Genome-wide association study of behavioural and psychiatric features in human prion disease.

Prion diseases are rare neurodegenerative conditions causing highly variable clinical syndromes, which often include prominent neuropsychiatric symptoms. We have recently carried out a clinical study of behavioural and psychiatric symptoms in a large prospective cohort of patients with prion disease in the United Kingdom, allowing us to operationalise specific behavioural/psychiatric phenotypes as traits in human prion disease. Here, we report exploratory genome-wide association analysis on 170 of these patients and 5200 UK controls, looking for single-nucleotide polymorphisms (SNPs) associated with three behavioural/psychiatric phenotypes in the context of prion disease. We also specifically examined a selection of candidate SNPs that have shown genome-wide association with psychiatric conditions in previously published studies, and the codon 129 polymorphism of the prion protein gene, which is known to modify various aspects of the phenotype of prion disease. No SNPs reached genome-wide significance, and there was no evidence of altered burden of known psychiatric risk alleles in relevant prion cases. SNPs showing suggestive evidence of association (P<10(-5)) included several lying near genes previously implicated in association studies of other psychiatric and neurodegenerative diseases. These include ANK3, SORL1 and a region of chromosome 6p containing several genes implicated in schizophrenia and bipolar disorder. We would encourage others to acquire phenotype data in independent cohorts of patients with prion disease as well as other neurodegenerative and neuropsychiatric conditions, to allow meta-analysis that may shed clearer light on the biological basis of these complex disease manifestations, and the diseases themselves.

PRION-1 scales analysis supports use of functional outcome measures in prion disease.

OBJECTIVES: Human prion diseases are heterogeneous but invariably fatal neurodegenerative disorders with no known effective therapy. PRION-1, the largest clinical trial in prion disease to date, showed no effect of the potential therapeutic quinacrine on survival. Although there are several limitations to the usefulness of survival as an outcome measure, there have been no comprehensive studies of alternatives. METHODS: To address this we did comparative analyses of neurocognitive, psychiatric, global, clinician-rated, and functional scales, focusing on validity, variability, and impact on statistical power over 77 person-years follow-up in 101 symptomatic patients in PRION-1. RESULTS: Quinacrine had no demonstrable benefit on any of the 8 scales (p > 0.4). All scales had substantial numbers of patients with the worst possible score at enrollment (Glasgow Coma Scale score being least affected) and were impacted by missing data due to disease progression. These effects were more significant for cognitive/psychiatric scales than global, clinician-rated, or functional scales. The Barthel and Clinical Dementia Rating scales were the most valid and powerful in simulated clinical trials of an effective therapeutic. A combination of selected subcomponents from these 2 scales gave somewhat increased power, compared to use of survival, to detect clinically relevant effects in future clinical trials of feasible size. CONCLUSIONS: Our findings have implications for the choice of primary outcome measure in prion disease clinical trials. Prion disease presents the unusual opportunity to follow patients with a neurodegenerative disease through their entire clinical course, and this provides insights relevant to designing outcome measures in related conditions.

General medical follow-up clinics - does the traditional model need to be updated for new traditional model need to be updated for new acute physicians?

The follow up arrangements were reviewed for 212 patients discharged from our Medical Admissions Unit (MAU) prior to the appointment of an acute medical consultant. 19 patients (9%) were referred to speciality clinics, with only 1 patient being followed-up in a 'general' medical clinic; the patient's GP was requested to follow up the majority of the outstanding results. Based on these results there appears little need or acute medical consultants to undertake 'traditional' outpatient follow-up clinics. Acute medical clinics may have other roles in enabling admission avoidance and reducing length of hospital stay.

Infantile scoliosis in Beals syndrome: the use of a non-fusion technique for surgical correction.

Beals syndrome (congenital contractural arachnodactyl) is a genetic disorder of the connective tissue phenotypically related to Marfan syndrome. It is characterised by dolichostenomelia, arachnodactyly, multiple joint contractures, crumpled ears, hypoplastic muscles and scoliosis. The latter, the most important clinical feature of this rare condition, presents in the infantile and juvenile age group and has a tendency to rapid progression. Bracing often fails to control the scoliosis and surgery is the recommended treatment. We present our experience of two cases managed with the paediatric Isola instrumentation and a non-fusion technique.

