Regional binding of tau and amyloid PET tracers in Down syndrome autopsy brain tissue.

INTRODUCTION: Tau pathology is a major age-related event in Down syndrome with Alzheimer's disease (DS-AD). Although recently, several different Tau PET tracers have been developed as biomarkers for AD, these tracers showed different binding properties in Alzheimer disease and other non-AD tauopathies. They have not been yet investigated in tissue obtained postmortem for DS-AD cases. Here, we evaluated the binding characteristics of two Tau PET tracers (3H-MK6240 and 3H-THK5117) and one amyloid (3H-PIB) ligand in the medial frontal gyrus (MFG) and hippocampus (HIPP) in tissue from adults with DS-AD and DS cases with mild cognitive impairment (MCI) compared to sporadic AD. METHODS: Tau and amyloid autoradiography were performed on paraffin-embedded sections. To confirm respective ligand targets, adjacent sections were immunoreacted for phospho-Tau (AT8) and stained for amyloid staining using Amylo-Glo. RESULTS: The two Tau tracers showed a significant correlation with each other and with AT8, suggesting that both tracers were binding to Tau deposits. 3H-MK6240 Tau binding correlated with AT8 immunostaining but to a lesser degree than the 3H-THK5117 tracer, suggesting differences in binding sites between the two Tau tracers. 3H-THK5117, 3H-MK6240 and 3H-PIB displayed dense laminar binding in the HIPP and MFG in adult DS brains. A regional difference in Tau binding between adult DS and AD was observed suggesting differential regional Tau deposition in adult DS compared to AD, with higher THK binding density in the MFG in adult with DS compared to AD. No significant correlation was found between 3H-PIB and Amylo-Glo staining in adult DS brains suggesting that the amyloid PIB tracer binds to additional sites. CONCLUSIONS: This study provides new insights into the regional binding distribution of a first-generation and a second-generation Tau tracer in limbic and neocortical regions in adults with DS, as well as regional differences in Tau binding in adult with DS vs. those with AD. These findings provide new information about the binding properties of two Tau radiotracers for the detection of Tau pathology in adults with DS in vivo and provide valuable data regarding Tau vs. amyloid binding in adult DS compared to AD.

Correction to: Unconstrained total knee arthroplasty in significant valgus deformity: a modified surgical technique to balance the knee and avoid instability.

The author would like to correct the following errors in the publication of the original article.

Knee manipulation for reduced flexion after Total Knee Arthroplasty. Is timing critical?

BACKGROUND: Reduced flexion following knee arthroplasty (TKA) may compromise patient's function and outcome. The timing of manipulation under anaesthesia (MUA) has been controversial. We present our experience in a high volume practice and analyse the impact of timing. METHODS: All TKA patients requiring MUA from February 1996 to June 2015 under the care of a single surgeon were analysed. MUA was offered to patients who had ≤ 75° of flexion post-op, providing that they had 30° more flexion preoperatively. To address the impact of timing from primary surgery to MUA on flexion gain we looked at 3 groups: Group I ≤ 90 days, Group II 91-180 days and Group III > 180 days. RESULTS: Sixty two out of 7,423 (0.84%) underwent MUA. The MUA patients were significantly younger than the overall TKA cohort 61.2 vs 70.5 years (p = < 0.01). The median duration between arthroplasty and MUA was 3.9 months (IQR 3.4, Range 1.6-72.5 months). Overall flexion gained at 6-12 Weeks and 1 year post MUA showed significant improvements of 20.9° (p = <0.01) and 25° respectively (p = < 0.01). The flexion gain in group I (≤ 90 days) was significantly better than group III ( > 180 days) both at 6 weeks and 1 year following MUA but not better than group II (90-180 days). CONCLUSIONS: MUA is an effective treatment for reduced flexion following TKA and should be the first line of management after failed physiotherapy. It can still have benefit beyond 6 months but the gains become less effective with time.

Dual endothelin-1 receptor antagonism attenuates platelet-mediated derangements of blood coagulation in Eisenmenger syndrome.

