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Background: Health technology assesment (HTA) requires scientifically rigorous experimentation involving patients as subjects. HTA itself is required so that treatment given to patients will be both effective and efficient; this requirement is itself ethical in nature. At the same time it is essential that the methods used in HTA are ethically sound. Most healthcare researchers agree that the most effective and soundest method for assessing treatments is the randomised controlled trial (RCT). However, some researchers believe that the RCT is unethical, either in essence, or for use in some forms of medical research and HTA. Furthermore, many patients seem unable to understand the principles and purposes of the RCT, a factor which is highly detrimental for the validity of informed consent. Informed consent is the key to the ethics of medical research, both in most theories and in all codes of research conduct. Many RCTs therefore risk being unethical in practice, even if ethical in principle., Aim of Report: To survey the main objections to the RCT and its alternatives. To assess the philosophical and methodological basis of these objections, and of the methods recommended for addressing them. To identify areas where objections are founded in social or cultural factors normally overlooked in ethical argument about the RCT methodology. To identify alternative arguments or methods which might resolve ethical conflicts in this area., How the Research Was Conducted: The methods used were adapted from systematic reviews in medicine. Systematic searches of Medline, Psychlit and Sociofile CD-ROM databases; hand-searches of the major journals in general medicine and surgery, medical ethics and philosophy; and searches of books were carried out. The literature survey was restricted to articles published or abstracted in English. A database of the most relevant and useful materials was compiled, and is accessible on the Internet (http://www.liv.ac.uk/sdthomps/page1.html)., Research Findings: UNDERSTANDING RCTS AND THEIR ALTERNATIVES: There is some evidence of difficulty in understanding the aims and methods of RCTs, and some disquiet about elements of the RCT methodologies. These objections are well known and much discussed, and concern the use of placebo, the continuation of trials after significant differentials in benefit or harm are apparent, and randomisation., Cultural or Religious Objections: There was an absence of evidence of cultural or religious objections to randomisation, placebo or other kinds of controlled prospective trials. This most likely reflects an absence of research rather than absence of objections. (ABSTRACT TRUNCATED)

This paper outlines the approaches of two apparently competing schools of statistics. The criticisms made by supporters of Bayesian statistics about conventional Frequentist statistics are explained, and the Bayesian claim that their method enables research into new treatments without the need for clinical trials is examined in detail. Several further important issues are considered, including: the use of historical controls and data routinely collected on patients; balance in randomised trials; the possibility of giving information to patients; patient choice and patient autonomy; and how widely the results of clinical trials can be used. It is concluded that good statistical techniques in the design and analysis of medical studies are essential, but the statistical school used in developing such techniques is relatively unimportant.

Energy intake and energy expenditure, nitrogen intake, and urinary nitrogen excretion (or urea production rates) were measured in 35 intravenously fed patients with multiple organ failure over the course of their illness to determine to what extent nutrient requirements were met despite fluid retention. Energy and nitrogen balance were related to serial measurements of midupper-arm circumference (MAC). The target feeding regimen of 176 kJ (42 kcal)/kg fat-free mass (FFM) was achieved in only three patients and the target of 0.24 g N/kg FFM in only four. Two patterns of change in MAC were noted: a steady decrease with time and no change with time. Serial muscle biopsy data indicated that all the patients were wasting away; the maintenance of MAC in the group with no change over time was due to fluid retention. Abnormal losses were not measured, but energy and nitrogen balance in the group in which arm circumference decreased had no apparent effect on the rate of wasting.

A prognostic index for patients with intrinsic supratentorial tumours based on prebiopsy findings was proposed on the basis of data bases of patients presenting between 1975 and 1989. The value of this index is confirmed from data on 76 patients who presented during 1991. Patients classified by the index as having a poor prognosis had a median survival of six months, and those classified as having a good prognosis had a median survival of five years. The expected duration of survival, allowing for this initial prognosis, also depended on whether a patient received resective surgery, radiotherapy, or steroids. Histological grade provided no additional information on survival.

Concentrations of 14 commonly-requested plasma hormones were measured in octuplicate in each of six subjects to determine their stability when unseparated from red cells for periods up to 1 week. Most of the analytes were stable when stored in this way and although statistically significant changes were recorded, in the great majority of cases the changes seen would have no bearing on the clinical interpretation of the result. In the light of these findings, we would confidently report results of analyses for these hormones in plasma that had remained in contact with red cells at ambient temperature for long periods of time.

