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Background: Thromboelastography is increasingly used to evaluate coagulation in massively bleeding patients. The aim of this study was to investigate how different combinations of blood components affect in vitro whole blood clotting measured by thromboelastography., Materials and Methods: Packed red blood cells, plasma and platelets from fresh and old blood components were mixed in vitro, in proportions of 4:4:1, 5:5:2, 8:4:1 and 2:1:0, and analysed with thromboelastography. For the ratio 4:4:1 the experiment was done at both 37 °C and 32 °C., Results: Thromboelastography curves were within normal reference values for the blood component proportions of 4:4:1 and 5:5:2. For 8:4:1, the angle and maximal amplitude were reduced below normal values, indicating low levels of fibrinogen and/or platelets. For the 2:1:0 proportion, all parameters were affected resulting in severely impaired in vitro clot formation. The reaction-time, reflecting the coagulation factor-dependent, initial clot formation, was slightly increased at a low temperature. Prolonged storage of the components did not affect the curve., Discussion: With the introduction of guidelines on the management of massive bleeding it is important to have tools for the assessment of the new protocols. In vitro evaluation of mixtures of packed red blood cells, plasma and platelets by thromboelastography may be relevant in the prediction of in vivo clot formation and haemostasis.

Nursing is evolving into new fields of health care including ambulance care, where a branch of specialist nursing is growing. Various views exist on the desired competence for the ambulance nurse and valid guidelines are lacking in Sweden. To increase knowledge of the field, professionals were asked to describe what competences an ambulance nurse should possess. The aim of this study was therefore to elucidate the desired professional competence of the specialist ambulance nurse, according to the professionals. A modified Delphi technique was used, where a panel of professional experts expressed their views on the desired competence of the ambulance nurse. This study reports, at a high level of agreement among the panel experts, that the desired competence of the specialist ambulance nurse consist of forty-four separate competences creating ten areas of competences: execute leadership, generic abilities, interpersonal communication, institutional collaboration, pedagogic skills, possession of relevant knowledge, professional judgement, professional skills, research activities, and technical skills. The high level of agreement among the professionals as well as the large number of competences reflects the high demands placed on the ambulance nurse by the professionals themselves., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

To assess whether children born to primiparous women around the time of a breast cancer diagnosis have an increased mortality risk. From the merged Swedish Multi-Generation and Cancer Registers, we identified 49,750 eligible children whose mother was diagnosed with breast cancer between 1958 and 2010. Mortality rates in offspring were compared to the background population using standardized mortality ratios (SMR), adjusted for calendar year of birth, attained age, and sex, and calculated for each category of timing of delivery (before, around, or after mother's diagnosis) and mother's parity status. Hazard ratios were assessed using a Cox proportional hazards model and adjusted for socioeconomic status, year of birth and mother's age at birth. Children born to a primiparous woman around a breast cancer diagnosis had a mortality rate five times greater than the background population (SMR 5.26, 95 % CI 1.93-11.5), whereas children born to a multiparous woman had a twofold increase (SMR 2.40, 95 % CI 1.10-4.55). Children of primiparous women born around diagnosis had an adjusted hazard ratio fourfold to that of children of primiparous women born before their mother's diagnosis (HR 4.29, 95 % CI 1.68-8.91), whereas hazard ratios for children of primiparous or multiparous women born at other times were not statistically significant. Children born to primiparous women around a breast cancer diagnosis have an increased relative mortality risk. Although relative risk is increased, in absolute terms children born from a cancer complicated pregnancy do relatively well. Additional investigations are needed to elucidate the reason(s) underlying this observation before the information can be used to inform patient counseling and clinical care.

Fibrinogen is of crucial importance in patients with ongoing bleeding. In this study, we compared fibrinogen concentration measured by thrombelastography (TEG®) with fibrinogen plasma concentration determined by Clauss. Sixty-three surgical patients and 38 healthy controls were included. For the whole group (patients and controls, n = 101), TEG® functional fibrinogen was on average 1.0 g/L higher than the plasma fibrinogen concentration (3.5 vs 2.5 g/L, 95% confidence interval for difference 0.8 to 1.2 g/L, P < 0.0001). Similar patterns were observed when patients and healthy controls were analysed separately. The fibrinogen level may be overestimated when assessed using TEG® compared with the fibrinogen plasma concentration measured by the conventional method.

Background: There is a paucity of instruments designed to evaluate the multiple dimensions of the workplace as an educational environment for undergraduate medical students., Aim: The aim was to develop and psychometrically evaluate an instrument to measure how undergraduate medical students perceive the clinical workplace environment, based on workplace learning theories and empirical findings., Method: Development of the instrument relied on established standards including theoretical and empirical grounding, systematic item development and expert review at various stages to ensure content validity. Qualitative and quantitative methods were employed using a series of steps from conceptualization through psychometric analysis of scores in a Swedish medical student population., Results: The final result was a 25-item instrument with two overarching dimensions, experiential learning and social participation, and four subscales that coincided well with theory and empirical findings: Opportunities to learn in and through work & quality of supervision; Preparedness for student entry; Workplace interaction patterns & student inclusion; and Equal treatment. Evidence from various sources supported content validity, construct validity and reliability of the instrument., Conclusion: The Undergraduate Clinical Education Environment Measure represents a valid, reliable and feasible multidimensional instrument for evaluation of the clinical workplace as a learning environment for undergraduate medical students. Further validation in different populations using various psychometric methods is needed.

Objective: About 20 years ago, the scientific community was first alerted to an enigmatic increase of oesophageal adenocarcinomas in the UK and USA. Subsequently, a virtual epidemic-still unexplained-was confirmed in several western countries. Detailed descriptive data might provide clues to its causes., Design: We collected data on incident cases of oesophageal adenocarcinoma from population-based cancer registries in Australia, Europe, North America and Asia. We calculated age-standardised incidence rates and fitted log-linear Poisson models to assess annual rate of increase and to disentangle age-period-cohort effects, linear spine models to estimate rate of increase since 1985, and Joinpoint models to identify possible inflection points., Results: With considerable between-registry variation in magnitude and timing, we found a consistent dramatic increase in incidence with an observed or estimated start between 1960 and 1990. The average annual increase ranged from 3.5% in Scotland to 8.1% in Hawaii with similar proportional increase among men and women in most registries and a maintained three to sixfold higher incidence among men. Generally, calendar period was a more important determinant of incidence trends than birth cohort. Where possible to conduct, Joinpoint analyses indicated that the onset of the epidemic varied considerably even between neighbouring countries., Conclusions: Given the preponderant period effect and the abrupt onset observed or inferred in most populations, the epidemic appears to be caused by some exposure that was first introduced around 1950. At least 30 years' variation in estimated time of onset opens prospects for hypothesis-generating ecological analyses.

