Digital Commons Network^™

Toxoplasma Gondii Infection Drives Conversion Of Nk Cells Into Ilc1-Like Cells, Eugene Park, Swapneel Patel, Qiuling Wang, Prabhakar Andhey, Konstantin Zaitsev, Sophia Porter, Maxwell Hershey, Michael Bern, Beatrice Plougastel-Douglas, Patrick Collins, Marco Colonna, Kenneth M. Murphy, Eugene Oltz, Maxim Artyomov, L David Sibley, Wayne M. Yokoyama

Open Access Publications

Innate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here, we describe

Association Of Baseline Inflammatory Biomarkers With Cancer Mortality In The Regards Cohort, Tomi Akinyemiju, Justin X. Moore, Maria Pisu, Michael Goodman, Virginia J. Howard, Monika Safford, Susan C. Gilchrist, Mary Cushman, Leann Long, Suzanne E. Judd

Open Access Publications

This study examines the association between inflammatory biomarkers and risk of cancer mortality by race. Data were obtained from 1,856 participants in the prospective REGARDS cohort who were cancer-free at baseline, and analyzed in relation to cancer mortality prospectively. Biomarkers were log-transformed and categorized into tertiles due to non-normal distributions, and Cox proportional hazard regression models were utilized to compute hazard ratios with 95% confidence intervals using robust sandwich methods. Individuals in the highest tertile of IL-6 had over a 12-fold increased risk of cancer mortality (HR: 12.97, 95% CI: 3.46-48.63); those in the highest tertile of IL-8 had over …

Sleep Disturbances In Wolfram Syndrome, Amy Licis, Gabriel Davis, Sarah A Eisenstein, Heather M Lugar, Tamara Hershey

Open Access Publications

BACKGROUND: Wolfram syndrome is a rare disorder associated with diabetes mellitus, diabetes insipidus, optic nerve atrophy, hearing and vision loss, and neurodegeneration. Sleep complaints are common but have not been studied with objective measures. Our goal was to assess rates of sleep apnea and objective and self-reported measures of sleep quality, and to determine the relationship of sleep pathology to other clinical variables in Wolfram syndrome patients.

METHODS: Genetically confirmed Wolfram syndrome patients were evaluated at the 2015 and 2016 Washington University Wolfram Syndrome Research Clinics. Patients wore an actigraphy device and a type III ambulatory sleep study device and …

Translocator Protein In Late Stage Alzheimer's Disease And Dementia With Lewy Bodies Brains, Jinbin Xu, Jianjun Sun, Richard J Perrin, Robert H Mach, Kelly R Bales, John C Morris, Tammie L S Benzinger, David M Holtzman

Open Access Publications

OBJECTIVE: Increased translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), in glial cells of the brain has been used as a neuroinflammation marker in the early and middle stages of neurodegenerative diseases, such as Alzheimer's disease (AD) and Dementia with Lewy Bodies (DLB). In this study, we investigated the changes in TSPO density with respect to late stage AD and DLB.

METHODS: TSPO density was measured in multiple regions of postmortem human brains in 20 different cases: seven late stage AD cases (Braak amyloid average: C; Braak tangle average: VI; Aged 74-88, mean: 83 ± 5 years), …

Cross-National Comparison Of Two General Population Job Exposure Matrices For Physical Work Exposures, Bradley Evanoff, Marcus Yung, Skye Buckner-Petty, Matthew Baca, Johan Hviid Andersen, Yves Roquelaure, Alexis Descatha, Ann Marie Dale

Open Access Publications

OBJECTIVES: Job exposure matrices (JEMs) are increasingly used to estimate physical workplace exposures. We conducted a cross-national comparison of exposure estimates from two general population JEMs to aid the interpretation of exposure-outcome associations across countries and to explore the feasibility of cross-national application of JEMs to provide workplace physical exposure estimates.

METHODS: We compared physical exposure estimates from two general population JEMs created from the French

RESULTS: All variable pairs measuring similar physical exposures demonstrated positive correlations. Among the 50 matched pairs, 33 showed high correlation (ρ≥0.70) and 46 showed at least moderate agreement (κ≥0.41). Exposures expected to be mutually …

Novel Cell Adhesion/Migration Pathways Are Predictive Markers Of Hdac Inhibitor Resistance In Cutaneous T Cell Lymphoma, Jared M Andrews, Jennifer A Schmidt, Kenneth R Carson, Amy C Musiek, Neha Mehta-Shah, Jacqueline E Payton

Open Access Publications

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy.

METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks …

Host And Viral Mechanisms Of Congenital Zika Syndrome, Brooke Liang, José Paulo Guida, Maria Laura Costa Do Nascimento, Indira U Mysorekar

Open Access Publications

In 2015-2016, in the Americas, and especially in northeast Brazil, a significant number of cases of microcephaly and other congenital brain abnormalities were linked with an outbreak of Zika virus (ZIKV) infection in pregnant women. While maternal symptoms of ZIKV are generally mild and self-limiting, clinical presentation in fetuses and newborns infected is extensive and includes microcephaly, decreased cortical development, atrophy and hypoplasia of the cerebellum and cerebellar vermis, arthrogryposis, and polyhydramnios. The term congenital ZIKV syndrome (CZS) was introduced to describe the range of findings associated with maternal-fetal ZIKV transmission. ZIKV is primarily transmitted by

Precision Delivery Of Ras-Inhibiting Sirna To Kras Driven Cancer Via Peptide-Based Nanoparticles, Matthew S. Strand, Bradley A. Krasnick, Hua Pan, Xiuli Zhang, Ye Bi, Candace Brooks, Christopher Wetzel, Narendra Sankpal, Timothy Fleming, S Peter Goedegebuure, David G. Denardo, William E. Gillanders, William G. Hawkins, Samuel A. Wickline, Ryan C. Fields

Open Access Publications

Over 95% of pancreatic adenocarcinomas (PDACs), as well as a large fraction of other tumor types, such as colorectal adenocarcinoma, are driven by KRAS activation. However, no direct RAS inhibitors exist for cancer therapy. Furthermore, the delivery of therapeutic agents of any kind to PDAC in particular has been hindered by the extensive desmoplasia and resultant drug delivery challenges that accompanies these tumors. Small interfering RNA (siRNA) is a promising modality for anti-neoplastic therapy due to its precision and wide range of potential therapeutic targets. Unfortunately, siRNA therapy is limited by low serum half-life, vulnerability to intracellular digestion, and transient …

Spinal V2b Neurons Reveal A Role For Ipsilateral Inhibition In Speed Control, Rebecca A. Callahan, Richard Roberts, Mohini Sengupta, Yukiko Kimura, Shin-Ichi Higashijima, Martha W. Bagnall

Open Access Publications

The spinal cord contains a diverse array of interneurons that govern motor output. Traditionally, models of spinal circuits have emphasized the role of inhibition in enforcing reciprocal alternation between left and right sides or flexors and extensors. However, recent work has shown that inhibition also increases coincident with excitation during contraction. Here, using larval zebrafish, we investigate the V2b (Gata3+) class of neurons, which contribute to flexor-extensor alternation but are otherwise poorly understood. Using newly generated transgenic lines we define two stable subclasses with distinct neurotransmitter and morphological properties. These V2b subclasses synapse directly onto motor neurons with differential targeting …

Situating Dissemination And Implementation Sciences Within And Across The Translational Research Spectrum, Aaron L Leppin, Jane E Mahoney, Kathleen R Stevens, Stephen J Bartels, Laura-Mae Baldwin, Rowena J Dolor, Enola K Proctor, Linda Scholl, Justin B Moore, Ana A Baumann, Catherine L Rohweder, Joan Luby, Paul Meissner

Open Access Publications

The efficient and effective movement of research into practice is acknowledged as crucial to improving population health and assuring return on investment in healthcare research. The National Center for Advancing Translational Science which sponsors Clinical and Translational Science Awards (CTSA) recognizes that dissemination and implementation (D&I) sciences have matured over the last 15 years and are central to its goals to shift academic health institutions to better align with this reality. In 2016, the CTSA Collaboration and Engagement Domain Task Force chartered a D&I Science Workgroup to explore the role of D&I sciences across the translational research spectrum. This special …

Low-Carbohydrate Diets For Gestational Diabetes, Sarah S Farabi, Teri L Hernandez

Open Access Publications

Nutrition therapy provides the foundation for treatment of gestational diabetes (GDM), and has historically been based on restricting carbohydrate (CHO) intake. In this paper, randomized controlled trials (RCTs) are reviewed to assess the effects of both low- and higher CHO nutrition approaches in GDM. The prevailing pattern across the evidence underscores that although CHO restriction improves glycemia at least in the short-term, similar outcomes could be achievable using less restrictive approaches that may not exacerbate IR. The quality of existing studies is limited, in part due to dietary non-adherence and confounding effects of treatment with insulin or oral medication. Recent …

Targeting Sporadic And Neurofibromatosis Type 1 (Nf1) Related Refractory Malignant Peripheral Nerve Sheath Tumors (Mpnst) In A Phase Ii Study Of Everolimus In Combination With Bevacizumab (Sarc016), Brigitte C. Widemann, Anglea C. Hirbe, Et Al

Open Access Publications

No abstract provided.

