Validation of a seven-question tool (PRISMA-7) in predicting prognosis of older adults in the emergency department: A prospective study.

OBJECTIVES: Older patients arrive at the emergency department (ED) with complex medical challenges, and the current ED triage models frequently undertriage the severity of illness in older adults. There is increasing awareness regarding the importance of identifying frailty in older patients in the context of urgent care. Therefore, this study aimed to assess the predictive accuracy of the seven-question tool of the Program on Research for Integrating Services of the Maintenance of Autonomy (PRISMA-7) in the ED for 28-day mortality among older adults. DESIGN: A prospective polycentric observational study. SETTING: West China Hospital of Sichuan University, Shangjinnanfu of West China Hospital, and People's Hospital of Henan Province. PARTICIPANTS: ED patients aged ≥65 years from the three tertiary care centers over an 8-week period. PRIMARY AND SECONDARY OUTCOMES: The primary outcome, 28-day all-cause mortality, was investigated using a Cox proportional hazards regression model to assess the predictive validity. The secondary endpoints, intensive care unit (ICU) transfer was investigated using multivariable logistic regression, compared with trained study assistants. RESULTS: The final study population comprised 1043 consecutive patients aged ≥65 years. The area under the receiver operating characteristic (ROC) curve (AUC) for 28-day mortality was 0.80 (95% confidence interval [CI]: 0.76-0.84), 0.73 (95% CI: 0.68-0.77), and 0.78 (95% CI: 0.73-0.83) for PRISMA-7, Emergency Severity Index (ESI), and quick Sepsis Related Organ Failure Assessment (qSOFA), respectively.There was no difference in the AUC between PRISMA-7 and qSOFA(p = 0.374).The AUC for ICU admission was 0.78 (95% CI: 0.75-0.80), 0.62 (95% CI: 0.59-0.66), and 0.68 (95% CI: 0.64-0.72) for PRISMA-7, ESI, and qSOFA, respectively.The AUC for ICU admission between PRISMA-7 and ESI(p<0.001), PRISMA-7 and qSOFA(p<0.001), qSOFA and ESI(p = 0.005) was statistically significant. CONCLUSION: Our findings reveal that PRISMA-7 improves the prediction of ICU admission, but there is no significant difference when it comes to all-cause mortality. PRISMA-7 appears to be a reliable and valid instrument for identifying frailty in the ED. TRIAL REGISTRATION NUMBER: ChiCTR2100046545.

Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles.

Fibroblast growth factor receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (SNAr) chemistry can be employed in a rational manner to generate highly potent and (isoform-)selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low to subnanomolar potency, efficient covalent inactivation kinetics, and excellent selectivity against the other FGFRs, the kinases with an equivalent cysteine, and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability, highlighting the potential of SNAr-based approaches in covalent inhibitor design.

Design and Synthesis of Pyrazole-Based Macrocyclic Kinase Inhibitors Targeting BMPR2.

Bone morphogenetic protein (BMP) signaling is mediated by transmembrane protein kinases that form heterotetramers consisting of type-I and type-II receptors. Upon BMP binding, the constitutively active type-II receptors activate specific type-I receptors by transphosphorylation, resulting in the phosphorylation of SMAD effector proteins. Drug discovery in the receptor tyrosine kinase-like (TKL) family has largely focused on type-I receptors, with few inhibitors that have been published targeting type-II receptors. BMPR2 is involved in several diseases, most notably pulmonary arterial hypertension, but also contributes to Alzheimer's disease and cancer. Here, we report that macrocyclization of the promiscuous inhibitor 1, based on a 3-amino-1H-pyrazole hinge binding moiety, led to a selective and potent BMPR2 inhibitor 8a.

Study of the interactions of a novel monoclonal antibody, mAb059c, with the hPD-1 receptor.

Programmed cell death 1 (PD-1) monoclonal antibodies have been approved by regulatory agencies for the treatment of various types of cancer, and the mechanism involves the restoration of T cell functions. We report herein the X-ray crystal structure of a fully human monoclonal antibody mAb059c fragment antigen-binding (Fab) in complex with the PD-1 extracellular domain (ECD) at a resolution of 1.70 Å. Structural analysis indicates 1) an epitope, comprising fragments from the C'D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C'D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact - ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds. Interface analysis reveals that N-glycosylation sites 49, 74 and 116 on PD-1 do not contact mAb059c; while N58 in the BC loop is recognized by mAb059c heavy chain CDR1 and CDR2. Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs.