Risk of mortality and recurrent cardiovascular events in patients with acute coronary syndromes on high intensity statin treatment.

Several randomized controlled trials have shown a benefit of high-dose intensive statin treatment in reducing risk of death and second cardiovascular disease (CVD) events in patients previously diagnosed with an acute coronary syndrome (ACS). Non-randomized studies in clinical settings support these findings, but large, long-term, observational studies addressing CVD and non-CVD endpoints are lacking. In this retrospective longitudinal study, we followed ACS patients in Sweden during 2001-2012 using national health registry and medical record data. A total of 49,857 patients were identified, of whom 10,092 (20.2%) received high dose statins and 21,174 (42.7%) received no statins. Royston-Parmar parametric time-to-event models were implemented to model hazard for second CVD events and death, stratified by gender and diabetes diagnosis. We found that risk of a second CVD event developed similarly in both treatment groups, but was much higher in the no statin group. Risk of CVD-related death remained relatively constant for the high-statin group, while it increased over time for the no-statin group. Interestingly, males had higher mortality rates in the no-statin group, but not in the high-statin group. All-cause mortality and non-CVD-related death followed similar trends to those observed for CVD-related death. This work provides additional real-world evidence for effect of statins in CVD-related mortality. The hazard functions presented here can provide a basis for future survival modeling and health economic evaluation.

Work productivity loss and indirect costs associated with new cardiovascular events in high-risk patients with hyperlipidemia: estimates from population-based register data in Sweden.

OBJECTIVES: To estimate productivity loss and associated indirect costs in high-risk patients treated for hyperlipidemia who experience cardiovascular (CV) events. METHODS: Retrospective population-based cohort study conducted using Swedish medical records linked to national registers. Patients were included based on prescriptions of lipid-lowering therapy between 1 January 2006 and 31 December 2011 and followed until 31 December 2012 for identification of CV events and estimation of work productivity loss (sick leave and disability pension) and indirect costs. Patients were stratified into two cohorts based on CV risk level: history of major cardiovascular disease (CVD) and coronary heart disease (CHD) risk equivalent. Propensity score matching was applied to compare patients with new events (cases) to patients without new events (controls). The incremental effect of CV events was estimated using a difference-in-differences design, comparing productivity loss among cases and controls during the year before and the year after the cases' event. RESULTS: The incremental effect on indirect costs was largest in the CHD risk equivalent cohort (n = 2946) at €3119 (P value <0.01). The corresponding figure in the major CVD history cohort (n = 4508) was €2210 (P value <0.01). There was substantial variation in productivity loss depending on the type of event. Transient ischemic attack and revascularization had no significant effect on indirect costs. Myocardial infarction (€3465), unstable angina (€2733) and, most notably, ischemic stroke (€6784) yielded substantial incremental cost estimates (P values <0.01). CONCLUSIONS: Indirect costs related to work productivity losses of CV events are substantial in Swedish high-risk patients treated for hyperlipidemia and vary considerably by type of event.

Healthcare costs associated with cardiovascular events in patients with hyperlipidemia or prior cardiovascular events: estimates from Swedish population-based register data.

OBJECTIVES: To estimate healthcare costs of new cardiovascular (CV) events (myocardial infarction, unstable angina, revascularization, ischemic stroke, transient ischemic attack, heart failure) in patients with hyperlipidemia or prior CV events. METHODS: A retrospective population-based cohort study was conducted using Swedish national registers and electronic medical records. Patients with hyperlipidemia or prior CV events were stratified into three cohorts based on CV risk level: history of major cardiovascular disease (CVD), coronary heart disease (CHD) risk-equivalent, and low/unknown risk. Propensity score matching was applied to compare patients with new events to patients without new events for estimation of incremental costs of any event and by event type. RESULTS: A CV event resulted in increased costs over 3 years of follow-up, with the majority of costs occurring in the 1st year following the event. The mean incremental cost of patients with a history of major CVD (n = 6881) was €8588 during the 1st year following the event. This was similar to that of CHD risk-equivalent patients (n = 3226; €6663) and patients at low/unknown risk (n = 2497; €8346). Ischemic stroke resulted in the highest 1st-year cost for patients with a history of major CVD and CHD risk-equivalent patients (€10,194 and €9823, respectively); transient ischemic attack in the lowest (€3917 and €4140). Incremental costs remained elevated in all cohorts during all three follow-up years, with costs being highest in the major CVD history cohort. CONCLUSIONS: Healthcare costs of CV events are substantial and vary considerably by event type. Incremental costs remain elevated for several years after an event.