How should we measure informed choice? The case of cancer screening.

Informed choice is increasingly recognised as important in supporting patient autonomy and ensuring that people are neither deceived nor coerced. In cancer screening the emphasis has shifted away from just promoting the benefits of screening to providing comprehensive information to enable people to make an informed choice. Cancer screening programmes in the UK now have policies in place which state that it is their responsibility to ensure that individuals are making an individual informed choice. There is a need to evaluate whether such policies mean that those people invited for screening are making informed choices, and how comprehensive information affects other variables such as uptake, cost effectiveness, and satisfaction. At the present time, there is no validated measure of informed choice in cancer screening. Such a measure could be used to evaluate the effectiveness of interventions to increase informed choice and levels of informed choice in a population invited for screening. It could encourage health professionals to be accountable. Factors important when measuring informed choice in cancer screening include an individual's understanding of the limitations of screening, the ability to make an autonomous choice, and the difference between choice and behaviour.

Do post-take ward round proformas improve communication and influence quality of patient care?

The post-take ward round is a critical time for reviewing the initial history, examination and results, and the stage at which further treatment and investigations will be determined. However documentation of this ward round is often inadequate, so the benefits of decision making are lost. The documentation of 95 ward rounds was assessed for key items of information before and after the introduction of a proforma sheet. The introduction of the proforma led to a significant improvement in the documentation of a diagnosis, management plan, prophylaxis for deep vein thrombosis, and resuscitation status (p<0.05), which will have a significant impact on patient care.

Emissions of N2O and CH4 during the composting of liquid swine manure.

Composted organic wastes have been shown to reduce emissions of N2O and CH4, but little is known about the release of these gases during the composting process. This research examined the emissions of N2O and CH4 during the composting of liquid swine manure and wheat straw at two operations, one with forced aeration and the other without. The lack of aeration increased CH4 emissions to 24 times that of composting with aeration, but had no significant effect on N2O production. When total N2O and CH4 emissions from composting were compared with liquid swine manure emissions, aerated composting was found to reduce emissions to as low as 30% of those from liquid manure storage, while non-aerated composting elevated emissions up to an estimated 330% of liquid manure storage.

Estimating implied rates of discount in healthcare decision-making.

OBJECTIVES: To consider whether implied rates of discounting from the perspectives of individual and society differ, and whether implied rates of discounting in health differ from those implied in choices involving finance or "goods". DESIGN: The study comprised first a review of economics, health economics and social science literature and then an empirical estimate of implied rates of discounting in four fields: personal financial, personal health, public financial and public health, in representative samples of the public and of healthcare professionals. SETTING AND PARTICIPANTS: Samples were drawn in the former county and health authority district of South Glamorgan, Wales. The public sample was a representative random sample of men and women, aged over 18 years and drawn from electoral registers. The health professional sample was drawn at random with the cooperation of professional leads to include doctors, nurses, professions allied to medicine, public health, planners and administrators. RESULTS: The literature review revealed few empirical studies in representative samples of the population, few direct comparisons of public with private decision-making and few direct comparisons of health with financial discounting. Implied rates of discounting varied widely and studies suggested that discount rates are higher the smaller the value of the outcome and the shorter the period considered. The relationship between implied discount rates and personal attributes was mixed, possibly reflecting the limited nature of the samples. Although there were few direct comparisons, some studies found that individuals apply different rates of discount to social compared with private comparisons and health compared with financial. The present study also found a wide range of implied discount rates, with little systematic effect of age, gender, educational level or long-term illness. There was evidence, in both samples, that people chose a lower rate of discount in comparisons made on behalf of society than in comparisons made for themselves. Both public and health professional samples tended to choose lower discount rates in health-related comparisons than in finance-related comparisons. It was also suggested that implied rates of discount, derived from responses to hypothetical questions, can be influenced by detail of question framing. CONCLUSIONS: The study suggested that both the lay public and healthcare professionals consider that the discount rate appropriate for public decisions is lower than that for private decisions. This finding suggests that lay people as well as healthcare professionals, used to making decisions on behalf of others, recognise that society is not simply an aggregate of individuals. It also implies a general appreciation that society is more stable and has a more predictable future than does the individual. There is fairly general support for this view in the theoretical literature and limited support in the few previous direct comparisons. Further research is indicated, possibly involving more in-depth interviewing and drawing inference on real, rather than hypothetical choices.

