Michael W. Kalichman, PhD, 1980, University of Toronto - US grants

The administration of epidural doses of the local anesthetic NESACAINE-CE (2-chloroprocaine) was the common factor in recent reports of long-lasting neurological deficits following regional anesthesia. Subsequent reviews of the clinical literature as well as numerous experimental studies have failed to discriminate if nerve injury should be attributed to some or all local anesthetics, the NESACAINE antioxidant, or the inadvertent administration of large epidural doses into the spinal cord subarachnoid space. It is not possible to explain these inconsistencies in the absence of information about the mechanisms of the observed injury. Using a rat sciatic nerve model, the applicant has demonstrated that local anesthetic-induced peripheral nerve injury is mediated by an initial increase in permeability of the perineurial sheath, followed by decreased nerve blood flow, dilution of normally hypertonic endoneurial fluid, increased endoneurial fluid pressure, injury of Schwann cells, and nerve fiber injury. In spinal cord the possible interactions between altered permeability of barrier systems, injury-induced fluid accumulation, and changes in interstitial fluid chemistry have not been considered previously for any model of central nervous system toxicity; therefore, it is important that studies in the sciatic nerve be extended to test the hypothesis that spinal cord toxicity following local anesthetic administration is mediated by changes in the interstitial environment affecting both structure and function. Specifically, neurological injury might be secondary to alterations in protective barrier systems and a compromise of nutritive blood flow. Commercial local anesthetic preparations will first be tested using quantitative measures of electrophysiological function in order to determine the relative toxicity of the epidural and subarachnoid routes of administration. Nerve conduction velocity and refractory periods will be determined for both dorsal roots and microfilaments. Using this model of functional deficit, the toxicity of local anesthetics, drug vehicles, and injection volume will be tested. Subsequent experiments will provide functional and structural evidence for corresponding changes in nerve fibers, the dura mater barrier, spinal cord blood flow, and interstitial fluid. These experiments will quantify changes in barrier permeability (penetration of horseradish peroxidase), blood flow (measured with a diffusible tracer), endoneurial fluid electrolytes (visualized with energy dispersive x-ray spectrometry), and fluid pressure.

DESCRIPTION: Candidate: This career development award will allow the candidate to shift his focus as a biomedical scientist toward an independent career in the field of research ethics. The proposed research program provides an ideal framework for his career development goals to acquire expertise in ethical theory, human subject research ethics and policy, and survey methodology. Career development activities will consist of guided reading and discussion with the mentor, auditing of selected courses, and participation in national courses, meetings, and workshops. Environment: The career development and research goals are necessarily multi-disciplinary and multi-institutional. The candidate's mentor, Dr. Lawrence Schneiderman, can contribute approximately 25 years of experience in ethical theory, social research, and biomedical ethics. The candidate's home institution also provides a highly supportive administration as well as faculty and programs with expertise and interest in ethics, clinical research, and social research methods. This will be supplemented by consultants from the Universities of Minnesota, Pittsburgh, and Washington. Research: The need to address research ethics, and specifically clinical research ethics, is driven by several recent trends. The lines between clinical practice and research are increasingly unclear, new technologies are raising difficult questions not previously imagined, and reported violations of the ethical, legal, and social principles governing research with human subjects continue to increase. Formal instruction in research ethics seems an obvious solution and is increasingly required. Unfortunately, empirical data have provided little or no support for the presumed benefits of this training. Therefore, the central hypothesis to be tested is that: Research ethics training has a positive impact on ethical decisionmaking. Specific Aims: Aim #1: Define characteristics of existing training programs that might have an impact on the skills and knowledge necessary for ethical decisionmaking. Aim #2: Conduct pilot assessment of the roles of the different training methods in producing acute and long-term changes in ethical decisionmaking skills and knowledge. Aim #3: Assess acute and long-term effects of ethics training at a wide range of institutions representative of the following dimensions: large, medium, and small; public and private; and historically black and minority colleges and universities. Completion of the proposed aims will provide: valuable new information about the effectiveness of training in research ethics; a foundation for the candidate's independent career in applied research ethics; and the experience and knowledge necessary for the candidate to be a resource to his institution and the research community.

[unreadable] DESCRIPTION (provided by applicant): Discussion of standards of responsible conduct of research (RCR) is recognized as an important part of RCR education. However, almost no empirical research has addressed the common practices of scientists, the views of scientists about ideal standards, or how practices and ideals vary among different research disciplines. We strongly believe that scientists are in the best position to identify and articulate selected standards of scientific conduct. Therefore, we propose to poll active research scientists about standards in [unreadable] three areas: data management, collaboration, and authorship. This will be accomplished with focus group discussions, interviews, and a survey. Recognizing that differences are likely to occur not only within research areas, but also between research areas, four different disciplines have been selected for study: microbiology, neuroscience, nursing, and psychology. The two specific aims of this project are: (1) Construct framework for national survey of RCR standards (focus group discussions with mixed discipline and discipline-specific groups of researchers) and (2) Conduct national survey of RCR standards (interviews of research scientists and Web-based survey of [unreadable] faculty in doctoral programs for each of the four disciplines). Variation of standards within research [unreadable] disciplines as well as differences between disciplines will be identified. The results of this investigation will provide an evidence-based rationale for what RCR course instructors should teach about the standards of responsible conduct. Effective teaching about standards of the [unreadable] responsible conduct of research will help to promote public health by fostering integrity in the conduct of biomedical research. [unreadable] [unreadable] [unreadable]

This Ethics Education in Science and Engineering project will build capacity for faculty to educate graduate students about research ethics in the context of the research environment. This approach is grounded in and flows from extensive empirical evidence that standards of conduct depend as much or more on the work environment than on participation in isolated courses or online tutorials.
The four project objectives include: 1. Consensus Conference to develop a framework to build a curriculum for Capacity-Building Workshops. 2. Curriculum Development for the Workshops. 3. Capacity-Building Workshops. 4. Outcome Assessments: Revise and finalize the Workshop curriculum based on feedback from faculty participants and their graduate student trainees.

This project will pilot the proposed workshops in 8 public and 7 private graduate institutions, including 3 Historically Black Colleges and Universities (HBCUs). To foster approaches responsive to the globalization of the research community, the proposed Expert Panel includes a member with extensive academic connections in China, and Chinese graduate students will be among those assisting with key aspects of curriculum development.

Broader impacts will derive from the activities, outputs and outcomes of this project and will enhance graduate ethics education for STEM graduate students while promoting the development of a diverse community of researchers better prepared to model the highest standards of scientific conduct. Results of the project will be promptly and widely disseminated through workshops conducted by participating faculty, established research ethics websites as well as the new National Center for Professional and Research Ethics.

DESCRIPTION (provided by applicant): Studies of HIV transmission within populations (i.e., transmission networks) have demonstrated the critical importance of highly connected individuals (i.e., defined by highly related HIV strains indicative of putative transmissions) in sustaining the rate of HIV epidemic spread. The high mutation rate associated with HIV replication provides a nearly unique HIV genetic sequence (i.e., a fingerprint equivalent) in infected individuals resulting in an opportunity to study patterns of transmission network structure. While molecular epidemiologic data are used to track changes in epidemic course and geography, they are rarely (if ever) applied in real time to refocus prevention and treatment interventions to discrete populations or clusters within a population. Because partial HIV-1 pol sequences are generated for routine drug resistance testing, the data necessary to perform molecular analyses are readily available. Paired with appropriate epidemiologic data, network analyses can be used to identify emerging epidemics within groups of individuals related by similar patterns of illicit substance use, drug resistance, sexually transmitted infection, venues f exposure and stage of HIV infection that are appropriate targets for treatment and prevention interventions. Despite the significant public health advantage to using HIV genetic data to study and potentially intervene on real-time network spread of disease, these studies have been limited by fears of loss of privacy related to hypothetical disclosure of potential transmission between two or more individuals. Such disclosure of putative transmission between two or more individuals represents a concern for both consumers and healthcare providers. Unfortunately, no metrics exist to quantify this risk, and no guidelines exist for the use of non-host genetics to target interventions for infectious epidemics. The lack of guidelines in this sensitive area limits progress and research in the molecular epidemiology of HIV. There is an urgent need for guidelines based on both perspectives of the diverse stakeholders and on better definition and quantification of the limits of privacy risk. Our overall goal is to characterize perceptions of privacy risk among stakeholders and reduce uncertainty regarding privacy risk in HIV network analysis. To address the ethical challenges highlighted by the conflict between the public health potential to limit HIV transmission and the need to maximally protect personal healthcare privacy, we propose two Specific Aims: 1) Assess perceptions regarding HIV transmission network analyses. and 2) demonstrate strong quantifiable privacy associated with transmission network analysis. This proposal will be the first to begin framing the risk-benefit ratio for the ue of HIV genetic data used for molecular epidemiologic analyses to target interventions based on HIV transmission networks. The outcomes of these analyses may serve as a foundation for future discussions of genetic investigations of outbreaks and spread of other human pathogens.

Most scientific ethics training programs rely heavily on online or in-person training, but such programs are limited in their efficacy and often fail to address the broader cultural aspects of scientific ethics and scientific misconduct. The goal of this project is to cultivate a culture of scientific ethics at the UC San Diego Jacobs School of Engineering. The investigators will do so by using a diversity of approaches at multiple levels within the school. A major component will be to empower faculty and other stakeholders to create a self-perpetuating culture of scientific ethics at their institution. Social surveys will be used to assess and understand the current ethical culture at UC San Diego. Next, the investigators will organize a retreat with deans, faculty, and administrators to discuss scientific ethics and hold a workshop based on findings from conversations at the retreat. The workshop will also be used to conduct a comprehensive literature review on pathways for creating a culture of scientific ethics, and to develop specific plans for doing so at UC San Diego. The final research component will be systematically testing and evaluating the impact of their activities on scientific ethics at their university.

The main goal of this study is to understand how to create a culture of scientific ethics at a major university and to then use that information to create institutional transformation at UC San Diego. The project moves beyond current approaches to studying and encouraging scientific ethics in four ways: (1) comparing faculty perceptions to gauge the presence of an ethical culture; (2) empowering faculty as agents of cultural change; (3) applying department specific approaches to encouraging and cultivating a culture of ethics; and (4) emphasizing the importance of local cultures and climates for shaping ethical behavior, rather than simply explaining it as the behavior of one or two unethical individuals. These four novel elements will advance understanding of research integrity and provide tools for affecting cultural changes towards ethical science at major research universities. Overall, the project will benefit society by promoting ethical teaching, training, and learning, and by nurturing a community of researchers who will be better prepared to engage in discussions about ethical dimensions of academia and research.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.