Ml277 Specifically Enhances The Fully Activated Open State Of Kcnq1 By Modulating Vsd-Pore Coupling, Panpan Hou, Jingyi Shi, Kelli Mcfarland White, Yuan Gao, Jianmin Cui

Open Access Publications

Upon membrane depolarization, the KCNQ1 potassium channel opens at the intermediate (IO) and activated (AO) states of the stepwise voltage-sensing domain (VSD) activation. In the heart, KCNQ1 associates with KCNE1 subunits to form I

Functional Outcome Of Adulthood Selective Dorsal Rhizotomy For Spastic Diplegia, T. S. Park, So Yeon Uhm, Deanna M. Walter, Nicole L. Meyer, Matthew B. Dobbs

Open Access Publications

Objective The medical evidence supporting the efficacy of selective dorsal rhizotomy (SDR) on children with spastic diplegia is strong. However, the outcome of SDR on adults with spastic diplegia remains undetermined. The aim is to study the effectiveness and morbidities of SDR performed on adults for the treatment of spastic diplegia. Methods Patients who received SDR in adulthood for the treatment of spastic diplegia were surveyed. The survey questionnaire addressed the living situation, education level, employment, health outcomes, postoperative changes of symptoms, changes in ambulatory function, adverse effects of SDR and orthopedic surgery after SDR. Results The study included 64 …

Diagnostic And Clinical Experience Of Patients With Pantothenate Kinase-Associated Neurodegeneration, Randall D Marshall, Abigail Collins, Maria L Escolar, H A Jinnah, Thomas Klopstock, Michael C Kruer, Aleksandar Videnovic, Amy Robichaux-Viehoever, Colleen Burns, Laura L Swett, Dennis A Revicki, Randall H Bender, William R Lenderking

Open Access Publications

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegenerative disorder with brain iron accumulation (NBIA).

OBJECTIVES: To assess PKAN diagnostic pathway, history, and burden across the spectrum of PKAN severity from patient and/or caregiver perspectives.

METHODS: Caregivers of patients (n = 37) and patients themselves (n = 2) were interviewed in a validation study of the PKAN-Activities of Daily Living (ADL) scale. The current study used quartiles of the PKAN-ADL total score to divide patients by severity of impairment (Lowest, Second Lowest, Third Lowest, Highest). Diagnostic and treatment history, healthcare utilization, disease burden, and caregiver experience were compared between …

A Sparse Covarying Unit That Describes Healthy And Impaired Human Gut Microbiota Development, Arjun S Raman, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Sathish Subramanian, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

Characterizing the organization of the human gut microbiota is a formidable challenge given the number of possible interactions between its components. Using a statistical approach initially applied to financial markets, we measured temporally conserved covariance among bacterial taxa in the microbiota of healthy members of a Bangladeshi birth cohort sampled from 1 to 60 months of age. The results revealed an "ecogroup" of 15 covarying bacterial taxa that provide a concise description of microbiota development in healthy children from this and other low-income countries, and a means for monitoring community repair in undernourished children treated with therapeutic foods. Features of …

Effects Of Microbiota-Directed Foods In Gnotobiotic Animals And Undernourished Children, Jeanette L Gehrig, Siddarth Venkatesh, Hao-Wei Chang, Matthew C Hibberd, Vanderlene L Kung, Jiye Cheng, Robert Y Chen, Sathish Subramanian, Carrie A Cowardin, Martin F Meier, David O'Donnell, Michael Talcott, Larry D Spears, Clay F Semenkovich, Christopher Sawyer, Richard D Head, Michael J Barratt, Jeffrey I Gordon, Et Al

Open Access Publications

To examine the contributions of impaired gut microbial community development to childhood undernutrition, we combined metabolomic and proteomic analyses of plasma samples with metagenomic analyses of fecal samples to characterize the biological state of Bangladeshi children with severe acute malnutrition (SAM) as they transitioned, after standard treatment, to moderate acute malnutrition (MAM) with persistent microbiota immaturity. Host and microbial effects of microbiota-directed complementary food (MDCF) prototypes targeting weaning-phase bacterial taxa underrepresented in SAM and MAM microbiota were characterized in gnotobiotic mice and gnotobiotic piglets colonized with age- and growth-discriminatory bacteria. A randomized, double-blind controlled feeding study identified a lead MDCF …

Estimating Implicit And Explicit Gender Bias Among Health Care Professionals And Surgeons, Arghavan Salles, Michael Awad, Laurel Goldin, Kelsey Krus, Jin Vivian Lee, Maria T. Schwabe, Calvin K. Lai

Open Access Publications

Importance: The Implicit Association Test (IAT) is a validated tool used to measure implicit biases, which are mental associations shaped by one's environment that influence interactions with others. Direct evidence of implicit gender biases about women in medicine has yet not been reported, but existing evidence is suggestive of subtle or hidden biases that affect women in medicine.

