The association between iron deficiency and outcomes: a secondary analysis of the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial.

In the intravenous iron therapy to treat iron deficiency anaemia in patients undergoing major abdominal surgery (PREVENTT) trial, the use of intravenous iron did not reduce the need for blood transfusion or reduce patient complications or length of hospital stay. As part of the trial protocol, serum was collected at randomisation and on the day of surgery. These samples were analysed in a central laboratory for markers of iron deficiency. We performed a secondary analysis to explore the potential interactions between pre-operative markers of iron deficiency and intervention status on the trial outcome measures. Absolute iron deficiency was defined as ferritin <30 µg.l-1 ; functional iron deficiency as ferritin 30-100 µg.l-1 or transferrin saturation < 20%; and the remainder as non-iron deficient. Interactions were estimated using generalised linear models that included different subgroup indicators of baseline iron status. Co-primary endpoints were blood transfusion or death and number of blood transfusions, from randomisation to 30 days postoperatively. Secondary endpoints included peri-operative change in haemoglobin, postoperative complications and length of hospital stay. Most patients had iron deficiency (369/452 [82%]) at randomisation; one-third had absolute iron deficiency (144/452 [32%]) and half had functional iron deficiency (225/452 [50%]). The change in pre-operative haemoglobin with intravenous iron compared with placebo was greatest in patients with absolute iron deficiency, mean difference 8.9 g.l-1 , 95%CI 5.3-12.5; moderate in functional iron deficiency, mean difference 2.8 g.l-1 , 95%CI -0.1 to 5.7; and with little change seen in those patients who were non-iron deficient. Subgroup analyses did not suggest that intravenous iron compared with placebo reduced the likelihood of death or blood transfusion at 30 days differentially across subgroups according to baseline ferritin (p = 0.33 for interaction), transferrin saturation (p = 0.13) or in combination (p = 0.45), or for the number of blood transfusions (p = 0.06, 0.29, and 0.39, respectively). There was no beneficial effect of the use of intravenous iron compared with placebo, regardless of the metrics to diagnose iron deficiency, on postoperative complications or length of hospital stay.

Understanding the impetus for major systems change: A multiple case study of decisions and non-decisions to reconfigure emergency and urgent care services.

OBJECTIVE: The optimal organisation of emergency and urgent care services (EUCS) is a perennial problem internationally. Similar to other countries, the Health Service Executive in Ireland pursued EUCS reconfiguration in response to quality and safety concerns, unsustainable costs and workforce issues. However, the implementation of reconfiguration has been inconsistent at a regional level. Our aim was to identify the factors that led to this inconsistency. METHODS: Using a multiple case study design, six case study regions represented full, partial and little/no reconfiguration at emergency departments (EDs). Data from documents and key stakeholder interviews were analysed using a framework approach with cross-case analysis. RESULTS: The impetus to reconfigure ED services was triggered by patient safety events, and to a lesser extent by having a region-specific plan and an obvious starting point for changes. However, the complexity of the next steps and political influence impeded reconfiguration in several regions. Implementation was more strategic in regions that reconfigured later, facilitated by clinical leadership and "lead-in time" to plan and sell changes. CONCLUSION: While the global shift towards centralisation of EUCS is driven by universal challenges, decisions about when, where and how much to implement are influenced by local drivers including context, people and politics. This can contribute to a public perception of inequity and distrust in proposals for major systems change.

Perspectives on the underlying drivers of urgent and emergency care reconfiguration in Ireland.

