SIDT2 Transports Extracellular dsRNA into the Cytoplasm for Innate Immune Recognition.

Double-stranded RNA (dsRNA) is a common by-product of viral infections and acts as a potent trigger of antiviral immunity. In the nematode C. elegans, sid-1 encodes a dsRNA transporter that is highly conserved throughout animal evolution, but the physiological role of SID-1 and its orthologs remains unclear. Here, we show that the mammalian SID-1 ortholog, SIDT2, is required to transport internalized extracellular dsRNA from endocytic compartments into the cytoplasm for immune activation. Sidt2-deficient mice exposed to extracellular dsRNA, encephalomyocarditis virus (EMCV), and herpes simplex virus 1 (HSV-1) show impaired production of antiviral cytokines and-in the case of EMCV and HSV-1-reduced survival. Thus, SIDT2 has retained the dsRNA transport activity of its C. elegans ortholog, and this transport is important for antiviral immunity.

Antigen identification and high-throughput interaction mapping by reprogramming viral entry.

Deciphering immune recognition is critical for understanding a broad range of diseases and for the development of effective vaccines and immunotherapies. Efforts to do so are limited by a lack of technologies capable of simultaneously capturing the complexity of adaptive immunoreceptor repertoires and the landscape of potential antigens. To address this, we present receptor-antigen pairing by targeted retroviruses, which combines viral pseudotyping and molecular engineering approaches to enable one-pot library-on-library interaction screens by displaying antigens on the surface of lentiviruses and encoding their identity in the viral genome. Antigen-specific viral infection of cell lines expressing human T or B cell receptors allows readout of both antigen and receptor identities via single-cell sequencing. The resulting system is modular, scalable and compatible with any cell type. These techniques provide a suite of tools for targeted viral entry, molecular engineering and interaction screens with broad potential applications.

Technical note: A simple method for patient-specific quality assurance for lateral targets on a 1.5 T MR-Linac.

The Elekta Unity magnetic resonance (MR) linac is limited to longitudinal couch motion and a sagittal-only laser, which restricts the ability to perform patient-specific quality assurance (PSQA) intensity-modulated radiotherapy (IMRT) measurements for very lateral targets. This work introduces a simple method to perform PSQA using the Sun Nuclear ArcCheck-MR phantom at left and right lateral positions without additional equipment or in-house construction. The proposed setup places the center of the phantom 1.3 cm vertical and 12.9 cm lateral to isocenter in either the left or right direction. Computed tomography (CT) scans are used to simulate the setup and create a QA plan template in the Monaco treatment planning system (TPS). The workflow is demonstrated for four patients, with an average axial distance from the center of the bore to the planning target volume (PTV) of 12.4 cm. Gamma pass rates were above 94% for all plans using global 3%/2 mm gamma criterion with a 10% threshold. Setup uncertainties are slightly larger for the proposed lateral setup compared to the centered setup on the Elekta platform (∼1 mm compared to ∼0.5 mm), but acceptable pass rates are achievable without optimizing shifts in the gamma analysis software. In general, adding the left and right lateral positions increases the axial area in the bore encompassed by the cylindrical measurement array by 147%, substantially increasing the flexibility of measurements for offset targets. Based on this work, we propose using the lateral QA setup if the closest distance to the PTV edge from isocenter is larger than the array radius (10.5 cm) or the percent of the PTV encompassed by the diode array would be increased with the lateral setup compared to the centered setup.

An exploration of financial toxicity among low-income patients with cancer in Central Texas: A mixed methods analysis.

