Venue For Treatment Research Articles

A small molecule inhibitor of Nox2 and Nox4 improves contractile function after ischemia\u2013reperfusion in the mouse heart

The NADPH oxidase enzymes Nox2 and 4, are important generators of Reactive oxygen species (ROS). These enzymes are abundantly expressed in cardiomyocytes and have been implicated in ischemia–reperfusion injury. Previous attempts with full inhibition of their activity using genetically modified animals have shown variable results, suggesting that a selective and graded inhibition could be a more relevant approach. We have, using chemical library screening, identified a new compound (GLX481304) which inhibits Nox 2 and 4 (with IC50 values of 1.25 µM) without general antioxidant effects or inhibitory effects on Nox 1. The compound inhibits ROS production in isolated mouse cardiomyocytes and improves cardiomyocyte contractility and contraction of whole retrogradely (Langendorff) perfused hearts after a global ischemia period. We conclude that a pharmacological and partial inhibition of ROS production by inhibition of Nox 2 and 4 is beneficial for recovery after ischemia reperfusion and might be a promising venue for treatment of ischemic injury to the heart.

Cannabinoid Receptors and Ligands: Lessons from CNS Disorders and the Quest for Novel Treatment Venues.

The potential use of cannabinoids for therapeutic purposes is at the forefront of cannabinoid research whichaims to develop innovative strategies to prevent, manage and treat a broad spectrum of human diseases. This chapter briefly reviews the pivotal role of the endocannabinoid system in modulating the central nervous system and its roles on neurodegenerative diseases and brain disorders. Ligand-induced modulation of cannabinoid 1 and 2 receptors to modulate immune response, decrease neurodegeneration and pain are aspects that are also discussed.

Growth Factor Roles in Soft Tissue Physiology and Pathophysiology.

Repair and healing of injured and diseased tendons has been traditionally fraught with apprehension and difficulties, and often led to rather unsatisfactory results. The burgeoning research field of growth factors has opened new venues for treatment of tendon disorders and injuries, and possibly for treatment of disorders of the aorta and major arteries as well. Several chapters in this volume elucidate the role of transforming growth factor β (TGFß) in pathogenesis of several heritable disorders affecting soft tissues, such as aorta, cardiac valves, and tendons and ligaments. Several members of the bone morphogenetic group either have been approved by the FDA for treatment of non-healing fractures or have been undergoing intensive clinical and experimental testing for use of healing bone fractures and tendon injuries. Because fibroblast growth factors (FGFs) are involved in embryonic development of tendons and muscles among other tissues and organs, the hope is that applied research on FGF biological effects will lead to the development of some new treatment strategies providing that we can control angiogenicity of these growth factors. The problem, or rather question, regarding practical use of imsulin-like growth factor I (IGF-I) in tendon repair is whether IGF-I acts independently or under the guidance of growth hormone. FGF2 or platelet-derived growth factor (PDGF) alone or in combination with IGF-I stimulates regeneration of periodontal ligament: a matter of importance in Marfan patients with periodontitis. In contrast, vascular endothelial growth factor (VEGF) appears to have rather deleterious effects on experimental tendon healing, perhaps because of its angiogenic activity and stimulation of matrix metalloproteinases-proteases whose increased expression has been documented in a variety of ruptured tendons. Other modalities, such as local administration of platelet-rich plasma (PRP) and/or of mesenchymal stem cells have been explored extensively in tendon healing. Though treatment with PRP and mesenchymal stem cells has met with some success in horses (who experience a lot of tendon injuries and other tendon problems), the use of PRP and mesenchymal stem cells in people has been more problematic and requires more studies before PRP and mesenchymal stem cells can become reliable tools in management of soft tissue injuries and disorders.

Clinical and Anatomic Complexity of Patients Undergoing Coronary Intervention With and Without On-Site Surgical Capabilities

