Digital Commons Network^™

Baseline Microglial Activation Correlates With Brain Amyloidosis And Longitudinal Cognitive Decline In Alzheimer Disease, Qing Wang, Gengsheng Chen, Suzanne E Schindler, Jon Christensen, Nicole S Mckay, Jingxia Liu, Sicheng Wang, Zhexian Sun, Jason Hassenstab, Shaney Flores, Russ Hornbeck, Lisa Cash, Carlos Cruchaga, Anne M Fagan, Zhude Tu, John C Morris, Yong Wang, Tammie L S Benzinger, Et Al

Open Access Publications

BACKGROUND AND OBJECTIVES: This study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline.

METHODS: Twenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of …

Three-Dimensional Quantification Of Cam Resection Using Mri Bone Models: A Comparison Of 2 Techniques, Thomas D Alter, Derrick M Knapik, Martina Guidetti, Alejandro Espinoza, Jorge Chahla, Shane J Nho, Philip Malloy

Open Access Publications

Background: The current clinical standard for the evaluation of cam deformity in femoroacetabular impingement syndrome is based on radiographic measurements, which limit the ability to quantify the complex 3-dimensional (3D) morphology of the proximal femur.

Purpose: To compare magnetic resonance imaging (MRI)-based metrics for the quantification of cam resection as derived using a best-fit sphere alpha angle (BFS-AA) method and using 3D preoperative-postoperative surface model subtraction (PP-SMS).

Study Design: Descriptive laboratory study.

Methods: Seven cadaveric hemipelvises underwent 1.5-T MRI before and after arthroscopic femoral osteochondroplasty, and 3D bone models of the proximal femur were reconstructed from the MRI scans. The …

Effect Of Active And Passive Function Of The Posterosuperior Rotator Cuff On Compensatory Muscle Loads In The Shoulder, Philipp Moroder, Aaron Chamberlain, Stefan M Gabriel, Marc C Jacofsky, Mehmet Z Sengun, David B Spenciner, John M Tokish, Lucca Lacheta

Open Access Publications

Background: Irreparable posterosuperior rotator cuff (PSRC) tears have been shown to result in shoulder pain and loss of function.

Purpose/Hypothesis: The purpose of this study was to determine the effect of the loss of active or passive function of the PSRC on compensatory muscle loads in the deltoid and the remaining rotator cuff. It was hypothesized that both deactivation and resection of the PSRC would result in load increases in the remaining muscles and that resection of the PSRC would result in even higher required compensatory forces than would mere deactivation.

Study Design: Controlled laboratory study.

Methods: A total of …

Shared And Unique Brain Network Features Predict Cognitive, Personality, And Mental Health Scores In The Abcd Study, Jianzhong Chen, Angela Tam, Valeria Kebets, Csaba Orban, Leon Qi Rong Ooi, Christopher L Asplund, Scott Marek, Nico U F Dosenbach, Simon B Eickhoff, Danilo Bzdok, Avram J Holmes, B T Thomas Yeo

Open Access Publications

How individual differences in brain network organization track behavioral variability is a fundamental question in systems neuroscience. Recent work suggests that resting-state and task-state functional connectivity can predict specific traits at the individual level. However, most studies focus on single behavioral traits, thus not capturing broader relationships across behaviors. In a large sample of 1858 typically developing children from the Adolescent Brain Cognitive Development (ABCD) study, we show that predictive network features are distinct across the domains of cognitive performance, personality scores and mental health assessments. On the other hand, traits within each behavioral domain are predicted by similar network …

Cisplatin Resistance Can Be Curtailed By Blunting Bnip3-Mediated Mitochondrial Autophagy, Caterina Vianello, Gerald W Dorn 2nd, Et Al

Open Access Publications

Cisplatin (CDDP) is commonly used to treat a multitude of tumors including sarcomas, ovarian and cervical cancers. Despite recent investigations allowed to improve chemotherapy effectiveness, the molecular mechanisms underlying the development of CDDP resistance remain a major goal in cancer research. Here, we show that mitochondrial morphology and autophagy are altered in different CDDP resistant cancer cell lines. In CDDP resistant osteosarcoma and ovarian carcinoma, mitochondria are fragmented and closely juxtaposed to the endoplasmic reticulum; rates of mitophagy are also increased. Specifically, levels of the mitophagy receptor BNIP3 are higher both in resistant cells and in ovarian cancer patient samples …

Persistent Methicillin-Susceptible Bacteremia Rapidly Cleared With Cefazolin And Ertapenem Combination Therapy In A Patient With Covid-19, Dan Ilges, Gayathri Krishnan, Elvin Geng

Open Access Publications

Methicillin-susceptible

Naturalistic Driving Measures Of Route Selection Associate With Resting State Networks In Older Adults, Julie K Wisch, Catherine M Roe, Ganesh M Babulal, Nicholas Metcalf, Ann M Johnson, Samantha Murphy, Jamie Hicks, Jason M Doherty, John C Morris, Beau M Ances

Open Access Publications

Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities.

Clinical Classification Of Symptomatic Heterotopic Pancreas Of The Stomach And Duodenum: A Case Series And Systematic Literature Review, Michael T. Lecompte, Brandon Mason, Keenan J. Robbins, Matoya Yano, Deyali Chatterjee, Ryan C. Fields, Steven M. Strasberg, William G. Hawkins

Open Access Publications

No abstract provided.

Machine Learning-Based Scoring Models To Predict Hematopoietic Stem Cell Mobilization In Allogeneic Donors, Jingyu Xiang, Min Shi, Mark A Fiala, Feng Gao, Michael P Rettig, Geoffrey L Uy, Mark A Schroeder, Katherine N Weilbaecher, Keith E Stockerl-Goldstein, Shamim Mollah, John F Dipersio

Open Access Publications

Mobilized peripheral blood has become the primary source of hematopoietic stem cells for both autologous and allogeneic stem cell transplantation. Granulocyte colony-stimulating factor (G-CSF) is currently the standard agent used in the allogeneic setting. Despite the high mobilization efficacy in most donors, G-CSF requires 4-5 days of daily administration, and a small percentage of the donors fail to mobilize an optimal number of stem cells necessary for a safe allogeneic stem cell transplant. In this study, we retrospectively reviewed 1361 related allogeneic donors who underwent stem cell mobilization at Washington University. We compared the standard mobilization agent G-CSF with five …

Opportunities For Penicillin Allergy Evaluation In Dental Clinics, Amanda Vivo, Michael J. Durkin, Iboula Kale, Taylor Boyer, Margaret A. Fitzpatrick, Charlesnika T. Evans, Marianne M. Jurasic, Gretchen Gibson, Katie J. Suda

Open Access Publications

No abstract provided.

Mendelian Randomization Supports Bidirectional Causality Between Telomere Length And Clonal Hematopoiesis Of Indeterminate Potential, Tetsushi Nakao, C Charles Gu, Lisa De Las Fuentes, Et Al

Open Access Publications

Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD.

Connectomic Profiling And Vagus Nerve Stimulation Outcomes Study (Connectivos): A Prospective Observational Protocol To Identify Biomarkers Of Seizure Response In Children And Youth, Lauren Siegel, Matthew D Smyth, Et Al

Open Access Publications

INTRODUCTION: Vagus nerve stimulation (VNS) is a neuromodulation therapy that can reduce the seizure burden of children with medically intractable epilepsy. Despite the widespread use of VNS to treat epilepsy, there are currently no means to preoperatively identify patients who will benefit from treatment. The objective of the present study is to determine clinical and neural network-based correlates of treatment outcome to better identify candidates for VNS therapy.

METHODS AND ANALYSIS: In this multi-institutional North American study, children undergoing VNS and their caregivers will be prospectively recruited. All patients will have documentation of clinical history, physical and neurological examination and …

Frequency Of The Dopamine Receptor D3 (Rs6280) Vs. Opioid Receptor Μ1 (Rs1799971) Polymorphic Risk Alleles In Patients With Opioid Use Disorder: A Preponderance Of Dopaminergic Mechanisms?, Marjorie C Gondré-Lewis, Igor Elman, Tanya Alim, Edwin Chapman, Beverlyn Settles-Reaves, Carine Galvao, Mark S Gold, David Baron, Shan Kazmi, Eliot Gardner, Ashim Gupta, Catherine Dennen, Kenneth Blum

Open Access Publications

While opioids are a powerful class of drugs that inhibit transmission of pain signals, their use is tarnished by the current epidemic of opioid use disorder (OUD) and overdose deaths. Notwithstanding published reports, there remain gaps in our knowledge of opioid receptor mechanisms and their role in opioid seeking behavior. Thus, novel insights into molecular, neurogenetic and neuropharmacological bases of OUD are needed. We propose that an addictive endophenotype may not be entirely specific to the drug of choice but rather may be generalizable to altered brain reward circuits impacting net mesocorticolimbic dopamine release. We suggest that genetic or epigenetic …

Brain Charts For The Human Lifespan, R A I Bethlehem, J Seidlitz, S R White, C Ortinau, C D Smyser, Et Al

Open Access Publications

No abstract provided.

A Benzodiazepine Activator Locks K V 7.1 Channels Open By Electro-Mechanical Uncoupling, Julian A Schreiber, Melina Möller, Mark Zaydman, Lu Zhao, Zachary Beller, Sebastian Becker, Nadine Ritter, Panpan Hou, Jingyi Shi, Jon Silva, Eva Wrobel, Nathalie Strutz-Seebohm, Niels Decher, Nicole Schmitt, Sven G Meuth, Martina Düfer, Bernhard Wünsch, Jianmin Cui, Guiscard Seebohm

Open Access Publications

Loss-of-function mutations in K

Delphi Consensus Recommendation For Optimization Of Pulmonary Hypertension Therapy Focusing On Switching From A Phosphodiesterase 5 Inhibitor To Riociguat, Franck Rahaghi, Vijay Balasubramanian, Robert Bourge, Charles Burger, Murali Chakinala, Michael Eggert, Jean Elwing, Jeremy Feldman, Christopher King, James Klinger, Stephen Mathai, John Mcconnell, Harold Palevsky, Ricardo Restrepo-Jaramillo, Zeenat Safdar, Jeffrey Sager, Namita Sood, Roxana Sulica, R. James White, Nicholas Hill

Open Access Publications

No abstract provided.

Vestibular Rehabilitation For Peripheral Vestibular Hypofunction: An Updated Clinical Practice Guideline From The Academy Of Neurologic Physical Therapy Of The American Physical Therapy Association, Courtney D Hall, Joel A Goebel, Et Al

Open Access Publications

BACKGROUND: Uncompensated vestibular hypofunction can result in symptoms of dizziness, imbalance, and/or oscillopsia, gaze and gait instability, and impaired navigation and spatial orientation; thus, may negatively impact an individual's quality of life, ability to perform activities of daily living, drive, and work. It is estimated that one-third of adults in the United States have vestibular dysfunction and the incidence increases with age. There is strong evidence supporting vestibular physical therapy for reducing symptoms, improving gaze and postural stability, and improving function in individuals with vestibular hypofunction. The purpose of this revised clinical practice guideline is to improve quality of care …

Reduced Neural Activity But Improved Coding In Rodent Higher-Order Visual Cortex During Locomotion, Amelia J Christensen, Jonathan W Pillow

Open Access Publications

Running profoundly alters stimulus-response properties in mouse primary visual cortex (V1), but its effect in higher-order visual cortex is under-explored. Here we systematically investigate how visual responses vary with locomotive state across six visual areas and three cortical layers using a massive dataset from the Allen Brain Institute. Although previous work has shown running speed to be positively correlated with neural activity in V1, here we show that the sign of correlations between speed and neural activity varies across extra-striate cortex, and is even negative in anterior extra-striate cortex. Nevertheless, across all visual cortices, neural responses can be decoded more …

Continuous Care Intervention With Carbohydrate Restriction Improves Physical Function Of The Knees Among Patients With Type 2 Diabetes: A Non-Randomized Study, Kade S Lyman, Shaminie J Athinarayanan, Amy L Mckenzie, Camy L Pearson, Rebecca N Adams, Sarah J Hallberg, James P Mccarter, Jeff S Volek, Stephen D Phinney, John P Andrawis

Open Access Publications

BACKGROUND: In a previous study, we assessed a novel, remotely monitored carbohydrate restricted diet regimen including nutritional ketosis in patients with type 2 diabetes and reported significant improvements in weight, glycemic control, abdominal fat and inflammation from baseline to 2 years. Knee outcome measures were collected as a secondary outcome in the trial. This study aims to assess the effect of this intervention on knee functional scores and to identify if changes in weight, central abdominal fat (CAF), glycemic status and high sensitivity C-reactive protein (hsCRP) were associated with its improvement.

