Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program.

BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.

Evaluating satisfaction with maternity care in women from minority ethnic communities: development and validation of a Sylheti questionnaire.

OBJECTIVE: To develop a reliable and valid questionnaire to evaluate satisfaction with maternity care in Sylheti-speaking Bangladeshi women. DESIGN: Two-stage, psychometric study. Firstly, focus groups, in-depth interviews and iterative methods for translation and cultural adaptation were used to develop a Sylheti questionnaire, called the survey of Bangladeshi women's experience of maternity services from an English language questionnaire. Secondly, quantitative psychometric methods were used to field test and evaluate the acceptability, reliability and validity of this questionnaire. SETTING: Four hospitals providing maternity services in London, UK. STUDY PARTICIPANTS: Two hundred and forty-two women from the London Bangladeshi communities, who were in the antenatal (at least 4 months pregnant) or postnatal phase (up to 6 months after delivery). Women spoke Sylheti; a language with no accepted written form. Two purposive samples of 40 women in the antenatal or postnatal phase, one convenience sample of six women in the antenatal phase and three consecutve samples of 60 women in the postnatal phase participated in stage one. In stage two, 135 women (main sample) completed the questionnaire two months after delivery (82% response rate); 50 women (retest sample) from the main sample completed a second questionnaire two weeks later (96% response rate). MAIN OUTCOME MEASURES: Women's views about maternity care elicited by qualitative methods and measured quantitatively using the survey of Bangladeshi women's experience of maternity services. RESULTS: The 121-item questionnaire was acceptable to women and showed good internal consistency (Cronbach's alphas 0.76-0.91), stability (test-retest reliability 0.72-0.84) and construct validity (e.g. able to detect group differences). CONCLUSION: By combining qualitative and quantitative methods, it is possible to adapt an instrument to provide an acceptable, reliable and valid Sylheti questionnaire. The approach taken in developing this questonnaire provides a model for developing outcome measures for use with other minority ethnic communities.

Implementing evidence-based practice in clinical situations.

Many nurses in a variety of clinical settings are facing the challenges posed by incorporating evidence-based practice in health care. Some of the steps involved in implementing evidence-based care in clinical practice are discussed and a two-step framework to assist practitioners in implementing evidence-based practice is outlined. Factors such as the relevance of specific guidelines or research, generalisability of research findings, the strength of the evidence relative to the risks and benefits of treatment, and patient preferences are discussed in terms of evidence-based decision making.

The development of a national guideline on the management of leg ulcers.

This paper describes the development of an evidence-linked clinical guideline for the management of uncomplicated venous leg ulcers. Guidelines are developed to provide recommendations for clinical practice which are based on summaries of good quality research evidence. The aim of the guideline discussed in this article is to direct primary health care practitioners to the most effective method of assessment and treatment of venous leg ulcers and to discourage practices that do not have convincing or sufficient evidence of effectiveness. The three most important steps to the development of a valid clinical guideline are: basing recommendations on the best available evidence; explicit linkage between guideline recommendations and quality of evidence; and the involvement of a multidisciplinary group. The steps are discussed in relation to the development of the guideline alongside an introductory presentation on the role guidelines can play in improving practice. Issues arising from guideline development such as valid ways of obtaining patient input and lack of evidence are also discussed.

Developing clinical guidelines: issues and challenges.

Clinical guidelines are viewed as an important tool in the quest to promote evidence based practice. Consequently, there has been a proliferation in guideline development at a national and local level. This paper describes what clinical guidelines are and how they have been developed by a national organisation--the Royal College of Nursing (RCN). Drawing on the development of two tissue viability guidelines: The Management of Patients with Venous Leg Ulcers and Risk Assessment and Prevention of Pressure Ulcers, some challenges inherent in guideline development are outlined. Certain desirable attributes that a clinical guideline should exhibit in order for it to be utilisable and effective in practice are outlined as these provide a standard for guideline developers. In reality the practice of guideline development will depend upon the topic, the experience of the guideline group, the purpose of the guidelines and the evidence available. Our experience suggests that producing a clinically valid and utilisable guideline is a labour and resource intensive process. It is also time consuming. An alternative strategy to developing local guidelines from scratch would be to adapt an existing guideline to local circumstances. A stepwise process is presented in the paper to assist people with this process.