Essentials Eisenmenger syndrome is characterised by thrombotic and hemorrhagic risks of unclear aetiology. Calibrated automated thrombography was used to assess these coagulation derangements. Platelet activity supported abnormalities in procoagulant and anticoagulant pathway function. Endothelin-1 antagonism appeared to ameliorate these derangements. SUMMARY: Aims The mechanisms underlying the competing thrombotic and hemorrhagic risks in Eisenmenger syndrome are poorly understood. We aimed to characterize derangements of blood coagulation and to assess the effect of dual endothelin-1 receptor antagonism in modulating hemostasis in this rare disorder. Methods In a 10-month recruitment period at a tertiary cardiology referral center, during which time there were over 14 000 outpatient consultations, consecutive subjects with Eisenmenger syndrome being considered for macitentan therapy (n = 9) and healthy volunteers (n = 9) were recruited. Plasma thrombin generation in platelet-rich and platelet-poor plasma was assessed by calibrated automated thrombography prior to and following therapy. Results Median peak plasma thrombin generation was higher in platelet-rich plasma obtained from Eisenmenger syndrome subjects relative to controls (median peak thrombin [25th-75th percentile]: 228.3 [206.5-258.6] nm vs. 169.9 [164.3-215.8] nm), suggesting a critical mechanistic role for platelets in supporting abnormal hypercoagulability in Eisenmenger syndrome. Abnormal enhanced sensitivity to the anticoagulant activity of activated protein C was also observed in platelet-rich plasma in Eisenmenger syndrome, suggesting that derangements of platelet activity may influence the activity of anticoagulant pathways in a manner that might promote bleeding in this disease state. Following 6 months of macitentan therapy, attenuations in the derangements in both procoagulant and anticoagulant pathways were observed. Conclusions Abnormal platelet activity contributes to derangements in procoagulant and anticoagulant pathways in Eisenmenger syndrome. Therapies targeting the underlying vascular pathology appear to ameliorate these derangements and may represent a novel strategy for the management of the competing prothrombotic and hemorrhagic tendencies in this disorder.

Five-year clinical and radiological outcomes in 257 consecutive cementless Oxford medial unicompartmental knee arthroplasties.

AIMS: Our aim was to examine the clinical and radiographic outcomes in 257 consecutive Oxford unicompartmental knee arthroplasties (OUKAs) (238 patients), five years post-operatively. PATIENTS AND METHODS: A retrospective evaluation was undertaken of patients treated between April 2008 and October 2010 in a regional centre by two non-designing surgeons with no previous experience of UKAs. The Oxford Knee Scores (OKSs) were recorded and fluoroscopically aligned radiographs were assessed post-operatively at one and five years. RESULTS: The median age of the 238 patients was 65.0 years (interquartile range (IQR) 59.0 to 73.0), the median body mas index was 30.0 (IQR 27.5 to 33.0) and 51.7% were male. There were no intra-operative complications. There was a significant improvement in the median OKS at six weeks (34, IQR 31.0 to 37.0), one year (38, IQR 29.0 to 43.0) and five years (37, IQR 27.0 to 42.0) when compared with the pre-operative scores (16, IQR 13.0 to 19.0) (all p = < 0.01). No patient had progressive radiolucent lines or loosening. A total of 16 patients had died by five years. The cumulative survival at five years was 98.8% and the mean survival time was 5.8 years (95% confidence interval 5.6 to 5.9). A total of seven OUKAs (2.7%) were revised; three within five years and four thereafter, between 5.1 and 5.7 years post-operatively. Five (1.9%) had re-operations within five years. CONCLUSION: The proportion of patients requiring revision at five years is lower than that generally reported for UKA. These findings add support for the use of the cementless OUKA outside the design centre. Longer follow-up is required. Cite this article: Bone Joint J 2017;99-B:623-31.

Unconstrained total knee arthroplasty in significant valgus deformity: a modified surgical technique to balance the knee and avoid instability.

