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Neural Mechanisms Of Economic Choices In Mice, Masaru Kuwabara, Ningdong Kang, Timothy E. Holy, Camillo Padoa-Schioppa

Open Access Publications

Economic choices entail computing and comparing subjective values. Evidence from primates indicates that this behavior relies on the orbitofrontal cortex. Conversely, previous work in rodents provided conflicting results. Here we present a mouse model of economic choice behavior, and we show that the lateral orbital (LO) area is intimately related to the decision process. In the experiments, mice chose between different juices offered in variable amounts. Choice patterns closely resembled those measured in primates. Optogenetic inactivation of LO dramatically disrupted choices by inducing erratic changes of relative value and by increasing choice variability. Neuronal recordings revealed that different groups of …

Pituitary Carcinoma: Two Case Reports And Review Of Literature, Lai Xu, Karam Khaddour, Jie Chen, Keith M. Rich, Richard J. Perrin, Jian Li Campian

Open Access Publications

BACKGROUND: Pituitary carcinoma is a rare type of malignancy that can be very difficult to diagnose and treat. Many cases were diagnosed at autopsy. Delays in diagnosis often adversely impact patients' outcomes. Even with prompt diagnosis, treatment decisions remain challenging in the absence of randomized controlled trials.

CASE SUMMARY: We report two cases of pituitary carcinoma in men with a history of pituitary adenoma. In the first case, a 55-year-old man was initially diagnosed with pituitary macroadenoma. He underwent subtotal debulking of the tumor followed by adjuvant radiotherapy. Subsequently, he developed relapsed disease and multifocal intracranial metastases and a diagnosis …

Continuous Representations Of Speed By Striatal Medium Spiny Neurons, Wambura C. Fobbs, Sebastiano Bariselli, Julia A. Licholai, Nanami L. Miyazaki, Bridget A. Matikainen-Ankney, Meaghan C. Creed, Alexxai V. Kravitz

Open Access Publications

The striatum is critical for controlling motor output. However, it remains unclear how striatal output neurons encode and facilitate movement. A prominent theory suggests that striatal units encode movements in bursts of activity near specific events, such as the start or end of actions. These bursts are theorized to gate or permit specific motor actions, thereby encoding and facilitating complex sequences of actions. An alternative theory has suggested that striatal neurons encode continuous changes in sensory or motor information with graded changes in firing rate. Supporting this theory, many striatal neurons exhibit such graded changes without bursting near specific actions. …

Clinical Care Recommendations For Cardiologists Treating Adults With Myotonic Dystrophy, Elizabeth M Mcnally, Douglas L Mann, Yigal Pinto, Deepak Bhakta, Gordon Tomaselli, Saman Nazarian, William J Groh, Takuhisa Tamura, Denis Duboc, Hideki Itoh, Leah Hellerstein, Pradeep P A Mammen

Open Access Publications

Myotonic dystrophy is an inherited systemic disorder affecting skeletal muscle and the heart. Genetic testing for myotonic dystrophy is diagnostic and identifies those at risk for cardiac complications. The 2 major genetic forms of myotonic dystrophy, type 1 and type 2, differ in genetic etiology yet share clinical features. The cardiac management of myotonic dystrophy should include surveillance for arrhythmias and left ventricular dysfunction, both of which occur in progressive manner and contribute to morbidity and mortality. To promote the development of care guidelines for myotonic dystrophy, the Myotonic Foundation solicited the input of care experts and organized the drafting …

Spatiotemporal Dynamics Of Multi-Vesicular Release Is Determined By Heterogeneity Of Release Sites Within Central Synapses, Dario Maschi, Vitaly A. Klyachko

Open Access Publications

A synaptic active zone (AZ) can release multiple vesicles in response to an action potential. This multi-vesicular release (MVR) occurs at most synapses, but its spatiotemporal properties are unknown. Nanoscale-resolution detection of individual release events in hippocampal synapses revealed unprecedented heterogeneity among vesicle release sites within a single AZ, with a gradient of release probability decreasing from AZ center to periphery. Parallel to this organization, MVR events preferentially overlap with uni-vesicular release (UVR) events at sites closer to an AZ center. Pairs of fusion events comprising MVR are also not perfectly synchronized, and the earlier event tends to occur closer …

