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Abstract Challenges in therapeutics development for neuropsychiatric disorders can be attributed, in part, to a paucity of translational models capable of capturing relevant phenotypes across clinical populations and laboratory animals. Touch-sensitive procedures are increasingly used to develop innovative animal models that better align with testing conditions used in human participants. In addition, advances in electrophysiological techniques have identified neurophysiological signatures associated with characteristics of neuropsychiatric illness. The present studies integrated these methodologies by developing a rat flanker task with electrophysiological recordings based on reverse-translated protocols used in human electroencephalogram (EEG) studies of cognitive control. Various touchscreen-based stimuli were evaluated for their ability to efficiently gain stimulus control and advance to flanker test sessions. Optimized stimuli were then examined for their elicitation of prototypical visual evoked potentials (VEPs) across local field potential (LFP) wires and EEG skull screws. Of the stimuli evaluated, purple and green photographic stimuli were associated with efficient training and expected flanker interference effects. Orderly stimulus-locked outcomes were also observed in VEPs across LFP and EEG recordings. These studies along with others verify the feasibility of concurrent electrophysiological recordings and rodent touchscreen-based cognitive testing and encourage future use of this integrated approach in therapeutics development.

This project shows that focus and information structure, as indicated by the focus particle “only” and pitch accents, influence syntactic attachment, in contrast to the well-known effects of prosodic boundaries on attachment. One written questionnaire, one completion study, and several auditory questionnaires show that the position of “only” strongly affects attachment preferences in ambiguous sentences, while contrastive pitch accents have smaller effects. The two types of focus marking do not interact but independently impact attachment. These results support a modified version of the Focus Attraction Hypothesis, with ambiguous material drawn to attach to the most important information in a sentence. This research shows that information structure can affect sentence structure as well as discourse coherence.

Introduction: Cluster randomized crossover trials are often faced with a dilemma when selecting an optimal model of consent, as the traditional model of obtaining informed consent from participant's before initiating any trial related activities may not be suitable. We describe our experience of engaging patient advisors to identify an optimal model of consent for the PREP-IT trials. This paper also examines surrogate measures of success for the selected model of consent. Methods: The PREP-IT program consists of two multi-center cluster randomized crossover trials that engaged patient advisors to determine an optimal model of consent. Patient advisors and stakeholders met regularly and reached consensus on decisions related to the trial design including the model for consent. Patient advisors provided valuable insight on how key decisions on trial design and conduct would be received by participants and the impact these decisions will have. Results: Patient advisors, together with stakeholders, reviewed the pros and cons and the requirements for the traditional model of consent, deferred consent, and waiver of consent. Collectively, they agreed upon a deferred consent model, in which patients may be approached for consent after their fracture surgery and prior to data collection. The consent rate in PREP-IT is 80.7%, and 0.67% of participants have withdrawn consent for participation. Discussion: Involvement of patient advisors in the development of an optimal model of consent has been successful. Engagement of patient advisors is recommended for other large trials where the traditional model of consent may not be optimal.

Introduction: Pragmatic trials in comparative effectiveness research assess the effects of different treatment, therapeutic, or healthcare options in clinical practice. They are characterized by broad eligibility criteria and large sample sizes, which can lead to an unmanageable number of participants, increasing the risk of bias and affecting the integrity of the trial. We describe the development of a sampling strategy tool and its use in the PREPARE trial to circumvent the challenge of unmanageable work flow. Methods: Given the broad eligibility criteria and high fracture volume at participating clinical sites in the PREPARE trial, a pragmatic sampling strategy was needed. Using data from PREPARE, descriptive statistics were used to describe the use of the sampling strategy across clinical sites. A Chi-square test was performed to explore whether use of the sampling strategy was associated with a reduction in the number of missed eligible patients. Results: 7 of 20 clinical sites (35%) elected to adopt a sampling strategy. There were 1539 patients excluded due to the use of the sampling strategy, which represents 30% of all excluded patients and 20% of all patients screened for participation. Use of the sampling strategy was associated with lower odds of missed eligible patients (297/4545 (6.5%) versus 341/3200 (10.7%) p