BACKGROUND: There is an increasing tendency to reconfigure acute hospital care towards a more centralised and specialised model, particularly for complex care conditions. Although centralisation is presented as "evidence-based", the relevant studies are often challenged by groups which hold perspectives and values beyond those implicit in the literature. This study investigated stakeholder perspectives on the rationale for the reconfiguration of urgent and emergency care in Ireland. Specifically, it considered the hypothesis that individuals from different stakeholder groups would endorse different positions in relation to the motivation for, and goals of, reconfiguration. METHODS: Documentary analysis of policy documents was used to identify official justifications for change. Semi-structured interviews with 175 purposively sampled stakeholders explored their perspectives on the rationale for reconfiguration. RESULTS: While there was some within-group variation, internal and external stakeholders generally vocalised different lines of argument. Clinicians and management in the internal stakeholder group proposed arguments in favour of reconfiguration based on efficiency and safety claims. External stakeholders, including hospital campaigners and local political representatives expressed arguments that focused on access to care. A "voter" argument, focused on the role of local politicians in determining the outcome of reconfiguration planning, was mentioned by both internal and external stakeholders, often in a critical fashion. CONCLUSION: Our study adds to an emerging literature on the interaction between a technocratic approach to health system planning advocated by clinicians and health service managers, and the experiential "non-expert" claims of the public and patients.

Association between age and access to immediate breast reconstruction in women undergoing mastectomy for breast cancer.

BACKGROUND: National guidelines state that patients with breast cancer undergoing mastectomy in England should be offered immediate breast reconstruction (IR), unless precluded by their fitness for surgery or the need for adjuvant therapies. METHODS: A national study investigated factors that influenced clinicians' decision to offer IR, and collected data on case mix, operative procedures and reconstructive decision-making among women with breast cancer having a mastectomy with or without IR in the English National Health Service between 1 January 2008 and 31 March 2009. Multivariable logistic regression was used to examine the relationship between whether or not women were offered IR and their characteristics (tumour burden, functional status, planned radiotherapy, planned chemotherapy, perioperative fitness, obesity, smoking status and age). RESULTS: Of 13 225 women, 6458 (48·8 per cent) were offered IR. Among factors the guidelines highlighted as relevant to decision-making, the three most strongly associated with the likelihood of an offer were tumour burden, planned radiotherapy and performance status. Depending on the combination of their values, the probability of an IR offer ranged from 7·4 to 85·1 per cent. A regression model that included all available factors discriminated well between whether or not women were offered IR (c-statistic 0·773), but revealed that increasing age was associated with a fall in the probability of an IR offer beyond that expected from older patients' tumour and co-morbidity characteristics. CONCLUSION: Clinicians are broadly following guidance on the offer of IR, except with respect to patients' age.

General practitioner views on the determinants of test ordering: a theory-based qualitative approach to the development of an intervention to improve immunoglobulin requests in primary care.

BACKGROUND: Research suggests that variation in laboratory requesting patterns may indicate unnecessary test use. Requesting patterns for serum immunoglobulins vary significantly between general practitioners (GPs). This study aims to explore GP's views on testing to identify the determinants of behaviour and recommend feasible intervention strategies for improving immunoglobulin test use in primary care. METHODS: Qualitative semi-structured interviews were conducted with GPs requesting laboratory tests at Cork University Hospital or University Hospital Kerry in the South of Ireland. GPs were identified using a Health Service Executive laboratory list of GPs in the Cork-Kerry region. A random sample of GPs (stratified by GP requesting patterns) was generated from this list. GPs were purposively sampled based on the criteria of location (urban/rural); length of time qualified; and practice size (single-handed/group). Interviews were carried out between December 2014 and February 2015. Interviews were transcribed verbatim using NVivo 10 software and analysed using the framework analysis method. Emerging themes were mapped to the theoretical domains framework (TDF), which outlines 12 domains that can enable or inhibit behaviour change. The behaviour change wheel and behaviour change technique (BCT) taxonomy were then used to identify potential intervention strategies. RESULTS: Sixteen GPs were interviewed (ten males and six females). Findings suggest that intervention strategies should specifically target the key barriers to effective test ordering, while considering the context of primary care practice. Seven domains from the TDF were perceived to influence immunoglobulin test ordering behaviours and were identified as 'mechanisms for change' (knowledge, environmental context and resources, social/professional role and identity, beliefs about capabilities, beliefs about consequences, memory, attention and decision-making processes and behavioural regulation). Using these TDF domains, seven BCTs emerged as feasible 'intervention content' for targeting GPs' ordering behaviour. These included instructions on how to effectively request the test (how to perform behaviour), information on GPs' use of the test (feedback on behaviour), information about patient consequences resulting from not doing the test (information about health consequences), laboratory/consultant-based advice/education (credible source), altering the test ordering form (restructuring the physical environment), providing guidelines (prompts/cues) and adding interpretive comments to the results (adding objects to the environment). These BCTs aligned to four intervention functions: education, persuasion, environmental restructuring and enablement. CONCLUSIONS: This study has effectively applied behaviour change theory to identify feasible strategies for improving immunoglobulin test use in primary care using the TDF, 'behaviour change wheel' and BCT taxonomy. The identified BCTs will form the basis of a theory-based intervention to improve the use of immunoglobulin tests among GPs. Future research will involve the development and evaluation of this intervention.