Neuronal Activity In The Primate Amygdala During Economic Choice, Ahmad Jezzini, Camillo Padoa-Schioppa

Open Access Publications

Multiple lines of evidence link economic choices to the orbitofrontal cortex (OFC), but other brain regions may contribute to the computation and comparison of economic values. A particularly strong candidate is the basolateral amygdala (BLA). Amygdala lesions impair performance in reinforcer devaluation tasks, suggesting that the BLA contributes to value computation. Furthermore, previous studies of the BLA have found neuronal activity consistent with a value representation. Here, we recorded from the BLA of two male rhesus macaques choosing between different juices. Offered quantities varied from trial to trial, and relative values were inferred from choices. Approximately one-third of BLA cells …

Quantitative Trait Variation In Asd Probands And Toddler Sibling Outcomes At 24 Months, Jessica B Girault, Kelly N Botteron, John N Constantino, Et Al

Open Access Publications

BACKGROUND: Younger siblings of children with autism spectrum disorder (ASD) are at increased likelihood of receiving an ASD diagnosis and exhibiting other developmental concerns. It is unknown how quantitative variation in ASD traits and broader developmental domains in older siblings with ASD (probands) may inform outcomes in their younger siblings.

METHODS: Participants included 385 pairs of toddler siblings and probands from the Infant Brain Imaging Study. ASD probands (mean age 5.5 years, range 1.7 to 15.5 years) were phenotyped using the Autism Diagnostic Interview-Revised (ADI-R), the Social Communication Questionnaire (SCQ), and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). Siblings …

Mechanism Of Differential Zika And Dengue Virus Neutralization By A Public Antibody Lineage Targeting The Diii Lateral Ridge, Haiyan Zhao, Lily Xu, Robin Bombardi, Rachel Nargi, Zengqin Deng, John M. Errico, Christopher A. Nelson, Kimberly A. Dowd, Theodore C. Pierson, James E. Crowe, Michael S. Diamond, Daved H. Fremont

Open Access Publications

We previously generated a panel of human monoclonal antibodies (mAbs) against Zika virus (ZIKV) and identified one, ZIKV-116, that shares germline usage with mAbs identified in multiple donors. Here we show that ZIKV-116 interferes with ZIKV infection at a post-cellular attachment step by blocking viral fusion with host membranes. ZIKV-116 recognizes the lateral ridge of envelope protein domain III, with one critical residue varying between the Asian and African strains responsible for differential binding affinity and neutralization potency (E393D). ZIKV-116 also binds to and cross-neutralizes some dengue virus serotype 1 (DENV1) strains, with genotype-dependent inhibition explained by variation in a …

Inhibition Of Rev-Erbs Stimulates Microglial Amyloid-Beta Clearance And Reduces Amyloid Plaque Deposition In The 5xfad Mouse Model Of Alzheimer's Disease, Jiyeon Lee, Do Eon Kim, Percy Griffin, Patrick W Sheehan, Dong-Hou Kim, Erik S Musiek, Seung-Yong Yoon

Open Access Publications

A promising new therapeutic target for the treatment of Alzheimer's disease (AD) is the circadian system. Although patients with AD are known to have abnormal circadian rhythms and suffer sleep disturbances, the role of the molecular clock in regulating amyloid-beta (Aβ) pathology is still poorly understood. Here, we explored how the circadian repressors REV-ERBα and β affected Aβ clearance in mouse microglia. We discovered that, at Circadian time 4 (CT4), microglia expressed higher levels of the master clock protein BMAL1 and more rapidly phagocytosed fibrillary Aβ

Emerging Priorities For Hiv Service Delivery, Nathan Ford, Elvin Geng, Et Al.