Background: Cancer is a leading cause of provoked venous thromboembolism (VTE) and requires use of anticoagulation. As the incidence of lobular breast carcinoma increases, more breast cancer patients experience gastrointestinal metastatic disease which often manifests with gastrointestinal bleeding. Herein we discuss the challenges associated with the diagnosis and management of breast cancer metastatic to the GI tract revealed by need for anticoagulation due to concurrent cancer-associated VTE. Case: A 72 year old woman with a past medical history of ER+ PR+ HER2- Stage IIIa left lobular breast carcinoma previously treated with neoadjuvant chemotherapy, bilateral mastectomies and radiation followed by adjuvant hormonal therapy with letrozole. After 2 years of adjuvant hormonal therapy, she was diagnosed with unprovoked VTE. She was started on rivaroxaban for indefinite anticoagulation. After 5 months she presented with complaints of melena and weakness and a hemoglobin of 7.1 g/dL and platelets of 110 x 109/L. Esophagoduodenoscopy was performed which showed acute gastritis with random gastric biopsies noted to be positive for metastatic lobular breast carcinoma. Due to GI bleeding, rivaroxaban was held, however the patient developed an acute proximal right femoral vein VTE. A second trial of anticoagulation with heparin did not reveal continued bleeding, so she was discharged on apixaban. Unfortunately, despite starting chemotherapy with ibrance and faslodex she developed worsening melena resulting in the need to the place an IVC filter and cessation of anticoagulation. Discussion: As lobular breast cancer can spread along serosal surfaces, new onset of GI bleeding in patients with history of lobular breast cancer should increase suspicion for GI metastatic disease. Use of anticoagulation may unmask bleeding in such patients. The increased risk of GI bleeding in cancer patients must be considered when selecting anticoagulation for the management of cancer-associated VTE. Management of cancer associated thrombosis is complex and hemostasis strategies for of mucosal bleeding from metastatic lobular breast cancer may require tailored approaches that compensate for the malignant cause. Furthermore, a thorough assessment of platelet counts and other coagulation factors should be considered as a minority of patients with metastatic disease can present with consumptive coagulopathy.

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.

Anxiety disorders disproportionately affect women compared to men, which may arise from sex differences in stress responses. MiRNAs are small non-coding RNAs known to regulate gene expression through actions on mRNAs. MiRNAs are regulated, in part, by factors such as stress and gonadal sex, and they have been implicated in the pathophysiology of multiple psychiatric disorders. Here, we assessed putative sex differences in miRNA expression in the bed nucleus of the stria terminalis (BNST) – a sexually dimorphic brain region implicated in anxiety – of adult male and female rats that had been exposed to social isolation (SI) stress throughout adolescence. To assess the translational utility of our results, we assessed if childhood trauma in humans resulted in changes in blood miRNA expression that are similar to those observed in rats. Male and female Sprague-Dawley rats underwent SI during adolescence or remained group housed (GH) and were tested for anxiety-like behavior in the elevated plus maze as adults. Small RNA sequencing was performed on tissue extracted from the BNST. Furthermore, we re-analyzed an already available small RNA sequencing data set from the Grady Trauma Project (GTP) from men and women to identify circulating miRNAs that are associated with childhood trauma exposure. Our results indicated that there were greater anxiogenic-like effects and changes in BNST miRNA expression in SI versus GH females compared to SI versus GH males. In addition, we found nine miRNAs that were regulated in both the BNST from SI compared to GH rats and in blood samples from humans exposed to childhood trauma. These studies emphasize the utility of rodent models in studying neurobiological mechanisms underlying psychiatric disorders and suggest that rodent models could be used to identify novel sex-specific pharmacotherapies for anxiety disorders.

While high-stakes testing has influenced music teacher evaluation, evidence of music teacher agency influencing the policy process has been scarce. One notable exception is the Tennessee Fine Arts Portfolio Model (TNFAPM), designed by music teachers in Tennessee as an alternative to music teacher evaluations that have been based, at least in part, on reading and math test scores. In place for nine years, the model is one of the few peer-reviewed teacher evaluation initiatives that has been in continuous use in public schools, enabling researchers to examine music teacher perceptions of evaluation in Tennessee, including perceptions of the portfolio. The purpose of this study was to examine two music teachers' perceptions regarding the different means of teacher evaluation (student reading/math test scores and the TNFAPM) used within the state of Tennessee. After analyzing data collected during the study, I sought to answer the following question: How have teacher evaluation practices and policies impacted music teachers' self-perceptions, classroom policies, and curriculum implementation in Tennessee? Findings suggest that administrative support, feedback delivery/reception, and value for music making shaped the participants' perceptions, policies, and classroom practices. Additionally, scores did not generate positive perceptions.

