Cross study analyses of SEND data: toxicity profile classification.

A SEND toxicology data transformation, harmonization, and analysis platform were created to improve the identification of unique findings related to the intended target, species, and duration of dosing using data from multiple studies. The lack of a standardized digital format for data analysis had impeded large-scale analysis of in vivo toxicology studies. The CDISC SEND standard enables the analysis of data from multiple studies performed by different laboratories.

Toward implementing virtual control groups in nonclinical safety studies.

Historical data from control groups in animal toxicity studies are currently mainly used for comparative purposes to assess validity and robustness of study results. Due to the highly controlled environment in which the studies are performed and the homogeneity of the animal collectives it has been proposed to use the historical data to build so-called virtual control groups, which could partly or entirely replace the concurrent control group. This would constitute a substantial contribution to the reduction of animal use in safety studies.

Analysis of secondary pharmacology assays received by the US Food and Drug Administration.

Secondary pharmacology studies are a time-efficient and cost-effective method for determining the safety profile of a potential new drug before it enters human trials. The results of these multi-target screens are commonly submitted with Investigational New Drug (IND) applications, but there currently is little guidance on how such information is presented and which targets are chosen for testing. In this study, we expand on our previous analysis of secondary pharmacology reports by manually curating and analyzing all secondary pharmacology results received by the FDA received as part of an IND submission.

A robust biostatistical method leverages informative but uncertainly determined qPCR data for biomarker detection, early diagnosis, and treatment.

As a common medium-throughput technique, qPCR (quantitative real-time polymerase chain reaction) is widely used to measure levels of nucleic acids. In addition to accurate and complete data, experimenters have unavoidably observed some incomplete and uncertainly determined qPCR data because of intrinsically low overall amounts of biological materials, such as nucleic acids present in biofluids. When there are samples with uncertainly determined qPCR data, some investigators apply the statistical complete-case method by excluding the subset of samples with uncertainly determined data from analysis (CO), while others simply choose not to analyze (CNA) these datasets altogether.

Development and validation of methods to visualize conventional aqueous outflow pathways in canine primary angle closure glaucoma.

Purpose: Angle closure glaucoma (PACG) is highly prevalent in dogs and is often refractory to medical therapy. We hypothesized that pathology affecting the post-trabecular conventional aqueous outflow pathway contributes to persistent intraocular pressure (IOP) elevation in dogs with PACG. The goal of this study was to determine the potential for aqueous angiography (AA) and optical coherence tomography (OCT) to identify abnormalities in post-trabecular aqueous outflow pathways in canine PACG.

Aggregation and analysis of secondary pharmacology data from investigational new drug submissions at the US Food and Drug Administration.

Secondary pharmacology studies are utilized by the pharmaceutical industry as a cost-efficient tool to identify potential safety liabilities of drugs before entering Phase 1 clinical trials. These studies are recommended by the Food and Drug Administration (FDA) as a part of the Investigational New Drug (IND) application. However, despite the utility of these assays, there is little guidance on which targets should be screened and which format should be used.

Leveraging the Value of CDISC SEND Data Sets for Cross-Study Analysis: Incidence of Microscopic Findings in Control Animals.

Implementation of the Clinical Data Interchange Standards Consortium (CDISC)'s Standard for Exchange of Nonclinical Data (SEND) by the United States Food and Drug Administration Center for Drug Evaluation and Research (US FDA CDER) has created large quantities of SEND data sets and a tremendous opportunity to apply large-scale data analytic approaches. To fully realize this opportunity, differences in SEND implementation that impair the ability to conduct cross-study analysis must be addressed. In this manuscript, a prototypical question regarding historical control data (see Table of Contents graphic) was used to identify areas for SEND harmonization and to develop algorithmic strategies for nonclinical cross-study analysis within a variety of databases.

Sub-region-Specific Optic Nerve Head Glial Activation in Glaucoma.

Glaucoma, a multifactorial neurodegenerative disease characterized by progressive loss of retinal ganglion cells and their axons in the optic nerve, is a leading cause of irreversible vision loss. Intraocular pressure (IOP) is a risk factor for axonal damage, which initially occurs at the optic nerve head (ONH). Complex cellular and molecular mechanisms involved in the pathogenesis of glaucomatous optic neuropathy remain unclear.

Wound leakage rates of ex vivo uniplanar versus biplanar phacoemulsification clear corneal incisions in dogs.

Objective: The purpose of this study was to compare the leakage rates of perilimbal uniplanar and biplanar clear corneal incisions in dogs when subjected to increased intraocular pressure (IOP) both from within the eye and via external pressure.

Procedure: Uniplanar clear corneal incisions were created in eight freshly enucleated canine eyes using a 3.2 mm straight slit knife while 8 fellow eyes received a biplanar clear corneal incision consisting of an approximately 300 μm deep groove followed by a 3.

SEND harmonization & cross-study analysis: A proposal to better harvest the value from SEND data.

The Standard for Exchange of Nonclinical Data (SEND) identifies an approach for representing nonclinical data in a structured format which has been widely adopted by the pharmaceutical industry as it is required for data submission to the United States Food & Drug Administration (US FDA). The SEND Implementation Guide (SENDIG) allows for considerable flexibility in how data is represented; interpretation of these guidelines has led to significant variability in the approach to SEND dataset creation. The purposes of this manuscript are to identify common variability in certain SEND domains and to describe how variability can be managed to enable valuable cross-study analysis use cases.

Imaging Distal Aqueous Outflow Pathways in a Spontaneous Model of Congenital Glaucoma.

Purpose: To validate the use of aqueous angiography (AA) in characterizing distal aqueous outflow pathways in normal and glaucomatous cats.

