Multi-centre cluster randomised trial comparing a community group exercise programme with home based exercise with usual care for people aged 65 and over in primary care: protocol of the ProAct 65+ trial

Background

Earlier diagnosis followed by multi-factorial cardiovascular risk intervention may improve outcomes in Type 2 Diabetes Mellitus (T2DM). Latent phase identification through screening requires structured, appropriately targeted population-based approaches. Providers responsible for implementing screening policy await evidence of clinical and cost effectiveness from randomised intervention trials in screen-detected T2DM cases. UK South Asians are at particularly high risk of abnormal glucose tolerance and T2DM. To be effective national screening programmes must achieve good coverage across the population by identifying barriers to the detection of disease and adapting to the delivery of earlier care. Here we describe the rationale and methods of a systematic community screening programme and randomised controlled trial of cardiovascular risk management within a UK multiethnic setting (ADDITION-Leicester).

Design

A single-blind cluster randomised, parallel group trial among people with screen-detected T2DM comparing a protocol driven intensive multi-factorial treatment with conventional care.

Methods

ADDITION-Leicester consists of community-based screening and intervention phases within 20 general practices coordinated from a single academic research centre. Screening adopts a universal diagnostic approach via repeated 75g-Oral Glucose Tolerance Tests within an eligible non-diabetic population of 66,320 individuals aged 40-75 years (25-75 years South Asian). Volunteers also provide detailed medical and family histories; complete health questionnaires, undergo anthropometric measures, lipid profiling and a proteinuria assessment. Primary outcome is reduction in modelled Coronary Heart Disease (UKPDS CHD) risk at five years. Seven thousand (30% of South Asian ethnic origin) volunteers over three years will be recruited to identify a screen-detected T2DM cohort (n = 285) powered to detected a 6% relative difference (80% power, alpha 0.05) between treatment groups at one year. Randomisation will occur at practice-level with newly diagnosed T2DM cases receiving either conventional (according to current national guidelines) or intensive (algorithmic target-driven multi-factorial cardiovascular risk intervention) treatments.

Discussion

ADDITION-Leicester is the largest multiethnic (targeting >30% South Asian recruitment) community T2DM and vascular risk screening programme in the UK. By assessing feasibility and efficacy of T2DM screening, it will inform national disease prevention policy and contribute significantly to our understanding of the health care needs of UK South Asians.

Trial registration

Clinicaltrial.gov (NCT00318032).     

The BSCC Code of Practice – exfoliative cytopathology (excluding gynaecological cytopathology)

Exfoliative cytopathology (often referred to as non‐gynaecological cytology) is an important part of the workload of all diagnostic pathology departments. It clearly has a role in the diagnosis of neoplastic disease but its role in establishing non‐neoplastic diagnoses should also be recognised. Ancillary tests may be required to establish a definitive diagnosis. Clinical and scientific teamwork is essential to establish an effective cytology service and staffing levels should be sufficient to support preparation, prescreening, on‐site adequacy assessment and reporting of samples as appropriate. Routine clinical audit and histology/cytology correlation should be in place as quality control of a cytology service. Cytology staff should be involved in multidisciplinary meetings and appropriate professional networks. Laboratories should have an effective quality management system conforming to the requirements of a recognised accreditation scheme such as Clinical Pathology Accreditation (UK) Ltd. Consultant pathologists should sign out the majority of exfoliative cytology cases. Where specimens are reported by experienced biomedical scientists (BMS), referred to as cytotechnologists outside the UK, this must only be when adequate training has been given and be defined in agreed written local protocols. An educational basis for formalising the role of the BMS in exfoliative cytopathology is provided by the Diploma of Expert Practice in Non‐gynaecological Cytology offered by the Institute of Biomedical Science (IBMS). The reliability of cytological diagnoses is dependent on the quality of the specimen provided and the quality of the preparations produced. The laboratory should provide feedback and written guidance on specimen procurement. Specimen processing should be by appropriately trained, competent staff with appropriate quality control. Microscopic examination of preparations by BMS should be encouraged wherever possible. Specific guidance is provided on the clinical role, specimen procurement, preparation and suitable staining techniques for urine, sputum, semen, serous cavity effusion, cerebrospinal fluid, synovial fluid, cyst aspirates, endoscopic specimens, and skin and mucosal scrapes.     

