Repair of oesophageal atresia by consultants and supervised trainees results in similar outcomes.

INTRODUCTION: Consultants and trainees require exposure to complex cases for maintaining and gaining operative experience. Oesophageal atresia (OA) repair is a neonatal surgical procedure with indicative numbers for completion of training. A conflict of interest may exist between adequate training, maintaining consultant experience and achieving good outcomes. We aimed to review outcomes of procedures performed primarily by trainees and those performed by consultants. METHODS: We carried out a retrospective case note review of all consecutive infants who underwent surgical repair of OA with distal tracheooesophageal fistula (TOF) between January 1994 and December 2014 at our institution. Only cases that underwent primary oesophageal anastomosis were included. Surgical outcomes were compared between cases that had a trainee and those that had a consultant listed as the primary operator. RESULTS: One hundred and twenty-two cases were included. A total of 52 procedures were performed by trainees, and 68 by consultants. Two cases were undeterminable and excluded. Infant demographics, clinical characteristics and duration of follow-up were similar between groups. All infants survived to discharge. Procedures performed by trainees and those performed by consultants as primary operators had a similar incidence of postoperative pneumothorax (trainees 4, consultants 3; p=0.46), anastomotic leak (trainees 5, consultants 3; p=0.29) and recurrent TOF (trainees 0, consultants 2; p=0.5). Overall 52% of cases had an anastomotic dilatation during follow-up, with no difference between the trainee and consultant groups (50% vs 53%; p=0.85). CONCLUSIONS: Surgical outcomes for repair of OA/TOF are not adversely affected by trainee operating. Trainees with appropriate skills should perform supervised OA/TOF repair. These data are important for understanding the interrelationship between provision of training and surgical outcomes.

Higher risk breast screening: cancer detection rates, recall rates, and attendance rates in Northern Ireland.

AIM: To evaluate the outcomes of higher risk screening in Northern Ireland (NI) and compare with the UK National Health Service Breast Screening Programme (NHSBSP). MATERIALS AND METHODS: Higher risk breast screening commenced in NI in April 2013. Data on the programme were audited retrospectively through the Higher Risk screening centre. As there are no national standards for attendance rates and cancer detection rates, screening data and standards from the NHSBSP were used as a baseline for comparison. RESULTS: Attendance rates for the higher risk screening population have increased each of the last 3 years up to 77.7%. Recall rates have improved year on year from initial 14.2%-8.6%. Cancer detection rates have varied each year with a range from 21.5 per 1,000 women screened to 30.9 per 1,000 women screened. CONCLUSION: The Higher Risk Breast Screening Programme in NI represents a success story in risk stratified screening. Performance outcomes are excellent. The data outcomes may be used to inform standards of acceptable practice in the wider NHSBSP.

Radon testing in rapid access lung clinics: an opportunity for secondary prevention.

BACKGROUND: Radon is a naturally occurring radioactive gas and a level 1 carcinogen. It acts synergistically with cigarette smoke to cause lung cancer. In Ireland, radon is estimated to be associated with 13 % of all lung cancers. Rapid access lung cancer clinics (RALC's) were established in the UK and Ireland to improve lung cancer management outcomes. There has been no attempt to date to provide advice on household radon exposure assessments in this setting. AIMS: We performed a prospective feasibility study of radon assessment in our RALC to test the hypothesis that patients would avail of this service and that it would provide an opportunity for secondary prevention in at risk persons. METHODS: We investigated household radon levels in consecutive patients who were newly referred with symptoms of lung cancer to the RALC in Galway University Hospital, Ireland over a 6-month period. RESULTS: Of 50 patients enrolled, 42 returned valid results. Overall 21 % of patients had radon levels recorded above the national reference level. Only 5 % of patients were aware of the association between radon gas and lung cancer. Smokers were significantly less likely to engage fully in radon testing. CONCLUSIONS: The development of RALC's offers a novel opportunity to integrate the concepts of radon exposure, cigarette smoking and the development of lung cancer, and to reinforce this message in the minds of at risk patients.

Women's and clinicians perspectives of presentation with reduced fetal movements: a qualitative study.