Background: Professional society consensus statements articulate the clinical and anatomic complexity of patients that may undergo percutaneous coronary intervention (PCI) without on-site cardiothoracic surgery, although compliance with these recommendations has not been assessed. We sought to evaluate the clinical and anatomic complexity of patients undergoing PCI with and without cardiothoracic surgery on-site. Methods: We identified all patients undergoing PCI in the Veterans Affairs health care system between October 2009 and September 2017. The clinical and anatomic complexity of patients treated at sites with or without cardiothoracic surgery was evaluated with a comparative interrupted time series, and mortality was ascertained in a propensity-matched cohort. Results: We identified 75 564 patients who underwent PCI, with the majority (53 708, 71%) treated at sites with cardiothoracic surgery. The overall clinical complexity was statistically greater for those treated at sites with cardiothoracic surgery (National Cardiovascular Data Registries CathPCI: 18.4) compared with those at sites without (17.8, P <0.001) throughout the study, with similar annual increases in complexity before (2% versus 3%; P =0.107) and after (3% versus 3%; P =0.704) January 2014. The anatomic complexity of patients treated was also statistically greater (Veterans Affairs SYNTAX: 11.0 versus 10.2; P <0.001) and increased at comparable rates (2% versus 1%, P =0.731) before 2014. After publication of the consensus statement, anatomic complexity declined at sites with cardiothoracic surgery (−2%) but increased at sites without on-site surgery (5%, P =0.025) such that it was similar at the end of the study ( P =0.622). Referrals for emergent cardiothoracic surgery were rare regardless of treatment venue (61, 0.08%) and the hazard for mortality was similar (hazard ratio, 0.883 [95% CI, 0.662–1.176]) after propensity matching. Conclusions: There are minor differences in complexity of patients undergoing coronary intervention at sites with and without cardiothoracic surgery. Clinical outcomes are similar regardless of treatment venue, suggesting an opportunity to improve access to complex interventional care without sacrificing quality.

Mortality After Adolescent Firearm Injury: Effect of Trauma Center Designation

PurposeTo determine the incidence and outcomes of firearm injuries in adolescents and the effect of trauma center (TC) designation on their mortality. MethodsThe National Trauma Data Bank (2010–2016) was queried for all encounters involving adolescents aged 13–16 years with firearm injuries. Multivariable logistic regression was employed to determine the association of covariates with mortality (α = .05). Propensity score matching was also used to explore the relationship between TC designation and mortality. ResultsA total of 9,029 adolescents met inclusion criteria. Patients aged 15 and 16 years compromised 77.8% of the cohort and were more often male (87.9% vs. 80.6%, p < .001), black (63.8% vs. 56.1%, p < .001), injured in the abdomen (25.4% vs. 22.4%, p = .007) or extremities (62.3% vs. 56.7%, p < .001), and incurred severe injuries (54.5% vs. 50.9%, p = .004) versus 13- and 14-year-old patients. Younger patients were more often injured in the head/neck (23.8% vs. 20.5%, p = .001). Multivariable logistic regression demonstrated no difference in mortality between age groups. Poor neurologic presentation, severe injury, abdominal, chest, and head injuries were all associated with an increased odds of death. Odds of mortality were 2.88 times higher at adult TCs compared to pediatric TCs (CI: 1.55–5.36, p = .001). However, using a 1:1 propensity score matching model, no difference in mortality was found between TC types (p = NS). ConclusionsVariability exists in outcomes for adolescents after firearm injuries. Understanding and identifying the potential differences between pediatric and adult TCs managing adolescent firearm victims may improve survival in all treatment venues, but these data support patients being treated at the closest available TC.

T12. THE RELATIONSHIP OF INTESTINAL PERMEABILITY FACTORS WITH SOCIODEMOGRAPHIC AND PHYSICAL HEALTH FACTORS AND PANSS SCORES IN SCHIZOPHRENIA PATIENTS AND HEALTHY CONTROLS

BackgroundRecent studies have pointed to the gut-brain axis as a new venue for treatment of psychiatric disorders, with increased inflammation stemming from increased intestinal permeability to further affect brain functioning in a significant subset of patients. Yet, this line of research is still in its infancy, with multiple studies showing increased intestinal permeability in schizophrenia and bipolar disorders, demonstrated as translocation of food and bacterial antigens, as well as intestinal microbiome disturbances.MethodsTherefore, we measured intestinal permeability markers soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP) in schizophrenia patients and healthy controls. Intestinal permeability markers were compared to several sociodemographic, including age, gender and BMI, and physical health variables, including CRP, glucose, cholesterol, triglycerides, HDL, LDL and non-HDL, and Positive and Negative Syndrome Scale (PANSS) scores. Of the control group (n = 43), 76.7% was male, with a mean age of 25.1 years. Of the schizophrenia group (n = 105) 75.2 % was male, with a mean age of 27.4 years and an average PANSS score of 57.2.ResultsLevels of LBP and sCD14 were not significantly different between schizophrenia patients and controls. LBP and sCD14 levels were neither correlated in the control group, nor in the schizophrenia group. In the control group Females had elevated LBP levels compared to males (p < 0.01), but not in the schizophrenia group. Quantitative levels of LBP, but not sCD14, correlated with triglycerides in the schizophrenia group (R2 = 0.049, p < 0.05). Furthermore, quantitative levels of sCD14, but not LBP, correlated with CRP in the schizophrenia group (R2 = 0.078, p < 0.05). Finally, LBP levels in patients correlated with PANSS negative scores (R2 = 0.055, p < 0.05). Neither a correlation of LBP and sCD14 with age, nor with BMI was observed in both the control and the schizophrenia group.DiscussionIn conclusion, these intestinal permeability markers showed few differences between the schizophrenia and the control group. We found weak, yet significant correlations with triglycerides, CRP and severity of negative symptoms, which may be caused by poor eating habits or metabolic syndrome leading to leaky gut in the more severely affected patients. These results are not in line with results of Severance et al. (2013), who performed a similar analysis and found differences in intestinal permeability markers between a control group and a schizophrenia group. Furthermore, they did observe a positive correlation between sCD14 and LBP in both the control and the schizophrenia group. The difference between that study and our current findings may stem from the different patients samples, as we assessed patients in their first five years after diagnosis, when metabolic syndrome was less abundant.