A roundtable on responsible innovation with autologous stem cells in Australia,Japan and Singapore

We report on a roundtable event hosted in Singapore that sought to identify some of the ethical and regulatory challenges in translating autologous cell-based interventions, particularly those claiming to involve stem cells, into safe and effective therapies and to propose some solutions to encourage responsible innovation with these products. Challenges are identified in the three areas of cell manufacturing and processing, innovative uses of autologous cells in clinical practice and standards of evidence. Proposed solutions are discussed within a co-operative model of statutory laws and regulations that can enable product development with autologous cells and professional codes and standards that can encourage ethical conduct in clinical practice. Future research should be directed toward establishing regional networks for the development of internationally consistent standards in manufacturing and ethical codes of conduct for innovating with stem cells, and other autologous cells, and fostering ongoing exchange between jurisdictions.     

Addressing long-term physical healthcare needs in a forensic mental health inpatient population using the UK primary care Quality and Outcomes Framework (QOF): an audit

Objectives This audit aims to evaluate the effectiveness of delivering an equivalent primary care service to a long-term forensic psychiatric inpatient population, using the UK primary care national Quality and Outcomes Framework (QOF).Method The audit compares the targets met by the general practitioner with special interest (GPwSI) service, using local and national QOF benchmarks (2005-2006), and determines the prevalence of chronic disease in a long-term inpatient forensic psychiatry population.Results The audit results show that the UK national QOF is a useful tool for assessment and evaluation of physical healthcare needs in a non-community based population. It shows an increased prevalence of all QOF-assessed long-term physical conditions when compared to the local East London population and national UK population, confirming previously reported elevated levels of physical healthcare need in psychiatric populations.Conclusions This audit shows that the UK General Practice QOF can be used as a standardised instrument for commissioning and monitoring the delivery of physical health services to in-patient psychiatric populations, and for the evaluation of the effectiveness of clinical interventions in long-term physical conditions. The audit also demonstrates the effectiveness of using a GPwSI in healthcare delivery in non-community based settings. We suggest that the findings may be generalisable to other long-term inpatient psychiatric and prison populations in order to further the objective of delivering an equivalent primary care service to all populations.The QOF is a set of national primary care audit standards and is freely available on the British Medical Association website or the UK Department of Health website. We suggest that primary care workers in health economies who have not yet developed their own national primary care standards can access and adapt these standards in order to improve the clinical standards of care given to the primary care populations that they serve.     

Laboratory Diagnosis and Characterization of Fungal Disease in Patients with Cystic Fibrosis (CF): A Survey of Current UK Practice in a Cohort of Clinical Microbiology Laboratories

There is much uncertainty as to how fungal disease is diagnosed and characterized in patients with cystic fibrosis (CF). A 19-question anonymous electronic questionnaire was developed and distributed to ascertain current practice in clinical microbiology laboratories providing a fungal laboratory service to CF centres in the UK. Analyses of responses identified the following: (1) current UK laboratory practice, in general, follows the current guidelines, but the scope and diversity of what is currently being delivered by laboratories far exceeds what is detailed in the guidelines; (2) there is a lack of standardization of fungal tests amongst laboratories, outside of the current guidelines; (3) both the UK CF Trust Laboratory Standards for Processing Microbiological Samples from People with Cystic Fibrosis and the US Cumulative Techniques and Procedures in Clinical Microbiology (Cumitech) Guidelines 43 Cystic Fibrosis Microbiology need to be updated to reflect both new methodological innovations, as well as better knowledge of fungal disease pathophysiology in CF; (4) there is a need for clinical medicine to decide upon a stratification strategy for the provision of new fungal assays that will add value to the physician in the optimal management of CF patients; (5) there is also a need to rationale what assays should be performed at local laboratory level and those which are best served at National Mycology Reference Laboratory level; and (6) further research is required in developing laboratory assays, which will help ascertain the clinical importance of ‘old’ fungal pathogens, as well as ‘emerging’ fungal pathogens.     