BACKGROUND: Worldwide maternal perception of fetal movements has been used for many years to evaluate fetal wellbeing. It is intuitively regarded as an expression of fetal well-being as pregnancies in which women consistently report regular fetal movements have very low morbidity and mortality. Conversely, maternal perception of reduced fetal movements is associated with adverse pregnancy outcomes. We sought to gain insight into pregnant women's and clinicians views and experiences of reduced movements. METHOD: We performed qualitative semi-structured interviews with pregnant women who experienced reduced fetal movements in their current pregnancy and health professionals who provide maternity care. Our aim was to develop a better understanding of events, facilitators and barriers to presentation with reduced fetal movements. Data analysis was conducted using framework analysis principles. RESULTS: Twenty-one women and 10 clinicians were interviewed. The themes that emerged following the final coding were influences of social network, facilitators and barriers to presentation and the desire for normality. CONCLUSIONS: This study aids understanding about why women present with reduced movements and how they reach the decision to attend hospital. This should inform professionals' views and practice, such that appreciating and addressing women's concerns may reduce anxiety and make presentation with further reduced movements more likely, which is desirable as this group is at increased risk of adverse outcome. To address problems with information about normal and abnormal fetal movements, high-quality information is needed that is accessible to women and their families.

Questioning assent: how are children's views included as families make decisions about clinical trials?

BACKGROUND: Assent is used to take children's wishes into account when they are invited into clinical trials, but the concept has attracted considerable criticism. We investigated children's accounts of decision-making with the aim of informing practice in supporting children when invited to join a clinical trial. METHODS: We audio-recorded qualitative, semi-structured interviews with 22 children aged 8-16 years about being invited to take part in a clinical trial. Most children were interviewed with their parents. Analysis of the transcribed interviews examined the content of participants' accounts thematically, whilst also drawing on principles of discourse analysis, which examines how individuals use talk to achieve certain effects or social practices. RESULTS: It was not possible to separate children's knowledge of the clinical trial, or their decision-making processes from that of their parents, with parents taking a substantial mediating role in producing their children's decisions. Decision-making gradually unfolded across time and events and was interwoven within the family context, rather than happening in one moment or in the clinical setting. Whilst children valued their parents' role, a case study of child-parent disagreement indicated how children can struggle to be heard. CONCLUSIONS: Decisions happen within a process of family dynamics, in contrast to ideas of assent that isolate it from this context. Parents have a substantial role in children's decisions, and thus how families come to provide consent. Reflecting this we argue that assent practices need to focus on supporting parents to support their children in learning and deliberating about trials. However, this needs to be accompanied by practitioners being alert to the possibility of divergence in child and parent views and enabling children's perspectives to be heard.

Pharmacogenetics of warfarin in a paediatric population: time in therapeutic range, initial and stable dosing and adverse effects.

Warfarin is used in paediatric populations, but dosing algorithms incorporating pharmacogenetic data have not been developed for children. Previous studies have produced estimates of the effect of polymorphisms in Cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) on stable warfarin dosing, but data on time in therapeutic range, initial dosing and adverse effects are limited. Participants (n=97) were recruited, and routine clinical data and salivary DNA samples were collected from all participants and analysed for CYP2C9*2, *3 and VKORC1-1639 polymorphisms.VKORC1 -1639 was associated with a greater proportion of the first 6 months' treatment time spent within the target International Normalised Ratio (INR) range, accounting for an additional 9.5% of the variance in the proportion of time. CYP2C9*2 was associated with a greater likelihood of INR values exceeding the target range during the initiation of treatment (odds ratio (OR; per additional copy) 4.18, 95% confidence interval (CI) 1.42, 12.34). CYP2C9*2 and VKORC1-1639 were associated with a lower dose requirement, and accounted for almost 12% of the variance in stable dose. VKORC1-1639 was associated with an increased likelihood of mild bleeding complications (OR (heterozygotes vs homozygotes) 4.53, 95% CI 1.59, 12.93). These data show novel associations between VKORC1-1639 and CYP2C9*2 and INR values in children taking warfarin, as well as replicating previous findings with regard to stable dose requirements. The development of pharmacogenomic dosing algorithms for children using warfarin has the potential to improve clinical care in this population.

Respiratory syncytial virus infection of airway epithelial cells, in vivo and in vitro, supports pulmonary antibody responses by inducing expression of the B cell differentiation factor BAFF.