ITTCA-Hybrid: Improved and robust identification of tumor T cell antigens by utilizing hybrid feature representation

In spite of the repertoire of existing cancer therapies, the ongoing recurrence and new cases of cancer poses a challenging health concern that prompts for novel and effective treatment. Cancer immunotherapy represents a promising venue for treatment by harnessing the body's immune system to combat cancer. Therefore, the identification of tumor T cell antigen represents an exciting area to explore. Computational tools have been instrumental in the identification of tumor T cell antigens and it is highly desirable to attain highly accurate models in a timely fashion from large volumes of peptides generated in the post-genomic era. In this study, we present a reliable, accurate, unbiased and automated sequence-based predictor named iTTCA-Hybrid for identifying tumor T cell antigens. The iTTCA-Hybrid approach proposed herein employs two robust machine learning models (e.g. support vector machine and random forest) constructed using five feature encoding strategies (i.e. amino acid composition, dipeptide composition, pseudo amino acid composition, distribution of amino acid properties in sequences and physicochemical properties derived from the AAindex). Rigorous independent test indicated that the iTTCA-Hybrid approach achieved an accuracy and area under the curve of 73.60% and 0.783, respectively, which corresponds to 4% and 7% performance increase than those of existing methods thereby indicating the superiority of the proposed model. To the best of our knowledge, the iTTCA-Hybrid is the first free web server (Available at http://camt.pythonanywhere.com/iTTCA-Hybrid) for identifying tumor T cell antigens presented by the MHC class I. The proposed web server allows robust predictions to be made without the need to develop in-house prediction models.

O-Glcnacylation Is Essential for Erythropoiesis

Understanding the molecular mechanisms of erythropoiesis is critical for treating anemia and other hematopoietic diseases, which affect roughly 3 million Americans and 28% of the global population. The role of post-translational modification (PTM) of proteins in regulating developmental and differentiation processes is understudied, but recently we established that O-GlcNAcylation regulates erythropoiesis. O-GlcNAc regulates numerous cellular functions, including stress response, transcription, and cell cycle progression. O-GlcNAc is a single O-linked β-N-acetyl-D-glucosamine moiety added to serine/threonine amino acids of nuclear, cytoplasmic, and mitochondrial proteins. O-GlcNAc transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes the modification, are responsible for the dynamic processing of the PTM. In response to environmental cues, the variable cycling of O-GlcNAc on and off proteins has potential effects on transcriptional pathways essential for differentiation. Previously, we demonstrated that O-GlcNAc plays a role in regulating human γ-globin gene transcription during development in human β-globin locus yeast artificial chromosome (β-YAC) transgenic mice and derivative immortalized bone marrow cells. O-GlcNAcylation modulates the formation of a GATA-1-FOG-1-NuRD repressor complex that binds the -566 GATA site of the Aγ-globin promoter when γ-globin gene expression is silent. OGT and OGA interact with GATA-1 and CHD4, a component of the NuRD complex. O-GlcNAcylation of CHD4 stimulates the formation of this repressor complex, blocking O-GlcNAcylation of CHD4 maintains Aγ-globin gene expression. Thus, O-GlcNAc cycling is a novel γ-globin regulatory mechanism, which might be modulated to increase fetal hemoglobin (HbF). Since O-GlcNAcylation involves input from multiple metabolic pathways, the modification acts as a general sensor of cellular homeostasis. Thus, in response to environmental cues, the addition and removal of O-GlcNAc from proteins may be variably altered with potential effects on biochemical and transcriptional pathways essential for erythropoiesis. To better understand how O-GlcNAcylation affects erythropoiesis in vivo, we developed several new, innovative mouse models. These include erythroid-specific OGT or OGA conditional knockout mice, and transgenic mice with erythroid-specific enforced expression of human OGT or OGA. OGT is an essential gene; erythroid-specific knockout results in fetal death due to severe anemia between day E12-14. OGA is not essential for erythropoiesis; no overt phenotype is observed. Based on previous our previous studies, we hypothesize that at the onset of erythroid lineage commitment, GATA-1 functions as an adaptor protein to deliver OGT and OGA to erythroid-specific cis-regulatory DNA elements, where they modify transcription complex or chromatin proteins responsible for directing transcriptional networks necessary for normal erythroid development and terminal differentiation. Currently, we are exploring how GATA-1-adaptor function mediates changes in the global O-GlcNAcylation pattern following the GATA-2 to GATA-1 switch that triggers erythroid differentiation. We are also examining the roles of OGT and OGA in the formation and function of the GATA-1-FOG-1-NuRD γ-globin repressor complex. Novel CRISPR/Cas9-based genome targeting tools were developed to probe these questions. We present phenotypic and molecular data related to the hematopoietic system, including anemia, blood cell histology and morphology, standard blood indices, and β-like globin gene expression during embryonic, fetal, and adult stages of erythropoiesis in our mouse models. In addition, we will show preliminary data using the enzymatically dead dCas9 tools we have synthesized, dCas9-OGT and dCas9-OGA protein fusions that are delivered to cis-regulatory elements controlling erythroid-specific genes involved in erythropoiesis and globin gene switching. The therapeutic outcome will be the identification of erythroid-specific protein targets whose activity can be modulated by altering their O-GlcNAcylation status. We emphasize that because the O-GlcNAc cycle has pleiotropic effects within the cell, it is not a good direct target for therapeutic intervention. However, many of the target proteins are likely to be suitable for treatment venues. Disclosures No relevant conflicts of interest to declare.

