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Nonclinical implantation studies are a common and often critical step for medical device safety assessment in the bench-to-market pathway. Nonclinical implanted medical devices or drug-device combination products require complex macroscopic and microscopic pathology evaluations due to the physical presence of the device itself and unique tissue responses to device materials. The Medical Device Implant Site Evaluation working group of the Society of Toxicologic Pathology’s (STP) Scientific and Regulatory Policy Committee (SRPC) was tasked with reviewing scientific, technical, and regulatory considerations for these studies. Implant site evaluations require highly specialized methods and analytical schemes that should be designed on a case-by-case basis to address specific study objectives. Existing STP best practice recommendations can serve as a framework when performing nonclinical studies under Good Laboratory Practices and help mitigate limitations in standards and guidances for implant evaluations (e.g., those from the International Organization for Standardization [ISO], ASTM International). This article integrates standards referenced by sponsors and regulatory bodies with practical pathology evaluation methods for implantable medical devices and combination products. The goal is to ensure the maximum accuracy and scientific relevance of pathology data acquired during a medical device or combination drug-device implantation study.

Mim8 is a novel, next-generation factor VIIIa mimetic in development for subcutaneous prophylactic treatment of patients with hemophilia A with and without inhibitors. In vitro and in vivo models indicate that Mim8 has a distinct hemostatic potential.To test the nonclinical safety and pharmacodynamics of Mim8.The Mim8 nonclinical safety program in cynomolgus monkeys consisted of three studies of 4-26 weeks in duration with Mim8 doses ranging from 0.3-60 mg/kg/week intravenously or subcutaneously. After sacrifice, macroscopic and microscopic pathological examinations were performed.Mim8 was well tolerated with no noteworthy clinical observations. No signs of excessive coagulation or pathological macroscopic or microscopic findings were observed at doses 0.3-3 mg/kg/week subcutaneous. Thrombosis-related findings were detected during histopathological examination in a small proportion of animals (16%) receiving doses ranging 6-20 mg/kg/week. Dose-dependent increases in factor X (FX) and factor IX (FIX) concentrations were observed. Shortening of activated partial thromboplastin time (APTT) and increased thrombin generation under ex vivo hemophilia A-like conditions were observed at all Mim8 dose levels.Thrombosis-related findings observed at doses above 6 mg/kg/week Mim8 may have been exaggerated pharmacological reactions to a procoagulant compound in normocoagulant animals. Increases in FX and FIX concentrations could be because of a half-life prolongation due to binding to Mim8, but were limited at clinically relevant exposure levels. Subcutaneous administration of up to 3 mg/kg/week (several fold greater than expected clinical exposure) for 26 weeks resulted in relevant pharmacodynamic effects, observed in thrombin generation and APTT, with no signs of thrombi or excessive coagulation activation.

Adverse childhood experiences (ACEs) are associated with poorer health and educational outcomes. With over 20% of children experiencing multiple ACEs, interventions must target protective factors to improve outcomes among these students. Teacher-student relationships (TSRs) integrated with the Whole School, Whole Community, Whole Child (WSCC) are one promising approach to building resilience to overcome ACEs.A narrative literature review was conducted on ACEs, resilience, TSRs, and the WSCC model to explore the evidence and potential of TSR interventions integrated within the WSCC model to build resilience in students experiencing ACEs.Supportive adult relationships are one of the strongest protective factors against ACEs. TSR interventions have improved student and relationship outcomes. Few studies have explored the relationship between TSRs and ACEs or TSR ACEs interventions. The WSCC model provides opportunities to integrate TSRs and other protective factors into a schoolwide health model to build resilience.TSRs and the WSCC model are promising approaches to target protective factors to mitigate ACEs. Research is needed to further establish TSRs as a protective factor, explore TSR ACEs interventions, and determine best practices for integrating TSRs and resilience in the WSCC model.

This article describes the Society of Toxicologic Pathology’s (STP) five recommended (“best”) practices for appropriate use of informed (non-blinded) versus masked (blinded) microscopic evaluation in animal toxicity studies intended for regulatory review. (1) Informed microscopic evaluation is the default approach for animal toxicity studies. (2) Masked microscopic evaluation has merit for confirming preliminary diagnoses for target organs and/or defining thresholds (“no observed adverse effect level” and similar values) identified during an initial informed evaluation, addressing focused hypotheses, or satisfying guidance or requests from regulatory agencies. (3) If used as the approach for an animal toxicity study to investigate a specific research question, masking of the initial microscopic evaluation should be limited to withholding only information about the group (control or test article-treated) and dose equivalents. (4) The decision regarding whether or not to perform a masked microscopic evaluation is best made by a toxicologic pathologist with relevant experience. (5) Pathology peer review, performed to verify the microscopic diagnoses and interpretations by the study pathologist, should use an informed evaluation approach. The STP maintains that implementing these five best practices has and will continue to consistently deliver robust microscopic data with high sensitivity for animal toxicity studies intended for regulatory review. Consequently, when conducting animal toxicity studies, the advantages of informed microscopic evaluation for maximizing sensitivity outweigh the perceived advantages of minimizing bias through masked microscopic examination.