Associations of HbA1c and educational level with risk of cardiovascular events in 32,871 drug-treated patients with Type 2 diabetes: a cohort study in primary care.

AIMS: To explore the association of HbA1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes. METHODS: A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose-lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA1c levels and educational level with risks of cardiovascular events and all-cause mortality were analysed. RESULTS: The associations of HbA1c with risk of all-cause and cardiovascular mortality were J-shaped, with the lowest risk observed for cardiovascular mortality at an HbA1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin-treated patients. The lowest risk observed for all-cause mortality was at an HbA1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin-treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2-2.1), P = 0.0008] at the lowest HbA1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8-1.6), P = 0.3873]. CONCLUSIONS: Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315).

IPECAD5--Fifth International Pharmaco-Economic Conference on Alzheimer's Disease.

The Fifth International Pharmaco-Economic Conference on Alzheimer's Disease was held in New York, on March 27-29 in 2008. The attendees included researchers and key opinion leaders within the academia, pharmaceutical industry, patient organizations and regulatory bodies, collecting the worldwide leading expertise in Alzheimer research today. A summary of the presentations and conclusions from the discussions are presented in this publication. Pharmaco-economics need to play a leading role in developing and communicating evidence of the value of anti-dementia drugs, now and in the future. For the development of evidence, the challenges include transparency and standardization of costs of care assessment, improved diagnostics for identifying target patient groups, improved endpoints for assessing outcomes and improved models for assessing the long term consequences of competing treatment strategies. For the communication of evidence, the challenge lies in convincing decision makers to recognize the integrated burden of the disease, including its interaction with co-morbidities and burden on caregivers, and to consider the consequences of competing treatment strategies from a societal perspective.

Assessment of the physical activity level with two questions: validation with doubly labeled water.

OBJECTIVE: To validate a two-question questionnaire on physical activity with the doubly labeled water (DLW) method. DESIGN: Cross-sectional study. SUBJECTS: Nine volunteers, age 33-75 years, with a mean body mass index (BMI) (kg m(-2)) of 27.4. MEASUREMENTS: A questionnaire with one question on physical activity at work and one question on physical activity during leisure time. The answers were converted into a PAL (physical activity level=energy expenditure/basal metabolic rate) value, which was validated with the DLW method. RESULTS: The mean values (s.d.) of PAL for the questionnaire and DLW measurements were 1.7 (0.1) and 1.7 (0.1), respectively, with a mean difference of 0.004 (0.172). CONCLUSIONS: The results were promising to the extent that they could be used in large-scale epidemiological studies.

Validity of reported energy expenditure and reported intake of energy, protein, sodium and potassium in rheumatoid arthritis patients in a dietary intervention study.

OBJECTIVES: The aim of the study was to validate a diet history interview (DHI) method and a 3-day activity registration (AR) with biological markers. SUBJECTS AND STUDY DESIGN: The reported dietary intake of 33 rheumatoid arthritis patients (17 patients on a Mediterranean-type diet and 16 patients on a control diet) participating in a dietary intervention study was assessed using the DHI method. The total energy expenditure (TEE), estimated by a 3-day AR, was used to validate the energy intake (EI). For nine subjects the activity registration was also validated by means of the doubly labelled water (DLW) method. The excretion of nitrogen, sodium and potassium in 24-h urine samples was used to validate the intake of protein, sodium and potassium. RESULTS: There was no significant difference between the EI and the TEE estimated by the activity registration or between the intake of protein, sodium and potassium and their respective biological markers. However, in general, the AR underestimated the TEE compared to the DLW method. No significant differences were found between the subjects in the Mediterranean diet group and the control diet group regarding the relationship between the reported intakes and the biological markers. CONCLUSION: The DHI could capture the dietary intake fairly well, and the dietary assessment was not biased by the dietary intervention. The AR showed a bias towards underestimation when compared to the DLW method. This illustrates the importance of valid biological markers.

Primary sepsis in a university hospital in northern Sweden: a retrospective study.

