A clinical comparison of indices of pulmonary gas exchange with changes in the inspired oxygen concentration

Several indices have been introduced as convenient alternatives to calculation of the physiological shunt fraction (Qs/QT) for the assessment of pulmonary gas exchange. These include: the arterial-alveolar oxygen tension ratio (a/APO2), the arterial oxygen tension-inspired oxygen concentration ratio (PaO2/FIO2), the respiratory index (RI), [A-a)DO2/PaO2) and the alveolar-arterial oxygen tension difference [A-a)Do2). These indices are in use clinically despite the fact that they may not accurately predict gas exchange in situations where FIO2, Qs/QT or arterial-venous oxygen content is changing. The clinical stability of each of these indices, relative to the behaviour of the physiological shunt, was therefore investigated prospectively in ten mechanically ventilated postoperative adults as FIO2 was varied from 0.30 to 1.00. None of the indices studied reliably reflected the behaviour of the physiological shunt. As FIO2 was increased incrementally from 0.30 to 1.00, 42 to 55 per cent of the measured changes in these indices were opposite in direction to the corresponding changes in the physiological shunt. The maximum magnitudes of the opposite changes were substantial; 24 and 22 per cent for the a/APO2 and PaO2/FIO2 ratio respectively, 67 per cent for the RI and 101 per cent for the (A-a)DO2. We conclude that the use of any of these indices for clinical assessment of a patient's gas exchange defect when FIO2 is varying can be substantially misleading.     

An analysis of multinucleated blastomere formation in human embryos

Human embryos were disaggregated into component blastomeres42–72 h after insemination. The blastomeres were scoredfor the number of nuclei present and blastomeres of known nuclearmorphology were returned to individual culture drops for 16–20h, after which they were scored for cleavage and nuclear morphology.In all, 48% of mononucleated blastomeres cleaved during thisperiod, but only 76% of these produced two mononucleated daughterblastomeres; in the remainder, one or more of the blastomereswas abnormally nucleated. During overnight culture, 30% of multinucleatedblastomeres and 30% of anucleate blastomeres cleaved, the majorityproducing abnormally nucleated daughter blastomeres. The majorityof blastomeres which showed no sign of cleavage after overnightculture retained the same nuclear morphology as when originallydisaggregated. However, a small number of mononucleated blastomerescontained two nuclei after culture, indicating that karyokinesismay have taken place in the absence of cytokinesis. Overall,30% of blastomeres with more than one nucleus seemed to ariseby this mechanism, the remainder probably arising by errorsof chromosome segregation and/or packaging at mitosis. In addition,25/111 mononucleated daughter cells arose either after abnormaldivision of mononucleated parent cells or after division ofmultinucleated cells, suggesting that 23% of newly formed mononucleatedcells might be chromosomally abnormal. The results of DNA quantitationindicated that very few (12/131, 9.2%) blastomeres (whetheruni-or multinucleated) had a DNA content outside the 2-4C range.The embryos used for these studies had been cultured in oneof three commonly used in-vitro fertilization (IVF) media: modifiedT6, Earle's balanced salts or Universal IVF medium (a commercialmedium from Medi-Cult). A retrospective analysis was carriedout of the number of embryos containing multinucleated blastomeresat disaggregation and of the total proportion of isolated blastomereswhich were multinucleated in three groups of embryos, each ofwhich had been cultured in one of the IVF media. Both theseparameters were found to vary between cohorts of embryos culturedin the different media. The mechanism(s) by which culture mediumcomposition might affect multinucleation of human blastomeresis discussed, as is the significance of these data for reliablepreimplantation diagnosis of genetic status. aberrant cleavage/acytokinesis/culture medium/multinucleated blastomeres     

'If a Patient is Too Costly They Tend to Get Rid of You:' The Impact of People's Perceptions of Rationing on the Use of Primary Care

Despite the increasing focus on rationing, and rationing decisions in the NHS, little attention has been given to patient's perceptions of rationing and the potential impact this might have on people's use of services. Drawing on the qualitative findings of a study conducted in the North West of England which was concerned with the pattern and processes of primary care help seeking, this paper sets out to examine perceptions and experiences of rationing in primary care and the potential impact this has on people's use of services. In relation to primary care services people had experienced rationing by deterrence, dilution and delay. There was some evidence that perceptions of rationing impacted on help seeking and the use of primary care services. The implications for understanding the way in which perceptions of rationing might influence the formulation of demand and help seeking by people using primary care services are discussed. This revised version was published online in August 2006 with corrections to the Cover Date.     

Public involvement in health care priority setting: an economic perspective

Background  Public involvement in health care decision making and priority setting in the UK is being promoted by recent policy initiatives. In 1993, the British Medical Association called for public consultation where rationing of services was to be undertaken. The approach to priority setting advocated by many health economists is the maximization of quality adjusted life years (QALYs). Typically, for a particular health care programme, the QALY calculation takes account of four features: (1) the number of patients receiving the programme, (2) the survival gain, (3) the gain in quality of life and, (4) the probability of treatment success. Only one feature, that relating to quality of life, is based upon public preferences. If the QALY is to be used as a tool for health care resource allocation at a societal level then it should incorporate broader societal preferences.
Methods  This study used an interview-based survey of 91 members of the general public to explore whether the traditional QALY maximization model is a good predictor of public responses to health care priority setting choices.
Results and conclusions  Many respondents did not choose consistently in line with a QALY maximization objective and were most influenced by quality of life concerns. There was little support for health care programmes that provided a prognostic improvement but left patients in relatively poor states of health. The level of respondent engagement in the survey exercise was not sensitive to the provision of supporting clinical information.     

