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The importance of sensory information in product purchasing decisions has gained increasing attention in recent years. Tactile properties of packaging are usually measured with the help of trained evaluators. An objective, fast and repeatable method that describes the mechanical interaction and does not rely on a panel would have many benefits. We propose and evaluate such a method for measuring the mechanical interaction between a deformable finger-like shaped sensor and a package. Evaluation of the method shows good repeatability, the variability in the measurement result is within a few percent in most cases. The method captures indentation differences at contact between sensor and package due to measurement position and package design., Funding Agencies:Gunnar Sundblad Research FoundationBillerud KorsnäsTetraPak

Background Studies suggest that the direct factor Xa inhibitor rivaroxaban compared to warfarin reduces the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT), but this has not been evaluated for oral direct thrombin inhibitors. Objectives To compare the long-term prevalence of PTS, recurrent venous thromboembolism (VTE), and health-related quality of life (HRQoL) in patients with acute DVT and/or pulmonary embolism (PE), randomized to treatment with dabigatran or warfarin in the phase III RE-COVER studies. Methods We conducted a cross-sectional follow-up study of patients randomized in Canada, Norway, and Sweden. PTS was assessed by the patient-reported Villalta scale (PRV) and HRQoL by EQ-5D and VEINES-QOL/Sym. Results We included 349 patients between December 2015 and November 2018; 166 were treated with dabigatran and 183 with warfarin. DVT (+/− PE) was index event in 255 patients, whereas 94 patients had PE only. Mean time from index event was 8.7 (standard deviation 1.4) years. PTS was diagnosed in 63% of patients with DVT and in 46% of patients with PE only, and did not differ between the treatment groups; the crude odds ratio (OR) for PTS in patients treated with dabigatran compared with warfarin was 1.1 (95% confidence interval [CI] 0.6–1.8) after DVT and 1.2 (95% CI 0.5–2.6) after PE only. The prevalence of recurrent VTE was 21% in both treatment groups. HRQoL scores did not differ between groups. Conclusion In this long-term cross-sectional study, the prevalence of PTS, recurrent VTE, and HRQoL were similar in patients treated with dabigatran and warfarin.

The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Post-hoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0–3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant non-major bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68–0.95 and RE-MEDY, HR 0.73; 95% CI 0.59–0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control.

Management of acute venous thromboembolism (VTE) with anticoagulants in elderly patients and those with chronic kidney disease poses special challenges. The RE-COVER and RE-COVER II trials showed that dabigatran 150 mg twice daily was as effective as warfarin over 6 months in preventing recurrent VTE, with a lower bleeding risk. We now assess the effects of old age and renal impairment (RI) on pooled trial outcomes in 5,107 patients: 4,504 aged

SummaryDabigatran was as effective as warfarin for the acute treatment of venous thromboembolism in the RE-COVER and RE-COVER II trials. We compared the incidence of bleeding with dabigatran versus warfarin in pooled data from these studies. The localisation, bleeding severity, and the impact of key factors on the incidence of bleeding, were compared between the dabigatran and warfarin treatment group. Altogether, 2553 patients received dabigatran and 2554 warfarin, each for a mean of 164 days. The incidence of any bleeding event was significantly lower with dabigatran (hazard ratio [HR] 0.70; 95 % confidence interval [CI], 0.61–0.79), as was the incidence of the composite of MBEs and clinically relevant non-major bleeding events (HR 0.62; 95 % CI, 0.50–0.76). The incidence of major bleeding events (MBEs) was also significantly lower with dabigatran in the double-dummy phase (HR, 0.60; 95 % CI, 0.36–0.99) but not statistically different between the two treatment arms when the entire treatment period is considered (HR 0.73 95 % CI, 0.48–1.11). Increasing age, reduced renal function, Asian ethnicity, and concomitant antiplatelet therapy were associated with higher bleeding rates in both treatment groups. The reduction in bleeding with dabigatran compared to warfarin was consistent among the subgroups and with a similar pattern for intracranial, and urogenital major bleeding. In conclusion, treatment of venous thromboembolism with dabigatran is associated with a lower risk of bleeding compared to warfarin. This reduction did not differ with respect to the location of bleeding or among predefined subgroups.

SummaryDabigatran was non-inferior to warfarin for prevention of recurrent venous thromboembolism (VTE), and dabigatran had a lower rate of bleeding compared with warfarin in two large-scale randomised trials, RE-COVER and RE-COVER II. In this study, we investigate the efficacy and safety of dabigatran versus warfarin according to the index event that qualified the patient for enrollment, either symptomatic pulmonary embolism (PE) with or without deep-vein thrombosis (DVT), or DVT alone. We then analyse the anticoagulant effect of dabigatran vs warfarin on patients enrolled with PE. The pooled dataset for the efficacy analysis consisted of 2553 and 2554 patients who were randomised to dabigatran and warfarin, respectively. Recurrent VTE/VTE-related death during the study period and additional 30-day follow-up occurred in 2.7 % of all patients on dabigatran and in 2.4 % on warfarin (hazard ratio [HR] 1.09 [95 % confidence interval 0.77, 1.54]). In patients with PE as their index event, recurrent VTE/VTE-related death occurred in 2.9 % vs 3.1 % of patients (HR 0.93 [0.53, 1.64]). There were significantly fewer major bleeding events in patients treated with dabigatran than with warfarin (HR 0.60 [0.36, 0.99]). The pattern was similar both in patients with PE and in those with DVT alone as the index event. These analyses of the pooled dataset from the RECOVER and RE-COVER II trials indicate that dabigatran is as effective as warfarin in preventing recurrent VTE, regardless of whether patients present with symptomatic PE (with or without DVT) or with symptomatic DVT alone. Dabigatran was also associated with a lower risk of bleeding than warfarin, regardless of the index event.

Aim This study aimed to estimate the prevalence, incidence rate, and lifetime risk of developing atrial fibrillation (AF) in a population-based study of Swedish men. Methods and results The study is a part of ‘The Study of Men Born in 1913’, which is a longitudinal prospective cohort study of 855 men born in 1913 and living in the city of Gothenburg in Sweden. They were followed from the age of 50 years until 98 years with repeated examinations and data from the Swedish National Hospital Discharge Register. A total of 185 (21.6%) men developed AF. The prevalence of AF increased from 0.4% at 50 years old, to 1.9% by 60 years old, to 4.6% by 70 years old, to 12.5% by 80 years old, and to 15.7% by 90 years old. The lifetime risk of developing AF was 22.5%. Conclusion Atrial fibrillation is rare at the age of 50 in Swedish men, but it increases exponentially with age, markedly accelerating after 70 years old. In nonagenarians, one of five men has or has had AF.

