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Aims: Surveillance of geographical variations in cardiovascular health is important in order to achieve the objectives of reducing regional health disparities. We aimed to explore differences in cardiovascular disease (CVD) mortality and prevalence of CVD diagnoses made in primary and in-patient care, as well as risk factor distribution by geographic regions (urban/rural) in Iceland. Methods: From nationwide health registers, we obtained data on CVD mortalities ( N = 7113), primary healthcare CVD contacts ( N = 58,246) and hospital CVD discharges ( N = 14,039), as well as data on CVD risk factors from a national health survey ( N = 5909; response rate 60.3%). Age-standardised annual mortality, primary healthcare contact and hospital discharge rates due to CVD were calculated per 100,000 population inside (urban) and outside (rural) the Capital Area (CA). Logistic regression was used to explore regional differences in CVD risk factors. Results: We observed slightly higher total CVD mortality rates among women outside compared to inside the CA (Standardised Rate Ratio (SRR) 1.06 (95% confidence interval (CI) 1.05–1.07)), particularly due to atrial fibrillation (SRR 1.47 (95% CI 1.46–1.48)), heart failure (SRR 1.29 (95% CI 1.27–1.31)) and ischemic heart disease (SRR 1.11 (95% CI 1.10–1.12)), while reduced mortality risk for cerebrovascular disease (SRR 0.81 (95% CI 0.80–0.83)). The rates of hospital discharges and primary care contacts for these diseases, as well as prevalence of several modifiable risk factors, were generally higher outside the CA, particularly among women. Conclusions:The higher prevalence of modifiable risk factors and CVD in rural areas, especially among women, calls for refined treatment and health-promoting efforts in rural areas.

BACKGROUND: Macroeconomic downturns have been associated with increased suicide rates. This study examined potential changes in suicide attempts and self-harm in Iceland during a period of major economic transition (2003-12). METHODS: Data were retrieved from the National University Hospital in Reykjavik (population size: 204.725), containing all ICD-10 diagnoses connected to potential suicidal behaviour. Poisson regression models were used to compare attendance rates before and after the 2008 economic collapse. RESULTS: During the study period, a total of 4537 attendances of 2816 individuals were recorded due to suicide attempts or self-harm. We noted a significant change in total attendance rates among men, characterized by an annual increase in attendance rate pre-collapse of 1.83 per 100.000 inhabitants and a decrease of 3.06 per 100.000 inhabitants post-collapse (P = 0.0067). Such pattern was not observed among women. When restricting to first attendances only, we found a reduced incidence post-crisis among both men (RR: 0.85; 0.76-0.96) and women (RR: 0.86; 0.79-0.92). We further found 1% increase in unemployment rate and balance of trade to be associated with reduced attendance rates among men (RR: 0.84; 0.76-0.93 and RR: 0.81; 0.75-0.88, respectively) but not among women. CONCLUSION: These data suggest no overall increase in attendance rates due to suicide attempts or self-harm following the 2008 Icelandic economic collapse. In fact, a high-point in self-harm and suicide attempts was observed among men at the height of the economic boom and a decrease in new attendances among both men and women after the economic collapse.© The Author 2016. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved. Language: en

Traumatic brain injury is a worldwide health issue and a significant cause of preventable deaths and disabilities. We aimed to describe population-based data on intensive care treated traumatic brain injury in Iceland over 15 years period.Retrospective review of all intensive care unit admissions due to traumatic brain injury at The National University Hospital of Iceland 1999-2013. Data were collected on demographics, mechanism of injury, alcohol consumption, glasgow come scale upon admission, Injury Severity Scoring, acute physiology and chronic health evaluation II score, length of stay, interventions and mortality (defined as glasgow outcome score one). All computerized tomography scans were reviewed for Marshall score classification.Intensive care unit admissions due to traumatic brain injury were 583. The incidence decreased significantly from 14/100.000/year to 12/100.000/year. Males were 72% and the mean age was 41 year. Majority of patients (42%) had severe traumatic brain injury. The most common mechanism of injury was a fall from low heights (36.3%). The mortality was 18.2%. Increasing age, injury severity score, Marshall score and acute physiology and chronic health evaluation II score are all independent risk factors for death. Glasgow coma scale was not an independent prognostic factor for outcome.Incidence decreased with a shift in injury mechanism from road traffic accidents to falls and an increased rate of traumatic brain injury in older patients following a fall from standing or low heights. Mortality was higher in older patients falling from low heights than in younger patients suffering multiple injuries in road traffic accidents. Age, injury severity score, acute physiology and chronic health evaluation II score and Marshall score are good prognostic factors for outcome. Traumatic brain injury continues to be a considerable problem and the increase in severe traumatic brain injury in the middle age and older age groups after a seemingly innocent accident needs a special attention.

