Structural lung disease in preschool children with cystic fibrosis: An 18 month natural history study.

Background: This study was performed to describe the natural history of CF lung disease in young children over an 18 month period to assess the use of CT scanning as an outcome measure for intervention trials.

Methods: Chest CT scans were obtained at baseline and after 18 months in 42 two- to six-year-old children with CF. CT scans were scored by 2 experienced radiologists for the presence and severity of bronchiectasis, mucous plugging, and air trapping.

Suppression of fibrin(ogen)-driven pathologies in disease models through controlled knockdown by lipid nanoparticle delivery of siRNA.

Fibrinogen plays a pathologic role in multiple diseases. It contributes to thrombosis and modifies inflammatory and immune responses, supported by studies in mice expressing fibrinogen variants with altered function or with a germline fibrinogen deficiency. However, therapeutic strategies to safely and effectively tailor plasma fibrinogen concentration are lacking.

Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression.

An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS).

Early Change in Fecal Calprotectin Predicts One-Year Outcome in Children Newly Diagnosed With Ulcerative Colitis.

Introduction: While fecal calprotectin (FC) is used to assess disease activity in ulcerative colitis (UC) there are little data concerning the role of serial FC levels at diagnosis in predicting clinical course. We sought to determine whether FC at diagnosis or early change following therapy predicts clinical outcomes in pediatric UC.Methods: Children with newly diagnosed UC were treated with standardized regimens of mesalamine or corticosteroids (CS).

Innate control of adaptive immunity and adaptive instruction of innate immunity: bi-directional flow of information.

The ability of the innate and adaptive immune systems to communicate with each other is central to protective immune responses and maintenance of host health. Myeloid cells of the innate immune system are able to sense microbial ligands, perturbations in cellular homeostasis, and virulence factors, thereby allowing them to relay distinct pathogen-specific information to naïve T cells in the form of pathogen-derived peptides and a unique cytokine milieu. Once primed, effector T helper cells produce lineage-defining cytokines to help combat the original pathogen, and a subset of these cells persist as memory or effector-memory populations.

Clinical guideline highlights for the hospitalist: Evaluation and management of well-appearing febrile infants 8 to 60 days old.

Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old RELEASE DATE: August 1, 2021 PRIOR VERSION(S): n/a DEVELOPER: American Academy of Pediatrics FUNDING SOURCE: American Academy of Pediatrics TARGET POPULATION: Well-appearing, otherwise healthy infants with fever, ages 8 to 60 days, excluding those with prematurity (<37 wk gestation), focal bacterial infections except acute otitis media, high suspicion for herpes simplex virus (vesicles), clinical bronchiolitis.

Non-hematopoietic IL-4Rα expression contributes to fructose-driven obesity and metabolic sequelae.

Objective: The risks of excess sugar intake in addition to high-fat diet consumption on immunopathogenesis of obesity-associated metabolic diseases are poorly defined. Interleukin-4 (IL-4) and IL-13 signaling via IL-4Rα regulates adipose tissue lipolysis, insulin sensitivity, and liver fibrosis in obesity. However, the contribution of IL-4Rα to sugar rich diet-driven obesity and metabolic sequelae remains unknown.

Ileal Derived Organoids From Crohn's Disease Patients Show Unique Transcriptomic and Secretomic Signatures.

Background & Aims: We used patient-derived organoids (PDOs) to study the epithelial-specific transcriptional and secretome signatures of the ileum during Crohn's disease (CD) with varying phenotypes to screen for disease profiles and potential druggable targets.

Methods: RNA sequencing was performed on isolated intestinal crypts and 3-week-old PDOs derived from ileal biopsies of CD patients (n = 8 B1, inflammatory; n = 8 B2, stricturing disease) and non-inflammatory bowel disease (IBD) controls (n = 13). Differentially expressed (DE) genes were identified by comparing CD vs control, B1 vs B2, and inflamed vs non-inflamed.

Cell type-specific roles of PAR1 in Coxsackievirus B3 infection.

Protease-activated receptor 1 (PAR1) is widely expressed in humans and mice, and is activated by a variety of proteases, including thrombin. Recently, we showed that PAR1 contributes to the innate immune response to viral infection. Mice with a global deficiency of PAR1 expressed lower levels of CXCL10 and had increased Coxsackievirus B3 (CVB3)-induced myocarditis compared with control mice.

Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth.

Background: We previously showed that fibrinogen is a major determinant of the growth of a murine model of colorectal cancer (CRC).

Objective: Our aim was to define the mechanisms coupling fibrin(ogen) to CRC growth.

Results: CRC tumors transplanted into the dorsal subcutis of Fib mice were less proliferative and demonstrated increased senescence relative to those grown in Fib mice.

Predicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen.