OBJECTIVE: Financial toxicity is of increasing concern in the United States. The Comprehensive Score for Financial Toxicity (COST) is a validated measure; however, it has not been widely utilized among low-income patients and may not fully capture financial toxicity in this population. Furthermore, the relationships between financial toxicity, quality of life (QOL), and patient well-being are poorly understood. We describe the experience of financial toxicity among low-income adults receiving cancer care. We hypothesized that higher financial toxicity would be associated with less income and lower quality of life. Qualitative interviews focused on the financial impact of cancer treatment. METHOD: This study was conducted at a cancer clinic in Central Texas. Quantitative and qualitative data were collected in Fall and Spring 2018, respectively. The quantitative sample (N = 115) was dichotomized by annual income (<$15,000 vs. >$15,000). Outcomes included financial toxicity (COST), quality of life (FACT-G), and patient well-being (PROMIS measures: Anxiety, Depression, Fatigue, Pain Interference, and Physical Function). Associations between quality of life, patient well-being, and financial toxicity were evaluated using linear regression. Sequential qualitative interviews were conducted with a subsample of 12 participants. RESULTS: Patients with <$15k had significantly lower levels of QOL and patient well-being such as depression and anxiety compared to patients with >$15k across multiple measures. A multivariate linear regression found QOL (Β = 0.17, 95% CI = 0.05, 0.29, p = 0.008) and insurance status (Β = -3.79, 95% CI = -7.42, -0.16, p = 0.04), but not income, were significantly associated with financial toxicity. Three qualitative themes regarding patient's access to cancer care were identified: obtaining healthcare coverage, maintaining financial stability, and receiving social support. SIGNIFICANCE OF RESULTS: Low-income patients with cancer face unique access barriers and are at risk for forgoing treatment or increased symptom burdens. Comprehensive assessment and financial navigation may improve access to care, symptom management, and reduce strain on social support systems.

SIDT1 Localizes to Endolysosomes and Mediates Double-Stranded RNA Transport into the Cytoplasm.

dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear. In this study, we show that Sidt1 expression is upregulated in response to dsRNA and type I IFN exposure and that SIDT1 interacts with SIDT2. Moreover, similar to SIDT2, SIDT1 localizes to the endolysosomal compartment, interacts with the long dsRNA analog poly(I:C), and, when overexpressed, enhances endosomal escape of poly(I:C) in vitro. To elucidate the role of SIDT1 in vivo, we generated SIDT1-deficient mice. Similar to Sidt2-/- mice, SIDT1-deficient mice produced significantly less type I IFN following infection with HSV type 1. In contrast to Sidt2-/- mice, however, SIDT1-deficient animals showed no impairment in survival postinfection with either HSV type 1 or encephalomyocarditis virus. Consistent with this, we observed that, unlike SIDT2, tissue expression of SIDT1 was relatively restricted, suggesting that, whereas SIDT1 can transport extracellular dsRNA into the cytoplasm following endocytosis in vitro, the transport activity of SIDT2 is likely to be functionally dominant in vivo.

Analysis of patient-specific quality assurance for Elekta Unity adaptive plans using statistical process control methodology.

The Elekta Unity MR-linac utilizes daily magnetic resonance imaging (MRI) for online plan adaptation. In the Unity workflow, adapt to position (ATP) and adapt to shape (ATS) treatment planning options are available which represent a virtual shift or full re-plan with contour adjustments respectively. Both techniques generate a new intensity modulated radiation therapy (IMRT) treatment plan while the patient lies on the treatment table and thus adapted plans cannot be measured prior to treatment delivery. A statistical process control methodology was used to analyze 512 patient-specific IMRT QA measurements performed on the MR-compatible SunNuclear ArcCheck with a gamma criterion of 3%/2 mm using global normalization and a 10% low dose threshold. The lower control limit (LCL) was determined from 68 IMRT reference plan measurements, and a one-sided process capability ratio ( C p , l ) was used to assess the pass rates from 432 measured ATP and 80 measured ATS plans. Further analysis was performed to assess differences between SBRT or conventional fractionation pass rates and to determine whether there was any correlation between the pass rates and plan complexity. The LCL of the reference plans was determined to be a gamma pass rate of 0.958, and the C p , l of the measured ATP plans and measured ATS plans were determined to be 1.403 and 0.940 for ATP and ATS plans, respectively, while a C p , l of 0.902 and 1.383 was found for SBRT and conventional fractionations respectively. For plan complexity, no correlation was found between modulation degree and gamma pass rate, but a statistically significant correlation was observed between the beam-averaged aperture area and gamma pass rate. All adaptive plans passed the TG-218 guidelines, but the ATS and SBRT plans tended to have a smaller beam-averaged aperture area with slightly lower gamma pass rates.