PURPOSE: Correction of valgus deformity in total knee arthroplasty (TKA) is technically challenging and has produced variable results. A modified surgical technique involving adapting the distal femoral cut with minimal soft tissue release is proposed. The authors hypothesise that using this technique would result in satisfactory radiological and functional outcome. METHODS: The technique involves balancing the knee in extension by changing the distal femoral resection angle and confining soft tissue release to only the posterolateral capsule if required. Retrospective analysis of 276 consecutive TKAs performed using this technique under the care of a single surgeon in patients with valgus knee deformity ≥10° was undertaken. An unconstrained mobile bearing implant was used in all knees with a medial para-patellar approach, and outcome scores were collected prospectively. Seventy-five percent of the knees were cementless. [corrected] RESULTS: Mean coronal alignment of the lower limb was corrected from 15.6° (±5.7°) to 3.8° (±2.5°). 97.8 % knees had their coronal alignment restored to ≤7°. Seventy-eight knees (28 %) were balanced by only changing the distal femoral resection angle. One hundred and ninety-eight knees (72 %) had release of the posterolateral capsule. Sixteen knees (5.8 %) also had release of iliotibial band. Lateral patellar release was performed in 39 knees (14 %). 93.1 % had central patello-femoral alignment. At between 5.8 and 10.5 year follow-up, there has been one spinout, managed by closed reduction, and one revision of tibial tray for subsidence. The mean American Knee Society clinical score improved from 19.1 to 86.5 (±12.2). CONCLUSION: Adequate correction of valgus knee deformity was successfully achieved using this modified technique with satisfactory medium-term outcome and avoidance of instability.

Aspirin for thromboprophylaxis after primary lower limb arthroplasty: early thromboembolic events and 90 day mortality in 11,459 patients.

AIMS: The aim of this study was to present data on 11 459 patients who underwent total hip (THA), total knee (TKA) or unicompartmental knee arthroplasty (UKA) between November 2002 and April 2014 with aspirin as the primary agent for pharmacological thromboprophylaxis. PATIENTS AND METHODS: We analysed the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) then compared the 90-day all-cause mortality with the corresponding data in the National Joint Registry for England and Wales (NJR). RESULTS: The incidence of PE was 0.6% after THA, 1.47% after TKA and 1.2% after UKA. The 90-day mortality was 0.39% after THA and 0.44% after TKA. No deaths occurred after UKA. The main causes of death were ischaemic heart disease and respiratory failure. PE was responsible for only 18% of deaths. There was a decline in 90-day mortality, from 0.64% between 2002 and 2007, to 0.21% between 2008 and 2013 after THA, and from 0.47% to 0.39% after TKA for the corresponding period. The standardised mortality ratio (SMR) declined from 86.5 (confidence interval (CI) 63.0 to 137.7) to 39.7 (CI 31.2 to 54.3) p = 0.024. The incidence of proximal DVT was 0.3%. TAKE HOME MESSAGE: With individualised risk assessment and as part of a multimodal approach, Aspirin is safe to use as the main thromboprophylactic agent in primary arthroplasty. It is not associated with an increased incidence of symptomatic DVT, PE or death.

Rapid assessment of cognitive function in down syndrome across intellectual level and dementia status.

BACKGROUND: Adults with Down syndrome (DS) are at risk of developing dementia and cognitive assessment is a fundamental part of the diagnostic process. Previously, we developed a Rapid Assessment for Developmental Disabilities (RADD), a brief, broadly focused direct test of cognition. In the current report, we assess whether the RADD is sensitive to dementia in DS and the degree to which it compares with other cognitive measures of dementia in this population. METHODS: In a sample of 114 individuals with DS, with dementia diagnosed in 62%, the RADD was compared with the Dementia Questionnaire for Mentally Retarded Persons (DMR), the Bristol Activities of Daily Living Scale, Severe Impairment Battery (SIB), and the Brief Praxis Test (BPT). RESULTS: The RADD showed predicted effects across intellectual disability (ID) levels and dementia status (p < 0.001). Six-month test-retest reliability for the subset of individuals without dementia was high (r(41) = 0.95, p < 0.001). Criterion-referenced validity was demonstrated by correlations between RADD scores and ID levels based upon prior intelligence testing and clinical diagnoses (rs (114) = 0.67, p = 0.001) and with other measures of cognitive skills, such as the BPT, SIB, and DMR-Sum of Cognitive scores (range 0.84 through 0.92). Using receiver operating characteristic curves for groups varying in pre-morbid severity of ID, the RADD exhibited high sensitivity (0.87) and specificity (0.81) in discriminating among individuals with and without dementia, although sensitivity was somewhat lower (0.73) for the subsample of dementia cases diagnosed no more than 2 years prior to their RADD assessment. CONCLUSION: Taken together, findings indicated that the RADD, a relatively brief, easy-to-administer test for cognitive function assessment across ID levels and dementia status, would be a useful component of cognitive assessments for adults with DS, including assessments explicitly focused on dementia.

