Ethics and methods in surgical trials.

This paper focuses on invasive therapeutic procedures, defined as procedures requiring the introduction of hands, instruments, or devices into the body via incisions or punctures of the skin or mucous membranes performed with the intent of changing the natural history of a human disease or condition for the better. Ethical and methodological concerns have been expressed about studies designed to evaluate the effects of invasive therapeutic procedures. Can such studies meet the same standards demanded of those, for example, evaluating pharmaceutical agents? This paper describes a research project aimed at examining the interplay and sometimes apparent conflict between ethical standards for human research and standards for methodological rigor in trials of invasive procedures. The paper discusses how the authors plan to develop a set of consensus standards that, if met, would result in substantial and much-needed improvements in the methodological and ethical quality of such trials.

Effects of storage and viral load on hepatitis C viral genotyping.

Hepatitis C virus (HCV) genotyping is important for determining the treatment protocol for hepatitis C patients. Since amplified material from the Roche HCV Monitor kit is compatible with the Innogenetics INNO-LiPA HCV II kit (line probe assay), amplicons from the Monitor assay can be used to identify the HCV genotype. The Monitor package insert recommends using amplicons within a 7-day period (at 4 degrees C) following amplification. It was hypothesized that storage of amplicons for 4 weeks and longer (at -20 degrees C) would not affect the sensitivity of the genotyping assay. After denaturation, amplicons from two genotypes were stored for 7-386 days prior to performing the genotyping assay. Storage of amplicons did not hamper the ability to identify the genotype. Additionally, the sensitivity of the assay was evaluated by analyzing five genotypes with low viral loads. HCV genotypes were detected most consistently at viral levels of 10,000 copies/mL. In conclusion, the Innogenetics genotyping assay can use stored amplicons, thus reducing the cost of the assay by avoiding additional PCR reactions. Determining the sensitivity of this assay facilitates the efficient use of this test by incorporating a sensitivity cutoff of >or=10,000 copies/mL.

A national survey of policies on disclosure of conflicts of interest in biomedical research.

BACKGROUND: Conflicts of interest pose a threat to the integrity of scientific research. The current regulations of the U.S. Public Health Service and the National Science Foundation require that medical schools and other research institutions report the existence of conflicts of interest to the funding agency but allow the institutions to manage conflicts internally. The regulations do not specify how to do so. METHODS: We surveyed all medical schools (127) and other research institutions (170) that received more than $5 million in total grants annually from the National Institutes of Health or the National Science Foundation; 48 journals in basic science and clinical medicine; and 17 federal agencies in order to analyze their policies on conflicts of interest. RESULTS: Of the 297 institutions, 250 (84 percent) responded by March 2000, as did 47 of the 48 journals and 16 of the 17 federal agencies. Fifteen of the 250 institutions (6 percent)--5 medical schools and 10 other research institutions--reported that they had no policy on conflicts of interest. Among the institutions that had policies, there was marked variation in the definition and management of conflicts. Ninety-one percent had policies that adhered to the federal threshold for disclosure ($10,000 in annual income or equity in a relevant company or 5 percent ownership), and 9 percent had policies that exceeded the federal guidelines. Only 8 percent had policies requiring disclosure to funding agencies, only 7 percent had such policies regarding journals, and only 1 percent had policies requiring the disclosure of information to the relevant institutional review boards or to research subjects. Twenty journals (43 percent) reported that they had policies requiring disclosure of conflicts of interest. Only four federal agencies had policies that explicitly addressed conflicts of interest in extramural research, and all but one of the agencies relied primarily on institutional discretion. CONCLUSIONS: There is substantial variation among policies on conflicts of interest at medical schools and other research institutions. This variation, combined with the fact that many scientific journals and funding agencies do not require disclosure of conflicts of interest, suggests that the current standards may not be adequate to maintain a high level of scientific integrity.

The prevalence of female genital operations in the Houston metropolitan area.

This study explored the prevalence of female genital operations (FGOs), also known as female circumcision, among women in the Houston metropolitan area. The medical ramifications of the procedure and the specific type of procedure undergone were examined as well as the nationality and religious background of these women and their views regarding their experience. To gather these data, we sent a questionnaire to practicing obstetrician-gynecologists in Harris County. This survey yielded a response rate greater than 36%, of which approximately 30% of physicians reported treating patients with FGOs at some time in their practice. The results of this study demonstrate that a notable proportion of women in Houston, particularly those of African background, have experienced an FGO of some type and, accordingly, our obstetrician-gynecologists and primary care physicians clearly need to be aware of this cultural practice among their patients.

Managing disagreements in the management of short bowel and hypoplastic left heart syndrome.