Objectives: To use data from IATs to assess (1) how health care professionals associate men and women with career and family and (2) how surgeons associate men and women with surgery and family medicine.

Design, Setting, and Participants: This data review and …

Effect Of Enhanced Medical Rehabilitation On Functional Recovery In Older Adults Receiving Skilled Nursing Care After Acute Rehabilitation: A Randomized Clinical Trial, Eric J. Lenze, Emily Lenard, Marghuretta Bland, Peggy Barco, J Philip Miller, Michael Yingling, Catherine E. Lang, Nancy Morrow-Howell, Carolyn M. Baum, Ellen F. Binder, Thomas L. Rodebaugh

Open Access Publications

Importance: Enhanced medical rehabilitation (EMR) is a systematic and standardized approach for physical and occupational therapists to engage patients. Higher patient engagement in therapy might lead to improved functional recovery in rehabilitation settings, such as skilled nursing facilities (SNFs).

Objective: To determine whether EMR improves older adults' functional recovery.

Design, Setting, and Participants: A double-blind, parallel-group, randomized clinical trial was conducted from July 29, 2014, to July 13, 2018, in 229 adults aged 65 years or older admitted to 2 US SNFs. Participants were randomized to receive EMR (n = 114) vs standard-of-care rehabilitation (n = 115). Intention-to-treat analysis was …

Trends In Medical Imaging During Pregnancy In The United States And Ontario, Canada, 1996 To 2016, Marilyn L. Kwan, James R. Duncan, Et Al

Open Access Publications

No abstract provided.

A Guinea Fowl Genome Assembly Provides New Evidence On Evolution Following Domestication And Selection In Galliformes, Alain Vignal, Simon Boitard, Noémie Thébault, Guiguigbaza-Kossigan Dayo, Valentine Yapi-Gnaore, Issaka Youssao Abdou Karim, Cécile Berthouly-Salazar, Nóra Pálinkás-Bodzsár, Daniel Guémené, Francoise Thibaud-Nissen, Wesley C Warren, Michèle Tixier-Boichard, Xavier Rognon

Open Access Publications

The helmeted guinea fowl Numida meleagris belongs to the order Galliformes. Its natural range includes a large part of sub-Saharan Africa, from Senegal to Eritrea and from Chad to South Africa. Archaeozoological and artistic evidence suggest domestication of this species may have occurred about 2,000 years BP in Mali and Sudan primarily as a food resource, although villagers also benefit from its capacity to give loud alarm calls in case of danger, of its ability to consume parasites such as ticks and to hunt snakes, thus suggesting its domestication may have resulted from a commensal association process. Today, it is …

Pituitary Adenoma In Pediatric And Adolescent Populations, Jie Chen, Robert E Schmidt, Sonika Dahiya

Open Access Publications

Pituitary adenomas are rare in children and adolescents and although mostly benign, they can sometimes be challenging to manage due to their locally invasive nature. In this study, we examined the clinicopathologic features of 42 pituitary adenomas in patients ≤21 years of age. The youngest patient was 8 years old (median age: 18 years), and the female-to-male ratio was 1.8:1. Five patients had recurrence after resection. There was no obvious difference between the recurrent rates in the typical (11.7%) and atypical adenomas (12.5%) based on the 2004 WHO classification. However, the recurrence rate was much higher in adenomas with an …

Is Duration Of Hospital Participation In Meaningful Use Associated With Value In Medicare?, Yanick N. Brice, Karen E. Joynt Maddox

Open Access Publications

Objectives: "Meaningful Use" (MU) of electronic health records (EHRs) is a measure used by Medicare to determine whether hospitals are comprehensively using electronic tools. Whether hospitals' engagement in value-based initiatives such as MU is associated with value-defined as high quality and low costs-is unknown. Our objectives were to describe hospital participation in MU, and determine whether duration of participation is associated with value.

