PROCESS FOR OBTAINING INFORMED CONSENT: WOMEN’S OPINIONS

In Brazil, every study involving human beings is required to produce an informed consent form that must be signed by study participants: this is stated in Resolution 196/96. 1 Consent must be obtained through a specific structured process. Objective: To present the opinions of women regarding how the process of obtaining informed consent should be conducted when women are invited to participate in studies on contraceptive methods. Subjects and Methods: Eight focus groups were conducted, involving a total of 51 women living in the metropolitan region of Campinas. The women involved in the study were either participating in a clinical trial in the area of women’s health or had participated in such a trial in the previous 12 months. A thematic guide was used to conduct the focus group discussions; the discussions were recorded, transcribed and a thematic analysis performed. Results: In general, the person who invites a woman to participate in a study should be a member of the research team but not the principal investigator. Information relating to the study should be given orally and in writing, both individually and in the group setting. Study volunteers should be informed about, among other things, the risks, possible side effects and discomforts, including long‐term effects. The use of audiovisual aids to provide information was suggested. Conclusion: The process for obtaining informed consent was seen as a means of establishing a relationship between the volunteers and the investigator/research team. The information that the study participants expected to be given coincides with the requirements established under Resolution 196/96. The use of audiovisual aids would improve understanding of the information provided.     

Group Membership Affects Spontaneous Mental Representation: Failure to Represent the Out-Group in a Joint Action Task

Predicting others’ actions is crucial to successful social interaction. Previous research on joint action, based on a reaction-time paradigm called the Joint Simon Task, suggests that successful joint action stems from the simultaneous representation of the self with the other. Performance on this task provides a read-out of the degree of intrusion from a partner that participants experience from acting jointly compared to acting alone, which in turn is a measure of the degree to which participants mentally represent their co-actors during the task. To investigate the role of perceived group membership in this type of joint action and its influence on the representation of others, we first subjected participants to a minimal group paradigm while manipulating differences in social competition. We then asked participants to do the Joint Simon Task in pairs with an in-group or out-group member. Only participants who acted with an “in-group” partner on the joint task showed altered reaction times compared to when acting alone, presumably a change caused by the simultaneous and automatic representation of their in-group partner. In contrast, participants who acted with an out-group partner were unaffected in their reactions when doing the joint task, showing no evidence of representation of their out-group partner. This effect was present in both the high-competition and low-competition conditions, indicating that the differential effects of group membership on representation during joint action were driven by perceived group membership and independent of the effects of social competition. We concluded that participants failed to represent out-group members as socially relevant agents not based on any personality or situational characteristics, but in reaction only to their status as “other”. In this way group membership appears to affect cognition on a very immediate and subconscious level.     

Estimating the cost of compensating victims of medical negligence.

The current system in Britain for compensating victims of medical injury depends on an assessment of negligence. Despite the sporadic pressure on the government to adopt a "no fault" approach, such as exists in Sweden, the negligence system will probably remain for the immediate future. The cost of this system was estimated to be 52.3m pounds for England 1990-1. The problem for the future, however, is one of forecasting accuracy at provider level: too high a guess and current patient care will suffer; too low a guess and future patient care will suffer. The introduction of a mutual insurance scheme may not resolve these difficulties, as someone will have to set the rates. Moreover, the figures indicate that if a no fault scheme was introduced the cost might be four times that of the current system, depending on the type of scheme adopted.     

A rank-based mixed model approach to multisite clinical trials.

New rank-based methods for analyzing data from multisite clinical trials are presented in the context of "mixed" linear models. In contrast to current rank methods, the new procedures test for a drug main effect in the presence of a random drug by site interaction (or drug by investigator interaction when there is only one investigator per site). Analogous procedures are also provided for the "fixed-effects" situation, and comparisons are made with current methods. The rationale for an analysis that assumes random investigator effects is described.     

