Patient and Caregiver Perceptions of Airway Clearance Methods Used for Cystic Fibrosis.

Introduction: Cystic Fibrosis Foundation guidelines recommend people with CF perform daily airway clearance. This can be difficult for patients, as some find it time consuming or uncomfortable. Data comparing airway clearance methods are limited.

A Triad of Pericarditis, Pericardial Effusion, and Pleural Effusion as the Predominant Presentation of Rheumatoid Arthritis - A Case Report.

We describe a case of a 67-year-old African American man who presented to the emergency department with a sharp, pleuritic chest pain and shortness of breath. After several admissions and extensive workup, he ultimately was diagnosed with a persistent pleural effusion, pericardial effusion, and secondary constrictive pericarditis due to rheumatoid arthritis. By highlighting immunological disorders such as rheumatoid arthritis in the differential diagnosis, in the setting of a refractory pericardial effusion and serositis, this case report addresses key aspects of the presentation both in the emergency and inpatient settings, reviews the criteria for a rheumatoid arthritis diagnosis, and emphasizes areas of importance in predominantly cardiopulmonary extra-articular manifestations of a typically musculoskeletal disease.

Making the case for multidisciplinary pediatric aerodigestive programs.

Multidisciplinary pediatric aerodigestive centers have been proposed to address the needs of children with complex multi-system problems affecting the respiratory and upper gastrointestinal tracts. The setup of a multidisciplinary service allows for the complex coordination needed between different subspecialties. This allows for rapid communication and family-centered decision making and agreement on further diagnostic and/or therapeutic next steps such as offering triple endoscopy when indicated.

Sulfides mediate the migration of nanoparticle mass out of nanocomposite plastics and into aqueous environments.

We show that inorganic sulfides strongly influence transfer (migration) of nanoparticle mass out of polymer nanocomposites (PNCs) and into aqueous environments. We first manufactured two families of PNCs: one incorporating silver nanoparticles (AgNPs) and one incorporating CdSe quantum dots (QDs). Then, we assessed migration out of these PNCs and into aqueous media containing NaS at concentrations ranging from 0 to 10 M.

RNASE6 is a novel modifier of APOE-ε4 effects on cognition.

Apolipoprotein E4 (APOE-ε4), the strongest common genetic risk factor for Alzheimer's disease (AD), contributes to worse cognition in older adults. However, many APOE-ε4 carriers remain cognitively normal throughout life, suggesting that neuroprotective factors may be present in these individuals. In this study, we leverage whole-blood RNA sequencing (RNAseq) from 324 older adults to identify genetic modifiers of APOE-ε4 effects on cognition.

Protective genes and pathways in Alzheimer's disease: moving towards precision interventions.

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that is characterized by neurodegeneration, cognitive impairment, and an eventual inability to perform daily tasks. The etiology of Alzheimer's is complex, with numerous environmental and genetic factors contributing to the disease. Late-onset AD is highly heritable (60 to 80%), and over 40 risk loci for AD have been identified via large genome-wide association studies, most of which are common variants with small effect sizes.

E-Cigarette, or Vaping, Product Use Associated Lung Injury (EVALI) with Acute Respiratory Failure in Three Adolescent Patients: a Clinical Timeline, Treatment, and Product Analysis.

Introduction: E-cigarette, or vaping, product use associated lung injury (EVALI) has become a recent concern among public health officials. Factors that contribute to the concern include an increasing number of cases over time, the severity of the illness, and an unknown understanding of the pathophysiology and etiology of the illness.

Case Series: We cared for three adolescent patients with acute respiratory failure secondary to EVALI.

Isolated testicular vasculitis due to immune checkpoint inhibitor.

Immune checkpoint inhibitors are increasingly being used to treat various malignancies; consequently, more rheumatological side effects, ranging from arthritis to vasculitis, are being reported. Here we present, for the first time, a case of vasculitis involving the testicle in the setting of an immune checkpoint inhibitor. As reported in previous cases, recurrence of a malignancy, as opposed to vasculitis, was initially suspected, thus creating a diagnostic dilemma.

Migration of Quaternary Ammonium Cations from Exfoliated Clay/Low-Density Polyethylene Nanocomposites into Food Simulants.

Clay/polymer nanocomposites (CPNs) are polymers incorporating refined clay particles that are frequently functionalized with quaternary ammonium cations (QACs) as dispersion aids. There is interest in commercializing CPNs for food contact applications because they have improved strength and barrier properties, but there are few studies on the potential for QACs in CPNs to transfer to foods under conditions of intended use. In this study, we manufactured low-density poly(ethylene) (LDPE)-based CPNs and assessed whether QACs can migrate into several food simulants under accelerated storage conditions.

Inactivation of CFTR by CRISPR/Cas9 alters transcriptional regulation of inflammatory pathways and other networks.

Background: Individuals with cystic fibrosis (CF) experience elevated inflammation in multiple organs, but whether this reflects an inherent feature of CF cells or is a consequence of a pro-inflammatory environment is not clear.

Method: Using CRISPR/Cas9-mediated mutagenesis of CFTR, 17 subclonal cell lines were generated from Caco-2 cells. Clonal lines with functional CFTR (CFTR) were compared to those without (CFTR) to directly address the role of CFTR in inflammatory gene regulation.

Ccl5 Mediates Proper Wiring of Feedforward and Lateral Inhibition Pathways in the Inner Retina.