Background: A small group of frequent visitors to emergency departments accounts for a disproportional large number of total emergency department visits. Previous interventions in this population have shown mixed results., Objective: To determine whether a nurse-managed telephone-based case-management intervention can reduce healthcare utilization and improve self-assessed health status in frequent emergency department users., Methods: We carried out a Zelen-design randomized-controlled trial among patients who were identified as frequent emergency department users (≥ 3 visits during the 6 months before inclusion) at the Karolinska University Hospital in Stockholm (Sweden). Patients included in the study (n = 268) were randomized to either the intervention group or the control group and followed for 1 year. Patients who declined to participate or could not be reached were also followed for the study outcome., Results: The telephone-based case-management intervention reduced the total number of outpatient visits (relative risk 0.80; 95% confidence interval 0.75-0.84), the number of emergency department visits (relative risk 0.77; 95% confidence interval 0.69-0.86), the number of days patients were admitted to hospitals as well as the total healthcare costs for hospital admissions. There was no difference in mortality or other identified adverse outcomes between the intervention and the control groups. Patient self-assessed health status improved for the patients who received the case-management intervention., Conclusion: Our results indicate that the nurse-managed telephone-based case-management intervention represents a possible strategy to improve care for frequent emergency department users as well as decrease outpatient visits, admission days and healthcare costs.

Background: It is unclear to what extent cancer history affects posttransplantation mortality in solid organ transplant recipients., Methods: We identified a Swedish population-based cohort of solid organ transplant recipients in the National Patient Register 1970 to 2008 and linked it to the Cancer and Cause-of-Death Register. Overall and cause-specific mortality was estimated using Cox regression., Results: Of 10,448 eligible recipients, 416 (4%) had a prior malignancy unrelated to the indication for transplantation diagnosed 2 months or more before surgery (median, 5.7 years). Mortality among cancer history recipients was 30% increased after transplantation, compared with other recipients (adjusted hazard ratio [HR], 1.3; 95% confidence interval [CI], 1.1-1.5; P<0.001), driven by cancer-specific death with no increase in cardiovascular, infectious, or other noncancer mortality. An increased rate of death due to cancer history was primarily observed among nonkidney recipients (adjusted HR(nonkidney), 1.8; 95% CI, 1.3-2.5; HR(kidney), 1.2; 95% CI, 1.0-1.4). Rates were greatest for patients with waiting times of 5 years or less but persisted with waiting times more than 10 years among kidney and nonkidney recipients with prior aggressive cancer types (gastrointestinal, breast, kidney/urothelial, and hematologic malignancies)., Conclusion: We conclude that organ transplant recipients with cancer history are at a moderately increased rate of death after transplantation, driven primarily by death due to cancer recurrence.

Background: A widespread approach today is to transfuse bleeding trauma patients with RBC concentrates and plasma at a 1:1 ratio. This regime is supported by a range of observational studies showing lower mortality in bleeding patients receiving equal volumes of plasma and RBCs. The rationale for this practice is still unclear with several studies failing to show any survival benefits of increased plasma use, perhaps due to a failure to account for the timing of transfused units., Objective: To study the association between plasma-to-RBC ratios and risk of death in trauma patients, using appropriate methods., Design, Settings, and Participants: In a retrospective cohort study, we assembled data on 741 transfused trauma patients at a large trauma center. Measures of transfusion therapy were assessed entirely time dependently, and relative risk of death was compared between patients receiving low to high plasma-to-RBC ratio (< 0.85 vs > 0.85)., Measurements and Results: In the time-dependent analyses, we saw no significant association between a low plasma ratio and the risk of death. However, age more than 75 years, injury severity score greater than 33, Glasgow Coma Scale less than 8, and systolic blood pressure lower than 90 mm Hg were all significantly associated with increased risk of death. Conversely, when the analyses were conducted with conventional methods, a strong protective effect of high plasma ratios was seen., Conclusions: The key finding in our study is the strikingly different results produced by time-dependent analyses and the conventional analyses when studying survival and plasma-to-RBC ratio, supporting recent claims that prior studies showing benefit of high plasma ratios might have suffered from survival bias. There is a great need for further studies on the subject to enable improvements in treatment of massively bleeding trauma patients.

Purpose: Tamoxifen treatment is associated with a reduction in mammographic density and an improved survival. However, the extent to which change in mammographic density during adjuvant tamoxifen therapy can be used to measure response to treatment is unknown., Patients and Methods: Overall, 974 postmenopausal patients with breast cancer who had both a baseline and a follow-up mammogram were eligible for analysis. On the basis of treatment information abstracted from medical records, 474 patients received tamoxifen treatment and 500 did not. Mammographic density was measured by using an automated thresholding method and expressed as absolute dense area. Change in mammographic density was calculated as percentage change from baseline. Survival analysis was performed by using delayed-entry Cox proportional hazards regression models, with death as a result of breast cancer as the end point. Analyses were adjusted for a range of patient and tumor characteristics., Results: During a 15-year follow-up, 121 patients (12.4%) died from breast cancer. Women treated with tamoxifen who experienced a relative density reduction of more than 20% between baseline and first follow-up mammogram had a reduced risk of death as a result of breast cancer of 50% (hazard ratio, 0.50; 95% CI, 0.27 to 0.93) compared with women with stable mammographic density. In the no-tamoxifen group, there was no statistically significant association between mammographic density change and survival. The survival advantage was not observed when absolute dense areas at baseline or follow-up were evaluated separately., Conclusion: A decrease in mammographic density after breast cancer diagnosis appears to serve as a prognostic marker for improved long-term survival in patients receiving adjuvant tamoxifen, and these data should be externally validated.