Methods: Ex vivo AA and optical coherence tomography (OCT) were performed in nine adult cat eyes (5 feline congenital glaucoma [FCG] and 4 normal), following intracameral infusion of 2.5% fluorescein and/or 0.

Correction: The effect of uncertainty in patient classification on diagnostic performance estimations.

[This corrects the article DOI: 10.1371/journal.pone.

The effect of uncertainty in patient classification on diagnostic performance estimations.

Background: The performance of a new diagnostic test is typically evaluated against a comparator which is assumed to correspond closely to some true state of interest. Judgments about the new test's performance are based on the differences between the outputs of the test and comparator. It is commonly assumed that a small amount of uncertainty in the comparator's classifications will negligibly affect the measured performance of a diagnostic test.

Tonometer validation and intraocular pressure reference values in the normal chinchilla (Chinchilla lanigera).

Objectives: To determine accuracy and precision of three commonly used tonometers (TonoVet and TonoLab (ICare Oy, Finland)-rebound tonometers, and Tono-Pen VET™ (Reichert, NY)-applanation tonometer) in normal chinchillas, and to establish a normal intraocular pressure (IOP) reference range in this species.

Methods: The anterior chambers of three chinchilla eyes were cannulated ex vivo and readings obtained at manometric IOPs from 5 to 80 mmHg, using each of the three tonometers in random order. Data were analyzed by linear regression, ANOVA, and Bland-Altman plots.

Sex Differences in μ-Opioid Receptor Regulation of the Rat Locus Coeruleus and Their Cognitive Consequences.

Stress-related neuropsychiatric pathologies are more prevalent in females compared with males. An important component of the stress response is activation of the locus coeruleus (LC)-norepinephrine system. Because LC activation is tempered by endogenous opioid release during stress, the magnitude of opioid regulation of the LC could determine stress vulnerability.

Towards theory driven structure elucidation of complex natural products: mandelalides and coibamide A.

The effectiveness of computational tools in determining relative configurations of complex molecules is investigated, using natural products mandelalides A-D and coibamide A, towards a generalized recipe for the scientific community at large. Ultimately, continuing efforts in this vein will accelerate and strengthen relative structure elucidation of complex molecules, such as natural products. Molecular mechanics conformational search, quantum mechanical NMR chemical shift predictions, and DP4 analyses led to confirmation of the revised structures of mandelalides A-D and coibamide A.

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses.

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,β-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated.

Diastereoselective Synthesis of and Mechanistic Understanding for the Formation of 2-Piperidinones from Imines and Cyano-Substituted Anhydrides.

2-Piperidinones are synthesized in a single step from imines and 2-cyano glutaric anhydrides. The reaction provides the products in good diastereoselectivity and generates a quaternary stereogenic center. Substitutions on the anhydride skeleton are well tolerated to provide 2-piperidinones with three stereogenic centers from a single transformation.

Corticotropin-releasing Factor in the Rat Dorsal Raphe Nucleus Promotes Different Forms of Behavioral Flexibility Depending on Social Stress History.

The stress-related neuropeptide, corticotropin-releasing factor (CRF) regulates the dorsal raphe nucleus-serotonin (DRN-5-HT) system during stress and this may underlie affective and cognitive dysfunctions that characterize stress-related psychiatric disorders. CRF acts on both CRF1 and CRF2 receptor subtypes in the DRN that exert opposing inhibitory and excitatory effects on DRN-5-HT neuronal activity and 5-HT forebrain release, respectively. The current study first assessed the cognitive effects of intra-DRN microinfusion of CRF or the selective CRF2 agonist, urocortin II in stress-naive rats on performance of an operant strategy set-shifting task that is mediated by the medial prefrontal cortex (mPFC).

The impact of social stress during adolescence or adulthood and coping strategy on cognitive function of female rats.

The age of stressor exposure can determine its neurobehavioral impact. For example, exposure of adolescent male rats to resident-intruder stress impairs cognitive flexibility in adulthood. The current study examined the impact of this stressor in female rats.

Repeated social stress increases reward salience and impairs encoding of prediction by rat locus coeruleus neurons.

Stress is implicated in psychopathology characterized by cognitive dysfunction. Cognitive responses to stress are regulated by the locus coeruleus-norepinephrine (LC-NE) system. As social stress is a prevalent human stressor, this study determined the impact of repeated social stress on the relationship between LC neuronal activity and behavior during the performance of cognitive tasks.

Cognitive impact of social stress and coping strategy throughout development.

Rationale: Stress experience during adolescence has been linked to the development of psychiatric disorders in adulthood, many of which are associated with impairments in prefrontal cortex function.

Objective: The current study was designed to determine the immediate and enduring effects of repeated social stress on a prefrontal cortex-dependent cognitive task.

Methods: Early adolescent (P28), mid-adolescent (P42), and adult (P70) rats were exposed to resident-intruder stress for 5 days and tested in an operant strategy-shifting task (OSST) during the following week or several weeks later during adulthood.

Preoperative measurement of ACL insertion sites.

This study was designed to evaluate preoperative predictions of the femoral and tibial ACL insertion lengths. Intraoperative measurements were made of the femoral and tibial ACL insertion lengths with an arthroscopic ruler. A musculoskeletal radiologist and a sports medicine orthopedic surgeon measured the ACL insertions from preoperative magnetic resonance imagings (MRIs) in a blinded fashion.

The Xenbase literature curation process.

Xenbase (www.xenbase.org) is the model organism database for Xenopus tropicalis and Xenopus laevis, two frog species used as model systems for developmental and cell biology.

Xenbase: expansion and updates of the Xenopus model organism database.

Xenbase (http://www.xenbase.org) is a model organism database that provides genomic, molecular, cellular and developmental biology content to biomedical researchers working with the frog, Xenopus and Xenopus data to workers using other model organisms.