Are there adverse consequences of quizzing during informed consent for HIV research?

INTRODUCTION: While quizzing during informed consent for research to ensure understanding has become commonplace, it is unclear whether the quizzing itself is problematic for potential participants. In this study, we address this issue in a multinational HIV prevention research trial enrolling injection drug users in China and Thailand. METHODS: Enrolment procedures included an informed consent comprehension quiz. An informed consent survey followed. RESULTS: 525 participants completed the informed consent survey (Heng County, China»255, Xinjiang, China»229, Chiang Mai, Thailand»41). Mean age was 33 and mean educational level was 8 yrs. While quizzing was felt to be a good way to determine if a person understands the nature of clinical trial participation (97%) and participants did not generally find the quiz to be problematic, minorities of respondents felt pressured (6%); anxious (5%); bored (5%); minded (5%); and did not find the questions easy (13%). In multivariate analysis, lower educational level was associated with not minding the quizzing (6e10 yrs vs 0e5 yrs: OR»0.27, p»0.03; more than 11 yrs vs 0e5 yrs: OR»0.18, p»0.03). There were also site differences (Heng County vs Xinjiang) in feeling anxious (OR»0.07; p»<0.01), not minding (OR»0.26; p»0.03), being bored (OR»0.25; p»0.01) and not finding the questions easy (OR»0.10; p»<0.01). CONCLUSIONS: Quizzing during the informed consent process can be problematic for a minority of participants. These problems may be associated with the setting in which research takes place and educational level. Further research is needed to develop, test and implement alternative methods of ensuring comprehension of informed consent. TRIAL REGISTRATION: clinicaltrials.gov number NCT00270257.

Unintended changes in cognition, mood, and behavior arising from cell-based interventions for neurological conditions: ethical challenges.

The prospect of using cell-based interventions (CBIs) to treat neurological conditions raises several important ethical and policy questions. In this target article, we focus on issues related to the unique constellation of traits that characterize CBIs targeted at the central nervous system. In particular, there is at least a theoretical prospect that these cells will alter the recipients' cognition, mood, and behavior-brain functions that are central to our concept of the self. The potential for such changes, although perhaps remote, is cause for concern and careful ethical analysis. Both to enable better informed consent in the future and as an end in itself, we argue that early human trials of CBIs for neurological conditions must monitor subjects for changes in cognition, mood, and behavior; further, we recommend concrete steps for that monitoring. Such steps will help better characterize the potential risks and benefits of CBIs as they are tested and potentially used for treatment.

Identification of a cell-type-specific and E2F-independent mechanism for repression of cdc2 transcription.

Human myeloid leukemia cells, such as HL60, U937, and THP1 cells, undergo macrophage differentiation and growth arrest following treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Surprisingly, we find that growth of a significant percentage of THP1 cells is arrested in the G2 phase of the cell cycle. G2 arrest correlates with cell-specific repression of the gene encoding p34cdc2, a crucial regulator of G2/M progression. Intriguingly, TPA-mediated repression of the cdc2 promoter was independent of the transcription factor E2F, distinguishing this pathway from mechanisms responsible for repression of cdc2 transcription in response to serum starvation. The region of the cdc2 promoter required for repression was located from bp -22 to -2 from the major transcriptional start site. This sequence, which we term the R box, directs the uncoupling of the basal promoter from upstream activators following TPA treatment. Analysis of THP1 nuclear proteins revealed a 55-kDa protein that was induced by TPA and interacted with the cdc2 promoter in an R-box-dependent manner. These observations provide evidence for the existence of cell-type- and promoter-specific pathways for the assembly of stable transcriptional initiation complexes that function to differentially regulate the expression of cell cycle control genes in mammalian cells.

Retinoic acid receptor alpha suppresses transformation by v-myb.