Dilemmas in the compassionate supply of investigational cancer drugs.

In Australia, patients who want to access medicines that are not yet approved have only two options: to enroll in a clinical trial if they are eligible, or obtain their medicine through 'compassionate supply', which is provided at the discretion of the manufacturer. In this article, we explore ethical issues associated with the provision of oncology medicines that are still in development, either prior to regulatory approval or government reimbursement.

Intra-operative and short term outcome of total knee arthroplasty in morbidly obese patients.

BACKGROUND: Longer operation times, poorer patient outcomes and increased early post-operative complications are reasons cited for not undertaking total knee arthroplasty (TKA) on morbidly obese patients. This study tests the hypothesis that there is no difference in intra-operative parameters between morbidly obese and non-obese patients, and no difference in patient outcome. METHODS: Intra-operative parameters, post-operative complications, patient outcomes and knee range of motion were compared between morbidly obese patients (BMI>40 kg/m2) and individually age and gender matched non-obese patients (BMI<30 kg/m2) undergoing cementless rotating platform TKA. RESULTS: Anaesthetic times and length of hospital stay were not significantly different between the morbidly obese and non-obese patients. Surgical time was significantly greater in morbidly obese patients. Improvements in patient outcomes following TKA were not significantly different between the morbidly obese and non-obese patients at early and short-term follow-up. CONCLUSIONS: In contrast to previous studies, post-operative complication rates within three months of surgery and up to one year post-operatively were not significantly higher for morbidly obese patients. LEVEL OF EVIDENCE: III.

The influence of immediate knee flexion on blood loss and other parameters following total knee replacement.

In an initial randomised controlled trial (RCT) we segregated 180 patients to one of two knee positions following total knee replacement (TKR): six hours of knee flexion using either a jig or knee extension. Outcome measures included post-operative blood loss, fall in haemoglobin, blood transfusion requirements, knee range of movement, limb swelling and functional scores. A second RCT consisted of 420 TKR patients randomised to one of three post-operative knee positions: flexion for three or six hours post-operatively, or knee extension. Positioning of the knee in flexion for six hours immediately after surgery significantly reduced blood loss (p = 0.002). There were no significant differences in post-operative range of movement, swelling, pain or outcome scores between the various knee positions in either study. Post-operative knee flexion may offer a simple and cost-effective way to reduce blood loss and transfusion requirements following TKR. We also report a cautionary note regarding the potential risks of prolonged knee flexion for more than six hours observed during clinical practice in the intervening period between the two trials, with 14 of 289 patients (4.7%) reporting lower limb sensory neuropathy at their three-month review.

Early postoperative predictors of satisfaction following total knee arthroplasty.

BACKGROUND: Despite the excellent total knee arthroplasty (TKA) results reported using traditional outcome measures, dissatisfaction rates of up to 30% are reported following surgery. Although several preoperative factors have been identified as possible predictors of satisfaction, there is conflicting evidence. Identification of dissatisfaction in the early postoperative assessment may therefore be an alternative consideration. METHODS: We examined the relationship between 12-month satisfaction, and early post-operative outcomes in a cohort of 486 TKA patients. Preoperative, and postoperative outcome measures at 3- and 12-months (Oxford knee score, pain score, SF12, and knee motion), were analysed and compared between patients who were satisfied and dissatisfied at 12-months following TKA. Mean scores, and postoperative change in scores were calculated. Postoperative outcomes were examined for correlation with satisfaction, and multivariate logistic regression models used to identify potential predictors of dissatisfaction. RESULTS: Overall satisfaction was 77.0%. No preoperative differences were observed between groups. Dissatisfaction was associated with worse postoperative status across all outcome measures (p<0.001), except the 3-month SF12-physical component (p=0.052). Dissatisfied patients demonstrated minimal further improvement or even worsening of outcome scores between 3- and 12-months postoperatively (p<0.02). Both the 3-month OKS (OR=1.15, p<0.001), and knee flexion (OR=1.03, p=0.009) were significant predictors of subsequent 12-month satisfaction. CONCLUSIONS: Dissatisfaction following TKA is associated with worse outcomes as early as 3months following surgery, with minimal further improvement subsequently achieved at 12-months. Early postoperative assessment following TKA should therefore be considered, including clinical assessment, to identify those patients at risk of dissatisfaction.