SCIDOT-40. THERAPEUTIC GENOME EDITING AS A NOVEL TREATMENT FOR GBM

Abstract Glioblastoma multiforme (GBM), is the most aggressive form of glioma, a brain tumor that arises from glial cells. GBM is considered a complex malignancy with multiple gene mutations, aberrations, and overexpression together with high infiltration rate and resistance to apoptosis. The current treatment consists of surgical resection, aggressive radiation and chemotherapy regimen. This therapeutic strategy had not changed since 2005 when the chemotherapy Temozolomide was approved. This therapeutic approach extended GBM patients’ life expectancy to approximately 15 months since diagnosis. Although recent progress in genomics and proteomics has paved the way for identifying potential therapeutic targets for treating GBM, the majority of these leading drug candidates remain ineffective. Therefore, novel and effective treatment to GBM presents an unmet need. Lipid nanoparticles (LNPs) are the most clinically advanced delivery platform to date for systemic administration of RNA therapeutics, with the recent approval of Patisiran, siRNA encapsulating LNPs. In recent years, several gene editing technologies have been discovered in bacteria, enabling precise and permanent manipulations at the DNA level. The most advanced and versatile system is based on the CRISPR nuclease Cas9. The recognition of its target chromosomal DNA by Cas9 results in a site-specific double-strand break (DSB), that eventually results in gene disruption. This approach opens multiple venues for research and treatment of diseases including cancer. We have utilized CRISPR encapsulating LNPs to promote a therapeutic gene editing by disrupting key GBM survival genes in vitro in murine and human GBM cell lines as well as in vivo in an aggressive syngeneic GBM mouse model. Our results suggest that treatment with our LNPs based system can specifically and efficiently target GBM cells in vitro and in vivo. Our CRISPR-LNPs based platform could potentially mature to a clinical trial, and ultimately might become a new therapeutic modality in GBM.

The Collaborative Chronic Care Model for Mental Health Conditions: From Evidence Synthesis to Policy Impact to Scale-up and Spread.

Background:Extensive evidence indicates that Collaborative Chronic Care Models (CCMs) improve outcome in chronic medical conditions and depression treated in primary care. Beginning with an evidence synthesis which indicated that CCMs are also effective for multiple mental health conditions, we describe a multistage process that translated this knowledge into evidence-based health system change in the US Department of Veterans Affairs (VA).Evidence Synthesis:In 2010, recognizing that there had been numerous CCM trials for a wide variety of mental health conditions, we conducted an evidence synthesis compiling randomized controlled trials of CCMs for any mental health condition. The systematic review demonstrated CCM effectiveness across mental health conditions and treatment venues. Cumulative meta-analysis and meta-regression further informed our approach to subsequent CCM implementation.Policy Impact:In 2015, based on the evidence synthesis, VA Office of Mental Health and Suicide Prevention (OMHSP) adopted the CCM as the model for their outpatient mental health teams.Randomized Implementation Trial:In 2015–2018 we partnered with OMHSP to conduct a 9-site stepped wedge implementation trial, guided by insights from the evidence synthesis.Scale-Up and Spread:In 2017 OMHSP launched an effort to scale-up and spread the CCM to additional VA medical centers. Seventeen facilitators were trained and 28 facilities engaged in facilitation.Discussion:Evidence synthesis provided leverage for evidence-based policy change. This formed the foundation for a health care leadership/researcher partnership, which conducted an implementation trial and subsequent scale-up and spread effort to enhance adoption of the CCM, as informed by the evidence synthesis.

