Health economics and quality of life in cancer trials: report based on a UKCCCR workshop. United Kingdom Coordinating Committee on Cancer Research.
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Clinical Trials as Topic↗
Biomedical subjects
L Davies
Publications and source records attributed to L Davies.
Delayed egg production and a possible group effect in the blowfly Calliphora vicina.
Protein-fed Calliphora vicina, F1 offspring of wild flies in two cages with lower and higher fly densities showed variable delay in starting oocyte vitellogenesis at ambient semi-natural temperatures in warm July-August weather in 1996 and 1997 at Durham in northern England (54 degrees 45' N). The high-density flies in 1996 showed no delay, in that the thermal sum (degree-days) experienced was 133, comparable to 18 degrees C constant, assuming the lower threshold for egg maturation to be 5 degrees C. Low-density cages and flies in a large outdoor cage (2 m3) in both years showed delays in production of first eggs of 34 days (thermal sum 293 degree-days) in 1996 and 32 days (396 degree-days) in 1997, and longer delays for other individuals. Delays in egg production at low densities relative to high densities seem to be a group effect of unknown mechanism.
Animals↗
The role of descending basal ganglia connections to the brain stem in parkinsonian akinesia.
Akinesia is the most disabling symptom of Parkinson's disease. The neural mechanisms underlying it probably involve the descending projections of the basal ganglia to the brain stem as it improves after a pallidotomy or subthalamic nucleotomy but not after a thalamotomy. We describe the effects of lesioning the pedunculopontine nucleus in the normal primate in generating an akinetic syndrome. The possible clinical implications of this study are discussed.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Fatty acid balance studies in term infants fed formula milk containing long-chain polyunsaturated fatty acids.
Long-chain polyunsaturated fatty acids (LCP) are thought to be required for optimal nervous system development in the newborn. A commercial milk formula containing LCP (Aptamil-LCP) with a fatty acid profile closely resembling breast milk, has recently been introduced for term infants. The absorption of fatty acids in term infants was examined in a double-blind randomized controlled trial comparing Aptamil-LCP (n = 20) and standard Aptamil (n = 20). Formula-fed newborn infants were studied from birth for 14 d. Fat balances (3 d) were performed from d 10. A 3-d stool collection was performed from d 10 in a parallel breastfed group (n = 21). Plasma samples were taken on d 6. Median fat excretion (mg kg[-1]) was 897.1, 615.0 and 355.2 with Aptamil, Aptamil-LCP and breastfeeding, respectively. The median total fat absorption coefficient in Aptamil-LCP-fed infants was higher than in those fed standard Aptamil (p < 0.01). These findings were accounted for by differences in the excretion and absorption of long-chain saturated fatty acids (C14:0, C16:0 and C18:0). Higher fat excretion was associated with bulkier and firmer stools. Only trace amounts of LCP were detected in the stools of all groups. This accounted for less than 4% of dietary intake in Aptamil-LCP-fed infants. No differences in the utilization of LCP from Aptamil-LCP and breast milk feeding were apparent. Plasma phospholipid fatty acid composition data reflected differences in dietary LCP intake. Thus, PL LCP levels were highest in the breastfed infants and lowest in the Aptamil-fed infants, with values for the Aptamil-LCP-fed group falling in between.
Analysis of Variance↗
Safety of plasmapheresis in the treatment of neurological disease.
BACKGROUND: Plasmapheresis is used as a treatment modality in several neurological disorders. Adverse reactions relating to vascular access, replacement fluid and anticoagulant use have been reported. AIMS: To establish the incidence of complications of therapeutic plasmapheresis in the treatment of neurological diseases. METHODS: A retrospective study was performed, in which case records of patients undergoing plasmapheresis for neurological indications between 1 April 1992 and 1 September 1996 were reviewed for fatalities and adverse reactions related to vascular access, transmission of Hepatitis B or C or Human Immunodeficiency Virus (HIV), fluid imbalance, allergic or febrile reactions, haematological complications, machine failure and citrate toxicity. RESULTS: In the study period, 1283 plasmapheresis procedures were performed on 73 patients with neurological disease. There were no fatalities, no cases of Hepatitis B or C or HIV transmission, no allergic or febrile reactions, thrombosis, bleeding diathesis or severe citrate toxicity. Infections related to venous access occurred in 0.5 per cent of procedures with septicaemia in 0.2 per cent of procedures (4.1% of patients). Less serious complications included hypotension in 1.2 per cent of procedures (11% of patients) and citrate toxicity manifesting as nausea, vomiting, cramping or paraesthesia in 1.2 per cent of procedures. Machine failure occurred in 0.2 per cent of procedures. CONCLUSIONS: Plasmapheresis is a safe procedure when performed for neurological indications by experienced personnel in a large pheresis unit. The most frequent adverse event is infection of the venous access site.