Socioeconomic deprivation and inpatient complication rates following mastectomy and breast reconstruction surgery.

BACKGROUND: Socioeconomic deprivation is known to influence the presentation of patients with breast cancer and their subsequent treatments, but its relationship with surgical outcomes has not been investigated. A national prospective cohort study was undertaken to examine the effect of deprivation on the outcomes of mastectomy with or without immediate breast reconstruction. METHODS: Data were collected on patient case mix, operative procedures and inpatient complications following mastectomy with or without immediate breast reconstruction in the English National Health Service between 1 January 2008 and 31 March 2009. Multivariable logistic regression was used to examine the relationship between patients' level of (regional) deprivation and the likelihood of local (mastectomy site, flap, flap donor and implant) and distant or systemic complications, after adjusting for potential confounding factors. RESULTS: Of 13,689 patients who had a mastectomy, 2849 (20.8 per cent) underwent immediate reconstruction. In total, 1819 women (13.3 per cent) experienced inpatient complications. The proportion with complications increased from 11.2 per cent among the least deprived quintile (Q1) to 16.1 per cent in the most deprived (Q5). Complication rates were higher among smokers, the obese and those with poorer performance status, but were not affected by age, tumour type or Nottingham Prognostic Index. Adjustment for patient-related factors only marginally reduced the association between deprivation and complication incidence, to 11.4 per cent in Q1 and 15.4 per cent in Q5. Further adjustment for length of hospital stay, hospital case volume and immediate reconstruction rate had minimal effect. CONCLUSION: Rates of postoperative complications after mastectomy and breast reconstruction surgery were higher among women from more deprived backgrounds.

Regional variation in use of immediate breast reconstruction after mastectomy for breast cancer in England.

AIMS: English national guidelines recommend that breast reconstruction is made available to women with breast cancer undergoing mastectomy. We examined the use of immediate reconstruction (IR) across English Cancer Networks, who are responsible for the regional organisation of cancer services and ensuring equitable access to treatment. METHODS: We analysed Hospital Episodes Statistics data for all women with breast cancer who underwent mastectomy in the English NHS between April 2006 and February 2009. IR rates were calculated for the 30 Networks. Multivariable logistic regression was used to adjust the rates for patient age, comorbidity, ethnicity and socioeconomic deprivation. RESULTS: Of 44 837 mastectomy patients, 7375 (16.5%) underwent IR. The IR rate was highest in women under 50 years (32.7%) and lowest in women aged 70 years or over (1.5%), and was lower in women with more comorbidities. Unadjusted IR rates varied from 8.4% to 31.9% among the 30 Networks (p<0.001). Adjusting for their patient characteristics did not appreciably reduce Network-level variation, with adjusted IR rates still ranging from 8.0% to 29.4% (p<0.001). The risk-model also suggested that non-white women and those from more deprived areas were less likely to undergo immediate reconstruction. CONCLUSIONS: There is substantial regional variation in immediate reconstruction use in England that is not explained by the characteristics of the local patient population. English Cancer Networks should act to reduce this variation. They should also examine why rates of reconstruction differ between particular patient groups.