Abstract 4952: Host lipocalin 2 protects against Kras mutant lung cancer development by maintaining an anti-tumor immune contexture

Abstract Relative to other lung adenocarcinomas (LUADs), Kras mutant LUAD displays dismal prognosis warranting the need for new strategies for early treatment of this lung cancer subtype. Limiting these advances is our poor understanding of events that drive Kras mutant LUAD development. In efforts to fill this void, we recently found that mice with knockout of G-protein coupled receptor 5A (Gprc5a-/-) and after tobacco carcinogen exposure (nicotine-specific nitrosamine ketone/NNK) developed LUADs harboring driver somatic Kras mutations. To understand early events preceding the onset of these Kras mutant LUADs, we performed RNA-sequencing (RNA-Seq) of normal airways in Gprc5a-/- mice and wild type (WT) littermates prior to NNK exposure. We found markedly elevated expression of the antimicrobial lipocalin 2 (Lcn2) gene in normal airways of Gprc5a-/- mice. Also, analysis of publicly available human datasets revealed elevated expression of LCN2 in human LUADs relative to normal lung tissues particularly in KRAS mutant tumors. We then sought to probe the role of Lcn2 in the pathogenesis of Kras mutant LUAD. Mice with knockout of host Lcn2 (Gprc5a-/-/Lcn2-/-) showed increased lung tumor development compared to Gprc5a-/- littermates. RNA-Seq of whole lungs at baseline and at seven months post-NNK (n = 9-10 mice each group) pinpointed differential expression profiles that denoted decreased anti-tumor immunity in Gprc5a-/-/Lcn2-/- mice. Computational estimation of immune infiltrates demonstrated increased levels of neutrophils post-NNK in Gprc5a-/-/Lcn2-/- mice but not in Gprc5a-/-littermates. By flow cytometry analysis of lung tissues, we found elevated numbers of various lymphoid and myeloid immune cells in both groups following NNK exposure and increased neutrophil counts in Gprc5a-/-/Lcn2-/- mice relative to Gprc5a-/- littermates. Histopathological assessment also revealed increased numbers of pro-inflammatory lesions in mice lacking Lcn2. Gprc5a-/-/Lcn2-/- mice at three months post-NNK were also found to exhibit increased production of IL-17A by lung-resident CD4+ and CD8+ T cells relative to Gprc5a-/- littermates concomitant with decreased expression of the anti-tumor Th1/cytolytic immune markers Ifnγ and Gzmb. Preliminary analysis also showed elevated expression of the major immune checkpoint PD-L1 on alveolar macrophages in Gprc5a-/-/Lcn2-/- mice relative to Gprc5a-/- mice with WT Lcn2. Lastly, we preliminarily found, by bacterial 16S rRNA sequencing of temporally collected fecal samples, globally altered microbiome profiles in mice lacking Lcn2. Our findings underscore novel cues in lung oncogenesis and suggest that Lcn2 decreases anti-tumor immunity, perturbs the host microbiome and promotes development of Kras mutant LUAD thereby offering new venues for early treatment of this fatal malignancy. Citation Format: Maya Hassane, Warapen Treekitkarnmongkol, Tina L. McDowell, Smruthy Sivakumar, Wenhua Lang, Joshua K. Ochieng, Sayuri Nunomura-Nakamura, Casey Finnicum, Christel Davis, Gareth E. Davies, Junya Fukuoka, Tina Cascone, Florencia McAllister, Ignacio I. Wistuba, Erik Ehli, Seyed J. Moghaddam, Paul Scheet, Junya Fujimoto, Humam Kadara. Host lipocalin 2 protects against Kras mutant lung cancer development by maintaining an anti-tumor immune contexture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4952.

Regulation of miRNA Biogenesis and Histone Modification by K63-Polyubiquitinated DDX17 Controls Cancer Stem-like Features.

