Digital Commons Network^™

Quantitative Signal Properties From Standardized Mris Correlate With Multiple Sclerosis Disability, Matthew R Brier, Abraham Z Snyder, Aaron Tanenbaum, Richard A Rudick, Elizabeth Fisher, Stephen Jones, Joshua S Shimony, Anne H Cross, Tammie L S Benzinger, Robert T Naismith

Open Access Publications

OBJECTIVE: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice.

METHODS: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in …

Obese Endometrial Cancer Survivors' Perceptions Of Weight Loss Strategies And Characteristics That May Influence Participation In Behavioral Interventions, Elise M Wilson, Abigail S Zamorano, Jingxia Liu, David Morris, Andrea Leon, Lindsay M Kuroki, Premal H Thaker, Carolyn K Mccourt, Katherine C Fuh, Matthew A Powell, David G Mutch, Graham A Colditz, Andrea R Hagemann

Open Access Publications

We aimed to evaluate obese endometrial cancer (EC) survivors' perceptions of weight loss barriers and previously attempted weight loss methods and to identify characteristics that predicted willingness to enroll in a behavioral intervention trial. We administered a 27-question baseline survey at an academic institution to EC survivors with body mass index ≥ 30 kg/m

A Phase 2, Double-Blind, Randomized, Dose-Ranging Trial Of Reldesemtiv In Patients With Als, Jeremy M. Shefner, Timothy M. Miller, Et Al

Open Access Publications

No abstract provided.

Placental Sampling For Understanding Viral Infections - A Simplified Protocol For The Covid-19 Pandemic, Guilherme De Moraes Nobrega, José Paulo Siqueira Guida, Rodolfo Rosa Japecanga, Arthur Antolini-Tavares, Indira Mysorekar, Maria Laura Costa

Open Access Publications

OBJECTIVE:  The coronavirus disease 2019 (COVID-19) is a pandemic viral disease, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The impact of the disease among the obstetric population remains unclear, and the study of the placenta can provide valuable information. Adequate sampling of the placental tissue can help characterize the pathways of viral infections.

METHODS:  A protocol of placental sampling is proposed, aiming at guaranteeing representativity of the placenta and describing the adequate conservation of samples and their integrity for future analysis. The protocol is presented in its complete and simplified versions, allowing its implementation in different complexity settings. …

A Target-Agnostic Screen Identifies Approved Drugs To Stabilize The Endoplasmic Reticulum-Resident Proteome, Mark J Henderson, Fumihiko Urano, Et Al

Open Access Publications

Endoplasmic reticulum (ER) dysregulation is associated with pathologies including neurodegenerative, muscular, and diabetic conditions. Depletion of ER calcium can lead to the loss of resident proteins in a process termed exodosis. To identify compounds that attenuate the redistribution of ER proteins under pathological conditions, we performed a quantitative high-throughput screen using the Gaussia luciferase (GLuc)-secreted ER calcium modulated protein (SERCaMP) assay, which monitors secretion of ER-resident proteins triggered by calcium depletion. We identify several clinically used drugs, including bromocriptine, and further characterize them using assays to measure effects on ER calcium, ER stress, and ER exodosis. Bromocriptine elicits protective effects …

Phenotype Of Peripheral Nk Cells In Latent, Active, And Meningeal Tuberculosis, José Alberto Choreño-Parra, Shabaana A. Khader, Et Al

Open Access Publications

No abstract provided.

Integrating Neuroimaging Biomarkers Into The Multicentre, High-Dose Erythropoietin For Asphyxia And Encephalopathy (Heal) Trial: Rationale, Protocol And Harmonisation, Jessica L Wisnowski, Robert C Mckinstry, Et Al

Open Access Publications

INTRODUCTION: MRI and MR spectroscopy (MRS) provide early biomarkers of brain injury and treatment response in neonates with hypoxic-ischaemic encephalopathy). Still, there are challenges to incorporating neuroimaging biomarkers into multisite randomised controlled trials. In this paper, we provide the rationale for incorporating MRI and MRS biomarkers into the multisite, phase III high-dose erythropoietin for asphyxia and encephalopathy (HEAL) Trial, the MRI/S protocol and describe the strategies used for harmonisation across multiple MRI platforms.