Materials and Methods: We linked national Medicare data with MU and other hospital-level and market data. We analyzed bivariate relationships to characterize duration of participation. We estimated inverse probability-weighted multilevel logistic regressions to evaluate whether duration of …

Organizational Supports For Research Evidence Use In State Public Health Agencies: A Latent Class Analysis, Hengrui Hu, Peg Allen, Yan Yan, Rodrigo S Reis, Rebekah R Jacob, Ross C Brownson

Open Access Publications

OBJECTIVE: Use of research evidence in public health decision making can be affected by organizational supports. Study objectives are to identify patterns of organizational supports and explore associations with research evidence use for job tasks among public health practitioners.

DESIGN: In this longitudinal study, we used latent class analysis to identify organizational support patterns, followed by mixed logistic regression analysis to quantify associations with research evidence use.

SETTING: The setting included 12 state public health department chronic disease prevention units and their external partnering organizations involved in chronic disease prevention.

PARTICIPANTS: Chronic disease prevention staff from 12 US state public …

Disseminating And Implementing A Lifestyle-Based Healthy Weight Program For Mothers In A National Organization: A Study Protocol For A Cluster Randomized Trial, Rachel G Tabak, Cynthia D Schwarz, Allison Kemner, Kenneth B Schechtman, Karen Steger-May, Veronda Byrth, Debra Haire-Joshu

Open Access Publications

BACKGROUND: Excessive weight gain among young adult women age 18-45 years is an alarming and overlooked trend that must be addressed to reverse the epidemics of obesity and chronic disease. During this vulnerable period, women tend to gain disproportionally large amounts of weight compared to men and to other life periods. Healthy Eating and Active Living Taught at Home (HEALTH) is a lifestyle modification intervention developed in partnership with Parents as Teachers (PAT), a national home visiting, community-based organization with significant reach in this population. HEALTH prevented weight gain, promoted sustained weight loss, and reduced waist circumference. PAT provides parent-child …

Training In Implementation Practice Leadership (Triple): Evaluation Of A Novel Practice Change Strategy In Behavioral Health Organizations, Enola Proctor, Alex T Ramsey, Matthew T Brown, Sara Malone, Cole Hooley, Virginia Mckay

Open Access Publications

BACKGROUND: Effective leadership for organizational change is critical to the implementation of evidence-based practices (EBPs). As organizational leaders in behavioral health organizations often are promoted from within the agency for their long-standing, effective work as counselors, they may lack formal training in leadership, management, or practice change. This study assesses a novel implementation leadership training designed to promote leadership skills and successful organizational change specific to EBP implementation.

METHODS: We conducted a pre-post outcome evaluation of the Training in Implementation Practice Leadership (TRIPLE), delivered via three in-person, half-day training sessions, with interim coaching and technical support. Sixteen mid-level leaders (75% …

Intracellular Retention Of Mutant Lysyl Oxidase Leads To Aortic Dilation In Response To Increased Hemodynamic Stress, Vivian S Lee, Carmen M Halabi, Thomas J Broekelmann, Philip C Trackman, Nathan O Stitziel, Robert P Mecham

Open Access Publications

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and …

Telemedicine Infectious Diseases Consultations And Clinical Outcomes: A Systematic Review And Meta-Analysis Protocol, Jason P Burnham, Stephanie A Fritz, Lauren H Yaeger, Graham A Colditz

Open Access Publications

BACKGROUND: Telemedicine use is increasing in many specialties, but its impact on clinical outcomes in infectious diseases has not been systematically studied and reviewed. The proposed systematic review will evaluate the current evidence regarding the effect of telemedicine infectious diseases consultation on a range of clinical outcomes, including mortality, hospital readmission, antimicrobial use, and cost.

METHOD/DESIGN: Standard systematic review methodology will be used, with searches of Ovid MEDLINE 1946-, https://embase.com/ 1947-, Scopus 1823-, Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), and https://clinicaltrials.gov/ 1997-. There will be no restriction on language or year of publication. …

Reactive Microglia And Il1Β/Il-1r1-Signaling Mediate Neuroprotection In Excitotoxin-Damaged Mouse Retina, Levi Todd, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh V Hoang, Warren A Campbell, Seth Blackshaw, Ning Quan, Andy J Fischer

Open Access Publications

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.

METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell …

Vesicular Glutamatergic Transmission In Noise-Induced Loss And Repair Of Cochlear Ribbon Synapses, Kyunghee X. Kim, Shelby Payne, Aizhen Yang-Hood, Song-Zhe Li, Bethany Davis, Jason Carlquist, Babak V-Ghaffari, Jay A. Gantz, Dorina Kallogjeri, James A.J. Fitzpatrick, Kevin K. Ohlemiller, Keiko Hirose, Mark A. Rutherford

Open Access Publications

Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3 (