Cementless fixation in Oxford unicompartmental knee replacement: a multicentre study of 1000 knees.

The Cementless Oxford Unicompartmental Knee Replacement (OUKR) was developed to address problems related to cementation, and has been demonstrated in a randomised study to have similar clinical outcomes with fewer radiolucencies than observed with the cemented device. However, before its widespread use it is necessary to clarify contraindications and assess the complications. This requires a larger study than any previously published. We present a prospective multicentre series of 1000 cementless OUKRs in 881 patients at a minimum follow-up of one year. All patients had radiological assessment aligned to the bone-implant interfaces and clinical scores. Analysis was performed at a mean of 38.2 months (19 to 88) following surgery. A total of 17 patients died (comprising 19 knees (1.9%)), none as a result of surgery; there were no tibial or femoral loosenings. A total of 19 knees (1.9%) had significant implant-related complications or required revision. Implant survival at six years was 97.2%, and there was a partial radiolucency at the bone-implant interface in 72 knees (8.9%), with no complete radiolucencies. There was no significant increase in complication rate compared with cemented fixation (p = 0.87), and no specific contraindications to cementless fixation were identified. Cementless OUKR appears to be safe and reproducible in patients with end-stage anteromedial osteoarthritis of the knee, with radiological evidence of improved fixation compared with previous reports using cemented fixation.

Attitudes of physicians and public to pharmaceutical industry 'gifts'.

BACKGROUND: Few studies have reported the attitudes of both individual doctors and members of the public toward the appropriateness of 'gifts' from pharmaceutical companies. AIMS: To investigate the attitudes of both doctors and members of the public toward the appropriateness of receiving particular 'gifts' from pharmaceutical companies, and to consider whether public acceptability is a suitable criterion for determining the ethical appropriateness of 'gifts'. METHODS: A survey questionnaire of medical specialists in Australia and a survey questionnaire of members of the public itemized 23 'gifts' (valued between AU$10 and AU$2500) and asked whether or not each was appropriate. RESULTS: Both medical specialists and members of the public believe certain 'gifts' from pharmaceutical companies are appropriate but not others. There was a tendency for members of the public to be more permissive than medical specialists. CONCLUSION: Although some professional guidelines place importance on the attitudes of the general public to 'gift' giving, and other guidelines give importance to a need for transparency and public accountability, we question whether public acceptability is a suitable criterion for determining the ethical appropriateness of 'gifts'. We suggest that more weight be given to the need for independence of clinical decision making, with empirical evidence indicating that even small 'gifts' can bias clinicians' judgments, and to important values such as the primacy of patient welfare, autonomy and social justice. We conclude that it is time to eliminate giving and receiving of promotional items between the pharmaceutical industry and members of health professions.

Disease mongering: expanding the boundaries of treatable disease.

Traditionally, the promotional activities of medical industries have been product specific. In recent years, however, there have been examples where companies have worked through partnerships, which have included clinicians, to expand the boundaries of treatable disorders. The main motivation appears to be to increase sales of commercial products. The term 'disease mongering' has been applied to these activities. Whereas some disease awareness programmes may bring benefits in the form of improved recognition and management of disorders, the presence of strong commercial interests probably distorts the traditional processes by which treatable diseases have been defined. This can result in individual patients being exposed to potential harms, with little expectation of benefit and will place an unwarranted burden on the publicly funded health-care system. None of this can happen without the collaboration of the medical profession that needs to be aware of the risks of becoming involved in commercially supported 'consensus' groups that are reviewing the definition and management of diseases.

