Citations

Abstract Chicago Classification v4.0 (CCv4.0) is the updated classification scheme for esophageal motility disorders using metrics from high‐resolution manometry (HRM). Fifty‐two diverse international experts separated into seven working subgroups utilized formal validated methodologies over two‐years to develop CCv4.0. Key updates in CCv.4.0 consist of a more rigorous and expansive HRM protocol that incorporates supine and upright test positions as well as provocative testing, a refined definition of esophagogastric junction (EGJ) outflow obstruction (EGJOO), more stringent diagnostic criteria for ineffective esophageal motility and description of baseline EGJ metrics. Further, the CCv4.0 sought to define motility disorder diagnoses as conclusive and inconclusive based on associated symptoms, and findings on provocative testing as well as supportive testing with barium esophagram with tablet and/or functional lumen imaging probe. These changes attempt to minimize ambiguity in prior iterations of Chicago Classification and provide more standardized and rigorous criteria for patterns of disorders of peristalsis and obstruction at the EGJ.

Airway inflammation plays a key role in asthma. In various diseases, inflammation leads to an increase in reactive oxygen species (ROS) generation and is associated with accumulation of unfolded proteins leading to endoplasmic reticulum (ER) stress. In response to ER stress, a homeostatic signaling cascade is triggered to restore normal function by halting protein translation and activating protein degradation and expression of molecular chaperones involved in protein folding. Three ER stress protein markers located at the ER membrane are involved in this signaling cascade: protein kinase RNA‐like endoplasmic reticulum kinase (PERK), activating transcription factor 6 (ATF6) and inositol‐requiring enzyme 1 (IRE1α). In particular, phosphorylation of IRE1α catalyzes the alternative splicing of XBP1 mRNA leading to expression of the active XBP1 transcription factor. In this study, we hypothesize that pro‐inflammatory cytokine TNFα induces ROS production triggering ER stress in human airway smooth muscle (hASM). hASM cells were isolated from lung specimen incidental to patient surgery and exposed to TNFα (20 ng/ml) for 1, 3, 6, 12 or 24 h. To measure ROS production, hASM cells were loaded with the general oxidative stress indicator CM‐H2DCFDA or with the mitochondrial superoxide indicator MitoSOX™ Red. The CM‐H2DCFDA and MitoSOX™ Red signals were visualized using a Nikon A1R confocal imaging system. Images were analyzed using ImageJ. Exposure of hASM to tunicamycin (2 μg/ml) was used as a positive control for ER stress. Expression of IRE1α and PERK were determined by Western blot. Phosphorylation of IRE1α was also evaluated by immunoprecipitation and Western blot (Wes Simple Western™ system). The expression of the spliced isoform of the transcription factor XBP1 was examined by quantitative real‐time PCR (RT‐PCR). We found that ROS production increased in hASM within 1 h of TNFα exposure, followed by an increase in IRE1α phosphorylation within 1–3 h. Finally after 3–6 h, there was an increase in alternative splicing of XBP1 mRNA. Together these results show that the pro‐inflammatory cytokine TNFα increases ROS generation in hASM cells and induces an ER stress response that includes an increase in IRE1α phosphorylation and splicing of XBP1. This ER stress response may affect many downstream targets, among which we believe Mfn2 is a major target which affects mitochondrial Ca 2+ buffering, with specific effects on hASM force and/or increased cell proliferation associated with asthma. Support or Funding Information NIH grant HL126451 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

The incidence, severity, and mortality of ongoing coronavirus infectious disease 19 (COVID-19) is greater in men compared with women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males versus females as a model, we explored the effect of estrogen versus testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared with males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared with vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.

AbstractIntroductionWe sought to assess longitudinal electronic health records (EHRs) using machine learning (ML) methods to computationally derive probable Alzheimer's Disease (AD) and related dementia subphenotypes.MethodsA retrospective analysis of EHR data from a cohort of 7587 patients seen at a large, multi‐specialty urban academic medical center in New York was conducted. Subphenotypes were derived using hierarchical clustering from 792 probable AD patients (cases) who had received at least one diagnosis of AD using their clinical data. The other 6795 patients, labeled as controls, were matched on age and gender with the cases and randomly selected in the ratio of 9:1. Prediction models with multiple ML algorithms were trained on this cohort using 5‐fold cross‐validation. XGBoost was used to rank the variable importance.ResultsFour subphenotypes were computationally derived. Subphenotype A (n = 273; 28.2%) had more patients with cardiovascular diseases; subphenotype B (n = 221; 27.9%) had more patients with mental health illnesses, such as depression and anxiety; patients in subphenotype C (n = 183; 23.1%) were overall older (mean (SD) age, 79.5 (5.4) years) and had the most comorbidities including diabetes, cardiovascular diseases, and mental health disorders; and subphenotype D (n = 115; 14.5%) included patients who took anti‐dementia drugs and had sensory problems, such as deafness and hearing impairment.The 0‐year prediction model for AD risk achieved an area under the receiver operating curve (AUC) of 0.764 (SD: 0.02); the 6‐month model, 0.751 (SD: 0.02); the 1‐year model, 0.752 (SD: 0.02); the 2‐year model, 0.749 (SD: 0.03); and the 3‐year model, 0.735 (SD: 0.03), respectively. Based on variable importance, the top‐ranked comorbidities included depression, stroke/transient ischemic attack, hypertension, anxiety, mobility impairments, and atrial fibrillation. The top‐ranked medications included anti‐dementia drugs, antipsychotics, antiepileptics, and antidepressants.ConclusionsFour subphenotypes were computationally derived that correlated with cardiovascular diseases and mental health illnesses. ML algorithms based on patient demographics, diagnosis, and treatment demonstrated promising results in predicting the risk of developing AD at different time points across an individual's lifespan.