Patient-Reported Outcome (PRO) Assessment in Clinical Trials: A Systematic Review of Guidance for Trial Protocol Writers

Background

Evidence suggests there are inconsistencies in patient-reported outcome (PRO) assessment and reporting in clinical trials, which may limit the use of these data to inform patient care. For trials with a PRO endpoint, routine inclusion of key PRO information in the protocol may help improve trial conduct and the reporting and appraisal of PRO results; however, it is currently unclear exactly what PRO-specific information should be included. The aim of this review was to summarize the current PRO-specific guidance for clinical trial protocol developers.

Methods and Findings

We searched the MEDLINE, EMBASE, CINHAL and Cochrane Library databases (inception to February 2013) for PRO-specific guidance regarding trial protocol development. Further guidance documents were identified via Google, Google scholar, requests to members of the UK Clinical Research Collaboration registered clinical trials units and international experts. Two independent investigators undertook title/abstract screening, full text review and data extraction, with a third involved in the event of disagreement. 21,175 citations were screened and 54 met the inclusion criteria. Guidance documents were difficult to access: electronic database searches identified just 8 documents, with the remaining 46 sourced elsewhere (5 from citation tracking, 27 from hand searching, 7 from the grey literature review and 7 from experts). 162 unique PRO-specific protocol recommendations were extracted from included documents. A further 10 PRO recommendations were identified relating to supporting trial documentation. Only 5/162 (3%) recommendations appeared in ≥50% of guidance documents reviewed, indicating a lack of consistency.

Conclusions

PRO-specific protocol guidelines were difficult to access, lacked consistency and may be challenging to implement in practice. There is a need to develop easily accessible consensus-driven PRO protocol guidance. Guidance should be aimed at ensuring key PRO information is routinely included in appropriate trial protocols, in order to facilitate rigorous collection/reporting of PRO data, to effectively inform patient care.     

Strategies for control of eyespot (Pseudocercosporella herpotrichoides) in UK winter wheat and winter barley

This review considers strategies for control of eyespot (Pseudocercosporella herpotrichoides) in winter wheat and winter barley in the UK. Varietal resistance to eyespot may take the form of direct resistance to the growth of the pathogen in the stem base or of indirect tolerance to eyespot through resistance to lodging. The French variety Cappelle-Desprez has been a source of resistance for most UK wheat varieties and a new source of resistance in wild goat grass has been discovered recently. Use of fungicides for control of eyespot increased rapidly after the introduction of the highly effective MBC fungicides in the 1970s, but has decreased recently because UK populations of P. herpotrichoides are now predominantly resistant to MBC fungicides and alternative fungicides are more expensive. Historically, cultural methods, especially crop rotation, have been important in the control of eyespot. The importance of cultural control of eyespot is now increasing because more non-cereal break crops are being grown and fungicide use is declining.     

Planned care for patients with bronchiectasis

Bronchiectasis, for which once only the most elementary palliation could be offered, now often can be cured by operation or well controlled by conservative therapy. Since true bronchiectasis implies irreversible anatomic changes, operation offers the only hope of cure, and it should be undertaken whenever it is not contraindicated by extent of involvement, age of the patient or other factors. Surgical results are excellent and mortality is at a minimum. When operation is prohibited, good results can still be anticipated by conservative measures. Such conservative therapy should combine prolonged use of antimicrobial drugs with adequate drainage of the diseased segments and general supportive measures. Any residual infection can be controlled by moderate use of appropriate antimicrobial agents. It is emphasized, however, that the control of bronchiectasis requires very careful diagnostic studies and a detailed analysis of the patient's condition, and that the therapy itself must be carefully adjusted in terms of the individual situation.     

