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.

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.

Chemoinformatics--a new name for an old problem?

Library chemistry and high-throughput screening require greater use of chemoinformatics to increase their effectiveness. Recent advances in chemoinformatics include new molecular descriptors and pharmacophore techniques, statistical tools and their applications. Visualisation methods and hardware development are also opening new opportunities. The advent of a chemically aware web language and cross-platform working is ensuring that chemoinformatics methods are becoming available to all chemists in a more appropriate manner. Much time will continue to be wasted with incompatible file types without internationally agreed standards.

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.

A series of penicillin-derived C2-symmetric inhibitors of HIV-1 proteinase: structural and modeling studies.

The binding modes of a series of penicillin-derived C2 symmetric dimer inhibitors of HIV-1 proteinase were investigated by NMR, protein crystallography, and molecular modeling. The compounds were found to bind in a symmetrical fashion, tracing and S-shaped course through the active site, with good hydrophobic interactions in the S1/S1' and S2/S2' pockets and hydrogen bonding of inhibitor amide groups. Interactions with the catalytic aspartates appeared poor and the protein conformation was very similar to that seen in complexes with peptidomimetics, in spite of the major differences in ligand structure.

A series of penicillin derived C2-symmetric inhibitors of HIV-1 proteinase: synthesis, mode of interaction, and structure-activity relationships.

The C2-symmetric diester 1 was identified by random screening as a novel inhibitor of HIV-1 proteinase. This led to the preparation of a series of related more potent amides from readily accessible penicillins. Many of the compounds showed potent antiviral activity in HIV-1-infected MT-4 cells and an ability to inhibit syncytia formation in infected C8166 cells, with no evidence of cytotoxicity. The compounds showed no activity against other aspartyl proteinases (renin, pepsin, and cathepsin D). Structure-activity relationships support a symmetrical interaction with the enzyme. Pharmacokinetic evaluation of the ethylamide 3 revealed it was subject to rapid plasma clearance and had low oral bioavailability.

Synthesis and anti-HIV-1 activity of a series of imidazo[1,5-b]pyridazines.

A series of substituted imidazo[1,5-b]pyridazines have been prepared and tested for inhibitory activity against the reverse transcriptase of HIV-1 (RT) and their ability to inhibit the growth of infected MT-4 cells. Crystal data are reported on two compounds, 15c and 33. From the structure-activity relationships developed within this and other series, it is proposed that key features of the interaction with RT include hydrogen-bond acceptor and aromatic pi-orbital bonding with the imidazopyridazine nucleus and a benzoyl function separated from the heterocycle by a suitable spacer group. Exceptional activity against the reverse transcriptase of HIV-1 (IC50 = 0.65 nM) was obtained with a 2-imidazolyl-substituted derivative, 7-[2-(1H-imidazol-1- yl)-5-methylimidazo-[1,5-b]pyridazin-7-yl]-1-phenyl-1-heptanone (33) which is attributed to additional binding of the imidazole sp2 nitrogen atom. A number of the compounds in this series also inhibit the replication of HIV-1 in vitro in MT-4 and C8166 cells at levels observed with the nucleoside AZT.

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.

Respiratory responses to CO2 rebreathing in lung transplant recipients.

To evaluate the respiratory responses after lung transplantation, we studied the hypercarbic ventilatory response in 20 patients with severe obstructive pulmonary disease and compared it with that of 10 normal subjects. Eleven patients underwent bilateral lung transplantation and 9 patients had single-lung transplantation. All patients had preoperative hypercapnia (51.3 +/- 9.7 mm Hg) and blunted slopes of CO2 rebreathing curves for minute ventilation (0.39 +/- 0.20 L.min-1.mm Hg-1) and inspiratory occlusion pressure (0.35 +/- 0.30 s-1). The hypercapnia and blunted ventilatory responses persisted at the initial postoperative test (5.8 +/- 2.0 days) despite improved pulmonary function (preoperative forced expiratory volume in 1 second [FEV1], 0.57 +/- 0.16 L; initial postoperative FEV1, 1.83 +/- 0.65 L; p < 0.001). By the 15th to 30th postoperative day (21.3 +/- 6.0 days), compared with preoperative and initial postoperative values, end-tidal CO2 had normalized (40.6 +/- 6.9 versus 51.3 +/- 9.7 and 49.6 +/- 10.3 mm Hg; p < 0.005) and was coupled with enhanced ventilatory responses for the rebreathing curve for minute ventilation (1.26 +/- 0.7 versus 0.39 +/- 0.20 and 0.32 +/- 0.32 L.min-1.mm Hg-1; p < 0.005) and the inspiratory occlusion pressure curve (0.98 +/- 7.4 versus 0.35 +/- 0.30 and 0.41 +/- 0.29 s-1; p < 0.005). These respiratory responses developed without a change in postoperative pulmonary function (initial postoperative FEV1, 1.83 +/- 0.65 L versus last postoperative FEV1, 1.96 +/- 0.66 L; p = not significant).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibition of human platelet aggregation by GR91669, a prototype fibrinogen receptor antagonist.