Medicine misuse or drug abuse? A critical appraisal of current issues and research in the UK

During the last decade consumption of licit medications and illicit drugs has risen substantially. It is estimated that the 100 000–200 000 severely dependent drug misusers in the UK generate social costs of 3–4 billion annually, while the cost of prescribed medicines for the entire population is currently 5 billion. Although attitudes and behaviours have been extensively researched, they remain complex and often contradictory. In particular, little is known of how perceptions of the benefits and risks of chemical substances influence behaviour. At an epidemiological level, new methods such as capture–recapture are being used to delineate forms of drug abuse which have previously not been detected in household surveys. There are few current data on the extent of inappropriate medicine prescribing, although there are various initiatives to promote rational and cost-effective prescribing. Reasons for inappropriate medicine use include patient expectations, prescribers' perceptions of patients and drug company marketing. Advances in basic science are revealing hitherto unsuspected consequences of both licit and illicit drug use. Examples include (1) the role of analgesics in causing severe headache and (2) suppression of immune functioning due to Ecstasy. One illustration of changing attitudes, as a result of public and medical pressure, is the growing call for the licensing of cannabis for medicinal use, particularly for intractable conditions such as multiple sclerosis. With the recently announced drug strategy promising a shift towards evidence-based decision-making, innovative research is required to improve the currently fragmentary view of the general population's attitudes and behaviour in relation to medicines and drugs.     

Testing the reliability of a new measure of life events and experiences in childhood: The Psychosocial Assessment of Childhood Experiences (PACE)

There are few well validated instruments for measuring the impact of life events and experiences in childhood and adolescence. This study examines the reliability of a new instrument, the Psychosocial Assessment of Childhood Experiences of PACE. Fifteen children and parents were interviewed on two cassions ten days apart for the main test-retest reliability study. About half of the events recorded were reported on both occasions (0.45% and 0.55% concordance). When the impact of specific events was examined much higher levels of agreement were found. Inter-rater reliability tests also yielded higher rate (Kappa 0.74 and above). Possible reasons for these important differences are discussed and the inherent methodological difficulties considered.

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Zusammenfassung Es existieren nur wenige gut validierte Meßinstrumente zur Erfassung von Lebensereignissen und Erfahrungen im Kindes- und Jugendalter. Diese Studie untersucht die Reliabilität eines neuen Verfahrens, des Psychosocial Assessment of Childhood Experiences oder PACE. 15 Kinder und Elternteile wurden zweimal im Abstand von 10 Tagen für die Überprüfung der Haupttest-Retest-Reliabilität interviewt. Ca. die Hälfte aller Ereignisse, die beim Interview berichtet wurden, wurdem beim Zweitinterview ebenfalls angegeben (Konkordanzen 0,45 und 0.55). Deutlich höhere Übereinstimmungen fanden sich bei Untersuchung der Auswirkungen spezifischer Ereignisse. Die Inter-Rater-Reliabilitätstests ergaben ebenfalls höhere Werte (Kappa 0.74). Mögliche Ursachen dieser wichtigen Unterschiede werden unter Berücksichtigung der inhärenten methodischen Schwierigkeiten diskutiert.

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Résumé II y a peu d'instruments correctement validés de mesures de l'impact des événements de vie des expériences dans l'enfance et l'adolescence. Cette étude examine la fiabilité d'un nouvel instrument, l'évaluation psycho-sociale des expériences infantiles (Psychosocial Assessment of Childhood Experiences ou PACE). 15 enfants et parents furent interrogés à deux reprises à 10 jours d'intervalle pour evaluer la fiabilité test-retest. Environ la moitié des événements rapportés le furent dans les deux occasions (0.45% et 0.55% de concordance). Quand l'impact des événements déviés spécifiques fut étudié un niveau plus élevé de concordance fut trouvé. La fidélité inter-cotateurs des tests obtinet également des taux plus élevés (kappa 0.74 et audessus). Les raisons possibles de ces différences sont discutées et les difficultés méthodologiques inhérentes prises en compte.

     

Pharmacokinetics and pharmacodynamics of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione in patients with postmenopausal breast cancer

Summary The pyridylglutarimide 3-ethyl-3-(4-pyridyl)-piperidine-2,6-dione (PyG) is a novel inhibitor of aromatase that was shown to cause effective suppression of plasma oestradiol levels in postmenopausal patients. In four patients receiving oral doses of PyG (500 mg) twice daily for 3–4 days, oestradiol levels fell to 31.1%±6.3% of baseline values within 48 h and remained suppressed during treatment. Of a further six patients who received oral PyG (1 g) as a single dose, five had quantifiable oestradiol levels. Oestradiol suppression was sustained for 36 h and recovery correlated with a fall of PyG concentrations below a threshold value of ca. 2 g/ml. The pharmacokinetics of PyG were non-linear and, when fitted to the integrated Michaelis-Menten equation, yielded good parameter estimates forC _o (21.7±1.82 g/ml),K _m (2.66±0.68 g/ml) and V_max (0.86±0.06 g ml^–1 h^–1). On subsequent repeated dosing with PyG, both theK _m (4.31±0.48 g/ml) and the V_max (1.83±0.13 g ml^–1 h^–1) values increased and recovery from oestradiol suppression was more rapid, indicating that PyG induces its own metabolism.Abbreviations PyG 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione - AG aminoglutethimide - CSCC cholesterol side-chain cleavage - HPLC high-performance liquid chromatography - AUC area under the concentration versus time curve This study was supported in part by grants to the Institute of Cancer Research (Royal Cancer Hospital) from the Cancer Research Campaign and Medical Research Council