Multiplex Polymerase Chain Reaction Versus Standard Bacterial Culture in Critically Ill Children With Suspected Pneumonia.

Background: Bacterial lower respiratory tract infection, particularly ventilator-associated pneumonia (VAP), is a significant cause of morbidity and mortality in children who require mechanical ventilation (MV). Microbiologic diagnosis has relied on bacterial culture, but reverse transcriptase polymerase chain reaction (RT-PCR) with bacterial targets is now available for clinical use. We compared the diagnostic performance of tracheal aspirate (TA) multiplex RT-PCR to culture in children requiring MV with suspected lower respiratory tract infection.

Clinical evaluation of PF614, a novel TAAP prodrug of oxycodone, versus OxyContin in a multi-ascending dose study with a bioequivalence arm in healthy volunteers.

PF614, a trypsin-activated abuse protection oxycodone prodrug designed to reduce recreational drug abuse, was compared to OxyContin for safety and pharmacokinetics (PKs) of plasma oxycodone following oral administration. This study was a two-part design including a multi-ascending dose (part A) and a bioequivalence (BE) study (part B) in healthy volunteers. In part A, 24 subjects were randomized 3:1 to receive PF614 (50, 100, or 200 mg, n = 6/cohort) or OxyContin (20, 40, or 80 mg; n = 2/cohort) in ascending cohorts, delivered every 12 h for a total of nine doses.

Molecular Phenotypes of Acute Respiratory Distress Syndrome in the ROSE Trial Have Differential Outcomes and Gene Expression Patterns That Differ at Baseline and Longitudinally over Time.

Two molecular phenotypes have been identified in acute respiratory distress syndrome (ARDS). In the ROSE (Reevaluation of Systemic Early Neuromuscular Blockade) trial of cisatracurium in moderate to severe ARDS, we addressed three unanswered questions: ) Do the same phenotypes emerge in a more severe ARDS cohort with earlier recruitment; ) Do phenotypes respond differently to neuromuscular blockade? and ) What biological pathways most differentiate inflammatory phenotypes? We performed latent class analysis in ROSE using preenrollment clinical and protein biomarkers. In a subset of patients ( = 134), we sequenced whole-blood RNA using enrollment and Day 2 samples and performed differential gene expression and pathway analyses.

The antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients.

Antimicrobial resistant lower respiratory tract infections are an increasing public health threat and an important cause of global mortality. The lung microbiome can influence susceptibility of respiratory tract infections and represents an important reservoir for exchange of antimicrobial resistance genes. Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene burden, however, corollary studies in the lung microbiome remain absent.

The role of primary care providers in testing for sexually transmitted infections in the MassHealth Medicaid program.

The objective of this study was to determine the prevalence and predictors of testing for sexually transmitted infections (STIs) under an accountable care model of health care delivery. Data sources were claims and encounter records from the Massachusetts Medicaid and Children's Health Insurance Program (MassHealth) for enrollees aged 13 to 64 years in 2019. This cross-sectional study examines the one-year prevalence of STI testing and evaluates social determinants of health and other patient characteristics as predictors of such testing in both primary care and other settings.

Changes in Health Care Utilization During the First 2 Years of Massachusetts Medicaid Accountable Care Organizations.

On March 1, 2018, the Massachusetts Medicaid and Children's Health Insurance Program (MassHealth) launched an ambitious accountable care organization (ACO) program that sought to integrate care across the physical, behavioral, functional, and social services continuum while holding ACOs accountable for cost and quality. The study objective was to describe changes in health care utilization among MassHealth members during the pre-ACO baseline (2015-2017) and post-implementation periods (2018 and 2019). Using MassHealth administrative data, the authors conducted a repeated cross-sectional study of MassHealth members enrolled in ACOs during 2015-2019.

The antibiotic resistance reservoir of the lung microbiome expands with age.

Antimicrobial resistant lower respiratory tract infections (LRTI) are an increasing public health threat, and an important cause of global mortality. The lung microbiome influences LRTI susceptibility and represents an important reservoir for exchange of antimicrobial resistance genes (ARGs). Studies of the gut microbiome have found an association between age and increasing antimicrobial resistance gene (ARG) burden, however corollary studies in the lung microbiome remain absent, despite the respiratory tract representing one of the most clinically significant sites for drug resistant infections.

Paying for Medical and Social Complexity in Massachusetts Medicaid.

Importance: The first MassHealth Social Determinants of Health payment model boosted payments for groups with unstable housing and those living in socioeconomically stressed neighborhoods. Improvements were designed to address previously mispriced subgroups and promote equitable payments to MassHealth accountable care organizations (ACOs).

Objective: To develop a model that ensures payments largely follow observed costs for members with complex health and/or social risks.

Identifying molecular phenotypes in sepsis: an analysis of two prospective observational cohorts and secondary analysis of two randomised controlled trials.

Background: In sepsis and acute respiratory distress syndrome (ARDS), heterogeneity has contributed to difficulty identifying effective pharmacotherapies. In ARDS, two molecular phenotypes (hypoinflammatory and hyperinflammatory) have consistently been identified, with divergent outcomes and treatment responses. In this study, we sought to derive molecular phenotypes in critically ill adults with sepsis, determine their overlap with previous ARDS phenotypes, and evaluate whether they respond differently to treatment in completed sepsis trials.

Integrated host/microbe metagenomics enables accurate lower respiratory tract infection diagnosis in critically ill children.

