Impact of psychosocial factors on rheumatoid arthritis

In the field of rheumatology, the research has been successful in the understanding of the molecular mechanisms of the underlying pathophysiology of rheumatoid arthritis (RA). As a result of this, targeted treatments have been developed, resulting in a dramatic improvement of disease outcome. Today, there is an ongoing work aiming for treating the disease in very early stage or even preventing the disease. However, the exact etiology for RA is not fully known and previous epidemiological research has indicted that contextual factors contributes to both the risk for disease and the development of structural joint damage. The aim of this thesis is to contribute to the understanding of how external factors, in particular socioeconomic characteristics, associate to the risk for developing, the onset of and the severity of rheumatoid arthritis. In study I, a case-control study within the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA), we investigated if low social support and low decision latitude at work, respectively, were associated with risk for RA. Further we investigated whether those two exposures were associated with other previously identified risk factors for disease. We retrieved information on social support from the EIRA I+II study (3724 cases and 5935 controls) and information on decision latitude at work from the EIRA I study (1998 cases and 2252 controls). We did not observe any association between low social support and risk for RA (OR 1.00 (95% CI 0.91– 1.11) in the multivariable model) as compared to not low social support. Nor did we observe any statistically significant association between low decision latitude at work and RA (OR 1.28 (95% CI 0.96–1.71) in the multivariable model) as compared to high decision latitude. Both investigated exposures were associated with smoking and low educational level but neither of them were associated with disease specific characteristics such as ACPA- or RF-status. In study II we analyzed the association between alcohol habits and the risk for development of RA and furthermore if there was an interaction with smoking. We retrieved information on alcohol- and smoking habits from the Swedish National March Cohort (n=41 068). Information on the outcome, i.e. incident RA, was obtained from the national patient register. During the follow-up time 577 individuals developed RA. We observed that overall, alcohol consumption was associated with a 30% reduced risk of RA (HR 0.69, 95% CI 0.55-0.86). The negative association between alcohol consumption and RA risk was more pronounced among smokers. We observed a statistically significant interaction between smoking and alcohol habits with an attributable proportion of 0.4. In study III we investigated whether low social support and low decision latitude at work, respectively, were associated to RA disease remission. Information on exposures was retrieved from the EIRA study and information on outcome, that is disease activity at 3, 12 and 60 months follow up, was captured from the Swedish Rheumatology Quality Register (SRQ). There were 2820 individuals with information from both EIRA and SRQ. In this study low social support was not associated with remission rate at any of the investigated time-points, as compared to not low social support. Low decision latitude at work was not associated to remission at any of the investigated time-points, compared to not low decision latitude at work. Our studies have contributed to the understanding of the impact of external factors on both disease risk and disease course in RA

Avoiding the capacity cost trap: Three means of smoothing under cyclical production planning

This is the author accepted manuscript. the final version is available from Elsevier via the DOI in this recordCompanies tend to set their master production schedule weekly, even when producing and shipping on a daily basis—the term for this is staggered deliveries. This practice is common even when there is no marginal cost of setting a new schedule. We argue that the practice is sound for companies that use the ubiquitous order-up-to (OUT) policy to control production of products with a significant capacity cost. Under these conditions, the length of the order cycle (time between schedule updates) has a damping effect on production, while a unit (daily) order cycle can cause significant capacity costs. We call this the capacity cost trap. Developing an analytical model based on industrial evidence, we derive capacity and inventory costs under the staggered OUT policy, showing that for this policy there is an optimal order cycle possibly greater than unity. To improve on this solution, we consider three approaches to smoothing: either levelling within the cycle, deferring excess production or idling to future cycles via a proportional OUT policy, or increasing the length of the cycle. By deriving exact cost expressions we compare these approaches, finding that smoothing by employing the proportional OUT policy is sufficient to avoid the capacity cost trap.Norwegian Research CouncilBIA programm

Inventory performance under staggered deliveries and autocorrelated demand

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordProduction plans often span a whole week or month, even when independent production lots are completed every day and service performance is tallied daily. Such policies are said to use staggered deliveries, meaning that the production rate for multiple days are determined at a single point in time. Assuming autocorrelated demand, and linear inventory holding and backlog costs, we identify the optimal replenishment policy for order cycles of length P. With the addition of a once-per-cycle audit cost, we optimize the order cycle length P∗ via an inverse-function approach. In addition, we characterize periodic inventory costs, availability, and fill rate. As a consequence of staggering deliveries, the inventory level becomes cyclically heteroskedastic. This manifests itself as ripples in the expected cost and service levels. Nevertheless, the cost-optimal replenishment policy achieves a constant availability by using time-varying safety stocks; this is not the case with suboptimal constant safety stock policies, where the availability fluctuates over the cycle

Mechanical ventilation worsens abdominal edema and inflammation in porcine endotoxemia