Implementation of a real-time, ultrasound-guided prostate HDR brachytherapy program.

This work presents a comprehensive commissioning and workflow development process of a real-time, ultrasound (US) image-guided treatment planning system (TPS), a stepper and a US unit. To adequately benchmark the system, commissioning tasks were separated into (1) US imaging, (2) stepper mechanical, and (3) treatment planning aspects. Quality assurance US imaging measurements were performed following the AAPM TG-128 and GEC-ESTRO recommendations and consisted of benchmarking the spatial resolution, accuracy, and low-contrast detectability. Mechanical tests were first used to benchmark the electronic encoders within the stepper and were later expanded to evaluate the needle free length calculation accuracy. Needle reconstruction accuracy was rigorously evaluated at the treatment planning level. The calibration length of each probe was redundantly checked between the calculated and measured needle free length, which was found to be within 1 mm for a variety of scenarios. Needle placement relative to a reference fiducial and coincidence of imaging coordinate origins were verified to within 1 mm in both sagittal and transverse imaging planes. The source strength was also calibrated within the interstitial needle and was found to be 1.14% lower than when measured in a plastic needle. Dose calculations in the TPS and secondary dose calculation software were benchmarked against manual TG-43 calculations. Calculations among the three calculation methods agreed within 1% for all calculated points. Source positioning and dummy coincidence was tested following the recommendations of the TG-40 report. Finally, the development of the clinical workflow, checklists, and planning objectives are discussed and included within this report. The commissioning of real-time, US-guided HDR prostate systems requires careful consideration among several facets including the image quality, dosimetric, and mechanical accuracy. The TPS relies on each of these components to develop and administer a treatment plan, and as such, should be carefully examined.

Impact of perforation size and predictive factors for successful pediatric gelfoam myringoplasty.

OBJECTIVES: Rates of success with pediatric myringoplasty range from 35 to 95%. The objective of this study is to evaluate the impact of perforation size on successful closure of the tympanic membrane (TM) after gelfoam myringoplasty. We also aim to identify variables that affect perforation closure rates and define predictive factors for successful TM closure. METHODS: A retrospective chart review of all patients that underwent gelfoam myringoplasty by a single surgeon from August 2008 through January 2015 was performed. RESULTS: One hundred fifty-nine patients met inclusion criteria and underwent a total of 219 procedures. Overall, gelfoam myringoplasty had an 83.1% rate of successful closure. Average perforation size was 15.31%. Classification tree analysis separated our cohort into three groups based on perforation size: Group 1 (<16.25%) had a 91% closure rate, group 2 (16.25% to <31.25%) had a 66.0% closure rate and group 3 (≥31.25%) had a 30.0% closure rate. Smaller perforations (P ≤0.001) were associated with increased success rates. Other factors associated with successful closure of the TM included younger age at the time of myringoplasty (P ≤0.001), fewer number of prior tympanostomy tubes (P = 0.016), and lesser duration of tube retention (P = 0.003). CONCLUSION: Gelfoam myringoplasty provides good overall TM closure rates and may be considered as a potential first-line option for repair of perforations, including those involving up to 40% of the TM. Younger patients with smaller perforations, fewer sets of tubes, shorter length of tube retention are more likely to have successful closure of the tympanic membrane.

New atrial fibrillation diagnosed by 30-day rhythm monitoring.