Psychometric validity of the 22-item Sinonasal Outcome Test.

OBJECTIVES: We set out to determine the psychometric validation of a disease-specific health related quality of life instrument for use in chronic rhinosinusitis, the 22 item Sinonasal Outcome Test (SNOT-22), a modification of a pre-existing instrument, the SNOT-20. DESIGN, SETTING AND PARTICIPANTS: The National Comparative Audit of Surgery for Nasal Polyposis and Chronic Rhinosinusitis was a prospective cohort study collecting data on 3128 adult patients undergoing sinonasal surgery in 87 NHS hospitals in England and Wales. Data were collected preoperatively and at 3 months after surgery, and analysed to determine validity of the SNOT-22. Test-retest reliability was assessed in a separate cohort of patients in a single centre. MAIN OUTCOME MEASURES: The SNOT-22, a derivative of the SNOT-20 was the main outcome measure. Patients were also asked to report whether they felt better, the same or worse following surgery. To evaluate the SNOT-22, the internal consistency, responsiveness, known group differences and validity were analysed. RESULTS: Preoperative SNOT-22 scores were completed by 2803 patients. 3-month postoperative SNOT-22 scores were available for 2284 patients of all patients who completed a preoperative form (81.5% response rate). The Cronbach's alpha scores for the SNOT-22 were 0.91 indicating high internal consistency. The test-retest reliability coefficient was 0.93, indicating high reliability of repeated measures. The SNOT-22 was able to discriminate between patients known to suffer with chronic rhinosinusitis and a group of healthy controls (P < 0.0001, t = 85.3). It was also able to identify statistically significant differences in sub-groups of patients with chronic rhinosinusitis. There was a statistically significant (P < 0.0001, t = 39.94) decrease in patient reported SNOT-22 scores at 3 months. At 3 months the overall effect size in all patients was 0.81, which is considered large. We found the minimally important difference that is the smallest change in SNOT-22 score that can be detected by a patient, to be 8.9 points. CONCLUSIONS: We have found the SNOT-22 to be valid and easy to use. It can be used to facilitate routine clinical practice to highlight the impact of chronic rhinosinusitis on the patient's quality of life, and may also be used to measure the outcome of surgical intervention. The minimally important difference allows us to interpret scores in a clinical context, and may help to improve patient selection for surgery.

A pilot study of the SNOT 22 score in adults with no sinonasal disease.

OBJECTIVE: To determine the SNOT 22 score in a normal population. STUDY DESIGN: Analysis of SNOT 22 scores participants with no sinonasal disease. SETTING: Bath, UK. PARTICIPANTS: 116 participants from a local hospital and tennis club. RESULTS: Results were obtained from 54 men and 62 women with a mean age of 40 (range 19-75). SNOT score ranged from 0-50 with a mean score of 9.3 (95% confidence interval range of 7.5-11.1). The modal score was 0 and the median score 7 (95% confidence interval range of 5-8). CONCLUSION: Due to the scewed nature of the data, the median score (7) is taken as the normal SNOT 22 score. We recommend that in an clincial situation a SNOT 22 score of 7 be used a a guide for "normal", and that care should be taken when suggesting treatment on patients with a score below this level.

Findings of the International Subarachnoid Aneurysm Trial and the National Study of Subarachnoid Haemorrhage in context.