Open Access Publications

Nathan Ford and co-authors discuss global priorities in the provision of HIV prevention and treatment services.

Circulating Ceramide Ratios And Risk Of Vascular Brain Aging And Dementia, Emer R Mcgrath, Jayandra J Himali, Vanessa Xanthakis, Meredith S Duncan, Jean E Schaffer, Daniel S Ory, Linda R Peterson, Charles Decarli, Matthew P Pase, Claudia L Satizabal, Ramachandran S Vasan, Alexa S Beiser, Sudha Seshadri

Open Access Publications

BACKGROUND: We determined the association between ratios of plasma ceramide species of differing fatty-acyl chain lengths and incident dementia and Alzheimer's disease (AD) dementia in a large, community-based sample.

METHODS: We measured plasma ceramide levels in 1892 [54% women, mean age 70.1 (SD 6.9) yr.] dementia-free Framingham Offspring Study cohort participants between 2005 and 2008. We related ratios of very long-chain (C24:0, C22:0) to long-chain (C16:0) ceramides to subsequent risk of incident dementia and AD dementia. Structural MRI brain measures were included as secondary outcomes.

RESULTS: During a median 6.5 year follow-up, 81 participants developed dementia, of whom 60 were …

The Prevalence And Clinical Implications Of Comorbid Back Pain In Shoulder Instability: A Multicenter Orthopaedic Outcomes Network (Moon) Shoulder Instability Cohort Study, Kevin Cronin, Robert Brophy, Matthew Smith, Rick Wright, Et Al

Open Access Publications

Background: Understanding predictors of pain is critical, as recent literature shows that comorbid back pain is an independent risk factor for worse functional and patient-reported outcomes (PROs) as well as increased opioid dependence after total joint arthroplasty.

Purpose/Hypothesis: The purpose of this study was to evaluate whether comorbid back pain would be predictive of pain or self-reported instability symptoms at the time of stabilization surgery. We hypothesized that comorbid back pain will correlate with increased pain at the time of surgery as well as with worse scores on shoulder-related PRO measures.

Study Design: Cross-sectional study; Level of evidence, 3.

Methods: …

2019 Hrs/Ehra/Aphrs/Lahrs Expert Consensus Statement On Catheter Ablation Of Ventricular Arrhythmias: Executive Summary, Edmond M Cronin, Phillip Cuculich, Et Al

Open Access Publications

Ventricular arrhythmias are an important cause of morbidity and mortality and come in a variety of forms, from single premature ventricular complexes to sustained ventricular tachycardia and fibrillation. Rapid developments have taken place over the past decade in our understanding of these arrhythmias and in our ability to diagnose and treat them. The field of catheter ablation has progressed with the development of new methods and tools, and with the publication of large clinical trials. Therefore, global cardiac electrophysiology professional societies undertook to outline recommendations and best practices for these procedures in a document that will update and replace the …

Endoscopic Mucosal Resection Of A Gastric Perineurioma, Michael Weaver, Rehan Rais, Jon Ritter, Vladimir Kushnir

Open Access Publications

No abstract provided.

Phase Ib/Ii Study Combining Tosedostat With Capecitabine In Patients With Advanced Pancreatic Adenocarcinoma, Patrick Grierson, Andrea Teague, Rama Suresh, Kian-Huat Lim, Manik Amin, Katrina Pedersen, Benjamin Tan, Jesse Huffman, Nick Boice, Lingling Du, Jingxia Liu, A. Craig Lockhart, Andrea Wang-Gillam

Open Access Publications

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC.