METHODS AND ANALYSIS: Neonates with moderate or severe encephalopathy enrolled in the multisite HEAL trial undergo MRI and MRS between 96 and 144 hours of age using …

A Microbiota-Directed Food Intervention For Undernourished Children, Robert Y Chen, Matthew C Hibberd, Arjun S Raman, Daniel Webber, Cyrus Zhou, Vinaik Sundaresan, Kazi Ahsan, Martin F Meier, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

BACKGROUND: More than 30 million children worldwide have moderate acute malnutrition. Current treatments have limited effectiveness, and much remains unknown about the pathogenesis of this condition. Children with moderate acute malnutrition have perturbed development of their gut microbiota.

METHODS: In this study, we provided a microbiota-directed complementary food prototype (MDCF-2) or a ready-to-use supplementary food (RUSF) to 123 slum-dwelling Bangladeshi children with moderate acute malnutrition between the ages of 12 months and 18 months. The supplementation was given twice daily for 3 months, followed by 1 month of monitoring. We obtained weight-for-length, weight-for-age, and length-for-age z scores and mid-upper-arm circumference …

Evolution Of Genetic Networks For Human Creativity, I Zwir, C Del-Val, C R Cloninger, Et Al

Open Access Publications

The genetic basis for the emergence of creativity in modern humans remains a mystery despite sequencing the genomes of chimpanzees and Neanderthals, our closest hominid relatives. Data-driven methods allowed us to uncover networks of genes distinguishing the three major systems of modern human personality and adaptability: emotional reactivity, self-control, and self-awareness. Now we have identified which of these genes are present in chimpanzees and Neanderthals. We replicated our findings in separate analyses of three high-coverage genomes of Neanderthals. We found that Neanderthals had nearly the same genes for emotional reactivity as chimpanzees, and they were intermediate between modern humans and …

Psychosocial Syndemics And Multimorbidity In Patients With Heart Failure, Kenneth E Freedland, Judith A Skala, Robert M Carney, Brian C Steinmeyer, Michael W Rich

Open Access Publications

Heart failure (HF) is a common cause of hospitalization and mortality in older adults. HF is almost always embedded within a larger pattern of multimorbidity, yet many studies exclude patients with complex psychiatric and medical comorbidities or cognitive impairment. This has left significant gaps in research on the problems and treatment of patients with HF. In addition, HF is only one of multiple challenges facing patients with multimorbidity, stressful socioeconomic circumstances, and psychosocial problems. The purpose of this study is to identify combinations of comorbidities and health disparities that may affect HF outcomes and require different mixtures of medical, psychological, …

Evidence For Dissociable Cognitive And Neural Pathways From Poverty Versus Maltreatment To Deficits In Emotion Regulation, Nourhan M Elsayed, Brent I Rappaport, Joan L. Luby, Deanna M Barch

Open Access Publications

Poverty and threat exposure (TE) predict deficits in emotion regulation (ER). Effective cognitive ER (i.e., reappraisal) may be supported by: (1) cognitive processes implicated in generating and implementing cognitive reappraisal, supported by activation in brain regions involved in cognitive control (e.g., frontal, insular, and parietal cortices) and (2) emotion processing and reactivity, involving identification, encoding, and maintenance of emotional states and related variation in brain activity of regions involved in emotional reactivity (i.e., amygdala). Poverty is associated with deficits in cognitive control, and TE with alterations in emotion processing and reactivity. Our goal was to identify dissociable emotional and cognitive …

Shock In The Setting Of Diamond-Blackfan Anemia Relapse, Metri Haddaden, Samir Husami, Modar Alom, Yifan Pang, Zaid Imam, Daniel Keena

Open Access Publications

Adult intensivists have increasing exposure to individuals with congenital diseases surviving into adulthood. Solid knowledge bases and early recognition of the possible sequelae of congenital disorders are crucial in caring for these patients. We present a challenging case of shock and relapse of Diamond-Blackfan anemia in a 42-year-old man lost to follow-up for 18 years and highlighted the importance of healthcare transitions into adulthood and the challenges faced by health care systems to develop new strategies successfully transitioning complex pediatric patients to adult care.