Survival in multiple myeloma (MM) has improved significantly during recent decades both in younger and older patients.1,2 The improved survival is considered to be primarily due to new treatment options in MM, including high-dose melphalan with autologous stem cell transplantation,3 the immunomodulatory drugs and proteasome inhibitors.4,5 Recently, second malignancies have gained great clinical and scientific attention in MM as three randomized clinical trials reported an increase in second malignancies associated with lenalidomide maintenance treatment.6 In a newly published meta-analysis, exposure to lenalidomide plus oral melphalan was found to significantly increase hematologic second malignancies.7 Previously we showed that MM patients had a 26% increased risk of developing any second malignancy when compared to the general population, and an 11-fold increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).8 In the United States, second or higher-order malignancies are the third most common cancer diagnoses.9 With improved survival in MM patients, second malignancies are expected to increase in the near future and possibly contribute to problems of disease management. Importantly, it has been shown that the cumulative risk of death from MM outweighs the risk of death due to second malignancies.6 For the individual patient who develops a second malignancy, however, the outcome is of great importance. We conducted a large population-based cohort study, including all patients diagnosed with MM in Sweden, over a period of more than 50 years. This study aimed to investigate the effects of second malignancies on survival and assess changes following the introduction of modern myeloma therapy. Furthermore, as AML/MDS is over-represented in MM patients, we assessed patterns of survival specifically in these patients.

BACKGROUND: The adverse health effects of high concentrations of hydrogen sulfide (H2S) exposure are well known, though the possible effects of low concentrations have not been thoroughly studied. The aim was to study short-term associations between modelled ambient low-level concentrations of intermittent hydrogen sulfide (H2S) and emergency hospital visits with heart diseases (HD), respiratory diseases, and stroke as primary diagnosis. METHODS: The study is population-based, using data from patient-, and population-registers from the only acute care institution in the Reykjavik capital area, between 1 January, 2007 and 30 June, 2014. The study population was individuals (≥18yr) living in the Reykjavik capital area. The H2S emission originates from a geothermal power plant in the vicinity. A model was used to estimate H2S exposure in different sections of the area. A generalized linear model assuming Poisson distribution was used to investigate the association between emergency hospital visits and H2S exposure. Distributed lag models were adjusted for seasonality, gender, age, traffic zones, and other relevant factors. Lag days from 0 to 4 were considered. RESULTS: The total number of emergency hospital visits was 32961 with a mean age of 70 years. In fully adjusted un-stratified models, H2S concentrations exceeding 7.00μg/m3 were associated with increases in emergency hospital visits with HD as primary diagnosis at lag 0 risk ratio (RR): 1.067; 95% confidence interval (CI): 1.024-1.111, lag 2 RR: 1.049; 95%CI: 1.005-1.095, and lag 4 RR: 1.046; 95%CI: 1.004-1.089. Among males an association was found between H2S concentrations exceeding 7.00μg/m3, and HD at lag 0 RR: 1.087; 95%CI: 1.032-1.146 and lag 4 RR: 1080; 95%CI: 1.025-1.138; and among those 73 years and older at lag 0 RR: 1.075; 95%CI: 1.014-1.140 and lag 3 RR: 1.072; 95%CI: 1.009-1.139. No associations were found with other diseases. CONCLUSIONS: The study showed an association between emergency hospital visits with HD as primary diagnosis and same day H2S concentrations exceeding 7.00μg/m3, more pronounced among males and those 73 years and older than among females and younger individuals.