Background: Several methods exist for evaluation of hypocoagulation in patients with perioperative bleeding, e.g. thromboelastography (TEG(®)) and conventional methods (platelet count, aPTT, INR and fibrinogen). Considering the vast experience of conventional methods it is important to investigate how well the methods correspond., Methods: Sixty surgical patients were included prospectively and blood samples were taken perioperatively. TEG(®) and conventional parameters were analyzed simultaneously. An assessment of coagulopathy, based on a synthesis of the conventional methods, was done by two experienced coagulation specialists, blinded from the results of TEG(®) and from the results of each other. Hypocoagulation, defined by TEG(®) parameters; reaction time (R-time), angle, maximal amplitude (MA) and fibrinolysis, was evaluated according to a commonly used algorithm., Results: To detect a platelet count below 150 × 10(9) L(-1), the sensitivity of TEG was 17% (95% CI, 7-36%) with angle and 25% (95% CI, 11-45%) with MA. The sensitivity to detect fibrinogen below 2 g/L was 11% (95% CI, 3-29%) with angle and 21% with MA (95% CI, 8-43%). To detect aPTT more than 40 s and INR more than 1.2 with R-time, the sensitivity was 19% (95% CI, 8-37%) and 0% (95% CI, 0-69%) respectively. The agreement of the evaluator's assessments of hypocoagulation was 100%, but the agreement with the overall TEG(®) analysis was poor with a sensitivity of 33% and a specificity of 95%., Conclusion: The agreement between conventional laboratory tests and TEG is poor, but it remains uncertain which type of coagulation tests that best reflects the actual bleeding risk.

Organ transplant recipients are at increased risk of a wide range of malignancies, especially cutaneous squamous cell carcinomas (SCC). Few previous population-based studies have quantified and compared cancer risks according to graft type and with long-term follow-up. Using nationwide Swedish registers, we identified 10,476 recipients transplanted from 1970 to 2008 and followed them for cancer occurrence. Relative risks of cancer in comparison with the general population were expressed as standardized incidence ratios (SIR) and within the transplanted cohort as incidence rate ratios (IRR). During a total follow-up of 93,432 person-years, patients were diagnosed with 1,175 cancers excluding SCC, and with 2,231 SCC, SIR(cancer excl SCC) 2.4 (95% CI, 2.2-2.5); SIR(SCC) 121 (95% CI, 116-127). Cancer risks were most increased among heart and/or lung recipients SIR(cancer excl SCC) 3.3 (95% CI, 2.8-4.0); SIR(SCC) 198 (95% CI, 174-224), followed by kidney SIR(cancer excl SCC) 2.3 (95% CI, 2.1-2.4); SIR(SCC) 121 (95% CI, 116-127) and liver recipients SIR(cancer excl SCC) 2.3 (95% CI, 1.9-2.8); SIR(SCC) 32 (95% CI, 24-42). During follow-up, risk of cancer excluding SCC remained stable while risk of SCC tripled over 20 years irrespective of graft type, partly due to a subgroup of patients developing new SCCs at a rapidly increasing rate. In summary, post-transplant cancer risk varied by transplanted organ and by cancer site, with the bulk of the excess risk driven by an exceptionally high and accelerating risk of SCC. These findings underscore the importance of regular skin screening in organ transplant recipients., (Copyright © 2012 UICC.)

Background: A growing proportion of men diagnosed with localized prostate cancer detected through prostate-specific antigen testing are dying from causes other than prostate cancer. Temporal trends in specific causes of death among prostate cancer patients have not been well described., Methods: We analyzed causes of death among all incident prostate cancer cases recorded in the nationwide Swedish Cancer Registry (1961-2008; n = 210 112) and in the US Surveillance, Epidemiology, and End Results Program (1973-2008; n = 490 341). We calculated the cumulative incidence of death due to seven selected causes that accounted for more than 80% of the reported deaths (including ischemic heart disease and non-prostate cancer) and analyzed mortality trends by calendar year and age at diagnosis and length of follow-up., Results: During follow-up through 2008, prostate cancer accounted for 52% of all reported deaths in Sweden and 30% of reported deaths in the United States among men with prostate cancer; however, only 35% of Swedish men and 16% of US men diagnosed with prostate cancer died from this disease. In both populations, the cumulative incidence of prostate cancer-specific death declined during follow-up, while the cumulative incidences of death from ischemic heart disease and non-prostate cancer remained constant. The 5-year cumulative incidence of death from prostate cancer among all men was 29% in Sweden and 11% in the United States., Conclusions: In Sweden and the United States, men diagnosed with prostate cancer are less likely to die from prostate cancer than from another cause. Because many of these other causes of death are preventable through changes in lifestyle, interventions that target lifestyle factors should be integrated into prostate cancer management.

Background and Purpose: Previous national epidemiological data on the characteristics and trends of patients with ankle fractures have been limited. We therefore analyzed data on Swedish inpatients with ankle fractures in this nationwide population study, based on data from 1987 through 2004., Patients and Methods: Data on all inpatients aged 15 years and older with ankle fracture were extracted from the Swedish National Patient Register for the period 1987-2004., Results: We identified 91,410 hospital admissions with ankle fracture, corresponding to an annual incidence rate of 71 per 10(5) person-years. During the study period, the number of hospital admissions increased by 0.2% annually, mainly from increase in fracture incidence in the elderly women. Mean age at admission was 45 (SD 19) years for men and 58 (18) for women. The major mechanism of injury was falling at the same level (64%)., Interpretation: This nationwide study of inpatients with ankle fractures showed an increase in fracture incidence, particularly in elderly women.