Membrane Transporter Dimerization Driven By Differential Lipid Solvation Energetics Of Dissociated And Associated States, Rahul Chadda, Nathan Bernhardt, Elizabeth G. Kelley, Susana C.M. Teixeira, Kacie Griffith, Alejandro Gil-Ley, Tuğba N. Öztürk, Lauren E. Hughes, Ana Forsythe, Venkatramanan Krishnamani, José D. Faraldo-Gómez, Janice L. Robertson

Open Access Publications

Over two-thirds of integral membrane proteins of known structure assemble into oligomers. Yet, the forces that drive the association of these proteins remain to be delineated, as the lipid bilayer is a solvent environment that is both structurally and chemically complex. In this study, we reveal how the lipid solvent defines the dimerization equilibrium of the CLC-ec1 Cl

Genomic Context Differs Between Human Dilated Cardiomyopathy And Hypertrophic Cardiomyopathy, Megan J Puckelwartz, Gerald W Dorn Ii, Et Al

Open Access Publications

Background Inherited cardiomyopathies display variable penetrance and expression, and a component of phenotypic variation is genetically determined. To evaluate the genetic contribution to this variable expression, we compared protein coding variation in the genomes of those with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). Methods and Results Nonsynonymous single-nucleotide variants (nsSNVs) were ascertained using whole genome sequencing from familial cases of HCM (n=56) or DCM (n=70) and correlated with echocardiographic information. Focusing on nsSNVs in 102 genes linked to inherited cardiomyopathies, we correlated the number of nsSNVs per person with left ventricular measurements. Principal component analysis and generalized linear models …

Sex And Race-Ethnic Disparities In Door-To-Ct Time In Acute Ischemic Stroke: The Florida Stroke Registry, Sai P Polineni, Enmanuel J Perez, Kefeng Wang, Carolina M Gutierrez, Jeffrey Walker, Dianne Foster, Chuanhui Dong, Negar Asdaghi, Jose G Romano, Ralph L Sacco, Tatjana Rundek, Florida Stroke Registry

Open Access Publications

Background Less than 40% of acute stroke patients have computed tomography (CT) imaging performed within 25 minutes of hospital arrival. We aimed to examine the race-ethnic and sex differences in door-to-CT (DTCT) ≤25 minutes in the FSR (Florida Stroke Registry). Methods and Results Data were collected from 2010 to 2018 for 63 265 patients with acute ischemic stroke from the FSR and secondary analysis was performed on 15 877 patients with intravenous tissue plasminogen activator-treated ischemic stroke. Generalized estimating equation models were used to determine predictors of DTCT ≤25. DTCT ≤25 was achieved in 56% of cases of suspected acute …

Adversity Is Linked With Decreased Parent-Child Behavioral And Neural Synchrony, Caroline P Hoyniak, Laura E Quiñones-Camacho, M Catalina Camacho, Jenna H Chin, Elizabeth M Williams, Lauren S Wakschlag, Susan B Perlman

Open Access Publications

Parent-child synchrony-parent-child interaction patterns characterized by contingent social responding, mutual responsivity, and co-regulation-has been robustly associated with adaptive child outcomes. Synchrony has been investigated in both behavioral and biological frameworks. While it has been demonstrated that adversity can influence behavioral parent-child synchrony, the neural mechanisms by which this disruption occurs are understudied. The current study examined the association between adversity, parent-child behavioral synchrony, and parent-child neural synchrony across lateral prefrontal cortical regions using functional near-infrared spectroscopy hyperscanning during a parent-child interaction task that included a mild stress induction followed by a recovery period. Participants included 115 children (ages 4-5) and …