The purpose of this study was to examine whether the National Scientific Council on the Developing Child (NSCDC) resilience framework statistically predicted whether a child with 4 or more adverse childhood experiences (ACEs) ever had a mental health issue. The study also explored which NSCDC modifiable resilience factors had the strongest relationship with mental health issues among children with 4 or more ACEs. Utilizing the 2019 National Survey of Children's Health, secondary data analysis was conducted using a sample of 1,225 children between 6 and 17 years old that had experienced 4 or more ACEs. Logistic regression examined whether the NSCDC framework was associated with a lower likelihood of mental health issues in school-aged children. Analysis found that the NSCDC framework predicted whether children with 4 or more ACEs ever had a mental health issue. Self-regulation had the strongest relationship with whether a child with 4 or more ACEs ever had a mental health issue. A supportive parent/caregiver relationship was also associated with a lower likelihood of ever having a mental health issue. The results demonstrate the promise of the NSCDC framework and modifiable protective factors to mitigate the impact of ACEs on mental health outcomes. Interventions that teach children skill-based self-regulation and parent/caregiver co-regulation while providing safe and supportive environments can build self-regulation to overcome ACEs. Promoting resilience-building parent-child relationships also have the potential to build resilience to mitigate ACEs.

Zinc|Manganese Dioxide (Zn|MnO2) are widely available as primary batteries for use in small-scale consumer electronics because of its low cost and high energy density. The last decade has seen a resurgence in research to make this chemistry rechargeable by materials engineering, additives and experimenting with various electrolytes. These important contributions have showed that Zn|MnO2 has all the prerequisites to be a post-lithium solution for grid-scale storage. At Urban Electric Power, we have been commercializing proton-insertion Zn|MnO2 batteries in cylindrical and prismatic form factors between 70 to 140Ah nameplate capacity. These batteries contain improved materials and electrode designs with improved utilizations of the cathode and anode theoretical capacity. Both the cathode and anode can achieve 40 to 60% of their theoretical capacity, which is currently the best in alkaline electrolytes and scaled-up cells. These improvements not only reflect the performance but also the manufacturability of cells on a large scale. In this talk, we will present the methodological approach we pursued to achieve these performance metrics and reduce the cost to 2 cells can achieve >6 years of performance for solar microgrid applications, which is better than lead acid batteries, the current battery of choice. We have also manufactured gelled Zn|MnO2 batteries that can be considered as “non-spillable” and thus, “non-hazardous” according to transportation regulations. These non-spillable cells manufacturing process and performance will also be presented in the talk. The talk will also expand on the future generations of Zn|MnO2 that are currently under development at Urban Electric Power like the conversion battery which access the complete 2nd electron capacity of the electrodes and the high voltage (>2.5V) battery. These batteries expand the application space of Zn|MnO2 batteries which make it a viable contender for post lithium-ion batteries.

Sunscreens protect the skin against erythemal radiation (Eer). But at the same time they reduce the effective radiation dose (EVD) responsible for the formation of previtamin D in the skin. The paper describes a calculation method for optimizing the ratio EVD/Eer behind sunscreens e.g. with SPF 5, 15 and 30 respectively. Taking into account that a majority of people in industrialized countries suffer from a shortage in vitamin D even in summer time, the ratio Evd/Eer is a new and important criterion for the quality of sunscreens. Furthermore the exposure time tvd needed per day for forming the equivalent of the recommended amount of 2000 IU of vitamin D per day for skin type 2 is estimated when sunscreens with different filter compositions are used. In vitro experiments show a significant increase of the conversion of 7-dehydrocholesterol (7-DHC) to previtamin D when exposed to artificial solar radiation behind an experimental sunscreen optimized for previtamin D production compared to a commercial sunscreen having the same SPF.

