A randomised controlled trial of nurse-managed trial conclusion following early phase cancer trial participation

The effect of a nurse-managed intervention, for early phase cancer trial participants at trial conclusion, on psychosocial outcomes was evaluated at two cancer centres in the Midlands, England using a randomised controlled trial. It involved 117 patients who were participating in an early phase cancer clinical trial. It was a nurse-managed trial exit, which included a trial exit interview, trial feedback information leaflet and telephone follow-up compared with standard care at trial conclusion. Psychological distress at 1 week and 4–6 weeks post-trial conclusion, patient's knowledge and understanding and patient's satisfaction were assessed. The results showed there was no significant difference between the two groups regarding scores for anxiety and depression at time one and time two. There is some suggestion that the intervention reduced anxiety from trial conclusion to follow-up (P=0.27). Patients in both groups felt they had contributed to cancer research through trial participation. However, intervention patients were more likely to feel that they knew how the trial was going (P<0.001), knew how other people in the trial were doing (P=0.001), had all the feedback they needed about the trial they took part in (P<0.01) and knew how they would be followed up (P=0.02). Patient satisfaction with the intervention was high (median score=4.5 where 5 is greatest satisfaction). In conclusion, nurse-managed trial conclusion led to positive outcomes for patients who had recently completed a clinical trial

Ethical issues, research and vulnerability : gaining the views of children and young people in residential care

Children and young people in residential care are some of the most vulnerable in our society. They may have experienced violence and physical, sexual or emotional abuse. They may be involved in offending or the misuse of drugs and alcohol. They are separated from their families and have to cope with living in a group situation with other young people and staff members. Children and young people in residential care also possess strengths, competencies and resilience. We have much to learn from their experiences and perspectives, both generally and surrounding their time in care. This paper will address the ethical issues which arise from gaining the views of children and young people in residential care, drawing on the experience of carrying out three studies in particular (Kendrick et al. 2004, The development of a residential unit working with sexually aggressive young men. In: H.G. Eriksson and T. Tjelflaat, eds. Residential care: horizons for the new century. Aldershot: Ashgate, 38-55; Docherty et al. 2006, Designing with care: interior design and residential child care. Farm7 and SIRCC. http://www.sircc.strath.ac.uk/publications/Designing_with_Care.pdf; Steckley, L. and Kendrick, A., 2005. Physical restraint in residential child care: the experiences of young people and residential workers. Childhoods 2005: Children and Youth in Emerging and Transforming Societies, University of Oslo, Norway, 29 June-3 July 2005, Steckley and Kendrick 2007, Young people's experiences of physical restraint in residential care: subtlety and complexity in policy and practice. In: M. Nunno, L. Bullard and D. Day, eds. For our own safety: examining the safety of high-risk interventions for children and young people. Washington, DC: Child Welfare League of America, forthcoming). The paper will discuss: information, consent and choice about involvement in the research; confidentiality, privacy and safety. It will also explore some of the more complex issues of ethical good practice which arise from researching children in their own living space. The negotiation of children's time and space must be approached carefully, with consideration of their rights and wishes. Sensitivity to children and young people's priorities and preoccupations must be paramount

Repeated Assessments of Informed Consent Comprehension among HIV-Infected Participants of a Three-Year Clinical Trial in Botswana

Informed consent (IC) has been an international standard for decades for the ethical conduct of clinical trials. Yet frequently study participants have incomplete understanding of key issues, a problem exacerbated by language barriers or lack of familiarity with research concepts. Few investigators measure participant comprehension of IC, while even fewer conduct interim assessments once a trial is underway.We assessed comprehension of IC using a 20-question true/false quiz administered in 6-month intervals in the context of a placebo-controlled, randomized trial for the prevention of tuberculosis among HIV-infected adults in Botswana (2004-2009). Quizzes were offered in both Setswana and English. To enroll in the TB trial, participants were required to have ≥ 16/20 correct responses. We examined concepts understood and the degree to which understanding changed over three-years. We analyzed 5,555 quizzes from 1,835 participants. The participants' highest education levels were: 28% primary, 59% secondary, 9% tertiary and 7% no formal education. Eighty percent of participants passed the enrollment quiz (Quiz1) on their first attempt and the remainder passed on their second attempt. Those having higher than primary education and those who took the quiz in English were more likely to receive a passing score on their first attempt (adjusted odds ratios and 95% confidence intervals, 3.1 (2.4-4.0) and 1.5 (1.2, 1.9), respectively). The trial's purpose or procedures were understood by 90-100% of participants, while 44-77% understood randomization, placebos, or risks. Participants who failed Quiz1 on their initial attempt were more likely to fail quizzes later in the trial. Pass rates improved with quiz re-administration in subsequent years.Administration of a comprehension quiz at enrollment and during follow-up was feasible in a large, international collaboration and efficiently determined IC comprehension by trial participants. Strategies to improve understanding of concepts like placebos and randomization are needed. Comprehension assessments throughout a study may reinforce key concepts