Isolation and culture of Sphaerothecum destruens from Sunbleak (Leucaspius delineatus) in the UK and pathogenicity experiments in Atlantic salmon (Salmo salar)

The sunbleak (Leucaspius delineatus), a cyprinid fish native to continental Europe and now established in the UK, is experiencing population decline which appears to be linked to the spread of the invasive Asian cyprinid (Pseudorasbora parva). A population of sunbleak in the UK has previously been identified as infected with S. destruens at low prevalence. Because Sphaerothaecum destruens has, on occasion, caused severe disease in cultured and wild salmonids the aim of this work was to establish laboratory cultures of S. destruens from sunbleak in the UK and use these cultures in challenge experiments to determine if the UK isolate of S. destruens from cyprinid species is a potential threat to Atlantic salmon (Salmo salar). The first isolation and culture of S. destruens in the UK and from a cyprinid species is described. Cultured S. destruens spores from sunbleak are infective to EPC, CHSE and FHM cells, replicating most rapidly in FHM and EPC cells. Spores can be induced to zoosporulate in water forming motile, uni-flagellated zoospores. Challenge experiments indicated the spores are able to replicate and disperse in Atlantic salmon and are associated with increased mortality (up to 90%) when injected intraperitonealy.     

Resection guided by antibodies (REGAJ) a reappraisal after 10 years

Between 1986 and 1990 50 patients with ovarian cancer were submitted to a procedure which we called REGAJ-resection guided by antibodies. Using the radiolabelled murine monoclonal antibody OC 125, microscopic ovarian tumors producing CA 125 were detected during second-look surgery by a hand-held probe. Retrospective analysis after 10 years revealed that this procedure resulted in the cure of 4 of 11 patients, who would otherwise have been considered tumor free during second-look surgery and not further treated. Previous problems associated with the method can now be solved so that the clinical value of the procedure should be reconsidered.     

A pragmatic cluster randomised controlled trial to evaluate the safety, clinical effectiveness, cost effectiveness and satisfaction with point of care testing in a general practice setting – rationale, design and baseline characteristics

The UK has a strong tradition of innovative evaluative health care research. There are, however, considerable forces impeding collaboration between clinicians, academics, patients and their advocates and industry. This paper argues that, if the UK is to regain a position at the forefront of clinical research into evaluation of care, some of these forces need to be overcome. Now, with explicit encouragement from funders within the UK's NHS, it is urgent that all parties discover better ways of working together so that more broad and meaningful research can be produced in a timely fashion.     

Multi-centre randomised controlled trial of a smart phone-based event recorder alongside standard care versus standard care for patients presenting to the Emergency Department with palpitations and pre-syncope - the IPED (Investigation of Palpitations in the ED) study: study protocol for a randomised controlled trial

Background

Palpitations and pre-syncope are together responsible for 300,000 annual Emergency Department (ED) attendances in the United Kingdom (UK). Diagnosis of the underlying rhythm is difficult as many patients are fully recovered on ED arrival; and examination and presenting electrocardiogram (ECG) are commonly normal. The only way to establish the underlying heart rhythm is to capture an ECG during symptoms. Recent technology advances have led to several novel ECG monitoring devices appearing on the market. This trial aims to compare the symptomatic rhythm detection rate at 90?days of one such smart phone-based event recorder (AliveCor Heart Monitor and AliveECG) with standard care for participants presenting to the ED with palpitations and pre-syncope and no obvious cause in the ED.

Methods/Design

This is a multi-centre hospital ED / Acute Medical Unit (AMU) open label, randomised controlled trial. Participants will be recruited in 10 tertiary and district general hospitals in the UK. Participants aged ≥?16?years presenting with an episode of palpitations or pre-syncope with no obvious cause and whose underlying ECG rhythm during these episodes remains undiagnosed after clinical assessment will be included. Participants will be randomised to either: (1) the intervention arm, standard care plus the use of a smart phone-based event recorder; or (2) the control arm, standard care. Primary endpoint will be symptomatic rhythm detection rate at 90?days. A number of secondary clinical, process and cost-effectiveness endpoints will be collected and analysed. Analysis will be on an intention-to-treat basis.