Retinoic acid (RA) is capable of inducing the differentiation of various myelomonocytic cell lines. During this differentiation process, the levels of c-myb expression decline, suggesting that the RA receptor (RAR) may act in part by down-regulating this proto-oncogene. We have now investigated whether the RAR can also inhibit the function of Myb proteins themselves. We have found that transcriptional activation of a Myb-responsive reporter gene can be inhibited by RA in a human monocytic cell line. This inhibition could not be overcome by the expression of exogenous Myb. The RAR did not interfere with DNA binding by Myb proteins in vitro, suggesting that the functional inhibition occurs at the level of transcriptional activation. To determine the biological relevance of the inhibition of Myb proteins by the RAR, we have used v-myb-transformed monoblasts. These cells differentiate into macrophages in the presence of phorbol ester (tetradecanoyl phorbol acetate [TPA]) but are normally unresponsive to RA treatment. The introduction of an inducible, exogenous RAR alpha into v-myb-transformed monoblasts permitted an RA-dependent differentiation into macrophage-like cells similar to those induced by TPA. These results demonstrate that transformation by v-myb is recessive to RAR alpha and imply that many types of non-RA-responsive leukemia cells may become responsive following the introduction of the RAR.

A comparison of the national registry of myocardial infarction 2 with the cooperative cardiovascular project.

OBJECTIVES: This study was performed to evaluate whether or not the simpler case identification and data abstraction processes used in National Registry of Myocardial Infarction two (NRMI 2) are comparable with the more rigorous processes utilized in the Cooperative Cardiovascular Project (CCP). BACKGROUND: The increased demand for quality of care and outcomes data in hospitalized patients has resulted in a proliferation of databases of varying quality. For patients admitted with myocardial infarction, there are two national databases that attempt to capture critical process and outcome data using different case identification and abstraction processes. METHODS: We compared case ascertainment and data elements collected in Medicare-eligible patients included in the industry-sponsored NRMI 2 with Medicare enrollees included in the Health Care Financing Administration-sponsored CCP who were admitted during identical enrollment periods. Internal and external validity of NRMI 2 was defined using the CCP as the "gold standard." RESULTS: Demographic and procedure use data obtained independently in each database were nearly identical. There was a tendency for NRMI 2 to identify past medical histories such as prior infarct (29% vs. 31%, p < 0.001) or heart failure (21% vs. 25%, p < 0.001) less frequently than the CCP. Hospital mortality was calculated to be higher in NRMI 2 (19.7% vs. 18.1%, p < 0.001) due mostly to the inclusion of noninsured patients 65 years and older in NRMI 2. CONCLUSIONS: We conclude that the simpler case ascertainment and data collection strategies employed by NRMI 2 result in process and outcome measures that are comparable to the more rigorous methods utilized by the CCP. Outcomes that are more difficult to measure from retrospective chart review such as stroke and recurrent myocardial infarction must be interpreted cautiously.

Prevalence of diagnosed hypertension among diabetic Navajo Indians.

Hypertension is more common among persons with non-insulin-dependent diabetes mellitus than among appropriately matched nondiabetic populations. The presence of hypertension in persons with non-insulin-dependent diabetes mellitus is associated with increased rates of the microvascular and macrovascular complications of non-insulin-dependent diabetes mellitus. A cross-sectional study of a cohort of 817 diabetic Navajo Indians was performed to determine the age-, sex-, and duration-specific prevalence of diagnosed hypertension. Persons with end-stage renal disease were excluded from the population. A total of 388 of the patients (47.5%) had diagnosed hypertension. The prevalence of hypertension increased with increasing age. Contrary to findings in other populations, women did not have higher rates of hypertension than men. The duration of diabetes did not have a consistent effect on the rates of hypertension. The current prevalence of hypertension among Navajos with diabetes is higher than that reported two decades ago.

Factors associated with veterans' decisions about living wills.

