Wave energy absorption by a submerged air bag connected to a rigid float.

A new wave energy device features a submerged ballasted air bag connected at the top to a rigid float. Under wave action, the bag expands and contracts, creating a reciprocating air flow through a turbine between the bag and another volume housed within the float. Laboratory measurements are generally in good agreement with numerical predictions. Both show that the trajectory of possible combinations of pressure and elevation at which the device is in static equilibrium takes the shape of an S. This means that statically the device can have three different draughts, and correspondingly three different bag shapes, for the same pressure. The behaviour in waves depends on where the mean pressure-elevation condition is on the static trajectory. The captured power is highest for a mean condition on the middle section.

The Patient Assessment of Chronic Illness Care produces measurements along a single dimension: results from a Mokken analysis.

BACKGROUND: As the worldwide prevalence of chronic illness increases so too does the demand for novel treatments to improve chronic illness care. Quantifying improvement in chronic illness care from the patient perspective relies on the use of validated patient-reported outcome measures. In this analysis we examine the psychometric and scaling properties of the Patient Assessment of Chronic Illness Care (PACIC) questionnaire for use in the United Kingdom by applying scale data to the non-parametric Mokken double monotonicity model. METHODS: Data from 1849 patients with long-term conditions in the UK who completed the 20-item PACIC were analysed using Mokken analysis. A three-stage analysis examined the questionnaire's scalability, monotonicity and item ordering. An automated item selection procedure was used to assess the factor structure of the scale. Analysis was conducted in an 'evaluation' dataset (n = 956) and results were confirmed using an independent 'validation' (n = 890) dataset. RESULTS: Automated item selection procedures suggested that the 20 items represented a single underlying trait representing "patient assessment of chronic illness care": this contrasts with the multiple domains originally proposed. Six items violated invariant item ordering and were removed. The final 13-item scale had no further issues in either the evaluation or validation samples, including excellent scalability (Ho = .50) and reliability (Rho = .88). CONCLUSIONS: Following some modification, the 13-items of the PACIC were successfully fitted to the non-parametric Mokken model. These items have psychometrically robust and produce a single ordinal summary score. This score will be useful for clinicians or researchers to assess the quality of chronic illness care from the patient's perspective.

Hierarchical radial and polar organisation of chromosomes in human sperm.

It is well established that chromosomes occupy distinct positions within the interphase nuclei, conferring a potential functional implication to the genome. In addition, alterations in the nuclear organisation patterns have been associated with disease phenotypes (e.g. cancer or laminopathies). The human sperm is the smallest cell in the body with specific DNA packaging and the mission of delivering the paternal genome to the oocyte during fertilisation. Studies of nuclear organisation in the sperm have postulated nonrandom chromosome position and have proposed a chromocentre model with the centromeres facing toward the interior and the telomeres toward the periphery of the nucleus. Most studies have assessed the nuclear address in the sperm longitudinally predominantly using centromeric or telomeric probes and to a lesser extent with whole chromosome paints. To date, studies investigating the radial organisation of human sperm have been limited. The purpose of this study was to utilise whole chromosome paints for six clinically important chromosomes (18, 19, 21, 22, X, and Y) to investigate nuclear address by assessing their radial and longitudinal nuclear organisation. A total of 10,800 sperm were analysed in nine normozoospermic individuals. The results have shown nonrandom chromosome position for all chromosomes using both methods of analysis. We present novel radial and polar analysis of chromosome territory localization within the human sperm nucleus. Specifically, a hierarchical organisation was observed radially with chromosomes organised from the interior to the periphery (chromosomes 22, 21, Y, X, 19, and 18 respectively) and polar organisation from the sperm head to tail (chromosomes X, 19, Y, 22, 21, and 18, respectively). We provide evidence of defined nuclear organisation in the human sperm and discuss the function of organisation and potential possible clinical ramifications of these results in regards to male infertility and early human development.

Is there still a place for emergency department thrombolysis following the introduction of the amended Joint Royal Colleges Ambulance Liaison Committee criteria for thrombolysis?