Concern has been expressed about the applicability of the findings of the International Subarachnoid Aneurysm Trial (ISAT) with respect to the relative effects on outcome of coiling and clipping. It has been suggested that the findings of the National Study of Subarachnoid Haemorrhage may have greater relevance for neurosurgical practice. The objective of this paper was to interpret the findings of these two studies in the context of differences in their study populations, design, execution and analysis. Because of differences in design and analysis, the findings of the two studies are not directly comparable. The ISAT analysed all randomized patients by intention-to-treat, including some who did not undergo a repair, and obtained the primary outcome for 99% of participants. The National Study only analysed participants who underwent clipping or coiling, according to the method of repair, and obtained the primary outcome for 91% of participants. Time to repair was also considered differently in the two studies. The comparison between coiling and clipping was susceptible to confounding in the National Study, but not in the ISAT. The two study populations differed to some extent, but inspection of these differences does not support the view that coiling was applied inappropriately in the National Study. Therefore, there are many reasons why the two studies estimated different sizes of effect. The possibility that there were real, systematic differences in practice between the ISAT and the National Study cannot be ruled out, but such explanations must be seen in the context of other explanations relating to chance, differences in design or analysis, or confounding.

The Postoperative Morbidity Survey was validated and used to describe morbidity after major surgery.

OBJECTIVES: To describe the reliability and validity of the Postoperative Morbidity Survey (POMS). To describe the level and pattern of short-term postoperative morbidity after major elective surgery using the POMS. STUDY DESIGN AND SETTING: This was a prospective cohort study of 439 adults undergoing major elective surgery in a UK teaching hospital. The POMS, an 18-item survey that address nine domains of postoperative morbidity, was recorded on postoperative days 3, 5, 8, and 15. RESULTS: Inter-rater reliability was perfect for 11/18 items (Kappa=1.0), with Kappa=0.94 for 6/18 items. A priori hypotheses that the POMS would discriminate between patients with known measures of morbidity risk, and predict length of stay were generally supported through observation of data trends, and there was statistically significant evidence of construct validity for all but the wound and neurological domains. POMS-defined morbidity was present in 325 of 433 patients (75.1%) remaining in hospital on postoperative day 3 after surgery, 231 of 407 patients (56.8%) on day 5, 138 of 299 patients (46.2%) on day 8, and 70 of 111 patients (63.1%) on day 15. Gastrointestinal (47.4%), infectious (46.5%), pain-related (40.3%), pulmonary (39.4%), and renal problems (33.3%) were the most common forms of morbidity. CONCLUSION: The POMS is a reliable and valid survey of short-term postoperative morbidity in major elective surgery. Many patients remain in hospital without any morbidity as recorded by the POMS.

The national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis.

OBJECTIVES: This study summarises the results of a National Audit of sino-nasal surgery carried out in England and Wales. It describes patient and operative characteristics as well as patient outcomes up to 36 months after surgery. DESIGN: Prospective cohort study. SETTING: NHS hospitals in England and Wales. PARTICIPANTS: Consecutive patients undergoing surgery for nasal polyposis and/or chronic rhinosinusitis. MAIN OUTCOME MEASURE: The total score derived from a 22-item version of the Sino-Nasal Outcome Test (SNOT-22). Lower scores represent better health-related quality of life. RESULTS: A total of 3128 consecutive patients at 87 NHS hospitals were enrolled. There is a large improvement in SNOT-22 scores from the pre-operative period (mean = 42.0) to 3 months after surgery (mean = 25.5). The scores for patients undergoing nasal polypectomy improved from 41.0 before surgery to 23.1 at 3 months after surgery, while the scores for patients undergoing surgery for chronic rhinosinusitis alone improved from 44.2 to 31.2. The SNOT-22 scores reported at 12 and 36 months after surgery were similar to those reported at 3 months. Excessive bleeding occurred in 5% of patients during the operation and in 1% of patients after the operation. Intra-orbital complications were reported in 0.2%. Of those patients undergoing primary surgery for bilateral grade I or II polyposis, 18% had not received a pre-operative course of steroid treatment. At the 36-month follow-up, 11.4% of patients had undergone revision surgery. CONCLUSIONS: The audit confirms that sino-nasal surgery is generally safe and effective. There is some evidence that patient selection for surgery could be improved.

Towards performance measurement in reconstructive surgery: a multicentre pilot study of free and pedicled flap procedures.