BACKGROUND: The mechanisms regulating antibody expression within the human lung during airway infection are largely unknown. In this study, our objectives were to determine if infection with respiratory syncytial virus (RSV) upregulates expression of the B cell differentiation factors A proliferation inducing ligand (APRIL) and B cell activating factor of the TNF family (BAFF), if this is a common feature of viral airway infection, and how this is regulated in human airway epithelial cells. METHODS: We measured BAFF and APRIL protein expression in bronchoalveolar lavage (BAL) fluid from infants with severe RSV disease, and healthy control children, and in nasopharyngeal aspirates from preschool children with other single respiratory viral infections. We also measured mRNA expression in bronchial brushings from RSV-infected infants, and in RSV-infected paediatric primary airway epithelial cell cultures (pAEC). Beas-2B cell cultures were used to examine mechanisms regulating BAFF expression. RESULTS: BAFF protein and mRNA were elevated (in marked contrast with APRIL) in BAL and bronchial brushings, respectively, from RSV-infected infants. BAFF protein was also found in upper airway secretions from children with human metapneumovirus, H1N1, bocavirus, rhinovirus, RSV and Mycoplasma pneumoniae infection. BAFF mRNA and protein were expressed following in vitro RSV infection of both pAEC and Beas-2B cultures, with mRNA expression peaking 12-h postinfection. BAFF induction was blocked by addition of a neutralising anti-interferon-ß antibody or palivizumab. CONCLUSIONS: BAFF, produced through an interferon-ß-dependent process, is a consistent feature of airway infection, and suggests a role for the airway epithelia in supporting protective antibody and B cell responses in the lung.

Primary airway epithelial cultures from children are highly permissive to respiratory syncytial virus infection.

BACKGROUND: Respiratory syncytial virus (RSV) infection of airway epithelial cells (AECs) is an important initial event in RSV bronchiolitis. AEC immunological responses are thought to be critical in driving the subsequent inflammation in the airway. This study examined viral replication, cytotoxicity and cytokine production in cultures of primary AECs from children compared with responses to RSV infection in an immortalised epithelial cell line and to those from infants with RSV bronchiolitis. METHODS: RSV replication, proinflammatory cytokine responses and cytotoxicity in RSV-infected primary AEC cultures derived from bronchial brushings from the lungs of children were compared with those seen in BEAS-2B cultures, as well as AECs and bronchoalveolar lavage fluid collected from children with and without RSV bronchiolitis. RESULTS: Viral replication, cytotoxicity and inflammatory cytokine production were greater in primary AEC cultures than in BEAS-2B cells. Different response patterns were observed, with RSV infection of primary AEC cultures causing distinct peaks of viral replication and matched cytotoxic responses. Some primary AEC culture immunological responses, such as interleukin 8, were similar in magnitude to those seen in clinical samples from the lungs of children with RSV bronchiolitis. Although variable amounts of RSV were detected by PCR in freshly isolated primary AECs, RSV was not detected by immunocytochemistry. CONCLUSION: This is one of the first studies to examine comprehensively the responses to RSV infection in primary AEC cultures from children and shows marked differences from those of a commercially available immortalised human cell line but reassuring similarities to results found in vivo. This suggests that future work investigating responses of AECs to RSV infection should use primary AEC cultures.

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.

Adverse drug reactions causing admission to a paediatric hospital: a pilot study.

WHAT IS KNOWN AND OBJECTIVE: It is known that adverse drug reactions (ADRs) cause admission to hospital in adults and children. A recent adult study showed that ADRs are an important and frequent cause of hospital admission. The objective of this study is to develop methodology to ascertain the current burden of ADRs through a prospective analysis of all unplanned admissions to a paediatric hospital. METHODS: Prospective observational study over a 2-week period. RESULTS AND DISCUSSION: There were 19 admissions to the main hospital wards related to an ADR, giving an estimated incidence of 4%, with the ADR directly leading to the admission in 71% of cases. There were no deaths attributable to ADR. 33% of the reactions were possibly avoidable. The drugs most commonly implicated in causing admissions were anti-neoplastic agents. The most common reactions were neutropenia, vomiting and diarrhoea. The health burden of ADRs in the paediatric population is likely to be significant. This pilot study will be used to inform a much larger prospective study providing more detailed evidence of the burden of ill-health from ADRs in children. This larger study will add to a body of research aiming to identify drug-related problems within children to aid paediatric pharmacovigilance. WHAT IS NEW AND CONCLUSION: This study provides knowledge regarding the methodology to be used for a larger study investigating ADRs in children. The study will allow authors who wish to replicate the study in their own populations (internationally) to avoid some of the pitfalls in planning a large epidemiological study of paediatric ADRs. The study also provides an estimate of the incidence and problem of admissions caused by ADRs in a UK paediatric population.

Processes in recruitment to randomised controlled trials of medicines for children (RECRUIT): a qualitative study.

OBJECTIVES: To investigate recruitment processes across a range of clinical trials and from the perspective of parents, young people and practitioners to identify strategies to improve recruitment and its conduct across the spectrum of trials of medicines for children. DESIGN: Qualitative interview and observational study. SETTING: Eleven paediatric clinical trial centres recruiting to four trials. PARTICIPANTS: Members of 60 families approached to consider entry to one of the participating trials and 31 practitioners. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Data were verbatim transcripts of (1) audio-recorded trial recruitment discussions between practitioners and families (n = 41) and (2) semi-structured interviews with parents (n = 62), young people (n = 22) and practitioners (19 doctors and 12 research nurses). Analyses were interpretive, following the general principles of the constant comparative method. RESULTS: Practitioners were concerned to avoid overburdening parents and some indicated that they found approaching families about trials to be aversive. By contrast, even in the most difficult situations, parents did not mind being asked about trials and they did not describe the approach as burdensome. Some parents viewed the trial approach as a positive or exciting opportunity. Parents and young people took little active part in the trial discussions and asked few questions. Despite this, they were satisfied with how they had been approached, and spoke of how they had felt involved, valued, cared for and comfortable to interject during the discussion. However, we identified several parents who had important misunderstandings about the trial. There were few differences between parents who consented and those who declined a trial. Regardless of whether they consented or declined, parents' trial decisions were influenced by their perceptions of the trial in relation to their child's safety and well-being, potential benefits to the child and family, potential benefits to others and the practicality of participation. Of these, parents' paramount consideration was safety. Parents', young people's and practitioners' views of what was important when considering a trial were broadly convergent, although families gave greater importance than practitioners to the trial's practical requirements. All parties valued the face-to-face trial discussion highly and wanted shorter and less complex written information. Parents did not feel pressured by the trial team to participate, but some described how their personal values made them reluctant to decline, and several parents who did decline described a passing sense of discomfort. CONCLUSIONS: The concerns of some practitioners that families would be overburdened were unfounded, as parents did not object to being asked about research. Practitioners may benefit from support that helps them feel personally more at ease in approaching families about trials. Parents and young people often described the trial discussions in strongly positive terms and emphasised the importance of the social and emotional aspects of these encounters. Informed consent training could be enhanced if it similarly emphasised these aspects of recruitment; the misunderstandings we identified indicate how this training could also help practitioners to improve the clarity of their trial discussions with families. Guidelines on informed consent documents should take account of findings that all groups thought that these documents should be shorter and more straightforward. FUNDING: This research was commissioned by the National Institute for Health Research Health Technology Assessment programme.

Frequency and reasons for outcome reporting bias in clinical trials: interviews with trialists.