ObjectivesAlarmins S100A8/A9 regulate pathology in experimental osteoarthritis (OA). Paquinimod is an immunomodulatory compound preventing S100A9 binding to TLR-4. We investigated the effect of paquinimod on experimental OA and human OA synovium.Materials and methodsTwo OA mouse models differing in level of synovial activation were treated prophylactic with paquinimod. Synovial thickening, osteophyte size and cartilage damage were measured histologically, using an arbitrary score, adapted Pritzker OARSI score or imaging software, respectively. Human OA synovia were stimulated with S100A9, with or without paquinimod.ResultsPaquinimod treatment of collagenase-induced OA (CIOA) resulted in significantly reduced synovial thickening (57%), osteophyte size at the medial femur (66%) and cruciate ligaments (67%) and cartilage damage at the medial tibia (47%) and femur (75%; n=7, untreated n=6). In contrast, paquinimod did not reduce osteophyte size and reduced cartilage damage at one location only in destabilised medial meniscus, an OA model with considerably lower synovial activation compared with CIOA. In human OA synovium, paquinimod blocked proinflammatory (interleukin (IL)-6, IL-8, tumour necrosis factor-α) and catabolic (matrix metalloproteinases 1 and 3) factors induced by S100A9 (n=5).ConclusionsProphylactic treatment of paquinimod reduces synovial activation, osteophyte formation and cartilage damage in experimental OA with high synovial activation (CIOA) and ameliorates pathological effects of S100A9 in OA synovium ex vivo.

The direct oral anticoagulants, e.g., dabigatran etexilate (DE), are effective and well tolerated treatments for venous thromboembolism (VTE). Net clinical benefit (NCB) is a useful concept in weighing potential benefits against potential harm of comparator drugs. The NCB of DE vs. warfarin in VTE treatment was compared. Post-hoc analyses were performed on pooled data from the 6-month RE-COVER® and RE-COVER™ II trials, and data from the RE-MEDY™ trial (up to 36 months), to compare the NCB of DE (150 mg twice daily) and warfarin [target international normalized ratio (INR) 2.0–3.0]. Patients (≥18 years old) had symptomatic proximal deep vein thrombosis and/or pulmonary embolism. NCB was the composite of cardiovascular endpoints (non-fatal events of recurrent VTE, myocardial infarction, stroke or systemic embolism), all-cause death, and bleeding outcomes, all weighted equally. A broad definition of NCB included major bleeding events (MBE) and clinically relevant non-major bleeding events as bleeding outcomes, while a narrow definition included just MBE. The pooled dataset totalled 5107 patients from RE-COVER/RE-COVER II and 2856 patients from RE-MEDY. When NCB was narrowly defined, NCB was similar between DE and warfarin. When broadly defined, NCB was superior with DE vs. warfarin [RE-COVER/RE-COVER II, hazard ratio (HR) 0.80; 95% confidence interval (CI), 0.68–0.95 and RE-MEDY, HR 0.73; 95% CI 0.59–0.91]. These findings were unaffected by warfarin time in therapeutic range. The NCB of DE was similar or superior to warfarin, depending on the NCB definition used, regardless of the quality of INR control.

It is unclear whether thrombophilia causes resistance to anticoagulant therapy. Post hoc analyses of data from RE-COVER®, RE-COVER™ II, and RE-MEDY™ were performed to compare dabigatran etexilate with warfarin for the treatment and prevention of venous thromboembolism (VTE) in patients with thrombophilia or antiphospholipid antibody syndrome (APS). There were no significant differences in symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. All bleeding event categories were less frequent with dabigatran etexilate than with warfarin, regardless of whether patients had thrombophilia, no thrombophilia, or were not tested. However, these differences did not reach significance in every group. In patients with APS, there was no significant difference in VTE/VTE-related deaths between the two treatment arms. Rates of bleeding events tended to be lower with dabigatran etexilate than with warfarin, reaching statistical significance for any bleeding event. In conclusion, the efficacy and safety of dabigatran etexilate were not significantly affected by the presence of thrombophilia or APS. ClinicalTrials.gov RECOVER Identifier: NCT00291330; RECOVER II Identifier: NCT00680186; RE-MEDY Identifier: NCT00329238

Background: The extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain. Methods: We calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies. Results: For people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators. Conclusion: Adult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases. Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2012; all rights reserved.

Objective. Hyperlipidemia, overweight, insulin resistance and hypertension are associated with non-alcoholic fatty liver disease. The knowledge about these conditions as etiologic factors in liver cirrhosis is, however, limited. In this study, we examined the relation between overweight and hypertriglyceridemia, and development of liver cirrhosis in a general population. Material and methods. An epidemiological, longitudinal study was conducted involving men at the age of 50 with 40 years of follow-up. Baseline data were collected in 1963 and 1967. Cases of liver cirrhosis were identified by searching the Swedish Hospital Discharge Register and death certificates of the Central Bureau of Statistics. The independent effect of BMI, triglyceride levels and alcohol habits for cirrhosis of the liver was calculated by using multiple logistic regression analysis. Results. Elevated BMI and triglycerides were significant independent risk factors for the development of liver cirrhosis (OR 1.27 and 1.99, respectively, p < 0.01). Conclusions. Overweight and hypertriglyceridemia are independent risk factors for liver cirrhosis in Swedish men.

Objectives. Increasing numbers of people reach old age. We wanted to identify variables of importance for reaching 90 years old and determine how the predictive ability of these variables might change over time. Setting and subjects. All men in the city of Gothenburg born in 1913 on dates divisible by 3, which is on the 3rd, 6th, 9th etc., were included in the study. Thus, 973 men were invited, and 855 were examined in 1963 at age 50. Further examinations were made at age 54, 60 and 67. Anthropometric data, lifestyle and parental factors, blood pressure, lung function, X-ray of heart and lungs and maximum work performance were recorded. The area under the receiver operating characteristic curve was used to analyse the predictive capacity of a variable. Results. A total of 111 men (13%) reached 90 years of age, men who reached 90 years were more likely at age 50 to be nonsmokers, consume less coffee, have higher socio-economic status and have low serum cholesterol levels than those who did not reach this age; however, at age 50 or 62, parents' survival was of no prognostic importance. Variables of greatest importance at higher ages were low blood pressure and measures related to good cardiorespiratory function. In multivariable analysis, including all examinations, being a nonsmoker, consuming small amounts of coffee, having high housing costs at age 50, good maximum working capacity and low serum cholesterol were related to a better chance of survival to age 90. Conclusions. Low levels of cardiovascular risk factors, high socio-economic status and good functional capacity, irrespective of parents' survival, characterize men destined to reach the age of 90.

Oral body temperature was measured in 816 men, 57 and 67 years old, sampled from the general population of Goteborg, Sweden, and 22 physically highly active men, sampled on clinical grounds. The measurements were taken in the morning for 14 months. After adding 0.3 degrees C to the readings to make them comparable with rectal readings, the mean body temperature was 36.8 +/- 0.4 degrees C. There was a seasonal variation with a peak during the winter and a trough during the summer. Body temperature was inversely correlated with height and positively correlated with weight and body fat but not with lean body mass. High physical activity and sensitivity to heat were associated with a higher than average body temperature. Sensitivity to cold was associated with a lower than average body temperature. Smoking prior to the measurements did not appear to affect body temperature.

The impact of prothrombotic abnormalities on the risk of recurrent venous thromboembolism (VTE) and bleeding in patients receiving long-term anticoagulation remains unclear. This analysis evaluated the influence of potential prothrombotic risk factors (antithrombin, protein C, protein S, factor V Leiden mutation, prothrombin gene G20210A mutation, cardiolipin antibodies, number of risk factors) on the risk of recurrent VTE or bleeding during treatment with oral ximelagatran (24 mg twice daily) or placebo for 18 months [THRombin Inhibitor in Venous thromboEmbolism (THRIVE) III trial]. Of the 1223 patients in the intention-to-treat population, prothrombotic state was analysed in 559 patients receiving ximelagatran and 540 patients receiving placebo. It is possible that patients at a high risk of recurrent VTE were poorly represented in this analysis because of selection bias. Prothrombotic risk factors were reported in 41% of patients (8% had > or = 2 factors). No significant interactions were found between ximelagatran treatment and potential prothrombotic risk factors for the risk of recurrent VTE or bleeding by Cox proportionate hazard modelling. There was no clear evidence for a higher risk of recurrent VTE or bleeding across subgroups according to the potential prothrombotic factors analysed in this study.

SummaryDespite numerous studies documenting the association between cancer and venous thromboembolism (VTE), the reason for the excessive risk in certain cancers remains obscure. No large-scale studies have yet investigated the independent effects of cancer type,site and growth pattern.Between 1970 and 1982, 23,796 standardised autopsies were performed, representing 84% of all in-hospital deaths in an urban Swedish population.The relationship between cancer and PE was evaluated with logistic regression.The overall PE prevalence was 23%, and 10% of the population had a fatal PE. Forty-two per cent of pancreatic cancer patients had PE (OR 2.55; 95% CI 2.10–3.09) (p

Objective. Although deep vein thrombosis (DVT) and pulmonary embolism (PE) are manifestations of the same disease, far from all patients develop PE. Our objective was to investigate risk-modifying factors. Setting, subjects and design. Between 1970 and 1982, 23 796 autopsies, representing 84% of all in-hospital deaths in the Malmo City population, were performed, using a standardized procedure. In a case-control study nested in a population-based cohort of patients with proximal DVT, the relationship between PE and body mass index (BMI), thoracic and abdominal subcutaneous (SC) fat thickness was evaluated. Results. Proximal DVT was found in 15%, of which 58% were women. Mean age in men was 4.5 years lower than in women (P < 0.001). Fifty per cent of the patients had PE, half of which were fatal. Similar age- and gender distribution was found in cases and controls. Patients in the upper tertile of BMI, abdominal and thoracic SC fat thickness had, in comparison with mid-tertile, and independent of age, gender and death from cancer disease, an increased odds (95% CI) for PE of 1.24 (1.04-1.47) (P = 0.014), 1.28 (1.07-1.53) (P = 0.006) and 1.35 (1.13-1.61) (P = 0.001), respectively, whereas in patients of the lower tertiles, a negative association was found. Conclusions. We found no differences in age- and gender distribution between PE cases and controls. BMI and SC fat thickness were markers of disease progression from proximal DVT to PE. The highly significant and independent association indicates that SC obesity may be of greater importance in venous thromboembolism as compared with cardiovascular diseases related to visceral (abdominal) obesity with lipid- and glucose metabolic disturbances. (Less)

Our objective was to characterize the pharmacokinetics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, and the relationship between melagatran exposure and clinical outcome in patients with acute deep vein thrombosis.A population pharmacokinetic analysis was performed on samples from patients with deep vein thrombosis participating in a randomized dose-finding study (THRombin Inhibitor in Venous thrombo-Embolism [THRIVE I]). Patients received fixed doses of oral ximelagatran (24, 36, 48, or 60 mg twice daily) for 12 to 16 days. Thrombus size was evaluated by venography before and after treatment. Exposure-response curves were characterized for the probability of regression, no change, and progression of the thrombus extension and of having a bleeding-related event, by use of logistic regression models.The pharmacokinetics of melagatran (1836 samples in 264 patients) was predictable, without significant time or dose dependencies. Clearance after oral administration (population mean, 27.3 L/h) was correlated with creatinine clearance (P10(-6)), and volume of distribution (population mean, 176 L) was correlated with body weight (P = 2 x 10(-5)). Gender, age, or smoking did not significantly influence melagatran pharmacokinetics after the influence of renal function and body weight was accounted for. Unexplained interpatient variability values in total plasma clearance and bioavailability were 19% and 21%, respectively. The median area under the plasma melagatran concentration versus time curve across all patients and dose levels was 3.22 h x micromol/L (5th-95th percentiles, 1.35-7.69). There was no significant relationship between area under the plasma concentration versus time curve and change in thrombus extension (P = .59) or bleeding-related events (P = .77), and the estimated exposure-response curves were relatively flat.The pharmacokinetics of melagatran in patients with acute deep vein thrombosis was predictable after oral ximelagatran administration. Shallow exposure-response curves for efficacy and bleeding indicate that there is no need for individualized dosing or therapeutic drug monitoring in the patient population studied.

Aims While right intracardiac thrombosis (IT) is a potential cause of pulmonary embo- lism (PE) similar to that of stroke in left-sided IT, its prevalence and prognostic significance has not been studied in the general population. The aim of this study was to assess the age- and gender-specific prevalence of IT and its relation to PE in a population-based autopsy cohort. Methods and Results Between 1970 and 1982, 23 796 autopsies, representing 84% of all in-hospital deaths in the Malmocity population, were performed, using a standar- dized procedure. The relationship between IT and PE was evaluated by cohort analyses and nested case-control studies. IT was present in 1706 (7.2%) patients, 727 and 747 of whom had right and left atrial IT, respectively. PE prevalence in patients with isolated left IT, isolated right IT, and combined IT was 28.5, 35.6, and 48.9%, with RR (95% CI) of 1.5 (1.3-1.8), 2.0 (1.6-2.5), and 3.5 (2.7-4.7), respectively, compared with age- and gender-matched controls. Patients dying from ischaemic heart disease had a 3.2 (2.7-3.6) times higher risk of right IT, which was associated with 43% PE prevalence. Of all patients with PE at autopsy, right IT was found in 354 (6.5%), and the only detected source of PE in 220 (4.0%). Conclusion Right cardiac thrombosis, though difficult to assess clinically, is as common as left cardiac thrombosis and is associated with an increased risk of PE. The diagnosis should be considered in all cases of PE, especially in patients with atrial fibrillation or myocardial infarction and in the absence of confirmed deep vein thrombosis.

SummaryThe oral direct thrombin inhibitor ximelagatran (24 mg twice daily) has been shown to significantly reduce the incidence of recurrent venous thromboembolism (VTE) vs. placebo over 18 months, with no significant influence on bleeding (THRIVE III). The influence of potential prognostic factors on the risk of recurrent VTE or major and/or minor bleeding and their impact on ximelagatran treatment was evaluated in theTHRIVE III study population. The effect of sex, age, body weight, renal function, malignancy, type of initialVTE event, and history of previousVTE events was investigated in the intention-to-treat population using Cox proportionate hazard modelling. Ximelagatran was administered to 612 patients and placebo to 611 patients. Within the placebo group, risk of recurrent VTE was higher among men than women (hazard ratio [HR]: 2.50,95% confidence interval [CI] 1.49, 4.17), and in patients with one or more than one previous VTE event (HR: 1.73, 95% CI 1.00, 2.99). There was a higher risk of bleeding among women than men in both the ximelagatran (HR: 1.49, 95% CI 1.06, 2.09) and placebo (HR: 1.48, 95% CI 1.01, 2.15) groups, and in placebo-treated patients with an initial pulmonary embolism (HR: 1.53, 95% CI 1.06, 2.23) compared to those with initial deep vein thrombosis. There were no significant interactions between treatment effect and any of the potential prognostic factors. In conclusion, the superior efficacy of ximelagatran vs. placebo was maintained in all subgroups. Long-term use of oral ximelagatran, without coagulation monitoring or dose adjustment, should be feasible and well tolerated in a wide cross-section of patients for the secondary prevention of VTE.

SummaryIn the randomized, double-blind THRIVE III trial, the oral direct thrombin inhibitor ximelagatran (24 mg twice daily) significantly reduced the incidence of recurrent venous thromboembolism (VTE) versus placebo over 18 months or until premature study drug discontinuation. A complementary follow-up analysis (intention-to-treat) was conducted post-study to evaluate the cumulative risks of locally-confirmed recurrent VTE and death (Kaplan-Meier procedure) over the full 18-month study period, regardless of whether patients discontinued study drug prematurely. Hazard ratios (HRs) between treatments were estimated using Cox proportional hazard modeling. Of 612 and 611 patients receiving ximelagatran and placebo, respectively, 149 and 181 discontinued treatment prematurely. Of these discontinuations, further information could not be collected for 14 and 13patients in the ximelagatran and placebo groups, respectively; among the remaining patients, four VTE events and four deaths occurred in the ximelagatran group, and oneVTE event and five deaths occurred in the placebo group. The resulting cumulative risks of VTE (3.2% vs. 12.7%; HR 0.21; 95% confidence interval [CI], 0.12, 0.36;P < 0.0001) and pulmonary embolism (0.8% vs. 5.2%; HR 0.13; 95% CI 0.04, 0.36;P < 0.0001) were significantly lower in the ximelagatran than in the placebo group over 18 months. Death from any cause over 18 months occurred in 10 and 12 patients, respectively (HR 0.83;95% CI 0.36,1.93;P = 0.7). This complementary follow-up analysis confirms the benefit of oral ximelagatran 24 mg twice daily, administered without coagulation monitoring or dose adjustment, for the long-term secondary prevention of VTE.

Despite the effectiveness of anticoagulant therapy for the treatment of acute venous thromboembolism and the prevention of recurrent venous thromboembolism, existing antithrombotic therapies are suboptimal. Unfractionated heparin, low-molecular-weight heparin (LMWH) and warfarin have practical limitations and carry the risk of treatment-related adverse events that restrict their clinical benefits and reduce cost-effectiveness. Efforts to achieve optimal venous thromboembolism prophylaxis by modifying the intensity of oral warfarin treatment have produced equivocal results, and there is a need for new, efficacious antithrombotic drugs providing predictable, well-tolerated oral dosing without the need for coagulation monitoring. Such agents would ideally have no significant food or drug interactions, and be suitable for both short- and long-term treatment. Ximelagatran, the first oral direct thrombin inhibitor, has the potential to fulfill many of the unmet needs in the management of venous thromboembolism.

Screening serum levels of prostate-specific antigen (PSA) is now a major strategy for early detection of prostate cancer (PC). Quantification of the lead time thus obtained is important both for understanding the development of PC and for evaluating the advantages and disadvantages of widespread screening. In our study, 1,233 randomly selected men living in Stockholm in 1988 were invited to participate in an early detection (ED) program, in which suspicious findings provided by digital rectal examination (DRE), transrectal ultrasonography (TRUS) and/or a PSA value greater than or equal to10.0 ng/mL were followed up by biopsy. The cumulative incidence (Kaplan-Meier) of PC in the 946 participants (ED) during 12 years of follow-up was compared to that of an age-matched, randomly selected reference population (RP) of 657 men for whom PSA values (from frozen serum samples) could also be obtained. The PC incidence in men in the RP with PSA values >3.0 ng/mL reached the corresponding level for the ED group after 10.6 years (the "catch-up" point). After 12 years of follow-up, the estimated median lead time for men with PSA values in this interval was 4.5 years in the ED population, compared to 7.8 years in the RP. With 20 years of follow-up, the estimated median lead time of the RP was enhanced to 10.7 years. The lead time in connection with PC was influenced by the initial PSA level (although with large variations), length of follow-up and sensitivity of the ED procedure employed. The ED program described here was not associated with major overdetection. (Less)

Background: The aims of this study were to measure the N-terminal fragment of pro-brain natriuretic peptide (proBNP) in plasma in medical conditions commonly found in primary care and to evaluate the utility of these measurements in identifying impaired cardiac function in elderly patients with symptoms associated with heart failure.Methods: We studied 415 patients (221 men and 194 women; mean age, 72 years) who had contacted a primary healthcare center for dyspnea, fatigue, and/or peripheral edema. One cardiologist evaluated the patients in terms of history, physical examination, functional capacity, electrocardiography, and suspicion of heart failure. Plasma N-terminal proBNP was measured by an in-house RIA. An ejection fraction ≤40% by Doppler echocardiography was regarded as reduced cardiac function. Abnormal diastolic function was defined as an abnormal mitral inflow defined as reduced ratio of peak early diastolic filling velocity to peak filling velocity at atrial contraction (E/A ratio), or as abnormal pulmonary venous flow pattern.Results: Patients with impaired functional capacity, impaired systolic function, and/or impaired renal function had significantly increased N-terminal proBNP concentrations. By multiple regression analysis, N-terminal proBNP concentrations were also influenced by ischemic heart disease, cardiac enlargement, and certain medications but not by increased creatinine. No gender differences were observed. Patients with isolated diastolic dysfunction attributable to relaxation abnormali-ties had lower concentrations than those with normal cardiac function, whereas those with pseudonormal E/A ratios or restrictive filling patterns had higher concentrations.Conclusions: Plasma N-terminal proBNP concentrations increase as a result of impaired systolic function, age, impaired renal function, cardiac ischemia and enlargement, and certain medications. Values are high in diastolic dysfunction with pseudonormal patterns, but not in patients with relaxation abnormalities. An increase in plasma N-terminal proBNP might be an earlier sign of abnormal cardiac function than abnormalities identified by currently used echocardiographic measurements.

We have previously shown that insulin is not a major risk factor for CHD. Our data have been re-analysed with longer follow-up and the homeostasis model assessment (HOMA) method.Prospective cohort study of 57- and 67-year-old men.Insulin resistance was estimated with the HOMA equation. Standard methods were used to measure risk factors. The endpoint (CHD) was the combination of non-fatal myocardial infarction and fatal CHD during 13 years of follow-up.The risk of CHD increased 2.5-fold in known diabetics compared with those with normal glucose tolerance, 2.2-fold among those in the highest compared with the lowest quintile of insulin resistance, and 2.4-fold among those in the highest compared with the lowest quintile of fasting insulin. Increased physical activity decreased the risk of CHD by 65%. Cholesterol was also a significant risk factor for CHD but blood pressure, obesity and smoking were not related to the incidence of CHD.Insulin resistance is a significant risk factor for CHD. Whether it is a causal risk factor remains to be proven. Regular physical activity protects against CHD.

Background: Heart failure (HF) is a challenge to diagnose and treat according to guidelines. Few studies have been performed in elderly subjects with symptoms that might be associated with HF in primary health care. Objective: To study elderly patients presenting with symptoms possibly associated with HF, with respect to systolic and diastolic function, B-type natriuretic peptide (BNP) levels and treatment. Methods: A cardiologist examined 415 elderly (65–82 years) patients with symptoms of dyspnoea, fatigue and/or peripheral oedema. All patients underwent echocardiography and plasma BNP determination. Systolic function was determined semiquantitatively, and ejection fraction (EF) Results: Forty-eight percent of the patients showed abnormal systolic (26%) or diastolic function (22%). A majority of the patients with diastolic HF had relaxation abnormalities and neither pseudonormal nor restrictive filling patterns. Increased levels of BNP were found in the group with impaired systolic function. More than half of those with EF Conclusion: Diagnostic tools that are more objective than clinical examination are needed for the diagnosis of HF.

Background Bundle branch block (BBB) has been regarded as a disease of the conduction system, but occurs in mice lacking connexin 40 (expressed in atria, proximal conduction system) or connexin 43 (expressed in Purkinje cells, cardiomyocytes). Objective The aim of this paper is to explore whether BBB is heritable, and whether polymorphisms at connexin 40 and connexin 43 loci are associated with BBB. Methods To assess BBB heritability, we screened descendants of men with BBB in the population cohort ‘The Study of Men Born 1913’. DNA samples from 80-year-old men with extreme QRS-duration phenotypes were used to search for polymorphisms at connexin 40 and 43 loci. Associations between identified polymorphisms and BBB were evaluated in an independent cohort (INTERGENE). Results Seventy-seven men from ‘The Study of Men Born 1913’ with BBB had 116 descendants. Among the 76 participating descendants, 2 sons (6.4%) had BBB at 54 years of age. At the same age, 0.9% of men born in 1913 had BBB. We identified 6 single nucleotide polymorphisms (SNPs) in connexin 40 and 1 polymorphism in connexin 43. In the INTERGENE cohort, the connexin 43 polymorphism was associated with left BBB (LBBB) (4 of 35 LBBB vs 16 of 232 without BBB, χ 2 =7.4, p=0.03), but not with right BBB (RBBB) or overall BBB. None of the connexin 40 SNPs or haplotypes were associated with LBBB or RBBB. Conclusions These findings indicate that conduction by connexin 43 within the ventricular muscle distal to the specialised conduction system may be important for LBBB development.

OBJECTIVE: To assess the risk of over-diagnosing and over-treating prostate cancer if population-based screening with serum prostate-specific antigen (PSA) is instituted. PATIENTS AND METHODS: From a serum bank stored in 1980, PSA was analysed in 658 men with no previously known prostate cancer from a well-defined cohort from Goteborg, Sweden (men born in 1913); the incidence of clinical prostate cancer was registered until 1995. From the same area, and with the same selection criteria, another cohort of 710 men born in 1930-31, who in 1995 accepted an invitation for PSA screening, was also analysed. RESULTS: Of men born in 1913, 18 (2.7%) had died from prostate cancer and the cumulative probability of being diagnosed with clinical prostate cancer was 11.1% (5.0% in those with a PSA level of 3 ng/mL, P 3 ng/mL) to clinical diagnosis was 7 years. The prostate cancer detection rate in men born in 1930-31 was 4.4% (22% among those with increased PSA levels) and 30 of 31 detected cancers were clinically localized. CONCLUSIONS: Screening and sextant biopsies resulted in a lower detection rate (22%) than the cumulative risk of having clinical prostate cancer (33%) in men with increased PSA levels, indicating that under-diagnosis rather than over-diagnosis is the case at least with 'one-time' screening. Even if the stage distribution in screening-detected cancers seems promising (and thus may result in reduced mortality) it is notable that screening 67-year-old men will result in treatment a mean of 7 years before clinical symptoms occur and only one in four men anticipated to develop prostate cancer will die from the disease within 15 years. Large randomized screening trials seem mandatory to further explore the benefits and hazards of PSA screening. (Less)

The primary aim of the study was to examine inter-rater reliability of the resource-oriented body examination method, which includes a physical examination of body posture, respiration, body function, and muscle palpation. A secondary aim was to determine the relationship between percentage of agreement and reliability as assessed by kappa coefficient. Two independent evaluators examined 19 apparently healthy persons, simultaneously and without the knowledge of one another's results. Inter-rater reliability was expressed as kappa coefficient and as percentage of agreement between raters. The median kappa findings for posture, respiration, body function, and muscle palpation, were 0.55, 0.54, 0.42, and 0.27, respectively. The percentage of median agreement for posture, respiration, body function, and muscle palpation were 74%, 82%, 84%, and 72% respectively. Significance of the kappa coefficients was seen for posture in 77%, for respiration in 75%, and for body function and muscle palpation in 45% of the i...

Background —Interest in bundle-branch block has focused primarily on its role as a predictor of mortality and coexisting cardiovascular diseases. Previous studies of prevalence, correlation to cardiovascular disease, and mortality have produced conflicting results. Methods and Results —We studied a random-sampled population of 855 men who were 50 years old in 1963 and followed them up for 30 years with repeated examinations. Men who developed bundle-branch block were studied with regard to cumulative incidence, relationship with cardiovascular disease/risk factors, and survival. The prevalence of bundle-branch block increases from 1% at age 50 years to 17% at age 80 years, resulting in a cumulative incidence of 18%. No significant relationship with ischemic heart disease or mortality was found. Men who would develop bundle-branch block had a bigger heart volume at age 50 years and developed diabetes mellitus and congestive heart disease during follow-up more often than control subjects. Conclusions —Bundle-branch block correlates strongly to age and is common in elderly men. Our results support the theory that bundle-branch block is a marker of a slowly progressing degenerative disease that also affects the myocardium.

SummaryThe aim of this multicentre, prospective, randomised, dose-ranging study was to compare the safety and efficacy of subcutaneous recombinant hirudin (HBW 023) against intravenous sodium heparin in acute lower limb deep venous thrombosis (DVT). Patients were randomized to treatment with either HBW 023 or heparin for 5 ±1 days. HBW 023 was given according to body-weight in three dose groups. Thromboembolic disease was assessed by phlebography and ventilation/perfusion (V/Q) scanning on Bay 1 and Day 5±1. One hundred and fifty-five patients were enrolled, of these 121 were evaluable for efficacy analysis. Significantly fewer patients on HBW 023 developed new V/Q abnormalities during the treatment period, (p = 0.006). There was no difference between the groups in thrombus extension or regression, major bleeding complications or serious adverse events. There were significantly fewer findings of new V/Q mismatch after treatment with HBW 023, and anticoagulant control was superior in these patients.

Background Atrial fibrillation is one of the most common arrhythmias in clinical practice and it is often diagnosed after a complication occurs. The study aimed to evaluate the predictive value of atrial natriuretic peptide (ANP) for atrial fibrillation in a male population-based study. Methods and results This study is a part of the "Study of Men Born in 1913 and 1923", a longitudinal prospective cohort study of men, living in the city of Gothenburg in Sweden. A population-based sample of 528 men was investigated in 1988 when they were aged 65years ( n =134) and 75years ( n =394), and they were followed up for 16years. Blood samples were collected from all 528 men at baseline and plasma ANP levels were analyzed by radioimmunoassay. Hazard ratios were estimated by competing-risk regression analysis. One hundred five participants were excluded because of a prior diagnosis of atrial fibrillation, congestive heart failure, severe hypertension, or severe chronic renal insufficiency. Of the remaining 423 participants, 90 men were diagnosed with atrial fibrillation over the 16-year follow-up. In multivariable analysis, men in the two highest quartiles of ANP levels had a significantly higher risk for atrial fibrillation compared with men in the lowest ANP quartile. The adjusted ratio was 3.14 (95% CI 1.59–6.20) for the third ANP quartile and 3.36 (95% CI 1.72–6.54) for the highest quartile of ANP level. Conclusions In this population-based longitudinal study, we found that elevated ANP levels at baseline predicted atrial fibrillation during a follow-up time of 16years.

Eighty-six patients with phlebographically verified deep vein thrombosis (DVT) of the femoral, iliac, and/or popliteal veins who had symptoms of up to 10 days' duration were enrolled in one of two prospective, multicenter, randomized, double-blind studies. In study A, each of the 47 patients received streptokinase therapy according to one of the following three dose schedules—3.0 million (M) IU of streptokinase over 2 hours (group 1), 6.0 M IU of streptokinase over 4 hours (group 2), or 9.0 M IU of streptokinase over 6 hours (group 3). In study B, each of the 39 enrolled patients received streptokinase according to one of the three dose schedules just described or according to a fourth schedule—4.5 M IU of streptokinase over 3 hours (group 4). Each patient received two infusions of the same dose on two successive days. Heparin was given between and after the infusions, followed by warfarin alone when the prothrombin time reached the therapeutic range. In the 76 patients evaluable for efficacy, phlebographically similar improvement in thrombus extension was observed in all groups without evidence of dose dependency. Group 2 had the highest success rate, while group 4 had the lowest. Eleven patients experienced streptokinase-related allergic reactions, which led to discontinuation of therapy in five patients, two of whom experienced serious adverse reactions. The frequency and severity of adverse events were not significantly different between groups. We conclude that the ultra-high-dose, short-term infusion regimen of streptokinase is more convenient than the conventional 3 to 5 days of continuous therapy in the treatment of DVT. Further studies are needed to establish an optimal dosage schedule.

BACKGROUND: Simple global self-ratings of health (SRH) have become increasingly used in national and international public health monitoring, and in recent decades recommended as a standard part of health surveys. Monitoring developments in population health requires identification and use of health measures, valid in relation to targets for population health. The aim of the present study was to investigate associations between SRH and sick leave, disability pension, hospital admissions, and mortality, adjusted for effects of significant covariates, in a large population-based cohort. METHODS: The analyses were based on screening data from eight population-based cohorts in southern and central Sweden, and on official register data regarding sick-leave, disability pension, hospital admissions, and death, with little or no data loss. Sampling was performed 1973--2003. The study population consisted of 11,880 women and men, age 25--99 years, providing 14,470 observations. Information on SRH, socio-demographic data, lifestyle variables and somatic and psychological symptoms were obtained from questionnaires. RESULTS: There was a significant negative association between SRH and sick leave (Beta -13.2, p

We followed 845 50-year-old men initially free of coronary heart disease (CHD) for 25 years. Blood pressure, serum cholesterol and smoking habits were significant and independent risk factors for CHD during the first 15 years of follow-up and for the whole follow-up period. CHD during the last 10 years of follow-up could be predicted by blood pressure, serum cholesterol and triglycerides and also by body mass index, but not by smoking habits in univariate analyses. Only blood pressure was an independent risk factor for CHD during the last 10 years of follow-up in multivariate analysis.

In 1980 we examined 707 67-year-old men, 656 of whom had no previous myocardial infarction. During 8 years of follow-up, 70 (10.7%) of the 656 men developed a first myocardial infarction or died from coronary heart disease (CHD). The incidence of CHD increased 1.6-fold from the lowest to the highest quintile of cholesterol levels, 2.7-fold from the lowest to the highest quintile of triglyceride levels, and 2.2-fold among those with diabetes. Blood pressure, smoking habits, and two measurements of obesity (body mass index and waist circumference) were not significantly related to the incidence of CHD. In multivariate analysis, serum triglyceride levels and blood glucose concentration remained as significant risk factors for CHD. This may reflect that disturbances in glucose and triglyceride metabolism (as part of a metabolic syndrome?) are more important CHD risk factors in older than in younger men.

Background A number of previous studies have investigated various predictors for being granted a disability pension. The aim of this study was to test the efficacy of sick-leave track record as a predictor of being granted a disability pension in a large dataset based on subjects sampled from the general population and followed for a long time. Methods Data from five ongoing population-based Swedish studies was used, supplemented with data on all compensated sick leave periods, disability pensions granted, and vital status, obtained from official registers. The data set included 8,218 men and women followed for 16 years, generated 109,369 person years of observation and 97,160 sickness spells. Various measures of days of sick leave during follow up were used as independent variables and disability pension grant was used as outcome. Results There was a strong relationship between individual sickness spell duration and annual cumulative days of sick leave on the one hand and being granted a disability pension on the other, among both men and women, after adjustment for the effects of marital status, education, household size, smoking habits, geographical area and calendar time period, a proxy for position in the business cycle. The interval between sickness spells showed a corresponding inverse relationship. Of all the variables studied, the number of days of sick leave per year was the most powerful predictor of a disability pension. For both men and women 245 annual sick leave days were needed to reach a 50% probability of transition to disability. The independent variables, taken together, explained 96% of the variation in disability pension grantings. Conclusion The sick-leave track record was the most important predictor of the probability of being granted a disability pension in this study, even when the influences of other variables affecting the outcome were taken into account.

Background Random samples of 50-year-old men living in Gothenburg have been examined every 10th year since 1963 with a focus on cardiovascular risk factors. The aims of the study were to acquire up-to-date information about risk factors in the fifth cohort of 50-year-old men and women, to re-examine those who were 50 years of age in 1993, and to analyse the prevalence of the metabolic syndrome (MetSyn) using different definitions. Methods A random sample of men and women born in 1953 were examined in 2003–2004 for cardiovascular risk factors. Men born in 1943 and that participated in the examination in 1993 were also invited. Descriptive statistics were calculated. Results The participation rate among men and women born in 1953 was 60 and 67% respectively. Among men born in 1943, the participation rate was 87%. The prevalence of obesity was from 15 to 17% (body mass index, BMI ≥ 30) in the three samples. The prevalence of known diabetes was 4% among the 50-year-old men and 6% among the 60-year-old men, and 2% among the women. Increased fasting plasma glucose varied substantially from 4 to 33% depending on cut-off level and gender. Mean cholesterol was 5.4 to 5.5 mmol/l. Smoking was more common among women aged 50 (26%) than among men aged 50 (22%) and 60 years (15%). The prevalence of the MetSyn varied with the definition used: from 10 to 15.8% among the women, from 16.1 to 26% among 50-year-old men, and from 19.9 to 35% among the 60-year-old men. Only 5% of the men and women had no risk factors. Conclusion This study provides up-to-date information about the prevalence of cardiovascular risk factors and the MetSyn in middle-aged Swedish men and women. Different definitions of the MetSyn create confusion regarding which definition to use.

To elucidate the differences in somatic, psychological and biochemical pattern between the subtypes of irritable bowel syndrome (IBS).Eighty IBS patients, 30 diarrhoea predominant (D-IBS), 16 constipation predominant (C-IBS) and 34 alternating IBS (A-IBS) underwent physiotherapeutic examinations for dysfunctions in body movements and awareness and were compared to an apparently healthy control group (AHC). All groups answered questionnaires for gastrointestinal and psychological symptoms. Biochemical variables were analysed in blood.The D-IBS group showed less body awareness, less psychological symptoms, a more normal sense of coherence and psychosocial rating as well as higher C-peptide values. C-IBS had a higher degree of body dysfunction and psychological symptoms, as well as the lowest sense of coherence compared to controls and D-IBS. They also demonstrated the most elevated prolactin levels. A-IBS had the lowest degree of body disturbance, deteriorated quality of life and affected biochemical pattern. All subtypes had higher pain scores compared to controls. In addition they all had significantly increased triglycerides and elevated morning cortisol levels, however, without statistical significance compared with the controls.IBS subtypes showed different profiles in body awareness, somatic and psychological symptoms and in biochemical variables. D-IBS differed compared to the other groups by lowered body awareness, less psychological symptoms and a higher sense of coherence and elevated C-peptide values. C-IBS and A-IBS subtypes suffered more from depression and anxiety, associated with a lower quality of life. These differences may be important and will be taken into account in our treatment of these patients.

Introduction: In the RE-COVER®/RE-COVER II™ global randomized trials investigating the treatment of acute venous thromboembolism (VTE), efficacy and safety outcomes of dabigatran etexilate (dabigatran) versus warfarin were compared. This sub-analysis of pooled RE-COVER®/RE-COVER II™ data compares the safety and efficacy of dabigatran versus warfarin in the Western European sub-population. Methods: In the RE-COVER®/RE-COVER II™ trials, patients with acute VTE, initially receiving parenteral anticoagulation, were randomized to warfarin (INR 2-3) or dabigatran (150 mg twice daily) for 6 months and followed up for 30 days. The primary efficacy outcome was recurrent, symptomatic VTE/VTE-related death. Safety outcomes were major bleeding events (MBEs), a composite of MBEs or clinically relevant non-major bleeding events (MBEs/CRBEs) and any bleeding during the 6-month, oral-only treatment period. All outcomes were centrally adjudicated. Data from the Western European sub-population were analyzed using a Cox regression model with factor treatment stratified by study, assuming different baseline hazards per study. Results: This sub-analysis included 1239 patients for the efficacy analysis (dabigatran n = 613; warfarin n = 626) and 1192 patients for safety (dabigatran n = 588; warfarin n = 604) from all 13 Western European countries participating in the RE-COVER®/RE-COVER II™ trials. For the primary efficacy outcome, the rate of VTE/VTE-related death in patients receiving dabigatran was 2.1% (n = 13) compared with 2.9% (n = 18) in those receiving warfarin. However, this difference did not reach statistical significance (hazard ratio [HR] 0.74; 95% confidence interval [CI], 0.36-1.5). Of the safety outcomes, rates of MBEs were similar between both treatment groups (1.4% for dabigatran [n = 8] and 1.3% for warfarin [n = 8]; HR 1.02; 95% CI, 0.38-2.71). Rates of MBEs/CRBEs were significantly lower in patients receiving dabigatran than in those receiving warfarin at 5.1% (n = 30) and 9.4% (n = 57), respectively (HR 0.52; 95% CI, 0.34-0.82). Any bleeding events were also statistically lower in the dabigatran group (17.5%; n = 103) compared with warfarin (23.8%; n = 144) (HR 0.7; 95% CI, 0.54-0.90). Conclusions: In this Western European sub-analysis of pooled data from the RE-COVER®/ RE-COVER II™ trials, dabigatran was as effective as warfarin in the treatment of acute VTE. There was a significant reduction in MBE/CRBE and in any bleeding events in the dabigatran treatment group. Disclosures Schellong: Boehringer Ingelheim: Consultancy. Eriksson:Boehringer Ingelheim: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy, Research Funding. Feuring:Boehringer Ingelheim: Employment. Hantel:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Kreuzer:Boehringer Ingelheim Pharma GmbH and Co. KG: Employment. Schulman:Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria; Baxter: Honoraria; Octapharma: Research Funding. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding.

Irritable bowel syndrome (IBS) is one of the most commonly diagnosed gastrointestinal conditions. It represents a significant healthcare burden and remains a clinical challenge. Over the years IBS has been described from a variety of different perspectives; from a strict illness of the gastrointestinal tract (medical model) to a more complex multi-symptomatic disorder of the brain-gut axis (biopsychosocial/psychosomatic model). In this article we present aspects of the pathophysiology and the non-pharmacological treatment of IBS based on current knowledge. Effects of conditioned stress and/or traumatic influences on the emotional system (top-down) as well as effects on the intestine through stressors, infection, inflammation, food and dysbiosis (bottom-up) can affect brain-gut communication and result in dysregulation of the autonomic nervous system (ANS), playing an important role in the pathophysiology of IBS. Conditioned stress together with dysregulation of the autonomic nervous system and the emotional system may involve reactions in which the distress inside the body is not recognized due to low body awareness. This may explain why patients have difficulty identifying their symptoms despite dysfunction in muscle tension, movement patterns, and posture and biochemical functions in addition to gastrointestinal symptoms. IBS shares many features with other idiopathic conditions, such as fibromyalgia, chronic fatigue syndrome and somatoform disorders. The key to effective treatment is a thorough examination, including a gastroenterological examination to exclude other diseases along with an assessment of body awareness by a body-mind therapist. The literature suggests that early interdisciplinary diagnostic co-operation between gastroenterologists and body-mind therapists is necessary. Re-establishing balance in the ANS is an important component of IBS treatment. This article discusses the current knowledge of body-mind treatment, addressing the topic from a practical point of view.

Background Several studies have shown a markedly higher mortality rate among disability pensioners than among non-retired. Since most disability pensions are granted because of non-fatal diseases the reason for the increased mortality therefore remains largely unknown. The aim of this study was to evaluate potential explanatory factors. Methods Data from five longitudinal cohort studies in Sweden, including 6,887 men and women less than 65 years old at baseline were linked to disability pension data, hospital admission data, and mortality data from 1971 until 2001. Mortality odds ratios were analyzed with Poisson regression and Cox's proportional hazards regression models. Results 1,683 (24.4%) subjects had a disability pension at baseline or received one during follow up. 525 (7.6%) subjects died during follow up. The subjects on disability pension had a higher mortality rate than the non-retired, the hazards ratio (HR) being 2.78 (95%CI 2.08–3.71) among women and 3.43 (95%CI 2.61–4.51) among men. HR was highest among individuals granted a disability pension at young ages (HR >7), and declined parallel to age at which the disability pension was granted. The higher mortality rate among the retired subjects was not explained by disability pension cause or underlying disease or differences in age, marital status, educational level, smoking habits or drug abuse. There was no significant association between reason for disability pension and cause of death. Conclusion Subjects with a disability pension had increased mortality rates as compared with non-retired subjects, only modestly affected by adjustments for psycho-socio-economic factors, underlying disease, etcetera. It is unlikely that these factors were the causes of the unfavorable outcome. Other factors must be at work.