BACKGROUND: Severe sepsis and septic shock are associated with high mortality rates. Data on sepsis outcome from Scandinavian countries are sparse. The aim of this study was to examine the length of stay (LOS) in the ICU, ICU mortality and costs of care for adult patients with primary sepsis in a university hospital in northern Sweden. METHODS: We performed a retrospective data analysis of records of 92 patients admitted over a 3-year period, under the diagnosis of sepsis or urosepsis. Demographic data, admission category, APACHE II score, aetiology and severity of sepsis, ICU LOS, mortality and TISS were analyzed. RESULTS: Eighty-one adult patients were identified by standard definitions as suffering from sepsis. The median ICU length of stay was 4.2 days, 6 days for survivors and 2.1 days for non-survivors. Thirteen out of 20 deaths occurred within the first 3 days after admission. Overall ICU mortality rate was 24.7% while the ICU mortality for patients with septic shock was 57.7%. The mean costs of care for patients with sepsis were 3139 Euros day(-1) and the cost of care per patient surviving sepsis was 38,494 Euros. CONCLUSION: The incidence of primary sepsis in our ICU was low. Previous reports on high mortality in association with severe sepsis and septic shock are valid also at our hospital. The ICU-LOS was shorter than previously reported, while our costs of care were in the same range as stated by others. This retrospective analysis is valid for interpretation of the applicability of currently available sepsis therapies.

Assessment of graded intestinal hypoperfusion and reperfusion using continuous saline tonometry in a porcine model.

OBJECTIVE: To evaluate effects of graded intestinal hypoperfusion and reperfusion on intestinal metabolic parameters as assessed by a modified continuous saline tonometry technique. MATERIALS: Twelve barbiturate-anaesthetized female pigs. METHODS: Measurements were performed prior to and during three predefined levels of superior mesenteric mean arterial blood pressure (P(SMA) 70, 50 and 30 mmHg, respectively, each 80 min long), obtained by an adjustable clamp around the origin of the superior mesenteric artery, and during reperfusion. We continuously measured jejunal mucosal perfusion (laser Doppler flowmetry), jejunal tissue oxygen tension (PO(2TISSUE); microoximetry) and intramucosal PCO(2) (continuous saline tonometry) and calculated net intestinal lactate production, mesenteric oxygenation, PCO(2) gap (jejunal mucosal PCO(2)-arterial PCO(2)) and pHi. RESULTS: At P(SMA) 70 and 50 mmHg mesenteric oxygen uptake and net lactate production remained unaltered, in spite of decreased oxygen delivery. At these P(SMA) levels PCO(2) gap increased, while pHi and PO(2TISSUE) decreased. At P(SMA) 30 mmHg pronounced increases in PCO(2) gap and mesenteric net lactate production as well as marked decreases in PO(2TISSUE) and pHi were demonstrated. Data indicate absence of anaerobic conditions at an intestinal perfusion pressure (IPP)> or =41 mmHg, a pHi> or =7.22 or PCO(2) gap< or =15.8 mmHg. CONCLUSIONS: Continuous saline tonometry detected intestinal ischemia as induced by graded reductions in IPP. A threshold could be defined above which intestinal ischemia does not occur.

Preload changes by positive pressure ventilation can be used for assessment of left ventricular systolic function.

BACKGROUND: Assessment of preload independent left ventricular function with conductance volumetry is traditionally accomplished by inflating a balloon in the inferior caval vein. Our aim was to investigate if a similar change in preload could be achieved by positive pressure ventilation with large tidal volume. METHODS: Conductance volumetry generating left ventricular pressure-volume loops was used in seven pentobarbital-anesthetized pigs. Changes in preload recruitable stroke work were studied, comparing the effects of inferior vena cava occlusion (IVCO) or large tidal volume (LTV). Cardiodepression was induced by halothane anesthesia and halothane + phenylephrine, and stimulation by epinephrine infusion. RESULTS: Although the decreasis in left ventricular end diastolic volume was slightly less with LTV (16.5 +/- 1.7 ml, mean +/- SEM) than with IVCO (22.4 +/- 1.7 ml) (P < 0.0001) the PRSW-slopes showed a high degree of correlation (r=0.80, P < 0.0001). Although peak tracheal pressures increased significantly to 27.8 +/- 0.9 mmHg during LTV, esophageal pressures (used as an indicator of pericardial pressure) were unchanged. CONCLUSIONS: Positive pressure ventilation with LTV is similar to IVCO in creating transient changes in preload, necessary for assessment of left ventricular systolic function. This observation was valid also during drug-induced cardiac depression and stimulation. The preload recruitable stroke work used for this validation was shown to be a reliable and stable method.

Assessment of myocardium at risk in pigs with single photon emission computed tomography and computerized vectorcardiography during transient coronary occlusion.