OBJECTIVE: To apply the current (2004) and the amended (2006) Joint Royal Colleges Ambulance Liaison Committee (JRCALC) criteria for paramedic initiated thrombolysis to all patients who received thrombolytic treatment in an emergency department (ED) to determine if the amendments increase the proportion suitable for paramedic initiated thrombolysis. DESIGN: Retrospective descriptive analysis. METHOD: The ED clinical notes, ambulance clinical record and the first recorded ECG (ED or ambulance) of all patients thrombolysed in the ED during a 12 month period were reviewed against the previous JRCALC guidelines (2004) and the amended JRCALC guidelines (2006) for thrombolysis. RESULTS: Using the JRCALC guidelines (2004), 26 of the 147 patients (17.7%) were eligible for paramedic initiated thrombolysis. Using the JRCALC guidelines (2006), this increased to 41 (27.9%). This difference was statistically significant (McNemar's I2 test with 1 degree of freedom = 15.00; p<0.001). The change to the blood pressure, age and pulse rate parameters has increased the percentage eligible for paramedic initiated thrombolysis by 10.2% (95% confidence interval 4.6% to 15.8%). CONCLUSION: The amended JRCALC guidelines (2006) for paramedic initiated thrombolysis have successfully increased the proportion of patients suitable for prehospital thrombolysis by approximately 10%, although the ED retains an important role in the provision of prompt thrombolytic treatment for a proportion of patients.

Dynamics of bone marrow changes in patients with chronic idiopathic myelofibrosis following allogeneic stem cell transplantation.

Scant knowledge exists about the dynamics of fibro-osteosclerotic bone marrow (BM) lesions and regeneration of hematopoiesis following allogeneic peripheral stem cell transplantation (SCT) in chronic idiopathic myelofibrosis. Therefore, an immunohistochemical and morphometric study was performed on BM biopsies in 20 patients before and at standardized intervals (days 30 through 384) following SCT. In responding patients, a total regression of the pretransplant increased fibrosis was completed in the posttransplant period after about six months, while the extent of osteosclerosis did not change significantly during observation time. The quantity of CD61+ megakaryocytes including precursors was strikingly variable after SCT and, by using planimetric methods, atypical microforms exhibiting a dysplastic aspect could be demonstrated. These anomalies may be responsible for posttransplant thrombocytopenia. CD34+ progenitor cells were increased before transplantation, however, their number declined rapidly to normal values in responding patients. Nucleated erythroid precursors revealed a decreased amount before and after SCT accounting for anemia. Large clusters of this cell lineage indicated an initial hematopoietic reconstitution comparable with the expansion of the neutrophil granulopoiesis. Proliferative activity and apoptosis showed an increase until one year after SCT that implied a still regenerating hematopoiesis in keeping with an enhanced cell turnover.

Prescribing patterns in high-need Health Authority populations: how does an ethnically mixed composition affect volume and cost?

BACKGROUND: Prescribing is the most common therapeutic intervention in primary care, and there is substantial variation in prescribing practice across England. We investigate broad patterns of prescribing across Health Authorities in England, concentrating on ethnically diverse populations. METHODS: Initially we examined the association between a number of prescribing indicators from the Prescribing Support Unit Prescribing Toolkit and 'Needs Profiles'. We then considered whether the observed patterns of prescribing were appropriate, that is, could be largely explained by variations in the prevalence of a medical condition for which the corresponding group of drugs would be prescribed. RESULTS: The volume and cost of prescribing was generally lower in more ethnically diverse Health Authority populations when compared with more elderly or deprived populations. There was a significant negative association between ethnic composition and net-ingredient-cost per patient of cardiovascular drugs, but this disappeared upon adjusting for mortality from coronary heart disease. CONCLUSIONS: The volume and cost of prescribing was generally lower in more ethnically diverse Health Authority populations relative to other high-need population profiles. Further work on this subject matter is merited, particularly if individual level data is available.