The olivieri case: Lessons for Australasia

The case of Dr. Nancy Olivieri, the Hospital for Sick Children, the University of Toronto, and Apotex Inc. vividly illustrates many of the issues central to contemporary health research and the safety of research participants. First, it exemplifies the financial and health stakes in such research. Second, it shows deficits in the ways in which research is governed. Finally, it was and remains relevant not only in Toronto but in communities across Canada and well beyond its borders because, absent appropriate policies, what happened in Toronto could have happened (and could well still happen) elsewhere. In Part One of this paper, we review the facts of the Olivieri case relevant to the issues we wish to highlight: first, the right of participants in a clinical trial to be informed of a risk that an investigator had identified during the course of the trial and the obligation of the investigator to inform participants (both her own and those of other investigators); and second, the obligation of institutions to protect and promote the well-being of research participants as well as academic freedom and research integrity, the obligations of research sponsors to inform participants, research regulators, and others about unforeseen risks, and the obligations of research regulators to ensure that participants are informed of unforeseen risks and to otherwise protect and promote research integrity. In Part Two, we relate these facts and issues to New Zealand and Australia. We also make detailed recommendations for changes to the various instruments used for the governance of research involving humans in Australasia.     

TREATMENT NEEDS IN HIV PREVENTION TRIALS: USING BENEFICENCE TO CLARIFY SPONSOR‐INVESTIGATOR RESPONSIBILITIES

Some participants will get HIV‐infected in HIV prevention trials, despite risk reduction measures. The subsequent treatment responsibilities of sponsor‐investigators have been widely debated, especially where access to antiretroviral therapy (ART) is not available. In this paper, we explore two accounts of beneficence to establish whether they can shed light on sponsor‐investigator responsibilities. We find the notion of general beneficence helpful insofar as it clarifies that some beneficent actions will be obligatory where they can be dispensed without scuppering the trial. We find the notion of specific beneficence helpful insofar as it directs investigators to attend to the needs of trial participants; however the range of interventions that could be provided remains unhelpfully broad. We then examine accounts of the investigator‐participant relationship to narrow the range of interventions that investigators should provide, concluding that health‐care, and HIV infection, are appropriate foci. We conclude that when investigators are able to meet the ART needs of their participants (e.g. referral, assisted referral or direct provision) without sacrificing trial quality, they must do so. However, there is little of this explicit direction to be found in the account of specific beneficence itself, but rather it is found in accounts of the relationship that are compatible with beneficence.     

Sensorimotor experience enhances automatic imitation of robotic action

Recent research in cognitive neuroscience has found that observation of human actions activates the 'mirror system' and provokes automatic imitation to a greater extent than observation of non-biological movements. The present study investigated whether this human bias depends primarily on phylogenetic or ontogenetic factors by examining the effects of sensorimotor experience on automatic imitation of non-biological robotic, stimuli. Automatic imitation of human and robotic action stimuli was assessed before and after training. During these test sessions, participants were required to execute a pre-specified response (e.g. to open their hand) while observing a human or robotic hand making a compatible (opening) or incompatible (closing) movement. During training, participants executed opening and closing hand actions while observing compatible (group CT) or incompatible movements (group IT) of a robotic hand. Compatible, but not incompatible, training increased automatic imitation of robotic stimuli (speed of responding on compatible trials, compared with incompatible trials) and abolished the human bias observed at pre-test. These findings suggest that the development of the mirror system depends on sensorimotor experience, and that, in our species, it is biased in favour of human action stimuli because these are more abundant than non-biological action stimuli in typical developmental environments.     

Four color compensation.

Four-color immunophenotyping can now be routinely performed using either a single laser or dual laser flow cytometer. When a single laser instrument is used, the fluorochromes evaluated are usually FITC, PE, PE-TR and PE-CY5 (or PerCP). For two-laser excitation APC is generally used in place of PE-TR. Since each tandem dye construct contains PE, three of the four detectors are affected and compensation can be problematic. In this report we show that each tandem conjugated antibody, whether different batches from the same supplier or conjugates from different suppliers all require unique compensation. This inconsistency results in erroneous data, negates the use of single labeled particles as a method for providing adequate compensation and requires dual and triple labeled cells of known pattern to verify compensation. It is also shown that improper compensation can reduce or eliminate completely the detection of fluorescence emission from PECY5 conjugated antibodies. These problems are caused by a variation in energy transfer between PE and either TR or CY5 because the chemistry involved in preparation and conjugation to antibodies is not sufficiently controlled to produce reagents with uniform compensation requirements. The variation in tandem dye compensation can be addressed by either using the same tandem conjugated antibody, by using the same second step tandem reagent to an appropriate first step antibody or by using software compensation. The latter provides an easy solution because a unique compensation matrix can be produced for each antibody tandem conjugate.     

