Multiple Model Optimal Sampling Promotes Accurate Vancomycin Area-Under-the-Curve Estimation Using a Single Sample in Critically Ill Children.

Background: Area-under-the-curve (AUC)-directed vancomycin therapy is recommended; however, AUC estimation in critically ill children is difficult owing to the need for multiple samples and lack of informative models.

Methods: The authors prospectively enrolled critically ill children receiving intravenous (IV) vancomycin for suspected infection and evaluated the accuracy of Bayesian estimation of AUC from a single, optimally timed sample. During the dosing interval, when clinical therapeutic drug monitoring was performed, an optimally timed sample was collected, which was determined for each subject using an established population pharmacokinetic model and the multiple model optimal function of Pmetrics, a nonparametric population pharmacokinetic modeling software.

Polymicrobial interactions influence co-existence and biofilm forming capabilities.

The lungs of patients with cystic fibrosis (CF) are vulnerable to persistent polymicrobial colonization by bacterial pathogens including , and the non-tuberculous mycobacterium (NTM) . The polymicrobial milieu within the CF lung impacts individual species fitness, influences biofilm-forming capabilities, pathogenicity, production of virulence factors and even antimicrobial responses, all potentially compromising therapeutic success. Interaction studies among these CF pathogens are very limited, especially studies on the influences of and on co-existence and virulence.

Basiliximab induction immunosuppression and lung transplant outcomes: Propensity analysis in a multicenter cohort.

Background: Basiliximab induction immunosuppression is increasingly employed in lung transplant recipients despite limited prospective evidence to support its use in this population. We sought to determine the relationship between basiliximab induction and development of acute rejection, chronic lung allograft dysfunction, and other clinically relevant outcomes in a multicenter lung transplant cohort with variable induction practice patterns.

Methods: We applied propensity-based statistical methods to rigorous, prospectively collected longitudinal data from 768 newly transplanted adult lung recipients at 5 North American centers (368 who received basiliximab induction immunosuppression and 400 who received no induction immunosuppression).

Predictors of donation after circulatory death lung utilization and allograft survival.

Background: Understanding donor factors associated with successful lung transplantation (LTx) following donation after circulatory death (DCD) is important in optimizing donor management. In this study, we examined critical care and ventilatory factors associated with DCD LTx and allograft survival using a unique detailed donor management database.

Methods: The Donor Management Goals national registry was queried for DCD donors between January 2016 and July 2023.

Long-Term Air Pollution Exposure and Severity of Idiopathic Pulmonary Fibrosis: Data from the IPF-PRO Registry.

Rationale: While exposure to air pollution is a known risk factor for adverse pulmonary outcomes, its impact in individuals with idiopathic pulmonary fibrosis (IPF) is less well understood.

Objective: To investigate the effects of long-term exposure to air pollution on disease severity and progression in patients with IPF and to determine whether genomic factors, such as MUC5B promoter polymorphism or telomere length, modify these associations.

Methods: We performed analyses at enrollment and after one year of follow-up in the IPF-PRO Registry, a prospective observational registry that enrolled individuals with IPF at 46 US sites from June 2014 to October 2018.

Prognosis and Risks for Probable Chronic Lung Allograft Dysfunction: A Prospective Multicenter Study.

Rationale: Chronic lung allograft dysfunction (CLAD) hinders lung transplant success. A 2019 consensus refined CLAD diagnosis, introducing probable or definite CLAD based on persistence of lung function decline. Outcomes and risks for probable CLAD remain uncertain.

Identification and validation of a threshold for early posttransplant bronchoalveolar fluid hyaluronan that distinguishes lung recipients at risk for chronic lung allograft dysfunction.

Background: Few tools exist for the early identification of patients at risk for chronic lung allograft dysfunction (CLAD). We previously showed hyaluronan (HA), a matrix molecule that regulates lung inflammation and fibrosis, accumulates in bronchoalveolar lavage fluid (BALF) and blood in CLAD. We aimed to determine if early posttransplant HA elevations inform CLAD risk.

Associations of circulating matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases with clinically relevant outcomes in idiopathic pulmonary fibrosis: Data from the IPF-PRO Registry.

Introduction: We assessed the prognostic utility of circulating levels of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry.

Methods: MMP and TIMP concentrations were quantified by ELISA in plasma from 300 patients. A Cox proportional hazard regression model was used to assess associations between select MMPs and TIMPs and death and disease progression (absolute decline in forced vital capacity ≥10% predicted, death, or lung transplant).

Design and baseline characteristics of the ILD-PRO registry in patients with progressive pulmonary fibrosis.

Background: To assess the characteristics of patients enrolled in the ILD-PRO Registry.

Methods: The ILD-PRO Registry is a multicentre US registry of patients with progressive pulmonary fibrosis. This registry is enrolling patients with an interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis who have reticular abnormality and traction bronchiectasis on HRCT, and who meet criteria for ILD progression within the prior 24 months.

Utility of the 52-Gene Risk Score to Identify Patients with Idiopathic Pulmonary Fibrosis at Greater Risk of Mortality in the Era of Antifibrotic Therapy.

Purpose: We investigated whether a 52-gene signature was associated with transplant-free survival and other clinically meaningful outcomes in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry, which enrolled patients who were and were not taking antifibrotic therapy.