The Patient Deficit Model Overturned: a qualitative study of patients' perceptions of invitation to participate in a randomized controlled trial comparing selective bladder preservation against surgery in muscle invasive bladder cancer (SPARE, CRUK/07/011)

BACKGROUND: Evidence suggests that poor recruitment into clinical trials rests on a patient ‘deficit’ model – an inability to comprehend trial processes. Poor communication has also been cited as a possible barrier to recruitment. A qualitative patient interview study was included within the feasibility stage of a phase III non-inferiority Randomized Controlled Trial (RCT) (SPARE, CRUK/07/011) in muscle invasive bladder cancer. The aim was to illuminate problems in the context of randomization. METHODS: The qualitative study used a ‘Framework Analysis’ that included ‘constant comparison’ in which semi-structured interviews are transcribed, analyzed, compared and contrasted both between and within transcripts. Three researchers coded and interpreted data. RESULTS: Twenty-four patients agreed to enter the interview study; 10 decliners of randomization and 14 accepters, of whom 2 subsequently declined their allocated treatment. The main theme applying to the majority of the sample was confusion and ambiguity. There was little indication that confusion directly impacted on decisions to enter the SPARE trial. However, confusion did appear to impact on ethical considerations surrounding ‘informed consent’, as well as cause a sense of alienation between patients and health personnel. Sub-optimal communication in many guises accounted for the confusion, together with the logistical elements of a trial that involved treatment options delivered in a number of geographical locations. CONCLUSIONS: These data highlight the difficulty of providing balanced and clear trial information within the UK health system, despite best intentions. Involvement of multiple professionals can impact on communication processes with patients who are considering participation in RCTs. Our results led us to question the ‘deficit’ model of patient behavior. It is suggested that health professionals might consider facilitating a context in which patients feel fully included in the trial enterprise and potentially consider alternatives to randomization where complex interventions are being tested. TRIAL REGISTRATION: ISRCTN6112646

R5-SHIV Induces Multiple Defects in T Cell Function during Early Infection of Rhesus Macaques Including Accumulation of T Reg Cells in Lymph Nodes

Background: HIV-1 is a pathogen that T cell responses fail to control. HIV-1gp120 is the surface viral envelope glycoprotein that interacts with CD4 T cells and mediates entry. HIV-1gp120 has been implicated in immune dysregulatory functions that may limit anti-HIV antigen-specific T cell responses. We hypothesized that in the context of early SHIV infection, immune dysregulation of antigen-specific T-effector cell and regulatory functions would be detectable and that these would be associated or correlated with measurable concentrations of HIV-1gp120 in lymphoid tissues. Methods: Rhesus macaques were intravaginally inoculated with a Clade C CCR5-tropic simian-human immunodeficiency virus, SHIV-1157ipd3N4. HIV-1gp120 levels, antigen-specificity, levels of apoptosis/anergy and frequency and function of Tregs were examined in lymph node and blood derived T cells at 5 and 12 weeks post inoculation. Results/Conclusions: We observed reduced responses to Gag in CD4 and gp120 in CD8 lymph node-derived T cells compared to the peripheral blood at 5 weeks post-inoculation. Reduced antigen-specific responses were associated with higher levels of PD-1 on lymph node-derived CD4 T cells as compared to peripheral blood and uninfected lymph node-derived CD4 T cells. Lymph nodes contained increased numbers of Tregs as compared to peripheral blood, which positively correlated with gp120 levels; T regulatory cell depletion restored CD8 T cell responses to Gag but not to gp120. HIV gp120 was also able to induce T regulatory cell chemotaxis in a dose-dependent, CCR5-mediated manner. These studies contribute to our broader understanding of the ways in which HIV-1 dysregulates T cell function and localization during early infection

Familial adenomatous polyposis

Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program