Introduction: Acute thoracic aortic dissection is a potentially lethal disease associated with high morbidity, however, contemporary data on incidence and mortality risk are lacking. Utilizing a nationwide data comprising the Icelandic population we aimed to determine the incidence, mortality and the time-dependent mortality risk of acute thoracic aortic dissection. Methods: Data was retrospectively collected using hospital discharge registries in Iceland from 1992-2013 as well as autopsy database from Medical Examiner Office. To capture all cases diagnostic codes for dissection (ICD-9: 441.1 and ICD-10: I71.0) were queried as well as for aortic aneurysm and arterial dissection. Total of 1811 charts were reviewed resulting in 153 confirmed diagnoses of acute thoracic aortic dissection. Demographics, medical history, risk factors and clinical symptoms were collected for all patients. Incidence was calculated using age and gender specific information provided by National Statistics Iceland. Results: Age and gender-adjusted incidence of acute thoracic aortic dissection was 2.5/100,000/year and no significant change in incidence was observed. The mean age was 66.9±13.6 years, 61% (94/153) were males and 66% (101/153) were Stanford type A. Of all patients diagnosed with dissection 18% (27/153) died prior to hospital arrival while the risk of death for all patients that arrived alive to a hospital was 21% (27/126) within 24 hours and 45% (57/126) at 30 days. Predictors for short-term mortality included female sex, renal disease and family history of dissection. The overall 10-year survival was 39% of which negative predictors included age, coronary artery disease, renal disease, peripheral vascular disease and family history of dissection. During the course of the study the 30-day mortality rate decreased by 0.96/year, (95% CI: 0.92- 0.99) and the 10-year survival improved significantly (p=0.04). Conclusions: Acute thoracic aortic dissection is uncommon but a lethal condition where two thirds of patients die within 30 days of the index event. The incidence remained constant but a decline in short-term mortality and increased long-term survival was observed indicating improved overall outcome in patients diagnosed with this complex condition.

In this paper the effect of SNPs on expression levels in Nimblegen RNA expression microarrays is investigated. A vast number of replicates of probe pairs representing both alleles of SNPs on 14 loci allows accurate estimation of the difference in signal intensities both within and between probe pairs. The majority of probe-pairs with sufficiently high expression have significant differences in expression levels within the pair and the difference shows concordance with the genotype of the samples. With two or more replicates of each probe, the allele-to-allele variance dominates the error in estimating the difference within the probe-pair, ten replicates are needed for adequate power in calling a true difference within a single probe-pair. Using the expression level of the probe within the probe-pair that has the higher value gives more accurate estimates. When using probes at loci containing known SNP's one should use probes containing both alleles of the SNP.

Background : The prevalence of smoking during pregnancy in Western societies has decreased in the last decades, whereas prevalence of overweight and obesity has increased. Our objective was to study secular trends and patterns of smoking and body weight among pregnant women in Iceland, during a period of dramatic changes in the nation’s economy. Methods : On the basis of the Medical Birth Registry, we used a random sample of 1329 births between 1 January 2001 and 31 December 2010. Information on smoking, body mass index and background factors during pregnancy was retrieved from the Medical Birth Register and maternity records. Trends in smoking, overweight, obesity and body mass index were assessed using logistic and linear regression analyses. Logistic regression analysis was used to examine the annual odds of smoking and obesity and by socio-demographic characteristics. Results : We found a decrease in the prevalence of continued smoking during pregnancy from 12.4% in 2001 to 7.9% in 2010 [odds ratio (OR) = 0.94, 95% confidence interval (CI) (0.88–1.00)], particularly among women with Icelandic citizenship [OR = 0.92, 95% CI (0.86–0.98)], whereas no changes in obesity [OR = 1.02, 95% CI (0.96–1.07)] were observed. The highest prevalence of maternal smoking and obesity was observed in 2005–06. Conclusion : Our results indicate that smoking during pregnancy decreased among Icelandic women in 2001–10, whereas an initial increase in obesity prevalence seemed to level off towards the end of the observation period. Interestingly, we found that both of these maternal risk factors reached their highest prevalence in 2005–06, which coincides with a flourishing period in the nation’s economy.