BACKGROUND AND OBJECTIVES: When innovative, not yet fully proven therapies are introduced, physicians may have neither experience nor sufficient data in the medical literature to assist in their decision to discuss them with and/or recommend them to patients. Little is known about how physicians deal with this uncertainty. Moreover, when multiple physicians caring for a single patient have reached different conclusions regarding this new therapy, the potential for disagreement exists that could give rise to ethical issues as well as cause confusion to the patient. To explore these topics, we investigated the attitudes of specialists to therapies for two life-threatening diseases: hypoplastic left heart syndrome (HLHS) and short bowel syndrome. METHODS: A forced choice questionnaire was distributed to the heads of neonatology, pediatric cardiology, and pediatric gastroenterology training programs asking about their outcome impressions and treatment recommendations and about the local availability of treatments. In addition, responses from specialists from the same institution were linked in a confidential manner to evaluate the frequency of disagreement within the same institution. Responses were analyzed using chi(2) and Wilcoxon matched pair analysis as appropriate. RESULTS: The overall rate of response was 79%. In institutions that had both neonatology and pediatric gastroenterology training programs, there was a 59% response rate compared with a 73% response rate from institutions that had both neonatology and cardiology programs. Significant differences were noted among specialists as to who would be involved in discussions of therapeutic options with patients in both HLHS and short bowel syndrome. Differences also were noted in the willingness of specialists to discuss and recommend therapies, in the perceived survival and quality of life by various specialists after transplant and palliative surgery, and in the local availability of various options. The neonatologists and gastroenterologists at the same institution disagreed on responses in 34% of the questions with only 1 of the 25 pairs in full agreement. In contrast, the neonatologists and pediatric cardiologists at the same institution disagreed in only 14% of the questions with 7 of the 28 pairs in full agreement. CONCLUSIONS: Substantial disagreement among specialists about new interventions was found. There seem to be fewer differences among specialists when dealing with the more mature therapy, HLHS. Two major ethical issues arise. First, there seems to be no accepted professional standard to which individuals can appeal when determining whether to discuss or recommend new, not-yet-fully-proven technologies. Second, there is the potential for much patient confusion when counseling physicians recommend different options. Colleagues as individuals and specialists as groups should talk to each other before individual discussions with families to ensure that there is a clear understanding of differing beliefs.

When are placebo-controlled trials no longer appropriate?

This paper presents a standard for assessing the validity of placebo-controlled trials in circumstances in which such trials might be unjustly denying appropriate therapies to members of the control group. This standard categorizes the types of risks that can or cannot be imposed upon consenting research subjects in such control groups. The paper also shows how needed research can be conducted while respecting the proposed ethical standard. Both the problem and the proposed standard are illustrated by reference to the major trials of the thrombolytic agents.

Role of cytology in the intraoperative diagnosis of HIV-positive patients undergoing stereotactic brain biopsy.

OBJECTIVE: To determine the accuracy of cytology in the intraoperative diagnosis of central nervous system (CNS) lesions in human immunodeficiency (HIV)-positive patients. STUDY DESIGN: We prospectively studied 75 cases of computed tomography- or magnetic resonance imaging-guided brain biopsies performed with stereotactic instrumentation and a Nashold biopsy cannula over the course of five years. Biopsy samples were sent for both frozen section and immediate cytologic evaluation. Crush preparations (Papanicolaou and Diff-Quik stained) were used for cytologic assessment. There were 23 cases of progressive multifocal leukoencephalopathy (PML), 8 of toxoplasmosis (toxo), 3 of herpes simplex virus, 26 of lymphoma, 3 of HIV encephalitis, 1 of melanoma, 1 of hamartoma and 10 of nonspecific changes (paraffin section). RESULTS: Using permanent hematoxylin and eosin-stained histologic sections as the "gold standard," frozen section had a sensitivity of 78% and a specificity of 90%, while cytology had a sensitivity of 88% and specificity of 90%. Most of the false negative cases in cytology and frozen section were due to the predominance of necrosis and/or gliosis, present in six cases of toxo. Two of the false positive cases in frozen section (diagnosed as lymphoma) showed toxo, while two false positive cases in cytology (diagnosed as PML) showed only gliosis with negative immunoperoxidase staining for PML in the permanent sections. CONCLUSION: First, cytology had higher sensitivity that frozen section. Second, cytology provided faster results in most instances, primarily due to the nature of specimen preparation. Third, most misdiagnoses occurred in infectious diseases, especially toxo; this should therefore be kept in mind when nonspecific changes with an atypical lymphocytic infiltrate are seen. Fourth, cytology can be an alternative to frozen section for the intraoperative diagnosis of CNS lesions in HIV-positive patients. Another advantage of cytology is elimination of the need for cutting potentially infectious fresh tissue.