METHODS: This prospective analysis included continuous care intervention (CCI, …

The Effects Of The Combination Of Mesenchymal Stromal Cells And Nanofiber-Hydrogel Composite On Repair Of The Contused Spinal Cord, Agnes E Haggerty, Ines Maldonado-Lasunción, Yohshiro Nitobe, Kentaro Yamane, Megan M Marlow, Hua You, Chi Zhang, Brian Cho, Xiaowei Li, Sashank Reddy, Hai-Quan Mao, Martin Oudega

Open Access Publications

A bone marrow-derived mesenchymal stromal cell (MSC) transplant and a bioengineered nanofiber-hydrogel composite (NHC) have been shown to stimulate nervous tissue repair in the contused spinal cord in rodent models. Here, these two modalities were combined to assess their repair effects in the contused spinal cord in adult rats. Cohorts of contused rats were treated with MSC in NHC (MSC-NHC), MSC in phosphate-buffered saline (MSC-PBS), NHC, or PBS injected into the contusion site at 3 days post-injury. One week after injury, there were significantly fewer CD68+ cells in the contusion with MSC-NHC and NHC, but not MSC-PBS. The reduction in …

Monospecific And Bispecific Monoclonal Sars-Cov-2 Neutralizing Antibodies That Maintain Potency Against B.1.617, Lei Peng, Yingxia Hu, Madeleine C Mankowski, Ping Ren, Rita E Chen, Michael S Diamond, Et Al

Open Access Publications

COVID-19 pathogen SARS-CoV-2 has infected hundreds of millions and caused over 5 million deaths to date. Although multiple vaccines are available, breakthrough infections occur especially by emerging variants. Effective therapeutic options such as monoclonal antibodies (mAbs) are still critical. Here, we report the development, cryo-EM structures, and functional analyses of mAbs that potently neutralize SARS-CoV-2 variants of concern. By high-throughput single cell sequencing of B cells from spike receptor binding domain (RBD) immunized animals, we identify two highly potent SARS-CoV-2 neutralizing mAb clones that have single-digit nanomolar affinity and low-picomolar avidity, and generate a bispecific antibody. Lead antibodies show strong …

Structural And Molecular Rationale For The Diversification Of Resistance Mediated By The Antibiotic_Nat Family, Peter J Stogios, Emily Bordeleau, Zhiyu Xu, Tatiana Skarina, Elena Evdokimova, Sommer Chou, Luke Diorio-Toth, Alaric W D'Souza, Sanket Patel, Gautam Dantas, Gerard D Wright, Alexei Savchenko

Open Access Publications

The environmental microbiome harbors a vast repertoire of antibiotic resistance genes (ARGs) which can serve as evolutionary predecessors for ARGs found in pathogenic bacteria, or can be directly mobilized to pathogens in the presence of selection pressures. Thus, ARGs from benign environmental bacteria are an important resource for understanding clinically relevant resistance. Here, we conduct a comprehensive functional analysis of the Antibiotic_NAT family of aminoglycoside acetyltransferases. We determined a pan-family antibiogram of 21 Antibiotic_NAT enzymes, including 8 derived from clinical isolates and 13 from environmental metagenomic samples. We find that environment-derived representatives confer high-level, broad-spectrum resistance, including against the atypical …

Therapeutic Drug Monitoring In Perianal Fistulizing Crohn's Disease, Mir Zulqarnain, Parakkal Deepak, Andres J Yarur

Open Access Publications

Perianal fistulas are a common complication of Crohn's disease (CD) that has, historically, been challenging to manage. Despite the strong available evidence that anti-tumor necrosis factor (anti-TNF) agents are useful in the treatment of perianal fistulizing Crohn's disease (PFCD), a significant number of these patients do not respond to therapy. The use of therapeutic drug monitoring (TDM) in patients with CD receiving biologic agents has evolved and is currently positioned as an important tool to optimize and guide biologic treatment. Considering the treatment of PFCD can represent a challenge; identifying novel tools to improve the efficacy of current treatments is …

A Bayesian Network To Predict The Risk Of Post Influenza Vaccination Guillain-Barré Syndrome: Development And Validation Study, Yun Huang, Chongliang Luo, Ying Jiang, Jingcheng Du, Cui Tao, Yong Chen, Yuantao Hao

Open Access Publications

BACKGROUND: Identifying the key factors of Guillain-Barré syndrome (GBS) and predicting its occurrence are vital for improving the prognosis of patients with GBS. However, there are scarcely any publications on a forewarning model of GBS. A Bayesian network (BN) model, which is known to be an accurate, interpretable, and interaction-sensitive graph model in many similar domains, is worth trying in GBS risk prediction.

OBJECTIVE: The aim of this study is to determine the most significant factors of GBS and further develop and validate a BN model for predicting GBS risk.