In this study we aimed to identify cancers where there is a consistent sex disparity, with the goal of identifying unexplained sex disparities that may offer promising opportunities for etiologic research. Age- and sex-specific cancer incidence data from Cancer Incidence in Five Continents, provided by the International Agency for Research on Cancer, were used to calculate incidence rate ratios for 35 cancer sites, comparing men to women, adjusting for attained age, gross domestic product (GDP), and geographical region. Genital cancers and breast cancer were excluded. The consistency of relative risks was examined by GDP and geographical region and, in a subset of longstanding cancer registers, by calendar year. For each cancer site, the sex disparity was broadly classified as plausibly explained by established environmental risk factors, partly explained, or unexplained. Cancer incidence was statistically significantly higher in men than women at 32 of 35 sites, with disparities >2-fold for 15 sites and >4-fold for 5 sites. For nearly all sites, the sex disparity was consistent across GDP groups and geographical regions. However, the incidence rate ratios varied considerably by age at diagnosis. The sex disparity for 13 cancer sites was considered to be entirely unexplained by known risk factors; these sites showed strikingly little variation in the incidence rate ratios over decades. Thus, the basis of many of the largest sex disparities in cancer incidence seems mostly unknown, highlighting the need for intensified research into its origins.

Background: One of the key elements for introducing a problem-based learning (PBL) programme is constructing good PBL cases. Good cases should reflect the educational principles of PBL including (a) integration of basic and clinical sciences together with professionalism and psychosocial components, (b) encouragement of discussion of cognitive domains such as identification of problems, generation of hypotheses, construction of an enquiry plan, weighing evidence for and against each hypothesis, interpretation of findings, construction of mechanisms, using evidence to refine the hypothesis and construction of a management plan, (c) encouragement of discussion of cases in small groups with an emphasis on student-centred learning, (d) promotion of collaborative learning and contribution of students to the case discussion and (e) encouragement of teamwork and self-directed learning strategies., Aims and Methods: Despite the importance of construction of good PBL cases to the success of a PBL programme, the art of construction of these cases is understudied or described in the literature. Based on our experience in PBL and evidence from literature, we described 12 tips for constructing good PBL cases., Results and Conclusions: Constructing good PBL cases is an art that necessitates teamwork and input from several different disciplines. Cases should be constructed using a template reflecting the educational objectives of the programme. This approach will ensure optimum learning outcomes and consistency in the design and delivery of cases.

Background: There is a paucity of research on the effects of interactive feedback methods and sustained assessment strategies in formative assessment of students in the workplace., Aims: To investigate the outcome of long-term use of an assessment tool., Methods: Retrospective analysis of summarised assessment tools from 3 years of 464 final-year students in general practice. Quantitative data were analysed using non-parametric tests and a multi-level approach. Qualitative data were subjected to content analysis., Results: Students' main deficiencies in the consultation were in the domains of working diagnoses and management plans; however, supervisors emphasised goals of patient-centred communication and structure of the medical interview. As a group, students underestimated their clinical performance, compared to supervisors' judgement. Most students were supplied with specific goals, 58% with specific follow-up feedback. The majority of students and supervisors were satisfied with the assessment strategy. Long-term experience with the tool significantly increased the proportion of specific goals and feedback to students, supervisors' stringency of the assessment, and their satisfaction with the tool., Conclusions: The summarised assessment strategy proved feasible and acceptable with students and supervisors in a continuous attachment with assigned personal supervisors. However, there was room for improvement in supervisors' provision of specific follow-up feedback.

Background: The Dundee Ready Educational Environment Measure (DREEM) has been used in various studies to evaluate the educational environment. However, psychometric evaluations of the instrument seem sparse, for all known versions of the instrument., Aim: The aim was to psychometrically evaluate the Swedish version of the DREEM instrument., Method: A total of 503 students (undergraduate medicine), aged 19-46 years, in semesters 2, 6 and 10 were included in the study. Validity was evaluated through analysis of construct validity and reliability., Results: The instrument had in general both acceptable validity and reliability. Due to a rather poor model fit in the confirmatory factor analysis, an explorative factor analysis was also employed which suggested a new five-factor solution for the instrument., Conclusions: The Swedish version of the DREEM instrument is shown to be valid and reliable, except for the factor structure. The new five-factor solution found in this study is not proven to be a superior measurement model compared with the original, but could be seen as an alternative model to the original, where the strong and weak areas are somewhat more easily identified.

Although anemia is widely considered an early sign of malignant disease, little is known about the pattern of hemoglobin decline before diagnosis. As an approach to understanding the duration of the preclinical phase of different types of malignant diseases, we investigated prediagnostic hemoglobin concentration changes in a large cohort of blood donors. Using a nested case-control design, we analyzed a population-based cohort comprising 1.1 million Scandinavian blood donors with complete follow-up through record linkage to population and cancer registers. A total of 16,375 cancer cases were identified, for whom we selected 161,995 controls. We used conditional logistic regression to estimate the risk of cancer in relation to hemoglobin concentration during the 5 years preceding the cancer diagnosis. Hemoglobin concentration decline began already 3 years before diagnosis of stomach cancer, multiple myeloma, and lymphatic leukemia; 2 years before diagnosis of small intestinal and colon cancer as well as of Hodgkin lymphoma. A decline was evident during the last year for non-Hodgkin lymphoma and myeloid/monocytic leukemia, whereas no change was found for cancer of the esophagus, breast or prostate. In conclusion, in this study, we have demonstrated that the pattern of declining hemoglobin concentration before cancer diagnosis varies considerably between malignancies without being a suitable screening tool for any of them. For some malignancies, however, the long duration of hemoglobin decline before clinical diagnosis suggests a substantial lead-time with systemic effects, during which earlier diagnosis should be achievable by emerging diagnostic tools.

Women who have been treated for breast cancer are typically followed up with regular mammography and palpation, with the aim of detecting recurrences and contralateral breast cancer (CBC). This study aims to investigate if the diagnostic work-up of breast cancer patients has improved over the last 25 years and resulted in earlier diagnoses of CBC. Two population-based cohorts were used; all CBCs in Sweden 1976-2004 (n: 2932), and all CBCs in Stockholm, Sweden, 1976-2005 (n: 626), both cohorts with a maximum of 3 years between the two cancers. Synchronous CBC was defined as two cancers <3 months apart, the remainder was defined as metachronous CBC. We calculated the odds ratio of being diagnosed synchronously, relative to metachronously, using logistic regression, adjusting for whether the second cancer was detected through clinical work-up or not. The odds of synchronous CBC were significantly increased: 1.27 (95% CI, 1.13-1.42) per 5-year period, compared to metachronous, and was not affected by detection mode, but seemed to be explained by adjuvant therapy. The proportion of CBCs detected by clinical work-up did not increase over the study period, and the mean size of the second tumor remained constant. We found an increase in the proportion of synchronous CBCs compared to metachronous, over calendar period, a change that was not associated with clinical work-up, but with adjuvant therapy. This study gives no indications that any improvement in diagnostic work-up of CBC have occurred over the last 25 years.