Markers of cancer stemness predispose patients to tumor aggressiveness, drug and immunotherapy resistance, relapse, and metastasis. DDX17 is a cofactor of the Drosha-DGCR8 complex in miRNA biogenesis and transcriptional coactivator and has been associated with cancer stem-like properties. However, the precise mechanism by which DDX17 controls cancer stem-like features remains elusive. Here, we show that the E3 ligase HectH9 mediated K63-polyubiquitination of DDX17 under hypoxia to control stem-like properties and tumor-initiating capabilities. Polyubiquitinated DDX17 disassociated from the Drosha-DGCR8 complex, leading to decreased biogenesis of anti-stemness miRNAs. Increased association of polyubiquitinated DDX17 with p300-YAP resulted in histone 3 lysine 56 (H3K56) acetylation proximal to stemness-related genes and their subsequent transcriptional activation. High expression of HectH9 and six stemness-related genes (BMI1, SOX2, OCT4, NANOG, NOTCH1, and NOTCH2) predicted poor survival in patients with head and neck squamous cell carcinoma and lung adenocarcinoma. Our findings demonstrate that concerted regulation of miRNA biogenesis and histone modifications through posttranslational modification of DDX17 underlies many cancer stem-like features. Inhibition of DDX17 ubiquitination may serve as a new therapeutic venue for cancer treatment. SIGNIFICANCE: Hypoxia-induced polyubiquitination of DDX17 controls its dissociation from the pri-miRNA-Drosha-DCGR8 complex to reduce anti-stemness miRNA biogenesis and association with YAP and p300 to enhance transcription of stemness-related genes.

The epidemiology and treatment of conjunctivitis at Urgent Care Centres in Israel.

Purpose: Conjunctivitis is the most common ocular condition diagnosed at emergency departments (ED) in the USA, although it is generally not an emergent condition. Treatment of conjunctivitis at Urgent Care Centres (UCC) could offer lower cost than ED. This study describes the demographics and outcomes of a cohort presenting with conjunctivitis to a nationwide UCC system.Methods: This retrospective study included 17 branches of UCC. Electronic Medical Record data (November 2015–October 2016) of patients diagnosed with conjunctivitis or ocular disorder were retrieved. Data included gender, age, diagnosis, treatment, discharge status and temperature. Patients without conjunctivitis, presenting to UCC during this period served as the control. Results were compared to all ED patients in Israel (from a public report). Descriptive statistics, Chi-square and Z-proportion test were used.Results: Altogether, 602,074 patients presented to UCC, of which 5,045 (0.84%, 95% CI 0.74–0.94%) were diagnosed with conjunctivitis. Conjunctivitis was more prevalent among young males (0–14, p<0.001) and older females. The conjunctivitis cohort at UCC was significantly younger than the ED cohort (p<0.01). UCC treated and released home 96.7% (95% CI 96.2–97.2%) of cases. This is significantly higher than the treatment rate for the entire UCC cohort (93.2%, CI 93.2–93.3%, p<0.05). Treatment in most cases (82.0%, 95% CI 80.9–83.0%) involved the prescription of ocular antibiotic.Conclusion: Similar to previous studies at ED, conjunctivitis patients are primarily young males. Most patients were treated with antibiotics at UCC and released home. This suggests that UCC may be a good venue for treatment of conjunctivitis.

Trends in Visits to Acute Care Venues for Treatment of Low-Acuity Conditions in the United States From 2008 to 2015

Over the past 2 decades, a variety of new care options have emerged for acute care, including urgent care centers, retail clinics, and telemedicine. Trends in the utilization of these newer care venues and the emergency department (ED) have not been characterized. To describe trends in visits to different acute care venues, including urgent care centers, retail clinics, telemedicine, and EDs, with a focus on visits for treatment of low-acuity conditions. This cohort study used deidentified health plan claims data from Aetna, a large, national, commercial health plan, from January 1, 2008, to December 31, 2015, with approximately 20 million insured members per study year. Descriptive analysis was performed for health plan members younger than 65 years. Data analysis was performed from December 28, 2016, to February 20, 2018. Utilization, inflation-adjusted price, and spending associated with visits for treatment of low-acuity conditions. Low-acuity conditions were identified using diagnosis codes and included acute respiratory infections, urinary tract infections, rashes, and musculoskeletal strains. This study included 20.6 million acute care visits for treatment of low-acuity conditions over the 8-year period. Visits to the ED for the treatment of low-acuity conditions decreased by 36% (from 89 visits per 1000 members in 2008 to 57 visits per 1000 members in 2015), whereas use of non-ED venues increased by 140% (from 54 visits per 1000 members in 2008 to 131 visits per 1000 members in 2015). There was an increase in visits to all non-ED venues: urgent care centers (119% increase, from 47 visits per 1000 members in 2008 to 103 visits per 1000 members in 2015), retail clinics (214% increase, from 7 visits per 1000 members in 2008 to 22 visits per 1000 members in 2015), and telemedicine (from 0 visits in 2008 to 6 visits per 1000 members in 2015). Utilization and spending per person per year for low-acuity conditions had net increases of 31% (from 143 visits per 1000 members in 2008 to 188 visits per 1000 members in 2015) and 14% ($70 per member in 2008 to $80 per member in 2015), respectively. The increase in spending was primarily driven by a 79% increase in price per ED visit for treatment of low-acuity conditions (from $914 per visit in 2008 to $1637 per visit in 2015). From 2008 to 2015, total acute care utilization for the treatment of low-acuity conditions and associated spending per member increased, and utilization of non-ED acute care venues increased rapidly. These findings suggest that patients are more likely to visit urgent care centers than EDs for the treatment of low-acuity conditions.