In order to produce more potent and specific fibrinogen receptor (GpIIb/IIIa) antagonists, the Arg-Gly of a chemical series based upon Arg-Gly-Asp was replaced by alkyl chains of varying lengths. The most potent in this series, GR91669, inhibited aggregation of human gel-filtered platelets (GFP) in vitro induced by ADP or the thromboxane A2 mimetic, U46619, with IC50 values of 200nM and 500nM respectively and was selected for further studies. Its inhibitory effects on GFP were reversed by addition of excess fibrinogen. The compound also inhibited ADP- or U46619-induced platelet aggregation in human whole blood (IC50 values of 700nM in both cases). 125I-Fibrinogen binding to ADP-stimulated platelets was inhibited by GR91669 with an IC50 (65nM) similar to that against platelet aggregation. GR91669 (1mM) did not inhibit U46619-induced platelet shape change or 14C-5HT secretion from platelets stimulated by collagen, U46619 or thrombin. Therefore GR91669 inhibits aggregation but has no significant effect on stimulus-response events, a profile consistent with fibrinogen receptor blockade. In addition, GR91669 (1mM), unlike echistatin or Gly-Arg-Gly-Asp-Ser, did not disrupt vitronectin recptor-dependent attachment of cultured HUVECS in vitro and similarly did not inhibit Mac-1 dependent adhesion of human granulocytes. Thus, of the integrins tested, GR91669 appears to be specific for GpIIb/IIIa. Following intravenous administration to marmosets of 1 or 10 mg/kg GR91669, ADP (10 microM)-induced platelet aggregation ex vivo was abolished for 15 and 60 minutes respectively. Greater than 50% inhibition was maintained for 30 minutes and 2 hours respectively. GR91669, therefore appears to be a potent, specific fibrinogen receptor antagonist in vitro and which is also active in vivo.

Improved potency and specificity of Arg-Gly-Asp (RGD) containing peptides as fibrinogen receptor blocking drugs.

A range of cyclic RGD based peptides have been developed to mimic the conformation of RGD within fibrinogen. These peptides, as well as echistatin (IC50 = 0.05 microM) and GRGDS (IC50 = 25 microM) fully inhibited adenosine diphosphate (ADP) (10 microM)-induced platelet aggregation of human gel-filtered platelets (GFP). RGDF was the most potent linear peptide in inhibiting ADP-induced aggregation (IC50 = 8 microM) but cyclisation, using a 6,5 bicyclic coupling group to produce GR83895, led to an approximately 10-fold increase in potency (IC50 = 0.9 microM). In GFP, ADP-induced 125I-fibrinogen binding was inhibited (> 80%) by echistatin, GRGDS or GR83895 at concentrations (IC50 values 0.05 microM, 25 microM and 1.4 microM respectively) similar to those needed to inhibit aggregation. All three compounds also completely inhibited ADP- and U46619-induced aggregation in both platelet rich plasma (PRP) and whole blood. In contrast to platelet aggregation, U-46619-induced 14C-5HT secretion in PRP was not inhibited by GR83895 or echistatin, indicating that agonist-induced signal transduction is not affected by either agent, a profile consistent with that predicted for a specific fibrinogen receptor blocking drug. To test specificity of action, echistatin, GR83895 and GRGDS were also examined for their ability to detach cultured human umbilical vein endothelial cells attached to plastic through a vitronectin receptor dependent process. GR83895 only caused detachment at concentrations 100-fold greater than those required to inhibit platelet aggregation, in contrast to GRGDS and echistatin which caused cell detachment at concentrations similar to those inhibiting aggregation. In summary, cyclisation of RGD-containing peptides has led to both improved potency and specificity of action. Such specificity of action may prove to be an important consideration for the successful development of a fibrinogen receptor blocking drug as an anti-thrombotic drug.

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.

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.

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.

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.

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.

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.

[Charge selectivity of peritoneal transport in CAPD patients under stable states and during peritonitis].

To investigate charge selectivity of peritoneal transport in CAPD, dialysate/plasma concentration ratios (D/P) were calculated for creatinine (Cr) and 3 amino acids with almost the same molecular weight but quite different charges: glutamic acid (Glu: negatively charged), glutamine (Gln: near neutrally charged) and lysine (Lys: positively charged). The study population consisted of 23 stable patients and 11 patients with peritonitis on CAPD. In the stable patients, the samples of dialysate were taken at 2 and 4 hours and blood samples were obtained at 4 hours after the infusion of 2 liters of 2.27 or 2.5% glucose CAPD dialysate; the samples of patients with peritonitis were obtained at 4.1 +/- 1.1 hours of dwell time. In stable patients, D/P of Glu was much lower than the values for Gln, Lys and Cr at both 2 and 4 hours (p < 0.01), and D/P of Lys was significantly lower than that of Gln (p < 0.01). There was no significant difference in D/P between Gln and Cr. In patients with peritonitis, D/P of Glu was also significantly lower than the values for Gln and Cr (p < 0.05 and p < 0.01), however, no significant differences were found between D/P of Lys and the values of Glu and Gln. Ratios of both [D/P Glu]/[D/P Lys] and [D/P Glu]/[D/P Gln] were much higher in peritonitis patients than in stable patients. In conclusion, peritoneal transport in stable CAPD patients shows charge selectivity, and the order of molecular charge for transperitoneal mobility among small solutes is neutral > positive > negative. The selectivity, however, is decreased or lost during peritonitis.