Developing Clinical Research Relationship: Views from Within

The nature of the relationship between clinical investigator and research participant continues to be contested. The related discussions have largely focused on the doctor‐researcher dichotomy thought to permeate the work of a clinical investigator with research participants, whom in turn occupy two corresponding roles: patient and subject. This paper contributes to current debates on the topic by providing a voice to research participants, whose perspectives have been largely invisible. It draws on 42 in‐depth interviews conducted in Ghana and South Africa with respondents at different stages of involvement in clinical research, ranging from no experience in clinical research to enrollment in several clinical trials. The perspectives of all respondents were largely congruent and rooted in the common view that clinical research contributed to the improvement of local health. They went beyond the researcher/participant versus doctor/patient dichotomy, long established in research ethics, and preferred to view participants and investigators as partners working together to find ways to address local health needs. The conceptualization of investigator‐participant relations as a partnership reinforced expectations of care, transparency and accountability, which were viewed as necessary expressions of mutuality and respect within equal collaborations. It is important to engage with these views in order to avoid antagonizing societal expectations and to build up long‐term public trust, crucial for the continuous operation of clinical research.     

Effectiveness of using an unskilled model in action observation combined with motor imagery training for early motor learning in elderly people: a preliminary study

Abstract

Aim of the study: To investigate a more available model for the early phase of motor learning after action observation combined with motor imagery training in elderly people. To address the purpose, we focused on a slow, unskilled model demonstrating an occasional error.

Materials and methods: A total of 36 elderly people participated in the current study and were assigned to either the unskilled or skilled model observation groups (n?=?12, respectively), or the control group (n?=?12). The participants in the observation groups observed the assigned a video clip of an unskilled or skilled model demonstrating a ball rotation task. During the observation, the participants were instructed to imagine themselves as the person in the video clip. The participants in the control group read a scientific paper during the equivalent period of action observation and motor imagery. We measured ball rotation performance (the time required for five rotations, the number of ball drops) in pre- and post-intervention (observation combined with motor imagery training for intervention groups or reading for control group).

Results: Ball rotation performance (ball rotation speed) significantly improved in the unskilled model observation group compared to the other two groups.

Conclusions: Intervention for action observation using unskilled model combined with motor imagery was effective for improving motor performance during the early phase of motor learning.     

Medicolegal audit in the West Midlands region: analysis of 100 cases.

One hundred medicolegal cases were analysed to obtain quantitative data about diagnoses and the causes of litigation that affect hospital doctors in the National Health Service. Sixteen actions concerned minor problems that are an unavoidable risk of treatment, and 39 were due to natural causes. In other cases it was debatable whether a medical accident or negligence was responsible. At the end of three years 73 actions had been withdrawn, 12 settled out of court, and one lost in court by the plaintiff, and 14 were pending. Of these 14, nine were likely to reach court on charges of negligence. Contributory causes were failure of communication in 27 and matters connected with the patient''s attitude or personality in 20. Because much time and money are spent on cases that should never have started a doctor should sit on the legal aid panel to give advice for medical cases. Also, solicitors should obtain an independent medical opinion when a complaint is first received from a patient. Consent forms should be more informative and give details of what can reasonably be expected from treatment and its possible risks.     

X chromosome dosage compensation and its relationship to sex determination in C. elegans

A genetic regulatory hierarchy controls all aspects of Caenorhabditis elegans sex determination and X chromosome dosage compensation in response to the primary sex-determining signal, the X/A ratio. Initially, these two processes are coordinately regulated by a group of genes that transmit this primary signal to downstream genes that preferentially control either sex determination or dosage compensation. The relationship between these two processes is complex: not only are they coordinately controlled, a feedback mechanism operates to allow a disruption in dosage compensation to affect sexual fate. We describe our genetic and molecular understanding of the regulatory hierarchy, the feedback control and the dosage compensation process itself.     