OBJECTIVES: To provide information on the frequency and reasons for outcome reporting bias in clinical trials. DESIGN: Trial protocols were compared with subsequent publication(s) to identify any discrepancies in the outcomes reported, and telephone interviews were conducted with the respective trialists to investigate more extensively the reporting of the research and the issue of unreported outcomes. PARTICIPANTS: Chief investigators, or lead or coauthors of trials, were identified from two sources: trials published since 2002 covered in Cochrane systematic reviews where at least one trial analysed was suspected of being at risk of outcome reporting bias (issue 4, 2006; issue 1, 2007, and issue 2, 2007 of the Cochrane library); and a random sample of trial reports indexed on PubMed between August 2007 and July 2008. SETTING: Australia, Canada, Germany, the Netherlands, New Zealand, the United Kingdom, and the United States. MAIN OUTCOME MEASURES: Frequency of incomplete outcome reporting-signified by outcomes that were specified in a trial's protocol but not fully reported in subsequent publications-and trialists' reasons for incomplete reporting of outcomes. RESULTS: 268 trials were identified for inclusion (183 from the cohort of Cochrane systematic reviews and 85 from PubMed). Initially, 161 respective investigators responded to our requests for interview, 130 (81%) of whom agreed to be interviewed. However, failure to achieve subsequent contact, obtain a copy of the study protocol, or both meant that final interviews were conducted with 59 (37%) of the 161 trialists. Sixteen trial investigators failed to report analysed outcomes at the time of the primary publication, 17 trialists collected outcome data that were subsequently not analysed, and five trialists did not measure a prespecified outcome over the course of the trial. In almost all trials in which prespecified outcomes had been analysed but not reported (15/16, 94%), this under-reporting resulted in bias. In nearly a quarter of trials in which prespecified outcomes had been measured but not analysed (4/17, 24%), the "direction" of the main findings influenced the investigators' decision not to analyse the remaining data collected. In 14 (67%) of the 21 randomly selected PubMed trials, there was at least one unreported efficacy or harm outcome. More than a quarter (6/21, 29%) of these trials were found to have displayed outcome reporting bias. CONCLUSION: The prevalence of incomplete outcome reporting is high. Trialists seemed generally unaware of the implications for the evidence base of not reporting all outcomes and protocol changes. A general lack of consensus regarding the choice of outcomes in particular clinical settings was evident and affects trial design, conduct, analysis, and reporting.

Reducing chimera formation during PCR amplification to ensure accurate genotyping.

Measurements of population diversity are fundamental to the reconstruction of the evolutionary and epidemiological history of organisms. Commonly used protocols to measure population diversity using the polymerase chain reaction (PCR) are prone to the introduction of artificial chimeras. These are often difficult to detect and can confound the correct interpretation of results due to the false generation of recombinants when the underlying DNA sample contains multiple distinct templates. This study presents a standardised procedure to suppress the formation of artificial chimeras during PCR amplification. The solution is based on the accurate determination of the efficiency and end point of the log-linear phase of a PCR. This procedure will facilitate the generation of data sets that more accurately reflect the underlying population diversity rather than artifacts introduced by the process itself.

Who is referred to neurology clinics?--the diagnoses made in 3781 new patients.

OBJECTIVE: Information on the nature and relative frequency of diagnoses made in referrals to neurology outpatient clinics is an important guide to priorities in services, teaching and research. Previous studies of this topic have been limited by being of only single centres or lacking in detail. We aimed to describe the neurological diagnoses made in a large series of referrals to neurology outpatient clinics. METHOD: Newly referred outpatients attending neurology clinics in all the NHS neurological centres in Scotland, UK were recruited over a period of 15 months. The assessing neurologists recorded the initial diagnosis they made. An additional rating of the degree to which the neurologist considered the patient's symptoms to be explained by disease was used to categorise those diagnoses that simply described a symptom such as 'fatigue'. RESULTS: Three thousand seven hundred and eighty-one patients participated (91% of those eligible). The commonest categories of diagnosis made were: headache (19%), functional and psychological symptoms (16%), epilepsy (14%), peripheral nerve disorders (11%), miscellaneous neurological disorders (10%), demyelination (7%), spinal disorders (6%), Parkinson's disease/movement disorders (6%), and syncope (4%). Detailed breakdowns of each category are provided. CONCLUSIONS: Headache, functional/psychological disorders and epilepsy are the most common diagnoses in new patient referral to neurological services. This information should be used to shape priorities for services, teaching and research.

Neurology out-patients with symptoms unexplained by disease: illness beliefs and financial benefits predict 1-year outcome.