In case of emergency: no need for consent.

The Food and Drug Administration (FDA) is amending its current informed consent regulations to permit harmonization of the Department of Health and Human Services' (DHHS) policies on emergency research and to reduce confusion on when such research can proceed without obtaining an individual subject's informed consent. This regulation provides a narrow exception to the requirement for obtaining and documenting informed consent from each human subject, or his or her legally authorized representative, prior to initiation of an experimental intervention. The exception would apply to a limited class of research activities involving human subjects who are in need of emergency medical intervention but who cannot give informed consent because of their life-threatening medical condition, and who do not have a legally authorized person to represent them. FDA is taking this action in response to growing concerns that current rules are making high quality acute care research activities difficult or impossible to carry out at a time when the need for such research is increasingly recognized.

Reduced cyclin D1 expression in the cerebella of nutritionally deprived rats correlates with developmental delay and decreased cellular DNA synthesis.

Nutritional deprivation in the early postnatal period severely inhibits cerebellar growth and development, which is related in part to reduced levels of growth factors. Cyclin D1 encodes a growth factor-inducible regulatory subunit of a serine/thereonine kinase that is capable of phosphorylating the tumor suppressor pRB, thereby allowing normal progression through the G1 phase of the cell-cycle. Because the abundance of cyclin D1 is rate limiting in this progression, we examined the regulation of cyclin D1 expression in vivo, using a model of nutritional deprivation. Cyclin D1 expression in cerebella of fed control rats was detected in the external granular layer and was associated with cellular proliferation within this layer. Nutritional deprivation of rats reduced cerebellar weight, as well as the thickness of the molecular layer that largely consists of cells migrating from the external granular layer. Refeeding partially restored cerebellar weight, molecular layer thickness and increased external granular layer cyclin D1 immunostaining. Since nutritional deprivation is accompanied by lower levels of circulating insulin-like growth factor-I (IGF-I), we determined whether IGF-I directly stimulated the cyclin D1 promoter. The human cyclin D1 promoter linked to the luciferase reporter gene was stably integrated into PC12 cells. IGF-I stimulated cyclin D1 promoter activity 4- to 6-fold at 6 hours (h). These findings are consistent with the notion that nutritional deprivation may affect proliferative growth by altering expression of cyclin D1 in the germinal cell layer and that regulation of cyclin D1 expression by growth factors may contribute to normal neonatal cerebellar development. The reduction in cyclin D1 expression as cells differentiate in the cerebellum is consistent with a potential role for cyclin D1 in this process.

Resource consumption and the extent of futile care among patients in a pediatric intensive care unit setting.

OBJECTIVES: To estimate resource consumption and the extent of futile care among patients admitted to the pediatric intensive care unit (PICU). STUDY DESIGN: A prospective cohort study of 353 consecutive admissions followed for 1334 patient-days during the PICU stay at the Texas Children's Hospital in Houston, Texas. Participants were 353 children and adolescents who were hospitalized in the PICU during September and October 1993. Three broad operational definitions of futility were developed to capture the maximum extent of resource consumption related to medical futility. Definition 1 (imminent demise futility) was developed by an objective, validated, severity of illness measure (Pediatric Risk of Mortality Score) to identify patients with high mortality risks. Definition 2 (lethal condition futility) was used to identify patients in the PICU whose long-term survival was unlikely. Definition 3 (qualitative futility) was used to identify patients with high morbidity. Resource consumption was measured according to the number of patient-days in the PICU and the Therapeutic Intervention Scoring System. RESULTS: Twenty-three (6.5%) patients representing 36 (2.7%) patient-days met at least one of the definitions of medical futility for some of the days when they were in the PICU. None of the patient-days that met any of the definitions of medical futility were associated with high resource consumption compared with non-futile care patient-days. CONCLUSIONS: Despite our use of broad definitions of medical futility, relatively small amounts of resources were used in futile PICU care. This suggests that attempts to reduce resource consumption in the PICU by focusing on medical futility are unlikely to be successful.

Diffusion of innovative approaches to managing hypoplastic left heart syndrome.