Most states have adopted legislation that allows patients to designate by advance directives the type of health care they would like to receive if they should become incompetent while suffering from a terminal illness. The living will is one of the most common of these legal instruments. Unlike most studies that have examined very sick or hospitalized patients' preferences regarding life-sustaining treatments, our study explores the concerns of 70 ambulatory veterans from a general medical clinic regarding living wills. Before the interview, 43% of patients reported never having heard of living wills. At interview, 4% of the patients had a living will, 33% intended to sign a living will but had not done so (INTEND), 54% were undecided about living wills (UNDECIDED), and 9% did not want a living will. Compared with UNDECIDED patients, all other patients did not differ in the use of health care services during the previous year or in diagnoses. INTEND patients, however, were significantly more likely to be white, to express poorer health status, to know someone with a living will, and to have previously discussed the topic. UNDECIDED patients were more likely than INTEND patients to report that religious beliefs about living wills affected their decision. Virtually all (91%) of the respondents believed that signing a living will would not affect their treatment. These data suggest that many patients may not know that they can have a living will and that discussions with those who already have a living will may be helpful in educational programs designed to promote informed patient decision-making.

Prevalence of diabetes and impaired glucose tolerance among Navajo Indians.

OBJECTIVE: To estimate the prevalence of diabetes mellitus and impaired glucose tolerance and the incidence of clinically diagnosed diabetes in a community of Navajo Indians. RESEARCH DESIGN AND METHODS: We conducted a survey of a representative Navajo community screened for diabetes 3 yr previously. We used 75-g oral glucose tolerance tests to determine the prevalence of diabetes mellitus and impaired glucose tolerance and conducted medical record reviews to identify cases of diabetes that were diagnosed during routine medical care after the earlier study. RESULTS: By World Health Organization diagnostic criteria, the age-adjusted diabetes prevalence among 419 Navajo Indians 20-74 yr of age was 13.9% (95% confidence interval [CI] 9.2-18.5) for men and 18.4% (95% CI 14-22.8) for women. The ratio of the prevalence of diabetes among the Navajo population studied to that in the general United States population was 2.5. The prevalence of impaired glucose tolerance was 8% (95% CI 3.3-12.7) among men and 12.9% (95% CI 7.9-17.9) among women. Based on clinical diagnoses of diabetes made during routine medical care, mean +/- SE age-adjusted incidence of diagnosed diabetes among men was 8.6 +/- 4.3/1000 person-yr and 11.1 +/- 4.4/1000 person-yr among women. CONCLUSIONS: Although lower than that of some other tribes, the prevalence of diabetes among Navajo Indians is substantially higher than that in the general U.S. population. The high rate of clinical diagnoses suggests that the prevalence of the disease may continue to rise.

Gestational diabetes is a herald of NIDDM in Navajo women. High rate of abnormal glucose tolerance after GDM.

OBJECTIVE: To estimate the rate of deterioration of glucose tolerance and evaluate risk factors for development of NIDDM in Navajo women with a history of gestational diabetes mellitus (GDM). RESEARCH DESIGN AND METHODS: A retrospective analysis of 111 GDM deliveries over a 4-year period, 1983-1987, was conducted in 1994 to determine glucose tolerance status. Patients who had not developed NIDDM were recalled for a 2-h glucose tolerance test (GTT). Tested and non-tested patients were compared, as estimate of conversion to NIDDM was calculated, and risk factors for NIDDM were evaluated. A life-table analysis was developed to estimate the probability of NIDDM after GDM. RESULTS: At the time of chart review, 32 patients (29%) had already been diagnosed with NIDDM. Of the patients, 79 were offered GTT testing, and 56 (71%) returned for follow-up; 15 were diagnosed with NIDDM and 17 with impaired glucose tolerance (IGT); 47 (42%) and 64 (58%) patients in the cohort had developed NIDDM or NIDDM/IGT at the conclusion of the study period. Patients who developed NIDDM had greater BMIs, parity, and infant weights. Fasting blood glucose > 5.83 mmol/l, GTT > 41.63 mmol/l, and recurrence of GDM were associated with later NIDDM. A life-table analysis estimated a 53% likelihood of having NIDDM at an 11-year follow-up; a second model, based only on patients with known NIDDM status, predicted a 70% rate of NIDDM at an 11-year follow-up. CONCLUSIONS: A high proportion of Navajo women with GDM progressed to NIDDM. Postpartum counseling and periodic GTTs are recommended.