Background: Disquieting reports of increased complication and death rates after transfusions of red blood cells (RBCs) stored for more than 14 days prompted us to perform an observational retrospective cohort study of mortality in relation to storage time., Study Design and Methods: We conducted a cohort study utilizing data on all recipients of at least one RBC transfusion in Sweden and Denmark between 1995 and 2002, as recorded in the Scandinavian Donations and Transfusions (SCANDAT) database. Relative risks of death in relation to storage time were estimated using Cox regression, adjusted for several possible confounding factors., Results: After various exclusions, 404,959 transfusion episodes remained for analysis. The 7-day risk of death was similar in all exposure groups, but a tendency for a higher risk emerged among recipients of blood stored for 30 to 42 days (hazard ratio, 1.05; 95% confidence interval [CI], 0.97-1.12), compared to recipients of blood stored for 10 to 19 days. With 2-year follow-up, this excess remained at the same level (hazard ratio, 1.05; 95% CI, 1.02-1.08). No dose-response pattern was revealed and no differential effect was seen when the analyses were restricted to recipients of leukoreduced units only., Conclusion: Although a small excess mortality was noted in recipients of the oldest RBCs, the risk pattern was more consistent with weak confounding than with an effect of the momentary exposure to stored RBCs. It seems, thus, that any excess mortality conferred by older RBCs in the combined Swedish and Danish transfusion recipient population is likely less than 5%, which is considerably smaller than in the hitherto largest investigation.

Background: Plasma from female donors has been implicated in the sometimes fatal complication known as transfusion-related acute lung injury. In studies of patients in intensive care units, worsened gas exchange of the lungs has also been attributed to female plasma. Despite a lack of population-based evidence, policies have already been introduced to exclude female donor plasma., Study Design and Methods: Short-term mortality after plasma transfusion was investigated using data from the Scandinavian Donations and Transfusions (SCANDAT) database. A cohort of 92,565 patients in 30 Swedish hospitals were followed for 14 days after their first plasma transfusion. The relative risk (RR) of death in recipients of female plasma compared to recipients of only male plasma was estimated from Poisson regression., Results: Recipients had median age 70 years, received a mean of 4.4 plasma units, and had an overall 14-day mortality of 8.43%. Sixty-eight percent were exposed to female plasma, with a 14-day mortality of 8.85% compared to 7.53% in the nonexposed group. After adjustment for potential confounding factors, the RRs were 1.16 (confidence interval [CI], 1.06-1.27) and 1.32 (CI, 1.17-1.49) for those receiving 3 to 4 and 5 or more units of female plasma, respectively. Risk estimates were increased in an analysis of deaths with a concomitant discharge diagnosis involving the respiratory or circulatory system or an adverse reaction., Conclusions: This large population-based cohort study of unselected patients suggests that transfusion of plasma from female donors confers a short-term survival disadvantage on recipients.

Background: Portfolios are highlighted as potential assessment tools for professional competence. Although students' self-reflections are considered to be central in the portfolio, the content of reflections in practice-based portfolios is seldom analysed., Aim: To investigate whether students' reflections include sufficient dimensions of professional competence, notwithstanding a standardized portfolio format, and to evaluate students' satisfaction with the portfolio., Methods: Thirty-five voluntary final-year medical students piloted a standardized portfolio in a general practice (GP) attachment at Lund University, Sweden. Students' portfolio reflections were based upon documentary evidence from practice, and aimed to demonstrate students' learning. The reflections were qualitatively analysed, using a framework approach. Students' evaluations of the portfolio were subjected to quantitative and qualitative analysis., Results: Among professional issues, an integration of cognitive, affective and practical dimensions in clinical practice was provided by students' reflections. The findings suggested an emphasis on affective issues, particularly on self-awareness of feelings, attitudes and concerns. In addition, ethical problems, clinical reasoning strategies and future communication skills training were subjects of several reflective commentaries. Students' reflections on their consultation skills demonstrated their endeavour to achieve structure in the medical interview by negotiation of an agenda for the consultation, keeping the interview on track, and using internal summarizing. The importance of active listening and exploration of patient's perspective was also emphasized. In students' case summaries, illustrating characteristic attributes of GP, the dominating theme was 'patient-centred care', including the patient-doctor relationship, holistic modelling and longitudinal continuity. Students were satisfied with the portfolio, but improved instructions were needed., Conclusions: A standardized portfolio in a defined course with a limited timeframe provided ample opportunities for reflections on professional issues. Support by mentors and a final examiner interview contributed to the success of the portfolio with students. The interview also allowed students to deepen their reflections and to receive feedback.

Background: Various blood safety initiatives have ensured a historically low risk of infection transmission through blood transfusion. Although further prevention of infection transmission is possible through, for example, nucleic acid testing and future introduction of pathogen inactivation, such initiatives are very costly in relation to the benefit they offer. Although estimation of the cost-effectiveness requires detailed information about the survival of transfusion recipients, previous cost-effectiveness analyses have relied on incorrect survival assumptions., Study Design and Methods: Based on empirical data of more than 1 million Scandinavian transfusion recipients followed for up to 20 years, we present two new survival functions. In a fictitious example we assessed the impact of survival assumptions on the estimated costs per quality-adjusted life-year (QALY) gained, by using the survival functions of three previous cost-effectiveness analyses along with the two new survival functions., Conclusions: We conclude that despite considerable costs, previous cost-effectiveness studies may have underestimated the costs per QALY gained by as much as 44%.

