Working together to deliver stratified medicine research effectively.

INTRODUCTION OR BACKGROUND: Stratified medicine is an important area of research across all clinical specialties, with far reaching impact in many spheres. Despite recently formulated global policy and research programmes, major challenges for delivering stratified medicine studies persist. Across the globe, clinical research infrastructures have been setup to facilitate high quality clinical research. SOURCES OF DATA: This article reviews the literature and summarizes views collated from a workshop held by the UK Pharmacogenetics and Stratified Medicine Network and the NIHR Clinical Research Network in November 2016. AREAS OF AGREEMENT: Stratified medicine is an important area of clinical research and health policy, benefitting from substantial international, cross-sector investment and has the potential to transform patient care. However there are significant challenges to the delivery of stratified medicine studies. AREAS OF CONTROVERSY: Complex methodology and lack of consistency of definition and agreement on key approaches to the design, regulation and delivery of research contribute to these challenges and would benefit from greater focus. GROWING POINTS: Effective partnership and development of consistent approaches to the key factors relating to stratified medicine research is required to help overcome these challenges. AREAS TIMELY FOR DEVELOPING RESEARCH: This paper examines the critical contribution clinical research networks can make to the delivery of national (and international) initiatives in the field of stratified medicine. Importantly, it examines the position of clinical research in stratified medicine at a time when pressures on the clinical and social services are mounting.

BOS response to article on 'Hold that smile' campaign.

The British Orthodontic Society launched a campaign called 'Hold that smile' to highlight to patients the importance of wearing retainers as a means of reducing relapse following orthodontic treatment. This opinion piece, on behalf of the British Orthodontic Society, is written in response to an article entitled 'British Orthodontic Society's initiative on orthodontic retention, A GDP's perspective' ( 2018; 224: 481-486). In this short opinion article, we take the opportunity to clarify the aims of the campaign, which set out to educate patients about orthodontic relapse and to highlight the importance of wearing, and taking responsibility for, retainers long-term.

Retention and relapse in clinical practice.

Maintaining teeth in their corrected positions following orthodontic treatment can be extremely challenging. Teeth have a tendency to move back towards the original malocclusion as a result of periodontal, gingival, occlusal and growth related factors. However, tooth movement can also occur as a result of normal age changes. Because orthodontics is unable to predict which patients are at risk of relapse, those which will remain stable and the extent of relapse that will occur in the long-term, clinicians need to treat all patients as if they have a high potential to relapse. To reduce this risk, long term retention is advocated. This can be a significant commitment for patients, and so retention and the potential for relapse must form a key part of the informed consent process prior to orthodontic treatment. It is vital that patients are made fully aware of their responsibilities in committing to wear retainers as prescribed in order to reduce the chance of relapse. If patients are unable or unwilling to comply as prescribed, they must be prepared to accept that there will be tooth positional changes following treatment. There is currently insufficient high quality evidence regarding the best type of retention or retention regimen, and so each clinician's approach will be affected by their personal, clinical experience and expertise, and guided by their patients' expectations and circumstances.

Retention in orthodontics.

Retention is necessary following orthodontic treatment to prevent relapse of the final occlusal outcome. Relapse can occur as a result of forces from the periodontal fibres around the teeth which tend to pull the teeth back towards their pre-treatment positions, and also from deflecting occlusal contacts if the final occlusion is less than ideal. Age changes, in the form of ongoing dentofacial growth, as well as changes in the surrounding soft tissues, can also affect the stability of the orthodontic outcome. It is therefore essential that orthodontists, patients and their general dental practitioners understand the importance of wearing retainers after orthodontic treatment. This article will update the reader on the different types of removable and fixed retainers, including their indications, duration of wear, and how they should be managed in order to minimise any unwanted effects on oral health and orthodontic outcomes. The key roles that the general dental practitioner can play in supporting their patients wearing orthodontic retainers are also emphasised.

Interdisciplinary management of severe intrusion injuries in permanent incisors: a case series.

Intrusion injuries to the permanent dentition are amoung the most severe types of dental injuries, occurring in 0.3-1.9% of all dental trauma cases. The current clinical guidelines in the management of intrusion injuries are based on level B evidence due to the infrequent nature of this type of injury, coupled with a lack of high quality evidence-based studies. This paper presents four cases of severe intrusion injuries that were successfully managed using an interdisciplinary approach. The cases described here highlight the benefits of orthodontic repositioning of severely intruded teeth in the short and medium terms. Although orthodontic repositioning was unsuccessful in the final case, this did not preclude subsequent surgical repositioning. Interdisciplinary collaboration allowed two of the cases described to be effectively managed with premolar autotransplantation alongside orthodontic treatment. The cases demonstrated here indicate the difficulties in providing the current recommended treatment modalities at non-specialist clinics. They accentuate the importance of an immediate referral of such complex cases to a specialist centre where interdisciplinary management is readily available.