Methods: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m

Results: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m

Conclusions: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic …

Perioperative Care Of The Geriatric Patient For Noncardiac Surgery, Jonathan D Wolfe, Natasha K Wolfe, Michael W Rich

Open Access Publications

Adults age 65 and over are the fastest growing segment of the population in the United States and around the world. As the size of this population expands, the number of older adults referred for surgical procedures will continue to increase. Due to the physiologic changes of aging and the increased frequency of comorbidities, older adults are at increased risk for adverse outcomes, and perioperative care is inherently more complex than in younger individuals. In this review, we discuss the physiologic changes of aging relevant to the surgical patient, comprehensive preoperative assessment, and postoperative management of common complications in older …

Parental Deployment And Distress, And Adolescent Disordered Eating In Prevention-Seeking Military Dependents, M K Higgins Neyland, Denise E Wilfley, Et Al

Open Access Publications

OBJECTIVE: Parental military deployment can lead to stress in the family system due to concerns about the deployed service-member's safety and increased responsibilities for those not deployed. Parent-related stress can impact adolescent disordered eating. Given the important role that stress plays in disordered eating and obesity, it is crucial to understand the impacts of unique stressors to which vulnerable populations are exposed.

METHOD: We studied 126 adolescent (14.3 ± 1.6 years; 59.5% girls; 44.4% non-Hispanic White; BMI-z, 1.91 ± .39) military dependents prior to entering an obesity and binge-eating disorder prevention trial. The Eating Disorder Examination was used to assess …

Targeting Refractory Sarcomas And Malignant Peripheral Nerve Sheath Tumors In A Phase I/Ii Study Of Sirolimus In Combination With Ganetespib (Sarc023), Aerang Kim, Brian A. Van Tine, Et Al

Open Access Publications

No abstract provided.

Zika Virus Infection In The Developing Mouse Produces Dramatically Different Neuropathology Dependent On Viral Strain, Kevin K. Noguchi, Brant S. Swiney, Sasha L. Williams, Jacob N. Huffman, Katherine Lucas, Sophie H. Wang, Kayla M. Kapral, Amber Li, Krikor T. Dikranian

Open Access Publications

Zika virus (ZIKV) infection during pregnancy has been causally linked to a constellation of neurodevelopmental deformities in the fetus resulting in a disease termed congenital Zika syndrome (CZS). Here we detail how ZIKV infection produces extensive neuropathology in the developing mouse brain and spinal cord of both sexes. Surprisingly, neuropathology differs depending on viral strain with a French Polynesian isolate producing primarily excitotoxicity and a Brazilian isolate being almost exclusively apoptotic but occurring over a prolonged period that is more likely to produce severe hypoplasia. We also show exposure can produce a characteristic pattern of infection that mirrors neuropathology and …

Multicenter Evaluation Of The New Etest Gradient Diffusion Method For Piperacillin-Tazobactam Susceptibility Testing Of Enterobacterales, Pseudomonas Aeruginosa, And Acinetobacter Baumannii Complex, Sergio García-Fernández, Yohann Bala, Tom Armstrong, María García-Castillo, Carey-Ann D. Burnham, Meghan A Wallace, Dwight Hardy, Gilles Zambardi, Rafael Cantón

Open Access Publications

Piperacillin-tazobactam (P/T) is a β-lactam-β-lactamase inhibitor combination frequently used in the hospital setting. Etest is a gradient diffusion method that represents an alternative to broth microdilution (BMD) for performing antimicrobial susceptibility testing. We conducted a multicenter evaluation of the performance of the new P/T Etest compared to that of BMD following U.S. Food and Drug Administration (FDA) and International Standards Organization (ISO) standard ISO 20776-2 criteria using Clinical and Laboratory Standards Institute (CLSI)-FDA and European Committee on Antimicrobial Susceptibility Testing (EUCAST) interpretive breakpoints, respectively. A total of 977 isolates (775

The Impact Of Due Process And Disruptions On Emergency Medicine Education In The United States, Al'ai Alvarez, Anne Messman, Melissa Platt, Megan Healy, Elaine B Josephson, Shawn London, Douglas Char

Open Access Publications

INTRODUCTION: Academic Emergency Medicine (EM) departments are not immune to natural disasters, economic or political forces that disrupt a training program's operations and educational mission. Due process concerns are closely intertwined with the challenges that program disruption brings. Due process is a protection whereby an individual will not lose rights without access to a fair procedural process. Effects of natural disasters similarly create disruptions in the physical structure of training programs that at times have led to the displacement of faculty and trainees. Variation exists in the implementation of transitions amongst training sites across the country, and its impact on …

