Procalcitonin decrease over 72 hours in US critical care units predicts fatal outcome in sepsis patients

Introduction: Close monitoring and repeated risk assessment of sepsis patients in the intensive care unit (ICU) is important for decisions regarding care intensification or early discharge to the ward. We studied whether considering plasma kinetics of procalcitonin, a biomarker of systemic bacterial infection, over the first 72 critical care hours improved mortality prognostication of septic patients from two US settings. Methods: This retrospective analysis included consecutively treated eligible adults with a diagnosis of sepsis from critical care units in two independent institutions in Clearwater, FL and Chicago, IL. Cohorts were used for derivation or validation to study the association between procalcitonin change over the first 72 critical care hours and mortality. Results: ICU/in-hospital mortality rates were 29.2%/31.8% in the derivation cohort (n = 154) and 17.6%/29.4% in the validation cohort (n = 102). In logistic regression analysis of both cohorts, procalcitonin change was strongly associated with ICU and in-hospital mortality independent of clinical risk scores (Acute Physiology, Age and Chronic Health Evaluation IV or Simplified Acute Physiology Score II), with area under the curve (AUC) from 0.67 to 0.71. When procalcitonin decreased by at least 80%, the negative predictive value for ICU/in-hospital mortality was 90%/90% in the derivation cohort, and 91%/79% in the validation cohort. When procalcitonin showed no decrease or increased, the respective positive predictive values were 48%/48% and 36%/52%. Discussion In septic patients, procalcitonin kinetics over the first 72 critical care hours provide prognostic information beyond that available from clinical risk scores. If these observations are confirmed, procalcitonin monitoring may assist physician decision-making regarding care intensification or early transfer from the ICU to the floor

Diabetic status and the relation of the three domains of glycemic control to mortality in critically ill patients: an international multicenter cohort study.

INTRODUCTION: Hyperglycemia, hypoglycemia, and increased glycemic variability have each been independently associated with increased risk of mortality in critically ill patients. The role of diabetic status on modulating the relation of these three domains of glycemic control with mortality remains uncertain. The purpose of this investigation was to determine how diabetic status affects the relation of hyperglycemia, hypoglycemia, and increased glycemic variability with the risk of mortality in critically ill patients. METHODS: This is a retrospective analysis of prospectively collected data involving 44,964 patients admitted to 23 intensive care units (ICUs) from nine countries, between February 2001 and May 2012. We analyzed mean blood glucose concentration (BG), coefficient of variation (CV), and minimal BG and created multivariable models to analyze their independent association with mortality. Patients were stratified according to the diagnosis of diabetes. RESULTS: Among patients without diabetes, mean BG bands between 80 and 140 mg/dl were independently associated with decreased risk of mortality, and mean BG bands >140 mg/dl, with increased risk of mortality. Among patients with diabetes, mean BG from 80 to 110 mg/dl was associated with increased risk of mortality and mean BG from 110 to 180 mg/dl with decreased risk of mortality. An effect of center was noted on the relation between mean BG and mortality. Hypoglycemia, defined as minimum BG 20%, was independently associated with increased risk of mortality only among patients without diabetes. Derangements of more than one domain of glycemic control had a cumulative association with mortality, especially for patients without diabetes. CONCLUSIONS: Although hyperglycemia, hypoglycemia, and increased glycemic variability is each independently associated with mortality in critically ill patients, diabetic status modulates these relations in clinically important ways. Our findings suggest that patients with diabetes may benefit from higher glucose target ranges than will those without diabetes. Additionally, hypoglycemia is independently associated with increased risk of mortality regardless of the patient's diabetic status, and increased glycemic variability is independently associated with increased risk of mortality among patients without diabetes.JOURNAL ARTICLESCOPUS: ar.jinfo:eu-repo/semantics/publishe

A Second-Generation Oral SARS-CoV‑2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug–drug interactions upon single-agent use of PF-07817883

A Second-Generation Oral SARS-CoV‑2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the in vitro pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883. PF-07817883 also demonstrated oral efficacy in a mouse-adapted SARS-CoV-2 model at plasma concentrations equivalent to nirmatrelvir. The preclinical in vivo pharmacokinetics and metabolism studies in human matrices are suggestive of improved oral pharmacokinetics for PF-07817883 in humans, relative to nirmatrelvir. In vitro inhibition/induction studies against major human drug metabolizing enzymes/transporters suggest a low potential for perpetrator drug–drug interactions upon single-agent use of PF-07817883