Background:The use of proton-pump inhibitors (PPIs) has grown worldwide, and there are concerns about increased unsubstantiated long-term use. The aim of the study was to describe the real-world use of PPIs over the past decade in an entire national population.Methods:This was a nationwide population-based drug-utilization study. Patterns of outpatient PPI use among adults in Iceland between 2003 and 2015 were investigated, including annual incidence and prevalence, duration of use, and dose of tablet used (lower versus higher), as well as the proportion of PPI use attributable to gastroprotection.Results:We observed 1,372,790 prescription fills over the entire study period, of which 95% were for higher-dose PPIs. Annual incidence remained stable across time (3.3–4.1 per 100 persons per year), while the annual prevalence increased from 8.5 per 100 persons to 15.5 per 100 persons. Prevalence increased with patient age and was higher among women than men. Duration of treatment increased with patients’ age (36% of users over 80 years remained on treatment after 1 year compared with 13% of users aged 19–39 years), and was longer among those initiating on a higher dose compared with a lower dose. The proportion of PPI users concurrently using nonsteroidal anti-inflammatory drugs decreased over the study period, while the proportion concurrently using acetylsalicylic acid, oral anticoagulants, or platelet inhibitors increased.Conclusions:In this nationwide study, a considerable increase in overall outpatient use of PPIs over a 13-year period was observed, particularly among older adults. Patients were increasingly treated for longer durations than recommended by clinical guidelines and mainly with higher doses.

Rapid fluctuations in factor VII during warfarin anticoagulation change the international normalised ratio (INR) but contribute little to the antithrombotic effect. We aimed to assess non-inferiority of anticoagulation stabilisation with a warfarin monitoring method affected only by factors II and X (Fiix-prothrombin time [Fiix-PT]) compared with standard PT-INR monitoring that includes factor VII measurement as well.The Fiix trial was a single centre, double-blind, prospective, non-inferiority, randomised controlled clinical trial. Ambulatory adults on warfarin with an INR target of 2-3 managed by an anticoagulation dosing service using software-assisted dosing at the National University Hospital of Iceland, Reykjavik, Iceland, were eligible for inclusion in this study. We excluded patients undergoing electroconversion and nursing home residents. Patients were randomly assigned (1:1) to either the Fiix-PT monitoring group or the PT monitoring group by block randomisation. A blinded research INR (R-INR) based on results of the respective test was reported to the dosing staff. Participants were contacted by a study nurse at 4-week intervals to elicit information about thromboembolism or bleeding otherwise unknown to the anticoagulation management centre. The primary efficacy outcome was a composite of objectively diagnosed non-fatal and fatal arterial or venous thromboembolism, including myocardial infarction and transient ischaemic attacks, assessed in all eligible patients who were randomised (intention-to-monitor population). The safety endpoint was major bleeding or other clinically relevant bleeding, assessed in the per-protocol population. We assumed a 3% annual thromboembolism incidence and a non-inferiority margin of 2·5%. This trial is registered with ClinicalTrials.gov, number NCT01565239.Between March 1, 2012, and Feb 28, 2014, we enrolled 1156 patients. 573 patients were assigned to Fiix-PT and 575 to PT-INR monitoring after exclusion of four patients from each group for various reasons. Median follow-up was 1·7 years (IQR 1·1-1·9). During days 1-720, ten (1·2% per patient year) thromboembolic events occurred in the Fiix-PT group versus 19 (2·3% per patient year) in the PT group (relative risk [RR] 0·52, 95% CI 0·25-1·13; pnon-inferiority0·0001). Major bleeding occurred in 17 of 571 patients in the Fiix group (2·2% per patient year) versus 20 of 573 patients in the PT group (2·5% per patient year; RR 0·85, 0·45-1·61; pnon-inferiority=0·0034). Anticoagulation stability was improved with Fiix-PT monitoring as manifested by fewer tests, fewer dose adjustments, increased time in range and less INR variability than reported with standard PT monitoring.Monitoring of warfarin with Fiix-PT improved anticoagulation and dosing stability and was clinically non-inferior to PT monitoring. Results from this trial suggest that during vitamin K antagonist treatment INR monitoring could be replaced by Fiix-PT and that this would lead to at least a non-inferior clinical outcome compared with monitoring with PT-INR.Innovation Center Iceland, University of Iceland Science Fund, Landspitali Science Fund and Actavis.