Are We Ready To Share Qualitative Research Data? Knowledge And Preparedness Among Qualitative Researchers, Irb Members, And Data Repository Curators, Jessica Mozersky, Heidi Walsh, Meredith Parsons, Tristan Mcintosh, Kari Baldwin, James M Dubois

Open Access Publications

Data sharing maximizes the value of data, which is time and resource intensive to collect. Major funding bodies in the United States (US), like the National Institutes of Health (NIH), require data sharing and researchers frequently share de-identified quantitative data. In contrast, qualitative data are rarely shared in the US but the increasing trend towards data sharing and open science suggest this may be required in future. Qualitative methods are often used to explore sensitive health topics raising unique ethical challenges regarding protecting confidentiality while maintaining enough contextual detail for secondary analyses. Here, we report findings from semi-structured in-depth interviews …

Atomistic Basis Of Opening And Conduction In Mammalian Inward Rectifier Potassium (Kir2.2) Channels, Eva-Maria Zangerl-Plessl, Sun-Joo Lee, Grigory Maksaev, Harald Bernsteiner, Feifei Ren, Peng Yuan, Anna Stary-Weinzinger, Colin G. Nichols

Open Access Publications

Potassium ion conduction through open potassium channels is essential to control of membrane potentials in all cells. To elucidate the open conformation and hence the mechanism of K+ ion conduction in the classic inward rectifier Kir2.2, we introduced a negative charge (G178D) at the crossing point of the inner helix bundle, the location of ligand-dependent gating. This "forced open" mutation generated channels that were active even in the complete absence of phosphatidylinositol-4,5-bisphosphate (PIP2), an otherwise essential ligand for Kir channel opening. Crystal structures were obtained at a resolution of 3.6 Å without PIP2 bound, or 2.8 Å in complex with …

Genome-Wide Association Study Of Opioid Cessation, Jiayi W Cox, Richard M Sherva, Kathryn L Lunetta, Emma C Johnson, Nicholas G Martin, Louisa Degenhardt, Arpana Agrawal, Elliot C Nelson, Henry R Kranzler, Joel Gelernter, Lindsay A Farrer

Open Access Publications

The United States is experiencing an epidemic of opioid use disorder (OUD) and overdose-related deaths. However, the genetic basis for the ability to discontinue opioid use has not been investigated. We performed a genome-wide association study (GWAS) of opioid cessation (defined as abstinence from illicit opioids for >1 year or <6 months before the interview date) in 1130 African American (AA) and 2919 European ancestry (EA) participants recruited for genetic studies of substance use disorders and who met lifetime Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) criteria for OUD. Association tests performed separately within each ethnic group were combined by meta-analysis with results obtained from the Comorbidity and Trauma Study. Although there were no genome-wide significant associations, we found suggestive associations with nine independent loci, including three which are biologically relevant: rs4740988 in

Design And Rationale Of The Hapin Study: A Multicountry Randomized Controlled Trial To Assess The Effect Of Liquefied Petroleum Gas Stove And Continuous Fuel Distribution, Thomas Clasen, Victor G. Davila-Roman, Et Al.

Open Access Publications

No abstract provided.

Antiretroviral Therapy Does Not Reduce Tuberculosis Reactivation In A Tuberculosis-Hiv Coinfection Model, Shashank R Ganatra, Shabaana A Khader, Et Al

Open Access Publications

While the advent of combination antiretroviral therapy (ART) has significantly improved survival, tuberculosis (TB) remains the leading cause of death in the HIV-infected population. We used Mycobacterium tuberculosis/simian immunodeficiency virus-coinfected (M. tuberculosis/SIV-coinfected) macaques to model M. tuberculosis/HIV coinfection and study the impact of ART on TB reactivation due to HIV infection. Although ART significantly reduced viral loads and increased CD4+ T cell counts in blood and bronchoalveolar lavage (BAL) samples, it did not reduce the relative risk of SIV-induced TB reactivation in ART-treated macaques in the early phase of treatment. CD4+ T cells were poorly restored specifically in the lung …