The use of a posterior lip augmentation device for a revision of recurrent dislocation after primary cemented Charnley/Charnley Elite total hip replacement: results at a mean follow-up of six years and nine months.

Between April 1992 and July 2005, 310 posterior lip augmentation devices were used for the treatment of recurrent dislocation of the hip in 307 patients who had received primary total hip replacements (THRs) using Charnley/Charnley Elite components with a cemented acetabulum. The mean number of dislocations before stabilisation with the device was five (1 to 16) with a mean time to this intervention from the first dislocation of 3.8 years (0 days to 22.5 years). The mean age of the patients at this reconstruction was 75.4 years (39 to 96). A retrospective clinical and radiological review was carried out at a mean follow-up of six years and nine months (4.4 months to 13 years and 7 months). Of the 307 patients, 53 had died at the time of the latest review, with a functioning THR and with the posterior lip augmentation device in situ. There were four revisions (1.3%), one for pain, two for deep infection and one for loosening of the acetabular component. Radiolucent lines around the acetabular component increased in only six cases after insertion of the device which was successful in eliminating instability in 302 patients, with only five further dislocations (1.6%) occurring after its insertion.

Possible compensatory events in adult Down syndrome brain prior to the development of Alzheimer disease neuropathology: targets for nonpharmacological intervention.

Adults with Down syndrome (DS) develop Alzheimer disease (AD) pathology progressively with age but clinical signs of dementia are delayed by at least 10 years after the first signs of disease. Some individuals with DS do not develop dementia despite extensive AD neuropathology. Given the discordance between clinical decline and AD neuropathology, compensatory events may be of particular relevance for this group. Imaging studies using PET suggest compensatory increases in metabolic rate in vulnerable brain regions in DS prior to the development of dementia. Neurobiological studies of similarly aged DS autopsy cases provide further evidence of activation of plasticity mechanisms. Genes that are overexpressed in DS (APP, DSCAM, MNB/DYRK1A, and RCAN1) produce proteins critical for neuron and synapse growth, development and maintenance. We present the hypothesis that these genes may lead to developmental cognitive deficits but paradoxically with aging, may participate in molecular cascades supporting neuronal compensation. Enhancing or supporting compensatory mechanisms in aging individuals with DS may be beneficial as suggested by intervention studies in animal models. In combination, adults with DS may be a unique group of individuals well-suited for studies involving the manipulation or upregulation of compensatory responses as an approach to promote successful brain aging in the general population.

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain.

Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alpha-secretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Abeta) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Abeta degradation and clearance.

Empirical uncertainty and moral contest: a qualitative analysis of the relationship between medical specialists and the pharmaceutical industry in Australia.

Alliances between the medical profession and the pharmaceutical industry have become increasingly widespread in recent years. While there are clearly benefits for doctors and their patients derived from the medical profession working with industry, concern has arisen that the commercial imperative of industry may conflict with physicians' independence and professional integrity. This paper reports the findings of an in-depth interview study with 50 Australian medical specialists undertaken to explore how and why they interact with the pharmaceutical industry and to gain insight into specialists' moral evaluation of the relationship and its consequences. Analysis of the qualitative data led to the categorizing medical specialists into three types--Confident Engagers, Ambivalent Engagers and Avoiders--based on their descriptions and evaluations of their relationship. The majority of interviewees believed that some relationship with the pharmaceutical industry was inevitable, that there were both risks and benefits associated with the relationship and that as individuals they were competent in minimizing the risks and maximizing the benefits. However, their views diverged on the extent and magnitude of the risks and benefits. The data suggested that there is considerable variance in specialists' judgments of what constituted appropriate industry largesse. Specialists' relationship with the pharmaceutical industry has inherent tensions that are managed by different doctors in different ways. Moral evaluation of the relationship and its consequences varies and the ethical concerns surrounding the relationship appeared as an area of contest. The findings suggest that in developing normative guidelines for academic and professional practice, policy makers should recognise and account for the complexity of the relationship and for the variation in medical specialists' views and feelings.