To the editor: Waldenstrom macroglobulinemia (WM) is a chronic lymphoproliferative disorder (LP) characterized by an immunoglobulin M monoclonal gammopathy in the presence of lymphoplasmacytic lymphoma (LPL) in the bone marrow.[1][1] We have previously shown in a large population-based study that

Background Data on the potential influence of macroeconomic recessions on maternal diseases during pregnancy are scarce. We aimed to assess potential change in prevalence of pregnancy-induced hypertensive disorders (preeclampsia and gestational hypertension) during the first years of the major national economic recession in Iceland, which started abruptly in October 2008. Methods and Findings Women whose pregnancies resulted in live singleton births in Iceland in 2005–2012 constituted the study population (N = 35,211). Data on pregnancy-induced hypertensive disorders were obtained from the Icelandic Medical Birth Register and use of antihypertensive drugs during pregnancy, including β-blockers and calcium channel blockers, from the Icelandic Medicines Register. With the pre-collapse period as reference, we used logistic regression analysis to assess change in pregnancy-induced hypertensive disorders and use of antihypertensives during the first four years after the economic collapse, adjusting for demographic and pregnancy characteristics, taking aggregate economic indicators into account. Compared with the pre-collapse period, we observed an increased prevalence of gestational hypertension in the first year following the economic collapse (2.4% vs. 3.9%; adjusted odds ratio [aOR] 1.47; 95 percent confidence interval [95%CI] 1.13–1.91) but not in the subsequent years. The association disappeared completely when we adjusted for aggregate unemployment rate (aOR 1.04; 95% CI 0.74–1.47). Similarly, there was an increase in prescription fills of β-blockers in the first year following the collapse (1.9% vs.3.1%; aOR 1.43; 95% CI 1.07–1.90), which disappeared after adjusting for aggregate unemployment rate (aOR 1.05; 95% CI 0.72–1.54). No changes were observed for preeclampsia or use of calcium channel blockers between the pre- and post-collapse periods. Conclusions Our data suggest a transient increased risk of gestational hypertension and use of β-blockers among pregnant women in Iceland in the first and most severe year of the national economic recession.

Background Few studies have compared the prognosis and liver-related mortality in patients with NAFLD (nonalcoholic fatty liver disease) and AFLD (alcoholic fatty liver disease). We aimed to investigate the etiology and liver-related mortality of patients with liver biopsy verified fatty liver disease in a population based setting. Methods In this retrospective study, all patients who underwent a liver biopsy 1984–2009 at the National University Hospital of Iceland were identified through a computerized pathological database with the code for fatty liver. Only patients with NAFLD and AFLD were included and medical records reviewed. The patients were linked to the Hospital Discharge Register, the Causes of Death Registry and Centre for Addiction Medicine. Results A total of 151 had NAFLD and 94 AFLD with median survival of 24 years and 20 years, respectively (p = NS). A total of 10/151 (7%) patients developed cirrhosis in the NAFLD group and 19/94 (20%) in AFLD group (p = 0.03). The most common cause of death in the NAFLD group was cardiovascular disease (48%). Liver disease was the most common cause of death in the AFLD group (36%), whereas liver-related death occurred in 7% of the NAFLD group. The mean liver-related death rate among the general population during the study period was 0.1% of all deaths. There was a significantly worse survival for patients in the AFLD group compared to the NAFLD group after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.16, p = 0.009). The survival for patients with moderate to severe fibrosis was significantly worse than for patients with mild fibrosis after adjusting for gender, calendar year of diagnosis and age at diagnosis (HR 2.09, p = 0.01). Conclusions Patients with fatty liver disease showed a markedly higher risk of developing liver-related death compared to the general population. The AFLD group had higher liver-related mortality and had a worse survival than the NAFLD group. Patients with more severe fibrosis at baseline showed a worse survival than patients with none or mild fibrosis at baseline.

Long non-coding ribonucleic acids (lncRNAs) have been proposed as biomarkers in prostate cancer. This paper proposes a selection method which uses data from tiled microarrays to identify relatively long regions of moderate expression independent of the microarray platform and probe design. The method is used to search for candidate long non-coding ribonucleic acids (lncRNAs) at locus 8q24 and is run on three independent experiments which all use samples from prostate cancer patients. The robustness of the method is tested by utilizing repeated copies of tiled probes. The method shows high consistency between experiments that used the same samples, but different probe layout. There also is statistically significant consistency when comparing experiments with different samples. The method selected the long non-coding ribonucleic acid PCNCR1 in all three experiments.