Carpal tunnel release in the United States and Sweden: reimbursement patterns, cost for treatment, and return to work

Cost containment plays an increasingly important role in health care, affecting providers and recipients. The present investigation addressed a limited number of factors that relate to the total cost for surgical treatment of carpal tunnel syndrome. The purpose of this study was to compare socioeconomic factors in two different societies and how worker's compensation plays a role in the cost, rehabilitation, and operative practices. To that purpose, the authors studied hospital and insurance records from a total of 123 female patients treated in two tertiary referral centers (University of Pittsburgh, Pa., and University of Umea, Sweden). The 123 patients were referred to three subgroups. Group A comprised patients from the University of Pittsburgh with worker's compensation (n = 34), group B comprised patients from the University of Pittsburgh without worker's compensation (n = 47), and group C comprised patients from the University of Umea (n = 42). The analyzed data showed a tendency toward longer duration of postoperative sick leave for those with worker's compensation than those without worker's compensation for patients from the University of Pittsburgh. However, operating room times and operating times, operative cost, use of postoperative therapy, and duration for sick leave were substantially less for patients treated at the University of Umea. There was no statistically significant difference in time off work between group A and group B. The results may indicate that the effect of compensation on a patient's ability or willingness to recover after treatment for carpal tunnel syndrome may be less important than factors that do not primarily relate to the patient or the surgical procedure.     

Positive and negative factors in defensive medicine: a questionnaire study of general practitioners.

OBJECTIVES--(a) To investigate defensive medical practices among general practitioners; (b) to compare any such practices with general practitioners'' understanding of certain aspects of the terms of service and medical negligence and practitioners'' concerns about the risk of being sued or having a complaint lodged. DESIGN--Postal questionnaire survey. Each questionnaire was followed by a reminder. SUBJECTS--500 systematically selected general practitioners on the membership list of the Medical Defence Union. MAIN OUTCOME MEASURES--Answers to questions on defensive medical practices, understanding of certain aspects of the terms of service and medical negligence, and concerns about the risk of being sued or having a complaint lodged. RESULTS--300 general practitioners returned the questionnaire (response rate 60%). 294 (98%) claimed to have made some practice changes as a result of the possibility of a patient complaining. Of the defensive medical practices adopted, the most common (over half of doctors stating likely or very likely) seemed to be increased diagnostic testing, increased referrals, increased follow up, and more detailed patient explanations and note taking. Respondents practised defensive medicine as a possible consequence of concerns about the risks of being sued or having a complaint lodged. This association was particularly strong for negative defensive practices. Defensive medical practice did not correlate with any misunderstanding about the law of negligence or the general practitioners'' terms of service. CONCLUSIONS--General practitioners are practising defensive medicine. Some defensive practices such as increased patient explanations or more detailed note taking are clearly beneficial. However, implementing the findings of the Wilson report may increase negative defensive medical practices.     

Promoting children's home safety.

Home accidents are the main cause of death and morbidity in early childhood. Working-class children are at greatest risk. A study in an inner city area of the effects of a national television campaign about child accident prevention and of a locally designed health education initiative showed that 55% of families with young children in the study area did not watch any of the television programmes. Only 9% of a group specially encouraged to watch the programmes took any action to make their homes safer. In a comparable group who also received a home visit at which specific advice was given 60% took action to make their homes safer. The families studied were well aware before the television campaign of the importance and preventability of children''s accidents. The problems disadvantaged families face are therefore not ones of ignorance or apathy about hazards but practical difficulties in converting their concern into action. Administrative arrangements must be developed for providing health workers--especially health visitors--with detailed local information to pass on to parents.     

Methods for detection of parent-of-origin effects in genetic studies of case-parents triads.

