Which treatment in acetabular fractures of the elderly: Osteosynthesis, osteosynthesis-THA or orthopedic treatment? 2-years retrospective outcomes of a therapeutic algorithm.

Introduction: Acetabular fractures account for 7% of osteoporotic fractures, with an epidemiological peak between 75 and 80 years of age. The aim of this study is to evaluate the results of treatment of these fractures in a population aged over 65.

Hypothesis: Surgical treatment would lead to better survival and functional outcomes in the management of acetabular fractures in subjects aged over 65.

Surgical site infection in severe trauma patients in intensive care: epidemiology and risk factors.

Background: Severe trauma is the leading cause of disability and mortality in the patients under 35 years of age. Surgical site infections (SSI) represent a significant complication in this patient population. However, they are often inadequately investigated, potentially impacting the quality of patient outcomes.

Predictions of tissue concentrations of myclobutanil, oxyfluorfen, and pronamide in rat and human after oral exposures via GastroPlus physiologically based pharmacokinetic modelling.

Heritage agrochemicals like myclobutanil, oxyfluorfen, and pronamide, are extensively used in agriculture, with well-established studies on their animal toxicity. Yet, human toxicity assessment relies on conventional human risk assessment approaches including the utilization of animal-based ADME (Absorption, Distribution, Metabolism, and Excretion) data. In recent years, Physiologically Based Pharmacokinetic (PBPK) modelling approaches have played an increasing role in human risk assessment of many chemicals including agrochemicals.

In vivo genotoxicity testing strategies: Report from the 8th International Workshop on Genotoxicity Testing (IWGT).

The in vivo working group (WG) considered three topics: acceptable maximum doses for negative erythrocyte micronucleus (MN) tests, validation status of MN assays in non-hematopoietic tissues, and nuisance factors in the comet assay. The WG reached agreement on many issues, including: negative erythrocyte MN studies should be acceptable if dosing is conducted to Organisation for Economic Co-operation and Development (OECD) test guideline (TG) 474 recommendations and if sufficient bone marrow exposure is demonstrated; consensus on the evidence required to demonstrate "sufficient" exposure was not reached. The liver MN test using six-week-old rats is sufficiently validated to develop an OECD TG, but the impact of animal age warrants additional study.

An integrated assessment of the 1,4-dioxane cancer mode of action and threshold response in rodents.

1,4-Dioxane is an environmental contaminant that has been shown to cause cancer in rodents after chronic high dose exposures. We reviewed and integrated information from recently published studies to update our understanding of the cancer mode of action of 1,4-dioxane. Tumor development in rodents from exposure to high doses of 1,4-dioxane is preceded by pre-neoplastic events including increased hepatic genomic signaling activity related to mitogenesis, elevation of Cyp2E1 activity and oxidative stress leading to genotoxicity and cytotoxicity.

Prediction of tissue and urine concentrations of 2-phenoxyethanol and its metabolite 2-phenoxyacetic acid in rat and human after oral and dermal exposures via GastroPlus physiologically based pharmacokinetic modelling.

A physiologically based pharmacokinetic (PBPK) model for the important chemical phenoxyethanol (PhE) and its metabolite phenoxyacetic acid (PhAA) was built via GastroPlus software (version 9.0) using currently available analytically measured plasma and urinary time-courses of both PhE and its metabolite PhAA. This model was validated and used to predict tissue and urine concentrations of PhE and its metabolite PhAA in rats and humans after oral and dermal exposures.

Bridging Sex-Specific Differences in the CAR-Mediated Hepatocarcinogenesis of Nitrapyrin Using Molecular and Apical Endpoints.

Nitrapyrin, a nitrification inhibitor, produces liver tumors in B6C3F1 mice. In a 2-year oncogenicity study, increased incidence of mice with hepatocellular tumors was observed following exposure to 125 (females only) or 250 mg/kg/day (males and females) nitrapyrin in the diet. Previous data was generated in male mice to support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor (NR) activation, increased hepatocellular proliferation, and subsequent hepatocellular foci and tumor formation.

Assessment of cellular and molecular metrics for dose selection in an in vivo comet assay: A case study with MDI.