Quality assessment for three common conditions in primary care: validity and reliability of review criteria developed by expert panels for angina, asthma and type 2 diabetes.

OBJECTIVES: To field test the reliability, validity, and acceptability of review criteria for angina, asthma, and type 2 diabetes which had been developed by expert panels using a systematic process to combine evidence with expert opinion. DESIGN: Statistical analysis of data derived from a clinical audit, and postal questionnaire and semi-structured interviews with general practitioners and practice nurses in a representative sample of general practices in England. SETTING: 60 general practices in England. MAIN OUTCOME MEASURES: Clinical audit results for angina, asthma, and type 2 diabetes. General practitioner and practice nurse validity ratings from the postal questionnaire. RESULTS: 54%, 59%, and 70% of relevant criteria rated valid by the expert panels for angina, asthma, and type 2 diabetes, respectively, were found to be usable, valid, reliable, and acceptable for assessing quality of care. General practitioners and practice nurses agreed with panellists that these criteria were valid but not that they should always be recorded in the medical record. CONCLUSION: Quality measures derived using expert panels need field testing before they can be considered valid, reliable, and acceptable for use in quality assessment. These findings provide additional evidence that the RAND panel method develops valid and reliable review criteria for assessing clinical quality of care.

Identifying predictors of high quality care in English general practice: observational study.

OBJECTIVES: To assess variation in the quality of care in general practice and identify factors associated with high quality care. DESIGN: Observational study. SETTING: Stratified random sample of 60 general practices in six areas of England. OUTCOME MEASURES: Quality of management of chronic disease (angina, asthma in adults, and type 2 diabetes) and preventive care (rates of uptake for immunisation and cervical smear), access to care, continuity of care, and interpersonal care (general practice assessment survey). Multiple logistic regression with multilevel modelling was used to relate each of the outcome variables to practice size, routine booking interval for consultations, socioeconomic deprivation, and team climate. RESULTS: Quality of clinical care varied substantially, and access to care, continuity of care, and interpersonal care varied moderately. Scores for asthma, diabetes, and angina were 67%, 21%, and 17% higher in practices with 10 minute booking intervals for consultations compared with practices with five minute booking intervals. Diabetes care was better in larger practices and in practices where staff reported better team climate. Access to care was better in small practices. Preventive care was worse in practices located in socioeconomically deprived areas. Scores for satisfaction, continuity of care, and access to care were higher in practices where staff reported better team climate. CONCLUSIONS: Longer consultation times are essential for providing high quality clinical care. Good teamworking is a key part of providing high quality care across a range of areas and may need specific support if quality of care is to be improved. Additional support is needed to provide preventive care to deprived populations. No single type of practice has a monopoly on high quality care: different types of practice may have different strengths.

Methodological issues in the development of a national database for primary care groups and trusts.

At the National Primary Care Research and Development Centre (NPCRDC) we have constructed a national database for all primary care groups (PCGs) in England. At its core, the database links information about population socio-economic and demographic characteristics to generic health status and to the organisation, resourcing and activities of general practice. In this paper we describe and discuss the problems with linking these data, and with defining the boundaries and the local populations of PCGs, given that they have been established on the basis of administrative expediency rather than geographical coherence. We then consider the implications of these difficulties for needs assessment in primary care groups.

Ozone absorption in the human nose during unidirectional airflow.

This study addresses the effect of gas flow rate and ozone (O(3)) concentration on the uptake of this air pollutant in the nose. A nasal exposure system was developed in which a constant flow of humidified air (V) containing a constant concentration of O(3) (C(inlet)) entered one nostril and then exited the other nostril while a subject closed the velopharyngeal aperture. Experiments were conducted on 10 healthy nonsmokers for whom O(3) concentration was measured at the inlet nostril and the outlet nostril to determine the fraction of inhaled O(3) that was absorbed into the nasal mucosa (Lambda(nose)). Lambda(nose) decreased from 0.80 +/- 0.02 to 0.33 +/- 0.02 (SE) when V was increased from 3 to 15 l/min and C(inlet) was fixed at 0.4 ppm. Analysis of these data with a mathematical model indicated that O(3) uptake was limited by diffusion reaction through mucus, rather than by convective diffusion through the respired gas. A small decrease in Lambda(nose) from 0.36 +/- 0.02 to 0.32 +/- 0.01 was also observed when C(inlet) was increased from 0.1 to 0.4 ppm at a fixed V of 15 l/min. This may have been due to nonlinear reaction kinetics between O(3) and reactive substrates in mucus or an active response by a physiological process such as mucus secretion or transepithelial water influx.