A novel direction of radiology research is better understanding the links between cognitive and personality factors and radiologists' accuracy and performance. This study examines relationships between Emotional Intelligence (EI) scores and observer performance by radiologists in breast cancer detection. Three separate samples were collected with Australian and US breast imaging radiologists. The radiologists were asked to undertake a mammographic interpretation task to identify malignant breast lesions and localise them, in addition to use a confidence rating scale to report confidence in the decision. Following this activity, the radiologists were administered the EI Trait (TEIQue-SF) questionnaire. The Trait EI test gives a Global EI score and 4 sub-scores in Well-being, Self-Control, Emotionality and Sociability. Sample 1 (Sydney 2012) radiologists were divided into 2 experience bands; radiologists practicing

Regulation of metabolic fuel homeostasis is a critical function of β-cells, which are located in the islets of Langerhans of the animal pancreas. Impairment of this β-cell function is a hallmark of pancreatic β-cell failure and may lead to development of type 2 diabetes mellitus. β-Cells are essentially "fuel sensors" that monitor and react to elevated nutrient load by releasing insulin. This response involves metabolic activation and generation of metabolic coupling factors (MCFs) that relay the nutrient signal throughout the cell and induce insulin biosynthesis and secretion. Glucose is the most important insulin secretagogue as it is the primary fuel source in food. Glucose metabolism is central to generation of MCFs that lead to insulin release, most notably ATP. In addition, other classes of nutrients are able to augment insulin secretion and these include members of the lipid and amino acid family of nutrients. Therefore, it is important to investigate the interplay between glucose, lipid, and amino acid metabolism, as it is this mixed nutrient sensing that generate the MCFs required for insulin exocytosis. The mechanisms by which these nutrients are metabolized to generate MCFs, and how they impact on β-cell insulin release and function, are discussed in detail in this article.

application/pdf, 女子大文学. 外国文学篇. 1999, 51, p.69-82

This paper describes a System Verilog Verification Methodology Manual (VMM) test bench architecture that is structured to gain maximum efficiency from both constrained random and directed test case development. We specify how a novel form of directed traffic can be implemented in parallel to a complete random traffic generator inside a reusable directory structure which takes full advantage of coverage and assertion techniques. The paper uses an IEEE-754 compliant Floating-Point adder model as part of a case study that illustrates a complete set of results from using this test bench solution.

This is the third part of a series of three articles on trimming instructions of rat and mouse protocol organs and tissues in regulatory type toxicity studies, covering the urinary, nervous, musculoskeletal, cardiovascular, and lymphoreticular systems. The article is based on the experience of the European RITA and American NACAD working groups and is an extended revision of trimming guides published in 1995 (BAHNEMANN et al.). The optimum localization for tissue preparation, the sample size, the direction of sectioning and the number of sections to be prepared is described organ by organ. These descriptions are illustrated for each organ by a schematic drawing and/or a macro-photograph showing the plane of section as well as a low magnification of the HE stained slide demonstrating the optimum "end-product". The objectives of this work, as addressed in detail in the first part (Ruehl-Fehlert et al. 2003), are to standardize tissue sampling and trimming for comparison of historical data obtained from different studies and different laboratories, ensure the presence of all relevant target sites for histopathological evaluation and provide technical advice for preparatory techniques during necropsy, fixation and trimming (Crissman et al. 2004).

This paper addresses the need for fathers of deaf children to be involved in a parent program. It describes an ongoing parent-education program specifically designed for fathers of young deaf children. The initial diagnosis of deafness in an infant produces startlement and shock in the majority of hearing parents, even though the condition may have been suspected for a long time. This shock gives rise to such emotional expressions as guilt, anger, grief, and repres- sion (Mindel & Vernon, 1971; Schlesinger & Meadow, 1972). Resolution of these feelings is contingent upon the opportunities for parents to understand the nature of the handicap and to voice their frustrations and fears. Initially, the long trek through clinics and educational settings serves to delay opportunities to resolve these feelings, primarily because this is such an arduous and confusing journey and one that is alien to most parents of handicapped children. As diagnosis leads to placement in a program for the deaf child, another barrier against parental understanding and acceptance emerges due to a basic cultural aspect of our society. Although the roles of family provider have been recently undergoing a transition, it is generally still the father in an intact family structure who functions as the primary economic provider. It thus becomes the mother's sole responsibility not only to attend meetings and parent-infant classes but also to provide feedback to the father as to the special nature and needs of their deaf child. This places both mother and father in an unfair position. It is unfair to the mother because of the overwhelming degree of respon- sibility placed on her alone; it is unfair to the father because it divorces him from his individ- ual feelings and attitudes and denies him the