The in vivo comet assay can evaluate the genotoxic potential of a chemical in theoretically any tissue that can be processed to a single cell suspension. This flexibility enables evaluation of point-of-contact tissues using a relevant route of test material administration; however, assessing cytotoxicity is essential for the interpretation of comet results. Histopathological evaluation is routinely utilized to assess cytotoxicity, but temporal- and cell-specific considerations may compromise applicability to the comet assay.

A 90-day drinking water study in mice to characterize early events in the cancer mode of action of 1,4-dioxane.

Studies demonstrate that with sufficient dose and duration, 1,4-dioxane (1,4-DX) induces liver tumors in laboratory rodent models. The available evidence aligns with a threshold-dependent, tumor promotion mode of action (MOA). The MOA and key events (KE) in rats are well developed but less so in the mouse.

Characterization of dermal sensitization potential for industrial or agricultural chemicals with EpiSensA.

The regulatory community is transitioning to the use of nonanimal methods for dermal sensitization assessments; however, some in vitro assays have limitations in their domain of applicability depending on the properties of chemicals being tested. This study explored the utility of epidermal sensitization assay (EpiSensA) to evaluate the sensitization potential of complex and/or "difficult to test" chemicals. Assay performance was evaluated by testing a set of 20 test chemicals including 10 methacrylate esters, 5 silicone-based compounds, 3 crop protection formulations, and 2 surfactant mixtures; each had prior in vivo data plus some in silico and in vitro data.

Investigation of potential early key events and mode of action for 1,2-dichloroethane-induced mammary tumors in female rats.

1,2-dichloroethane (DCE or EDC) is a chlorinated hydrocarbon used as a chemical intermediate, including in the synthesis of polyvinyl chloride. Although DCE has induced tumors in both rats and mice, the overall weight-of-evidence suggests a lack of in vivo mutagenicity. The present study was conducted to explore a potential mode of action further for tumor formation in rat mammary tissue.

Surgical management of proximal femoral metastasis: Fixation or hip replacement? A 309 case series.

Introduction: The proximal femur is the most frequent operative site for metastasis, but there is no consensus between internal fixation and hip replacement. The present multicenter retrospective observational study sought: (1) to compare early clinical results between internal fixation and hip replacement for proximal femoral metastasis (PFM), and (2) to assess events affecting survival.

Hypothesis: The study hypothesis was that internal fixation and hip replacement give comparable clinical results, operative site complications rates and survival.

Functional results and survival after surgery for peripheral skeletal metastasis: A 434-case multicenter retrospective series.

Introduction: Peripheral skeletal metastasis (PSM) has a negative impact on quality of life. New treatments for the primary tumor or the osteolysis hold out hope of improved survival. The few published French series were small, and we therefore undertook a multicenter retrospective analysis of PSM surgery between 2005 and December 2016, with the aim of assessing: 1) rate and type of complications, 2) functional results, and 3) overall survival and corresponding risk factors.

Surgical treatment of tibial metastases: Retrospective, multicenter, observational study of 25 patients.

Introduction: Long bone metastasis to the tibia is somewhat rare and has only been studied in a few publications with a limited number of cases. This led us to carry out a large multicenter, observational, retrospective study to 1) evaluate the clinical and radiological outcomes of surgical treatment at this location and 2) highlight the specific risks associated with this condition.

Hypothesis: We hypothesized that the clinical outcomes and survivorship were comparable to those reported in the literature.

Use of connectivity mapping to support read across: A deeper dive using data from 186 chemicals, 19 cell lines and 2 case studies.

We previously demonstrated that the Connectivity Map (CMap) (Lamb et al., 2006) concept can be successfully applied to a predictive toxicology paradigm to generate meaningful MoA-based connections between chemicals (De Abrew et al., 2016).

Genetic instability of in vitro cell lines: Implications for genetic toxicity testing.

