Improved influenza vaccine responses after expression of multiple viral glycoproteins from a single mRNA.

Influenza viruses cause substantial morbidity and mortality every year despite seasonal vaccination. mRNA-based vaccines have the potential to elicit more protective immune responses, but for maximal breadth and durability, it is desirable to deliver both the viral hemagglutinin and neuraminidase glycoproteins. Delivering multiple antigens individually, however, complicates manufacturing and increases cost, thus it would be beneficial to express both proteins from a single mRNA.

Headless hemagglutinin-containing influenza viral particles direct immune responses toward more conserved epitopes.

Seasonal influenza vaccines provide mostly strain-specific protection due to the elicitation of antibody responses focused on evolutionarily plastic antigenic sites in the hemagglutinin head domain. To direct the humoral response toward more conserved epitopes, we generated an influenza virus particle where the full-length hemagglutinin protein was replaced with a membrane-anchored, "headless" variant while retaining the normal complement of other viral structural proteins such as the neuraminidase as well as viral RNAs. We found that a single administration of a headless virus particle-based vaccine elicited high titers of antibodies that recognized more conserved epitopes on the major viral glycoproteins.

Conceptualizing Adult Dysphagia in the United States Within the International Classification of Functioning, Disability and Health (ICF).

Despite the well-documented safety concerns and effect on quality of life, there does not yet exist a wide-reaching framework that links the etiologies of swallowing disorders to the potential short- and long-term outcomes in the context of International Classification of Functioning, Disability and Health (ICF). This paper introduces an expert-reviewed conceptual framework to highlight common etiologies of dysphagia as well as integrate immediate outcomes of dysphagia with long-term outcomes of dysphagia in terms of medical problems, health-related quality of life, functional effect, and psychosocial features. It also outlines the potential cyclical nature of long-term dysphagia outcomes perpetuating the original dysphagia.

Phase 1b trial of tagraxofusp in combination with azacitidine with or without venetoclax in acute myeloid leukemia.

CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2.

A Novel Quantitative Measure of Pharyngeal Shortening.

Background: Little is known about pharyngeal shortening (PShort) during swallowing. This observational study measured PShort during swallowing in healthy adults and compared it to patients with swallowing impairments of different aetiologies.

Methods: 275 healthy volunteers (19-99 years) and 75 dysphagic patients (25 with head and neck cancer, 25 with Parkinson's, 25 with stroke) underwent videofluoroscopy.

Segmented, Negative-Sense RNA Viruses of Humans: Genetic Systems and Experimental Uses of Reporter Strains.

Negative-stranded RNA viruses are a large group of viruses that encode their genomes in RNA across multiple segments in an orientation antisense to messenger RNA. Their members infect broad ranges of hosts, and there are a number of notable human pathogens. Here, we examine the development of reverse genetic systems as applied to these virus families, emphasizing conserved approaches illustrated by some of the prominent members that cause significant human disease.

A low-background, fluorescent assay to evaluate inhibitors of diverse viral proteases.

Multiple coronaviruses (CoVs) can cause respiratory diseases in humans. While prophylactic vaccines designed to prevent infection are available for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), incomplete vaccine efficacy, vaccine hesitancy, and the threat of other pathogenic CoVs for which vaccines do not exist have highlighted the need for effective antiviral therapies. While antiviral compounds targeting the viral polymerase and protease are already in clinical use, their sensitivity to potential resistance mutations as well as their breadth against the full range of human and preemergent CoVs remain incompletely defined.

Dysphagia and dementia: a 'double dilemma'.

Purpose Of Review: Dementia and its variants, including Alzheimer's disease, become more prevalent with age. Dysphagia, that is, difficulty swallowing, also occurs with aging, and is often associated with dementia. Currently, there is no cure for dementia, and dysphagia, unrecognized or untreated, can have life-altering, even fatal consequences.

Absent epiglottic inversion as seen on flexible endoscopic evaluations of swallowing (FEES) is associated with a gestalt reduction in swallowing mechanics.

Purpose: Epiglottic inversion, which provides one layer of the requisite protection of the airway during swallowing, is dependent on a number of biomechanical forces. The aim of this study was to examine the association between swallowing mechanics, as visualized during a Modified Barium Swallow (MBS) exam, and the rating of epiglottic inversion as seen on Flexible Endoscopic Evaluation of Swallowing (FEES).

Methods: This study analyzed twenty-five adult outpatients referred for a simultaneous FEES/MBS exams.

Pixel-Based Swallow Measurements: Correcting Nonsquare Pixels.

Purpose: This research note illustrates the effects of video data with nonsquare pixels on the pixel-based measures obtained from videofluoroscopic swallow studies (VFSS).

Method: Six pixel-based distance and area measures were obtained from two different videoflouroscopic study units; both yielding videos with nonsquare pixels with different pixel aspect ratios (PARs). The swallowing measures were obtained from the original VFSS videos and from the videos after their pixels were squared.

Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease.

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells.

Bolus Clearance Ratio Elevated in Patients With Neurogenic Dysphagia Compared With Healthy Adults: A Measure of Pharyngeal Efficiency.

Purpose: Postswallow pharyngeal residue is a risk factor for aspiration, implies swallowing inefficiency, and increases the work of eating. The Bolus Clearance Ratio (BCR) is a derived metric that relates quantities of bolus material observed in the pharynx at two different points: before and after a swallow. The ratio provides a percentage estimate of bolus clearance.

Ipilimumab plus decitabine for patients with MDS or AML in posttransplant or transplant-naïve settings.

