Sputum induction for tuberculosis diagnosis in an Arctic setting: a cost comparison.

SETTING: Tuberculosis (TB) incidence was 234 per 100 000 in Nunavut, Canada, in 2012. Until recently, some individuals seen in local clinics for presumed TB required costly air evacuation to Southern Canada (Ottawa) for investigation if they were unable to produce sputum spontaneously. OBJECTIVE: To estimate the cost per individual evaluated for TB, associated with the establishment of a sputum induction programme in Iqaluit, Nunavut, Canada. DESIGN: A decision analysis model compared the total cost per individual for two strategies: 1) initial investigation in Iqaluit, with transport to Ottawa for those requiring sputum induction; and 2) sputum induction at the hospital in Iqaluit, with further investigation in Ottawa only if needed. The model simulated diagnostic and treatment paths from the initial clinic visit to completion of TB investigation or treatment (when applicable). RESULTS: The estimated cost per person evaluated for TB with sputum induction in 1) Ottawa vs. 2) Iqaluit was CAD4798 (95% uncertainty range 2923-6650) vs. CAD2479 (1206-4256), respectively. Total costs were influenced by underlying TB prevalence, but local sputum induction consistently yielded cost savings. CONCLUSION: Providing sputum induction in a high-incidence Arctic community such as Iqaluit is projected to generate substantial cost savings in the investigation and management of individuals with presumed TB.

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.

Cell-based interventions for neurologic conditions: ethical challenges for early human trials.

BACKGROUND: Attempts to translate basic stem cell research into treatments for neurologic diseases and injury are well under way. With a clinical trial for one such treatment approved and in progress in the United States, and additional proposals under review, we must begin to address the ethical issues raised by such early forays into human clinical trials for cell-based interventions for neurologic conditions. METHODS: An interdisciplinary working group composed of experts in neuroscience, cell biology, bioethics, law, and transplantation, along with leading disease researchers, was convened twice over 2 years to identify and deliberate on the scientific and ethical issues raised by the transition from preclinical to clinical research of cell-based interventions for neurologic conditions. RESULTS: While the relevant ethical issues are in many respects standard challenges of human subjects research, they are heightened in complexity by the novelty of the science, the focus on the CNS, and the political climate in which the science is proceeding. CONCLUSIONS: Distinctive challenges confronting US scientists, administrators, institutional review boards, stem cell research oversight committees, and others who will need to make decisions about work involving stem cells and their derivatives and evaluate the ethics of early human trials include evaluating the risks, safety, and benefits of these trials, determining and evaluating cell line provenance, and determining inclusion criteria, informed consent, and the ethics of conducting early human trials in the public spotlight. Further study and deliberation by stakeholders is required to move toward professional and institutional policies and practices governing this research.

Lessons from the failure of human papillomavirus vaccine state requirements.

The licensure in 2006 of a vaccine against the subtypes of human papillomavirus (HPV) responsible for the majority of cervical cancers and genital warts was heralded as a watershed moment for vaccination, cancer prevention, and global health. A safe and effective vaccine against HPV has long been viewed as an enormous asset to cervical cancer prevention efforts worldwide. This is particularly true for places lacking robust Pap screening programs where cervical cancer has the greatest prevalence and mortality. Well before its licensure, however, some observers noted significant obstacles that would need to be addressed in order for an HPV vaccination program to succeed. These included the vaccine's relatively high cost, availability, and opposition from socially conservative groups. Such concerns associated with the implementation of HPV vaccination were soon overwhelmed by the furor that followed the unexpectedly early efforts by the US state governments to require the vaccine as a condition of attendance in public schools, proposals imprecisely referred to as "mandates." In this study, we review the controversy surrounding this debate and its effects on important ethical and public health issues that still need to be addressed.

Effectiveness of a rural pediatric diabetes management program.

BACKGROUND: Children with type 1 diabetes living in rural areas may have limited access to specialty diabetes care compared to children living in urban areas. To address this issue, providers have developed outreach services in which specialists travel periodically to rural communities. OBJECTIVE: To determine whether the care of children with type 1 diabetes treated by pediatric endocrinologists in a rural outpatient clinic is comparable to the care of children treated in an urban medical center by the same diabetes team. METHODS: We carried out a retrospective cohort study comparing the number of patient visits with physicians, behavioral specialists, and dietitians and the frequency of hemoglobin A1c (HbA1c) measurements over a 12-month period treated in a rural clinic with a matched group treated in an urban children's hospital clinic. RESULTS: We found that urban patients (n = 38) were more likely to complete four visits per year compared to a matched group (n = 19) at the rural clinic (55.3% vs. 15.8%; p < 0.004), were significantly more likely than those in the rural clinic to have had four HbA1c measurements per year (55.3% vs. 21.1%; p < 0.014), and more likely to have had an assessment by a behavioral specialist (31.6% vs. 0%). Children at the rural clinic site were more likely to have had a visit with a nutritionist during the year (89.5% vs. 36.8%; p < 0.005). CONCLUSION: We conclude that diabetes care provided using a rural outreach model closely approximates, but does not entirely duplicate, care provided in the urban setting.

Attitudes of maternal-fetal specialists concerning maternal-fetal surgery.