Adult↗
Elevated levels of NO in both unchallenged and LPS-challenged C. parvum-primed mice are attributable to the activity of a cytokine-inducible isoform of iNOS.
Elevated levels of nitric oxide (NO2-/NO3-) were detected in the serum of mice 3-7 days after priming with Corynebacterium parvum (Propionibacterium acnes). The serum NO2-/NO3- response was completely inhibited when C. parvum-primed (C. parrum) mice were treated with N(G)-monomethyl-L-arginine (L-NMMA) or aminoguanidine (AG) on days 6 and 7 post priming. The response was also inhibited when the mice were treated with interleukin-10 (IL-10) and the cytokine was most effective when given in multiple doses beginning on the day of priming. In contrast to L-NMMA and AG, IL-10 had no effect on the serum NO2-/NO3- response when administered to the mice on days 6 and 7 post priming. The inducible isoform of NOS (iNOS) appeared to be responsible for the elevated NO2-/NO3- response in C. parvum mice because iNOS transcripts were readily detected in their livers. Moreover, these transcripts as well as the circulating levels of NO2-/NO3- were dramatically reduced when the mice were treated with anti-tumor necrosis factor alpha (anti-TNF-alpha) or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibodies (mAbs) during the priming interval. There was a modest increase (less than twofold) in the serum NO2-/NO3- response following a lipopolysaccharide (LPS) challenge to C. parvum mice (C. parvum/LPS mice). LPS had a more dramatic stimulatory effect if the levels of NO2-/NO3- preexisting in C. parvum/LPS mice were reduced by treatment with L-NMMA, AG, or IL-10 before the challenge. Thus the levels of NO2-/NO3- that preexisted in C. parvum/LPS mice appeared to influence their ability to mount a NO2-/NO3- response subsequent to the LPS challenge. The NO2-/NO3- response did not contribute to lethality in C. parvum/LPS mice because anti-TNF-alpha and anti-IFN-gamma mAbs were protective but had no effect on serum NO2-/NO3- levels when administered to mice 24 h before the LPS challenge.
Animals↗
Clonic perseveration following thalamofrontal disconnection: a distinctive movement disorder.
We describe four patients who developed asymmetrical, rhythmic, stereotyped, and repetitive movements of the upper and lower limbs hours to days after infarction that involved the thalamus and/or basal ganglia. The movements appeared to occur spontaneously and were initially labeled as focal motor seizures, ballism, or tremor; they could however, be induced by passive movement of the limbs. The movements most commonly observed were scratching or rubbing movements of the hands that were of such persistence as to cause trauma to the skin; in the lower limbs, the heel was run up and down the bed sheet, often until it bled. The movements were part of a syndrome characterised initially by a reduced level of consciousness and followed by aspontaneity, usually with mutism and frontal release signs. One patient who had relatively preserved cognition and language repeated words or phrases again and again when encouraged to speak, but had no difficulty changing responses appropriately to different cues. In drawing, he overwrote each figure but could change the figure on command. The distinctive movement disorder in these patients was due to clonic perseveration. We suggest that clonic perseveration results from disconnection of prefrontal cortico-basal ganglia-thalamo-cortical loops that are important for the termination of motor plans. Clonic perseveration should be recognised as a movement disorder following thalamic lesions.
Aged↗
Quality managing in practice--using ISO 9002.
The value of an International Quality Standard in Orthodontic Practice is discussed. The nature of the process is described and relevant sources presented for further exploration of the subject. The relevance of ISO 9002 to orthodontic practice is highlighted.
Certification↗
Who contributes to the public health function?
BACKGROUND: This paper describes the current nature and distribution of staff making an active contribution to the public health function in Health Authorities in England, so as to assess the extent to which the public health function is truly multidisciplinary and to begin to consider the National Health Service public health capability. METHODS: A pre-piloted questionnaire was administered by Regional Directors of Public Health (RDsPH) to their respective District Directors of Public Health (DDsPH) in all Health Authorities in England over the period June 1995-April 1996. The questionnaire asked for details of all staff in Health Authorities contributing to the public health function as defined by the DDsPH. This provided distributions of: Public Health Physicians; Consultants in Dental Public Health (CsDPH); Trainees in Public Health Medicine (PHM); Epidemiologists; Research Officers; Nurses; Medical Advisers; Pharmacists; Directors of Health Promotion; Others (job titles specific to public health) in Health Authorities in England. RESULTS: Staff contributing to the public health function were distributed as follows: Public Health Physicians (32 per cent); Research or Information Officers and Epidemiologists (16 per cent); Trainees in Public Health Medicine (16 per cent); Nurses (8 per cent); Pharmacists (6 per cent); Medical Advisers (5 per cent); Directors of Health Promotion (4 per cent); Consultants in Dental Public Health (3 per cent); Others (job titles specific to public health) (11 per cent). CONCLUSION: The public health function is multidisciplinary, but the skill mix within Health Authorities is variable. The contribution of all disciplines to Health Authority public health functions needs recognition, not least in the provision of training, accreditation schemes and continuing professional development for all staff so as to secure an effective public health function at local levels to deliver the health agenda.
