Gait kinematics and kinetics in patients with chronic ankle instability and healthy controls: A statistical parametric mapping analysis.

Background: Chronic ankle instability (CAI) is associated with changes in gait biomechanics which may be related to chronic dysfunction. Traditional statistical models may be limited in their ability to assess the complex 3D movement of the lower extremity during gait. Multivariate analysis of the lower extremity kinematics may reveal unique biomechanical differences associated with CAI.

Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency.

A thorough literature review was undertaken to understand how the pathways of -nitrosamine transformation relate to mutagenic potential and carcinogenic potency in rodents. Empirical and computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at the α-carbon; it is responsible for both activation, leading to the formation of DNA-reactive diazonium species, and deactivation by denitrosation. There are competing sites of CYP metabolism (e.

Principles and Procedures for Assessment of Acute Toxicity Incorporating Methods.

Acute models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed.

Use of the bacterial reverse mutation assay to predict carcinogenicity of N-nitrosamines.

Under ICH M7, impurities are assessed using the bacterial reverse mutation assay (i.e., Ames test) when predicted positive using in silico methodologies followed by expert review.

Utility of a next-generation framework for assessment of genomic damage: A case study using the pharmaceutical drug candidate etoposide.

We present a hypothetical case study to examine the use of a next-generation framework developed by the Genetic Toxicology Technical Committee of the Health and Environmental Sciences Institute for assessing the potential risk of genetic damage from a pharmaceutical perspective. We used etoposide, a genotoxic carcinogen, as a representative pharmaceutical for the purposes of this case study. Using the framework as guidance, we formulated a hypothetical scenario for the use of etoposide to illustrate the application of the framework to pharmaceuticals.

Single leg aerobic capacity and strength in individuals with surgically repaired anterior cruciate ligaments.

Objectives: Compare single-leg aerobic capacity and strength differences between the surgically repaired ACL leg (injured) and the uninjured leg.

Design: Cross-sectional study.

Setting: Laboratory.

Nonclinical safety assessment of epigenetic modulatory drugs: Current status and industry perspective.

Pharmaceutic products designed to perturb the function of epigenetic modulators have been approved by regulatory authorities for treatment of advanced cancer. While the predominant effort in epigenetic drug development continues to be in oncology, non-oncology indications are also garnering interest. A survey of pharmaceutical companies was conducted to assess the interest and concerns for developing small molecule direct epigenetic effectors (EEs) as medicines.

Analysis of historical negative control group data from the rat in vivo micronucleus assay.

A database of micronuclei counts for historical negative control data from rat in vivo micronuclei tests performed in 10 different laboratories was established. Data were available from over 4000 negative control rats from 10 laboratories. The mean frequency of micronucleated cells (MN)/1000 cells ranged from 0.

Application of the adverse outcome pathway framework to genotoxic modes of action.

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP.

Chemical Markers for Short- and Long-Term Areca Nut Exposure.

Areca nut (AN) chewing causes oral cancer. AN cessation programs are the most effective approach to reduce AN chewing induced cancers but require biomarkers to determine program compliance and success. To explore chemical markers for short- and long-term AN exposure using non-invasively collected saliva, buccal cells (BCs), and scalp hair of chewers.

Genetic toxicology in silico protocol.

In silico toxicology (IST) approaches to rapidly assess chemical hazard, and usage of such methods is increasing in all applications but especially for regulatory submissions, such as for assessing chemicals under REACH as well as the ICH M7 guideline for drug impurities. There are a number of obstacles to performing an IST assessment, including uncertainty in how such an assessment and associated expert review should be performed or what is fit for purpose, as well as a lack of confidence that the results will be accepted by colleagues, collaborators and regulatory authorities. To address this, a project to develop a series of IST protocols for different hazard endpoints has been initiated and this paper describes the genetic toxicity in silico (GIST) protocol.

The Effects of Cognitive Loading on Motor Behavior in Injured Individuals: A Systematic Review.

Background: Research suggests that individuals with musculoskeletal injury may have difficulty negotiating physical tasks when they are combined with cognitive loads.

Objective: Our objective was to conduct a systematic review to understand the effects of increased cognitive demand on movement patterns among individuals with musculoskeletal injuries.

Methods: A comprehensive search of PubMed, MEDLINE, the Cumulative Index for Nursing and Allied Health Literature (CINAHL), and SPORTDiscus was conducted to find research reports that included a population that had previously experienced an ankle, knee, or low back injury, included an uninjured control group, and assessed a dual-task paradigm.

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model.

A Case of Urethral Diverticulum with Surgical Repair Using Cadaveric Pericardial Tissue.