Objective: To determine life expectancy of children with cerebral palsy., Design: Cohort analysis, by means of register compiled from multiple sources of ascertainment, of all children with cerebral palsy born during 1966-84 to mothers resident in Mersey region. Status of children was determined by flagging through NHS central register., Subjects: 1258 subjects with idiopathic cerebral palsy, of whom 1251 were traced and included in analysis., Main Outcome Measures: Effect of functional ability (ambulation, manual dexterity, and mental ability), sex, birth weight, and gestational age on survival., Results: 20 year survival for whole cohort was 89.3% for females and 86.9% for males. For subjects with no severe functional disabilities 20 year survival was 99% (95% confidence interval 98% to 100%), while subjects severely disabled in all three functional groups had 20 year survival of 50% (42% to 58%). Subjects with birth weight < or = 2500 g had 20 year survival of 92% (89% to 95%), while those with birth weight > 2500 g had survival of 87% (84% to 89%). Subjects with gestational age of > 37 weeks had 20 year survival of 93% (91% to 96%), while those with gestational age > or = 37 weeks had survival of 85% (83% to 88%). Birth weight and gestational age were less predictive of survival than functional disability. Best statistical model used gestational age and number of severe functional disabilities as predictors., Conclusions: Life expectancy of this cohort of children with cerebral palsy was greater than has been suggested in some previous studies. This has important implications for social, educational, and health services.

A prospective study was undertaken to determine the potential benefits in patient management and cost effectiveness of physiotherapists employed by general practitioners compared with direct hospital access and access via consultants. The study involved 401 patients from three rural general practices in south Cheshire and north Staffordshire and took place over six months. On-site physiotherapy in general practice premises resulted in higher referral rates to the physiotherapist compared with the practice using direct hospital access or the practice with access via consultants. Both on site and direct access physiotherapy were associated with fewer prescriptions and lower overall prescribing costs per patient than access to physiotherapy via consultants. There was less time lost from work and normal duties for patients attending the practice with on site physiotherapy compared with those attending the practice which required referral via hospital consultants. Access to physiotherapy via hospital specialists resulted in considerably longer delays than on site physiotherapy and greatly increased the financial costs for the patient. Physiotherapy in general practice premises is a cost effective way of dealing with joint and soft tissue complaints. Direct access to the physiotherapy department within hospitals results in longer delays but provides a satisfactory service. There is little to recommend the utilization of hospital consultants as a means of access to physiotherapy.

Renal weight (left-right combined), as a parameter of renal development, is required to be less than half the normal value for age for a statistically confident diagnosis of hypoplasia. "Medullary ray glomerular counting" (MRGC), counting cortical glomerular generations, has been proposed as a simple technique of possibly greater sensitivity. Recent development of the Disector method for the unbiased stereological estimation of total glomerular number has provided a, hitherto unavailable, "golden standard" with which to determine the diagnostic potential of MRCG. Both "true" (actual number of generations seen) and "assumed" (a subjective "guess" of the total number of generations) MRGC counts were determined in 11 pairs of kidneys from spontaneously aborted, normally developed, non-malformed fetuses (gestational age: 15-40 weeks). Each kidney was randomly analysed blind and on two separate occasions by two paediatric pathologists using a written protocol. Results were compared with unbiased stereological estimates of glomerular number. Intra- and inter-observer and intra- and inter-(left-right)renal reproducibility were analysed. In conclusion, MRGC, using "real" counts, is a highly reproducible parameter of renal development from 15-36 weeks' gestation. Sensitivity for detection of both hypoplasia and maturation delay increase with gestational age and generally exceeds that of renal weight.

The clinical course of intrinsic supratentorial tumours is variable. Prediction of outcome would be useful in defining patients for specific treatment policies. A retrospective analysis of 560 patients with intrinsic supratentorial tumours was performed. Proportional hazards models for survival were derived by using a stepwise selection procedure with only clinical and CT features as possible explanatory variables. The variables of prognostic importance were age, a first symptom of epilepsy, focal signs at presentation, a cystic lesion on CT scan, and duration of symptoms before presentation. The model defined a group with a good prognosis (score less than or equal to 9, n = 211) and a group with a poor prognosis (score greater than 9, n = 344). The median survival was 27 months for those with a score less than or equal to 9 or less and three months for those with score greater than 9. An alternative model, not including duration of symptoms, is also capable of defining groups with long (score less than or equal to 16, n = 234) and short (score greater than 16, n = 325) survival. The model may provide a means of classifying patients for inclusion in prospective randomised studies.