Real-life experience of managing vulval erosive lichen planus: a case-based review and U.K. multicentre case note audit.

BACKGROUND: There is a lack of published evidence for treatment and outcome measures for vulval erosive lichen planus (ELPV). OBJECTIVES: To conduct a multicentre case note review to examine real-life management of ELPV comparing current U.K. practice against an agreed audit standard. METHODS: Criteria for standards of care for which to evaluate current service provision were set following communication with experts from the British Society for the Study of Vulval Disease. Participants from 10 U.K. centres included nine dermatologists and one gynaecologist who run specialist vulval clinics. Standards examined the documentation of disease severity/impact measures, the use of diagnostic biopsies, treatments used and assessment of treatment response. RESULTS: Audit data were collected from 172 patients. Documentation of symptoms/clinical findings was excellent (99%, 170/172). A schematic diagram was present in the notes of 87% (150/172). Patient-related disease impact measures including Dermatology Life Quality Index (3%, 6/172) or visual analogue scales (1%, 2/172) were less well documented. Biopsies were performed in 78% (135/172); 71% (96/135) showed histological features consistent with erosive lichen planus. Squamous cell carcinoma developed in four patients (two vulval, two oral) and vulval intraepithelial neoplasia in two further patients. Recommended first-line treatment with a very potent topical steroid was used in 75% (129/172) with improvement in 66% (85/129). Significant variation in second-line therapy was seen. CONCLUSIONS: Wide variation in U.K. practice demonstrates the absence of standardized guidance for treating ELPV and the need for vulval-specific outcomes. This audit should act as a framework towards improving ELPV management and to plan future research in this area.

Extending the clinical research network approach to all of healthcare.

The development of Clinical Research Networks (CRN) has been central to the work conducted by Health Departments and research funders to promote and support clinical research within the NHS in the UK. In England, the National Institute for Health Research has supported the delivery of clinical research within the NHS primarily through CRN. CRN provide the essential infrastructure within the NHS for the set up and delivery of clinical research within a high-quality peer-reviewed portfolio of studies. The success of the National Cancer Research Network is summarized in Chapter 5. In this chapter progress in five other topics, and more recently in primary care and comprehensively across the NHS, is summarized. In each of the 'topic-specific' networks (Dementias and Neurodegenerative Diseases, Diabetes, Medicines for Children, Mental Health, Stroke) there has been a rapid and substantial increase in portfolios and in the recruitment of patients into studies in these portfolios. The processes and the key success factors are described. The CRN have worked to support research supported by pharmaceutical, biotechnology and medical device companies and there has been substantial progress in improving the speed, cost and delivery of these 'industry' studies. In particular, work to support the increased speed of set up and delivery of industry studies, and to embed this firmly in the NHS, was explored in the North West of England in an Exemplar Programme which showed substantial reductions in study set-up times and improved recruitment into studies and showed how healthcare (NHS) organizations can overcome delays in set up times when they actively manage the process. Seven out of 20 international studies reported that the first patient to be entered anywhere in the world was from the UK. In addition, the CRN have supported research management and governance, workforce development and clinical trials unit collaboration and coordination. International peer reviews of all of the CRN have been positive and resulted in the continuation of the system for a further 5 years in all cases.

Paraproteinaemia after allo-SCT, association with alemtuzumab-based conditioning and CMV reactivation.

Paraproteinaemia following allo-SCT is common. We analysed 91 consecutive patients undergoing allo-SCT; conditioning included alemtuzumab in 42% of the patients. Paraproteinaemia incidence at 2 years was 32%. In univariate analysis paraproteinaemia was associated with unrelated donor, age, recipient seropositivity for CMV and alemtuzumab conditioning (hazard ratio (HR) 3.93, P=0.0006). Paraproteinaemia was not associated with haematological diagnosis; disease status at transplant; varicella zoster, herpes simplex or EBV serology; reduced-intensity vs myeloablative conditioning or GVHD. CMV reactivation-more frequent in alemtuzumab recipients-was associated with paraproteinaemia (HR 7.52, P<0.0001). In multivariate analysis, only increasing age (HR 1.04 per year, P=0.048) and CMV reactivation (HR 5.74, P=0.001) were significantly associated with paraproteinaemia. Alemtuzumab without CMV reactivation, however, resulted in significantly more paraproteinaemia, suggesting an effect that is independent of CMV reactivation. OS was poorer in patients with paraproteinaemia (HR 2.54, P=0.04) and relapse increased (HR 2.38, P=0.087). Paraproteinaemia was not significantly independently associated with decreased survival on multivariate analysis. Post transplant paraproteinaemia is associated with CMV reactivation, is more frequent in alemtuzumab-conditioned transplants and is not associated with improved OS.

Are general dental practitioners effective in the management of non-apnoeic snoring using mandibular advancement appliances?

OBJECTIVE: This study assessed the effectiveness of general dental practitioners (GDPs) in the management of subjects with non-apnoeic snoring using a mandibular advancement appliance (MAA), following a one day training course. SUBJECTS AND METHODS: Sixty subjects suffering from simple, non-apnoeic snoring were treated by 15 GDPs, in three hospital centres, using a monobloc mandibular advancement appliance design. All GDPs attended a one day training course prior to the study which covered theoretical and practical training in the use of mandibular advancement appliances. Snoring and level of disturbance were assessed using a questionnaire completed by their sleeping partner before and after a three month treatment period. Daytime sleepiness was assessed by the patients using the Epworth sleepiness scale questionnaire (ESS) before and after a three month treatment period. In addition, patients completed an outcome questionnaire, to assess side-effects experienced from the MAA. RESULTS: A success rate of 48% (95% CI 0.35, 0.61) was achieved in partner-assessed snoring and disturbance levels, following a three month period of MAA treatment. The median ESS score reduced from 9 to 7.5 (95% CI 0, 3). General dental practitioners experienced problems during protrusive bite registrations, with 10% being judged inadequate. CONCLUSION: GDPs were not effective in the management of non-apnoeic snoring using a monobloc appliance after a one day training course. Further training and/or selection of a different design of appliance should be considered for GDPs to become highly competent in this area.

The many faces of secondary syphilis: a re-emergence of an old disease.

There has been a recent dramatic re-emergence of syphilis in the UK. This article describes the varied clinical manifestations of secondary syphilis and describes the diagnosis and current guidelines for treatment, especially in association with human immunodeficiency virus infection.

Vulval skin disease: clinical features, assessment and management.

This article outlines the issues involved in assessing and managing patients who present with a vulval skin condition. It describes the anatomy of the vulval area, many of the skin conditions that nurses may encounter in their practice and potential treatment options for these conditions. The importance of accurate history-taking is emphasised and described, and appropriate referral to a specialist is also discussed.

How can experience in clinical and community settings contribute to early medical education? A BEME systematic review.

REVIEW DATE: Review period January 1992-December 2001. Final analysis July 2004-January 2005. BACKGROUND AND REVIEW CONTEXT: There has been no rigorous systematic review of the outcomes of early exposure to clinical and community settings in medical education. OBJECTIVES OF REVIEW: Identify published empirical evidence of the effects of early experience in medical education, analyse it, and synthesize conclusions from it. Identify the strengths and limitations of the research effort to date, and identify objectives for future research. SEARCH STRATEGY: Ovid search of: BEI, ERIC, Medline, CINAHL and EMBASE Additional electronic searches of: Psychinfo, Timelit, EBM reviews, SIGLE, and the Cochrane databases. Hand-searches of:Medical Education, Medical Teacher, Academic Medicine, Teaching and Learning in Medicine, Advances in Health Sciences Education, Journal of Educational Psychology. EXPERIENCE: Authentic (real as opposed to simulated) human contact in a social or clinical context that enhances learning of health, illness and/or disease, and the role of the health professional. Early: What would traditionally have been regarded as the preclinical phase, usually the first 2 years. Inclusions: All empirical studies (verifiable, observational data) of early experience in the basic education of health professionals, whatever their design or methodology, including papers not in English. Evidence from other health care professions that could be applied to medicine was included. EXCLUSIONS: Not empirical; not early; post-basic; simulated rather than 'authentic' experience. DATA COLLECTION: Careful validation of selection processes. Coding by two reviewers onto an extensively modified version of the standard BEME coding sheet. Accumulation into an Access database. Secondary coding and synthesis of an interpretation. HEADLINE RESULTS: A total of 73 studies met the selection criteria and yielded 277 educational outcomes; 116 of those outcomes (from 38 studies) were rated strong and important enough to include in a narrative synthesis of results; 76% of those outcomes were from descriptive studies and 24% from comparative studies. Early experience motivated and satisfied students of the health professions and helped them acclimatize to clinical environments, develop professionally, interact with patients with more confidence and less stress, develop self-reflection and appraisal skill, and develop a professional identity. It strengthened their learning and made it more real and relevant to clinical practice. It helped students learn about the structure and function of the healthcare system, and about preventive care and the role of health professionals. It supported the learning of both biomedical and behavioural/social sciences and helped students acquire communication and basic clinical skills. There were outcomes for beneficiaries other than students, including teachers, patients, populations, organizations and specialties. Early experience increased recruitment to primary care/rural medical practice, though mainly in US studies which introduced it for that specific purpose as part of a complex intervention. CONCLUSIONS: Early experience helps medical students socialize to their chosen profession. It helps them acquire a range of subject matter and makes their learning more real and relevant. It has potential benefits for other stakeholders, notably teachers and patients. It can influence career choices.

Twin-block re-activation.

This paper briefly reviews reasons for re-activating Twin-blocks, discussing different approaches and describing a new, simple, cost effective approach, which can be undertaken at the chairside.

Retention procedures for stabilising tooth position after treatment with orthodontic braces.

BACKGROUND: Retention is the phase of orthodontic treatment that attempts to keep teeth in the corrected positions after treatment with orthodontic (dental) braces. Without a phase of retention there is a tendency for the teeth to return to their initial position (relapse). To prevent relapse almost every patient who has orthodontic treatment will require some type of retention. OBJECTIVES: To evaluate the effectiveness of different retention strategies used to stabilise tooth position after orthodontic braces. SEARCH STRATEGY: The Cochrane Oral Health Group's (OHG) Trials Register, CENTRAL, MEDLINE and EMBASE were searched. Handsearching of orthodontic journals was undertaken in keeping with the Cochrane OHG search programme. No language restrictions were applied. Authors of randomised controlled trials (RCTs) were identified and contacted to identify unpublished trials. Most recent search: May 2005. SELECTION CRITERIA: RCTs on children and adults, who have had retainers fitted or adjunctive procedures undertaken, following orthodontic treatment with braces to prevent relapse. The outcomes were: how well the teeth were stabilised, survival of retainers, adverse effects on oral health and quality of life. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two review authors. As no two studies compared the same retention strategies (interventions) it was not possible to combine the results of any studies. MAIN RESULTS: Five trials satisfied the inclusion criteria. These trials all compared different interventions: circumferential supracrestal fiberotomy (CSF) combined with full-time removable retainer versus a full-time removable retainer alone; CSF combined with a nights-only removable retainer versus a nights-only removable retainer alone; removable Hawley retainer versus a clear overlay retainer; multistrand wire retainer versus a ribbon-reinforced resin bonded retainer; and three types of fixed retainers versus a removable retainer. There was weak unreliable evidence, based on data from one trial, that there was a statistically significant increase in stability in both the mandibular (lower) (P < 0.001) and maxillary (upper) anterior segments (P < 0.001) when the CSF was used, compared with when it was not used. There was also weak, unreliable evidence that teeth settle quicker with a Hawley retainer than with a clear overlay retainer after 3 months. The quality of the trial reports was generally poor. AUTHORS' CONCLUSIONS: There are insufficient research data on which to base our clinical practice on retention at present. There is an urgent need for high quality randomised controlled trials in this crucial area of orthodontic practice.

Head injuries: a study evaluating the impact of the NICE head injury guidelines.

BACKGROUND: The NICE head injury guidelines recommend a different approach in the management of head injury patients. It suggests that CT head scan should replace skull x ray (SXR) and observation/admission as the first investigation. We wished to determine the impact of NICE on SXR, CT scan, and admission on all patients with head injury presenting to the ED setting and estimate the cost effectiveness of these guidelines, which has not been quantified to date. DESIGN: Study of head injury patients presenting to two EDs before and after implementation of NICE guidelines METHODS: The rate of SXR, CT scan, and admission were determined six months before and one month after NICE implementation in both centres. The before study also looked at predicted rates had NICE been applied. This enabled predicted and actual cost effectiveness to be determined. RESULT: 1130 patients with head injury were studied in four 1 month periods (two in each centre). At the teaching hospital, the CT head scan rate more than doubled (3% to 7%), the SXR declined (37% to 4%), while the admission rate more than halved (9% to 4%). This represented a saving of 3381 pounds sterling per 100 head injury PATIENTS: greater than predicted with no adverse events. At the District General Hospital, the CT head scan rate more than quadrupled (1.4% to 9%), the SXR dropped (19 to 0.57%), while the admission rate declined (7% to 5%). This represented a saving of 290 pounds sterling per 100 head injury patients: less than predicted. CONCLUSION: The implementation of the NICE guidelines led to a two to fivefold increase in the CT head scan rate depending on the cases and baseline departmental practice. However, the reduction in SXR and admission appears to more than offset these costs without compromising patient outcomes.