Ambient Fine Particulate Matter Air Pollution And Risk Of Weight Gain And Obesity In United States Veterans: An Observational Cohort Study, Benjamin Bowe, Andrew K. Gibson, Yan Xie, Yan Yan, Aaron Van Donkelaar, Randall V. Martin, Ziyad Al-Aly

Open Access Publications

BACKGROUND: Experimental evidence and studies of children and adolescents suggest that ambient fine particulate matter [particulate matter

OBJECTIVES: Our goal was to characterize the association between

METHODS: We followed 3,902,440 U.S. Veterans from 2010 to 2018 (median 8.1 y, interquartile range: 7.3-8.4) and assigned time-updated

RESULTS: A

DISCUSSION:

A Clinician’S Guide For Navigating The World Of Attention Deficit Hyperactivity Disorder Medications, Gregory W. Mattingly, Joel Young

Open Access Publications

No abstract provided.

Variant Recurrence Confirms The Existence Of A Fbxo31-Related Spastic-Dystonic Cerebral Palsy Syndrome, Ivana Dzinovic, Matej Škorvánek, Petra Pavelekova, Chen Zhao, Boris Keren, Sandra Whalen, Somayeh Bakhtiari, Sheng Chih Jin, Michael C Kruer, Robert Jech, Juliane Winkelmann, Michael Zech

Open Access Publications

The role of genetics in the causation of cerebral palsy has become the focus of many studies aiming to unravel the heterogeneous etiology behind this frequent neurodevelopmental disorder. A recent paper reported two unrelated children with a clinical diagnosis of cerebral palsy, who carried the same de novo c.1000G > A (p.Asp334Asn) variant in FBXO31, encoding a widely studied tumor suppressor not previously implicated in monogenic disease. We now identified a third individual with the recurrent FBXO31 de novo missense variant, featuring a spastic-dystonic phenotype. Our data confirm a link between variant FBXO31 and an autosomal dominant neurodevelopmental disorder characterized by …

Idiopathic Non-Cirrhotic Portal Hypertension And Porto-Sinusoidal Vascular Disease: Review Of Current Data, Michel Kmeid, Xiuli Liu, Samuel Ballentine, Hwajeong Lee

Open Access Publications

Idiopathic non-cirrhotic portal hypertension (INCPH) is a clinicopathologic disease entity characterized by the presence of clinical signs and symptoms of portal hypertension (PH) in the absence of liver cirrhosis or known risk factors accountable for PH. Multiple hematologic, immune-related, infectious, hereditary and metabolic risk factors have been associated with this disorder. Still, the exact etiopathogenesis is largely unknown. The recently proposed porto-sinusoidal vascular disease (PSVD) scheme broadens the spectrum of the disease by also including patients without clinical PH who are found to have similar histopathologic findings on core liver biopsies. Three histomorphologic lesions have been identified as specific for …

An Open-Source Device For Measuring Food Intake And Operant Behavior In Rodent Home-Cages, Bridget A. Matikainen-Ankney, Thomas Earnest, Eric Casey, Justin G. Wang, Alex A. Legaria, Kia M. Barclay, Makenzie R. Norris, Yu-Hsuan Chang, Eric Lin, Sineadh M. Conway, Ream Al-Hasani, Jordan G. Mccall, Meaghan C. Creed, Alexxai V. Kravitz, Et Al

Open Access Publications

Feeding is critical for survival, and disruption in the mechanisms that govern food intake underlies disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: the Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of …

