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Human genetic research involves the study of inherited human traits. Much of this research is aimed at identifying DNA mutations that can help cause specific health problems, developing methods of identifying those mutations in patients, and improving the interventions available to help patients address those problems. The identification of genetic mutations enables clinicians to predict the likelihood that persons will develop a given health problem in the future or pass on a health risk to their children. For many disorders, however, there will be a considerable time lag between the ability to determine the likelihood of disease and the ability to treat the disease.
Efforts to isolate DNA mutations involved in disease in order to understand the origins of the pathophysiological process are becoming increasingly common across the broad sweep of biomedical research, from cardiology to oncology to psychiatry. Institutional review boards (IRB) should expect to see more of these kinds of studies in the future. The U.S. Human Genome Project (HGP) (part of the worldwide research effort known as the Human Genome Initiative) is one of the genetic toolmaking efforts that is facilitating this growth, through the production of better genetic maps and sequencing technology.
The ethical issues raised by this scientific trend primarily concern the management of psychosocially potent personal genetic information. For researchers and IRBs, the major challenge in addressing these issues is the fact that genetic studies typically involve families; the research subjects involved in genetic studies are usually related to each other. As a result, research findings about individual subjects can have direct implications for other subjects, information flow between subjects is increased, and participation decisions are not made entirely independently. A second set of ethical issues emerge in cases in which the results of these studies are used to develop therapeutic interventions at the genetic level. Such concerns involve the special safety precautions and subject selection considerations required for gene therapy research.
Some of the areas described in this section present issues for which no clear guidance can be given at this point, either because not enough is known about the risks presented by the research, or because no consensus on the appropriate resolution of the problem yet exists. IRBs need to become familiar with the issues and be prepared to address them in the context in which they arise in their particular research setting. Because of the uncertainties involved in genetic research, IRBs may not, for some time, be able to set clear standards for investigators. What IRBs can do, however, is ensure that investigators have thought through the factors that may affect the rights and welfare of human subjects (e.g., risks to privacy, psychological risks, employment and insurance risks). IRBs should require investigators to explain their thoughts on these problems, how they plan to handle them, and how they plan to communicate them to subjects.
IRBs would do well to work together with investigators, so that investigators see the IRB, as they should, as a partner in developing research protocols that adequately protect the participants. For example, IRBs may want to sponsor workshops within their institutions to help inform investigators of what the IRB will be looking for, or invite investigators to consult with the IRB prior to developing genetic research protocols.
Voluntary organizations involved in supporting research on various genetic disorders (e.g., genetic disease support groups and voluntary health associations) can also be useful sources of information for IRBs. Through consultation with voluntary organizations, IRBs can obtain useful information on the human subjects concerns of prospective research participants. These groups can also help act as intermediaries for subject recruitment, which may be particularly helpful for family studies, and can help provide counseling and support services. Not only can they help IRBs (e.g., in subject recruitment), but both IRBs and voluntary organizations benefit when their constituent publics are well-informed about what IRBs do (and do not do).
The issues raised in this section of the guidebook are addressed with particular reference to genetic research. General discussion of these issues (e.g., risk/benefit analysis, informed consent, privacy and confidentiality, and vulnerable populations) will also be useful to IRBs, and are found in other chapters of the guidebook (primarily Chapter 3, "Basic IRB Review," Chapter 4, "Considerations of Research Design," and Chapter 6, "Special Classes of Subjects").
Lod Score: An expression of the probability that a gene and a marker are linked.
Genotype: The genetic constitution of an individual.
Phenotype: The physical manifestation of a gene function.
Proband: The person whose case serves as the stimulus for the study of other members of the family to identify the possible genetic factors involved in a given disease, condition, or characteristic.
It may be useful to think of genetic research as being carried out on a continuum comprising four stages: (1) pedigree studies (to discover the pattern of inheritance of a disease and to catalog the range of symptoms involved); (2) positional cloning studies (to localize and identify specific genes); (3) DNA diagnostic studies (to develop techniques for determining the presence of specific DNA mutations); and (4) gene therapy research (to develop treatments for genetic disease at the DNA level).
Unlike the risks presented by many biomedical research protocols considered by IRBs, the primary risks involved in the first three types of genetic research are risks of social and psychological harm, rather than risks of physical injury. Genetic studies that generate information about subjects' personal health risks can provoke anxiety and confusion, damage familial relationships, and compromise the subjects' insurability and employment opportunities. For many genetic research protocols, these psychosocial risks can be significant enough to warrant careful IRB review and discussion. The fact that genetic studies are often limited to the collection of family history information and blood drawing should not, therefore, automatically classify them as "minimal risk" studies qualifying for expedited IRB review.
When investigators attempt to document and study the natural history of an inherited disease, condition, or characteristic, they do so by identifying individual members of families presenting the disease, condition, or characteristic and obtaining information about them and the other members of their family. The result is a pedigree analysis, which, in addition to tracing the natural history of a disease and documenting the range of symptoms involved, may also reveal information about family members that individual members may not have known about previously (e.g., the existence of previously unknown relatives or the presence of stigmatizing diseases, such as mental illness). It may also reveal information about the likelihood that individual members of the family either are carriers of genetic defects or will be affected by the disease.
The familial nature of the research cohorts involved in pedigree studies can pose challenges for ensuring that recruitment procedures are free of elements that unduly influence decisions to participate. The very nature of the research exerts pressure on family members to take part, because the more complete the pedigree, the more reliable the resulting information will be. For example, revealing who else in the family has agreed to participate may act as an undue influence on an individual's decision, as may recruiting individuals in the presence of other family members. (Both would also constitute a breach of confidentiality. The problem of confidentiality will be dealt with later in this section.)
Recruitment plans, some of which are described here, can attempt to address these problems; each approach has its own strengths and weaknesses. One strategy is to use the proband as the point of contact for recruiting. This approach insulates families from pressure by the investigator, but presents the risk that the proband may be personally interested in the research findings and exert undue pressure on relatives to enroll in the study. Furthermore, the proband may not want to act as a recruiter for fear that other family members will then know that he or she is affected by the disease. Another approach is direct recruitment by the investigator through letters or telephone calls to individuals whose identity is supplied by the proband. Direct recruitment by the investigator may, however, be seen as an invasion of privacy by family members. (Similar issues arise in epidemiologic research. See guidebook,Chapter 4, Section E.) A third approach is to recruit participants through support groups or lay organizations. Adopting this strategy requires investigator and IRB confidence that these organizations will be as scrupulous in their own efforts to protect subjects as the investigator would be. A fourth possibility is to contact individuals through their personal physicians. Prospective subjects contacted by their physician may, however, feel that their health care will be compromised if they do not agree to participate. In the end, the IRB must ensure that the recruitment plan minimizes the possibility of coercion or undue influence [Federal Policy §116].
In contrast to inappropriate pressure placed on prospective participants to join the study is the possibility that a subject may agree to participate out of a misguided effort to obtain therapy. The purposes of the research and how subjects will or will not benefit by participation must be clearly explained. (See discussion below on informed consent.)
Investigators and IRBs need to consider each of these concerns in arriving at a recruitment strategy that protects these various interests.
Potential risks and benefits should be discussed thoroughly with prospective subjects. In genetic research, the primary risks, outside of gene therapy, are psychological and social (referred to generally as "psychosocial") rather than physical. IRBs should review genetic research with such risks in mind.
Psychological risk includes the risk of harm from learning genetic information about oneself (e.g., that one is affected by a genetic disorder that has not yet manifested itself). Complicating the communication of genetic information is that often the information is limited to probabilities. Furthermore, the development of genetic data carries with it a margin of error; some information communicated to subjects will, in the end, prove to be wrong. In either event, participants are subjected to the stress of receiving such information. For example, researchers involved in developing presymptomatic tests for Huntington's disease (HD) have been concerned that the emotional impact of learning the results may lead some subjects to attempt suicide. They have therefore asked whether prospective participants should be screened for emotional stability prior to acceptance into a research protocol.
Note that these same disclosures of information can also be beneficial. One of the primary benefits of participation in genetic research is that the receipt of genetic information, however imperfect, can reduce uncertainty about whether participants will likely develop a disease that runs in their family (and possibly whether they have passed the gene along to their children). Where subjects learn that they will likely develop or pass along the disease, they might better plan for the future.
To minimize the psychological harms presented by pedigree research, IRBs should make sure that investigators will provide for adequate counseling to subjects on the meaning of the genetic information they receive. Genetic counseling is not a simple matter and must be done by persons qualified and experienced in communicating the meaning of genetic information to persons participating in genetic research or persons who seek genetic testing.
Social risks include stigmatization, discrimination, labeling, and potential loss of or difficulty in obtaining employment or insurance. Changes in familial relationships are also social ramifications of genetic research. For example, an employer who knew that an employee had an 80 percent chance of developing HD in her 40s might deny her promotion opportunities on the calculation that their investment in training would be better spent on someone without this known likelihood. Of course, the company may be acting irrationally (the other candidate might be hit by a car the next day, or have some totally unknown predisposition to debilitating disease), but the risk for our subject of developing HD is real, nonetheless. One problem with allowing third-parties access to genetic information is the likelihood that information, poorly understood, will be misused. Likewise, an insurer with access to genetic information may be likely to deny coverage to applicants when risk of disease is in an unfavorable balance. Insuring against uncertain risks is what insurance companies do; when the likelihood of disease becomes more certain, they may refuse to accept the applicant's "bet."
Debate about the social policy implications of genetic information is vitally important and is occurring on a national and international level, but is not literally a concern for IRBs. The IRB's concern is, first, to ensure that these risks will be disclosed to subjects, and, second, to protect subjects against unwarranted disclosures of information.
See also guidebook, Chapter 3, Section A, "Risk/Benefit Analysis," and Chapter 3 Section B "Informed Consent," for further discussion of these issues.
Privacy and Confidentiality Protections. Special privacy and confidentiality concerns arise in genetic family studies because of the special relationship between the participants. IRBs should keep in mind that within families, each person is an individual who deserves to have information about him - or herself kept confidential. Family members are not entitled to each other's diagnoses. Before revealing medical or personal information about individuals to other family members, investigators must obtain the consent of the individual.
Another problem that arises in genetic family studies that is also common in other areas of research involving interviews with subjects is the provision by a subject of information about another person. In pedigree studies, for example, the proband or other family member is usually asked to provide information about other members of the family. The ethical question presented by this practice is whether that information can become part of the study without the consent of the person about whom the data pertains. While no consensus on this issue has yet been reached, IRBs may consider collection of data in this manner acceptable, depending on the nature of the risks and sensitivities involved. It may be helpful, for example, to draw a distinction between information about others provided by a subject that is also available to the investigator through public sources (e.g., family names and addresses) and other personal information that is not available through public sources (e.g., information about medical conditions or adoptions).
IRBs should require investigators to establish ahead of time what information will be revealed to whom and under what circumstances, and to communicate these conditions to subjects in clear language. For example, if the pedigree is revealed to the study participants, family members will learn not only about themselves but about each other. The possibility that family members who did not participate might also learn of the pedigree data should not be overlooked. Subjects should know and agree ahead of time to what they might learn (and what they will not learn), both about themselves and others, and what others might learn about them. One approach would be never to reveal the pedigree to participating subjects. Many investigators record their pedigrees using code numbers rather than names. IRBs should note, however, that when a study involves a rare disease or a "known" family, the substitution of numbers for names does not eliminate the problem.
Even where the protocol calls for providing certain information to subjects, participants in genetic studies should be given the option of not receiving genetic information about themselves or others that they do not wish to receive. In genetic research, the potential for psychosocial harm accruing to persons who express a desire not to receive information gained through the study and the uncertainties surrounding the disease-predictive value of the early phases of contemporary genetic research is felt to outweigh benefits of required disclosure. (A possible exception involving circumstances where early treatment of genetically-linked disease improves prognoses is discussed in the section on identifying and deciphering genes, below.)
Data must be stored in such a manner that does not directly identify individuals. In general, except where directly authorized by individual subjects, data may not be released to anyone other than the subject. An exception to requiring explicit authorization for the release of data may be secondary research use of the data, where the data are not especially sensitive and where confidentiality can be assured. IRBs should exercise their discretion in reviewing protocols that call for the secondary use of genetic data. Furthermore, when reviewing a consent documents, IRBs should note agreements made by investigators not to release information without the express consent of subjects. Subsequent requests for access to the data are subject to agreements made in the consent process. For studies involving socially sensitive traits or conditions, investigators might also consider requesting a certificate of confidentiality. [See guidebook Chapter 3, Section D, "Privacy and Confidentiality."]
Informed Consent. The information presented to subjects in the informed consent process should be as specific as possible. Subjects should be told both the known risks, as well as the uncertainty surrounding the risks of participation. Among the uncertainties is the likelihood that useful information will result from the study (it may not). Prospective participants often come into genetic studies with unrealistic expectations of how they will benefit from the study, and without an appreciation of low-probability risks that are not well-understood by anyone. To the extent possible, unrealistic expectations should be dispelled in the informed consent process.
The provision of relevant information should take place as a thoughtful discussion with prospective subjects. Through this process, subjects should be informed:
Information should be given to subjects in clear language, suitable to their age, cultural background, and physical and mental capabilities. Accommodations should be made for persons with learning disabilities (as distinguished from persons who suffer diminished mental capacity). The consent process should take place in the subject's native language, through an interpreter, if necessary; consent documents should be translated into the subject's native language. The IRB should satisfy itself that great care will be taken by the investigator to ensure that prospective subjects fully understand the risks and benefits involved in participation.
Disposition of DNA Samples. When tissue samples are to be collected for later DNA analysis, numerous issues must be addressed by investigators and IRBs. Primary among them are through what mechanism samples should be collected, who can have access to the samples and for what purposes, who owns the DNA, and how incorrect genetic information (due, for example, to faulty laboratory analysis) can be corrected. The American Society of Human Genetics' Ad Hoc Committee on DNA Technology has published a set of Points to Consider on DNA Banking and DNA Analysis (1987), with which IRBs may wish to acquaint themselves. While not all of the society's recommendations may be directly applicable to the IRB's concerns, it is worth noting the importance the Society places on appropriate counseling and limited access to familial genotypes.
The genetic information (and tissue samples, where applicable) collected under a research protocol are of continuing importance to the families involved in the research. An important question for IRBs to consider is what will happen to the data (and samples) when funding for the research ends. Particular attention should be paid to protecting the confidentiality of the data and obtaining consent from the participants for any use of the data (and samples) that is not strictly within the original uses to which the participants agreed.
Withdrawal from Participation. Attention should be paid to subjects' rights when they decide to withdraw from participation in the study. The federal regulations clearly require that subjects be free to withdraw from participation without penalty or loss of benefits to which they are otherwise entitled [Federal Policy §116(a)(8)]. What the regulations do not address, however, is how to treat data or tissue samples obtained from subjects who subsequently withdraw from the study. A similar question was addressed by the California Supreme Court in the Moore case [John Moore v. The Regents of the University of California (1990)]. While Moore constitutes binding legal authority only in California and has not, as of this writing, been adopted in other jurisdictions, the court's findings may be helpful for exploring possible approaches to handling the treatment of data and tissue samples when a subject withdraws from a genetic study.
In Moore, the California Supreme Court held that cell lines established from a donated sample are not the property of the person who donated the sample. Extrapolating to the broader context of genetic research generally, the underlying principle would be that withdrawal releases the subject from providing further information or tissue samples, and perhaps requires the removal of the subject's identity from all research records, but does not require the investigator to eliminate the resulting data from the study or to destroy the cell line.
In pedigree studies, for example, investigators may respond to a request tn withdraw by removing all information about that person and his or her spouse and children from the pedigree, but it is not clear that removal of the information is required by the human subjects regulations or any other legal principle.
Secondary Use of Tissue Samples. Where a new study proposes to use samples collected for a previously conducted study, IRBS should consider whether the consent given for the earlier study also applies to the new study. Where the purposes of the new study diverge significantly from the purposes of the original protocol, and where the new study depends on the familial identifiability of the samples, new consent should be obtained.
Vulnerable Populations. IRBS should ensure that the investigator conduct the research with sensitivity to the specific mental and physical manifestations of the particular disorders being investigated. Depending on the diseases and, therefore, the likely presenting population, investigators should be prepared to communicate effectively and with sensitivity with persons who have physical limitations (e.g., deafness or blindness), learning disabilities, cognitive impairments or any other life circumstance that may affect their participation (e.g., severe pain).
The nature of genetic research raises some special concerns when the research will involve children, physically or cognitively impaired persons, older persons, or any subject population likely to have special needs. Not only must the IRB ensure that their participation is fully voluntary and informed, IRBS must also be sure to evaluate the risks and benefits of the research as they apply to these special populations. The risk of participation for an adult differs from that of children; persons who suffer from diminished mental capacities may be subject to different risks than persons who do not. If children will be involved in the research, IRBs should seriously consider consulting with experts in child development and others knowledgeable about risks to children and families. Similarly, if physically or cognitively impaired persons will be involved in the research, IRBs should consider consulting with experts who can advise them on the special concerns their participation raises. Where applicable, 45 CFR 46 Subparts B, C, and D (pertaining to women, fetuses, prisoners, and children) must be followed. [See also Guidebook Chapter 6, Section C, "Children and Minors," Section D, "Cognitively Impaired Persons," Section G, "Terminally III Patients," Section H, "Elderly/Aged Persons," and Section I, "Minorities. "]
The involvement of children in genetic research raises many concerns, including pressure brought by family members on the child to participate and the potential for harm that may result from disclosure of genetic or incidental information. Even seemingly harmless research may actually present serious risks of harm to children. For example, interviewing children for genetic research on psychological disorders, such as schizophrenia or depression, or on alcoholism may inadvertently convey information about family members (the child may well wonder why he or she is being asked about alcoholism in the family) or cause self-doubt or stigmatization on the part of the child. Furthermore, disclosures of data to third-parties may result in children being labelled or stigmatized as, for example, potential alcohol abusers. IRBs must look carefully at both the questions that will be asked of children and the information that will be directly conveyed to them to determine whether the research involves more than minimal risk. The advisability of including children in studies of untreatable, fatal disorders such as HD has been strongly questioned [MacKay (1984), p. 3].
IRBs should also consider the mental capacities of participants in genetic research. In some diseases, such as Alzheimer's disease, patients will suffer loss of mental capacity over a period of time. In addition, it is possible that a family member might be comatose or legally incompetent for reasons unrelated to the disease under study. Special attention should be paid to methods of ensuring voluntary consent by the subject or the subject's legally authorized representative [Federal Policy §102(c), .116]. Under the regulations, a "legally authorized representative" is defined as "an individual or judicial or other body authorized under applicable law to consent on behalf of a prospective subject to the subject's participation in the procedure(s) involved in the research" [Federal Policy §102(c)]. IRBs should pay particular attention to state and local laws relating to persons authorized to give permission for participation in research on behalf of prospective subjects, noting that such "proxy" consent to participation in research that does not involve a direct medical benefit may differ from consent to receive medical treatment. Where possible, the subject's assent should be sought; his or her dissent should be honored. [See also Guidebook Chapter 6, Section D, "Cognitively Impaired."]
In appropriate circumstances the IRB might consider granting waivers of consent or alteration of the consent process. [See MacKay (1984), pp. 3-4, and Levine (1986).] The federal regulations allow for waivers or alterations in the consent process where the IRB finds that: (1) the research involves no more than minimal risk; (2) the waiver or alteration will not adversely affect the rights and welfare of the subject; (3) the research could not practicably be carried out without the waiver or alteration; and (4) whenever appropriate, the subjects will be provided with additional pertinent information after participation [Federal Policy §116(d)]. Again, IRBs should carefully consider whether the research qualifies as "minimal risk."
Publication Practices. One final issue involving consent is the publication of research data. The publication of pedigrees can easily result in the identification of study participants. Where a risk of identification exists, participants must consent, in writing, to the release of personal information. Various authors have noted the problem of obtaining consent for the publication of identifying data, and have recommended that consent to the publication be obtained immediately prior to the publication, rather than as part of the consent to treatment or participation in research. [See, e.g., Rost and Cohen (1976) and Murray and Pagon (1984).] It is worth noting, however, that to address this concern, IRBs must also resolve the following questions: Who determines the risk of identification, and on what grounds? Who are defined as participants? (Is it everyone listed in the pedigree, some of whom have been contacted by investigators, some of whom have had information about them provided by a family member?)
While IRBs must be careful to avoid inappropriate restrictions on investigators' research publications, some evaluation of publication plans is important as part of the IRB's overall interest in preserving the confidentiality of research subjects. One approach for investigators to use in evaluating their publication plans might be to work in a step-wise fashion: First, is publication of the pedigree essential? If publication of the pedigree or other identifying data (e.g., case histories, photographs, or radiographs) is essential, can some identifying data be omitted without changing the scientific message? (The practice of altering data such as changing the birth order and gender is controversial, and no clear professional consensus yet exists as to whether this is an appropriate practice.) Finally, if the pedigree must be published, and if identifying data cannot be omitted in an appropriate manner without changing the scientific message, subjects must give their permission for publication of data that may reveal their identity.
Another concern about publication is the potential for publicity of the research results, and the exposure of participants to such publicity. Consent by individuals to such publicity does not resolve the question. Because genetic research involves families, the agreement of one subject to participate in releases of information to the media (including interviews and the like) has significant implications for other members of the family, particularly where the research is of a sensitive nature. IRBs should ensure that the investigator has addressed this possibility.
Expedited Review and Exemption from Review. The expedited review process is available for minimal risk research where the research activity is limited to one of a specified category (as published in the Federal Register), including the provision of blood samples [Federal Policy §110; Federal Register 46 (January 26, 1981): 8392]. In genetic studies that involve a blood draw, the additional psychosocial risks are likely to raise the risk beyond the "minimal risk" level allowable for expedited review. When an expedited review is requested, IRBs should review the question of minimal risk carefully.
With respect to exemption from review, the development of a pedigree through interviews with family members is likely to create identifying information, even where individuals will not be identified. Such research would not, therefore, qualify for exemption from review under the federal regulations [Federal Policy §lOl(b)(2)].
Research focusing on identifying the specific genetic component of a particular disease, condition, or characteristic relies upon DNA analysis of tissue samples taken from the members of families in which the condition appears. Many issues raised by pedigree analysis are relevant to this stage of research as well: pressure or coercion in recruiting subjects; informing prospective subjects of the possible harms; minimizing psychological harm through counseling and education; protection of confidentiality (which is particularly problematic when family members constitute the subject population); control over the use of DNA tissue samples; and protecting particularly vulnerable persons, all of which were discussed in the previous section. Additional issues include: determining when the data constitute "information;" additional risks presented by this stage of research (e.g., the possibility of incidental findings); and possible conflicts between subjects' rights and investigators' duties with respect to revealing the results of the study to subjects [i.e., telling subjects whether they (or their relatives) carry the defect, and the meaning of their status with respect to the likelihood of suffering from the disease or passing it along to their children].
Access to Data: Interim Findings. An issue that must be resolved prior to beginning any genetic study is who will have access to the data and the stage in the research at which they will have access. The issue of information transfer is vitally important in all genetic research, but particularly in the first three stages of investigation. A crucial question investigators and IRBs must address is whether (and which) interim findings will be communicated to subjects.
Experts disagree about whether interim or inconclusive findings should be communicated to subjects, although most agree that they should not (that only confirmed, reliable findings constitute "information"). Persons who oppose revealing interim findings argue that the harms that could result from revea]ing preliminary data whose interpretation changes when more precise or reliable data become available are serious, including anxiety or irrational and possibly harmful medical interventions. They argue that such harms are avoidable by controlling the flow of information to subjects and limiting communications to those that constitute reliable information. MacKay (1984), writing about the development of genetic tests, argues against revealing interim findings, contending that preliminary results do not yet constitute "information" since "until an initial fmding is confirmed, there is no reliable information" to communicate to subjects, and that "even...confirmed findings may have some unforseen limitations" [p. 3]. He argues that subjects should not be given information about their individual test results until the findings have been confirmed through the "development of a reliable, accurate, safe and valid presymptomatic test" [pp. 2-3; see also Fost and Farrell (1990)]. Others have argued that all interim results should be shared with subjects, based on the principle of autonomy that subjects have a right to know what has been learned about them.
These arguments are equally relevant at any of the first three stages of genetic research. IRBs should consider these arguments, weighing the possible harms and benefits. Investigators should determine, prior to initiation of the study, the point at which the data will be considered solid enough to be constitute information that should be provided to subjects. Investigators should further consider coding the data and separating the research records from individuals' medical records, so that neither the investigators nor the subjects may gain access to them [MacKay (1984), p. 3].
Reilly (1980) suggests that IRBs develop general policies governing the disclosure of information to subjects, to help make these determinations. He suggests that at least the following three factors be considered: "(1) the magnitude of the threat posed to the subject, (2) the accuracy with which the data predict that the threat will be realized, and (3) the possibility that action can be taken to avoid or ameliorate the potential injury" [p. 5]. IRBs should ask investigators to define three categories of disclosure: (1) "findings that are of such potential importance to the subject that they must be disclosed immediately;" (2) "data that are of importance to subjects ... , but about which [the investigator] should exercise judgment about the decision to disclose ... [i]n effect, these are data that trigger a duty to consider the question of disclosure;" and (3) "data that do not require special disclosure" [pp. 5, 12].
IRBs should consider whether the investigator's approach appropriately balances the risks and benefits involved in providing access to the data. Subjects should be told, as part of the consent process, whether, when, and what information they will receive. Any disclosures of genetic information should be accompanied by appropriate counseling by trail,ed genetic counselors. However the IRB resolves this question, investigators should explain to prospective subgects the basis according to which they will decide which data will be disclosed to whom, and when those disclosures will be made.
Access to Data: The Subjects' Right Not to Know. Subjects generally retain the right not to receive information about the results of a study that reveals their genetic status. A possible exception involves circumstances where early treatment of genetically-linked disease could improve the subject's prognosis. In such circumstances, investigators may have a duty to inform the subject about the existence of the genetic defect and to advise him or her to seek medical advice. [See, e.g., Andrews (1991).] (As of this writing, a legal duty of investigators to inform subjects about the existence of genetic defects has not been firmly established.)
Furthermore, the existence of a genetic defect that is linked to disease may have important implications for family members; can or should the confidentiality of subjects' data be compromised to allow other family members to be warned? The President's Commission (1983), addressed this question with respect to information generated from genetic screening. The commission's discussion may also be relevant to information obtained as the result of genetic research, at stages that precede genetic screening. The commission concluded that:
[The] ethical duty of [providing confidentiality] can be overridden only if several conditions are satisfied: (1) reasonable efforts to elicit voluntary consent to disclosure have failed; (2) there is a high probability both that harm will occur if the information is withheld and that the disclosed information will actually be used to avert harm; (3) the harm that identifiable individuals would suffer would be serious; and (4) appropriate precautions are taken to ensure that only the genetic information needed for diagnosis and/or treatment of the disease in question is disclosed. [p. 44]
The commission further advised that, to the extent possible, persons undergoing genetic screening should be asked to consent in advance to the disclosure of genetic information to relatives in the event that such useful information is discovered [pp. 43-44]. Whether a legal duty exists to warn relatives of possible genetic defects has not yet been established. [See Robertson (1992), pp. 92-94.]
Access to Data: Incidental Findings. IRBs should also ensure that investigators adequately deal with how they will handle incidental findings; that is, what will be done with genetic information that is learned during the course of the study that does not directly relate to the research. For example, in intergenerational pedigree analyses, questions of paternity or parentage can come up. DNA analysis will reveal information indicating that an individual's biological parents are not who he or she thought they were; blood typing may reveal similar information. DNA analysis may also reveal information about diseases or conditions other than the disease or condition under study. Prospective subjects should be informed during, he consent process that the discovery of such information is possible. Appropriate counseling should be provided to educate subjects about the meaning of the genetic information they have received, and to assist them in coping with any psychosocial effects of participation.
Access to Data: Secondary Use. Investigators should also address secondary use of research data (e.g., by other investigators, or by themselves for different research purposes). Where secondary uses can be foreseen, consent to the use should be sought. Express consent to access to data for secondary uses should be obtained for sensitive data and for circumstances under which confidentiality cannot be assured.
Testing individuals to determine the presence of genetic defects falls into four basic categories:
Protocols involving genetic testing raise somewhat different issues, depending on whether the tests are under development or are already established as reliable. IRBs are concerned with research aimed at developing genetic tests.
The ethical issues raised by the various kinds of genetic testing largely concern the concept of autonomy or self-determination. Before consenting to undergo genetic tests, whether new tests that are being developed, or already-established genetic tests, subjects should fully understand what it is they are going to learn about themselves, what they are not going to learn about themselves, and how reliable the information will be. Subjects must have information on which to base their decisions whether or not to go ahead with the testing.
When the research involves the development of a genetic test, however, the uncertainties involved make the consent process problematic: How does one adequately alert subjects to the psychosocial risks of testing when the point of the study is to try to help define those risks? Research on pre-test education in effect experiments with the informed consent process. Can subjects consent to research knowing that one of the risks is that they may not be adequately informed about what they are agreeing to? The federal regulations allow IRBs to approve consent procedures that do not include or that alter some or all of the elements of informed consent; one of the requirements is that the research must involve no more than minimal risk [Federal Policy §116(d)]. Research that involves deliberate withholding of information or deception is reviewed pursuant to those provisions. Even where it is permitted, purposeful nondisclosure of pertinent information is allowed only to the extent necessary to conduct the study (e.g., when disclosure of the information would affect the outcome of the study). Furthermore, subjects must consent to the nondisclosure; that is, they must be told that there is some relevant information about the study that they will not be told prior to consenting to participate. [See Levine (1986, p. 117) and discussion in Guidebook Chapter 3, Section B, "Informed Consent."]
In genetic testing research, however, the nondisclosure is not purposeful; rather, the nature and extent of the psychosocial risks involved is simply unknown. IRBs must look carefully at such studies to ensure that subjects are adequately protected. Investigators should provide the IRB their assessment of unknown risks. Subjects should be informed, in clear, understandable language, of the possibility of undisclosed risks, including any information the investigator has about their possible nature and extent.
Research results should be communicated to the subject by someone who possesses the appropriate medical and counseling expertise with which to explain the meaning of the test results. That person should ensure that the subject comprehends the information that has been provided to him or her, regardless of the time that may be involved. Furthermore, it may be appropriate to provide counseling not just for the subjects themselves, but also for their families. Consent to involve family members, should the need arise, should be sought as part of the consent to be tested.
Smurl and Weaver (1987) have developed a set of proposed ethical guidelines for the clinical testing of risk assessment tests for HD. IRBs reviewing investigations of risk assessment receives any support for recombinant DNA research from NIH must be reviewed by the Recombinant DNA Advisory Committee (RAC) at NIH. At present, the RAC will consider human somatic cell gene therapy protocols, but not germline cell gene therapy protocols. The process of review is as follows: The Human Gene Therapy Subcommittee conducts a public review of the protocol, then submits its recommendation to the RAC; if the RAC approves the protocol, it is forwarded to the director of NIH for final approval.
The RAC, through a Points to Consider Subcommittee, has established "Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA into Human Subjects." Among the ethical concerns that investigators must address are subject selection, informed consent, and privacy and confidentiality. Investigators must also justify the use of recombinant DNA techniques against alternative methodologies and delineate the risks and benefits of the research. A summary of the Points to Consider follows; IRBs would be wellserved to follow a similar line of inquiry when reviewing protocols that involve the transfer of recombinant DNA into human subjects.
The RAC Points to Consider. The following points should be addressed by all protocols involving somatic cell gene therapy:
IRB Considerations. The potential risks associated with gene therapy may weigh against the involvement of human subjects in gene therapy trials. As Walters (1989) has described it:
There are clearly some risks and some unknowns associated with even this simplest type of gene therapy [somatic cell gene therapy]. For example, it is not presently possible to control where the retroviral vectors will "touch down" when they reach the nuclei of the patient's ... cells. In other words, currently-available vectors are unguided missiles. There is some concern among researchers that the vectors may disrupt properly-functioning genes and therefore kill some cells or, more seriously, that the vectors may activate some previously dormant cancercausing genes. It is also possible that the domesticated retroviral vectors will recombine with other DNA or other viruses and so recapture their native capacity to produce more retroviruses and to infect large number of cells. [p. 222]
IRBs need to consider the risks and benefits of gene therapy carefully, and, if a protocol is approved, ensure that subjects will be thoroughly informed of the risks and benefits involved in the procedure. It must be made clear to subjects that the investigation has both a therapeutic intent and the goal of lcquiring scientific knowledge. Investigators should be careful not to raise unrealistically the hopes of the subjects and their families. [Fletcher (1985) p. 298]
Protocols involving children are subject to the special provisions of 45 CFR 46 Subpart D. IRBs should pay particular attention to protecting children, including obtaining assent from child-participants, wherever possible. IRBs may want to consider using a consultant, an IRB member, or a "group consent auditor" to oversee the consent process, ensuring that the child's best interests have been carefully considered [Fletcher (1985), pp. 298-99]. Fletcher argues that TRBs should refrain from allowing the hopeless situation of subjects to overshadow the consideration of acceptable risk. He concludes that "even if the degree of risk does not approach the level of 'dangerous'...[d]esperation about [a] child's condition is not a sound premise for experimental gene therapy. Children in imminent danger of death should not be selected as subjects for the first trials." [p. 297] [See also Guidebook Chapter 6, Section C, "Children and Minors."]
Special attention should also be paid to the possibility of mental impairment. [See Guidebook Chapter 6, Section D, "Cognitively Impaired."]
Some of the questions arising from the conduct of large pedigree studies were addressed at an NIH workshop jointly sponsored by the National Center for Human Genome Research (NCHGR) and the Office for Protection from Research Risks (OPRR) in October of 1992. For further information on the availability of the papers presented at the workshop (listed in "Suggestions for Further Reading," below), contact:
Dr. Eric T. Juengst
National Center for Human Genome Research
National Institutes of Health
Building 38A, Room 617
Bethesda, MD 20892
Phone: (301) 402-0911
Dr. Joan P. Porter
Office for Protection from Research Risks
National Institutes of Health
Building 31, Room SB63
Bethesda, MD 20892
Phone: (301) 496-7005
Federal Policy for the Protection of Human Subjects
Federal Policy §116 [Informed consent]
45 CFR 46 Subpart D [DHHS: Additional protections for children involved as subjects in research]
Federal, state, and local laws or regulations governing confidentiality of information.
Federal, state, and local laws or regulations pertaining to insurance.
There are currently no laws or regulations specifically governing the involvement of human subjects in genetic research, but the following guidelines may be useful:
U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. "Federal Guidelines for Recombinant DNA Molecule Research." 51 Federal Register (May 7, 1986): 16958.
U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. "Recombinant DNA Molecule Research, Proposed Actions under Guidelines; Notice." 50 Federal Register (August 19, 1985): 33462-33467.
U.S. Department of Health and Human Services. Public Health Service. National Institutes of Health. Recombinant DNA Advisory Committee. Points to Consider Subcommittee. "Points to Consider in the Design and Submission of Protocols for the Transfer of Recombinant DNA into Human Subjects." Recombinant DNA Technical Bulletin 12 (No. 3, September 1989): 151-170.
Last Reviewed: October 1, 2012
Policy and Legislation: Includes guidelines, regulations and federal legislation
Ethical, Legal and Social Implications Research Program


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Friday Night Fever Takes UW Students to the Movies for Free
University of Wyoming students can see three of today's most popular movies for free Friday, March 30, at the Storyteller Fox Cinema, located at 505 S. 20th St. in Laramie.
Students must show their valid UW ID card, and tickets will be given out on a first-come, first-served basis starting an hour before each showing.
"Dr. Seuss' the Lorax" will be shown at 9:20 p.m.; the comedy "21 Jump Street" will show at 9:40 p.m.; and a special showing of the "The Hunger Games" will be at midnight.

subset: commoncrawl


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Constantine I, byname Constantine the Great, Latin in full Flavius Valerius Constantinus, (born February 27, after 280 ce?, Naissus, Moesia [now Niš, Serbia]—died May 22, 337, Ancyrona, near Nicomedia, Bithynia [now İzmit, Turkey]), the first Roman emperor to profess Christianity. He not only initiated the evolution of the empire into a Christian state but also provided the impulse for a distinctively Christian culture that prepared the way for the growth of Byzantine and Western medieval culture.
How did the Roman Empire change under Constantine I the Great?
What was Constantine's relationship with Christianity?
What wars did Constantine fight?
What did Constantine build?
What was Constantine's family life like?
Constantine was born probably in the later 280s ce. A typical product of the military governing class of the later 3rd century, he was the son of Flavius Valerius Constantius, an army officer, and his wife (or concubine) Helena. In 293 ce his father was raised to the rank of Caesar, or deputy emperor (as Constantius I Chlorus), and was sent to serve under Augustus (emperor) Maximian in the West. In 289 Constantius had separated from Helena in order to marry a stepdaughter of Maximian, and Constantine was brought up in the Eastern Empire at the court of the senior emperor Diocletian at Nicomedia (modern İzmit, Turkey). Constantine was seen as a youth by his future panegyrist, Eusebius, bishop of Caesarea, passing with Diocletian through Palestine on the way to a war in Egypt.
Career and conversion
Constantine's experience as a member of the imperial court—a Latin-speaking institution—in the Eastern provinces left a lasting imprint on him. Educated to less than the highest literary standards of the day, he was always more at home in Latin than in Greek: later in life he had the habit of delivering edifying sermons, which he would compose in Latin and pronounce in Greek from professional translations. Christianity he encountered in court circles as well as in the cities of the East; and from 303, during the great persecution of the Christians that began at the court of Diocletian at Nicomedia and was enforced with particular intensity in the eastern parts of the empire, Christianity was a major issue of public policy. It is even possible that members of Constantine's family were Christians.
In 305 the two emperors, Diocletian and Maximian, abdicated, to be succeeded by their respective deputy emperors, Galerius and Constantius. The latter were replaced by Galerius Valerius Maximinus in the East and Flavius Valerius Severus in the West, Constantine being passed over. Constantius requested his son's presence from Galerius, and Constantine made his way through the territories of the hostile Severus to join his father at Gesoriacum (modern Boulogne, France). They crossed together to Britain and fought a campaign in the north before Constantius's death at Eboracum (modern York) in 306. Immediately acclaimed emperor by the army, Constantine then threw himself into a complex series of civil wars in which Maxentius, the son of Maximian, rebelled at Rome; with his father's help, Maxentius suppressed Severus, who had been proclaimed Western emperor by Galerius and who was then replaced by Licinius. When Maximian was rejected by his son, he joined Constantine in Gaul, only to betray Constantine and to be murdered or forced to commit suicide (310). Constantine, who in 307 had married Maximian's daughter Fausta as his second wife, invaded Italy in 312 and after a lightning campaign defeated his brother-in-law Maxentius at the Milvian Bridge near Rome. He then confirmed an alliance that he had already entered into with Licinius (Galerius having died in 311): Constantine became Western emperor and Licinius shared the East with his rival Maximinus. Licinius defeated Maximinus and became the sole Eastern emperor but lost territory in the Balkans to Constantine in 316. After a further period of tension, Constantine attacked Licinius in 324, routing him at Adrianople and Chrysopolis (respectively, modern Edirne and Üsküdar, Turkey) and becoming sole emperor of East and West.
Throughout his life, Constantine ascribed his success to his conversion to Christianity and the support of the Christian God. The triumphal arch erected in his honour at Rome after the defeat of Maxentius ascribed the victory to the "inspiration of the Divinity" as well as to Constantine's own genius. A statue set up at the same time showed Constantine himself holding aloft a cross and the legend "By this saving sign I have delivered your city from the tyrant and restored liberty to the Senate and people of Rome." After his victory over Licinius in 324, Constantine wrote that he had come from the farthest shores of Britain as God's chosen instrument for the suppression of impiety, and in a letter to the Persian king Shāpūr II he proclaimed that, aided by the divine power of God, he had come to bring peace and prosperity to all lands.
Constantine's adherence to Christianity was closely associated with his rise to power. He fought the Battle of the Milvian Bridge in the name of the Christian God, having received instructions in a dream to paint the Christian monogram () on his troops' shields. This is the account given by the Christian apologist Lactantius. A somewhat different version, offered by Eusebius, tells of a vision seen by Constantine during the campaign against Maxentius, in which the Christian sign appeared in the sky with the legend "In this sign, conquer." Despite the emperor's own authority for the account, given late in life to Eusebius, it is in general more problematic than the other, but a religious experience on the march from Gaul is suggested also by a pagan orator, who in a speech of 310 referred to a vision of Apollo received by Constantine at a shrine in Gaul.
Yet to suggest that Constantine's conversion was "politically motivated" means little in an age in which every Greek or Roman expected that political success followed from religious piety. The civil war itself fostered religious competition, each side enlisting its divine support, and it would be thought in no way unusual that Constantine should have sought divine help for his claim for power and divine justification for his acquisition of it. What is remarkable is Constantine's subsequent development of his new religious allegiance to a strong personal commitment.
Commitment to Christianity
Shortly after the defeat of Maxentius, Constantine met Licinius at Mediolanum (modern Milan) to confirm a number of political and dynastic arrangements. A product of this meeting has become known as the Edict of Milan, which extended toleration to the Christians and restored any personal and corporate property that had been confiscated during the persecution. The extant copies of this decree are actually those posted by Licinius in the eastern parts of the empire. But Constantine went far beyond the joint policy agreed upon at Mediolanum. By 313 he had already donated to the bishop of Rome the imperial property of the Lateran, where a new cathedral, the Basilica Constantiniana (now San Giovanni in Laterano), soon rose. The church of St. Sebastian was also probably begun at this time, and it was in these early years of his reign that Constantine began issuing laws conveying upon the church and its clergy fiscal and legal privileges and immunities from civic burdens. As he said in a letter of 313 to the proconsul of Africa, the Christian clergy should not be distracted by secular offices from their religious duties "…for when they are free to render supreme service to the Divinity, it is evident that they confer great benefit upon the affairs of state." In another such letter, directed to the bishop of Carthage, Constantine mentioned the Spanish bishop Hosius, who was important later in the reign as his adviser and possibly—since he may well have been with Constantine in Gaul before the campaign against Maxentius—instrumental in the conversion of the emperor.
Constantine's personal "theology" emerges with particular clarity from a remarkable series of letters, extending from 313 to the early 320s, concerning the Donatist schism in North Africa. The Donatists maintained that those priests and bishops who had once lapsed from the Christian faith could not be readmitted to the church. Constantine's chief concern was that a divided church would offend the Christian God and so bring divine vengeance upon the Roman Empire and Constantine himself. Schism, in Constantine's view, was inspired by Satan. Its partisans were acting in defiance of the clemency of Christ, for which they might expect eternal damnation at the Last Judgment. Meanwhile, it was for the righteous members of the Christian community to show patience and long-suffering. In so doing they would be imitating Christ, and their patience would be rewarded in lieu of martyrdom—for actual martyrdom was no longer open to Christians in a time of peace for the church. Throughout, Constantine had no doubt that to remove error and to propagate the true religion were both his personal duty and a proper use of the imperial position. His claim to be "bishop of those outside the church" may be construed in this light. Other such pronouncements, expressed in letters to imperial officials and to Christian clergy, demonstrate that Constantine's commitment to Christianity was firmer and less ambiguous than some have suggested. Eusebius confirmed what Constantine himself believed: that he had a special and personal relationship with the Christian God.
Constantine's second involvement in an ecclesiastical issue followed the defeat of Licinius, but the controversy over Arianism, with its intricate explorations of the precise nature of the Trinity that were couched in difficult Greek, was as remote from Constantine's educational background as it was from his impatient, urgent temperament. The Council of Nicaea, which opened in the early summer of 325 with an address by the emperor, had already been preceded by a letter to the chief protagonist, Arius of Alexandria, in which Constantine stated his opinion that the dispute was fostered only by excessive leisure and academic contention, that the point at issue was trivial and could be resolved without difficulty. His optimism was not justified: neither this letter nor the Council of Nicaea itself nor the second letter, in which Constantine urged acceptance of its conclusions, was adequate to solve a dispute in which the participants were as intransigent as the theological issues were subtle. Indeed, for more than 40 years after the death of Constantine, Arianism was actually the official orthodoxy of the Eastern Empire.
The Council of Nicaea coincided almost exactly with the celebrations of the 20th anniversary of the reign of Constantine, at which, returning the compliment paid by the emperor's attendance at their council, the bishops were honoured participants. But Constantine's visit to the West in 326, to repeat the celebrations at Rome, brought the greatest political crisis of the reign. During his absence from the East, and for reasons that remain obscure, Constantine had his eldest son, the deputy emperor Crispus, and his own wife Fausta, Crispus's stepmother, slain. Nor was the visit to Rome a success. Constantine's refusal to take part in a pagan procession offended the Romans, and, when he left after a short visit, it was never to return.
Final years
These events set the course of the last phase of the reign of Constantine. After his defeat of Licinius he had renamed Byzantium as Constantinople, and immediately upon his return from the West he began to rebuild the city on a greatly enlarged pattern as his permanent capital and the "second Rome." The dedication of Constantinople (May 330) confirmed the divorce, which had been in the making for more than a century, between the emperors and Rome. Rome had long been unsuited to the strategic needs of the empire. It was now to be left in splendid isolation, as an enormously wealthy and prestigious city—still the emotional focus of the empire—but of limited political importance.
It was perhaps in some sense to atone for the family catastrophe of 326 that Constantine's mother, Helena, embarked on a pilgrimage to the Holy Land. Her journey was attended by almsgiving and pious works and was distinguished by her church foundations at Jerusalem and at Bethlehem. By the initiative of Eutropia, Constantine's mother-in-law, a church was also built at Mamre, where, according to an interpretation of the Book of Genesis shared by Constantine and Eusebius, Christ had first shown himself to humanity in God's appearance to the Hebrew patriarch Abraham, but the most famous of these foundations followed the sensational discovery of the Holy Sepulchre at Jerusalem. The discovery was taken up with enthusiasm by Constantine, who instigated the building of a great new basilica at the spot, offering unlimited help with labour and materials and suggestions as to design and decoration.
Constantine's interest in church building was expressed also at Constantinople, particularly in churches of the Holy Wisdom (the original Hagia Sophia) and of the Apostles. At Rome, the great church of St. Peter was begun in the later 320s and lavishly endowed by Constantine with plate and property. Meanwhile, churches at Trier, Aquileia, Cirta in Numidia, Nicomedia, Antioch, Gaza, Alexandria, and elsewhere owed their development, directly or indirectly, to Constantine's interest.
The emperor was an earnest student of his religion. Even before the defeat of Licinius, he had summoned to Trier the theologian and polemicist Lactantius to be the tutor of Crispus. In later years he commissioned new copies of the Bible for the growing congregations at Constantinople. He composed a special prayer for his troops and went on campaigns with a mobile chapel in a tent. He issued numerous laws relating to Christian practice and susceptibilities: for instance, abolishing the penalty of crucifixion and the practice of branding certain criminals; enjoining the observance of Sunday and saints' days; and extending privileges to the clergy while suppressing at least some offensive pagan practices.
Constantine had hoped to be baptized in the Jordan River, but perhaps because of the lack of opportunity to do so—together possibly with the reflection that his office necessarily involved responsibility for actions hardly compatible with the baptized state—he delayed the ceremony until the end of his life. It was while preparing for a campaign against Persia that he fell ill at Helenopolis. When treatment failed, he made to return to Constantinople but was forced to take to his bed near Nicomedia. There, Constantine received baptism, putting off the imperial purple for the white robes of a neophyte; and he died in 337. He was buried at Constantinople in his church of the Apostles, whose memorials, six on each side, flanked his tomb. Yet this was less an expression of religious megalomania than of Constantine's literal conviction that he was the successor of the evangelists, having devoted his life and office to the spreading of Christianity.
The reign of Constantine must be interpreted against the background of his personal commitment to Christianity. His public actions and policies, however, were not entirely without ambiguity. Roman opinion expected of its emperors not innovation but the preservation of traditional ways; Roman propaganda and political communication were conditioned, by statement, allusion, and symbol, to express these expectations. It is significant, for instance, not that the pagan gods and their legends survived for a few years on Constantine's coinage but that they disappeared so quickly: the last of them, the relatively inoffensive "Unconquered Sun," was eliminated just over a decade after the defeat of Maxentius.
Some of the ambiguities in Constantine's public policies were therefore exacted by the respect due to established practice and by the difficulties of expressing, as well as of making, total changes suddenly. The suppression of paganism, by law and by the sporadic destruction of pagan shrines, is balanced by particular acts of deference. A town in Asia Minor mentioned the unanimous Christianity of its inhabitants in support of a petition to the emperor; while, on the other hand, one in Italy was allowed to hold a local festival incorporating gladiatorial games and to found a shrine of the imperial dynasty—although direct religious observance there was firmly forbidden. In an early law of Constantine, priests and public soothsayers of Rome were prohibited entry to private houses; but another law, of 320 or 321, calls for their recital of prayer "in the manner of ancient observance" if the imperial palace or any other public building were struck by lightning. Traditional country magic was tolerated by Constantine. Classical culture and education, which were intimately linked with paganism, continued to enjoy enormous prestige and influence; provincial priesthoods, which were as intimately linked with civic life, long survived the reign of Constantine. Constantinople itself was predominantly a Christian city, its dedication celebrated by Christian services; yet its foundation was also attended by a well-known pagan seer, Sopatros.
An objective assessment of Constantine's secular achievements is not easy—partly because of the predominantly religious significance with which the emperor himself invested his reign, partly because the restlessly innovatory character that dissenting contemporaries saw in his religious policy was also applied by them to the interpretation of his secular achievement. Some of Constantine's contributions can, in fact, be argued to have been already implicit in the trends of the last half century. So may be judged the further development, taking place in his reign, of the administrative court hierarchy and an increasing reliance upon a mobile field army, to what was considered the detriment of frontier garrisons. The establishment by Constantine of a new gold coin, the solidus, which was to survive for centuries as the basic unit of Byzantine currency, could hardly have been achieved without the work of his predecessors in restoring political and military stability after the anarchy of the 3rd century. Perhaps more directly linked with Constantine's own political and dynastic policies was the emergence of regional praetorian prefectures with supreme authority over civil financial administration but with no direct control over military affairs; this they yielded to new magistri, or "masters," of the cavalry and infantry forces. The reduction of the prefects' powers was seen by some as excessively innovatory, but the principle of the division of military and civil power had already been established by Diocletian. A real innovation, from which Constantine could expect little popularity, was his institution of a new tax, the collatio lustralis. It was levied every five years upon trade and business and seems to have become genuinely oppressive.
A lavish spender, Constantine was notoriously openhanded to his supporters and was accused of promoting beyond their deserts men of inferior social status. More to the point is the accusation that his generosity was only made possible by his looting of the treasures of the pagan temples as well as by his confiscations and new taxes; and there is no doubt that some of his more prominent supporters owed their success, at least partly, to their timely adoption of the emperor's religion.
The foundation of Constantinople, an act of crucial long-term importance, was Constantine's personal achievement. Yet it, too, had been foreshadowed; Diocletian enhanced Nicomedia to an extent that was considered to challenge Rome. The city itself exemplified the "religious rapacity" of the emperor, being filled with the artistic spoils of the Greek temples, while some of its public buildings and some of the mansions erected for Constantine's supporters soon showed signs of their hasty construction. Its Senate, created to match that of Rome, long lacked the aristocratic pedigree and prestige of its counterpart.
In military policy Constantine enjoyed unbroken success, with triumphs over the Franks, Sarmatians, and Goths to add to his victories in the civil wars; the latter, in particular, show a bold and imaginative mastery of strategy. Constantine was totally ruthless toward his political enemies, while his legislation, apart from its concessions to Christianity, is notable mainly for a brutality that became characteristic of late Roman enforcement of law. Politically, Constantine's main contribution was perhaps that, in leaving the empire to his three sons, he reestablished a dynastic succession, but it was secured only by a sequence of political murders after his death.
Above all, Constantine's achievement was perhaps greatest in social and cultural history. It was the development, after his example, of a Christianized imperial governing class that, together with his dynastic success, most firmly entrenched the privileged position of Christianity; and it was this movement of fashion, rather than the enforcement of any program of legislation, that was the basis of the Christianization of the Roman Empire. Emerging from it in the course of the 4th century were two developments that contributed fundamentally to the nature of Byzantine and Western medieval culture: the growth of a specifically Christian, biblical culture that took its place beside the traditional Classical culture of the upper classes; and the extension of new forms of religious patronage between the secular governing classes and bishops, Christian intellectuals and holy men. Constantine left much for his successors to do, but it was his personal choice made in 312 that determined the emergence of the Roman Empire as a Christian state. It is not hard to see why Eusebius regarded Constantine's reign as the fulfillment of divine providence—nor to concede the force of Constantine's assessment of his own role as that of the 13th Apostle.J.F. Matthews Donald MacGillivray Nicol
Learn More in these related Britannica articles:
ancient Rome: The reign of ConstantineConstantine and Licinius soon disputed among themselves for the empire. Constantine attacked his adversary for the first time in 316, taking the dioceses of Pannonia and Moesia from him. A truce between them lasted 10 years. In 316 Diocletian died in Salona, which he…
history of Europe: Late antiquity: the reconfiguration of the Roman world…capital built by the emperor Constantine—Constantinople (now Istanbul)—and far more economic, political, and military resources than the western half. The administration of the entire empire was restructured to finance immense military expenditures, giving the western European provinces and frontier areas greater importance but fewer resources. Most of the population of…
history of Europe: The organization of late imperial Christianity…the legalization of Christianity by Constantine about 313 and the adoption of Christianity as the legal religion of Rome by the emperor Theodosius I in 380, Christian communities received immense donations of land, labour, and other gifts from emperors and wealthy converts. The Christian clergy, originally a body of community…
France: Gaul under the late Roman Empire (c. 250–c. 400)…emperors and usurpers (in particular, Constantine I [reigned 306–337], Julian [355–363], Valentinian I [364–375], Gratian [375–383], and Magnus Maximus [383–388]) resided there for at least part of their reigns. Their seat of government was usually Augusta Treverorum (now Trier, Germany), the former
civitas-capital of the Treveri and capital of Belgica,…
Christianity: The alliance between church and empireConstantine the Great, declared emperor at York, Britain (306), converted to Christianity, convened the Council of Arles (314), became sole emperor (324), virtually presided over the ecumenical Council of Nicaea (325), founded the city of Constantinople (330), and died in 337. In the 4th century…
More About Constantine I57 references found in Britannica articles
Assorted References
- major reference
- disbanding of Praetorian Guard
- granting of privileges to clergy
- In clergy
- promotion of cross
- In cross
- role of prefect
- In prefect
- tribute to Saint Peter
association with
- Constans I
- In Constans I
- Constantius II
- Crispus
- In Crispus
- Eusebius of Caesarea


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Stephanie sy necesitaba un nuevo diseño de logotipo y lanzó un concurso de diseño en 99designs.
Un ganador ha sido elegido entre 235 diseños de 27 diseñadores freelance.
SexyStilettos Dance
Stephanie Sy, an accomplished triple threat Performer, Instructor, and
Choreographer born in Vancouver, BC, has cemented her reputation in the Canadian dance scene & has infiltrated the American entertainment industry. Her range of movement disciplines include but are not limited to classical ballet, jazz, hip hop, contemporary, and salsa. She began training from the age of 5 at the Richmond Academy of Dance, the Goh Ballet Academy, and Danzmode Productions. Her passion and talents gave her the opportunity to
travel the world and train on scholarships at the most prestigious institutions in both Canada & the USA including the National Ballet School, the Royal Winnipeg Ballet School, and EDGE Performing Arts Center. Stephanie's extensive credits span all genres of the entertainment industry to include working in film, television, commercials, music videos, and live shows. Credits: movie "Another Cinderella Story", 20th Century Fox feature film "John Tucker Must Die", Warner Bros. hit series "Smallville", music videos for SLANK "Too Sweet To Forget", Lisette Bustamante "I, Bittersweet", and Reddnation "Wiggle Dem Toes"; Commercials for Coca-Cola, Sony Ericsson Mobile Communications & Burger King.
For ladies in their late teens through to adults (16 and up). A sexy, sassy and sophisticated dance program to empower women, help them get healthy and seductive in a fun and flirtatious! Formerly known as the pussycat dollz style program. (very much like the PCD grp - funky, sexy, sassy, seductive, classy, fun, flirtatious) Logo to be used on website, print, potentially apparel, instructional dvds, etc.
would like LOGO to read as:
SexyStilettos Dance
Created & Choreographed by Stephanie Sy (*in smaller font)
potentially to include SS since brand and name "share" common intials. would like to make sure it doesnt just look like a shoe line but is dance related.
The dance classes currently run as "PCD style" & now rebranding as SexyStilettos Dance to STAND OUT from the imitations.
go to http://www.StephanieSy.com under SYTV to watch the dvd teaser if necessary for inspiration.
Target audience is mainly women but occasionally male dancers will participate in class. Dance class is done 30 minutes in sneakers and 30 minutes in high heels (any heel - pumps, stilettos, dance shoe, knee high boots etc) Ladies learn sexy dance moves that are visible in music videos and pop culture, and are motivated to be proud to be a woman with sexy curves, & inspired to be sexy and intelligent.
caters also to stagette parties for women!
every women secretly wants to FEEL SEXY AND WANTED!
SexyStilettos Dance (Brand name) with R for Registered trademark
Created & Choreographed by Stephanie Sy (*in smaller font)
- use of SS initials since SS is shared btwn brand name & creators name (SS back to back, creating a heart shape or something of that nature)
- feminine (script-ish, caligraphy) type font but still legible
- sexy, sassy, classy, confident, seductive, yet simple and clean
- use of a sexy ladies high heel shoe(s), & incorporating a silhouette of a sexy woman or image of a woman
- STANDS OUT but Femine
- try to incorporate dance so that it doesnt look like a shoe company
- a RICH FEEL to the logo (very classy not trashy)
(*website currently in works for the new dance program)
Descubre cómo funciona un concurso de diseño u obtén más información sobre nuestros servicios de diseño de logo.


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SOI (silicon-on-insulator) is a semiconductor technology which enables a full isolation of each electronic component on an integrated circuit by using a buried oxide layer. The heart of a SOI wafer is an ultra-thin, monocrystalline, conductive layer on a silicon wafer. All electronic operations take place, on this isolated layer, enabling higher switching frequencies and lower power consumption all the while avoiding unwanted heat production. SOI chips have been used recently in consumer goods and applications, such as computing, gaming, automotive, networking and imaging, as well as generally in devices requiring ultra low power consumption.
An accurate wafer bonding process is the key factor in obtaining high quality, single crystalline silicon films on insulating substrates. For SOI wafer manufacturing, a thermally oxidized silicon wafer will typically be bonded together with another silicon wafer that has a native oxide layer. This technique is called oxide-oxide bonding. Molecular, fusion or direct wafer bonding are other synonyms for this bonding method. Wet bench cleaning needs to be done prior to subsequent processes.Ultra clean handling of wafers in class 1 environments throughout the whole process assures high-yield and void-free bonds. All essential steps from cleaning and alignment to pre-bonding and IR-inspection have to be combined in one high volume production system.Cleaning - as controlled cleanliness is a must to guarantee proper surface conditioning - and plasma activation are important steps prior bonding. A mechanical flat-to-flat or notch-to-notch alignment is done on the same process station directly before bonding, followed by a controlled initiation of the bond front which is essential for void- and stress-free bonding. The bonding itself can take place under ambient atmosphere or vacuum. After the bonding is finished, a first quality investigation takes place using IR inspection. Please see our related product EVG®850 for detailed information.
SOI wafers produced using Smart Cut® technology. Courtesy of SOITEC.
Power PC Chip manufactured on an SOI wafer. Courtesy of IBM.
EV Group Partners with NSI to Enable First Wafer-Level Heterogeneous Integration of GaAs on Silicon for RF Front-End Module Manufacturing
more news ..
Imec Technology Forum 2019
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SCons / ImportingEnvironmentSettings
The SCons wiki has moved to https://github.com/SCons/scons/wiki/ImportingEnvironmentSettings
SCons attempts to be a clean build tool and only generates the environment for build operations that is necessary for success of those build operations. This is the philosophical other end of the scale from make, where all of the environment variables of the process are automatically active within the build statements.
This is a good thing, since it prevents hidden dependencies and other problems (even trojan horses) from affecting the build environment from one user or platform to another.
However, sometimes you do want to import settings from your environment (see the ExternalTools example).
/!\ First, you should think about importing ONLY those settings you want:
env = Environment() env.Append(CCACHEDIR = os.environ['CCACHEDIR'])
If this is too awkward, /!\ think again, and again!
Do you really want to open this Pandora's box?!
If you still do, then you could use the simple method shown in ExternalTools:
env = Environment(ENV = os.environ)
but this is likely to break for some platforms (e.g. Win32) because the Platform initialization of SCons may have already prepared some settings (like paths, etc.) that would be overwritten and lost by the above substitution. The following method is a little more involved, but makes sure that combinative elements like paths are correctly concatenated rather than replaced:
def ENV_update(tgt_ENV, src_ENV): for K in src_ENV.keys(): if K in tgt_ENV.keys() and K in [ 'PATH', 'LD_LIBRARY_PATH', 'LIB', 'INCLUDE' ]: tgt_ENV[K]=SCons.Util.AppendPath(tgt_ENV[K], src_ENV[K]) else: tgt_ENV[K]=src_ENV[K] env = Environment() ENV_update(env, os.environ)
I tried the above and got the following error
AttributeError: SConsEnvironment instance has no attribute 'keys': File "SConstruct", line 14: ENV_update(env, os.environ) File "SConstruct", line 7: if K in tgt_ENV.keys() and K in [ 'PATH', 'LD_LIBRARY_PATH',
I suspect ENV_update is supposed to be called as follows
ENV_update(env['ENV'], os.environ)
SCons 0.96.1; Python 2.4.1; WinXP; - TomHoward
Sorry to ruin this page. I run scons 0.95 on Windows ME with VC6. I alway get the anonying messages of 'Bad command or filename' when invoking cl.exe or link.exe, and my environment is OK. Finally, I change
args = [sh, '/C', escape(string.join(args))]
in Platform\win32.py to
args = [sh, '/E:4096 /C', string.join(args)]
Everything seems right then. That's all.


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Science Friday® is produced by the Science Friday Initiative, a 501(c)(3) nonprofit organization.
Science Friday® and SciFri® are registered service marks of Science Friday, Inc. Site design by Pentagram; engineering by Mediapolis.
|Reporting in the journal PNAS, researchers say drinking water containing potentially hazardous methane levels has been found near natural gas wells in Pennsylvania and New York. Ira Flatow and guests discuss the study, and its implications for "fracking" for natural gas.


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Loose: 3 Females Stomp Out Big Girl In A Crowd While Cassidy Performs "Henny & Bacardi" With Nate Robinson Of The Boston Celtics On Stage!
Footage courtesy of D. Gomez Films
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We brought world rally champion Petter "Mr. Hollywood" Solberg on to Jalopnik today and it was as fantastic as we'd imagined. Here are the six best things he said.
Which rally driver has/had the biggest balls of all?
Also, would you consider taking Loeb on in WTCC?
I know who has the prettiest ones.. And you're talking with him now.
You can tell a Finn, but you can't tell him much
What is your favorite surface to race on, tarmac, gravel, snow?
I like Blondes, then Brunnettes... Wait, I'm supposed to be saying something about driving here? Oh well, I like it all.
Hi Mr Solberg. How do you prepare for such intense rally stages, knowing that each stage is different and a slight miscalculation of turning may lead to serious injury or even death?
You're thinking too much man... We just listen to the notes, keep our eyes up, and keep the throttle down.
Does it piss you off when Americans call you "Peter"?
I like it better when they say it with two T's as Petter, as the name sounds faster.
I'm useless when I leave the tarmac. Can I have your magical driving powers?
No... They're mine.
are you Jesus
No, but we are close.
There you go folks. He's a legend.


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Filter Effect
Show MoreLess
Now Viewing:
The Hoya 77mm 85 Hoya Multi-Coated (HMC) Glass filter will produce natural colors when shooting with tungsten film outdoors.
What do you do when you must take some photos outdoors and all you have left is tungsten film? Using tungsten film in daylight will produce a bluish cast in the photograph. The 85 series of filters will "bring back", i.e. color balance the tones in your images. These yellow filters are used to correct differences in color temperature between the recording medium (film/video) and the light source.
It should be noted that an 85 filter produces slightly cooler results than an 85B (with tungsten film in daylight) whereas an 85B converts tungsten film to daylight. The 85C produces the coolest results - more than either the 85 or 85B. However, it is interesting to remember that an 85C is also useful as a creative warming filter with daylight film in daylight.
Multicoated to minimize reflection at the filter surfaces which reduces flare and ghosting.
Note: Whereas the 85 series is used for tungsten film under daylight conditions, use the 80 series of filters when using daylight film under tungsten lighting
|Color Conversion
|Filter Factor
|1.8 (+2/3 stop)
|Yes Hoya Multi-Coated (HMC)
|Removes excessive blue from images and produces more natural colors
|When pleasing color balance is desired when shooting with tungsten film outdoors
|Color Temperature
|Decreases the color temperature from 5500-3400° Kelvin
|Front Filter Thread Size
|77 mm
|Front Lens Cap Size
|77 mm
|Packaging Info
|Package Weight
|0.15 lb
|Box Dimensions (LxWxH)
|4.2 x 3.6 x 0.5"


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Because my eyes are so often tired and sore I treat them to new eye drops every now and then.
My most recent purchase is this Rohto Japan eye drop which is supposed to be moisturising, cleansing, relieving etc. A bit of everything really!
The thing about Japanese eye drops, you must know, is that they tend to contain some kind of menthol which means it makes your eyes go ZING! By ZING I mean burn…I mean burn as in salt in wound type of burn.
Mind you not everyone is like that. Maybe my peepers are just delicate. The first time I tried one of these eye drops I writhed around on the floor like a baby, wondering who was cruel enough to swap my eye drops for acid.
But you get used to it.
Looks like Chinese menthol oil – it's a oil you can use on bites and stings or if you have a headache! Do not get those two mixed up!
These eye drops are pretty good – you get the sting, but it's not as bad as some others I have tried and it does a good job of making my eyes feel cleansed and rested. It made my eyes look a tiny bit whiter but not loads.
Active Ingredients
1. Potassium L-Aspartate
– promotes "breathing" of eye cells and helps relief from tiredness
2. d-alpha-tocopherol acetate
– nourishes eyes, promote blood circulation, and effectively relief from eye tiredness
3. Sodium Chondroitin Sulphate
– mildly nourishes cornea, and relier from discomfort caused by lens
4. Sodium Hyaluronate
– a common and effective moisturiser with high powder of moisture replenishment
Taurine! I give my cats taurine!
Nice eye drops for people who have dry and very tired eyes. Cost me about £7 from eBay.


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Before and After Facelift Surgery Photos
Facelift (also known as rhytidectomy) is a facial plastic surgery procedure designed to combat the telltale signs of aging that appear on the face, including deep lines and wrinkles, nasolabial folds, sagging cheeks and jowls. For patients considering a face lift, viewing before and after photos can be very useful. By examining photos of patients with facial characteristics and signs of aging similar to their own, patients can get a sense for the potential benefits, as well as the limitations, of the procedure. In this way, the patient can develop realistic expectations prior to agreeing to surgery. In addition, when choosing a surgeon, it is essential to view before and after pictures of the surgeon's previous patients to ensure that he or she has the skills and aesthetic judgment you require. The following photos have been chosen for your education. Other before and after galleries in this website show photos provided by local facial plastic surgeons for rhinoplasty before and after results and blepharoplasty before and after results.
Experience: More than 20 years of plastic surgery experience
Training: Advanced fellowship training in cosmetic and craniofacial surgery
Positions: Chief of plastic surgery, Northwest Hospital
Ronald H. Schuster, MD
Baltimore, Maryland
(800) 572-1096
Media: Featured on numerous TV networks and in popular print publications
Positions: Assistant Clinical Professor at Albert Einstein College of Medicine
Charitable Involvement: New York City Director of The R.O.S.E. Fund
Yael Halaas, MD, FACS
Board-Certified Facial Surgeon
New York City
(877) 831-4250
Credentials: Double board-certified facial plastic surgeon
Affiliations: AAFPRS, AAO-HNS and ACS
Awards: Top Beauty Doctor 2015
Dilip D. Madnani, MD
New York
(212) 203-8591
Credentials: Double board-certified facial plastic surgeon
Affiliations: AAFPRS, AAO-HNS and ACS
Awards: Top Beauty Doctor 2015
Dilip D. Madnani, MD
New York
(212) 203-8591
Face lift is a complex procedure that requires a skilled surgeon with years of experience and training. Prior to agreeing to surgery, patients should carefully consider all the factors involved in undergoing the procedure, including the facelift cost, the risks of facelift and the face lift recovery process. In addition to facelift, many plastic surgeons offer minimally invasive facial procedures, including Botox injections and microdermabrasion, which can produce impressive facial rejuvenation results.


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Why expression templates matter ?
Imagine we are using a matrix library, with a naive implementation of +, that simply adds column and row-wise each coefficient. Thus, for a, m1, m2, m3 being for example square matrices of order n, if we want to compute the sum of m1, m2 and m3 and to put the result in a, corresponding to the following code :
a = m1 + m2 + m3
then the computation will look like the following tree :
Thus, there will be a first for loop to compute m1 + m2 which will result in a matrix we'll call t, then another one to compute t + m3. For 3×3 matrices, it's ok. Imagine n is actually 40000. Doing two for loops of 40000 iterations where we would do a single one… quite annoying, isn't it ? Actually, we would rather want an evaluation tree like the following :
Here comes expression templates 😉
It'll need a bit of refactoring though. First, let's say our matrix type is the following (we'll only deal with float to avoid ambedding an additional typename template parameter representing the number type we use) :
template <unsigned int N> class matrix { float data[N*N]; public: float operator()(unsigned int row, unsigned int col) const { return data[row + N*col]; } float& operator()(unsigned int row, unsigned int col) { return data[row + N*col]; } }; template <unsigned int N> std::ostream & operator<<(std::ostream& o, const matrix<N>& m) { o << "["; for(unsigned int row = 0; row < N; row++) { for(unsigned int col = 0; col < N; col++) { o << m(row,col); if(col != N-1) o << ";"; } if(row != N-1) o << "\n"; } o << "]"; return o; }
Now, we'll have to define a Domain Specific Embedded Language for matrix operations. Like in any language people design, we will have a tree representing what's happening in the code. In our case, it'll represent the evaluation tree of the matrix operations we're dealing with. Thus, like in any expression tree, we need an Expression type. Ours will look like this :
template <typename LeftOperandType, typename OperationTag, typename RightOperandType> struct Expression { const LeftOperandType& l; const RightOperandType& r; Expression(const LeftOperandType& l_, const RightOperandType& r_) : l(l_), r(r_) { } float operator() (unsigned int row, unsigned int col) const { return OperationTag::apply(l(row, col), r(row,col)); } };
Ok, now, what should an OperationTag look like ? Well, we'll implement the operation tag corresponding to additions :
struct plus { static float apply(float a, float b) { return a+b; } };
and the + operator that'll let us create an expression with a 'plus' operation.
template <typename L, typename R> Expression<L, plus, R> operator+(const L& l, const R& r) { return Expression<L, plus, R>(l, r); }
Thanks to the definition of Expression, we can embed matrix operations in Expressions, but for the moment we can't do the reverse way, that is we can't convert an Expression to a matrix. So let's write an operator= in the matrix class.
// inside the matrix class template <typename ExprType> matrix<N>& operator=(const ExprType& e) { for(unsigned int row = 0; row < N; row++) { for(unsigned int col = 0; col < N; col++) { (*this)(row, col) = e(row, col); } } return (*this); }
So you see, this is the only moment where we call the operator()(unsigned int, unsigned int) of the Expression type. Thus, this is the only moment when the whole expression is being evaluated. Let's study the following code.
#include <iostream> #include "matrix.h" #include "expression.h" int main() { matrix<2> m1; m1(0,0) = 1.0; m1(1,0) = 0.0; m1(0,1) = 4.0; m1(1,1) = 1.0; matrix<2> m2; m2(0,0) = 0.0; m2(1,0) = -1.0; m2(0,1) = 1.0; m2(1,1) = 2.0; matrix<2> m3; m3(0,0) = 1.0; m3(1,0) = -2.0; m3(0,1) = 3.0; m3(1,1) = 5.0; matrix<2> a; a = m1 + m2 + m3; std::cout << a << std::endl; }
Here, "m1 + m2 + m3" crates an
Expression< Expression<matrix<2>, plus, matrix<2> >, plus, matrix<2> >
instance. The coefficients aren't computed until operator= is called. Indeed, we have the following expression tree.
That is, we know which operations we have to call, on which matrices, but nothing is evaluated. The only place where we call operator() (unsigned int, unsigned int) on a value of type Expression is in matrix<N>::operator=, and this call actually computes each coefficient, one by one, applying the whole computation tree (here, two calls to '+') for each coefficient. This way, we only execute the two for loops once, and it'll remain the same whatever the number of computations is. Moreover, the only change we had to make to our matrix class was to add an operator= to be able to assign an expression to a matrix.
By the way, the output of our main function is the following.
I hope you enjoyed this post 😉