A urethral diverticulum is a relatively uncommon finding. The estimated prevalence is approximately 1-5% in the general population. While the definitive treatment is surgical correction, there are limited studies guiding the best approach to repair.

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: is aromatic N-oxide a structural alert for predicting DNA-reactive mutagenicity?

(Quantitative) structure-activity relationship or (Q)SAR predictions of DNA-reactive mutagenicity are important to support both the design of new chemicals and the assessment of impurities, degradants, metabolites, extractables and leachables, as well as existing chemicals. Aromatic N-oxides represent a class of compounds that are often considered alerting for mutagenicity yet the scientific rationale of this structural alert is not clear and has been questioned. Because aromatic N-oxide-containing compounds may be encountered as impurities, degradants and metabolites, it is important to accurately predict mutagenicity of this chemical class.

In silico toxicology protocols.

The present publication surveys several applications of in silico (i.e., computational) toxicology approaches across different industries and institutions.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals.

[F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling.

Purpose: [F]fluorocholine PET/CT can detect hepatocellular carcinoma (HCC) based on imaging the initial steps of phosphatidylcholine synthesis. To relate the diagnostic performance of [F]fluorocholine positron emission tomography (PET)/x-ray computed tomography (CT) to the phospholipid composition of liver tumors, radiopathologic correspondence was performed in patients with early-stage liver cancer who had undergone [F]fluorocholine PET/CT before tumor resection.

Procedures: Tumor and adjacent liver were profiled by liquid chromatography mass spectrometry, quantifying phosphatidylcholine species by mass-to-charge ratio.

The Effects of Local Vibration on Balance, Power, and Self-Reported Pain After Exercise.

Context: Muscle fatigue and acute muscle soreness occur after exercise. Application of a local vibration intervention may reduce the consequences of fatigue and soreness.

Objective: To examine the effects of a local vibration intervention after a bout of exercise on balance, power, and self-reported pain.

Novel statistical approach for evaluating flow cytometric in vitro micronucleus data.

Statistical methods currently recommended for analysis of in vitro micronucleus data are based on small sample sizes. The tests are designed to evaluate linear trends and differences between treated and control samples. When using flow cytometric analysis, >5 times the number of cells are easily evaluated, and the variance estimates from these large samples are small.

Extending (Q)SARs to incorporate proprietary knowledge for regulatory purposes: A case study using aromatic amine mutagenicity.

Statistical-based and expert rule-based models built using public domain mutagenicity knowledge and data are routinely used for computational (Q)SAR assessments of pharmaceutical impurities in line with the approach recommended in the ICH M7 guideline. Knowledge from proprietary corporate mutagenicity databases could be used to increase the predictive performance for selected chemical classes as well as expand the applicability domain of these (Q)SAR models. This paper outlines a mechanism for sharing knowledge without the release of proprietary data.

Principles and procedures for implementation of ICH M7 recommended (Q)SAR analyses.

The ICH M7 guideline describes a consistent approach to identify, categorize, and control DNA reactive, mutagenic, impurities in pharmaceutical products to limit the potential carcinogenic risk related to such impurities. This paper outlines a series of principles and procedures to consider when generating (Q)SAR assessments aligned with the ICH M7 guideline to be included in a regulatory submission. In the absence of adequate experimental data, the results from two complementary (Q)SAR methodologies may be combined to support an initial hazard classification.

Establishing best practise in the application of expert review of mutagenicity under ICH M7.

The ICH M7 guidelines for the assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals allows for the consideration of in silico predictions in place of in vitro studies. This represents a significant advance in the acceptance of (Q)SAR models and has resulted from positive interactions between modellers, regulatory agencies and industry with a shared purpose of developing effective processes to minimise risk. This paper discusses key scientific principles that should be applied when evaluating in silico predictions with a focus on accuracy and scientific rigour that will support a consistent and practical route to regulatory submission.

Pilot study for the establishment of biomarkers for radiation damage after computed tomography in children.

Computed tomography (CT) is an imaging modality that exposes patients to ionizing radiation (IR). We review and report findings from our pilot study evaluating whether blood markers are altered in 17 children undergoing medically indicated CT scans. Blood was drawn before ('pre-CT') and 1 hour after ('post-CT' CT scans.

Composition of betel specific chemicals in saliva during betel chewing for the identification of biomarkers.

Betel nut chewing causes cancer in humans, including strong associations with head and neck cancer in Guam. In the search for biomarkers of betel chewing we sought to identify chemicals specific for the 3 most commonly consumed betel preparations in Guam: nut ('BN'), nut + Piper betle leaf ('BL'), and betel quid ('BQ') consisting of nut + lime + tobacco + Piper betle leaf. Chemicals were extracted from the chewing material and saliva of subjects chewing these betel preparations.