Regional differences in incidence of gastric and colonic cancer in the Maori of New Zealand.

BACKGROUND: It is known that there are ethnic differences in cancer in New Zealand between Maori (the indigenous people) and non-Maori, however, until now no regional comparisons have been made. STUDY DESIGN: A retrospective study of patients diagnosed at Whangarei Hospital, New Zealand between 1995 and 1997 with gastric or colonic cancer was combined with population data from the 1996 census for Whangarei District to calculate incidence figures. The incidence of cancer was compared to national rates. RESULTS: Between 1995 and 1997, 19 Maori and 24 non-Maori were diagnosed with gastric cancer, and 10 Maori and 125 non-Maori with colonic cancer. The age standardised rates (per 100,000) for Maori and non-Maori with gastric caner were 68.3 and 7.9 respectively. Gastric cancer is known to be increased in the Maori, but in Whangarei was significantly higher than the national Maori rates (20.5). There was no difference in the rate of colonic cancer in the Maori and non-Maori in Whangarei, again this differs from the national trends, in which the Maori are protected against cancer. CONCLUSION: This study highlights that there is still much more to be learnt in understanding the aetiology of gastrointestinal cancers, to explain such strong regional differences.

A simplified Galveston technique for the stabilisation of pathological fractures of the sacrum.

Mechanical stabilisation of pathological fractures of the sacrum is technically challenging. There is often inadequate purchase in the sacrum, and stabilisation has to be achieved between the lumbar vertebrae and ilium. We present a simplification of the Galveston technique. We treated a total of six patients with this technique, four for metastatic disease and two for primary tumours. Our technique consists of the formation of a proximal stable construct using ISOLA pedicle screws linked distally using a modular system of connectors to threaded iliac bolts with cross linkages. Neurological decompression and fusion was performed as appropriate. The benefits of this method are: ease of access to the ilium, a solid purchase to the ilium, less rod contouring and shorter operating time. We have had no operative complications from this procedure. All patients were discharged home mobile, with a reduced opiate requirement.

Autologous bone grafting in staged scoliosis surgery. The patient as bone bank.

STUDY DESIGN: A prospective clinical study in which autologous rib graft, harvested during the thoracotomy in staged scoliosis correction, is stored within the patient for use during the second stage (posterior intrumentation and fusion). OBJECTIVE: To determine whether the bone stored by this technique is biologically viable and microbiologically safe. SUMMARY OF BACKGROUND DATA: To the authors' knowledge, this method of storage of bone has never been described previously. METHODS: During the first operation, the excised rib was divided into 3-5 cm fragments and stored in a sub-muscular plane adjacent to the posterior elements of the spine before closure. The graft was then retrieved at the second stage. Samples were sent for histologic and microbiologic examination before implantation. RESULTS: On histologic examination, more than 50% of the osteocytes retained their basophilic staining, indicating that they were viable. In addition, osteoclastic activity was notably absent. There was no significant bacterial contamination of the samples. Clinically, all patients achieved satisfactory bone fusion. CONCLUSION: Homeostatic equilibrium in humans provides the ideal environment in which bone graft can be stored. There is no increased risk of infection, and the osteogenic potential of the graft is retained.

Spinal instrumentation for Duchenne's muscular dystrophy: experience of hypotensive anaesthesia to minimise blood loss.