In the search for improved stool biomarkers for inflammatory bowel disease (IBD), an aptamer-based screen of 1129 stool proteins was conducted using stool samples from an IBD cohort. Here we report that of the 20 proteins subsequently validated by ELISA, stool Ferritin, Fibrinogen, Haptoglobin, Hemoglobin, Lipocalin-2, MMP-12, MMP-9, Myeloperoxidase, PGRP-S, Properdin, Resistin, Serpin A4, and TIMP-1 are significantly elevated in both ulcerative colitis (UC) and Crohn's disease (CD) compared to controls. When tested in a longitudinal cohort of 50 UC patients at 4 time-points, fecal Fibrinogen, MMP-8, PGRP-S, and TIMP-2 show the strongest positive correlation with concurrent PUCAI and PGA scores and are superior to fecal calprotectin.

Distant and Hidden Figures: Foregrounding Patients in the Development, Content, and Implementation of Entrustable Professional Activities.

Entrustable professional activities (EPAs) describe activities that qualified professionals must be able to perform to deliver safe and effective care to patients. The entrustable aspect of EPAs can be used to assess learners through documentation of entrustment decisions, while the professional activity aspect can be used to map curricula. When used as an assessment framework, the entrustment decisions reflect supervisory judgments that combine trainees' relational autonomy and patient safety considerations.

Primary mucinous adenocarcinoma of the thymus; a rare type of thymic carcinoma. Case Report.

Mucinous adenocarcinoma of the thymus is a particularly rare type among thymic carcinomas. Here, we report a patient who underwent complete surgical resection of the primary mucinous adenocarcinoma of the thymus. She was 74 years old and presented with a 60-mm multilocular cystic tumor in her right anterior mediastinum.

Severe Acute Kidney Injury and Mortality in Extremely Low Gestational Age Neonates.

Background And Objectives: AKI is associated with poor short- and long-term outcomes. Questions remain about the frequency and timing of AKI, and whether AKI is a cause of death in extremely low gestational age neonates.

Design, Setting, Participants, & Measurements: The Recombinant Erythropoietin for Protection of Infant Kidney Disease Study examines the kidney outcomes of extremely low gestational age neonates enrolled in the Preterm Epo Neuroprotection study, a randomized, placebo-controlled trial of recombinant human erythropoietin.

Questioning medical competence: Should the Covid-19 crisis affect the goals of medical education?

The COVID-19 pandemic has disrupted many societal institutions, including health care and education. Although the pandemic's impact was initially assumed to be temporary, there is growing conviction that medical education might change more permanently. The International Competency-based Medical Education (ICBME) collaborators, scholars devoted to improving physician training, deliberated how the pandemic raises questions about medical competence.

PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease.

Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease (NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanisms of hepatic Th17 cells, however, remain unknown. Here, we uncover and characterize a distinct population of inflammatory hepatic CXCR3Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis.

High Prevalence of Anal High-Grade Squamous Intraepithelial Lesions, and Prevention Through Human Papillomavirus Vaccination, in Young Men Who Have Sex With Men Living With Human Immunodeficiency Virus.

Background: Men who have sex with men (MSM) are at high risk for human papillomavirus (HPV)-related anal cancer. Little is known about the prevalence of low-grade squamous intraepithelial lesions (LSILs) and the anal cancer precursor, high-grade squamous intraepithelial lesions (HSILs), among young MSM with HIV (MSMLWH). HPV vaccination is recommended in this group, but its safety, immunogenicity, and protection against vaccine-type HPV infection and associated LSILs/HSILs have not been studied.

CRISPRi-mediated functional analysis of NKX2-1-binding sites in the lung.

The transcription factor NKX2-1/TTF-1 is involved in lung pathophysiology, including breathing, innate defense and tumorigenesis. To understand the mechanism by which NKX2-1 regulates genes involved in such pathophysiology, we have previously performed ChIP-seq and identified genome-wide NKX2-1-binding sites, which revealed that NKX2-1 binds to not only proximal promoter regions but also multiple intra- and inter-genic regions of the genes regulated by NKX2-1. However, the roles of such regions, especially non-proximal ones, bound by NKX2-1 have not yet been determined.

Adipocyte inflammation and pathogenesis of viral pneumonias: an overlooked contribution.

Epidemiological evidence establishes obesity as an independent risk factor for increased susceptibility and severity to viral respiratory pneumonias associated with H1N1 influenza and SARS-CoV-2 pandemics. Given the global obesity prevalence, a better understanding of the mechanisms behind obese susceptibility to infection is imperative. Altered immune cell metabolism and function are often perceived as a key causative factor of dysregulated inflammation.

Clinical and Host Biological Factors Predict Colectomy Risk in Children Newly Diagnosed With Ulcerative Colitis.

Background: Develop a clinical and biological predictive model for colectomy risk in children newly diagnosed with ulcerative colitis (UC).

Methods: This was a multicenter inception cohort study of children (ages 4-17 years) newly diagnosed with UC treated with standardized initial regimens of mesalamine or corticosteroids (CS) depending upon initial disease severity. Therapy escalation to immunomodulators or infliximab was based on predetermined criteria.