Mid-regional Proadrenomedullin Biomarker Predicts Coronavirus Disease 2019 Clinical Outcomes: A US-Based Cohort Study.

Background: Mid-regional proadrenomedullin (MR-proADM) is a biomarker released following endothelial damage. Studies have shown a correlation in predicting coronavirus disease 2019 (COVID-19) outcomes with MR-proADM levels. Our study aimed to investigate baseline MR-proADM as a predictor of a wider range of clinical outcomes of varying severity in patients admitted with COVID-19, and to compare to other biomarkers. Methods: Data from the Boston Area COVID-19 Consortium (BACC) Bay Tocilizumab Trial was used in this study. Patients with biomarker determinations, and not admitted to the intensive care unit (ICU) on admission, were included. MR-proADM cutoff of 0.87 nmol/L was assessed in predicting clinical outcomes. Results: Of 182 patients, 11.0% were mechanically ventilated or dead within 28 days. Of patients with MR-proADM >0.87 nmol/L, 21.1% were mechanically ventilated or dead within 28 days, compared with 4.5% of those with MR-proADM ≤0.87 nmol/L (P < .001). The sensitivity, specificity, negative predictive value, and positive predictive value of MR-proADM cutoff of 0.87 nmol/L in predicting mechanical ventilation or death were 75%, 65%, 95%, and 21%, respectively, with an area under the receiver operating characteristic curve of 0.76. On multivariable logistic regression analysis, MR-proADM >0.87 nmol/L was independently associated with mechanical ventilation or death, ICU admission, prolonged hospitalization beyond day 4, and day 4 COVID-19 ordinal scale equal to or worse than day 1. Conclusions: MR-proADM functions as a valuable biomarker for the early risk stratification and detection of severe disease progression of patients with COVID-19. In the prediction of death, MR-proADM performed better compared to many other commonly used biomarkers.

Baseline procalcitonin as a predictor of bacterial infection and clinical outcomes in COVID-19: A case-control study.

PURPOSE: Coronavirus disease-2019 (COVID-19) is associated with a wide spectrum of clinical symptoms including acute respiratory failure. Biomarkers that can predict outcomes in patients with COVID-19 can assist with patient management. The aim of this study is to evaluate whether procalcitonin (PCT) can predict clinical outcome and bacterial superinfection in patients infected with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). METHODS: Adult patients diagnosed with SARS-CoV-2 by nasopharyngeal PCR who were admitted to a tertiary care center in Boston, MA with SARS-CoV-2 infection between March 17 and April 30, 2020 with a baseline PCT value were studied. Patients who were presumed positive for SARS-CoV-2, who lacked PCT levels, or who had a positive urinalysis with negative cultures were excluded. Demographics, clinical and laboratory data were extracted from the electronic medical records. RESULTS: 324 patient charts were reviewed and grouped by clinical and microbiologic outcomes by day 28. Baseline PCT levels were significantly higher for patients who were treated for true bacteremia (p = 0.0005) and bacterial pneumonia (p = 0.00077) compared with the non-bacterial infection group. Baseline PCT positively correlated with the NIAID ordinal scale and survival over time. When compared to other inflammatory biomarkers, PCT showed superiority in predicting bacteremia. CONCLUSIONS: Baseline PCT levels are associated with outcome and bacterial superinfection in patients hospitalized with SARS-CoV-2.

Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results From the Multicenter Procalcitonin MOnitoring SEpsis (MOSES) Study.