Discussion

The Investigation of Palpitations in the ED (IPED) study aims to recruit 242 participants across 10 hospital sites. It will be the first study to investigate the ability of a smart phone-based event recorder to detect symptomatic cardiac rhythms compared to standard care for ED patients with palpitations and pre-syncope with no obvious cause in the ED. This smart phone event recorder will allow ED patients who have presented with palpitations or pre-syncope to record their ECG tracing if they have a further episode and may increase the rate of underlying rhythm diagnosis.

Trial registration

ClinicalTrials.gov, NCT02783898. Registered on 26 May 2016.

     

Electronic Laboratory Medicine ordering with evidence-based Order sets in primary care (ELMO study): protocol for a cluster randomised trial

Background

Laboratory testing is an important clinical act with a valuable role in screening, diagnosis, management and monitoring of diseases or therapies. However, inappropriate laboratory test ordering is frequent, burdening health care spending and negatively influencing quality of care. Inappropriate tests may also result in false-positive results and potentially cause excessive downstream activities. Clinical decision support systems (CDSSs) have shown promising results to influence the test-ordering behaviour of physicians and to improve appropriateness. Order sets, a form of CDSS where a limited set of evidence-based tests are proposed for a series of indications, integrated in a computerised physician order entry (CPOE) have been shown to be effective in reducing the volume of ordered laboratory tests but convincing evidence that they influence appropriateness is lacking. The aim of this study is to evaluate the effect of order sets on the quality and quantity of laboratory test orders by physicians. We also aim to evaluate the effect of order sets on diagnostic error and explore the effect on downstream or cascade activities.

Methods

We will conduct a cluster randomised controlled trial in Belgian primary care practices. The study is powered to measure two outcomes. We will primarily measure the influence of our CDSS on the appropriateness of laboratory test ordering. Additionally, we will also measure the influence on diagnostic error. We will also explore the effects of our intervention on cascade activities due to altered results of inappropriate tests.

Discussion

We have designed a study that should be able to demonstrate whether the CDSS aimed at diagnostic testing is not only able to influence appropriateness but also safe with respect to diagnostic error. These findings will influence a lager, nationwide implementation of this CDSS.

Trial registration

ClinicalTrials.gov, NCT02950142.

     

Review human papillomaviruses (HPV) in gynaecological cytology: from molecular biology to clinical testing

Molecular epidemiological and pathological studies show that different HPV types are associated with different cervical lesions allowing classification of the viruses into types associated with 'high', 'intermediate' and 'low' risk of cervical neoplasia. However, HPV infection often regresses and, where it is associated with neoplasia, is an early event. This suggests that other factors are involved in the carcinogenic process, and there is some mechanistic basis for the interaction of epidemiologically defined factors with HPV infection in the process of cervical carcinogenesis. With the refinement of techniques for HPV detection in clinical material, HPV testing is now a realistic possibility, but how this should be performed and in what clinical situation(s) is still uncertain. Particular areas of interest are: (i) the assessment of patients with borderline cytological changes or mild dyskaryosis; and (ii) the definition of those patients at greater risk of invasi ve disease. Clinical trials are needed before the utility of HPV testing can be properly assessed.     

Improving the care of people with traumatic brain injury through the Neurotrauma Evidence Translation (NET) program: protocol for a program of research

ABSTRACT: The Neurotrauma Evidence Translation (NET) program was funded in 2009 to increase the uptake of research evidence in the clinical care of patients who have sustained traumatic brain injury. This paper reports the rationale and plan for this five-year knowledge translation research program. The overarching aims of the program are threefold: to improve outcomes for people with traumatic brain injury; to create a network of neurotrauma clinicians and researchers with expertise in knowledge translation and evidence-based practice; and to contribute knowledge to the field of knowledge translation research. The program comprises a series of interlinked projects spanning varying clinical environments and disciplines relevant to neurotrauma, anchored within four themes representing core knowledge translation activities: reviewing research evidence; understanding practice; developing and testing interventions for practice change; and building capacity for knowledge translation in neurotrauma. The program uses a range of different methods and study designs, including: an evidence fellowship program; conduct of and training in systematic reviews; mixed method study designs to describe and understand factors that influence current practices (e.g., semistructured interviews and surveys); theory-based methods to develop targeted interventions aiming to change practice; a cluster randomised trial to test the effectiveness of a targeted theory-informed intervention; stakeholder involvement activities; and knowledge translation events such as consensus conferences.     