BACKGROUNDLower respiratory tract infection (LRTI) is a leading cause of death in children worldwide. LRTI diagnosis is challenging because noninfectious respiratory illnesses appear clinically similar and because existing microbiologic tests are often falsely negative or detect incidentally carried microbes, resulting in antimicrobial overuse and adverse outcomes. Lower airway metagenomics has the potential to detect host and microbial signatures of LRTI.

Plasma metabolic profiling implicates dysregulated lipid metabolism and glycolytic shift in hyperinflammatory ARDS.

Using latent class analysis (LCA) of clinical and protein biomarkers, researchers have identified two phenotypes of the acute respiratory distress syndrome (ARDS) with divergent clinical trajectories and treatment responses. We investigated whether plasma metabolites differed among patients with LCA-derived hyperinflammatory and hypoinflammatory ARDS, and we tested the prognostic utility of adding metabolic clusters to LCA phenotypes. We analyzed data from 93 patients with ARDS and sepsis enrolled in a multicenter prospective cohort of critically ill patients, comparing 970 metabolites between the two LCA-derived phenotypes.

A 2-Gene Host Signature for Improved Accuracy of COVID-19 Diagnosis Agnostic to Viral Variants.

The continued emergence of SARS-CoV-2 variants is one of several factors that may cause false-negative viral PCR test results. Such tests are also susceptible to false-positive results due to trace contamination from high viral titer samples. Host immune response markers provide an orthogonal indication of infection that can mitigate these concerns when combined with direct viral detection.

Integrated host-microbe plasma metagenomics for sepsis diagnosis in a prospective cohort of critically ill adults.

We carried out integrated host and pathogen metagenomic RNA and DNA next generation sequencing (mNGS) of whole blood (n = 221) and plasma (n = 138) from critically ill patients following hospital admission. We assigned patients into sepsis groups on the basis of clinical and microbiological criteria. From whole-blood gene expression data, we distinguished patients with sepsis from patients with non-infectious systemic inflammatory conditions using a trained bagged support vector machine (bSVM) classifier (area under the receiver operating characteristic curve (AUC) = 0.

Upper airway gene expression shows a more robust adaptive immune response to SARS-CoV-2 in children.

Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults whereas disease burden in children is lower. To investigate whether differences in the upper airway immune response may contribute to this disparity, we compare nasopharyngeal gene expression in 83 children (<19-years-old; 38 with SARS-CoV-2, 11 with other respiratory viruses, 34 with no virus) and 154 older adults (>40-years-old; 45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes is robustly activated in both children and adults with SARS-CoV-2 infection compared to the respective non-viral groups, with only subtle distinctions.

Intraoperative analysis of patellofemoral joint morphology before and after total knee arthroplasty : A feasibility study.

Background: Patellofemoral problems after total knee arthroplast (TKA) are frequent and often associated with a change in the geometry of the trochlear groove.

Objective: The present study aimed to analyze the feasibility of intraoperative examination of the patellofemoral joint geometry before and after the implantation of bicondylar total knee replacements without exposing the patient to radiation.

Material And Methods: The patellofemoral joint morphology geometries of 33 patients before and after implantation of a bicondylar total knee replacement was intraoperatively analyzed using a digital scanning method.

Increased risk of severe clinical course of COVID-19 in carriers of HLA-C*04:01.

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, there has been increasing urgency to identify pathophysiological characteristics leading to severe clinical course in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Human leukocyte antigen alleles (HLA) have been suggested as potential genetic host factors that affect individual immune response to SARS-CoV-2. We sought to evaluate this hypothesis by conducting a multicenter study using HLA sequencing.

Upper airway gene expression reveals a more robust innate and adaptive immune response to SARS-CoV-2 in children compared with older adults.

Unlike other respiratory viruses, SARS-CoV-2 disproportionately causes severe disease in older adults and only rarely in children. To investigate whether differences in the upper airway immune response could contribute to this disparity, we compared nasopharyngeal gene expression in 83 children (<19-years-old; 38 with SARS-CoV-2, 11 with other respiratory viruses, 34 with no virus) and 154 adults (>40-years-old; 45 with SARS-CoV-2, 28 with other respiratory viruses, 81 with no virus). Expression of interferon-stimulated genes (ISGs) was robustly activated in both children and adults with SARS-CoV-2 compared to the respective non-viral groups, with only relatively subtle distinctions.

Tracheal aspirate RNA sequencing identifies distinct immunological features of COVID-19 ARDS.

The immunological features that distinguish COVID-19-associated acute respiratory distress syndrome (ARDS) from other causes of ARDS are incompletely understood. Here, we report the results of comparative lower respiratory tract transcriptional profiling of tracheal aspirate from 52 critically ill patients with ARDS from COVID-19 or from other etiologies, as well as controls without ARDS. In contrast to a "cytokine storm," we observe reduced proinflammatory gene expression in COVID-19 ARDS when compared to ARDS due to other causes.

Allele-Specific Knockdown of Mutant Huntingtin Protein via Editing at Coding Region Single Nucleotide Polymorphism Heterozygosities.

Huntington's disease (HD) is a devastating, autosomal dominant neurodegenerative disease caused by a trinucleotide repeat expansion in the huntingtin (HTT) gene. Inactivation of the mutant allele by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 based gene editing offers a possible therapeutic approach for this disease, but permanent disruption of normal HTT function might compromise adult neuronal function. Here, we use a novel HD mouse model to examine allele-specific editing of mutant HTT (mHTT), with a BAC97 transgene expressing mHTT and a YAC18 transgene expressing normal HTT.