AbstractObjectiveWe sought to evaluate the feasibility and safety of carotid access transcatheter aortic valve replacement (TAVR) by performing a meta‐analysis of published cases.BackgroundSeveral case series and regional data have provided initial basis for carotid access TAVR in patients with prohibitive femoral approach. We performed this meta‐analysis to provide further evidence of feasibility and safety of carotid TAVR.MethodsWe searched PubMed, EMBASE, CINAHL, and Cochrane CENTRAL for any study on carotid access TAVR involving ⩾5 patients since inception till March 1, 2020. Random‐effects model was used to compute overall effects. The outcomes analyzed were all‐cause mortality, Transient ischemic attack (TIA)/stroke, need for permanent pacemaker (PPM) implantation, pericardial tamponade, access site complications, major bleeding, and length of stay.ResultsThere was a total of 17 retrospective studies (n = 2082) with a median follow‐up of 1 month. Mean age of the patient was 80 years. Mean Euroscore and STS scores were 15 ± 6.2 and 7.9 ± 3.3, respectively. The procedural success rate was 99%. The rate of all‐cause mortality was 6.7% (range 4.6–9.7%, p < .001, I2 = 67%). Incidence of TIA/stroke was 3.9% (range 3.1–4.8%, p < .001, I2 = 0%) and PPM implantation was 16.7% (range 12.5–21.9%, p < .001, I2 = 56%). Rate of pericardial tamponade, vascular complication, and major bleeding were 1.7, 2.5, and 7%, respectively. Average length of hospital stay was 7.7 days.ConclusionOur results show that transcarotid approach is a feasible option in patients with prohibitive femoral access for TAVR.

Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.

e20626 Background: It is important to increase our understanding of recruitment barriers in the elderly population to improve their participation in clinical trials. The primary objective of this study was to describe the demographics, treatment, toxicity, and overall survival (OS) of all patients ≥ 65 years who presented to the Phase I clinical trials service at KCI between 1995–2005. Methods: Patient demographics, co-morbidities, tumor type, reason not enrolled on a Phase 1 clinical trial, toxicities, and OS were obtained by retrospective chart reviews. The patients were divided into 3 mutually exclusive groups: patients considered but not enrolled (PC), enrolled but not treated (PE), and treated (PT). OS was compared across these three groups. Results: 216 patients met the study criteria. Of these, there were 114 PC, 7 PE, and 95 PT. Lack of enrollment was due to ineligibility (30%), loss to follow-up (12%), refusal (8%), or no trial available (2%). Median age was 71 years, 63% were males and 87% were Caucasian. 59% had performance status (PS) 1; 16% had PS 2. 66% of patients had a history of cardiovascular disease but renal, liver, hematological diseases were found in less than 7% of patients at baseline. Colorectal (27%), lung (15%) and prostate (8%) were the 3 most common cancers. 54% received a cytotoxic agent, 62% a biologic agent, and 17% combination therapy. The 3 most common Grade 3–4 toxicities were: 15% leucopenia, 11% electrolyte abnormalities, and 4% anemia. The median OS for PC, PE, and PT was 3.9 mos, 2.2 mos, and 8.4 mos, respectively (p < 0.001 between any pair). However, PS 0–1 patients comprised 47%, 75%, and 73% of those 3 patient subgroups, respectively. Conclusions: More than half of the elderly patients initially considered for Phase 1 clinical trials at KCI were not enrolled due to ineligibility, refusal, or lost to follow up. Phase I chemotherapy appears feasible in patients age ≥ 65 years old. OS was significantly longer for patients treated on Phase I trials compared to those who were not, although that may be confounded by PS differences. More detailed OS comparisons will be presented. No significant financial relationships to disclose.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Abstract Preterm infants can develop airway hyperreactivity and impaired bronchodilation following supplemental O 2 (hyperoxia) in early life, making it important to understand mechanisms of hyperoxia effects. Endogenous hydrogen sulfide (H 2 S) has anti‐inflammatory and vasodilatory effects with oxidative stress. There is little understanding of H 2 S signaling in developing airways. We hypothesized that the endogenous H 2 S system is detrimentally influenced by O 2 and conversely H 2 S signaling pathways can be leveraged to attenuate deleterious effects of O 2 . Using human fetal airway smooth muscle (fASM) cells, we investigated baseline expression of endogenous H 2 S machinery, and effects of exogenous H 2 S donors NaHS and GYY4137 in the context of moderate hyperoxia, with intracellular calcium regulation as a readout of contractility. Biochemical pathways for endogenous H 2 S generation and catabolism are present in fASM, and are differentially sensitive to O 2 toward overall reduction in H 2 S levels. H 2 S donors have downstream effects of reducing [Ca 2+ ] i responses to bronchoconstrictor agonist via blunted plasma membrane Ca 2+ influx: effects blocked by O 2 . However, such detrimental O 2 effects are targetable by exogenous H 2 S donors such as NaHS and GYY4137. These data provide novel information regarding the potential for H 2 S to act as a bronchodilator in developing airways in the context of oxygen exposure.