We have developed nanoparticle γ-cyclodextrin dexamethasone (DexNP) and dorzolamide (DorzNP) eye drops that provide sustained high drug concentrations on the eye surface. To test these characteristics, we measured dexamethasone and dorzolamide levels in tear fluid in humans following eye drop administration.Concentration of dexamethasone was measured by mass spectrometry. One drop of DexNP was instilled into one eye. Tear fluid was sampled with microcapillary pipettes at seven time-points after drop instillation. Control eyes received Maxidex(®) (dexamethasone). The same procedure was performed for dorzolamide with DorzNP and Trusopt(®) .Six subjects were included in each group. The peak concentration (μg/ml ± standard deviation) of dexamethasone for DexNP eye drops (636.6 ± 399.1) was up to 19-fold higher than with Maxidex(®) (39.3 ± 18.9) (p 0.001). At 4 hr, DexNP was still 10 times higher than Maxidex(®) . In addition, DexNP resulted in about 30-fold higher concentration of dissolved dexamethasone in the tear fluid of extended time period allowing more drug to partition into the eye tissue. The overall concentration of dorzolamide was about 50% higher for DorzNP (59.5 ± 76.9) than Trusopt(®) (40.0 ± 76.7) (p 0.05).The results indicate high and extended concentration of dissolved dexamethasone with DexNP, which can explain the greater and longer lasting effect of dexamethasone in the cyclodextrin nanoparticle drug delivery platform. Dexamethasone seems to fit the cyclodextrin nanoparticle suspension drug delivery platform with longer duration and higher concentrations in tear fluid than available commercial drops, while dorzolamide is less suitable.

Introduction The complete blood count is one of the most frequently ordered patient blood test. It provides the most basic hematological measurements including hematocrit (Hct), white blood cell count (WBC), and platelet count (PLT). An increase in some of these markers have been shown to be associated an increased thrombotic risk. Most notablyHctfor patients with polycythemiaveraand WBC and PLT in cancer patients. Some population studies have shown an increased propensity of thrombosis among healthy individuals with elevatedHct. However these studies have not included sufficient clinical data to account for potential confounders. The aim of this study is to assess whether elevation of these hematological markers are risk factors for thrombosis in the general population. Methods Complete blood count and baseline characteristics were obtained from participants in the Reykjavik-AGES study at enrollment in 2002. The Reykjavik-AGES study, a nationwide screening study of 5755 elderly individuals, includes thorough medical history, physical examination, and blood measurements. Lifetime incidents of thrombotic events were recorded up to 2015 in the Icelandic National Health Service and cross-linked to the participants of the study through the National Registry of the total Population. Primary outcomes of arterial and venous thrombosis were considered separately 10 years before and after enrollment. Hct, WBC, and PLT were used to determine exposure and stratified into five quintiles in four respective analyses. The second quintile was used as a reference group. Cox proportional hazard regression was used to determine hazard ratios and confidence intervals. We then adjusted for age, gender, body mass index, diabetes mellitus, cigarette smoking (in pack years), hypertension and statin use. For arterial thrombosis we also adjusted for family history of arterial thrombosis and for venous thrombosis we censored at diagnosis of malignant neoplasm. In the analysis of WBC we also adjusted for C-reactive protein, an acute phase protein. Individuals with abnormal values of these parameters were excluded from the study (PLT < 150x109/L, WBC > 13x109/L or < 2.0,Hct < 35% were excluded) Results Crude analyses ofHctrevealed a dose dependent increased risk of arterial (hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.08-1.33, p Conclusion In this large population-based prospective cohort study including detailed clinical information on 5755 elderly individuals, we observed no association of elevatedHctor PLT with risk of arterial or venous thrombosis after adjusting for confounders. However, we found a clear increase in the thrombotic risk associated with higher WBC, especially for arterial thrombosis. We speculate this may be due to a higher baseline of leukocyte activation and a low-grade inflammatory state. These factors have been shown to play a part in thrombotic pathways. We therefore conclude WBC to be a marker for thrombotic risk within the general population. Table Table. Disclosures No relevant conflicts of interest to declare.