When affected probands and their biological parents are genotyped at a candidate gene or a marker, the resulting case-parents-triad data enable powerful tests for linkage in the presence of association. When linkage disequilibrium has been detected in such a study, the investigator may wish to look further for possible parent-of-origin effects. If, for example, the transmission/disequilibrium test restricted to fathers is statistically significant, whereas that restricted to mothers is not, the investigator might interpret this as evidence for nonexpression of the maternally derived disease gene-that is, imprinting. This report reviews existing methods for detection of parent-of-origin effects, showing that each can be invalid under certain scenarios. Two new methods are proposed, based on application of likelihood-based inference after stratification on both the parental mating type and the inherited number of copies of the allele under study. If there are no maternal genetic effects expressed prenatally during gestation, the parental-asymmetry test is powerful and provides valid estimation of a parent-of-origin parameter. For diseases for which there could be maternal effects on risk, the parent-of-origin likelihood-ratio test provides a robust alternative. Simulations based on an admixed population demonstrate good operating characteristics for these procedures, under diverse scenarios.     

Genes That Implement the Hermaphrodite Mode of Dosage Compensation in Caenorhabditis Elegans

We report a genetic characterization of several essential components of the dosage compensation process in Caenorhabditis elegans. Mutations in the genes dpy-26, dpy-27, dpy-28, and the newly identified gene dpy-29 disrupt dosage compensation, resulting in elevated X-linked gene expression in XX animals and an incompletely penetrant maternal-effect XX-specific lethality. These dpy mutations appear to cause XX animals to express each set of X-linked genes at a level appropriate for XO animals. XO dpy animals are essentially wild type. Both the viability and the level of X-linked gene expression in XX animals carrying mutations in two or more dpy genes are the same as in animals carrying only a single mutation, consistent with the view that these genes act together in a single process (dosage compensation). To define a potential time of action for the gene dpd-28 we performed reciprocal temperature-shift experiments with a heat sensitive allele. The temperature-sensitive period for lethality begins 5 hr after fertilization at the 300-cell stage and extends to about 9 hr, a point well beyond the end of cell proliferation. This temperature-sensitive period suggests that dosage compensation is functioning in XX animals by mid-embryogenesis, when many zygotically transcribed genes are active. While mutations in the dpy genes have no effect on the sexual phenotype of otherwise wild-type XX or XO animals, they do have a slight feminizing effect on animals whose sex-determination process is already genetically perturbed. The opposite directions of the feminizing effects on sex determination and the masculinizing effects on dosage compensation caused by the dpy mutations are inconsistent with the wild-type dpy genes acting to coordinately control both processes. Instead, the feminizing effects are most likely an indirect consequence of disruptions in dosage compensation caused by the dpy mutations. Based on the cumulative evidence, the likely mechanism of dosage compensation in C. elegans involves reducing X-linked gene expression in XX animals to equal that in XO animals via the action of the dpy genes.     

The Nature of Quantitative Genetic Variation in Drosophila. III. Mechanism of Dosage Compensation for Sex-Linked Abdominal Bristle Polygenes

Seventeen lines, each homozygous for a different X chromosome but all with a common autosomal genetic background, were constructed and assayed for abdominal bristle number to determine whether dosage compensation operates for sex-linked genes affecting this character.—The regression coefficient of male mean on female mean using a logarithmic scale was 0.90 ± 0.13 and the genetic regression coefficient 0.92, neither differing significantly from unity. The genetic components of variance in males and females were also very similar (0.000234 or 0.000228, respectively). These results indicate that dosage compensation is complete (or nearly so) for sex-linked genes affecting this character. The bristle scores of females did not differ in reciprocal crosses between these lines, thus dosage compensation does not operate by paternal X inactivation.—The question of an adequate scale for abdominal bristle number had to be examined during the study. A logarithmic scale appeared to be adequate for both genotypic and environmental differences.     

napts, a mutation affecting sodium channel activity in Drosophila, is an allele of mle, a regulator of X chromosome transcription.

napts is a recessive mutation that affects the level of sodium channel activity and, at high temperature, causes paralysis associated with a loss of action potentials. We show, by genetic complementation tests, germline transformation, and analysis of mutations, that napts is a gain-of-function mutation of mle, a gene required for X chromosome dosage compensation and male viability. Molecular analyses of nap and mle mutations indicate that mle+, nap+, and napts activities are encoded by the same open reading frame and suggest that napts is due to a single amino acid substitution. Although napts is known to act via para+, an X-linked sodium channel structural gene, its effect is not due to a simple defect in para+ dosage compensation.