It is not known whether conservative or early aggressive (resective surgery with or without radiotherapy) management is better for tumours presenting with epilepsy. The prognosis of 560 patients with a clinical and CT diagnosis of intrinsic supratentorial tumour was examined retrospectively. Epilepsy was the first symptom in 164 patients. Histological confirmation of diagnosis was available in 391 (70%) of cases. Median survival was 37 months in the group presenting with epilepsy and six months in those presenting with other symptoms (p less than 0.0001). Patients presenting with epilepsy were more likely to have a normal clinical examination, a non-enhancing low density lesion on CT scan and a low grade tumour. From Cox's stepwise proportional hazards model, significant independent variables adversely affecting prognosis were increasing age, focal neurological signs and enhancing CT lesions at diagnosis, non-resective surgery and male sex. Of those presenting with epilepsy 80 patients had surgical treatment within two months of CT diagnosis. The Cox's model failed to identify any beneficial effects for either early resective surgery or radiotherapy. In primary intracerebral tumours with presentations other than epilepsy, resective surgery and radiotherapy were amongst the important factors associated with prolonged survival. Primary intracerebral tumours presenting with epilepsy are relatively benign and their outcome appears to be chiefly determined by clinical factors.

Between January 1975 and December 1989, 13 men were treated for carcinoma of the scrotum; 11 lesions were squamous cell and 2 basal cell carcinomas. Eleven patients initially underwent local wide excision and 1 local excision with inguinal node dissection. Two patients died of recurrent disease and 4 from unrelated causes, giving a corrected 5-year survival rate of 62.5%.

This study investigated whether British women prefer to crouch over public toilet seats, and measured the effect of such a voiding position on urine flow rate and residual urine volume. Of 528 consecutive women who attended a general gynaecological clinic and completed an anonymous questionnaire, 85% usually crouched over the toilet when using a public convenience, 12% applied paper to the seat and 2% sat directly on public toilet seats. When using a friend's bathroom 38% of the women voided by crouching. Results were similar for 155 patients attending a urodynamic clinic, 80 of whom were studied while voiding in both positions. There was a 21% reduction in average urine flow rate and a 149% increase in residual urine volume in the crouching position. Women undergoing urodynamic tests should be asked which voiding position they used before abnormal results are interpreted. Patients with a reduced functional bladder capacity may benefit from being encouraged to sit comfortably on the toilet whenever possible.

Platelet concentrates stored for up to 5 days at room temperature or irradiated with 15 Gy immediately prior to transfusion were evaluated for their ability to increase the platelet count in thrombocytopenic patients. Platelets irradiated with a dose of 15 Gy immediately prior to transfusion achieved corrected increments (CI) at 1 and 20 h after transfusion no different from those achieved by non-irradiated platelets. Storage for 5 days reduced the mean 1-hour CI to 5.7 compared with a mean of 12.3 achieved by platelets transfused after only 1-day storage (p = 0.008). Similarly, the frequency of a repeat transfusion being indicated within 24 h increased with increasing storage time (p = 0.005).

The urinary excretion rate of creatinine was measured over 89 days in 31 infants of gestational ages 25-34 weeks in the first week of life. Creatinine excretion was shown to have a significant positive correlation with weight and postconceptional age. Creatinine excretion factored by body weight was also positively correlated with weight and postconceptional age. Pooled analysis of published data together with our own, confirms that this correlation is important. Muscle mass was estimated from creatinine excretion rate. A regression equation was derived predicting muscle mass from birth-weight and gestational age. Muscle mass increases from 12% of birthweight at 25 weeks gestation to 19% at 34 weeks and 24% at 40 weeks. This is in agreement with classic dissection studies which showed muscle mass to be 25% of body weight at term.

