Ecological Assessment of Executive Function in Traumatic Brain Injury

Executive dysfunction is a common outcome in children who have sustained traumatic brain injury (TBI). Appropriate assessment of these complex interrelated regulatory functions is critical to plan for the necessary interventions yet present a challenge to our traditional methodologies. Ecological validity has become an increasingly important focus in neuropsychological assessment with particular relevance for the executive functions, which coordinate one's cognitive and behavioral capacities with real-world demand situations. The Behavior Rating Inventory of Executive Function (BRIEF) was developed to capture the real-world behavioral manifestations of executive dysfunction. Its development and various forms of validity, including ecological validity, are described. Application of the BRIEF's methodology to the assessment of executive dysfunction in TBI is provided. We advocate a multilevel approach to understanding executive function outcome in TBI, including traditional test-based measures of executive function, real-world behavioral manifestation of executive dysfunction, and the environmental system factors that impact the child. In this model, ecologically valid assessment of executive dysfunction provides an important bridge toward understanding the impact of component-level (i.e., test-based) deficits on the child's everyday adaptive functioning, which can assist the definition of targets for intervention.     

In utero Exposure to Genotoxicants Leading to Genetic Mosaicism: An Overlooked Window of Susceptibility in Genetic Toxicology Testing?

In utero development represents a sensitive window for the induction of mutations. These mutations may subsequently expand clonally to populate entire organs or anatomical structures. Although not all adverse mutations will affect tissue structure or function, there is growing evidence that clonally expanded genetic mosaics contribute to various monogenic and complex diseases, including cancer. We posit that genetic mosaicism is an underestimated potential health problem that is not fully addressed in the current regulatory genotoxicity testing paradigm. Genotoxicity testing focuses exclusively on adult exposures and thus may not capture the complexity of genetic mosaicisms that contribute to human disease. Numerous studies have shown that conversion of genetic damage into mutations during early developmental exposures can result in much higher mutation burdens than equivalent exposures in adults in certain tissues. Therefore, we assert that analysis of genetic effects caused by in utero exposures should be considered in the current regulatory testing paradigm, which is possible by harmonization with current reproductive/developmental toxicology testing strategies. This is particularly important given the recent proposed paradigm change from simple hazard identification to quantitative mutagenicity assessment. Recent developments in sequencing technologies offer practical tools to detect mutations in any tissue or species. In addition to mutation frequency and spectrum, these technologies offer the opportunity to characterize the extent of genetic mosaicism following exposure to mutagens. Such integration of new methods with existing toxicology guideline studies offers the genetic toxicology community a way to modernize their testing paradigm and to improve risk assessment for vulnerable populations. Environ. Mol. Mutagen. 61:55–65, 2020. © 2019 The Authors. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.     

Genetic variations as cancer prognostic markers: review and update

Cancer molecular epidemiology traditionally studies the relationship between genetic variations and cancer risk. However, recent studies have also focused on disease outcomes. The application and design of disease outcome studies have been an extension of disease risk assessment. Yet there are a number of unique considerations important in outcome assessments. We review how genetic approaches used for disease susceptibility, such as candidate gene and genome‐wide association study (GWAS) approaches, can be adapted carefully to systematically identify cancer prognostic and predictive alleles. We discuss the interrelatedness among the disease susceptibility, treatment response, and prognosis at the genetic level and focus on how the emerging technologies and approaches can uniquely benefit the genetic prognosis studies. Hum Mutat 30:1–9, 2009. © 2009 Wiley‐Liss, Inc.     

An analysis of pharmaceutical experience with decades of rat carcinogenicity testing: support for a proposal to modify current regulatory guidelines

Data collected from 182 marketed and nonmarketed pharmaceuticals demonstrate that there is little value gained in conducting a rat two-year carcinogenicity study for compounds that lack: (1) histopathologic risk factors for rat neoplasia in chronic toxicology studies, (2) evidence of hormonal perturbation, and (3) positive genetic toxicology results. Using a single positive result among these three criteria as a test for outcome in the two-year study, fifty-two of sixty-six rat tumorigens were correctly identified, yielding 79% test sensitivity. When all three criteria were negative, sixty-two of seventy-six pharmaceuticals (82%) were correctly predicted to be rat noncarcinogens. The fourteen rat false negatives had two-year study findings of questionable human relevance. Applying these criteria to eighty-six additional chemicals identified by the International Agency for Research on Cancer as likely human carcinogens and to drugs withdrawn from the market for carcinogenicity concerns confirmed their sensitivity for predicting rat carcinogenicity outcome. These analyses support a proposal to refine regulatory criteria for conducting a two-year rat study to be based on assessment of histopathologic findings from a rat six-month study, evidence of hormonal perturbation, genetic toxicology results, and the findings of a six-month transgenic mouse carcinogenicity study. This proposed decision paradigm has the potential to eliminate over 40% of rat two-year testing on new pharmaceuticals without compromise to patient safety.     

Genotoxicity of nanomaterials: Refining strategies and tests for hazard identification

A workshop addressing strategies for the genotoxicity assessment of nanomaterials (NMs) was held on October 23, 2010 in Fort Worth Texas, USA. The workshop was organized by the Environmental Mutagen Society and the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute. The workshop was attended by more than 80 participants from academia, regulatory agencies, and industry from North America, Europe and Japan. A plenary session featured summaries of the current status and issues related to the testing of NMs for genotoxic properties, as well as an update on international activities and regulatory approaches. This was followed by breakout sessions and a plenary session devoted to independent discussions of in vitro assays, in vivo assays, and the need for new assays or new approaches to develop a testing strategy for NMs. Each of the standard assays was critiqued as a resource for evaluation of NMs, and it became apparent that none was appropriate without special considerations or modifications. The need for nanospecific positive controls was questioned, as was the utility of bacterial assays. The latter was thought to increase the importance of including mammalian cell gene mutation assays into the test battery. For in‐vivo testing, to inform the selection of appropriate tests or protocols, it was suggested to run repeated dose studies first to learn about disposition, potential accumulation, and possible tissue damage. It was acknowledged that mechanisms may be at play that a standard genotoxicity battery may not be able to capture. Environ. Mol. Mutagen. 54:229–239, 2013. © 2013 Wiley Periodicals, Inc.     

Child-Focused Behavioral Assessment and Modification

Argues that behavioral principles have been translated into practice with children too literally and that a more integrative framework is required to guide assessment and treatment. The framework advocated is Staats's (1996) psychological behaviorism. This is a consistently behavioristic, positivist paradigm, using multilevel theory to emphasize the integration of social learning, developmental, and personality principles. Psychological behaviorism thus allows for a much more expansive approach than has typically been the case within child behavior therapy. Given the complexity of this perspective, I selected four broad tenets of the theory and suggested their implications for clinical contexts. The further translation from clinical models to specific clinical practices is quite difficult but may yield more flexible and substitutable practices than do unidimensional treatment outcome studies. Of special importance, the principles demonstrate how children themselves can retain the central focus of child behavioral assessment and modification. Specific practices still need to be constructed according to an understanding of the multiple sources of influence on children as well as the culture of childhood itself.     

Quantitative risk assessment: qualms and questions

Within the past ten years, quantitative risk assessment has come to play a central role in the federal regulation of carcinogens. Federal agencies use quantitative risk both to set priorities and to establish exposure levels. The use of quantitative risk assessment is mandated by Executive Orders requiring performance of cost-benefit analysis, although performance of assessments has often been ascribed to the Supreme Court decision in the 1980 "benzene" case. Quantitative risk assessment is a deeply flawed methodology with results that give a false sense of certainty and objectivity. Also, the nature of quantitative risk assessment methodologies currently in use makes it difficult for members of the public to scrutinize and assess regulatory actions. Quantitative risk assessment should not be used for regulation of carcinogens, especially not for establishing exposure levels. Instead, alternative methodologies should be utilized, which are appropriately reflective of uncertainty and which are more readily accessible to public scrutiny and participation.     

Hereditary breast and ovarian cancer: Referral source for genetic assessment and communication regarding assessment with nongenetic clinicians in the community setting

PurposeTo examine referral source to cancer genetic services; communication of results of genetic evaluation to clinicians; role of clinicians in postcounseling management; and use of alternative information sources after cancer genetic risk assessment/counseling in the community setting.MethodsRetrospective telephone survey. Setting: A community/private hospital-based cancer genetic counseling service.PatientsWomen, at least 21 years of age, who had undergone cancer genetic counseling with (1) at least a 10% predicted likelihood of carrying a BRCA1/2 mutation or (2) a documented BRCA1/2 mutation.InterventionA 121-item telephone survey. Main outcome measure: (1) initial referral source to cancer genetic services; (2) women's communication of results of cancer genetic assessment to primary and (nongenetic) specialist clinician(s); (3) education and support role played by subjects' physician(s); and (4) use of other hereditary breast and ovarian cancer (HBOC) information resources.ResultsOf 225 women eligible for study, 69 (31%) completed the survey. Sixty-two percent were referred by their medical oncologist; 13% by their primary care physician, and fewer by their surgeon (6%) or gynecologist (4%). Results of the cancer genetic assessment were not shared with 19% of primary care clinicians, 26% of primary gynecologists, 12% of oncologists, and 36% of surgeons. Twenty-six percent of participants noted that their primary care clinician had not been involved in their HBOC-related, cancer prevention decisions, 16% had not included their gynecologist, 2% had not involved their oncologist, and 20% replied that their surgeon had not been involved in these decisions. Overall, clinicians were perceived as supportive when it came to a participants' information and decision support needs. One exception was that 21% of respondents reported the use by clinicians of medical terms, without definition. Over two-thirds had sought alternative “self-help” HBOC-related materials, most Internet based.ConclusionsThese results have implications for interdisciplinary communication and decision support for those with or at risk for HBOC, cared for in the community setting.     

Exploring attitudes,beliefs, and communication preferences of Latino community members regarding BRCA1/2 mutation testing and preventive strategies

PurposeTo inform development of a culturally sensitive hereditary breast and ovarian cancer communication initiative and related clinical genetic services.MethodsFive focus groups were conducted with 51 female and male Latinos. Educational materials were designed to communicate information about hereditary breast or ovarian cancer and availability of relevant clinical services or prevention strategies. Focus groups explored participants' knowledge, attitudes, and beliefs about hereditary breast and ovarian cancer, BRCA1/2 testing, and communication preferences for hereditary breast and ovarian cancer health messages.ResultsOverall, awareness of familial breast and ovarian cancer and availability of genetic risk assessment was low. Once informed, participants held favorable attitudes toward risk assessment and counseling services. Critical themes of the research highlighted the need to provide bilingual media products and use of a variety of strategies to increase awareness about hereditary cancer risk and availability of clinical genetic services. Important barriers were identified regarding family cancer history communication and cancer prevention services. Strategies were suggested for communicating cancer genetic information to increase awareness and overcome these barriers; these included both targeted and tailored approaches.ConclusionThis research suggests that cancer genetic communication efforts should consider community and cultural perspectives as well as health care access issues before widespread implementation.     

Opportunities to integrate new approaches in genetic toxicology: An ILSI‐HESI workshop report

Genetic toxicity tests currently used to identify and characterize potential human mutagens and carcinogens rely on measurements of primary DNA damage, gene mutation, and chromosome damage in vitro and in rodents. The International Life Sciences Institute Health and Environmental Sciences Institute (ILSI‐HESI) Committee on the Relevance and Follow‐up of Positive Results in In Vitro Genetic Toxicity Testing held an April 2012 Workshop in Washington, DC, to consider the impact of new understanding of biology and new technologies on the identification and characterization of genotoxic substances, and to identify new approaches to inform more accurate human risk assessment for genetic and carcinogenic effects. Workshop organizers and speakers were from industry, academe, and government. The Workshop focused on biological effects and technologies that would potentially yield the most useful information for evaluating human risk of genetic damage. Also addressed was the impact that improved understanding of biology and availability of new techniques might have on genetic toxicology practices. Workshop topics included (1) alternative experimental models to improve genetic toxicity testing, (2) Biomarkers of epigenetic changes and their applicability to genetic toxicology, and (3) new technologies and approaches. The ability of these new tests and technologies to be developed into tests to identify and characterize genotoxic agents; to serve as a bridge between in vitro and in vivo rodent, or preferably human, data; or to be used to provide dose response information for quantitative risk assessment was also addressed. A summary of the workshop and links to the scientific presentations are provided. Environ. Mol. Mutagen. 56:277–285, 2015. © 2014 Wiley Periodicals, Inc.     

From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals

Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti‐drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA ‘incidence’ rates can vary greatly between same‐class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product‐specific and patient‐specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths.     

Methodologies for assessing telemedicine: a systematic review of reviews

Background and objectives

Previous reviews have expressed concerns about the quality of telemedicine studies. There is debate about shortcomings and appropriate methodologies. The aim of this review of systematic reviews of telemedicine is to summarize methodologies used in telemedicine research, discuss knowledge gaps and recommendations and suggest methodological approaches for further research.

Methods

We conducted a review of systematic reviews of telemedicine according to a protocol listing explicit methods, selection criteria, data collection and quality assessment procedures. We included reviews where authors explicitly addressed and made recommendations for assessment methodologies. We did a qualitative analysis of the reviews included, sensitized by two broad methodological positions; positivist and naturalistic approaches. The analysis focused on methodologies used in the primary studies included in the reviews as reported by the review authors, and methodological recommendations made by the review authors.

Results

We identified 1593 titles/abstracts. We included 50 reviews that explicitly addressed assessment methodologies. One group of reviews recommended larger and more rigorously designed controlled studies to assess the impacts of telemedicine; a second group proposed standardisation of populations, and/or interventions and outcome measures to reduce heterogeneity and facilitate meta-analysis; a third group recommended combining quantitative and qualitative research methods; and others applying different naturalistic approaches including methodologies addressing mutual adaptations of services and users; politically driven action research and formative research aimed at collaboration to ensure capacity for improvement of services in natural settings.

Conclusions

Larger and more rigorous studies are crucial for the production of evidence of effectiveness of unambiguous telemedicine services for pre defined outcome measures. Summative methodologies acknowledging telemedicine as complex innovations and outcomes as partly contingent on values, meanings and contexts are also important. So are formative, naturalistic methodologies that acknowledge telemedicine as ongoing collaborative achievements and engage with stakeholders, including patients to produce and conceptualise new and effective telemedicine innovations.     

Using Alzheimer's disease as a model for genetic risk disclosure: implications for personal genomics

Susceptibility testing for common, complex adult-onset diseases is projected to become more commonplace as the rapid pace of genomic discoveries continues, and evidence regarding the potential benefits and harms of such testing is needed to inform medical practice and health policy. Apolipoprotein E (APOE) testing for risk of Alzheimer's disease (AD) provides a paradigm in which to examine the process and impact of disclosing genetic susceptibility for a prevalent, severe and incurable neurological condition. This review summarizes findings from a series of multi-site randomized clinical trials examining psychological and behavioral responses to various methods of genetic risk assessment for AD using APOE disclosure. We discuss challenges involved in disease risk estimation and communication and the extent to which participants comprehend and perceive utility in their genetic risk information. Findings on the psychological impact of test results are presented (e.g. distress), along with data on participants' health behavior and insurance purchasing responses (e.g. long-term care). Finally, we report comparisons of the safety and efficacy of intensive genetic counseling approaches to briefer models that emphasize streamlined processes and educational materials. The implications of these findings for the emerging field of personal genomics are discussed, with directions identified for future research.     

Effects of genetic risk information on children's psychosocial wellbeing: A systematic review of the literature

PurposeAs advances in research have made a growing number of genetic tests available, clinicians will increasingly be faced with making decisions about when offering genetic testing services to children is appropriate. A key factor in such decisions involves determining whether knowledge of genetic health risks might have an impact on children's psychosocial wellbeing.MethodsWe conducted a systematic review of the literature using five online databases to identify studies that assessed the impact of communicating nondiagnostic carrier or presymptomatic genetic test results to children.ResultsA total of 17 articles met the inclusion criteria for this review. These studies used a wide range of methodologies to explore carrier and predictive testing. Although there was little quantitative evidence that receiving genetic test results led to a significant impact on children's psychosocial wellbeing, it was found that methodological inconsistencies, small samples, and reliance on assessments most appropriate for psychopathology make any firm conclusions about the impact of genetic testing on children premature.ConclusionCurrently, there is insufficient evidence to inform a nuanced understanding of how children respond to genetic testing. This suggests a strong need for further research that uses rigorous approaches to address children's emotional states, self-perception, and social wellbeing.     

Neuropsychological assessment of young people at high genetic risk for developing schizophrenia compared with controls: preliminary findings of the Edinburgh High Risk Study (EHRS)

BACKGROUND: Finding risk indicators for schizophrenia among groups of individuals at high genetic risk for the disorder, has been the driving force of the high risk paradigm. The current study describes the preliminary results of a neuropsychological assessment battery conducted on the first 50% of subjects from the Edinburgh High Risk Study. METHODS: One hundred and four high risk subjects and 33 normal controls, age and sex matched, were given a neuropsychological assessment battery. The areas of function assessed and reported here include intellectual function, executive function, perceptual motor speed, mental control/ encoding, verbal ability and language, learning and memory measures, and handedness. RESULTS: The high risk subjects performed significantly more poorly than the control subjects in the following domains of neuropsychological function: intellectual function, executive function, mental control/encoding and learning, and memory. Controlling for IQ, high risk subjects made significantly more errors on the Hayling Sentence Completion Test (HSCT), took longer to complete section A of the HSCT, had lower scores on the delayed recall condition of the visual reproductions subtest of the Wechsler Memory Scale-Revised, and had significantly poorer Rivermead Behavioural Memory Test (RBMT) standardized scores. The presence of significant group by IQ interactions for the RBMT and time to complete section A of the HSCT suggested that differences among the groups were more marked in the lower IQ range. Performance on the HSCT was found to be related to the degree of family history of schizophrenia. CONCLUSIONS: High risk subjects performed more poorly than controls on all tests of intellectual function and on aspects of executive function and memory.     

Pregnancy drugs,fetal germline epigenome,and risks for next-generation pathology: A call to action

Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the unique molecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined with empirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long-term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we (1) suggest that pregnancy drugs common in the postwar decades should be investigated as potential contributors to the “missing heritability” of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drug safety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol, a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. Environ. Mol. Mutagen. 60:445–454, 2019. © 2019 Wiley Periodicals, Inc.     

国内外定制式增材制造医疗器械监管法规概述及对行业发展的思考

目的 概述国内外定制式增材制造医疗器械监管法规,分析医疗器械监管科学研究对增材制造医疗器械行业发展的意义,以期能够为生产企业及监管机构未来的工作提供参考。方法 该文通过对国内外关于定制式增材制造医疗器械监管法规及注册体系进行分析,剖析定制式增材制造医疗器械监管法规及注册体系的创新发展对于我国医疗器械行业发展的拉动效应。结果 美国、欧盟、澳大利亚、加拿大、中国均已建立定制式增材制造医疗器械监管法规及注册体系,给出了定制式医疗器械的定义,明确了定制式医疗器械临床使用和上市后监管的要求,但各国间还存在一定的差异,使得各国对于定制式医疗器械的监管模式也稍有差异,建立医疗器械科学监管模式将推动增材制造医疗器械行业发展。结论 构建基于精准风险控制的评价监管体系,加强监管人员、审评人员与科研、医疗人员间的相互协同作用将有助于定制式增材制造医疗器械科学监管模式的构建。     

The Genome Clinic: A Multidisciplinary Approach to Assessing the Opportunities and Challenges of Integrating Genomic Analysis into Clinical Care

Our increasing knowledge of how genomic variants affect human health and the falling costs of whole‐genome sequencing are driving the development of individualized genetic medicine. This new clinical paradigm uses knowledge of an individual's genomic variants to guide health care decisions throughout life, to anticipate, diagnose, and manage disease. While individualized genetic medicine offers the promise of transformative change in health care, it forces us to reconsider existing ethical, scientific, and clinical paradigms. The potential benefits of presymptomatic identification of at risk individuals, improved diagnostics, individualized therapy, accurate prognosis, and avoidance of adverse drug reactions coexist with the potential risks of uninterpretable results, psychological harm, outmoded counseling models, and increased health care costs. Here, we review the challenges of integrating genomic analysis into clinical practice and describe a prototype for implementing genetic medicine. Our multidisciplinary team of bioinformaticians, health economists, ethicists, geneticists, genetic counselors, and clinicians has designed a “Genome Clinic” research project that addresses multiple challenges in genomic medicine—ranging from the development of bioinformatics tools for the clinical assessment of genomic variants and the discovery of disease genes to health policy inquiries, assessment of clinical care models, patient preference, and the ethics of consent.