The tumor microenvironment is a critical modulator of carcinogenesis; however, in many tumor types, the influence of the stroma during preneoplastic stages is unknown. Here we explored the relationship between pre-tumor cells and their surrounding stroma in malignant progression of the cerebellar tumor medulloblastoma (MB). We show that activation of the vascular regulatory signalling axis mediated by Norrin (an atypical Wnt)/Frizzled4 (Fzd4) inhibits MB initiation in the Ptch+/− mouse model. Loss of Norrin/Fzd4-mediated signalling in endothelial cells, either genetically or by short-term blockade, increases the frequency of pre-tumor lesions and creates a tumor-permissive microenvironment at the earliest, preneoplastic stages of MB. This pro-tumor stroma, characterized by angiogenic remodelling, is associated with an accelerated transition from preneoplasia to malignancy. These data expose a stromal component that regulates the earliest stages of tumorigenesis in the cerebellum, and a novel role for the Norrin/Fzd4 axis as an endogenous anti-tumor signal in the preneoplastic niche.

Both the development and relief of stress-related psychiatric conditions such as major depression (MD) and post-traumatic stress disorder (PTSD) have been linked to neuroplastic changes in the brain. One such change involves the birth of new neurons (neurogenesis), which occurs throughout adulthood within discrete areas of the mammalian brain, including the dorsal hippocampus (HIP). Stress can trigger MD and PTSD in humans, and there is considerable evidence that it can decrease HIP neurogenesis in laboratory animals. In contrast, antidepressant treatments increase HIP neurogenesis, and their efficacy is eliminated by ablation of this process. These findings have led to the working hypothesis that HIP neurogenesis serves as a biomarker of neuroplasticity and stress resistance. Here we report that local alterations in the expression of Sprouty2 (SPRY2), an intracellular inhibitor of growth factor function, produces profound effects on both HIP neurogenesis and behaviors that reflect sensitivity to stressors. Viral vector-mediated disruption of endogenous Sprouty2 function (via a dominant negative construct) within the dorsal HIP of adult rats stimulates neurogenesis and produces signs of stress resilience including enhanced extinction of conditioned fear. Conversely, viral vector-mediated elevation of SPRY2 expression intensifies the behavioral consequences of stress. Studies of these manipulations in HIP primary cultures indicate that SPRY2 negatively regulates fibroblast growth factor-2 (FGF2), which has been previously shown to produce antidepressant- and anxiolytic-like effects via actions in the HIP. Our findings strengthen the relationship between HIP plasticity and stress responsiveness, and identify a specific intracellular pathway that could be targeted to study and treat stress-related disorders.

In vitro studies have identified LIMK2 as a key downstream effector of Rho GTPase-induced changes in cytoskeletal organization. LIMK2 is phosphorylated and activated by Rho associated coiled-coil kinases (ROCKs) in response to a variety of growth factors. The biochemical targets of LIMK2 belong to a family of actin binding proteins that are potent modulators of actin assembly and disassembly. Although numerous studies have suggested that LIMK2 regulates cell morphology and motility, evidence supportive of these functions in vivo has remained elusive. In this study, a knockout mouse was created that abolished LIMK2 biochemical activity resulting in a profound inhibition of epithelial sheet migration during eyelid development. In the absence of LIMK2, nascent eyelid keratinocytes differentiate and acquire a pre-migratory phenotype but the leading cells fail to nucleate filamentous actin and remain immobile causing an eyes open at birth (EOB) phenotype. The failed nucleation of actin was associated with significant reductions in phosphorylated cofilin, a major LIMK2 biochemical substrate and potent modulator of actin dynamics. These results demonstrate that LIMK2 activity is required for keratinocyte migration in the developing eyelid.