Nineteen patients with Duchenne's muscular dystrophy underwent segmental spinal instrumentation and posterior fusion between 1989 and 1994. The indication for surgery was loss of the ability to walk and development of scoliosis with sitting discomfort. Preoperative assessment included evaluation of pulmonary function. Average age at operation was 12.5 years. Instrumentation and fusion extended from upper thoracic levels to L-5 or the sacrum. A Hartshill rectangle was used in all cases, with banked allograft bone. Severe intraoperative blood loss was avoided by use of hypotensive anaesthesia. Peroperatively, systolic blood pressure was maintained between 75 and 85 mm Hg. Average blood loss was 1,246 ml (range, 400-3,100) or 30% of estimated total blood volume. Average transfusion requirements were 3 units of packed cells. Postoperative analgesia was provided by infusion via an epidural catheter. There were no postoperative wound or chest infections. Three patients required catheterisation for urinary retention. Postoperatively patients were fitted with a Neofract jacket to allow early mobilisation and discharge. Mean postoperative length of stay was 16 days. Posterior spinal fusion by using the Hartshill rectangle provided good correction and fixation. Hypotensive anaesthesia permitted surgery to be performed rapidly in a relatively dry field and avoided the complications of severe intraoperative blood loss and massive transfusion.

Convex spinal epiphysiodesis in the management of progressive infantile idiopathic scoliosis.

STUDY DESIGN: Retrospective review of patient records with current clinical and radiographic assessment. OBJECTIVE: To evaluate the long-term result of anterior and posterior convex spinal growth arrest, with or without instrumentation, in managing infantile idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: There were 12 male and 10 female patients studied, with a mean follow-up period of 10 years, 9 months. The mean Cobb angle before surgery was 65 degrees. All had a rib vertebral angle difference more than 20 degrees. The mean age at surgery was 6 years. Nine patients had epiphysiodesis alone; nine patients also underwent Harrington instrumentation simultaneously, and four underwent Harrington instrumentation 2-4 years later. METHOD: Clinical evaluation and sequential measurements of Cobb angle were done. RESULTS: The epiphysiodesis-only group had a mean preoperative Cobb angle of 72 degrees, mean progression of curves of +12 degrees, and mean rate of progression of +2.5 degrees per year: the group's postoperative figures were 92 degrees, +15 degrees, and +3 degrees per year, respectively. The epiphysiodesis and late Harrington rod group had a mean preoperative Cobb angle of 56 degrees, mean progression of +12 degrees, and a mean rate of progression of +5 degrees per year; the group's postoperative Cobb angle averaged 62 degrees, progression +6 degrees, and rate of progression +1 degree per year. The epiphysiodesis with simultaneous Harrington rod group had a preoperative mean Cobb angle of 60 degrees, mean progression of +18 degrees, and mean rate of progression of +6 degrees per years. After surgery, these improved to 58 degrees, correction of 2 degrees, and rate of correction of 0.5 degree per year. CONCLUSION: Combined anterior and posterior convex spinal growth arrest alone does not prevent progression of deformity in infantile idiopathic scoliosis. The addition of posterior instrumentation can slow or arrest deformity progression but not reverse it.

Atlantoaxial instability in Lesch-Nyhan syndrome.

STUDY DESIGN: A clinical case report of two brothers with Lesch-Nyhan syndrome found to have atlantoaxial instability is reported. OBJECTIVES: To report the clinical and radiologic findings and the operative outcome in these patients. SUMMARY OF BACKGROUND DATA: Both patients had biochemically proven Lesch-Nyhan syndrome. No previous cases of cervical instability have been reported in this group of patients. METHODS: The first patient presented with neck pain and progressive quadriplegia. Radiology including computed tomography scanning showed fracture of the tip of the odontoid and forward subluxation of the atlas. He was treated with a C1-C2 Gallie fusion. The second patient (his brother) was found to have similar radiologic findings but had not developed quadriplegia. He has not required surgery. RESULTS: At surgery, attempted correction of the subluxation produced severe bradycardia. An in situ fusion was performed that relieved the patient's neck pain. The child's neurologic status has remained the same during a 16-month follow-up period, despite failure of the posterior wire fixation 12 months after surgery. CONCLUSIONS: Patients with Lesch-Nyhan syndrome may develop atlantoaxial instability with subsequent neck pain and quadriplegia that may be masked by their underlying disease. Posterior fusion produced symptomatic relief but no improvement in neurologic status in our patient. Posterior fusion probably should be augmented by rigid cervical immobilization until fusion is confirmed in this type of patient.