OBJECTIVES: To pilot the acceptability and feasibility of clinical audit in free and pedicled flap reconstruction. To establish a baseline flap failure rate in participating units, so that a sample size calculation could be performed for future national audit. METHODS: A proforma was piloted over a 3-month period in four participating units, during which time data on 93 reconstructive procedures involving free and pedicled flaps was collected. The patients included those where large transfers of tissue were required such as for coverage of grade IIIb compound tibial fractures and breast reconstruction after mastectomy, and also smaller flap transfers such as after skin cancer excision. RESULTS: The proforma was found to be acceptable to clinicians and the feasibility of the data collection process was established. Overall there was a total flap survival of 89% and secondary operations to the donor or recipient sites were required in 11% of patients. CONCLUSIONS: This study demonstrates the feasibility of comparative audit for free and pedicled flap procedures using the methods proposed. Based on the incidence of flap failure observed in this pilot study, at least 18 months of prospective data collection on consecutive patients is required to fulfil the statistical requirements of comparative audit. The establishment of a routinely collected minimum dataset is proposed as one means of meeting these requirements.

The Patient Outcomes of Surgery-Head/Neck (POS-head/neck): a new patient-based outcome measure.

OBJECTIVES: To develop a new patient-based outcome measure in plastic surgery for head/neck skin lesions for use in audit, clinical trials and effectiveness studies. DESIGN AND SUBJECTS: Questionnaire development and validation study. Qualitative methods, including interviews with 27 patients, were carried out to develop a preliminary version of the questionnaire. The questionnaire was then field tested by postal survey of 141 pre- and 250 post-surgery patients to produce a shortened (item-reduced) questionnaire and to evaluate acceptability, reliability, validity and responsiveness. A second field test was carried out by postal survey in an independent sample of 67 pre-surgery patients to further evaluate the reliability and validity of the questionnaire. MAIN OUTCOME MEASURES: Psychometric properties of acceptability, reliability, validity, and responsiveness were assessed. RESULTS: We developed a new measure, the Patient Outcomes of Surgery-Head/Neck (POS-Head/Neck), which includes a six- and nine-item pre- and post-surgery questionnaire, respectively. Results confirmed the acceptability (missing data <10%, evenly distributed endorsement frequencies), reliability (Cronbach alphas >0.76, item-total correlations >0.22), validity (scale inter-correlations r=0.50, scaling assumptions, correlations with age and sex < -0.25) and responsiveness (effect size=0.63) of the questionnaire. CONCLUSIONS: The POS-Head/Neck is a new surgical outcome measure that can be used to evaluate outcomes in malignant and benign head/neck skin lesions before and after surgery is acceptable to patients and satisfies rigorous scientific criteria.

The Patient Outcomes of Surgery-Hand/Arm (POS-Hand/Arm): a new patient-based outcome measure.

The purpose of this study was to develop and validate a new patient-based outcome measure for hand/arm disorders for use in audit, clinical trials and effectiveness studies. There were three stages. First, we carried out interviews with 40 patients with hand/arm disorders to develop and pilot questionnaire content. Second, in a postal survey with 165 pre- and 181 post-surgery patients, we reduced the number of items and identified scales. Third, in a postal survey with 132 pre- and 204 post-surgery patients we evaluated the psychometric properties of the measure. Findings confirmed the acceptability, reliability, validity and responsiveness to clinical change of the questionnaire. The Patient Outcomes of Surgery-Hand/Arm (POS-Hand/Arm) is a new surgical outcome measure that can be used before and after surgery (29 and 33 items, respectively) to evaluate and compare new techniques, surgical teams and units.

Patient-based measures of outcome in plastic surgery: current approaches and future directions.