OBJECTIVE: We examined the attitudes of members of the Society for Maternal-Fetal Medicine regarding the clinical, scientific, ethical, and policy issues in maternal-fetal surgery. STUDY DESIGN: A 43-question survey was distributed to all members of the Society for Maternal-Fetal Medicine. Two mailings and one electronic mail reminder were sent, each with instructions to submit the survey either via US mail or the Internet. The survey included questions in six categories: physician demographic data, experience with maternal-fetal surgery, views on innovative therapies, scientific validation of currently used and proposed procedures, ethical issues, and future directions in public policy. RESULTS: Of the 1639 United States members sent questionnaires, 943 replied (response rate = 59%). Forty-seven percent had referred patients for open fetal surgery for nonlethal conditions, and 69% believed physicians were obligated to inform patients of this option. Seventy-eight percent believed that innovative therapies should be performed only under institutional review board-approved protocols. Although the majority of respondents believed that certain proposed benefits of open fetal surgery for myelomeningocele could offset the risks, the majority (56%) also indicated that the procedure has not been validated. Fifty-seven percent believed that a moratorium should be imposed on open fetal surgery for nonlethal conditions, such as myelomeningocele, until a multicenter-controlled clinical trial is completed. CONCLUSIONS: The use of maternal-fetal surgery for nonlethal conditions is highly controversial. The majority of maternal-fetal specialists we surveyed support further research before such procedures are integrated into clinical practice.

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.

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.

So much for keeping secrets: the importance of considering patients' perspectives on maintaining confidentiality.

Little data are available from patients' perspectives regarding the maintenance of confidentiality by care providers. Such data may be useful in determining the importance of confidentiality to patients and in developing appropriate policies and procedures regarding confidentiality. Three focus groups were conducted with support groups of rural HIV-positive patients. Text was coded inductively and analyzed with software designed for qualitative analysis. Participants perceived breaches of confidentiality in hospitals, clinics and health departments that occurred by word of mouth, computers, facsimile and written materials. Patients included sharing stigmatizing medical information among medical providers without prior consent as a breach. They made decisions about where to seek care based on the degree of professionalism of medical staff (which included respecting confidentiality), clinic location or the level of security of the organization's computer network since they believed that computers increase information access. Finally, participants believed that medical personnel should be taught the importance of maintaining confidentiality and that those who violated confidentiality should be punished. Patients would like confidentiality policies that require providers to: (1) explain procedures for sharing information, (2) request patients' specific consent for access to their medical records, even among other providers, and (3) punish those who breach confidentiality.

Monitoring and ensuring safety during clinical research.

Increased numbers of clinical trials, many of which are large, multicenter, and sometimes international, and the marked shift of funding for clinical trials to industry have made apparent the inadequacy of mechanisms for protecting human subjects that were developed when clinical research was generally carried out on a small scale at single institutions. To address concerns regarding the protection of human subjects, a group of professionals with expertise in various aspects of clinical trials was assembled in May 2000. Participants described and evaluated the mechanisms by which clinical trials are monitored, focusing on adverse event reporting and the processes by which various parties with oversight responsibilities interact in the course of these trials. In this article, we describe the manner in which adverse event reporting might function to enhance safety and the role of data monitoring committees in using aggregate data from these reports, outline the problems that now exist for institutional review boards as they are faced with multiple adverse event reports from clinical trials while conducting continuing review, and offer recommendations for improving the current approach.

Teaching professional development in medical schools.

Doctors must increasingly be aware of what they should be, as well as what they should know. Professionalism, including a value system that supports the compassionate care of patients, is a means of encapsulating and prioritising these competing responsibilities. Accordingly, in this article, we assume that professionalism is an essential aspect of medical practice that needs to be taught to those entering medicine. We first describe critiques of professionalism and current challenges to it, in practice and in medical education. We then assess the current efforts of curriculum reform to incorporate professionalism and the methods used to teach it. Adopting and assessing such approaches to ensure that they are effective is of central importance in the education of future clinicians.

Variability among institutional review boards' decisions within the context of a multicenter trial.

BACKGROUND: Institutional review boards (IRBs) are given discretion to interpret and apply the federal regulations governing the protection of human subjects in research. OBJECTIVE: To determine the extent of the variability among different IRBs on their approved research practices and informed consent forms within the context of a multicenter trial that used a common protocol. DESIGN: Descriptive analysis of survey information and informed consent forms. SETTING AND PARTICIPANTS: Sixteen IRBs from the institutions participating in a multicenter trial comparing lower vs. traditional tidal volume ventilation in patients with acute lung injury. MEASUREMENTS: Analysis of survey information on IRBs' approved research practices. Analysis of informed consent forms for the presence and the adequacy of description of each basic element of informed consent specified in the federal regulations. Reading levels of informed consent forms. MAIN RESULTS: Surveys and IRB-approved consent forms were obtained from all of the contacted IRBs (n = 16). Variability was observed among several of the research practices; one IRB waived the requirement for informed consent, five IRBs permitted telephone consent, and three IRBs allowed prisoners to be enrolled. Three consent forms contained all of the basic elements of informed consent outlined in the federal regulations, and 13 forms had varying numbers of these elements absent (six forms without one element, four without two, one without three, and two without four). Reading levels of the consent forms ranged from grades 8.2 to 13.4 (mean +/- sd was 11.6 +/- 1.2 grade level). CONCLUSIONS: Within a multicenter trial, IRBs reviewing a common protocol varied in several of their approved research practices and in the extent to which the basic elements of informed consent were included in their consent forms.