Since myocardium at risk (MAR) is the major prognosticator of final infarct size and outcome in patients with acute myocardial infarction, it is highly desirable to estimate the size of the acutely ischemic myocardium, that is the MAR, in these patients. We assessed MAR size by Tc-99m-sestamibi-SPECT and computerized vectorcardiography using autoradiography as reference method. Transient myocardial ischemia was achieved in 12 pigs by coronary artery occlusion with PTCA catheters. During the procedure, computerized vectorcardiography was continuously recorded. After injection of Tc-99m-sestamibi and gadolinium-153-labelled microspheres, MAR size was estimated by SPECT and post-mortem autoradiography. Different cut-off levels (50-70%) were compared with respect to MAR-SPECT. Tc-99m-sestamibi-SPECT showed a good correlation with autoradiography (r = 0.94). Computerized vectorcardiography showed a good correlation with autoradiography as well as with Tc-99m-sestamibi-SPECT (STC-VM: r = 0.75 and 0.80, respectively, ST-VM: 0.75 and 0.87, respectively). It was found that 1) MAR assessed by Tc-99m-sestamibi-SPECT correlates closely with the autoradiographic reference; 2) a lower cut-off point of 60% of maximum uptake for MAR by Tc-99m-sestamibi-SPECT gives the closest correlation with the autoradiographic reference; and 3) ST-VM and STC-VM correlate well with MAR assessed by Tc-99m-sestamibi-SPECT and autoradiography.

Design and evaluation of a software prototype for participatory planning of environmental adaptations.

A software prototype to support the planning process for adapting home and work environments for people with physical disabilities was designed and later evaluated. The prototype exploits low-cost three-dimensional (3-D) graphics products in the home computer market. The essential features of the prototype are: interactive rendering with optional hardware acceleration, interactive walk-throughs, direct manipulation tools for moving objects and measuring distances, and import of 3-D-objects from a library. A usability study was conducted, consisting of two test sessions (three weeks apart) and a final interview. The prototype was then tested and evaluated by representatives of future users: five occupational therapist students, and four persons with physical disability, with no previous experience of the prototype. Emphasis in the usability study was placed on the prototype's efficiency and learnability. We found that it is possible to realise a planning tool for environmental adaptations, both regarding usability and technical efficiency. The usability evaluation confirms our findings from previous case studies, regarding the relevance and positive attitude towards this kind of planning tool. Although the prototype was found to be satisfactorily efficient for the basic tasks, the paper presents several suggestions for improvement of future prototype versions.

Validation with biological markers for food intake of a dietary assessment method used by Swedish women with three different dietary preferences.

OBJECTIVES: To validate a dietary assessment method, a 4-day food record together with a duplicate portion technique, with biological markers for food intake. DESIGN: Four days of duplicate portions were collected in parallel with food recording. A 24-h urine sample and the faeces corresponding to the food intake (using a coloured marker) were collected. Completeness of urine and faeces collections was assessed using para-aminobenzoic acid (PABA) in urine and cadmium in faeces, respectively. Biomarkers of food intake (energy, protein, fibre, sodium, potassium, calcium) were measured in urine and faeces. SETTING: Swedish west coast. SUBJECTS: Non-smoking Swedish women, 20-50 years of age, consuming a mixed diet (n = 34), a mixed diet rich in shellfish (n = 17) or a vegetarian/high-fibre diet (n = 23). RESULTS: The average ratio (food intake according to the dietary assessment methods/ biological marker) for protein, sodium, potassium and calcium was 0.86. This indicates an underestimation of the food intake by approximately 15%. The ratio of stated fibre intake to biological marker was 1.20 for the mixed diet and the vegetarian diet group, indicating an overestimation by approximately 20%. CONCLUSIONS: The underestimation of the intake of protein, sodium, potassium and calcium by all three groups and the overestimation of the fibre intake by two groups indicate that underreporting is selective to certain nutrients and foods and to various groups of people. The two dependent dietary assessment methods were equally good in measuring protein intake, which indicates that the women recorded what they actually duplicated.

Validation of dietary intakes of protein and energy against 24 hour urinary N and DLW energy expenditure in middle-aged women, retired men and post-obese subjects: comparisons with validation against presumed energy requirements.