BACKGROUND: Recent studies of patients with pacemakers and implantable cardioverter/defibrillators have shown that subclinical atrial fibrillation (AF) is common and is associated with thromboembolic risk. We sought to evaluate the frequency, characteristics, and impact of new AF diagnosed by ambulatory 30-day rhythm monitoring. METHODS: The 30-day rhythm monitoring data from January 2010 to August 2015 at our institution were reviewed. Medical record review was performed on patients that had a new or preexisting diagnosis of AF. RESULTS: Of 2,326 patients without a previous diagnosis of AF, 78 had a new diagnosis of AF (3.4%) during 30-day monitoring. Patients with a new diagnosis of AF (mean age of 68.5 years, 56% female) had a mean CHA2DS2-VASc score of 3.2 (±1.8). The median time to diagnosis was 6 days, and 86% were diagnosed within 14 days. In 31 patients (40%), AF was exclusively detected automatically by the monitor. Of 46 patients that had manually activated the monitor, 34 also had automatically detected AF. Each patient had a median of 7 episodes, with the median duration of the longest episode being approximately 2 hours. Following the diagnosis of AF, 37 (47%) were started on anticoagulation and 9 (12%) were prescribed aspirin. CONCLUSIONS: A total of 3.4% of patients who underwent 30-day rhythm monitoring for any indication were found to have a new diagnosis of AF (402 per 1000 patient-years). Most of these episodes were detected automatically, corresponding to device-detected subclinical AF. The most common intervention following diagnosis of AF was initiation of oral anticoagulation.

Spiritual assessment and spiritual care offerings as a standard of care in pediatric oncology: A recommendation informed by a systematic review of the literature.

Children with cancer and their families experience shifts in spiritual wellness from diagnosis through treatment and survivorship or bereavement. An interdisciplinary team conducted a systematic review of quantitative and qualitative research on spiritual assessments, interventions, and outcomes in childhood cancer following PRISMA guidelines using a PROSPERO registered protocol. Thirty-nine well-designed studies were included in the final analysis. The findings from this systematic review indicate the need for early spiritual assessment with offering of continued support for the spiritual functioning of children with cancer and their families as a standard of care.

Paradoxical vocal fold motion (PVFM) in pediatric otolaryngology.

INTRODUCTION: Paradoxical vocal fold motion (PVFM) is a condition in which the vocal cords exhibit inappropriate inspiratory adduction, and it has been poorly studied in the pediatric population. METHODS: Pediatric patients diagnosed with PVCM by a pediatric otolaryngologist and doctor of speech pathology from 2008 to 2012 were reviewed. Patients in whom another cause for their respiratory disturbance was eventually identified were excluded. Patient demographics, characteristics, treatment, and outcomes were reviewed. The study was approved by the Institutional Review Board at our institution. RESULTS: Thirty patients met criteria for inclusion; one with chiari malformation was excluded. 17/29 (59%) were female. Body mass index (BMI) numbers ranged from 16 to 25 with a mean of 21. 9/29 (31%) competed at the highest level of a sport; only 3/29 (10%) did not participate in athletics. Average age of onset was 12.0years; average diagnosis delay was 1.3years. Mean follow up was 2.3years. 24/29 (83%) were previously treated for asthma. 23/29(79%) were previously treated for reflux. 25/29(86%) completed at least one session of respiratory and laryngeal control therapy with overall average of 2.2 sessions completed. All patients who attended a second therapy session were recorded as having improvement in symptoms. CONCLUSIONS: Pediatric patients with PVFM often participate in high levels of organized sports and the frequency of concurrent asthma and reflux symptoms in this population supports the theory that laryngeal hypersensitivity contributes to the pathophysiology of PVFM. These patients were not found to have any associated psychiatric diagnoses. Pediatric patients with PVFM have an excellent prognosis when treated with speech therapy and for comorbid conditions as indicated.

Alcohol consumption and burden of disease in the Americas in 2012: implications for alcohol policy.

OBJECTIVE: To describe the volume and patterns of alcohol consumption up to and including 2012, and to estimate the burden of disease attributable to alcohol consumption as measured in deaths and disability-adjusted life years (DALYs) lost in the Americas in 2012. METHODS: Measures of alcohol consumption were obtained from the World Health Organization (WHO) Global Information System on Alcohol and Health (GISAH). The burden of alcohol consumption was estimated in both deaths and DALYs lost based on mortality data obtained from WHO, using alcohol-attributable fractions. Regional groupings for the Americas were based on the WHO classifications for 2004 (according to child and adult mortality). RESULTS: Regional variations were observed in the overall volume of alcohol consumed, the proportion of the alcohol market attributable to unrecorded alcohol consumption, drinking patterns, prevalence of drinking, and prevalence of heavy episodic drinking, with inhabitants of the Americas consuming more alcohol (8.4 L of pure alcohol per adult in 2012) compared to the world average. The Americas also experienced a high burden of disease attributable to alcohol consumption (4.7% of all deaths and 6.7% of all DALYs lost), especially in terms of injuries attributable to alcohol consumption. CONCLUSIONS: Alcohol is consumed in a harmful manner in the Americas, leading to a high burden of disease, especially in terms of injuries. New cost-effective alcohol policies, such as increasing alcohol taxation, increasing the minimum legal age to purchase alcohol, and decreasing the maximum legal blood alcohol content while driving, should be implemented to decrease the harmful consumption of alcohol and the resulting burden of disease.