Clinical Competence↗
Morbidity and mortality of open lung biopsy in children.
OBJECTIVE: In patients with diffuse pulmonary infiltrates, when empiric therapy or less-invasive diagnostic procedures fail, physicians frequently resort to open lung biopsy (OLB) to provide a definite diagnosis and to help redirect therapeutic treatment. OLB is still widely regarded as a safe diagnostic procedure, even in the critically ill child. The objective of this study is to evaluate the accuracy of this view with regard to children with acute respiratory failure (ARF) and, for this purpose, compares the mortality and morbidity of such patients with those without ARF. DESIGN: Retrospective chart review. SETTING: University hospital. PATIENTS: Forty-two patients (mean age, 6.6 years) underwent 47 OLBs for undiagnosed diffuse pulmonary infiltrates between July 1984 and December 1994. Twenty-six patients (55%) were in ARF. Fifteen of these patients were intubated and receiving mechanical ventilatory support before the OLB procedure. RESULTS: The overall incidence of serious complications associated with the OLB procedure was 51%. Of the patients with ARF, 17 (65%) had at least one major complication compared with 3 (14%) of the patients without ARF. Pleural air complications (62% of the total) occurred only in patients with ARF: pneumothoraces and/or prolonged air leaks developed in 10 (38%) after their OLBs; 9 of these patients died, and 7 had pneumothorax complicating their chest tube removal, which required replacement chest tubes. All patients with ARF preoperatively required prolonged ventilatory support after the OLB procedure, whereas 90% of the patients without ARF could be extubated within 24 hours. Overall, 10 patients (24%) died after the OLB procedure. All deaths occurred in patients with ARF. Both ARF preoperatively and the presence of postoperative complications were significantly associated with decreased survival. CONCLUSIONS: The morbidity and mortality rates of children with ARF undergoing OLB for diffuse pulmonary infiltrates differ considerably from those of children without ARF. For children with ARF, OLB is associated with the risk of prolonged ventilatory support, recurrent pneumothoraces, and air leaks. These complications may be attributable to such patients' having diseased lungs with poor healing. Moreover, these complications may, in turn, contribute to the patients' poor outcomes.
Acute Disease↗
Cardiovascular consequences of fibreoptic bronchoscopy.
Fibreoptic bronchoscopy (FOB) is now commonly performed, and the number of elderly patients undergoing the procedure is increasing. Problems with oxygenation during FOB are well-recognised, but there are few data about its cardiovascular effects. Forty five patients (median age 65 yrs) undergoing elective FOB were studied prospectively. Patients were connected to a 12-lead computerized electrocardiographic recorder, a finger plethysmographic blood pressure (FPBP) monitor and pulse oximeter. Forty three patients were sedated with fentanyl and droperidol, and all were given 5 mL 2.5% cocaine intratracheally and xylocaine spray to the pharynx. Mean sphygmomanometric cuff blood pressure was raised initially (167/88 mmHg). Mean blood pressure recorded by FPBP rose on intratracheal injection (178/96 mmHg) and remained high throughout the procedure. Mean (SD) initial cardiac frequency was 93 (5.1) beats x min(-1) and rose to 134 (7.5) beats x min(-1) during the procedure. Four of the 45 patients showed unexpected ST segment depression of >1 mm for >1 min, and a further three developed bundle branch block. These seven patients had significantly greater tachycardia (152 vs 131 beats x min(-1)) and higher blood pressure (238/131 vs 207/109 mmHg). They were older (72 vs 61 yrs), had smoked more (63 vs 39 pack-years), but had similar lung function and similar changes in oxygen saturation. Oxygen desaturation occurred in 19 patients and this was associated with poor lung function (69 vs 84% predicted forced expiratory volume in one second), but was independent of the cardiovascular changes. Significant cardiovascular changes occur during fibreoptic bronchoscopy, with evidence of cardiac strain in 21% of patients over the age of 60 yrs.
Adjuvants, Anesthesia↗
A very peculiar practice.
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Capital Punishment↗
Intracerebroventricular neuropeptide Y produces hyperinsulinemia in the presence and absence of food.