Factors associated with failure to complete treatment for diabetic retinopathy among Navajo Indians.

OBJECTIVE: To determine the proportion of patients with suspected proliferative diabetic retinopathy who did not receive the recommended follow-up ophthalmological evaluation and care, and to examine associations between various patient characteristics and the failure to obtain care. RESEARCH DESIGN AND METHODS: The study cohort included all Navajo Indians identified by a retrospective review of records who had proliferative diabetic retinopathy diagnosed at an Indian Health Service Optometry Clinic between 1 October 1985 and 30 September 1988. Follow-up data were obtained by medical record reviews and by interviews with subjects. RESULTS: Of 69 patients identified, 57 of 61 living patients were interviewed. Twenty-three (40.4%) had failed to obtain recommended follow-up. The RR for incomplete treatment among those without a vehicle in the household compared with those with a vehicle was 1.91 (95% CI 1.32-2.76). Other factors associated with incomplete treatment were female sex and marital status other than currently married. Twelve (21%) patients answered "no" to the question, "Have you been told that diabetes was affecting your eyes?" Eight of 38 (21%) who confirmed that they had been told that diabetes was affecting their eyes responded "no" to the question, "Do you think that diabetes is affecting your eyes?" However, the answers to these questions did not distinguish between patients who obtained or did not obtain recommended care. CONCLUSIONS: Interventions to increase the proportion of Navajo Indians with diabetic retinopathy who receive appropriate ophthalmologic care must address the issue of transportation.

Use of the therapeutic footwear benefit among diabetic medicare beneficiaries in three states, 1995.

OBJECTIVE: To determine the extent to which Medicare provided reimbursement for therapeutic footwear to diabetic Medicare beneficiaries in Washington, Alaska, and Idaho in 1995. RESEARCH DESIGN AND METHODS: Using inpatient, outpatient, and durable medical equipment claims data, we selected a cohort of diabetic Medicare beneficiaries. Therapeutic footwear claims were identified using a set of billing codes intended only for the diabetes footwear benefit. People at "high risk" or "possibly increased risk" for foot problems who might benefit from therapeutic footwear were identified using a combination of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes in any of the databases. RESULTS: Among 608,804 beneficiaries, 10.2% (62,170) met the inclusion criteria for diabetes. Of the diabetic beneficiaries, 13.0% (8,079) had at least one "high risk" diagnosis, and 14.0% (8,686) had at least one "possibly increased risk" diagnosis. The percentage of diabetic beneficiaries with therapeutic footwear claims was 2.9% among those with diagnoses high risk, 0.7% among those with diagnoses indicating possibly increased risk, and 0.1% among those with no diagnosis from the list. Altogether, only 0.6% of beneficiaries meeting the diabetes case ascertainment criteria had a therapeutic footwear claim in 1995. CONCLUSIONS: Few diabetic Medicare beneficiaries in Washington, Alaska, and Idaho had claims for reimbursement for therapeutic footwear in 1995. The low utilization of the footwear benefit may represent an important opportunity to improve care for Medicare beneficiaries with diabetes. Further work should be done to characterize the use of the benefit in other regions and to assess whether the low level of usage reflects underutilization.

Evidence for a secular change in obesity, height, and weight among Navajo Indian schoolchildren.