Using genetics to inform re-introduction strategies for the Chequered Skipper butterfly (Carterocephalus palaemon, Pallas) in England

The Chequered Skipper butterfly (Carterocephalus palaemon) is extinct in England but extant in Scotland and Continental Europe. The possibility of re-introducing the species is under active consideration by conservation bodies, but ecological differences between Scottish and English populations raise the question of which populations should donate individuals, Continental European, or Scottish? We used mitochondrial DNA sequences (CO I, CO II and Cyt b) from potential donor populations to test the hypothesis that ecological differences could have arisen as a result of differing routes of post-glacial colonisation from separate refugia and subsequent isolation of UK populations. Shared haplotypes between populations in Belgium, Norway, Scotland and England provides no evidence to support the hypothesis that populations in Scotland result from an alternative post-glacial colonisation route. As the genetic evidence remains equivocal we suggest that choice of donor stock for a re-introduction to England should be made primarily on ecological grounds.     

Mapping out structural features in clinical care calling for ethical sensitivity: a theoretical approach to promote ethical competence in healthcare personnel and clinical ethical support services (CESS)

Clinical ethical support services (CESS) represent a multifaceted field of aims, consultancy models, and methodologies. Nevertheless, the overall aim of CESS can be summed up as contributing to healthcare of high ethical standards by improving ethically competent decision-making in clinical healthcare. In order to support clinical care adequately, CESS must pay systematic attention to all real-life ethical issues, including those which do not fall within the 'favourite' ethical issues of the day. In this paper we attempt to capture a comprehensive overview of categories of ethical tensions in clinical care. We present an analytical exposition of ethical structural features in judgement-based clinical care predicated on the assumption of the moral equality of human beings and the assessment of where healthcare contexts pose a challenge to achieving moral equality. The account and the emerging overview is worked out so that it can be easily contextualized with regards to national healthcare systems and specific branches of healthcare, as well as local healthcare institutions. By considering how the account and the overview can be applied to i) improve the ethical competence of healthcare personnel and consultants by broadening their sensitivity to ethical tensions, ii) identify neglected areas for ethical research, and iii) clarify the ethical responsibility of healthcare institutions' leadership, as well as specifying required institutionalized administration, we conclude that the proposed account should be considered useful for CESS.     

Comparative studies on populations of Pauesia juniperorum (Hymenoptera: Braconidae), a biological control agent for Cinara cupressivora (Hemiptera: Aphididae)

Pauesia juniperorum (Stary), a solitary endoparasitoid which attacks several Cinara spp. in the subgenus Cupressobium, was introduced into Africa for the control of the cypress aphid Cinara cupressivora Watson & Voegtlin (previously identified as Cinara cupressi (Buckton)) and is now established. Data on its biology including a comparison of populations from different hosts and geographical locations are presented. From the UK this consisted of populations reared from Cinara cupressivora, Cinara fresai Blanchard and Cinara juniperi De Geer, and from France, Cinara ?fresai. Between different populations, the duration of development varied within a narrow range (15.5-18.1 days) at 22 degrees C. Data on duration of development over a range of temperatures (15-26 degrees C) for two populations, from the UK and France ranged between 14.0-31.4 days for males and 14.7-32.8 days for females. The threshold temperature for development was 6.2 degrees C and 4.1 degrees C for the populations from the UK and France, respectively. The mean egg load for different populations ranged between 46.4 and 78.5 eggs. The host species had a significant effect on egg load which was directly related to size of the respective host aphids. The lowest egg load was recorded on specimens reared from C. cupressivora which was the smallest aphid. The population from the UK had a higher intrinsic rate of increase (0.232) than the one from France (0.207).