Multimorbidity Is Associated with Preclinical Alzheimer’s Disease Neuroimaging Biomarkers

Background: Identifying comorbidities that influence preclinical Alzheimer’s disease (AD) can give some insight into the AD early stages trajectories to allow new treatment venues and to guide public health systems to prevent subsequent dementia. Objective: To examine the association of multimorbidity with AD neuroimaging markers in cognitively normal older adults. Methods: This study had a cross-sectional design. Data regarding 14 comorbidities were obtained for all 318 adults aged 70–85 years, recruited from the community to an ongoing prospective monocentric cohort. They underwent standardized neuropsychological and neuroimaging assessment with automated methods that measured hippocampal volumes, white matter hyperintensity volumes, fluorodeoxyglucose positron emission tomography (FDG-PET) standardized uptake values (SUV) in AD signature regions, and amyloid positron emission tomography (amyloid-PET) SUV ratios. Linear regression was used to assess the association of multimorbidity with AD neuroimaging biomarkers. Results: Multimorbidity is signif icantly associated with lower hippocampal volumes (–0.03 ± 0.01; p = 0.012; R² = 0.017) and lower FDG-PET SUV (–0.027 ± 0.009; p = 0.005; R² = 0.022), with no association with amyloid deposition (0.001 ± 0.007; p = 0.884; R² = 0.0001). Taken individually, obesity and excessive alcohol use are associated with lower FDG-PET values, whereas obstructive sleep apnea and mood disorders are related to lower amyloid-PET SUV ratios. Conclusion: Multimorbidity is associated with preclinical AD imaging markers of neurodegeneration, but not with amyloid.

Along the Central Dogma-Controlling Gene Expression with Small Molecules.

The central dogma of molecular biology, that DNA is transcribed into RNA and RNA translated into protein, was coined in the early days of modern biology. Back in the 1950s and 1960s, bacterial genetics first opened the way toward understanding life as the genetically encoded interaction of macromolecules. As molecular biology progressed and our knowledge of gene control deepened, it became increasingly clear that expression relied on many more levels of regulation. In the process of dissecting mechanisms of gene expression, specific small-molecule inhibitors played an important role and became valuable tools of investigation. Small molecules offer significant advantages over genetic tools, as they allow inhibiting a process at any desired time point, whereas mutating or altering the gene of an important regulator would likely result in a dead organism. With the advent of modern sequencing technology, it has become possible to monitor global cellular effects of small-molecule treatment and thereby overcome the limitations of classical biochemistry, which usually looks at a biological system in isolation. This review focuses on several molecules, especially natural products, that have played an important role in dissecting gene expression and have opened up new fields of investigation as well as clinical venues for disease treatment.

Cysteinyl-tRNA synthetase (CARS) controls endogenous hydropersulfide production and mitochondrial respiration

Cysteine persulfide and polysulfide produced in cells exist in abundance in both low-molecular -weight and protein fractions. They can act as an antioxidant and thus protect cells from harmful free radicals and oxidative stress that may cause various diseases. However, how these reactive sulfur molecules are formed, or what role they play exactly within the cells and tissues, has not been well understood. We recently demonstrated that cysteinyl-tRNA synthetase (CARS) is novel cysteine persulfide synthase. CARS is involved in protein polysulfidation that is coupled with translation. The mitochondria biogenesis and bioenergetics are also supported and up-regulated by cysteine persulfide derived from mitochondrial CARS (also known as CARS2). Targeted and functional disruption of a gene encoding mitochondrial CARS (CARS2) and sulfide-quinone reductase (SQR) in mice revealed that persulfides derived from CARS2 are critically involved in the mitochondrial energy metabolism in cooperation with SQR, which is known for a long time as sulfur respiration in anaerobic microorganisms. CARS2- and SQR-dependent sulfur respiration could prolong life and increase the quality of life and may open up a new venue for diagnosis, prevention and treatment for various diseases.

Hepatitis C Treatment Outcomes for People Who Inject Drugs Treated in an Accessible Care Program Located at a Syringe Service Program.