Adult-onset Still's disease with atypical cutaneous features.

INTRODUCTION: The diagnosis of adult-onset Still's disease (AOSD) can be very difficult. There are no specific tests and reliance is usually placed on a symptom complex and the well described typical rash seen in most patients. In recent years, however, other cutaneous manifestations of AOSD have been reported but these are not so well known. OBSERVATIONS: We report a patient with urticaria and fixed plaques and review the other 'atypical' cutaneous findings associated with AOSD. CONCLUSIONS: The diagnosis of AOSD can be made in the absence of the typical Still's rash but in the presence of other atypical cutaneous features.

Retention procedures for stabilising tooth position after treatment with orthodontic braces.

BACKGROUND: Retention is the phase of orthodontic treatment that attempts to keep teeth in the corrected positions after orthodontic (dental) braces. Without a phase of retention there is a tendency for the teeth to return to their initial position (relapse). To prevent relapse almost every patient who has orthodontic treatment will require some type of retention. OBJECTIVES: To evaluate the effectiveness of different retention strategies used to stabilise tooth position after orthodontic braces. SEARCH STRATEGY: The Cochrane Oral Health Group's Trials Register, CENTRAL, MEDLINE and EMBASE were searched. Several journals were handsearched. No language restrictions were applied. Authors of randomised controlled trials (RCTs) were identified and contacted to identify unpublished trials. Most recent search: December 2002. SELECTION CRITERIA: RCTs on children and adults, who have had retainers fitted or adjunctive procedures undertaken, following orthodontic treatment with braces to prevent relapse. The outcomes are: how well the teeth are stabilised, survival of retainers, adverse effects on oral health and quality of life. DATA COLLECTION AND ANALYSIS: Screening of eligible studies, assessment of the methodological quality of the trials and data extraction were conducted in duplicate and independently by two reviewers. As no two studies compared the same retention strategies (interventions) it was not possible to combine the results of any studies. MAIN RESULTS: Four trials satisfied the inclusion criteria. These trials all compared different interventions: circumferential supracrestal fiberotomy (CSF) combined with full-time removable retainer versus a full-time removable retainer alone; circumferential supracrestal fiberotomy (CSF) combined with a nights-only removable retainer versus a nights-only removable retainer alone; removable Hawley retainer versus a clear overlay retainer; and three types of fixed retainers versus a removable retainer. There was weak unreliable evidence, based on data from one trial, that there was a statistically significant increase in stability in both the mandibular (p < 0.001) and maxillary anterior segments (p < 0.001) when the CSF was used, compared with when it was not used. There was also weak, unreliable evidence that teeth settle quicker with a Hawley retainer than with a clear overlay retainer after 3 months. The quality of the trial reports was generally poor. REVIEWER'S CONCLUSIONS: There are insufficient research data on which to base our clinical practice on retention at present. There is an urgent need for high quality randomised controlled trials in this crucial area of orthodontic practice.

A randomized controlled trial to investigate brackets bonded with a hydrophilic primer.

OBJECTIVE: To compare the clinical failure rates of brackets bonded using a prototype hydrophilic primer, designed to be insensitive to moisture, with brackets bonded with a conventional primer. DESIGN: Single centre randomised controlled clinical study. Thirty-three patients were bonded using a split mouth technique: randomly allocating the hydrophilic primer to one side of the mouth and a conventional primer to the other. SETTING: Hospital orthodontic department, Bradford, UK. SUBJECTS: Orthodontic patients requiring fixed appliances. MAIN OUTCOME MEASURES: The site and time to bond failure was recorded for each bracket that failed over 6 months. RESULTS: Using survival analysis, there was an increased risk of bracket failure when bonded with the hydrophilic primer compared with the conventional primer (hazard ratio = 2.2, 95% confidence interval: 1.1 to 4.5, P = 0.01). CONCLUSIONS: This hydrophilic primer cannot be recommended for routine clinical use.

The role of removable appliances in contemporary orthodontics.

The contemporary uses of removable appliances are considerably more limited than in the past. This article discusses possible reasons for their declining use, including recognition of their limitations. It is possible to achieve adequate occlusal improvement with these appliances providing that suitable cases are chosen. Specific indications for their appropriate use on their own in the mixed dentition are presented. Removables can also be used as an adjunct to more complex treatments, to enhance the effect of fixed appliances, headgear or in preparation for functional appliances. Further research is required to confirm whether their use in conjunction with more complex treatments enhances the quality and efficiency of treatment or not.