General practitioner services in primary care groups in England: is there inequity between service availability and population need?

This study examined the coverage of minor surgery, child health surveillance and chronic disease management for asthma and diabetes in relation to population need and key organisational features of general practice in the 481 primary care groups (PCGs) in England. PCG-level summary scores were developed to estimate the relative availability of all four services and their relative importance in discriminating between high and low levels of service provision. The coverage of services was widespread and, in such circumstances, there was no systematic evidence of poorer service availability for PCGs with higher population need (the 'inverse care' law). Rather this relation was localised, being most predominant for PCGs covering London and its suburbs. In these PCGs, there was no association between indicators of lack of capacity, such as single-handed practice, and levels of service provision.

Molecular complexity and its impact on the probability of finding leads for drug discovery.

Using a simple model of ligand-receptor interactions, the interactions between ligands and receptors of varying complexities are studied and the probabilities of binding calculated. It is observed that as the systems become more complex the chance of observing a useful interaction for a randomly chosen ligand falls dramatically. The implications of this for the design of combinatorial libraries is explored. A large set of drug leads and optimized compounds is profiled using several different properties relevant to molecular recognition. The changes observed for these properties during the drug optimization phase support the hypothesis that less complex molecules are more common starting points for the discovery of drugs. An extreme example of the use of simple molecules for directed screening against thrombin is provided.

Novel three-dimensional capillary electrophoresis system for complex and trace analysis.

A novel triple column capillary electrophoresis system is described. Design specifications facilitate method development and analyses by providing on-line, selective, pre-concentration and clean-up of both high (ml) and low (microl) volumes of specific analytes in two dimensions and separation via an additional third dimension. The system described additionally provides four distinct detection capabilities via both contactless conductivity and UV. The addition of a third dimension to the previously reported "coupled-column" systems, and further modifications made, has allowed for optimal identification, separation, and quantitation of micro-components in complex mixtures. The ability to perform both capillary zone electrophoretic and isotachophoretic separations on-line and in any combination enhances the scope for rapid analytical method development and analysis of complex or trace sample components.

Where are the GaPs? A rational approach to monomer acquisition and selection.

Gridding and partitioning (GaP) is a computational method for the classification and selection of monomers for combinatorial libraries. The molecules are described in terms of the pharmacophoric groups they contain and where those pharmacophoric groups can be located in three-dimensional space. The approach involves a detailed conformational analysis of each molecule. This conformational analysis is done within a common coordinate frame, thus enabling the monomers to be compared. The use of a partitioned space is central to this particular application as it facilitates the identification of regions of space which are not well represented by existing compounds. Several ways to extend the use of partitioned pharmacophore spaces are described. Applications of the approach in monomer acquisition and in library design are outlined.

Symptom attribution and the recognition of psychiatric morbidity.

OBJECTIVE: Patients' interpretation of ambiguous physical symptoms may influence illness presentation in primary care. The present study sought to investigate the influence of symptom attribution style on the recognition of psychiatric morbidity by general practitioners (GPs). METHODS: Patients consulting GPs completed assessments of attribution style and General Health Questionnaires (GHQs), while GPs provided independent ratings of psychiatric distress. Analysis examined the relationship between patient demographic variables, attribution style (using the Symptom Interpretation Questionnaire [SIQ]), and GP and GHQ assessments of patients' mental health. RESULTS: The results indicate that severity of disorder and patient age were reliable predictors of recognition: normalizing and psychological attributions were additional predictors in some analyses, but their effects were inconsistent. CONCLUSIONS: The results provide some support for the role of symptom attribution in the recognition of psychiatric morbidity, but suggest that the predictive value of such attributions may be relatively modest. The SIQ may not be the optimum instrument for the measurement of attributions.