Two articles in this week’s issue focus on the use of ipilimumab and decitabine for patients with myelodysplasia (MDS) and acute myeloid leukemia (AML) before and after hematopoietic stem cell transplantation (HSCT) for high-risk disease. In the first article, Garcia et al report on the results of a phase 1 trial of the combination in 54 patients, demonstrating overall response rate of 52% in patients who are HSCT-naïve and 20% in patients post-HSCT; responses are usually short-lived. In the second article, Penter and colleagues characterize gene expression responses to therapy and conclude that decitabine acts directly to clear leukemic cells while ipilimumab acts on infiltrating lymphocytes in marrow and extramedullary sites.

Effects of Orthoses on Standing Postural Control and Muscle Activity in Children With Cerebral Palsy.

Purpose: This exploratory study assessed postural control and muscle activity in children with cerebral palsy while standing barefoot (BF), in prescribed ankle-foot orthoses (AFOs) and in distal control orthoses (DCOs), which stabilized foot-ankle and deliberately aligned the shank.

Methods: This within-subject study evaluated 10 participants, Gross Motor Functional Classification System level III, across the 3 ankle-foot conditions in: (1) static standing duration and (2) modified Clinical Test of Sensory Interaction on Balance with electromyography (EMG) on 7 muscles.

Results: Participants had significantly decreased center of gravity (COG) velocity sway in DCO versus BF and AFO, decreased loss of balance (LOB), and increased standing for DCO versus BF.

Residue Ratings on FEES: Trends for Clinical Application of Residue Measurement.

Considering that measurement is a critical part of diagnostic technique for evaluating swallowing dysfunction, there is a need for a better foundational understanding of what influences residue measurement on flexible endoscopic evaluation of swallowing (FEES). This study investigated two factors and their potential influence on trends in residue ratings on FEES: (1) bolus consistency, and (2) residue severity levels on two different types of rating scales. Thirty-three clinicians were asked to rate their overall impressions of pharyngeal residue on 75 FEES videos representing a wide range of residue severities for thin liquid, applesauce, and cracker boluses.

Predicting aspiration risk in patients with dysphagia: Evidence from fluoroscopy.

Objective: To investigate the potential of timing and displacement measures from fluoroscopic swallow studies for predicting aspiration in dysphagic patients.

Methods: Timing and displacement variables for a 20-ml liquid bolus were extracted from fluoroscopic swallow studies of 5923 patients reflecting a variety of dysphagia etiologies. Patients were divided into aspirators and non-aspirators, and variables were compared between groups, and to a group of 148 normal control subjects.

Reliability of Untrained and Experienced Raters on FEES: Rating Overall Residue is a Simple Task.

The purpose of this study was to investigate the reliability of residue ratings on Fiberoptic Endoscopic Evaluation of Swallowing (FEES). We also examined rating differences based on experience to determine if years of experience influenced residue ratings. A group of 44 raters watched 81 FEES videos representing a wide range of residue severities for thin liquid, applesauce, and cracker boluses.

Rethinking Residue: Determining the Perceptual Continuum of Residue on FEES to Enable Better Measurement.

The goal of this work was to better understand perceptual judgments of pharyngeal residue on flexible endoscopic evaluation of swallowing (FEES) and the influence of a visual analog scale (VAS) versus an ordinal scale on clinician ratings. The intent was to determine if perceptual judgments of residue were more accurately described by equal or unequal intervals. Thirty-three speech language pathologists rated pharyngeal residue from 75 FEES videos representing a wide range of residue severities for thin liquid, applesauce, and cracker boluses.

2014 section on pediatrics knowledge translation lecture: clinicians and researchers on the same path toward facilitating family goals for mobility and participation.

Background: The knowledge translation (KT) lecture at the Combined Sections Meeting 2014 was a personal perspective from a researcher who had been a therapist and a longtime clinician, now a PhD candidate.

Objective: To better integrate research and clinical care, KT is a seamless rather than separate process.

Key Points: Knowledge translation can be enhanced by improved receptivity to evidence, and increasing use of research designs that encourage and even require clinician involvement, from single-subject designs to large-scale pragmatic trials.

Pharyngeal weakness and upper esophageal sphincter opening in patients with unilateral vocal fold immobility.

Objectives/hypothesis: To evaluate pharyngeal strength and upper esophageal sphincter opening in patients with unilateral vocal fold immobility (UVFI).

Study Design: Case control study.

Methods: Charts of individuals with UVFI who underwent a videofluoroscopic swallow study were reviewed.

Effects of bolus rheology on aspiration in patients with Dysphagia.

Bolus manipulation is a primary treatment strategy in the management of oral-pharyngeal dysphagia. The use of thickening agents to alter bolus rheology is particularly commonplace; however, the precise effects of these alterations on swallowing remain uncertain. The purpose of our study, a prospective, double-blind clinical trial (Level 1b), was to investigate the effects of viscosity on aspiration.

Voice quality after organ-preservation therapy with definitive radiotherapy for laryngeal cancer.

Background: The purpose of this study was to analyze voice quality among patients treated by definitive radiotherapy for laryngeal cancer.

Methods: Ten patients with laryngeal cancer who had completed radiotherapy were involved in this pilot study. A standardized protocol was administered assessing: (1) sustained vowel production following maximal inspiration, (2) sustained vowel production for a 7-second duration repeated 5 times, and (3) spontaneous speech for 10 seconds.

Pharyngeal wall differences between normal younger and older adults.

Previous research has demonstrated differences in pharyngeal size and constriction between normal younger and older adults. The distance between the larynx and the hyoid bone at rest is greater in older persons, as is the anteroposterior width of the pharynx when it is maximally expanded during swallow. In addition, pharyngeal clearing during swallow is reduced with aging.