Long-term results of combined anterior and posterior convex epiphysiodesis for congenital scoliosis due to hemivertebrae.

STUDY DESIGN: Retrospective review of patient records with recent clinical and radiologic assessment. OBJECTIVE: To evaluate the long-term result of anterior and posterior convex ephiphysiodesis in the management of congenital scoliosis resulting from fully segmented nonincarcerated hemivertebra. SUMMARY OF BACKGROUND DATA: Thirty patients (16 male/14 female patients) were reviewed. Follow-up was a minimum of 3 years (average, 8 years 10 months; range, 3-22.5 years). Nineteen patients were skeletally mature, and the mean age of the remaining 11 was 11.75 years. METHOD: Clinical evaluation and sequential measurements of Cobb angle was made independently by two observers. RESULTS: Compared with preoperative values, the rate of change in Cobb angle was reversed in 23 patients, arrested or slowed in five patients, and unchanged or progressed in two patients. The annual rate of change in Cobb angle was +1.9 degrees before surgery and -1.2 degrees after surgery, a difference of 3.1 degrees. This is highly statistically significant (P < 0.001). Total correction in Cobb angle correlates with age at time of surgery (P < 0.03). The rate of correction in Cobb angle after surgery correlates with the total correction achieved (P < 0.001) and with age at time of surgery (P < 0.05). The greater correction is achieved when surgery is performed at a young age. The preoperative rate of increase in Cobb angle does not correlate with correction (P < 0.76). The site of the hemivertebrae influenced final outcome with best results in the lumbar spine. CONCLUSION: Combined anterior and posterior convex epiphysiodesis is a reliable method for the correction of deformity resulting from hemivertebrae.

Expectations as determinants of patient satisfaction: concepts, theory and evidence.

The apparent lack of conceptual agreement and the inconsistency in the approach to understanding expectations prompted this analysis of the literature in the field of patient satisfaction. A review of 18 journals over the last few years, as well as a number of relevant books, provided the evidence for the state of the current theory. An attempt has been made to distill the main definitions in use, to illustrate practical models of the relationship between expectations and satisfaction, to identify the influential personal and social variables, and to consider the special nature of health care. Some of the empirical methods and findings are then presented, with conclusions made about how the theory of expectations may be developed to assist in understanding patient satisfaction.

Surgical management of haemangioendothelioma of the spine.

Four patients with haemangioendothelioma of the spine which was treated surgically are presented. Two were male and two female, mean age 30 years (range 5-60). All tumours were sited in the thoracic spine between T5 and T10; three were primary and one metastatic from a hepatic haemangioendothelioma. Each patient had a significant neurological deficit at presentation; three were paraplegic. A diagnosis of vertebral neoplastic disease was suggested on plain radiographs, and in three cases this was supported by computed tomography or magnetic resonance imaging. Two patients underwent anterior decompression and posterior instrumented stabilisation, one anterior decompression alone and one posterior decompression followed by tumour vessel embolisation and then anterior decompression. Intra-operative blood loss was a significant feature despite the use of hypotensive anaesthetic techniques and local haemostatic agents. Three of the tumours were tested for Factor VIII (a tumour for vascular tumours), and all proved positive. In these, sufficient histological material was available to grade the tumours according to the classification of Campanacci et al. [1]. All were grade II. Three patients recovered completely from paraglegia; one had residual mild spasticity which required the use of a walking aid. The mean improvement in Frankel grade was 2.5 (range 1-4). In two the tumour recurred outside the spine within 18 months; one had subsequently died. The presentation, investigation and results of surgery for haemangioendothelioma of the spine are presented. Particular attention is drawn to the neurological status at presentation, the effect of pre-operative tumour embolisation and the dramatic recovery that can be achieved in these patients following surgery.