OBJECTIVES: To prospectively validate that the inability to decrease procalcitonin levels by more than 80% between baseline and day 4 is associated with increased 28-day all-cause mortality in a large sepsis patient population recruited across the United States. DESIGN: Blinded, prospective multicenter observational clinical trial following an Food and Drug Administration-approved protocol. SETTING: Thirteen U.S.-based emergency departments and ICUs. PATIENTS: Consecutive patients meeting criteria for severe sepsis or septic shock who were admitted to the ICU from the emergency department, other wards, or directly from out of hospital were included. INTERVENTIONS: Procalcitonin was measured daily over the first 5 days. MEASUREMENTS AND MAIN RESULTS: The primary analysis of interest was the relationship between a procalcitonin decrease of more than 80% from baseline to day 4 and 28-day mortality using Cox proportional hazards regression. Among 858 enrolled patients, 646 patients were alive and in the hospital on day 4 and included in the main intention-to-diagnose analysis. The 28-day all-cause mortality was two-fold higher when procalcitonin did not show a decrease of more than 80% from baseline to day 4 (20% vs 10%; p = 0.001). This was confirmed as an independent predictor in Cox regression analysis (hazard ratio, 1.97 [95% CI, 1.18-3.30; p < 0.009]) after adjusting for demographics, Acute Physiology and Chronic Health Evaluation II, ICU residence on day 4, sepsis syndrome severity, antibiotic administration time, and other relevant confounders. CONCLUSIONS: Results of this large, prospective multicenter U.S. study indicate that inability to decrease procalcitonin by more than 80% is a significant independent predictor of mortality and may aid in sepsis care.

miR-124-regulated RhoG reduces neuronal process complexity via ELMO/Dock180/Rac1 and Cdc42 signalling.

The small GTPase RhoG plays a central role in actin remodelling during diverse biological processes such as neurite outgrowth, cell migration, phagocytosis of apoptotic cells, and the invasion of pathogenic bacteria. Although it is known that RhoG stimulates neurite outgrowth in the rat pheochromocytoma PC12 cell line, neither the physiological function nor the regulation of this GTPase in neuronal differentiation is clear. Here, we identify RhoG as an inhibitor of neuronal process complexity, which is regulated by the microRNA miR-124. We find that RhoG inhibits dendritic branching in hippocampal neurons in vitro and in vivo. RhoG also inhibits axonal branching, acting via an ELMO/Dock180/Rac1 signalling pathway. However, RhoG inhibits dendritic branching dependent on the small GTPase Cdc42. Finally, we show that the expression of RhoG in neurons is suppressed by the CNS-specific microRNA miR-124 and connect the regulation of RhoG expression by miR-124 to the stimulation of neuronal process complexity. Thus, RhoG emerges as a cellular conductor of Rac1 and Cdc42 activity, in turn regulated by miR-124 to control axonal and dendritic branching.

B56beta, a regulatory subunit of protein phosphatase 2A, interacts with CALEB/NGC and inhibits CALEB/NGC-mediated dendritic branching.

The development of dendritic arbors is critical in neuronal circuit formation, as dendrites are the primary sites of synaptic input. Morphologically specialized dendritic protrusions called spines represent the main postsynaptic compartment for excitatory neurotransmission. Recently, we demonstrated that chicken acidic leucine-rich epidermal growth factor (EGF) -like domain-containing brain protein/neuroglycan C (CALEB/NGC), a neural member of the EGF family, mediates dendritic tree and spine complexity but that the signaling pathways in the respective processes differ. For a more detailed characterization of these signal transduction pathways, we performed a yeast two-hybrid screen to identify proteins that interact with CALEB/NGC. Our results show that B56beta, a regulatory subunit of protein phosphatase 2A, interacts with CALEB/NGC and inhibits CALEB/NGC-mediated dendritic branching but not spine formation. Binding of B56beta to CALEB/NGC was confirmed by several biochemical and immunocytochemical assays. Using affinity chromatography and mass spectrometry, we demonstrate that the whole protein phosphatase 2A trimer, including structural and catalytic subunits, binds to CALEB/NGC via B56beta. We show that CALEB/NGC induces the phosphorylation of Akt in dendrites. Previously described to interfere with Akt signaling, B56beta inhibits Akt phosphorylation and Akt-dependent dendritic branching but not Akt-independent spine formation induced by CALEB/NGC. Our results contribute to a better understanding of signaling specificity leading to neuronal process differentiation in sequential developmental events.