A survey measuring heights and weights of 1969 schoolchildren residing on the Navajo Indian Reservation was conducted in 1989. The findings were compared with National Center for Health Statistics (NCHS) reference data and with surveys of Navajo children from 1955, 1968, and 1981. Approximately twice as many children exceeded the 95th percentile of weight-for-age (11.2% of girls, 12.5% of boys) than would be expected for the NCHS reference population. The mean weight-for-height z scores exceeded those for the NCHS reference population for all ages in both sexes. Compared with data from 1955, mean heights increased 6.1% among boys and 4.4% among girls whereas mean weights increased 28.8% among boys and 18.7% among girls across all age groups. The data suggest that there has been a secular change in height, weight, and obesity in Navajo Indian children over the past 35 y.

A left-ear advantage for identifying the emotional quality of tonal sequences.

Tonal sequences differing in emotional quality were presented dichotically. Subjects listened to a specified ear and judged the emotional tone of the stimulus heard at that ear. Accuracy was better for identifying the emotional tone of stimuli presented to the left ear. This left ear advantage was greatest where the target and competing stimuli were of different affect. The findings provide further evidence for the role of the right hemisphere in processing emotional information.

Impact of facility size and profit status on intermediate outcomes in chronic dialysis patients.

Little information is available regarding the influence of dialysis facility size or profit status on intermediate outcomes in chronic dialysis patients. We have combined data from the Health Care Financing Administration (HCFA) Core Indicators Project; the end-stage renal disease (ESRD) facility survey; and the HCFA On-Line Survey, Certification, and Reporting System to analyze trends in this area. For hemodialysis patients, larger facilities were more likely than smaller facilities to perform dialysis on patients who were younger than 65 years of age, black, or undergoing dialysis 2 years or more (P < 0.001). Nonprofit facilities were more likely to perform dialysis on patients with diabetes mellitus as a cause of ESRD and less likely to perform dialysis on patients with hypertension as a cause of ESRD compared with for-profit units (P < 0.05). By multivariate analysis, larger facility size was modestly associated with a greater Kt/V value and urea reduction ratio, but not with hematocrit or serum albumin values. Facility profit status was not associated with these intermediate outcomes. For peritoneal dialysis patients, there were no significant differences in patient demographics based on facility size. More patients in nonprofit units had been undergoing dialysis 2 or more years than patients in for-profit units (P < 0.05). By univariate analysis, patients in larger facilities were more likely to have an adequacy measure performed than patients from smaller facilities (P < 0.05). There were few substantial differences in intermediate outcomes in chronic dialysis patients based on facility size or profit status.

Getting meaningful informed consent from older adults: a structured literature review of empirical research.

OBJECTIVES: To perform a structured literature review of the published empirical research on informed consent with older adults in order to make recommendations to improve the informed consent process and to highlight areas needing further examination. DESIGN: Relevant literature was identified by searching electronic databases (AGELINE, BIOETHICSLINE, CancerLit, Ethics Index, Health, LegalTrac, MEDLINE, PAIS International, PsycInfo, and Sociofile). Studies were included if they were reports of primary research data about informed consent and, if patients or other subjects were used, older subjects were included in the sample. Data related to the aspect of informed consent under study (recruitment, decision-making capacity, voluntariness, disclosure of information, understanding of information, consent forms, authorization, and policies and procedures) were abstracted and entered into a specially designed database. MEASUREMENTS: Characterization of the population, age of subjects, setting, whether informed consent was being studied in the context of research or treatment, study design, the nature of outcome or dependent variables, independent variables (e.g., experimental conditions in a randomized controlled trial or patient/subject characteristics in a nonrandomized comparison), and results according to the aspect of informed consent under study. RESULTS: A total of 99 articles met all the inclusion criteria and posed 289 unique research questions covering a wide range of aspects of informed consent: recruitment (60); decision making capacity (21); voluntariness (6); disclosure (30); understanding (139); consent forms (7); authorization (11); policies (13); and other (2). In the secondary analyses of numerous studies, diminished understanding of informed consent information was associated with older age and fewer years of education. Older age was also sometimes associated with decreased participation in research. Studies of disclosure of informed consent information suggest strategies to improve understanding and include a variety of novel formats (e.g., simplified, storybook, video) and procedures (e.g., use of health educators, quizzing subjects, multiple disclosure sessions). CONCLUSIONS: A systematic review of the published literature on informed consent reveals evidence for impaired understanding of informed consent information in older subjects and those with less formal education. Effective strategies to improve the understanding of informed consent information should be considered when designing materials, forms, policies, and procedures for obtaining informed consent. Other than empirical research that has investigated disclosure and understanding of informed consent information, little systematic research has examined other aspects of the informed consent process. This deficit should be rectified to ensure that the rights and interests of patients and of human subjects who participate in research are adequately protected.