INTRODUCTION: We hypothesized that mechanical ventilation per se increases abdominal edema and inflammation in sepsis and tested this in experimental endotoxemia. METHODS: Thirty anesthetized piglets were allocated to one of five groups: healthy control pigs breathing spontaneously with continuous positive pressure of 5 cm H(2)O or mechanically ventilated with positive end-expiratory pressure of 5 cm H(2)O, and endotoxemic piglets during mechanical ventilation for 2.5 hours and then continued on mechanical ventilation with positive end-expiratory pressure of either 5 or 15 cm H(2)O or switched to spontaneous breathing with continuous positive pressure of 5 cm H(2)O for another 2.5 hours. Abdominal edema formation was estimated by isotope technique, and inflammatory markers were measured in liver, intestine, lung, and plasma. RESULTS: Healthy controls: 5 hours of spontaneous breathing did not increase abdominal fluid, whereas mechanical ventilation did (Normalized Index increased from 1.0 to 1.6; 1 to 3.3 (median and range, P < 0.05)). Endotoxemic animals: Normalized Index increased almost sixfold after 5 hours of mechanical ventilation (5.9; 4.9 to 6.9; P < 0.05) with twofold increase from 2.5 to 5 hours whether positive end-expiratory pressure was 5 or 15, but only by 40% with spontaneous breathing (P < 0.05 versus positive end-expiratory pressure of 5 or 15 cm H(2)O). Tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 in intestine and liver were 2 to 3 times higher with mechanical ventilation than during spontaneous breathing (P < 0.05) but similar in plasma and lung. Abdominal edema formation and TNF-α in intestine correlated inversely with abdominal perfusion pressure. CONCLUSIONS: Mechanical ventilation with positive end-expiratory pressure increases abdominal edema and inflammation in intestine and liver in experimental endotoxemia by increasing systemic capillary leakage and impeding abdominal lymph drainage

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OBJECTIVE: It has previously been shown that a combination of inhaled nitric oxide (iNO) and intravenous (IV) steroid attenuates endotoxin-induced organ damage in a 6-hour porcine endotoxemia model. We aimed to further explore these effects in a 30-hour model with attention to clinically important variables. DESIGN: Randomized controlled trial. SETTING: University animal laboratory. SUBJECTS: Domestic piglets (n = 30). INTERVENTIONS: Animals were randomized into 5 groups (n = 6 each): 1) Controls, 2) LPS-only (endotoxin/lipopolysaccharide (LPS) infusion), 3) LPS + iNO, 4) LPS + IV steroid, 5) LPS + iNO + IV steroid. MEASUREMENTS AND MAIN RESULTS: Exposure to LPS temporarily increased pulmonary artery mean pressure and impeded renal function with elevated serum creatinine and acidosis compared to a control group over the 30-hour study period. Double treatment with both iNO and IV steroid tended to blunt the deterioration in renal function, although the only significant effect was on Base Excess (p = 0.045). None of the LPS + iNO + IV steroid treated animals died during the study period, whereas one animal died in each of the other LPS-infused groups. CONCLUSIONS: This study suggests that combined early therapy with iNO and IV steroid is associated with partial protection of kidney function after 30 hours of experimental LPS infusion

Long-term clinical, histological and virological outcomes after sustained virologic response in patients with chronic hepatitis C

Successful antiviral treatment of chronic hepatitis C (HCV), resulting in Sustained Virologic Response (SVR) has been shown to reduce the risk for liver related complications, hepatocellular carcinoma (HCC) and death. Several studies have also shown that liver histology improves after achieved SVR. In a small sub-set of patients, however, liver fibrosis will persist and sometimes even progress to cirrhosis after SVR. Furthermore, a risk to develop HCC seems to remain many years after SVR has been achieved. The aim of this thesis was to study the long-term effect of sustained virologic response on clinical, histological and virological outcomes, and to identify risk factors associated with persisting advanced fibrosis and a continued risk to develop HCC after SVR. In study I we investigated the effect of antiviral treatment on liver-related complications, HCC and death. We included 351 patients with HCV related cirrhosis in a prospective cohort study. Mean follow-up time was 5.3 years. The risk to develop liver-related complications, HCC, and liver-related and all-cause mortality was 0.9, 1.0, 0.7 and 1.9 per 100 person years for patients with achieved SVR, compared to 4.9, 4.0, 4.5 and 5.1 per 100 person years for patients never treated for HCV. In study II we investigated the prevalence and clinical implications of occult hepatitis C. In a cross-sectional study, 54 patients with all stages of pre-treatment liver fibrosis and SVR 5-20 years prior to inclusion were tested for HCV RNA using a highly sensitive method. Three patients (6%) tested positive for HCV RNA in peripheral blood mononuclear cells (PBMCs), but this did not correlate to clinical, histological or immunological evidence of persisting liver disease. In study III we investigated the long-term risk and risk factors for the development of HCC after achieved SVR. In this cohort study we included 399 patients with SVR and pre-treatment advanced fibrosis or cirrhosis. Median follow-up time was 7.8 years. The incidence rate of HCC was 0.15 and 0.95 per 100 person years for patients with advanced fibrosis and cirrhosis respectively. The main risk factor for the development of HCC was pre-treatment cirrhosis, low serum albumin and diabetes mellitus. The risk to develop HCC diminished with longer follow-up time. In study IV we investigated fibrosis regression and risk factors for persisting advanced fibrosis after achieved SVR. In a cross-sectional study 269 patients were examined with transient elastography. Median follow-up time was 7.7 years. A majority of patients regressed to a lower fibrosis stage at follow-up, but 24% had persisting advanced fibrosis. This proportion, however, diminished over time. Risk factors associated with persisting advanced fibrosis were pre-treatment cirrhosis, higher age and high body mass index. Our studies have contributed to the growing evidence of the positive effects of SVR in chronic HCV. With long follow-up time, we were also able to show that disease regression continues over time. We identified established cirrhosis and co-morbidity with metabolic disease as important risk factors for persisting advanced fibrosis and a continued risk to develop HCC after SVR has been achieved