Cryo-Em Structure Of The Rous Sarcoma Virus Octameric Cleaved Synaptic Complex Intasome, Krishan K Pandey, Sibes Bera, Ke Shi, Michael J Rau, Amarachi V Oleru, James A J Fitzpatrick, Alan N Engelman, Hideki Aihara, Duane P Grandgenett

Open Access Publications

Despite conserved catalytic integration mechanisms, retroviral intasomes composed of integrase (IN) and viral DNA possess diverse structures with variable numbers of IN subunits. To investigate intasome assembly mechanisms, we employed the Rous sarcoma virus (RSV) IN dimer that assembles a precursor tetrameric structure in transit to the mature octameric intasome. We determined the structure of RSV octameric intasome stabilized by a HIV-1 IN strand transfer inhibitor using single particle cryo-electron microscopy. The structure revealed significant flexibility of the two non-catalytic distal IN dimers along with previously unrecognized movement of the conserved intasome core, suggesting ordered conformational transitions between intermediates that …

Parabrachial Opioidergic Projections To Preoptic Hypothalamus Mediate Behavioral And Physiological Thermal Defenses, Aaron J. Norris, Jordan R. Shaker, Aaron L. Cone, Imeh B. Ndiokho, Michael R. Bruchas

Open Access Publications

Maintaining stable body temperature through environmental thermal stressors requires detection of temperature changes, relay of information, and coordination of physiological and behavioral responses. Studies have implicated areas in the preoptic area of the hypothalamus (POA) and the parabrachial nucleus (PBN) as nodes in the thermosensory neural circuitry and indicate that the opioid system within the POA is vital in regulating body temperature. In the present study we identify neurons projecting to the POA from PBN expressing the opioid peptides dynorphin and enkephalin. Using mouse models, we determine that warm-activated PBN neuronal populations overlap with both prodynorphin (Pdyn) and proenkephalin (Penk) …

Coding Of Sexual Assault By Emergency Physicians: A Nationally Representative Study, Vithya Murugan, Katherine J Holzer, Michael G Vaughn, Jason T Carbone, Dylan B Jackson, Cindy C Bitter

Open Access Publications

INTRODUCTION: Sexual assault is a public health problem that affects many Americans and has multiple long-lasting effects on victims. Medical evaluation after sexual assault frequently occurs in the emergency department, and documentation of the visit plays a significant role in decisions regarding prosecution and outcomes of legal cases against perpetrators. The American College of Emergency Physicians recommends coding such visits as sexual assault rather than adding modifiers such as "alleged."

METHODS: This study reviews factors associated with coding of visits as sexual assault compared to suspected sexual assault using the 2016 Nationwide Emergency Department Sample.

RESULTS: Younger age, female gender, …

The Novel Use Of A Commercially Available Video-Conference Platform To Facilitate Multidisciplinary Target Volume Review And Delineation For Skull-Base Radiation Therapy During The Coronavirus Disease 2019 Pandemic, Amit Roy, Neal Andruska, Hilary L P Orlowski, Patrik Pipkorn, Mackenzie D Daly

Open Access Publications

Multidisciplinary involvement in radiation therapy (RT) treatment planning is currently underused. A radiation oncologist sought input for generating target contours from a neuro-radiologist (NR) and otolaryngologist (OL) for 3 patients requiring skull-base RT during the coronavirus disease 2019 pandemic. A Health Insurance Portability and Accountability Act compliant virtual meeting between the radiation oncologist, NR, and OL was arranged. Involvement of the OL and NR led to significant changes in the clinical target volume for all patients. Our experience highlights the feasibility of using commercially available video-conference platforms for multidisciplinary target volume delineation for complex RT cases. Further applications include interdisciplinary …

Bidirectional Regulation Of Glial Potassium Buffering - Glioprotection Versus Neuroprotection, Hailun Li, Lorenzo Lones, Aaron Diantonio

Open Access Publications

Glia modulate neuronal excitability and seizure sensitivity by maintaining potassium and water homeostasis. A salt inducible kinase 3 (SIK3)-regulated gene expression program controls the glial capacity to buffer K