Methods: The 52-gene risk signature was implemented to classify patients as being at "high risk" or "low risk" of disease progression and mortality. Transplant-free survival and other outcomes were compared between patients with a low-risk versus high-risk signature.

Comparative Genomic Analysis of Prophages in Human Vaginal Isolates of .

Prophages, viral genomes integrated into bacterial genomes, are known to enhance bacterial colonization, adaptation, and ecological fitness, providing a better chance for pathogenic bacteria to disseminate and cause infection. (Group B Streptococcus or GBS) is a common bacterium found colonizing the genitourinary tract of humans. However, GBS-colonized pregnant women are at risk of passing the organism to the neonate, where it can cause severe infections.

Factors associated with tracheostomy-associated infection treatment: A multicenter observational study.

Objective: To characterize factors that influence the decision to treat suspected pediatric bacterial tracheostomy-associated respiratory infections (bTRAINs; e.g., pneumonia, tracheitis).

Rescue of impaired blood-brain barrier in tuberous sclerosis complex patient derived neurovascular unit.

Background: Tuberous sclerosis complex (TSC) is a multi-system genetic disease that causes benign tumors in the brain and other vital organs. The most debilitating symptoms result from involvement of the central nervous system and lead to a multitude of severe symptoms including seizures, intellectual disability, autism, and behavioral problems. TSC is caused by heterozygous mutations of either the TSC1 or TSC2 gene and dysregulation of mTOR kinase with its multifaceted downstream signaling alterations is central to disease pathogenesis.

Transcriptome profiles of macrophages upon infection by morphotypic smooth and rough variants of Mycobacterium abscessus.

Mycobacterium abscessus (Mab) infection can be deadly in patients with chronic lung diseases like cystic fibrosis (CF). In vitro and in vivo, Mab may adopt a smooth (S) or rough (R) morphotype, the latter linked to more severe disease conditions. In vitro studies revealed differences in pathogenicity and immune response to S and R morphotypes.

In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects.

RPEM: Randomized Monte Carlo parametric expectation maximization algorithm.

Inspired from quantum Monte Carlo, by sampling discrete and continuous variables at the same time using the Metropolis-Hastings algorithm, we present a novel, fast, and accurate high performance Monte Carlo Parametric Expectation Maximization (MCPEM) algorithm. We named it Randomized Parametric Expectation Maximization (RPEM). We compared RPEM with NONMEM's Importance Sampling Method (IMP), Monolix's Stochastic Approximation Expectation Maximization (SAEM), and Certara's Quasi-Random Parametric Expectation Maximization (QRPEM) for a realistic two-compartment voriconazole model with ordinary differential equations using simulated data.

Modeling Pharmacokinetics in Individual Patients Using Therapeutic Drug Monitoring and Artificial Population Quasi-Models: A Study with Piperacillin.

Population pharmacokinetic (pop-PK) models constructed for model-informed precision dosing often have limited utility due to the low number of patients recruited. To augment such models, an approach is presented for generating fully artificial quasi-models which can be employed to make individual estimates of pharmacokinetic parameters. Based on 72 concentrations obtained in 12 patients, one- and two-compartment pop-PK models with or without creatinine clearance as a covariate were generated for piperacillin using the nonparametric adaptive grid algorithm.

Contractile and Genetic Characterization of Cardiac Constructs Engineered from Human Induced Pluripotent Stem Cells: Modeling of Tuberous Sclerosis Complex and the Effects of Rapamycin.

The implementation of three-dimensional tissue engineering concurrently with stem cell technology holds great promise for in vitro research in pharmacology and toxicology and modeling cardiac diseases, particularly for rare genetic and pediatric diseases for which animal models, immortal cell lines, and biopsy samples are unavailable. It also allows for a rapid assessment of phenotype-genotype relationships and tissue response to pharmacological manipulation. Mutations in the and genes lead to dysfunctional mTOR signaling and cause tuberous sclerosis complex (TSC), a genetic disorder that affects multiple organ systems, principally the brain, heart, skin, and kidneys.

Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. In vitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied.

Circulating metabolic profile in idiopathic pulmonary fibrosis: data from the IPF-PRO Registry.

Background: The circulating metabolome, reflecting underlying cellular processes and disease biology, has not been fully characterized in patients with idiopathic pulmonary fibrosis (IPF). We evaluated whether circulating levels of metabolites correlate with the presence of IPF, with the severity of IPF, or with the risk of clinically relevant outcomes among patients with IPF.

Methods: We analyzed enrollment plasma samples from 300 patients with IPF in the IPF-PRO Registry and 100 individuals without known lung disease using a set of targeted metabolomics and clinical analyte modules.

Myositis-Associated Autoantibodies in Patients With Juvenile Myositis Are Associated With Refractory Disease and Mortality.

Objective: Myositis-associated autoantibodies (MAAs) have been associated with overlap myositis, certain disease manifestations such as interstitial lung disease (ILD), and worse prognosis in the idiopathic inflammatory myopathies. MAAs overall remain largely uncharacterized in patients with juvenile-onset myositis. Moreover, it is unknown whether the number of MAAs is associated with disease severity.