The β-chemokine Ccl5 and its receptors are constitutively expressed in neurons of the murine inner retina. Here, we examined the functional and structural significance of this constitutive Ccl5 signaling on retinal development. We compared outcomes of electrophysiology, ocular imaging and retinal morphology in wild-type mice (WT) and mice with Ccl5 deficiency ( ).

Influence of Different Acids on the Transport of CdSe Quantum Dots from Polymer Nanocomposites to Food Simulants.

We fabricated polymer nanocomposites (PNCs) from low-density polyethylene and CdSe quantum dots (QDs) and used these materials to explore potential exposure after long-term storage in different acidic media that could be encountered in food contact applications. While the low-level release of QD-associated mass into all the food simulants was observed, exposure to dilute acetic acid resulted in more than double the mass transfer compared to that which occurred during exposure to dilute hydrochloric acid at the same pH. Conversely, exposure to citric acid resulted in a suppression of QD release.

Overgrowth Versus Galvanic Replacement: Mechanistic Roles of Pd Seeds during the Deposition of Pd-Pt.

Here, a systematic study of the roles played by Pd seeds during seed-mediated coreduction of Pd-Pt is presented. Either nanoparticles with porous, hollow architectures or concave nanocubes were achieved, depending on whether the synthesis conditions favored galvanic replacement or overgrowth. Prior works have shown that the galvanic replacement reaction between seeds and a precursor can be suppressed by introducing a faster, parallel reaction that removes one of the reagents (e.

Pretreatment with Human Chorionic Gonadotropin Protects the Neonatal Brain against the Effects of Hypoxic-Ischemic Injury.

Introduction: Though the human fetus is exposed to placentally derived human chorionic gonadotropin (hCG) throughout gestation, the role of hCG on the fetal brain is unknown. Review of the available literature appears to indicate that groups of women with higher mean levels of hCG during pregnancy tend to have offspring with lower cerebral palsy (CP) risk. Given that newborn cerebral injury often precedes the development of CP, we aimed to determine whether hCG may protect against the neurodegenerative effects of neonatal brain injury.

Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M positive allosteric modulator (PAM) chemotype via scaffold hopping.

This Letter details our efforts to replace the 3-amino moiety, an essential pharmacophore for M PAM activity in most M PAMs to date, within the thieno[2,3-b]pyridine core, as the β-amino carboxamide motif has been shown to engender poor solubility, varying degrees of P-gp efflux and represents a structural alert. A scaffold hopping exercise identified a novel 2,4-dimethylquinoline carboxamide core that provided M PAM activity and good CNS penetration without an amino moiety. In addition, MacMillan photoredox catalysis chemistry was essential for construction of the 2,4-dimethylquinoline core.

Design and Synthesis of -Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu NAMs.

Herein, we detail the optimization of the mGlu NAM, VU0650786, via a reductionist approach to afford a novel, simplified mGlu NAM scaffold that engenders potent and selective mGlu inhibition (mGlu IC = 245 nM, mGlu IC > 30 μM) with excellent central nervous system penetration (rat brain/plasma = 1.2, = 0.40).

Design and Synthesis of mGlu NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

Herein, we detail the optimization of the mGlu negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu NAM scaffold. This new chemotype not only affords potent and selective mGlu inhibition, as exemplified by VU6001966 (mGlu IC = 78 nM, mGlu IC > 30 μM), but also excellent central nervous system (CNS) penetration ( = 1.9, = 0.

Discovery of a novel, CNS penetrant M PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core.

This Letter details the discovery and subsequent optimization of a novel M PAM scaffold based on an 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core, which represents a distinct departure from the classical M PAM chemotypes. Optimized compounds in this series demonstrated improved M PAM potency on both human and rat M (4 to 5-fold relative to HTS hit), and displayed attractive physicochemical and DMPK profiles, including good CNS penetration (rat brain:plasma K=5.3, K=2.

Discovery and optimization of 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazines as novel, CNS penetrant pan-muscarinic antagonists.

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M antagonists, based on a 3-(4-aryl/heteroarylsulfonyl)piperazin-1-yl)-6-(piperidin-1-yl)pyridazine core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at human M (hM ICs<200nM), with only moderate species differences noted, and with enantioselective inhibition. Moreover, CNS penetration proved attractive for this series (rat brain:plasma K=2.

Seed-mediated co-reduction in a large lattice mismatch system: synthesis of Pd-Cu nanostructures.

Metal nanoparticles (NPs) are of interest for applications in catalysis, electronics, chemical sensing, and more. Their utility is dictated by their composition and physical parameters such as particle size, particle shape, and overall architecture (e.g.

Challenges in the development of an M PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.

This letter details the continued chemical optimization of a novel series of M positive allosteric modulators (PAMs) based on a 5-amino-thieno[2,3-c]pyridazine core by incorporating a 3-amino azetidine amide moiety. The analogs described within this work represent the most potent M PAMs reported for this series to date. The SAR to address potency, clearance, subtype selectivity, CNS exposure, and P-gp efflux are described.

Synthesis and evaluation of 4,6-disubstituted pyrimidines as CNS penetrant pan-muscarinic antagonists with a novel chemotype.

This letter describes the synthesis and structure activity relationship (SAR) studies of structurally novel M antagonists, based on a 4,6-disubstituted core, identified from a high-throughput screening campaign. A multi-dimensional optimization effort enhanced potency at both human and rat M (ICs<300nM), with no substantial species differences noted. Moreover, CNS penetration proved attractive for this series (brain:plasma K=0.