Background: The medical programme at Lund University, Sweden, has undergone curricular reform over several stages, which is still ongoing. Students have been somewhat negative in their evaluations of the education during this time., Aim: To find out how the students perceived the educational climate using the Dundee Ready Education Environment Measure (DREEM), and to compare the findings taken at two given points in time., Method: The DREEM instrument was distributed in semesters 2, 6 and 10 in 2003 and 2005, to a total of 503 students., Results: The students rated their climate as positive. The total DREEM score (145) was somewhat higher than other published results and in the same range as for other reformed curricula. There was hardly any difference between the genders in their perceptions of the climate. Certain items were rated low and became subject of development between the measurements. These items concerned a perceived lack of a support system for stressed students and a lack of feedback and constructive criticism from teachers. Some improvement was detected in 2005., Conclusion: The educational climate was high in a reformed curriculum and could be maintained high during on-going curricular reform. Educational development resulted in better results on some items.

Background: Although essential for the evaluation of blood transfusion safety, the prevalence of blood transfusion in the general population is not presently known. This study estimated the exposure to blood transfusion in the general Scandinavian population., Study Design and Methods: Population-based registry data of more than 600,000 transfusion recipients and general population data from 2000 to 2002 in Denmark and 1996 to 2002 in Sweden were reviewed. Outcome measures were the unit exposure rate, the 1-year period prevalence, the incidence rate, and the prevalence of exposure to blood transfusion., Results: The unit exposure rate was 71.9 per 1000 population per year in Denmark and 60.9 in Sweden, corresponding to 29 percent more blood units being transfused in Denmark than in Sweden. The 1-year period prevalence was 8.8 and the incidence rate was 7.2 per 1000 population per year in Denmark, being 37 and 25 percent higher than in Sweden, respectively. The prevalences of blood transfusion in Danish males at 20, 40, 60, and 80 years of age were 1.9, 3.1, 7.6, and 18.1 percent, respectively. In Danish females, the corresponding prevalences were 1.6, 5.9, 11.1, and 20.5 percent. A similar but slightly lower prevalence was found in Sweden., Conclusion: Exposure to blood transfusion is frequent in Denmark and Sweden. At age 80 years, approximately one in five persons in the general population had received blood at least once.

Background: Long-term survival of transfusion recipients has rarely been studied. This study examines short- and long-term mortality among transfusion recipients and reports these as absolute rates and rates relative to the general population., Study Design and Methods: Population-based cohort study of transfusion recipients in Denmark and Sweden followed for up to 20 years after their first blood transfusion. Main outcome measure was all-cause mortality., Results: A total of 1,118,261 transfusion recipients were identified, of whom 62.0 percent were aged 65 years or older at the time of their first registered transfusion. Three months after the first transfusion, 84.3 percent of recipients were alive. One-, 5-, and 20-year posttransfusion survival was 73.7, 53.4, and 27.0 percent, respectively. Survival was slightly poorer in men than in women, decreased with increasing age, and was worst for recipients transfused at departments of internal medicine. The first 3 months after the first transfusion, the standardized mortality ratio (SMR) was 17.6 times higher in transfusion recipients than in the general population. One to 4 years after first transfusion, the SMR was 2.1 and even after 17 years the SMR remained significantly 1.3-fold increased., Conclusion: The survival and relative mortality patterns among blood transfusion recipients were characterized with unprecedented detail and precision. Our results are relevant to assessments of the consequences of possible transfusion-transmitted disease as well as for cost-benefit estimation of new blood safety interventions.

Background: Long-term deleterious effects of repeated blood donations may be masked by the donors' healthy lifestyle. To investigate possible effects of blood donation and iron loss through blood donation on cancer incidence while minimizing "healthy donor effects," we made dose-response comparisons within a cohort of Swedish and Danish blood donors., Methods: We used a nested case-control study design, in which case patients were defined as all donors who were diagnosed with a malignancy between their first recorded blood donation and study termination (n = 10866). Control subjects (n = 107140) were individually matched on sex, age, and county of residence. Using conditional logistic regression, we estimated relative risks of cancer according to number of blood donations made or estimated iron loss 3-12 years before a case patient was diagnosed with cancer. All statistical tests were two-sided., Results: No clear association was observed between number of donations and risk of cancer overall. However, between the lowest (< or = median, < 0.75 g) and highest (> 90th percentile, > 2.7 g) categories of estimated iron loss, there was a trend (P(trend) < .001) of decreasing risk for cancers of the liver, lung, colon, stomach, and esophagus, which are thought to be promoted by iron overload (combined odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.58 to 0.84), but only among men and only with a latency of 3-7 years. The risk of non-Hodgkin lymphoma was higher among frequent plasma donors (> 25 vs 0 donations, OR = 2.14, 95% CI = 1.22 to 3.74)., Conclusions: Repeated blood donation was not associated with increased or decreased risk of cancer overall. The lack of consistency across latency periods casts doubt on an apparent association between reduced cancer risk and iron loss in men. The positive association between frequent plasma donation and risk of non-Hodgkin lymphoma deserves further exploration.

Background: Blood transfusions may influence the recipients' cancer risks both through transmission of biologic agents and by modulation of the immune system. However, cancer occurrence in transfusion recipients remains poorly characterized., Methods: We used computerized files from Scandinavian blood banks to identify a cohort of 888,843 cancer-free recipients transfused after 1968. The recipients were followed from first registered transfusion until the date of death, emigration, cancer diagnosis, or December 31, 2002, whichever came first. Relative risks were expressed as ratios of the observed to the expected numbers of cancers, that is, standardized incidence ratios (SIRs), using incidence rates for the general Danish and Swedish populations as a reference. All statistical tests were two-sided., Results: During 5,652,918 person-years of follow-up, 80,990 cancers occurred in the transfusion recipients, corresponding to a SIR of 1.45 (95% confidence interval [CI] = 1.44 to 1.46). The SIR for cancer overall decreased from 5.36 (95% CI = 5.29 to 5.43) during the first 6 months after transfusion to 1.10 or less for follow-up periods more than 2 years after the transfusion. However, the standardized incidence ratios for cancers of the tongue, mouth, pharynx, esophagus, liver, and respiratory and urinary tracts and for squamous cell skin carcinoma remained elevated beyond 10 years after the transfusion., Conclusions: The marked increase in cancer risk shortly after a blood transfusion may reflect the presence of undiagnosed occult cancers with symptoms that necessitated the blood transfusion. The continued increased risk of tobacco- and alcohol-related cancers suggests that lifestyle and other risk factors related to conditions prompting transfusion rather than transfusion-related exposures per se are important to the observed cancer occurrence in the recipients.