How proxies make decisions about research for patients with Alzheimer's disease.

We examined the proxy decision-making and informed consent processes for clinical research involving 49 patient-subjects with dementia in an outpatient setting by performing serial in-depth, structured, open-ended telephone interviews. Interviews were tape recorded and transcribed. Transcripts were then coded and analyzed. Although in all cases proxy consent was obtained for research from a legally authorized representative, proxies reported considerable ambiguity regarding who made the decision to participate in research, or to what degree the decision was that of the proxy or of the patient. Reasons proxies gave for participating in research included: hope of direct or indirect benefits to the patient, caregiver, or patient's descendents; desperation; trust in the investigator; belief in the goodness of research; and altruism. These reasons varied according to the type of research. For instance, in drug trials hope of direct benefit prevailed; in studies not evaluating a potential therapy more altruistic concerns predominated. Being a proxy decision maker for research can be burdensome. The degree of burden related to making a decision to participate in research seems influenced by a number of intersecting factors, most importantly, the risk and nature of the study, the extent to which patients were able to participate in the decision, and the duration and severity of dementia. Proxy decision-making concerning participation in research for patients with dementia can be a difficult task. The process might be improved by emphasizing that proxy consent is being sought because the nature of the patient's underlying medical condition can preclude the ability to make meaningful decisions. In addition, clinical researchers should recognize that giving proxy consent might place additional burdens on caregivers and discuss this explicitly when proxy consent is solicited.

Toward the ethical evaluation and use of maternal-fetal surgery.

BACKGROUND: Important clinical, social, and ethical questions are associated with the evaluation and use of surgical approaches aimed at correcting fetal anatomic abnormalities. In particular, the expansion of maternal-fetal surgery to ameliorate nonlethal fetal conditions has intensified the need to address issues about the adequacy of technology assessment and the safety of those who undergo these novel procedures. APPROACH: After discussions at a multidisciplinary conference, we reviewed the development and current practices of maternal-fetal surgery and analyzed the relevant ethical issues concerning the use of maternal-fetal surgery for nonlethal conditions, focusing on the correction of myelomeningocele. FINDINGS: Characterizing nonvalidated maternal-fetal surgery procedures as "innovative therapy" blurs the boundaries between research and therapy and creates uncertainty about the obligations of clinicians and researchers. Further, maternal-fetal surgery raises ethical issues related to maternal risks and benefits, informed consent, distinguishing lethal from nonlethal conditions, withholding unproven treatments, entrepreneurship, and prioritization. RECOMMENDATIONS: To help ensure that maternal-fetal surgery will be studied and eventually applied in a scientifically and ethically sound manner, we offer several recommendations. First, innovation in maternal-fetal surgery should be conducted and evaluated as research. Second, women must be considered research subjects in these trials. Third, the informed consent process must ensure adequate comprehension and genuine voluntariness in those considering participation. Fourth, discriminatory and fearful attitudes toward individuals with disabilities should be addressed explicitly prior to making a decision to proceed with maternal-fetal surgery in an attempt to correct such disabilities. Fifth, maternal-fetal surgery should not be performed for cosmetic indications unless and until there is reliable evidence that maternal-fetal surgery can be performed safely and that long-term side effects on women and their offspring are minimal. Sixth, centers of excellence should be established for conducting research and providing maternal-fetal surgery. Seventh, funding for research on maternal-fetal surgery should be considered in the context of societal needs.