Disease-Modifying Treatments and Their Future in Alzheimer's Disease Management.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, a loss of cholinergic neurons, and cognitive decline that insidiously progresses to dementia. The pathoetiology of AD is complex, as genetic predisposition, age, inflammation, oxidative stress, and dysregulated proteostasis all contribute to its development and progression. The histological hallmarks of AD are the formation and accumulation of amyloid-ß plaques and interfibrillar tau tangles within the central nervous system. These histological hallmarks trigger neuroinflammation and disrupt the physiological structure and functioning of neurons, leading to cognitive dysfunction. Most treatments currently available for AD focus only on symptomatic relief. Disease-modifying treatments (DMTs) that target the biology of the disease in hopes of slowing or reversing disease progression are desperately needed. This narrative review investigates novel DMTs and their therapeutic targets that are either in phase three of development or have been recently approved by the U.S. Food and Drug Administration (FDA). The target areas of some of these novel DMTs consist of combatting amyloid or tau accumulation, oxidative stress, neuroinflammation, and dysregulated proteostasis, metabolism, or circadian rhythm. Neuroprotection and neuroplasticity promotion were also key target areas. DMT therapeutic target diversity may permit improved therapeutic responses in certain subpopulations of AD, particularly if the therapeutic target of the DMT being administered aligns with the subpopulation's most prominent pathological findings. Clinicians should be cognizant of how these novel drugs differ in therapeutic targets, as this knowledge may potentially enhance the level of care they can provide to AD patients in the future.

Re-centauring T cell antigen discovery around CD4+ T cells.

In a recent issue of Cell, Dezfulian et al. develop a genome-scale platform to enable high-throughput identification of CD4+ T cell epitopes. This platform enables unbiased screens to discover antigens recognized by CD4+ T cells in cancer, infectious diseases, and autoimmunity.

A biomaterial platform for T cell-specific gene delivery.

Efficient T cell engineering is central to the success of CAR T cell therapy but involves multiple time-consuming manipulations, including T cell isolation, activation, and transduction. These steps add complexity and delay CAR T cell manufacturing, which takes a mean time of 4 weeks. To streamline T cell engineering, we strategically combine two critical engineering solutions - T cell-specific lentiviral vectors and macroporous scaffolds - that enable T cell activation and transduction in a simple, single step. The T cell-specific lentiviral vectors (referred to as STAT virus) target T cells through the display of an anti-CD3 antibody and the CD80 extracellular domain on their surface and provide robust T cell activation. Biocompatible macroporous scaffolds (referred to as Drydux) mediate robust transduction by providing effective interaction between naïve T cells and viral vectors. We show that when unstimulated peripheral blood mononuclear cells (PBMCs) are seeded together with STAT lentivirus on Drydux scaffolds, T cells are activated, selectively transduced, and reprogrammed in a single step. Further, we show that the Drydux platform seeded with PBMCs and STAT lentivirus generates tumor-specific functional CAR T cells. This potent combination of engineered lentivirus and biomaterial scaffold holds promise for an effective, simple, and safe avenue for in vitro and in vivo T cell engineering. STATEMENT OF SIGNIFICANCE: Manufacturing T cell therapies involves lengthy and labor-intensive steps, including T cell selection, activation, and transduction. These steps add complexity to current CAR T cell manufacturing protocols and limit widespread patient access to this revolutionary therapy. In this work, we demonstrate the combination of engineered virus and biomaterial platform that, together, enables selective T cell activation and transduction in a single step, eliminating multistep T cell engineering protocols and significantly simplifying the manufacturing process.