemokine-like receptor 1 (CMKLR1)─a G protein-coupled receptor─has functional roles in the immune system and related diseases, including psoriasis and metabolic diseases. Psoriasis is a chronic inflammatory disease characterized by skin redness, scaliness, and itching. In this study, we sought to develop novel CMKLR1 antagonists by screening our in-house GPCR-targeting compound library. Moreover, we optimized a phenylindazole-based hit compound with antagonistic activities and evaluated its oral pharmacokinetic properties in a murine model. A structure-based design on the human CMKLR1 homology model identified S-26d as an optimized compound that serves as a potent and orally available antagonist with a pIC50 value of 7.44 in hCMKLR1-transfected CHO cells. Furthermore, in the imiquimod-induced psoriasis-like mouse model, oral administration of S-26d for 1 week significantly alleviated modified psoriasis area and severity index scores (severity of erythema, scaliness, skin thickness) compared with the control group.

Discovery of benzimidazole-indazole derivatives as potent FLT3-tyrosine kinase domain mutant kinase inhibitors for acute myeloid leukemia.

The FMS-like tyrosine kinase 3 (FLT3) gene encodes a class III receptor tyrosine kinase that is expressed in hematopoietic stem cells. The mutations of FLT3 gene found in 30% of acute myeloid leukemia (AML), leads to an abnormal constitutive activation of FLT3 kinase of the receptor and results in immature myeloblast cell proliferation. Although small molecule drugs targeting the FLT3 kinase have been approved, new FLT3 inhibitors are needed owing to the side effects and drug resistances arising from kinase domain mutations, such as D835Y and F691L. In this study, we have developed benzimidazole-indazole based novel inhibitors targeting mutant FLT3 kinases through the optimization of diverse chemical moieties substituted around the core skeleton. The most optimized compound 22f exhibited potent inhibitory activities against FLT3 and FLT3/D835Y, with IC50 values of 0.941 and 0.199 nM, respectively. Furthermore, 22f exhibited strong antiproliferative activity against an AML cell line, MV4-11 cells with a GI50 of 0.26 nM. More importantly, 22f showed single-digit nanomolar GI50 values in the mutant FLT kinase expressed Ba/F3 cell lines including FLT-D835Y (GI50 = 0.29 nM) and FLT3-F691L (GI50 = 2.87 nM). Molecular docking studies indicated that the compound exhibits a well-fitted binding mode as a type 1 inhibitor in the homology model of active conformation of FLT3 kinase.

Analysis of Mortality in Intracerebral Hemorrhage Patients with Hyperacute Ischemic Stroke Treated Using Thrombolytic Therapy: A Nationwide Population-based Cohort Study in South Korea.

This study investigated the impact of intracerebral hemorrhage (ICH) on the cumulative mortality of patients with hyperacute ischemic stroke. This population-based retrospective cohort study used claims data from the National Health Insurance Service customized database of South Korea. The recruitment period was 2005−2018. The study population included patients with hyperacute ischemic stroke who had received intravenous thrombolysis. The primary endpoint was 12-month cumulative mortality, which was analyzed in both the ICH and no-ICH groups. Of the 50,550 patients included, 2567 (5.1%) and 47,983 (94.9%) belonged to the ICH and no-ICH groups, respectively. In the univariable analysis for 12-month mortality, ICH patients were substantially more prevalent among dead patients than among patients who survived (11.6% versus 3.6%; p < 0.001). The overall 12-month cumulative mortality rate was 18.8%. Mortality in the ICH group was higher than that in the no-ICH group (42.8% versus 17.5%; p < 0.001). In the multivariable analysis, the risk of 12-month cumulative mortality was 2.97 times higher in the ICH group than in the no-ICH group (95% confidence interval, 2.79−3.16). The risk of 12-month cumulative mortality in hyperacute ischemic stroke can increase approximately threefold after the occurrence of spontaneous ICH following intravenous thrombolysis.

Prognostic Effect of Underlying Chronic Kidney Disease and Renal Replacement Therapy on the Outcome of Patients after Out-of-Hospital Cardiac Arrest: A Nationwide Observational Study.

Background and Objectives: This study assessed the prognostic value of underlying chronic kidney disease (CKD) and renal replacement therapy (RRT) on the clinical outcomes from out-of-hospital cardiac arrest (OHCA). Materials and Methods: This retrospective study was conducted utilizing the population-based OHCA data of South Korea between 2008 and 2018. Adult (>18 years) OHCA patients with a medical cause of cardiac arrest were included and classified into three categories based on the underlying CKD and RRT: (1) non-CKD group; (2) CKD without RRT group; and (3) CKD with RRT group. A total of 13,682 eligible patients were included (non-CKD, 9863; CKD without RRT, 1778; CKD with RRT, 2041). From the three comparison subgroups, data with propensity score matching were extracted. The influence of CKD and RRT on patient outcomes was assessed using propensity score matching and multivariate logistic regression analyses. The primary outcome was survival at hospital discharge and the secondary outcome was a good neurological outcome at hospital discharge. Results: The two CKD groups (CKD without RRT and CKD with RRT) showed no significant difference in survival at hospital discharge compared with the non-CKD group (CKD without RRT vs. non-CKD, p > 0.05; CKD with RRT vs. non-CKD, p > 0.05). The non-CKD group had a higher chance of having good neurological outcomes than the CKD groups (non-CKD vs. CKD without RRT, p < 0.05; non-CKD vs. CKD with RRT, p < 0.05) whereas there was no significant difference between the two CKD groups (CKD without RRT vs. CKD with RRT, p > 0.05). Conclusions: Compared with patients without CKD, the underlying cause of CKD­regardless of RRT­may be linked to poor neurological outcomes. Underlying CKD and RRT had no effect on the survival at hospital discharge.