OBJECTIVES: To compare validation of reported dietary intakes from weighed records against urinary nitrogen excretion and energy expenditure measured by DLW, and to examine the utility of the Goldberg cut-off for EI:BMR in the identification of under-reporters. DESIGN: Energy (EI) and nitrogen (protein) intake (NI) were measured by 16 d of weighed diet records collected over 1 y. They were validated against urinary nitrogen excretion in 5-8 (mean 6.0) 24 h urine collections and total energy expenditure (EE) measured by doubly labelled water (DLW). Basal metabolic rate (BMR) as measured by whole body calorimetry in women or bedside ventilated hood (Deltatrac) in men. Individual subjects were identified as under-reporters if Urine N:NI was > 1.00 or if EI:EE was < 0.79. The agreement between the two ratios in detecting under-reporting was examined. The results from the direct validation by DLW were also compared with validation using the Goldberg cut-off for EI:BMR (Goldberg et al, 1991). SUBJECTS: Eighteen women aged 50-65 y and 27 men aged 55-87 y were selected from participants in two larger dietary surveys as representing the full range of dietary reporting as measured by Urine N:NI. Data from a previous study of 11 post-obese subjects were also included. RESULTS: The two ratios, Urine N:NI and EI:EE, were significantly related (r = -0.48, P < 0.01). Using the above cut-offs, seven (4F, 3M) subjects were identified as under-reporters by both methods, one (1M) by Urine N:NI only and 8 (3F, 5M) by EI:EE only. There was close agreement in post-obese subjects where 6 subjects showed a substantial degree of under-reporting by both methods (r = -0.87, P < 0.001). The correlation between direct validation by DLW and EI:BMRest was 0.65 (P < 0.001). Some limitations of the Goldberg cut-off for identifying individual under-reporters were demonstrated. CONCLUSIONS: EI:EE provides an estimate of the degree of under-reporting of energy at the group and individual level. Urine N:NI identifies under-reporting of protein intake and the most obvious under-reporters of energy, but is probably of lesser value in estimating the overall degree of under-reporting of energy at group level. Good validation by EI:BMR depends on knowledge of physical activity at both group and individual level. However, the correlation of 0.65 between EI:EE and EI:BMRest suggests that EI:BMR could be usefully incorporated into analysis of data from epidemiological studies. Validation measures consisting of at least predicted EI:BMR ratios and urinary measures should be incorporated into dietary surveys. SPONSORSHIP: This work was funded by the Ministry of Agriculture Fisheries and Food, the Medical Research Council, the Cancer Research Council and the Swedish Medical Research Council and the Henning and Johan Throne-Holst Foundation.

Young adults' views on dental care--a qualitative analysis.

The aim of the present study was to determine young adults' views on dental care. The gathered data were gleaned from interviews and analysed in accordance with comparative method. It was possible to discern the views from two perspectives: the patients' opinions regarding costs in relation to given functions within dental care, and the attitudes to given functions in dental care per se. Costs for information and service were deemed questionable, whereas the costs for examination and treatment were accepted. The patients' stance was active with respect to information and treatment, whereas a greater degree of passivity prevailed within the areas of examination and service. According to this report, maintaining cheap dental care rates was deemed important. The patients questioned having to pay for information perceived as irrelevant to dental care. They expressed a hidden wish to assume an active role while being given more information, and to exercise greater influence with reference to own dental care, but were not in the habit of stating their views to dental staff. Thus, continuous patient satisfaction studies are vital in order to meet this group's needs. One suggestion for further research is to study how young adults regard dental care based on the theory presented.

The 1,4-beta-D-glucan glucanohydrolases from Phanerochaete chrysosporium. Re-assessment of their significance in cellulose degradation mechanisms.

A physico-chemical, functional and structural characterization, including partial sequence data, of three major 1,4-beta-D-glucan glucanohydrolases (EC. 3.2.1.4) isolated from the culture filtrate of the white-rot fungus Phanerochaete chrysosporium, shows that all three enzymes belong to a single family of cellulases. EG44, pI 4.3, (named after its apparent molecular mass in kDa), shows a clear homology with Schizopyllum commune Endoglucanase I (EGI); whereas EG38, pI 4.9, (named in the same manner) is related more closely to Trichoderma reesei (Trichoderma longibrachiatum) Endoglucanase III (EGIII). EG36, pI 5.6-5.7, is probably an EG38 protein lacking its cellulose binding domain. Strong synergistic action is induced by the enzymes acting in concert with cellobiohydrolases (CBHI and CBHII) from the same organism, indicating a highly effective enzymatic system for cellulose degradation. Controlled proteolysis with papain has allowed a so far unique cleavage of endoglucanases EG44 and EG38 into two domains: a core protein, which virtually lacks the capacity to absorb onto microcrystal-line cellulose but retains full catalytic activity against carboxymethyl cellulose and low molecular weight soluble substrates; and a peptide fragment corresponding to the cellulose binding domain. The latter appears to be of paramount significance in the mechanisms involved in the hydrolysis of microcrystalline cellulose.

Job demands and stress reactions in repetitive and uneventful monotony at work.

Monotonous work has been analyzed from sociological and social psychological perspectives in terms of consequences for job satisfaction, life satisfaction, leisure activities, and health. In this article, a distinction is made between repetitive and uneventful monotony. Psychobiological reactions to these tasks are analyzed and related to possible long-term consequences for health. Strategies for work reform required for the two types of monotony are discussed.