Background: Transfusion safety rests heavily on the health of blood donors. Although they are perceived as being healthier than average, little is known about their long-term disease patterns and to which extent the blood banks' continuous efforts to optimize donor selection has resulted in improvements. Mortality and cancer incidence among blood donors in Sweden and Denmark was investigated., Study Design and Methods: All computerized blood bank databases were compiled into one database, which was linked to national population and health data registers. With a retrospective cohort study design, 1,110,329 blood donors were followed for up to 35 years from first computer-registered blood donation to death, emigration, or December 31, 2002. Standardized mortality and incidence ratios expressed relative risk of death and cancer comparing blood donors to the general population., Results: Blood donors had an overall mortality 30 percent lower (99% confidence interval [CI] 29%-31%) and cancer incidence 4 percent lower (99% CI 2%-5%) than the background population. Mortality rates and cancer incidence were lowest for outcomes that are recognized as being related to lifestyle factors such as smoking or to the selection criteria for blood donation. Blood donors recruited in more recent years exhibited a lower relative mortality than those who started earlier., Conclusion: Blood donors enjoy better than average health. Explicit and informal requirements for blood donation in Scandinavia, although mostly of a simple nature, have successfully refined the selection of a particularly healthy subpopulation.

A portfolio assessment system has been introduced into a biomedical science programme to promote both continuous learning and deep approaches to learning. Attention has been focused on creating harmony between the assessment system and the PBL curriculum of the programme. Biomedicine and laboratory work are central in the curriculum. The portfolio included evidence of laboratory work, personal reflections and certificates from the PBL tutor. The portfolio was assessed on three occasions over 20 weeks. The grades were 'pass' or 'fail'. The tutor certificate appeared to be a crucial part of the portfolio since a 'fail' in this part usually led to an overall 'fail'. Both students and teachers were concerned about ensuring that enough factual knowledge, as measured by a traditional test, had been achieved. The agreement was good enough for the pass or fail level but some expected differences were found at the detailed level. The course, including the portfolio, was evaluated orally during weekly whole-group meetings and using a questionnaire at the end. The students felt comfortable with the portfolio system and preferred it to a traditional test. The teachers felt that they needed to develop their teacher-student discussion skills and to improve their feedback on the reflections. Peer assessment between students is proposed as a line of action to enhance the credibility of the crucial tutor certificate. The portfolio might be an efficient tool for the students to concentrate their efforts on the most central concepts of medical laboratory work. The model will be developed through further discussions and better consensus among faculty.

In this study the Delphi technique has been used to develop a core curriculum for education of the biomedical scientist. The rapid development in biomedicine and the corresponding changes in methodology in biomedical laboratories demand careful planning of the education of biomedical scientists. The Delphi technique uses an anonymous panel of experts for suggestions and assessments aiming at consensus. Twenty-six experts from different kinds of hospital and university laboratories took part in the investigation. They suggested and assessed necessary competences for a recently graduated biomedical scientist, and if 75% or more of the participants agreed on a competence, it was included in the core curriculum. The final list consisted of 66 competences of varying depth, in three categories. This list contained several generic competences, concerning for example basic laboratory methods, handling of samples, dealing with apparatus and applying relevant rules and laws; basic knowledge in chemistry, preclinical medicine and laboratory methods; and finally attitudes that the panel expected in the recently graduated person. The core was sufficiently restricted to be used in a three-year programme and still leave space for about one year of electives/special study modules. It became rather traditional, e.g. it did not include competences that many recent reports consider important for the future professional.

The neuropeptides pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are structurally and functionally related. Their actions have been shown to be mediated by three different receptor subtypes: PAC1-R, which has exclusive affinity for PACAP, and VPAC1-R and VPAC2-R, which have equal affinity for PACAP and VIP. We recently showed that PACAP38 induces lipolysis in rat adipocytes, and in the present study we examined whether VIP has similar effects and which of the three receptors mediates this PACAP/VIP action. We showed by RT-PCR that all three receptor subtypes are present in rat adipocytes. We demonstrated that VIP (1-100 nm), like PACAP38, stimulates lipolysis in isolated adipocytes, as determined by glycerol release. By a pharmacological approach, using antagonists and agonists specific for the receptor subtypes, we elucidated the mechanisms by which PACAP38 and VIP mediate their lipolytic effects. We found that antagonists of PAC1-R [PACAP(6-38)] and VPAC1-R (PG97-269) did not affect lipolysis induced by 0.1-100 nm PACAP38 or VIP, and that a VPAC1-R agonist [K15, R16, L27VIP(1-7)GRF(8-27)] did not affect lipolysis at 1-1000 nm. However, two different VPAC2-R agonists [Hexa-VIP(1-28) and Ro25-1553] clearly mimicked the lipolytic effect of PACAP38 and VIP. In addition, the VPAC2-R antagonist PG99-465 (100 nm) caused right-shifted dose-response curves of PACAP38- and VIP-induced lipolysis. These results therefore provide evidence that all three PACAP/VIP receptor subtypes are expressed in primary rat adipocytes, but that the VPAC2-R subtype is responsible for mediating the lipolytic effects induced by PACAP38 and VIP.

Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide that exerts its effects throughout the body by elevating the intracellular amounts of cAMP. In adipocytes, an increased amount of cAMP is associated with increased lipolysis. In this work we evaluated the effects of PACAP38 on triglyceride metabolism in primary rat adipocytes. Stimulation of adipocytes with PACAP (0.1-100 nm) resulted in stimulation of lipolysis to the same extent as isoproterenol. Lipolysis was blocked by 25 microm of the protein kinase A inhibitor H-89 and potentiated in the presence of 10 microm OPC3911, a phosphodiesterase 3 inhibitor. In addition, PACAP38 induced activation of protein kinase A. Insulin efficiently inhibited PACAP38-induced lipolysis in a phosphatidyl inositol 3-kinase and phosphodiesterase 3-dependent manner. Interestingly, we also found that PACAP38, as well as isoproterenol, induced potentiation of lipogenesis in the presence of insulin. These results show that PACAP38 and isoproterenol mediate catabolic as well as anabolic effects in adipocytes, depending on the concentration of insulin present. We speculate that in the early postprandial state and during fasting, when insulin levels are low, PACAP and beta-adrenergic catecholamines induce lipolysis, whereas when higher levels of insulin are present, these agents potentiate the anabolic effect of insulin, i.e. storage of triglycerides.