Forty-three consecutive patients previously unexposed to platelets and undergoing treatment for acute leukaemia or autografting for relapsed Hodgkin's lymphoma were randomized to receive transfused platelets of either their own ABO group (OG) or of a major mismatched group (MMG). The 26 evaluable patients were equally distributed between the two study groups. Nine of 13 (69%) MMG patients became refractory with a median onset at transfusion 7 (15 d), compared with only one of 13 (8%) OG patients (P = 0.001). Refractoriness was associated with the formation of high titre isoagglutinins, anti-HLA and platelet specific antibodies. In one patient refractoriness appeared to be due to high titre isoagglutinins alone. Six other patients developed an increase in isoagglutinin titre sufficient to adversely affect platelet increments. Patients receiving ABO-mismatched platelets had a higher incidence of anti-HLA antibodies (5 v. 1) and platelet specific antibodies (4 v. 1). ABO-mismatched platelets transfused prior to the onset of refractoriness resulted in increments similar to those achieved by ABO-matched platelets. The study demonstrates that ABO-mismatched platelets are as effective as matched platelets in patients with low titre isoagglutinins requiring only few transfusions. However, the greater incidence of early refractoriness induced in MMG patients indicates that ABO-mismatched platelets should not be given to patients with marrow failure requiring long-term support.

Although many women relate the onset of urinary symptoms to the operation of simple hysterectomy, many also have symptoms prior to surgery. Prospective study is therefore the most valid method of objective analysis of the effects of this operation upon micturition. To determine whether total hysterectomy is associated with increased postoperative vesicourethral abnormality, the incidences of urinary symptoms and urodynamic abnormality were assessed pre and postoperatively in 36 women undergoing hysterectomy. Preoperative symptoms were present in 58.3%, although urodynamically proven dysfunction was found in only 38.9%. After hysterectomy, 75% of women were symptomatic with a further 30.6% developing a urodynamic abnormality. The operation of total (simple) hysterectomy is associated with a significant increase in the subjective and objective incidence of vesicourethral dysfunction.

The relationship between sodium handling and alveolar-arterial oxygen gradient (AaDO2) was studied in 26 preterm babies requiring ventilation from birth. The difference between sodium intake and urinary sodium excretion was determined in sequential, four hourly periods throughout the course of the respiratory illness. Sodium retention changed from positive (mean 1.42 mmol kg-1 day-1) during the phase of deteriorating respiratory function to negative (mean - 1.99 mmol kg-1 day-1) during improving respiratory function. This difference is highly significant (P less than 0.001). A temporal relationship is also shown, in the form of individual time plots of AaDO2 and sodium retention for each baby; changes in sodium handling parallel changes in AaDO2. The diuresis that accompanies improving respiratory function is characterised as a natriuresis, with free water clearance remaining unchanged before and after the point of improvement. We suggest that a primary change in sodium handling, triggered by postnatal respiratory adaptation, may initiate the contraction in extracellular fluid volume that characterises early postnatal existence.

To investigate the effect of needle size and number of passes into a tumour mass on the cell yield from a fine needle aspirate, an in vitro study was undertaken in 19 consecutive tumours removed surgically for biopsy. Different needle sizes (23G, 21G, 19G) passed in random order, five, ten and fifteen times into the tumours, were compared. The type of tumour, needle size and number of passes independently and significantly influenced cell yield. A 21G(green) needle passed into the tumour at least 10 times was the most efficient in obtaining cells. This in vitro study could explain the variation in the reported accuracy of fine needle aspiration cytology from groups using different techniques and is perhaps one reason why the highest diagnostic accuracy and the lowest rate of unsatisfactory aspirates comes from a centre which uses a 21G needle and at least 10 passes through the tumour.

Many women who present with symptoms of bladder dysfunction relate the onset to the operation of simple hysterectomy. A group of 42 women undergoing simple hysterectomy was studied prospectively. Urinary symptoms, urodynamic findings and sacral reflex latencies (SRLs) were assessed pre- and post-operatively. After hysterectomy the incidence of urinary symptoms increased from 58.3 to 75.0%. Vesicourethral dysfunction was altered in 30.6% of patients, 72.7% of whom had evidence of pelvic neuropathy as detected by SRLs. The results show that simple hysterectomy is associated with a significant incidence of post-operative vesicourethral dysfunction and that there is an identifiable neurological abnormality incurred at operation which is pertinent to the subsequent disordered voiding.

The development of elastic fibres in the upper urinary tract was studied in 31 fetuses ranging in ovulatory age from 10 to 24 weeks using special staining techniques for elastic fibres. The number, orientation and distribution of elastic fibres are described and correlated with age, ureteric level, and fetal weight. Significantly, before 10 weeks, elastic fibres were few in number, poorly developed, and randomly arranged. After 12 weeks, these fibres became more numerous at each level of the urinary tract, and were seen to develop specific orientation. The findings are described and potential clinical implications are discussed.