METHODS: Large-scale influenza vaccine postmarketing surveillance data, including 79,165 US …

Sorl1 Polymorphisms In Mexican Patients With Alzheimer's Disease, Danira Toral-Rios, Elizabeth Ruiz-Sánchez, Nancy Lucero Martínez Rodríguez, Marlene Maury-Rosillo, Óscar Rosas-Carrasco, Fernando Becerril-Pérez, Francisco Mena-Barranco, Rosa Carvajal-García, Daniela Silva-Adaya, Yair Delgado-Namorado, Gerardo Ramos-Palacios, Carmen Sánchez-Torres, Victoria Campos-Peña

Open Access Publications

The present study evaluated the risk effect of 12 Single Nucleotide Polymorphisms in the SORL1 gene in the Mexican population using Late-Onset Alzheimer's Disease (LOAD) and control subjects. Considering APOE as the strongest genetic risk factor for LOAD, we conducted interaction analyses between single nucleotide polymorphisms (SNPs) and the APOE genotype.

METHODS: Patients were interviewed during their scheduled visits at neurologic and geriatric clinics from different institutions. The LOAD diagnosis included neurological, geriatric, and psychiatric examinations, as well as the medical history and neuroimaging. Polymorphisms in

RESULTS: The A/A genotype in rs1784933 might be associated with an increased LOAD risk. …

Increasing Dorsal Tilt In Distal Radius Fractures Does Not Increase Median Nerve Strain, Chukwuka Obiofuma, Christopher Dy, Leanne E Iannucci, Spencer P Lake, David Brogan

Open Access Publications

Although extensive research shows an association between distal radius fractures and the development of median nerve related pathologies such as carpal tunnel syndrome, none directly track how the resulting angular deformity relates to likelihood of development of median nerve pathology.

Methods: Median nerve strain was measured with a custom-built system using a camera, optical markers, and a proprietary segmentation algorithm. After initial validation of the system in a cadaver model, our system was used to assess strain in 10 cadaver arms with a simulated distal radius fracture and increasing dorsal angulation. The measured strain at each angle was then analyzed …

Spherical Nucleic Acids As Precision Therapeutics For The Treatment Of Cancer—From Bench To Bedside, Akanksha S Mahajan, Alexander H Stegh

Open Access Publications

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their "free" form. Early phase …

The Bacterial Microbiota Regulates Normal Hematopoiesis Via Metabolite-Induced Type 1 Interferon Signaling, Hannah Yan, Forrest C Walker, Arushana Ali, Hyojeong Han, Lin Tan, Lucas Veillon, Philip L Lorenzi, Megan T Baldridge, Katherine Y King

Open Access Publications

Antibiotic therapy, especially when administered long term, is associated with adverse hematologic effects such as cytopenia. Signals from the intestinal microbiota are critical to maintain normal hematopoiesis, and antibiotics can cause bone marrow suppression through depletion of the microbiota. We reported previously that STAT1 signaling is necessary for microbiota-dependent hematopoiesis, but the precise mechanisms by which the gut microbiota signals to the host bone marrow to regulate hematopoiesis remain undefined. We sought to identify the cell type(s) through which STAT1 promotes microbiota-mediated hematopoiesis and to elucidate which upstream signaling pathways trigger STAT1 signaling. Using conditional knockout and chimeric mice, we …

A Phase Ii Trial Of An Alternative Schedule Of Palbociclib And Embedded Serum Tk1 Analysis, Jairam Krishnamurthy, Jingqin Luo, Rama Suresh, Foluso Ademuyiwa, Caron Rigden, Timothy Rearden, Katherine Clifton, Katherine Weilbaecher, Ashley Frith, Anna Roshal, Mathew Cherian, Tracy Summa, Brittney Haas, Shana Thomas, Leonel Hernandez-Aya, Lindsey Peterson, Cynthia X Ma, Et Al

Open Access Publications

Palbociclib 3-weeks-on/1-week-off, combined with hormonal therapy, is approved for hormone receptor positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer (MBC). Neutropenia is the most frequent adverse event (AE). We aim to determine whether an alternative 5-days-on/2-days-off weekly schedule reduces grade 3 and above neutropenia (G3 + ANC) incidence. In this single-arm phase II trial, patients with HR+/HER2- MBC received palbociclib 125 mg, 5-days-on/2-days-off, plus letrozole or fulvestrant per physician, on a 28-day cycle (C), as their first- or second-line treatment. The primary endpoint was G3 + ANC in the first 29 days (C1). Secondary endpoints included AEs, efficacy, and serum thymidine kinase …

Mitochondrial Phenotypes In Genetically Diverse Neurodegenerative Diseases And Their Response To Mitofusin Activation, Xiawei Dang, Emily K Walton, Barbara Zablocka, Robert H Baloh, Michael E Shy, Gerald W Dorn Ii

Open Access Publications

Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect …