Protection Of Human Research Participants Research Articles

Greater Blood Heavy Metal Levels in the Participants of National ALS Biorepository Compared to the Participants of National Health And Nutrition Examination Survey (P2-5.024)

<h3>Objective:</h3> To determine the demographic and environmental exposure characteristics of participants in the National ALS Biorepository (Biorepository) and compare the blood levels of cadmium (Cd), lead (Pb), selenium (Se), manganese (Mn), and total mercury (tHg) to National Health and Nutrition Examination Survey (NHANES) participants. <h3>Background:</h3> Amyotrophic lateral sclerosis (ALS) is a rare and fatal disease of the upper and lower motor neurons. While 10% of ALS cases is hereditary, a gene-environment interaction is believed to be the main contributor in many sporadic cases. Elevated heavy metals in blood have been implicated in the pathology of several neurodegenerative diseases. We hypothesize the ALS cohort to have greater levels of blood heavy metals than NHANES participants. <h3>Design/Methods:</h3> Blood samples from Biorepository participants (n=549) collected in 2013–2015 and 2017 were analyzed following the same protocol used to analyze the subset of NHANES cohort (n=10,809) during 2013–2018. We report descriptive summary in demographic (age/sex/race/education/military history) and comparison of blood metal level means using t-test. Further, self-reported occupational- and non-occupational environmental exposures to pesticides, chemicals, and metals were described for Biorepository participants with available environmental risk factor data. NHANES analyses used survey weights and accounted for the complex design to generate nationally representative estimates. <h3>Results:</h3> ALS Biorepository participants had higher geometric means of blood level Cd, Pb, Se, and tHg compared to NHANES cohort. Among the Biorepository participants, exposure to pesticides (90.3%), chemicals (80.7%) and metals (85.8%) from non-occupational settings were self-reported in higher frequency than occupational exposure to these substances. <h3>Conclusions:</h3> Blood metal levels were elevated in ALS Biorepository participants compared to NHANES. Self-reported non-occupational exposures to pesticides, chemicals, and metals were more common than occupational exposures. Determining a potential association between blood metals and exposure history in our cohort can help further understand the role of environmental exposure in the etiology of ALS. <b>Disclosure:</b> Dr. Han has nothing to disclose. Theodore Larson has nothing to disclose. Maureen Orr has nothing to disclose. Jaime Raymond MPH has nothing to disclose. Laurie Wagner has nothing to disclose. Dr. Kaye has received personal compensation for serving as an employee of McKing Consulting Corporation. Dr. Kaye has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Association for the Protection of Human Research Participants. Paul Mehta has nothing to disclose. D. Kevin Horton has nothing to disclose.

Human Subjects Protection and Federal Regulations of Clinical Trials.

To explore the federal regulations governing clinical trials and human subject protection, the importance of research participant's informed consent, and the role the oncology clinical research nurse has within the clinical trial setting. Peer-reviewed journal articles, internet, book chapters, white papers. Federal regulations mandate the conduct of a clinical research trial, human research participant protection, and the informed consent process. The oncology nurse supports the autonomy and safe conduct of the human research participant during a clinical research trial and provides education and support through the informed consent process.

A brief introduction to institutional review boards in the United States.

China has become one of the main fields for international drug and device trials in the last twenty years. Although China has greatly strengthened the protection of human research participants over this time, there is still room for improvement. In order for Chinese investigators to participate in international clinical trials, compliance with internationally recognized ethical regulations is essential. In the United States (U.S.), research involving human subjects is reviewed by an ethics committee called the Institutional Review Board (IRB). In this article, we briefly introduce the background, composition, and function of the IRB in the U.S. to our Chinese investigators.

Single IRBs in Multisite Trials

On June 21, 2016, the US government announced changes that are arguably the most significant of the last quarter century concerning the protection of human research participants—a requirement for use of central or single institutional review boards (IRBs) in multisite National Institutes of Health (NIH)–funded research. Specifically, the NIH announced a new policy (effective September 25, 2017) to mandate that nonexempt multisite research with humans funded by the NIH be reviewed by a single IRB.1 On January 19, 2017, final amendments to the federal human research participant protection regulations (the Common Rule) were also published, requiring use of a single IRB,2 although implementation will be delayed until January 20, 2020. The NIH directive seems straightforward, but effective implementation will require that institutions, researchers, and policy makers decide how to address a number of critical issues. The Common Rule amendments explicitly recognize that further guidance will need to be developed, necessitating that these stakeholders confront several dilemmas.

ESTABLISHMENT OF A SUB-REGIONAL ETHICS COMMITTEE IN CENTRAL AFRICA TO ADDRESS THE NEEDS OF MULTICOUNTRY PROJECTS: AN OCEAC INITIATIVE

BackgroundThe Universal Declaration on Bioethics and Human Rights, adopted by UNESCO, requires that governments establish National Ethics Committees (NECs) capable of reviewing ethical and scientific aspects on research involving human...

The Role of the Virtuous Investigator in Protecting Human Research Subjects.

In his famous 1966 New England Journal of Medicine article, Henry Beecher concluded that a critical safeguard for protecting human participants, more reliable than informed consent, was the "presence of an intelligent, informed, conscientious, compassionate, responsible investigator." This article examines Beecher's appeal to reliance on the "virtuous" investigator in light of the critical role that investigators play in research ethics and the systems of research protections that have been developed since Beecher's writing. It addresses the extent to which research ethics rely on virtuous investigators; the meaning of virtuous, as distinct from compliance with the rules and regulations that guide ethical research; the particular virtues that it might be important for investigators to have; and the impact of the existing system of human subjects protections on the virtuous investigator. The virtuous investigator who is motivated to take ethical responsibilities seriously is an essential safeguard for the protection of human research participants and an important complement to the system of oversight protections. However, since the current human subjects protection system does not promote virtue or ethical resourcefulness by investigators, attention to enhancing a culture of professional responsibility might serve to forge a synergy between the protections afforded by the current oversight system and those provided by the virtuous investigator.

Protection of human research participants: accreditation of programmes in the Indian context

The recent negative media reports on the status of participants in clinical trials in India, together with the concerns expressed by the regulatory bodies, have raised questions regarding India's credibility in the conduct of clinical research. Even though the regulations require the registration of trials with the Clinical Trial Registry-India and despite the recently mandated registration of ethics committees (ECs) with the Drugs Controller General of India, the lack of governmental audit and accreditation procedures and bodies has resulted in inadequate protection of human participants in clinical research. Institutions and research sites would benefit by implementing a human research protection programme, which would safeguard the rights, safety and wellbeing of participants in clinical trials, in addition to improving the processes and procedures for the conduct of the trial. The Jehangir Clinical Development Centre, Pune has received accreditation from the Association for the Accreditation of Human Research Protection Programme (AAHRPP). A unique feature of the AAHRPP is the integrative nature of the programme, wherein the sponsors of the trial, investigators, EC members and institution work towards the common goal of protecting research participants. Here, we discuss the improvement needed in the quality standards of institutions for them to be able to meet the requirements of the AAHRPP. We also suggest the need for a governmental accreditation body, which will be required for the future promotion of and improvement in the standards for clinical practice in India.

Protection of human research participants through routine inspection of ongoing HIV prevention and treatment clinical trials: experiences from Zimbabwe

Background The Medical Research Council of Zimbabwe (MRCZ) is the National Ethics Committee in Zimbabwe. MRCZ was established in 1974 under the Research Act of 1959 and Government Notice No. 225 of 1974 to promote and coordinate health research in Zimbabwe. The main mandate of MRCZ is the scientific review, ethics approval and oversight of all ongoing medical research studies in Zimbabwe inspection of all on going research studies involving humans using an established Human Protection System. Routine inspections and ‘for cause’ inspections are carried out to ensure utmost protection of research participants and to ensure protocol adherence and ICH-GCP compliance. HIV prevention and HIV drug treatment clinical trials receive more detailed attention during inspections as they are delicate and complicated.

Continuous Patient Engagement in Comparative Effectiveness Research

THE GOAL OF COMPARATIVE EFFECTIVENESS RESEARCH (CER) is to provide patients, their advocates and caregivers, health care professionals, federal officials, policy makers, and payers with evidence-based information to make informed health care decisions. Previously, CER studies were designed by researchers and had relatively little input from patients. Patient engagement has rapidly gained acceptance as crucial to the successful translation of CER for all interested parties. Experiences with patient engagement in research, including community-based participatory research, suggest that success hinges on patients being interested and emotionally involved in the research question and understanding their role in the CER process. Evaluation of information from the Agency for Healthcare Research and Quality and the Patient-Centered Outcomes Research Institute suggests that CER may be enhanced through continuous patient engagement. The framework for doing so, as proposed in this Viewpoint, reflects pragmatic experiences and observations in which patient engagement has helped to shape and translate CER for patients and health care professionals; however, the framework needs to be tested empirically (FIGURE). This proposed 10-step process for CER describes how patient engagement might guide CER toward patient-centered outcomes research and offers suggestions for the process and purpose of patient engagement across the 10 steps. Each step has different purposes, advantages and disadvantages, and implications for time and resources. The proposed framework is intended to span the entire “life cycle” of a CER project. At the first step, patients could help identify understudied CER topics. By soliciting input from diverse patients, the process could generate a broad array of topics, from which a more narrow focus could be achieved by framing specific research questions. When designing a potential framework for a specific CER question, patients would provide a “reality check,” indicating the extent to which the proposed framework reflects their personal experiences. When CER involves primary data collection, patient input could help determine the best practices for data collection, provide input about the proposed content of the data collection tool, and participate in pilot testing survey items. Traditionally, patient feedback is infrequently used during the development of the analysis plan. However, this framework proposes that patients could assist in helping to define or categorize variables even if they do not have training in research methods. When reviewing and interpreting results, patients could reflect on whether results are plausible and believable, what other factors should be considered, and how results may vary across subgroups of patients. In the translation phase, patients could identify which results are easy or difficult to understand. If the results do not affect patients or are counterintuitive, CER findings will not be translated into medical practice. Patients could also offer suggestions for how best to explain study findings to other patients. Patients could help determine the best dissemination strategies, provide dissemination channels, and craft specific messages targeted to patients who will benefit most. Thoughtful consideration should be given to determining which approach would best elicit the patient’s perspective at each particular step. For example, during the early stages of research, it may be most beneficial to engage patients through patient forums or telephone conversations to solicit potential topics of importance. As research progresses to protocol development, involving patients in stakeholder meetings could provide an opportunity for robust discussion regarding which outcomes to assess, populations to include, and treatment options to compare. Input on the patient experience also could be obtained from indirect means of engagement. For example, using online patient forums in which groups of patients talk about their disease may be a source of valuable information provided the process adheres to ethical standards of protection of human research participants. When creating the conceptual framework, collecting data, and specifying the analysis plan, more in-depth information and patient input may be required. Methods of engagement such as in-person meetings, focus groups, and individual patient interviews could allow patients to give more detailed input. Patients could assist in framing the message, creating plain language summaries, targeting audi-

In the wake of Guatemala: the case for voluntary compensation and remediation.

Recently unearthed records reveal that between 1946 and 1948, researchers with the US Public Health Service engaged in nonconsensual inoculation of vulnerable Guatemalan populations with syphilis, gonorrhea, or chancroid. The US government has issued formal public apologies to the Guatemalan government and its people, and the Presidential Commission for the Study of Bioethical Issues has been tasked with reviewing the historical record and the adequacy of protection of human research participants. We argue that the US response is insufficient and call for a restitution program directed at the aggrieved parties. We review the lessons of two earlier analogous cases and propose guiding principles upon which such a restitution program could be crafted with the Guatemalan people in mind.

Protecting Research Participants While Reducing Regulatory Burdens

THE DEPARTMENT OF HEALTH AND HUMAN SERVICES (HHS) has proposed sweeping revisions to the federal regulations for the protection of human research participants. The goal is to “enhance protection while simultaneously eliminating unreasonable burdens.” Although the goal is admirable, some changes intended to remove unnecessary regulatory burdens may allow serious risks (ie, the probability of harm is significant, not merely possible or conceivable), particularly to highly vulnerable participants (ie, participants’ ability to give free and informed consent is seriously compromised). In this Commentary, 3 major issues in the Advance Notice of Proposed Rule-Making (ANPRM)—ensuring riskbased protections, institutional review board (IRB) reviews of multisite studies, and informed consent—are discussed. New policies to reduce regulatory burdens should be coupled with procedures to protect participants if research poses serious risks, involve highly stigmatizing conditions, or include significantly vulnerable participants.

A Systematic Review of the Empirical Literature Evaluating IRBs: What We Know and What We Still Need to Learn

Institutional review boards (IRBs) are integral to the U.S. system of protection of human research participants. Evaluation of IRBs, although difficult, is essential. To date, no systematic review of IRB studies has been published. We conducted a systematic review of empirical studies of U.S. IRBs to determine what is known about the function of IRBs and to identify gaps in knowledge. A structured search in PubMed identified forty-three empirical studies evaluating U.S. IRBs. Studies were included if they reported an empirical investigation of the structure, process, outcomes, effectiveness, or variation of U.S. IRBs. The authors reviewed each study to extract information about study objectives, sample and methods, study results, and conclusions. Empirical evidence collected in forty-three published studies shows that for review of a wide range of types of research, U.S. IRBs differ in their application of the federal regulations, in the time they take to review studies, and in the decisions made. Existing studies show evidence of variation in multicenter review, inconsistent or ambiguous interpretation of the federal regulations, and inefficiencies in review. Despite recognition of a need to evaluate effectiveness of IRB review, no identified published study included an evaluation of IRB effectiveness. Multiple studies evaluating the structure, process, and outcome of IRB review in the United States have documented inconsistencies and inefficiencies. Efforts should be made to address these concerns. Additional research is needed to understand how IRBs accomplish their objectives, what issues they find important, what quality IRB review is, and how effective IRBs are at protecting human research participants.

Ethical concerns of nursing reviewers: An international survey

Editors of scientific literature rely heavily on peer reviewers to evaluate the integrity of research conduct and validity of findings in manuscript submissions. The purpose of this study was to describe the ethical concerns of reviewers of nursing journals. This descriptive cross-sectional study was an anonymous online survey. The findings reported here were part of a larger investigation of experiences of reviewers. Fifty-two editors of nursing journals (six outside the USA) agreed to invite their review panels to participate. A 69-item forced-choice and open-ended survey developed by the authors based on the literature was pilot tested with 18 reviewers before being entered into SurveyMonkey(TM). A total of 1675 reviewers responded with useable surveys. Six questions elicited responses about ethical issues, such as conflict of interest, protection of human research participants, plagiarism, duplicate publication, misrepresentation of data and 'other'. The reviewers indicated whether they had experienced such a concern and notified the editor, and how satisfied they were with the outcome. They provided specific examples. Approximately 20% of the reviewers had experienced various ethical dilemmas. Although the majority reported their concerns to the editor, not all did so, and not all were satisfied with the outcomes. The most commonly reported concern perceived was inadequate protection of human participants. The least common was plagiarism, but this was most often reported to the editor and least often led to a satisfactory outcome. Qualitative responses at the end of the survey indicate this lack of satisfaction was most commonly related to feedback provided on resolution by the editor. The findings from this study suggest several areas that editors should note, including follow up with reviewers when they identify ethical concerns about a manuscript.

TRAINING NEEDS ASSESSMENT IN RESEARCH ETHICS EVALUATION AMONG RESEARCH ETHICS COMMITTEE MEMBERS IN THREE AFRICAN COUNTRIES: CAMEROON, MALI AND TANZANIA

As actors with the key responsibility for the protection of human research participants, Research Ethics Committees (RECs) need to be competent and well-resourced in order to fulfil their roles. Despite recent programs designed to strengthen RECs in Africa, much more needs to be accomplished before these committees can function optimally. To assess training needs for biomedical research ethics evaluation among targeted countries. Members of RECs operating in three targeted African countries were surveyed between August and November 2007. Before implementing the survey, ethical approvals were obtained from RECs in Switzerland, Cameroon, Mali and Tanzania. Data were collected using a semi-structured questionnaire in English and in French. A total of 74 respondents participated in the study. The participation rate was 68%. Seventy one percent of respondents reported having received some training in research ethics evaluation. This training was given by national institutions (31%) and international institutions (69%). Researchers and REC members were ranked as the top target audiences to be trained. Of 32 topics, the top five training priorities were: basic ethical principles, coverage of applicable laws and regulations, how to conduct ethics review, evaluating informed consent processes and the role of the REC. Although the majority of REC members in the targeted African countries had received training in ethics, they expressed a need for additional training. The results of this survey have been used to design a training program in research ethics evaluation that meets this need.

The use of placebo control in clinical trials: An overview of the ethical issues involved for the protection of human research participants.

A placebo-controlled clinical trial is a trial where some of the volunteers are given the new drug being tested, and the other volunteers are given a placebo. A placebo looks exactly like the experimental drugs in every respect both in appearance and wrappings which, is prescribed in identical way to the real drug. The experimental group receives the real drugs while the control group receives the placebo. When patients believe that a certain medication will improve their condition, that fact alone can cause certain positive effects when combine with pill, an injection or even a surgical procedure. Researchers can utilize such adventitious effects and more precisely determine the actual therapeutic benefit of a new treatment. However, the use of placebo in clinical trials has been controversial with many stake holders in clinical research expressing different opinions. It is usually not problematic to use a placebo in clinical trials when testing a new treatment in absence of a known treatment. On the other hand, resort to placebo controls becomes ethically controversial when researchers wish to introduce a new treatment as a possible successor or competitor drugs whose use is currently a standard practice. More problematic and controversial is the use of invasive placebo in interventions in surgical trials. This article is therefore, a critical presentation of the ethical issues involved in the protection of human research participants in the presence of placebo controlled clinical trials

Enhancing communication among data monitoring committees and institutional review boards

Data Monitoring Committees (DMC) and Institutional Review Boards (IRB) each can play important roles in protecting the rights and interests of research participants and ensuring the integrity of research. While both IRBs and DMCs have unique responsibilities, promoting a robust human research participant protection program requires integration of these efforts. Communication about DMC actions and considerations to IRBs is arguably an important component of integration. We sought to explore whether and how DMCs actions are currently communicated to IRBs as a basis for recommendations to improve such communications. Evidence of communication was sought in files related to research conducted by faculty, staff, and students affiliated with the Johns Hopkins Medical Institutions and the Johns Hopkins Bloomberg School of Public Health. Overall, we found a lack of consistency in the way that DMC actions are communicated to IRBs. While national policy encourages that actions taken by DMCs be communicated to IRBs and there is not a clear consensus about either who should be responsible for disseminating the information to the IRB or what information ought to be considered standard. Such standards promise to enhance the quality of ethics oversight of research.

How do we know that research ethics committees are really working? The neglected role of outcomes assessment in research ethics review.

BackgroundCountries are increasingly devoting significant resources to creating or strengthening research ethics committees, but there has been insufficient attention to assessing whether these committees are actually improving the protection of human research participants.DiscussionResearch ethics committees face numerous obstacles to achieving their goal of improving research participant protection. These include the inherently amorphous nature of ethics review, the tendency of regulatory systems to encourage a focus on form over substance, financial and resource constraints, and conflicts of interest. Auditing and accreditation programs can improve the quality of ethics review by encouraging the development of standardized policies and procedures, promoting a common base of knowledge, and enhancing the status of research ethics committees within their own institutions. However, these mechanisms focus largely on questions of structure and process and are therefore incapable of answering many critical questions about ethics committees' actual impact on research practices.The first step in determining whether research ethics committees are achieving their intended function is to identify what prospective research participants and their communities hope to get out of the ethics review process. Answers to this question can help guide the development of effective outcomes assessment measures. It is also important to determine whether research ethics committees' guidance to investigators is actually being followed. Finally, the information developed through outcomes assessment must be disseminated to key decision-makers and incorporated into practice. This article offers concrete suggestions for achieving these goals.ConclusionOutcomes assessment of research ethics committees should address the following questions: First, does research ethics committee review improve participants' understanding of the risks and potential benefits of studies? Second, does the process affect prospective participants' decisions about whether to participate in research? Third, does it change participants' subjective experiences in studies or their attitudes about research? Fourth, does it reduce the riskiness of research? Fifth, does it result in more research responsive to the local community's self-identified needs? Sixth, is research ethics committees' guidance to researchers actually being followed?

Sustaining Public Trust: Falling Short in the Protection of Human Research Participants

Sustaining Public Trust: Falling Short in the Protection of Human Research Participants Anna C. Mastroianni (bio) An aura of complacency surrounds the protection of human research participants in the United States. From investigators to policy-makers, many involved in research are exhibiting bureaucratic resignation, allowing paperwork compliance and checkboxes to protect the rights and interests of participants. The routinizing of ethics gives some tangible assurance that a system is in place, but it also undermines deliberate attention to ethical issues. Meanwhile, there is a disconnect between oversight practices and public perceptions. In a March 2008 survey conducted jointly by USA Today, the Kaiser Family Foundation, and the Harvard School of Public Health, 28 percent of respondents believed that most pharmaceutical companies acted unethically when testing new drugs on people.1 Since the line between public and private sector research has blurred, this perception could readily affect attitudes toward public sector drug development as well. Maintaining public trust is absolutely crucial to the research enterprise. Without trust, volunteers will be impossible to recruit, and the public will be unwilling to fund research. Here I venture some preliminary thoughts on some of the central marks of public trust in the research enterprise: creating accountability in research, instilling confidence in the integrity of process, ensuring fairness and transparency in the research enterprise, and affirming a commitment to the protection of human participants by all involved in research. To create accountability, the public needs to be assured that processes are in place to protect research participants. We have those systems in the form of regulations and oversight bodies, such as institutional review boards, the Office of Human Research Protections, the Food and Drug Administration, and Congress. Although the system has been subject to legitimate criticism, some level of standardization (and bureaucracy) is required to ensure a common approach to research protections. In the USA Today survey, 44 percent said that government regulation was insufficient to ensure that prescription drugs are safe.2 Perhaps the movement toward voluntary accreditation of human research protection programs through the Association for the Accreditation of Human Research Protection Programs offers a way to certify public accountability by establishing performance standards above federal and state requirements. Accreditation may become more desirable in an increasingly competitive research environment. Indeed, public, private, and international entities are paying attention, and nearly one hundred and twenty institutions have received accreditation to date.3 The public also needs to be confident that the system is working as intended and is being maintained. Are we falling short in instilling public confidence in research? Although infrastructure deficiencies in research approval and oversight have been heavily scrutinized in the scholarly literature, they rarely attract public attention until something goes wrong. A surge in litigation for research injuries and declining confidence in the FDA show that the public is indeed paying attention—and that its confidence is shaken. Over the years, the volume of research has grown tremendously, and research has come to involve more complex and invasive technologies. Given the litigious climate in health care, it is no surprise that litigation for research injuries is on the rise.4 Every death and injury (preventable or not) can have a negative impact on the public’s perception of the research enterprise. Participants surely expect that if they are injured while providing benefit to society, they will receive prompt treatment and be reimbursed at least for the real costs imposed on them (such as medical expenses and loss of work), if not also for “pain and suffering.” Yet the regulations require only that participants be informed about whether compensation and medical treatment for research injury is available, not that researchers or sponsors actually provide compensation or treatment. More than twenty-five years after the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research articulated ethical justifications for no-fault compensation for research injuries (reinforced by similar recommendations by a number of blue ribbon committees5), only a relatively few research institutions have policies in place to compensate injured research participants, and these pay only for medical expenses.6 No wonder litigation looks attractive. In the medical malpractice context, there is some evidence that...

Final Report of the Experts Committee for Human Research Participant Protection in Canada

Final Report of the Experts Committee for Human Research Participant Protection in Canada

IRBs and Psychological Science: Ensuring a Collaborative Relationship

Institutional Review Boards (IRBs) are federally-mandated, locally-administered groups charged with evaluating risks and benefits of human participant research at their institution. To a greater or lesser extent, risks and potential benefits exist in virtually any research with human participants, including research in the behavioral/social sciences. Federal law and APA standards require IRB review of all human participant research projects. IRB review and approval will likely bring an investigator into contact with two in- ter-related groups: the IRB and the professional staff that administers IRB activities. Due to a variety of factors, including increased IRB and faculty workload and enhanced federal oversight, the potential for conflict among IRB members, IRB administrators, and investigators may be great. Indeed, anecdotal evidence suggests that this potential for conflict may be particularly high for behav- ioral scientists, and that dissatisfaction with IRB review may jeopardize compliance with federal regulations, research participant protection, and research itself. The purpose of this paper is to suggest specific strategies that IRB members, IRB administrators, and investigators can use to avoid potential conflict and facilitate human research participant protection. We contend that when these groups understand and face these responsibilities collaboratively, conflict will be minimized and safe, ethical, high quality research will flourish.