Tumor Infiltrating Neutrophils Are Enriched In Basal-Type Urothelial Bladder Cancer, Giulio Eugenio Mandelli, Francesco Missale, Debora Bresciani, Luisa Benerini Gatta, Patrizia Scapini, Elena Caveggion, Elisa Roca, Mattia Bugatti, Matilde Monti, Luca Cristinelli, Sandra Belotti, Claudio Simeone, Stefano Calza, Laura Melocchi, William Vermi

Open Access Publications

BACKGROUND: Urothelial bladder cancers (UBCs) are distinct in two main molecular subtypes, namely basal and luminal type. Subtypes are also diverse in term of immune contexture, providing a rationale for patient selection to immunotherapy.

METHODS: By digital microscopy analysis of a muscle-invasive BC (MIBC) cohort, we explored the density and clinical significance of CD66b

RESULTS: Basal type BC contained a significantly higher density of CD66b

CONCLUSIONS: TAN are recruited in basal type MIBC by pro-inflammatory CKs. This finding establishes a groundwork for a better understanding of the UBC immunity and its relevance.

Confidential Genetic Testing And Electronic Health Records: A Survey Of Current Practices Among Huntington Disease Testing Centers, Celeste C Eno, Stacey K Barton, Naghmeh Dorrani, Stephen D Cederbaum, Joshua L Deignan, Wayne W Grody

Open Access Publications

BACKGROUND: Clinical care teams providing presymptomatic genetic testing often employ advanced confidentiality practices for documentation and result storage. However, patient requests for increased confidentiality may be in conflict with the legal obligations of medical providers to document patient care activities in the electronic health record (EHR). Huntington disease presents a representative case study for investigating the ways centers currently balance the requirements of EHRs with the privacy demands of patients seeking presymptomatic genetic testing.

METHODS: We surveyed 23 HD centers (53% response rate) regarding their use of the EHR for presymptomatic HD testing.

RESULTS: Our survey revealed that clinical care …

Gene-By-Gene Interactions Associated With The Risk Of Conotruncal Heart Defects, Chen Lyu, Daniel M Webber, Stewart L Macleod, Charlotte A Hobbs, Ming Li, National Birth Defects Prevention Study

Open Access Publications

BACKGROUND: The development of conotruncal heart defects (CTDs) involves a complex relationship among genetic variants and maternal lifestyle factors. In this article, we focused on the interactions between 13 candidate genes within folate, homocysteine, and transsulfuration pathways for potential association with CTD risk.

METHODS: Targeted sequencing was used for 328 case-parental triads enrolled in the National Birth Defects Prevention Study (NBDPS). To evaluate the interaction of two genes, we applied a conditional logistic regression model for all possible SNP pairs within two respective genes by contrasting the affected infants with their pseudo-controls. The findings were replicated in an independent sample …

Targeting Cd47 As A Novel Immunotherapy For Multiple Myeloma, Jennifer Sun, Barbara Muz, Kinan Alhallak, Matea Markovic, Shannon Gurley, Zhe Wang, Nicole Guenthner, Katherine Wasden, Mark Fiala, Justin King, Daniel Kohnen, Noha Nabil Salama, Ravi Vij, Abdel Kareem Azab

Open Access Publications

Multiple myeloma (MM) remains to be incurable despite recent therapeutic advances. CD47, an immune checkpoint known as the "don't eat me" signal, is highly expressed on the surface of various cancers, allowing cancer cells to send inhibitory signals to macrophages and impede phagocytosis and immune response. In this study, we hypothesized that blocking the "don't eat me" signaling using an anti-CD47 monoclonal antibody will induce killing of MM cells. We report that CD47 expression was directly correlated with stage of the disease, from normal to MGUS to MM. Moreover, MM cells had remarkably higher CD47 expression than other cell populations …