OBJECTIVES: To evaluate current approaches to patient-based outcome measurement in plastic surgery and make recommendations for future research. METHODS: Comprehensive review of the plastic surgery literature relevant to patient-based outcomes. RESULTS: Two main types of patient-based outcome measure have been used in the plastic surgery literature: generic and disease-specific. The majority of studies using generic measures investigate aspects of psychological functioning with fewer studies focussing on wider aspects of health-related quality of life. Disease-specific measures are mainly used to assess symptoms. However, almost all of these are ad-hoc measures produced for a particular study, with no psychometric evaluation. CONCLUSIONS: There is a lack of psychometrically sound measures, and there is scope for improvement in methodology used in plastic surgery research. The development and psychometric testing of new plastic surgery specific measures is encouraged.

Association of calmodulin with cytoskeletal structures at different stages of HeLa cell division, visualized by a calmodulin-EGFP fusion protein.

The fusion protein of calmodulin (CaM) with the enhanced green fluorescent protein EGFP has been expressed in a stably transfected HeLa cell line in order to visualise the localisation of calmodulin during the cell cycle on a continuous basis in live cells, and for immunofluorescence colocalisation with cytoskeletal structures. High-resolution images of CaM-EGFP in the mitotic apparatus show the characteristic strongly convoluted structure of the centrosome. CaM-EGFP also apparently associates with both polar and mitotic microtubules, and with a specific intracentrosomal structure. During cytokinesis, CaM-EGFP is also found decorating selected oriented filaments in close proximity to microtubules in the midbody region. In interphase cells, it is seen with filamentous and punctuate localisation at the nuclear envelope. The intensity and continuity of the CaM-EGFP images suggest that a significant fraction of the cellular calmodulin remains attached to cytoplasmic structures during the cell cycle.

NMR approaches for monitoring domain orientations in calcium-binding proteins in solution using partial replacement of Ca2+ by Tb3+.

This work shows that the partial replacement of diamagnetic Ca2+ by paramagnetic Tb3+ in Ca2+/calmodulin systems in solution allows the measurement of interdomain NMR pseudocontact shifts and leads to magnetic alignment of the molecule such that significant residual dipolar couplings can be measured. Both these parameters can be used to provide structural information. Species in which Tb3+ ions are bound to only one domain of calmodulin (the N-domain) and Ca2+ ions to the other (the C-domain) provide convenient systems for measuring these parameters. The nuclei in the C-domain experience the local magnetic field induced by the paramagnetic Tb3+ ions bound to the other domain at distances of over 40 A from the Tb3+ ion, shifting the resonances for these nuclei. In addition, the Tb3+ ions bound to the N-domain of calmodulin greatly enhance the magnetic susceptibility anisotropy of the molecule so that a certain degree of alignment is produced due to interaction with the external magnetic field. In this way, dipolar couplings between nuclear spins are not averaged to zero due to solution molecular tumbling and yield dipolar coupling contributions to, for example, the one-bond 15N-1H splittings of up to 17 Hz in magnitude. The degree of alignment of the C-domain will also depend on the degree of orientational freedom of this domain with respect to the N-domain containing the Tb3+ ions. Pseudocontact shifts for NH groups and 1H-15N residual dipolar couplings for the directly bonded atoms have been measured for calmodulin itself, where the domains have orientational freedom, and for the complex of calmodulin with a target peptide from skeletal muscle myosin light chain kinase, where the domains have fixed orientations with respect to each other. The simultaneous measurements of these parameters for systems with domains in fixed orientations show great potential for the determination of the relative orientation of the domains.

Health-related quality-of-life studies in urology: conceptual and methodological considerations.

This paper provides an overview of the scientific and practical aspects of assessing health-related quality of life (HRQL). The paper provides a brief overview of developments in the field and then discusses the definition of HRQL. The different types of HRQL measure available to researchers are described, with specific references to urology measures. The paper then focuses on the conceptual and methodological difficulties inherent in patient-centred measures and describes the various means of ensuring scientific soundness in such measures. It concludes that HRQL measures offer much potential to those interested in patient outcomes but that their widespread introduction into research and practice must be carried out with caution.