Hepatitis C virus (HCV) is a significant public health problem that disproportionately afflicts people who inject drugs. We describe outcomes of HCV treatment co-located within a syringe services program (SSP). Fifty-three participants started therapy, and 91% achieved sustained virologic response. SSPs provide an effective venue for HCV treatment.

Loss of Angelman Syndrome Protein E6AP Disrupts a Novel Antagonistic Estrogen-Retinoic Acid Transcriptional Crosstalk in Neurons.

Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size (microcephaly), and problems with movement and balance (ataxia). AS individuals usually have microdeletion of the maternal copy of 15q11.2-15q13 region of chromosome 15. The E6-associated protein (E6AP, an E3 ubiquitin protein ligase enzyme) is encoded by the gene UBE3A, which is located in this region, and it has been shown that deregulation of E6AP gives rise to AS and neuropathology of autism spectrum disorders (ASDs) (e.g., autism and Rett syndromes). We have shown that E6AP also acts as a coactivator of the estrogen receptor (ER). ER is a ligand-induced transcription factor that exerts potent and wide-ranging effects on the developing brain. Furthermore, the expression pattern of ER in the brain overlaps with that of E6AP. Up till now, all the published studies have examined the role of the ubiquitin-protein ligase activity of E6AP in the development of AS, and it is not known what role the newly discovered coactivation functions of E6AP and ER plays in the pathology of AS. Here, we demonstrate that E6AP and ER co-immunoprecipitate and are in the same protein complex in neuronal cells (Neuro2a). In addition, both colocalize in nuclear and cytoplasmic compartments of the mouse hippocampal neurons and Neuro2a cells. Moreover, we identified a novel E6AP and ER direct transcriptional regulation of a gene Cyp26b1 known to be involved in learning and memory processes. This transcriptional regulation involves recruitment of E6AP and ER to a newly discovered functional estrogen response element (ERE) located at the Cyp26b1 gene promoter and is associated with transcription permissive epigenetic events leading to increase of active transcription of the gene in neurons upon estrogen treatment. This novel transcriptional regulation was also validated in the AS mouse model where E6AP expression is abrogated in the mouse brain. In fact, Cyp26b1 expression is decreased by 31% in AS mice versus age-matched control (Ctrl) mice hippocampi. Also, retinoic acid transcriptional signaling was shown to be amplified as evidenced by specific increased Rarβ and decreased Erbb4 mRNA expression in AS mice versus Ctrl mice hippocampi. These transcript level changes were also supported by the same trend of changes at the protein level. Collectively, our data present a proof of principle that the transcriptional coactivation function of E6AP may have a crucial role in the pathobiology of AS. This function, yet to be thoroughly investigated, reveals the possibility of harnessing the antagonistic estrogen-retinoic acid transcriptional signaling crosstalk and potentially other unknown effectors for the investigation of important possible targets as putative novel treatment modalities and venues for reversing neurological manifestations in AS and related syndromes like ASDs.

Qualitative Evaluation of Healthcare Provider Trust (And Mistrust) Among Patients with Symptomatic Peripheral Artery Disease

Communication between patients and providers is required for shared decision making, and their interpersonal interaction directly impacts treatment choices. We conducted a focus group study of patients with symptomatic peripheral artery disease (PAD) to identify factors relevant for treatment decisions. This analysis specifically explores provider trust and communication as an important, process-related theme. Patients with symptomatic PAD were recruited to participate in moderated focus groups. Focus groups lasted for approximately one hour, used a structured moderator’s guide, and were audio recorded. Verbatim transcripts were imported into a qualitative analytic software program and analyzed to identify key attributes and themes. Comments related to patient-provider interaction, communication, and trust were extracted and analyzed using thematic analysis, word frequency coding, and hierarchy charts. 51 participants with symptomatic PAD were recruited. Mean participant age was 66.2 ±13.9 years, 35% were women, and 43% were white. Provider trust and interaction emerged as unanticipated but important themes. Interpersonal interaction was discussed in terms of provider specialty, treatment venues, and information sharing. Provider trust was discussed in terms of need for second opinions, disclosure of treatment alternatives and risks, and access to outpatient clinic visits and specific treatments. Participants expressed positive attitudes toward involvement in shared decisions, receipt of educational information, detailed counseling, and discussion of treatment options under consideration. Negative attitudes were expressed toward treatment in the emergency room, delay of appropriate treatment, provider misinformation or withholding of information, inconsistent recommendations between providers, patient abandonment, and pain medication as a treatment. Attitudes about provider specialty, provider trust, and experienced decision roles were mixed. Provider trust is inconsistent among patients with symptomatic PAD and may be affected by a variety of factors, some of which are not provider-specific. Understanding barriers to patient-provider trust may identify opportunities to improve interaction, facilitating shared decision-making.