Acute administration of neuropeptide Y into the hypothalamus or cerebral ventricles produces hyperphagia and hyperinsulinemia. However, it is not known to what extent the hyperinsulinemia depends on the food intake. Consequently, serum insulin and glucose, as well as food and water consumption, were measured over 3 h, following injection of 1-20 micrograms neuropeptide Y into the third ventricle of adult female rats. In the presence of food, 1-10 micrograms neuropeptide Y produced a dose-dependent increase in food and water intake and serum insulin. Insulin levels were closely correlated with the quantity of food ingested. In the absence of food, 1-20 micrograms neuropeptide Y produced a dose-dependent increase in water intake, whereas 1-5 micrograms produced a does-dependent increase in serum insulin. We concluded that ICV neuropeptide Y can stimulate insulin secretion even at low doses and this response does not completely depend on food intake.
Animals↗
A multinational economic evaluation of rhDNase in the treatment of cystic fibrosis.
Economic evaluations of pharmaceuticals are increasingly being conducted in conjunction with randomized phase III clinical trials to meet the demand for pharmacoeconomic data when new products are launched. While the need for such data is often global, the trials in which relevant information may be collected are often conducted in only one or a limited number of countries. A critical issue is how data from pivotal clinical trials in one setting can serve as the basis for pharmacoeconomic evaluations in others. We address this issue and report on four economic evaluations that we undertook in conjunction with a recent U.S. phase III clinical trial of recombinant human deoxyribonuclease (rhDNase), which is used to improve pulmonary function in patients with cystic fibrosis (CF). The objective of these evaluations was to estimate the potential impact of rhDNase therapy in France, Germany, Italy, and the United Kingdom on the direct costs of medical care for the treatment of respiratory tract infections (RTIs) in patients with CF. Analyses of economic impact were undertaken both with and without adjustment for differences in practice patterns between the United States and the countries of interest. Our findings suggest that rhDNase therapy may reduce the cost of RTI-related care by between US$600 and US$1,100 over a 24-week period; the cost of rhDNase is not included in these figures, as a price was unavailable when our analyses were undertaken. Despite methodologic challenges, economic evaluations that meet the information needs of decision makers in diverse countries can nonetheless be undertaken in conjunction with phase III clinical trials.
Clinical Trials, Phase III as Topic↗
Vasculitis confined to peripheral nerves.
The clinical, electrophysiological and pathological features and prognosis of 25 patients with vasculitis selectively affecting the peripheral nervous system were evaluated. Although most patients had a history of mononeuritis multiplex or an asymmetrical neuropathy six out of 25 had a symmetrical neuropathy, both clinically and on neurophysiological testing, by the time of presentation. There were no signs of accompanying systemic vasculitis in any of the patients and serological abnormalities were limited to an elevated erythrocyte sedimentation rate (ESR) in nine out of 21 patients and low titre anti-nuclear antibodies in four out of 20 patients. Most patients had a necrotizing vasculitis on nerve biopsy, although in some cases the diagnosis was made on the association of inflammatory cell infiltrates with extensive axonal degeneration and immune complex deposition on immunofluorescence studies. The mean time from symptom onset to diagnosis was 46 weeks. All patients were treated with corticosteroids and most with additional immunosuppressive therapy. In contrast to vasculitic neuropathy associated with systemic vasculitis the prognosis was good with 24 out of 25 survivors at a mean of 176 weeks follow-up having a mean improvement of 1.4 units on a six-point disability scale.
Adult↗
Vacuolar H(+)-ATPase and weak base action in Dictyostelium.
Amoebae of Dictyostelium discoideum release ammonia during development, and the accumulation of this weak base is believed to be responsible for inhibiting fruiting-body formation and switching aggregates into migrating slugs. Exposure to weak bases can also inhibit aggregation and cell-type specific gene expression. The pathway by which weak bases influence development is not understood. We show here that the development of a set of mutants defective in acidification of intracellular acidic compartments is abnormally sensitive to inhibition by weak bases. Moreover even in the absence of added weak bases these mutants are delayed in aggregation and have a protracted migratory phase. The same behaviour is observed in transformants harbouring an antisense construct for one of the vacuolar H(+)-ATPase subunits. These results support the idea that weak bases exert their effects by inhibiting acidification of an intracellular acidic compartment.
Acids↗
Bilateral total deafness due to pontine haematoma.
A 64 year old woman with a predominantly midline pontine tegmental haemorrhage presented with bilateral total deafness. One week later reasonable pure-tone thresholds appeared but she still had total bilateral loss of speech discrimination. At that time contralateral acoustic reflexes were bilaterally absent, whereas ipsilateral acoustic reflexes and waves IV and V of the brainstem auditory evoked potential were bilaterally preserved. It is proposed that this patient's hearing deficit was due to inactivation of the ventral acoustic striae decussating in the trapezoid body. This case supports the contention that in humans the ventral pontine acoustic decussation carries most of the neural signals required for hearing and perhaps all the neural signals required for speech perception.
Brain↗
Lung volume reduction surgery in chronic obstructive pulmonary disease.
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Humans↗