OBJECTIVE: To study the perceptions of outcome and the diffusion into practice of innovative approaches such as palliative surgery and heart transplantation to treat hypoplastic left heart syndrome. DESIGN: A forced-choice questionnaire was sent to 108 US neonatology section heads. Responses were analyzed using Wilcoxon matched pairs, chi 2 analysis, and multivariant logistic regression. RESULTS: Ninety-three questionnaires (86%) were returned. All respondents discussed palliative surgery or transplantation or both with parents; 71 (76%) of 93 also discussed comfort care. Nineteen (24%) of 80 recommended comfort care only, 51 (64%) of 80 recommended surgery only, and 10 (12%) of 80 recommended both. Of the 61 respondents recommending one or both surgical procedures, palliative surgery was recommended by 44 and transplantation by 33. Respondents perceived that transplantation was associated with a lower 1-year mortality than palliative surgery (P < .001) and with a better quality of life (P < .001). CONCLUSIONS: Palliative surgery and transplantation are widely used to treat hypoplastic left heart syndrome. The continued availability of comfort care suggests that these surgical procedures are still in transition from experimental technology to standard of care.

Cytomorphology of primary CNS lymphoma: review of 23 cases and evidence for the role of EBV.

Primary non-Hodgkin's lymphoma of the central nervous system (PCNSL) has recently increased in incidence, due primarily to an enlarging immunosuppressed patient population. The pathogenetic role of Epstein-Barr virus (EBV) is of interest due to its established role in other lymphoproliferative disorders in immunosuppressed patients. Twenty-three cases of histologically confirmed PCNSL with corresponding cytology were identified, all obtained under stereotactic guidance. Twenty patients were human immunodeficiency virus (HIV) positive, two were HIV negative, and one was of unknown status. Papanicolaou-stained slides were selected from each case and evaluated for the presence of EBV RNA via in situ hybridization (ISH) utilizing a biotinylated probe specific for EBER 1 RNA, and detected by a conventional streptavidin-peroxidase system. The cases included immunoblastic (12), large cell (10), and mixed small and large cell lymphoma (1). The predominant immunophenotype was B-cell (19), although T-cell (2) and biphenotypic (1) cases were also identified. ISH showed nuclear positivity for EBV RNA in 19 of 23 cases (83%). This study confirms the presence of EBV in PCNSL in immunosuppressed patients and implies a potential etiologic role. The ability to demonstrate EBV RNA in cytologic preparations by ISH also raises the possibility of early identification of high-risk patients through detection of EBV-infected lymphocytes in CSF specimens.

Cytomorphology of progressive multifocal leukoencephalopathy (PML): review of sixteen cases occurring in HIV-positive patients.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disorder of the central nervous system (CNS) resulting from infection of oligodendrocytes by JC virus. Although all patients immunocompromised by any congenital, acquired, or iatrogenic condition are at risk, the population which currently accounts for the majority of new cases is that infected with the human immunodeficiency virus (HIV). Though the clinical/radiologic presentation is characteristic, biopsy confirmation is necessary, as these patients are at risk for other primary CNS disorders which may produce similar clinical findings. Immediate assessment of tissue adequacy by cytologic smear is generally preferred in these specimens due to its relative reduced risk of disease transmission when compared to conventional frozen section. We report here the cytologic findings seen in touch imprints and squash preparations of 16 cases of PML, all occurring in HIV-positive patients and obtained by stereotactic guided needle biopsy. Typical cytomorphologic findings are described and correlated with histologic sections. In addition, features useful in the exclusion of other differential diagnostic possibilities are discussed.

The low frequency of futility in an adult intensive care unit setting.

BACKGROUND: It is widely assumed that "futile" treatment consumes significant health care resources. This is a prospective cohort study. SETTING: The setting was the medical intensive care unit of Ben Taub General Hospital, a large public hospital in Houston, Tex. OBJECTIVE: To assess the frequency of intensive care unit patients meeting any of three broad definitions of futility. SUBJECTS: Subjects consisted of 129 consecutive patients admitted to the study intensive care unit during a 6-week period in the fall of 1993. MAIN OUTCOME MEASURES: Operational definitions for three types of futility described in the literature were developed: Imminent demise futility, death imminent regardless of intervention, was assessed by using the APACHE II (Acute Physiology and Chronic Health Evaluation II) scoring system to determine the likelihood of mortality at more than the 90%, 95%, and 99% probabilities. Lethal condition futility, conditions incompatible with long-term survival, included five separate disease processes. Qualitative futility, conditions with an unacceptable quality of life, was assessed as a persistent vegetative state or as meeting criteria for poor prognosis due to a hypoxic ischemic coma. RESULTS: Only 2 bed-days (0.3%) were used by patients with more than 90% predicted mortality; 22 bed-days (3.6%) were used by patients with poor prognosis due to hypoxic ischemic coma; and 101 bed-days (16.4%) were used by patients satisfying criteria for the five lethal conditions. CONCLUSIONS: The frequency of futile interventions appears to be low unless one is willing to accept a definition that includes patients who could survive for many months. If confirmed in other settings, this suggests that concepts of futility will not play a major role in costs containment.