PLUMS: a program for the rapid optimization of focused libraries.

PLUMS is a new method to perform rational monomer selection for combinatorial chemistry libraries. The algorithm has been developed to optimize focused libraries with specific two-dimensional and/or three-dimensional properties. A preliminary step is the identification of those molecules in the initial virtual library which satisfy the imposed property constraints; we define these molecules as the virtual hits. From the virtual hits, PLUMS generates a starting library, which is the true combinatorial library that includes all the virtual hits. Monomers are then removed in an iterative fashion, thus reducing the size of the library. At each iteration, the worst monomer is removed. Each sublibrary is selected using a global scoring function, which balances effectiveness and efficiency. The iterative process continues until one is left with a library that consists entirely of virtual hits. The optimal library, which is the best compromise between effectiveness and efficiency, can then be selected according to the score. During the iterative process, equivalent solutions may well occur and are taken into account by the algorithm, according to a user-defined parameter. The number of monomers for each substitution site and the size of the library are parameters that can be either optimized or used to constrain the selection. The results obtained on two test libraries are presented. PLUMS was compared with genetic algorithms (GA) and monomer frequency analysis (MFA), which are widely used for monomer selection. For the two test libraries, PLUMS and GA gave equivalent results. MFA is the fastest method, but it can give misleading solutions. Possible advantages and disadvantages of the different methods are discussed.

Implementation of a system for reagent selection and library enumeration, profiling, and design.

We describe an integrated suite of computational tools which are used to assist in the selection of compounds for biological assays and the design of combinatorial libraries. These functions are delivered in a platform-independent manner via a corporate intranet and are used by computational experts and nonexperts alike. While the system was primarily designed to be used prior to synthesis, it can also be used to provide structural information for library registration and for decoding beads in tagged libraries. We describe a simple statistical method for monomer selection and compare it to computationally more demanding approaches.

Strategic pooling of compounds for high-throughput screening.

Bringing new medicines to the market depends on the rapid discovery of new and effective drugs, often initiated through the biological testing of many thousands of compounds in high-throughput screening (HTS). Mixing compounds together into pools for screening is one way to accelerate this process and reduce costs. This paper contains both theoretical and experimental data which suggest that careful selection of compounds to be pooled together is necessary in order to reduce the risk of reactivity between compounds within the pools.

The effect of panel membership and feedback on ratings in a two-round Delphi survey: results of a randomized controlled trial.

BACKGROUND: Past observational studies of the RAND/UCLA Appropriateness Method have shown that the composition of panels affects the ratings that are obtained. Panels of mixed physicians make different judgments from panels of single specialty physicians, and physicians who use a procedure are more likely to rate it more highly than those who do not. OBJECTIVES: To determine the effect of using physicians and health care managers within a panel designed to assess quality indicators for primary care and to test the effect of different types of feedback within the panel process. METHOD: A two-round postal Delphi survey of health care managers and family physicians rated 240 potential indicators of quality of primary care in the United Kingdom to determine their face validity. Following round one, equal numbers of managers and physicians were randomly allocated to receive either collective (whole sample) or group-only (own professional group only) feedback, thus, creating four subgroups of two single-specialty panels and two mixed panels. RESULTS: Overall, managers rated the indicators significantly higher than physicians. Second-round scores were moderated by the type of feedback received with those receiving collective feedback influenced by the other professional group. CONCLUSIONS: This paper provides further experimental evidence that consensus panel judgments are influenced both by panel composition and by the type of feedback which is given to participants during the panel process. Careful attention must be given to the methods used to conduct consensus panel studies, and methods need to be described in detail when such studies are reported.