Implementing clinical guidelines: how can informatics help?

Clinical guidelines are heralded as a positive contribution to improving quality of care and ensuring the effectiveness of care. From the perspective of the health services researcher, the authors propose a model of how informatics can support the implementation of clinical guidelines and their integration into systems for decision support and clinical audit. Each element of the model is discussed in turn.

RCN guideline on the management of leg ulcers.

The treatment of uncomplicated leg ulcers has not always been carried out effectively. In this article, the authors introduce an evidence-based clinical guideline for the treatment of uncomplicated leg ulcers and highlight some of the key recommendations. This is to be launched at Nursing Standard's conference on evidence-based nursing this week.

The RCN strategy on clinical guidelines.

There is increasing interest in the potential of clinical guidelines to improve the quality of health care. In this report, Lesley Duff outlines areas of activity currently being undertaken by the RCN Institute to address these needs.

Making sense of clinical guidelines.

In a companion article to their paper on clinical effectiveness (McClarey and Duff 1997), the authors discuss the issues surrounding clinical guidelines. How they are developed and how they can be adapted to local practice are described to allow practitioners to base their practice on the most up-to-date research evidence.

Implementation of nutrition standards for older adults.

This article reports on a study exploring the process of implementing nationally developed standards for the nutritional care of older adults. In particular, the study focused on issues which enabled or hindered the effective implementation of the standards. A multisite case study design was used. The intervention involved a two-day workshop on facilitated teamwork and implementation strategies. The standards were implemented over a six-month period and a number of semi-structured interviews were conducted in each of the homes throughout this period. Pre- and post-audit data of nutritional care were collected in each of the homes to ascertain the extent to which care had changed. The standards were used effectively as a basis for making significant changes to the way staff provided nutritional care. The research highlighted the importance of using a strategic and well planned approach which addresses four important factors: ensuring the topic area is a priority; using a teamwork approach; identifying a facilitator; and providing necessary educational opportunities.

Clinical effectiveness and evidence-based practice.

In the first of two articles, the authors address some of the most common questions asked by practitioners about clinical effectiveness. The second article, on clinical guidelines, will appear in Nursing Standard in two weeks.

Clinical guidelines: an introduction to their development and implementation.

There is a great deal of interest in the United Kingdom in clinical guidelines as a means of assisting practitioner and patient decision making about care options and in improving the quality of the care provided. Confusion remains, however, over what is meant by a clinical guideline and how it differs from and relates to protocols and standards. This paper was written under the auspices of the Royal College of Nursing Steering Group for the college's work on clinical guidelines, with the aim of clarifying some of the terminology used in the field and introducing ways in which clinical guidelines might be used by practitioners and patients to readers. At the moment just how effective the use of clinical guidelines can be on care is poorly established. What is known, however, is that crucial to their success are the strategies and methods used for their implementation. Such strategies and methods raise questions about how a sense of ownership can be engendered in those using the clinical guidelines and how they may be best operationalized. These questions are considered in this paper.

Quality improvement of nursing care in hospitals in India: the dynamic approach.

A workshop was held in Calcutta in August 1992 by the Nurses' Research Society of India (NRSI), in partnership with the Royal College of Nursing of the UK, Dynamic Quality Improvement Programme (DQIP), to introduce an approach to quality improvement to nurses in India interested in evaluating and improving the care they provide. Since then, three sites have implemented the system for standard setting and audit (Dynamic Standard Setting System) which is the method for evaluating care used within that approach. An appraisal of the progress of the sites to date indicates that, in the clinical setting, nurses are progressing well with the writing of standards and have experienced little difficulty in understanding the theory and processes involved. They are currently revising the standards written with a view to implementing them and auditing them in the near future. This article outlines the introduction of dynamic quality improvement and the Dynamic Standard Setting System to the nurses in India and describes the progress of one of the test-sites currently working on its implementation.