Norovirus Evolution In Immunodeficient Mice Reveals Potentiated Pathogenicity Via A Single Nucleotide Change In The Viral Capsid, Forrest C Walker, Ebrahim Hassan, Stefan T. Peterson, Rachel Rodgers, Lawrence A. Schriefer, Cassandra E. Thompson, Yuhao Li, Gowri Kalugotla, Carla Blum-Johnston, Dylan Lawrence, Broc T. Mccune, Vincent R. Graziano, Larissa Lushniak, Sanghyun Lee, Alexa N. Roth, Stephanie M. Karst, Timothy J. Nice, Jonathan J. Miner, Craig B. Wilen, Megan T. Baldridge

Open Access Publications

Interferons (IFNs) are key controllers of viral replication, with intact IFN responses suppressing virus growth and spread. Using the murine norovirus (MNoV) system, we show that IFNs exert selective pressure to limit the pathogenic evolutionary potential of this enteric virus. In animals lacking type I IFN signaling, the nonlethal MNoV strain CR6 rapidly acquired enhanced virulence via conversion of a single nucleotide. This nucleotide change resulted in amino acid substitution F514I in the viral capsid, which led to >10,000-fold higher replication in systemic organs including the brain. Pathogenicity was mediated by enhanced recruitment and infection of intestinal myeloid cells and …

Response-Adapted Therapy With Infusional Epoch Chemotherapy Plus Rituximab In Hiv-Associated, B-Cell Non-Hodgkin's Lymphoma, Joseph A. Sparano, Jeannette Y. Lee, Lawrence D. Kaplan, Juan Carlos Ramos, Richard F. Ambinder, William Wachsman, David Aboulafia, Ariela Noy, David H. Henry, Lee Ratner, Ethel Cesarman, Amy Chadburn, Ronald Mitsuyasu, Aids Malignancy Consortium

Open Access Publications

Four cycles of rituximab plus CHOP chemotherapy is as effective as 6 cycles in low-risk diffuse large B-cell lymphoma (DLBCL). Here we report a post-hoc analysis of a prospective clinical trial in patients with HIV-associated DLBCL and high-grade lymphoma treated with 4-6 cycles of EPOCH plus rituximab based a response-adapted treatment strategy. 106 evaluable patients with HIV-associated DLBCL or high-grade CD20-positive non-Hodgkin's lymphoma were randomized to receive rituximab (375 mg/m2) given either concurrently prior to each infusional EPOCH cycle, or sequentially (weekly for 6 weeks) following completion of EPOCH. EPOCH consisted of a 96-hour IV infusion of etoposide, doxorubicin, and …

Not All Lymphoid Aggregates In Chronic Lymphocytic Leukemia (Cll) Patients Are Due To Cll!, Lily Mahapatra, Tianjiao Wang, Yi-Shan Lee, John L Frater

Open Access Publications

Infection is a common cause of morbidity and mortality in chronic lymphocytic leukemia and should be considered when examining bone marrow specimens to identify a potentially treatable pathogen.

Increased Functional Coupling Between Vta And Hippocampus During Rest In First-Episode Psychosis, David F Gregory, Jane M Rothrock, Maria Jalbrzikowski, William Foran, David F Montez, Beatriz Luna, Vishnu P Murty

Open Access Publications

Animal models suggest that interactions between the hippocampus and ventral tegmental area (VTA) underlie the onset and etiology of psychosis. While a large body of research has separately characterized alterations in hippocampal and VTA function in psychosis, alterations across the VTA and hippocampus have not been characterized in first-episode psychosis (FEP). As the phase of psychosis most proximal to conversion, studies specifically focused on FEP are valuable to psychosis research. Here, we characterize alterations in VTA-hippocampal interactions across male and female human participants experiencing their first episode of psychosis using resting state functional magnetic resonance imaging (rsfMRI). In comparison to …