Cell line-based in vitro testing has been widely used as an important component of the genotoxicity testing battery; however, the use of cell lines is constrained by several limitations, including the genetic drift and variability. A study recently reported in the literature comprehensively examined genomic changes in a large number of cell lines and reported extensive genetic variations within the same cell lines across passage numbers and laboratories, even for single-cell derived subclones. The primary objective of this communication is to raise awareness and stimulate discussion within the genotoxicity testing community of the extent of genetic variability of cell lines in general and how these variables could potentially influence the results and reproducibility of genotoxicity testing.

An industry perspective: A streamlined screening strategy using alternative models for chemical assessment of developmental neurotoxicity.

Developmental neurotoxicity (DNT) is an important endpoint for the safety assessment of chemicals. However, the current in vivo animal model for DNT assessment is resource-intensive and may not fully capture all mechanisms that may be relevant to DNT in humans. As a result, there is a growing need for more reliable, time- and cost-efficient approaches for DNT evaluation.

A comparison of transgenic rodent mutation and in vivo comet assay responses for 91 chemicals.

A database of 91 chemicals with published data from both transgenic rodent mutation (TGR) and rodent comet assays has been compiled. The objective was to compare the sensitivity of the two assays for detecting genotoxicity. Critical aspects of study design and results were tabulated for each dataset.

Interprosthetic femoral fractures: Morbidity and mortality in a retrospective, multicenter study.

Introduction: Interprosthetic femoral fractures (IFF) are becoming more frequent; however they have not been the subject of many publications and the largest study on this topic includes only 30 cases. The complication rate and clinical outcomes have only been evaluated in small case series. This led us to conduct a retrospective, multicenter, observational study in IFF patients with at least 12 months' follow-up to (1) determine the mortality and morbidity (2) determine the clinical and radiological outcomes and (3) identify elements of the treatment indications.

Pilot studies evaluating the nongenotoxic rodent carcinogens phenobarbital and clofibrate in the rat Pig-a assay.

The Pig-a assay is an emerging and promising in vivo method to determine mutagenic potential of chemicals. Since its development in 2008, remarkable progress has been made in harmonizing and characterizing the test procedures, primarily using known mutagenic chemicals. The purpose of the present study was to evaluate specificity of the Pig-a assay using two nongenotoxic and well-characterized rodent liver carcinogens, phenobarbital and clofibrate, in male F344/DuCrl rats.

Minimum datasets to establish a CAR-mediated mode of action for rodent liver tumors.

Methods for investigating the Mode of Action (MoA) for rodent liver tumors via constitutive androstane receptor (CAR) activation are outlined here, based on current scientific knowledge about CAR and feedback from regulatory agencies globally. The key events (i.e.

Integration of novel approaches demonstrates simultaneous metabolic inactivation and CAR-mediated hepatocarcinogenesis of a nitrification inhibitor.

Nitrapyrin, a nitrification inhibitor, produces liver tumors in mice at high doses. Several experiments were performed to investigate molecular, cellular, and apical endpoints to define the key events leading to the tumor formation. These data support a mode-of-action (MoA) characterized by constitutive androstane receptor (CAR) nuclear receptor activation, increased hepatocellular proliferation leading to hepatocellular foci and tumor formation.

Applying the erythrocyte Pig-a assay concept to rat epididymal sperm for germ cell mutagenicity evaluation.

The Pig-a assay, a recently developed in vivo somatic gene mutation assay, is based on the identification of mutant erythrocytes that have an altered repertoire of glycosylphosphatidylinositol (GPI)-anchored cell surface markers. We hypothesized that the erythrocyte Pig-a assay concept could be applied to rat cauda epididymal spermatozoa (sperm) for germ cell mutagenicity evaluation. We used GPI-anchored CD59 as the Pig-a mutation marker and examined the frequency of CD59-negative sperm using flow cytometry.

Global regulatory requirements for mutagenicity assessment in the registration of industrial chemicals.

Mutagenicity is an important toxicological endpoint that requires thorough evaluation during the industrial chemical registration process. Regulatory requirements for mutagenicity assessment in registration of industrial chemicals vary in geographic regions (and in some cases by intended application). Here we compile the mutagenicity testing requirements for registration of industrial chemicals from representative geographic regions (in alphabetical order), that is Australia, Brazil, Canada, China, European Union (EU), India, Japan, South Korea, Taiwan, and United States (US).