Clinicians use several measures to ascertain whether individual patients will tolerate liberation from mechanical ventilation, including the rapid shallow breathing index (RSBI). Given varied use of different thresholds, patient populations, and measurement characteristics, how well does RSBI predict successful extubation? We searched six databases from inception through September 2019 and selected studies reporting the accuracy of RSBI in the prediction of successful extubation. We extracted study data and assessed quality independently and in duplicate. We included 48 studies involving RSBI measurements of 10,946 patients. Pooled sensitivity for RSBI of< 105 in predicting extubation success was moderate (0.83 [95%CI, 0.78-0.87], moderate certainty), whereas specificity was poor (0.58 [95%CI, 0.49-0.66], moderate certainty) with diagnostic ORs (DORs) of 5.91 (95%CI, 4.09-8.52). RSBI thresholds of< 80 or 80 to 105 yielded similar sensitivity, specificity, and DOR. These findings were consistent across multiple subgroup analyses reflecting different patient characteristics and operational differences in RSBI measurement. As a stand-alone test, the RSBI has moderate sensitivity and poor specificity for predicting extubation success. Future research should evaluate its role as a permissive criterion to undergo a spontaneous breathing trial (SBT) for patients who are at intermediate pretest probability of passing an SBT. PROSPERO; No. CRD42020149196.PROSPERO; No. CRD42020149196. Preclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation. Are circulating NE and elafin levels abnormal in PAH and are they associated with clinical severity? In an observational Stanford University PAH cohort (n= 249), plasma NE and elafin levels were measured in comparison with those of healthy control participants (n= 106) and then were related to clinical features and relevant ancillary biomarkers. Cox regression models were fitted with cubic spline functions to associate NE and elafin levels with survival. To validate prognostic relationships, we analyzed two United Kingdom cohorts (n= 75 and n= 357). Mixed-effects models evaluated NE and elafin changes during disease progression. Finally, we studied effects of NE-elafin balance on pulmonary artery endothelial cells (PAECs) from patients with PAH. Relative to control participants, patients with PAH showed increased NE levelsnds and outcomes. PAH PAECs exhibited increased apoptosis and attenuated angiogenesis when exposed to NE at the level observed in patients' blood. Elafin rescued PAEC homeostasis, yet the required dose exceeded levels found in patients. NE level is increased and elafin level is deficient across PAH subtypes. NE level is associated with disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin.NE level is increased and elafin level is deficient across PAH subtypes. NE level is associated with disease severity and outcomes, and this target-specific biomarker could facilitate therapeutic development of elafin. During pulp inflammation, recruited macrophages can differentiate into 2 phenotypes proinflammatory M1 and anti-inflammatory M2. Pulp fibroblasts have previously been shown to regulate pulp inflammation via cytokine and growth factor secretion. We hypothesized that upon carious injury, pulp fibroblasts interact with macrophages and modulate their differentiation. Cultures of pulp fibroblasts were physically injured and incubated with lipoteichoic acid (LTA) to mimic the pulp environment underlying a carious lesion. Physical injuries without LTA were performed on cultured fibroblasts to simulate the surrounding pulp tissue. Fibroblast supernatants were collected and added to undifferentiated macrophages to study their differentiation into M1 or M2 phenotypes by investigating cytokine secretion profiles and phagocytosis capacity. Histologic staining and immunofluorescence were performed on healthy and carious human tooth sections to localize the 2 macrophage phenotypes. LTA-stimulated fibroblasts induced ated at the periphery of the inflammatory zone induced macrophage differentiation to anti-inflammatory M2. The fine balance between the 2 phenotypes may represent a prerequisite for initiating the healing process.Serum- and glucocorticoid-regulated kinase 3 (Sgk3) is a serine/threonine protein kinase activated by the phospholipid phosphatidylinositol 3-phosphate (PI3P) downstream of growth factor signaling via class I phosphatidylinositol 3-kinase (PI3K) signaling and by class III PI3K/Vps34-mediated PI3P production on endosomes. Upregulation of Sgk3 activity has recently been linked to a number of human cancers; however, the precise mechanism of activation of Sgk3 is unknown. Here, we use a wide range of cell biological, biochemical, and biophysical techniques, including hydrogen-deuterium exchange mass spectrometry, to investigate the mechanism of activation of Sgk3 by PI3P. We show that Sgk3 is regulated by a combination of phosphorylation and allosteric activation. We demonstrate that binding of Sgk3 to PI3P via its regulatory phox homology (PX) domain induces large conformational changes in Sgk3 associated with its activation and that the PI3P-binding pocket of the PX domain of Sgk3 is sequestered in its inactive conformation. Finally, we reconstitute Sgk3 activation via Vps34-mediated PI3P synthesis on phosphatidylinositol liposomes in vitro. learn more In addition to identifying the mechanism of Sgk3 activation by PI3P, our findings open up potential therapeutic avenues in allosteric inhibitor development to target Sgk3 in cancer.Tyrosyl DNA phosphodiesterase 1 (TDP1) and DNA Ligase IIIα (LigIIIα) are key enzymes in single-strand break (SSB) repair. TDP1 removes 3'-tyrosine residues remaining after degradation of DNA topoisomerase (TOP) 1 cleavage complexes trapped by either DNA lesions or TOP1 inhibitors. It is not known how TDP1 is linked to subsequent processing and LigIIIα-catalyzed joining of the SSB. Here we define a direct interaction between the TDP1 catalytic domain and the LigIII DNA-binding domain (DBD) regulated by conformational changes in the unstructured TDP1 N-terminal region induced by phosphorylation and/or alterations in amino acid sequence. Full-length and N-terminally truncated TDP1 are more effective at correcting SSB repair defects in TDP1 null cells compared with full-length TDP1 with amino acid substitutions of an N-terminal serine residue phosphorylated in response to DNA damage. TDP1 forms a stable complex with LigIII170-755, as well as full-length LigIIIα alone or in complex with the DNA repair scaffold protein XRCC1.