BACKGROUND: Patients whose symptoms are 'unexplained by disease' often have a poor symptomatic outcome after specialist consultation, but we know little about which patient factors predict this. We therefore aimed to determine predictors of poor subjective outcome for new neurology out-patients with symptoms unexplained by disease 1 year after the initial consultation. METHOD: The Scottish Neurological Symptom Study was a 1-year prospective cohort study of patients referred to secondary care National Health Service neurology clinics in Scotland (UK). Patients were included if the neurologist rated their symptoms as 'not at all' or only 'somewhat explained' by organic disease. Patient-rated change in health was rated on a five-point Clinical Global Improvement (CGI) scale ('much better' to 'much worse') 1 year later. RESULTS: The 12-month outcome data were available on 716 of 1144 patients (63%). Poor outcome on the CGI ('unchanged', 'worse' or 'much worse') was reported by 482 (67%) out of 716 patients. The only strong independent baseline predictors were patients' beliefs [expectation of non-recovery (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.40-2.96), non-attribution of symptoms to psychological factors (OR 2.22, 95% CI 1.51-3.26)] and the receipt of illness-related financial benefits (OR 2.30, 95% CI 1.37-3.86). Together, these factors predicted 13% of the variance in outcome. CONCLUSIONS: Of the patients, two-thirds had a poor outcome at 1 year. Illness beliefs and financial benefits are more useful in predicting poor outcome than the number of symptoms, disability and distress.

Perspectives of normal child development in rural Malawi - a qualitative analysis to create a more culturally appropriate developmental assessment tool.

BACKGROUND: Child development in developing countries is often evaluated using assessment tools created for 'Western' settings. Recent work has demonstrated that, for certain developmental milestones, 'Western' tools may be inaccurate as they include items unfamiliar to children of different cultural settings. METHODS: We used qualitative methods to gather information about normal development in an African setting. Ten village and two professional focus group discussions (FGDs) were conducted. We used purposive sampling methods to recruit groups of mothers, grandmothers and men in four areas of Southern Malawi for village FGDs. Separate FGDs were carried out with professionals working in areas relating to child development. A thematic content analysis established main patterns and themes and dissemination of results and continued feedback allowed for respondent validation and reflection of results. The information then gathered was used to create questions for a revised Malawian developmental assessment tool. RESULTS: Social and gross motor milestones were the main focus of interest for village and professional FGDs with the latter creating new language and fine motor concepts. Social milestones highlighted included 'duties and chores', 'sharing' and 'taking up leadership roles'. Language milestones included 'reporting events' and 'shrugging to indicate no' and fine motor milestones included 'peeling bananas', 'sorting maize' and 'making patterns with bottle tops'. Intelligence was described in relation to social and community integrity rather than 'Western' concepts of numeracy and literacy. CONCLUSIONS: Concepts, ideas and language relating to normal development in a sub-Saharan African setting have been gathered in this study. These have been used to create items for a more culturally appropriate developmental assessment tool.

Symptoms 'unexplained by organic disease' in 1144 new neurology out-patients: how often does the diagnosis change at follow-up?

It has been previously reported that a substantial proportion of newly referred neurology out-patients have symptoms that are considered by the assessing neurologist as unexplained by 'organic disease'. There has however been much controversy about how often such patients subsequently develop a disease diagnosis that, with hindsight, would have explained the symptoms. We aimed to determine in a large sample of new neurology out-patients: (i) what proportion are assessed as having symptoms unexplained by disease and the diagnoses given to them; and (ii) how often a neurological disorder emerged which, with hindsight, explained the original symptoms. We carried out a prospective cohort study of patients referred from primary care to National Health Service neurology clinics in Scotland, UK. Measures were: (i) the proportion of patients with symptoms rated by the assessing neurologist as 'not at all' or only 'somewhat explained' by 'organic disease' and the neurological diagnoses recorded at initial assessment; and (ii) the frequency of unexpected new diagnoses made over the following 18 months (according to the primary-care physician). One thousand four hundred and forty-four patients (30% of all new patients) were rated as having symptoms 'not at all' or only 'somewhat explained' by 'organic disease'. The most common categories of diagnosis were: (i) organic neurological disease but with symptoms unexplained by it (26%); (ii) headache disorders (26%); and (iii) conversion symptoms (motor, sensory or non-epileptic attacks) (18%). At follow-up only 4 out of 1030 patients (0.4%) had acquired an organic disease diagnosis that was unexpected at initial assessment and plausibly the cause of the patients' original symptoms. Eight patients had died at follow-up; five of whom had initial diagnoses of non-epileptic attacks. Seven other types of diagnostic change with very different implications to a 'missed diagnosis' were found and a new classification of diagnostic revision is presented. One-third of new neurology out-patients are assessed as having symptoms 'unexplained by organic disease'. A new diagnosis, which with hindsight explained the original symptoms, rarely became apparent to the patient's primary care doctor in the 18 months following the initial hospital consultation.