Skin fibroblasts treated with brefeldin A produce a recycling variant of glypican (a glycosylphosphatidylinositolanchored heparan-sulfate proteoglycan) that is resistant to inositol-specific phospholipase C and incorporates sulfate and glucosamine into heparan sulfate chains (Fransson, L.-A. et al., Glycobiology, 5, 407-415, 1995). We have now investigated structural modifications of recycling glypican, such as fatty acylation from [3H]palmitate, and degradation and assembly of heparan sulfate side chains. Most of the 3H-radioactivity was recovered as lipid-like material after de-esterification. To distinguish between formation of heparan sulfate at vacant sites, elongation of existing chains or degradation followed by re-elongation of chain remnants, cells were pulse-labeled with [3H]glucosamine and then chase-labeled with [14C]glucosamine. Material isolated from the cells during the chase consisted of proteoglycan and mostly [3H]-labeled heparan-sulfate degradation products (molecular mass, 20-80 kDa) showing that the side chains were degraded during recycling. The degradation products were initially glucuronate-rich, but became more iduronate-rich with time. The glypican proteoglycan formed during the chase was degraded either with alkali to release intact side chains or with heparinase to generate distally located chain fragments that were separated from the core protein, containing the proximally located, covalently attached chain remnants. All of the [14C]-radioactivity incorporated during the pulse was found in peripheral chain fragments, and the chains formed were not significantly longer than the original ones. We therefore conclude that newly made heparan-sulfate chains were neither made on vacant sites, nor by extension of existing chains but rather by re-elongation of degraded chain remnants. The remodeled chains made during recycling appeared to be more extensively modified than the original ones.

Hormone-sensitive lipase (HSL) plays a key role in lipid metabolism and overall energy homoeostasis, by controlling the release of fatty acids from stored triglycerides in adipose tissue. Lipases and esterases form a protein superfamily with a common structural fold, called the alpha/beta-hydrolase fold, and a catalytic triad of serine, aspartic or glutamic acid and histidine. Previous alignments between HSL and lipase 2 of Moraxella TA144 have been extended to cover a much larger part of the HSL sequence. From these extended alignments, possible sites for the catalytic triad and alpha/beta-hydrolase fold are suggested. Furthermore, it is proposed that HSL contains a structural domain with catalytic capacity and a regulatory module attached, as well as a structural N-terminal domain unique to this enzyme. In order to test the proposed domain structure, rat HSL was overexpressed and purified to homogeneity using a baculovirus/insect-cell expression system. The purification, resulting in > 99% purity, involved detergent solubilization followed by anion-exchange chromatography and hydrophobic-interaction chromatography. The purified recombinant enzyme was identical to rat adipose-tissue HSL with regard to specific activity, substrate specificity and ability to serve as a substrate for cAMP-dependent protein kinase. The recombinant HSL was subjected to denaturation by guanidine hydrochloride and limited proteolysis. These treatments resulted in more extensive loss of activity against phospholipid-stabilized lipid substrates than against water-soluble substrates, suggesting that the hydrolytic activity can be separated from recognition of lipid substrates. These data support the concept that HSL has at least two major domains.

By catalyzing the rate-limiting step in adipose tissue lipolysis, hormone-sensitive lipase (HSL) is an important regulator of energy homeostasis. The role and importance of HSL in tissues other than adipose are poorly understood. We report here the cloning and expression of a testicular isoform, designated HSLtes. Due to an addition of amino acids at the NH2-termini, rat and human HSLtes consist of 1068 and 1076 amino acids, respectively, compared to the 768 and 775 amino acids, respectively, of the adipocyte isoform (HSLadi). A novel exon of 1.2 kb, encoding the human testis-specific amino acids, was isolated and mapped to the HSL gene, 16 kb upstream of the exons encoding HSLadi. The transcribed mRNA of 3.9 kb was specifically expressed in testis. No significant similarity with other known proteins was found for the testis-specific sequence. The amino acid composition differs from the HSLadi sequence, with a notable hydrophilic character and a high content of prolines and glutamines. COS cells, transfected by the 3.9-kb human testis cDNA, expressed a protein of the expected molecular mass (M(r) approximately 120,000) that exhibited catalytic activity similar to that of HSLadi. Immunocytochemistry localized HSL to elongating spermatids and spermatozoa; HSL was not detected in interstitial cells.

We have used suramin and brefeldin A to investigate the nature of a heparan sulphate proteoglycan that appears to recycle from the cell surface to intracellular compartments which synthesize new heparan sulphate chains. Suramin, which would block internalization and deglycanation of a putative recycling cell surface proteoglycan, markedly increases the yield of a membrane-bound proteoglycan with a core protein of 60-70 kDa and unusually long heparan sulphate side chains. When transport of newly made core proteins to their Golgi sites for glycosaminoglycan assembly is blocked, by using brefeldin A, [3H]glucosamine and [35S]sulphate incorporation into cell surface-bound heparan sulphate proteoglycan can still take place. After chemical biotinylation of cell surface proteins in brefeldin A-treated cells, followed by metabolic [35S]sulphation in the presence of the same drug, biotin-tagged [35S]proteoglycan can be demonstrated, indicating the presence of recycling proteoglycan species. By pre-labelling cells with [3H]leucine or [3H]inositol in the presence of suramin, followed by chase labelling with [35S]sulphate in the presence of brefeldin A, a 3H- and 35S-labelled, hydrophobic heparan sulphate proteoglycan with a core protein of 60-65 kDa is obtained. The proteoglycan loses its hydrophobicity when glucosamine-inositol bonds are cleaved, indicating that it is membrane bound via a glycosylphosphatidylinositol anchor. However, treatment with phosphatidylinositol-specific phospholipase C has no effect, suggesting that the inositol moiety may be acylated. We propose that a portion of the lipid-anchored proteoglycan glypican is internalized, recycled via the Golgi, where heparan sulphate chains are added, and finally re-deposited at the cell surface.