Background: All multiple myeloma (MM) cases are preceded by the premalignant state, monoclonal gammopathy of undetermined significance (MGUS). The etiology of MM and MGUS is to a large extent unknown. Few studies on the effect of diet on MM have been conducted and the results have been inconclusive. No studies have been conducted on the effect of diet on MGUS. Studying dietary patterns offers broader view of food consumption and possible effects of diet on diseases since many nutrients and other substances in foods act together. The aim of this study was to identify different dietary patterns at three time points throughout the lifespan and examine whether adherence to these patterns was associated with risk of MGUS and light chain MGUS (LC-MGUS) and progression to MM and other lymphoproliferative diseases. Methods: This study was based on participants from the AGES-Reykjavik Study (N=5,764; mean age 77 years). Participants gave information on frequency of intake of common foods from early life (14-19 years old), midlife (45-55 years old), and currently at study baseline (67 years and older). All participants were screened for MGUS and LC-MGUS by serum protein electrophoresis and serum free light-chain assay. We identified MM and other lymphoproliferative diseases by cross linking with the Icelandic Cancer Registry. Principal component analysis was used to extract dietary patterns. This method is data driven and forms new linear factors, (dietary patterns) by reducing data dimension and grouping correlated variables (food intake). For each pattern extracted a new variable is created, ranking participants on their adherence to that particular pattern. We used logistic regression to test association between adherence to the early life and midlife dietary patterns and MGUS and LC-MGUS, and Cox proportional hazard regression to test association between adherence to the late life patterns and progression to MM and other lymphoproliferative diseases. Results: A total of 300 (5.2%) MGUS cases and 52 (0.9%) LC-MGUS cases were identified. During 11 years of follow-up 18 cases had progressed to MM and 10 to other lymphoproliferative diseases. We extracted four dietary patterns from early life, four from midlife, and six from baseline. When analyzing MGUS and LC-MGUS cases combined we found that high adherence to pattern I from early life, the old traditional Icelandic diet (high intake of salted/smoked meat and fish, blood and liver sausage, rye bread, milk, oatmeal, and potatoes), decreased the risk (odds ratio (OR) = 0.89, 95% confidence interval (CI) 0.79-1.00), however no association was found when analyzing MGUS and LC-MGUS separately (Table 1). When analyzing midlife patterns we found that the estimate for pattern I, the old traditional Icelandic diet (high intake of salted/smoked meat and fish, blood and liver sausage, fish in salad or on bread, and meat meals) was similar to the findings from early life, although it did not reach a statistical significance (OR = 0.90, 95% CI 0.80 - 1.02). High adherence to pattern III (high intake of potatoes, whole wheat bread, milk, rye bread, and fish) from midlife decreased the risk of combined MGUS (OR = 0.88, 95% CI 0.79-0.98). When analyzing MGUS and LC-MGUS separately we found that high adherence to pattern III decreased the risk of LC-MGUS (OR = 0.69, 95% CI 0.53-0.90) but not MGUS. We did not find an association between the six patterns from late life and progression to MM. However when analyzing progression to MM and other lymphoproliferative diseases combined we found that high adherence to pattern VI (high intake of meat and milk, low intake of fish) increased the risk of progression (HR = 1.82, 95% CI 1.24-2.67). Further results can be seen in Table 1. Conclusion: Our findings suggest that high adherence to the old traditional Icelandic diet consumed during early and mid 19th century, including salted or smoked meat and fish, blood or liver sausage, rye bread, and potatoes decreases the risk of MGUS/LC-MGUS later in life. They additionally suggest an increased risk of progression to MM and other lymphoproliferative diseases, with high adherence to a pattern with high meat and low fish intake. The mechanisms for these findings are unknown but our study suggests that food intake can alter the risk of developing MGUS/LC-MGUS as well as the risk of progression to MM. Disclosures Korde: Medscape: Honoraria. Landgren:Medscape Myeloma Program: Honoraria; BMS: Honoraria; Takeda: Honoraria; Merck: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma and other lymphoproliferative disorders. In individuals with MGUS, the average risk of progression to a lymphoproliferative disorder has been estimated to be 1% per year, however, most previous studies have been performed on clinically established cohorts and very few have been population-based. A high monoclonal (M)-protein concentration, non-isotype IgG, and skewed free light chain (FLC) ratio are routinely taken into account when assessing risk for progression. Other risk factors have also been identified, such as low serum albumin. Methods The cohort under study consisted of 299 individuals, 158 men and 141 women, with MGUS, identified through screening the participants of the population-based, longitudinal AGES-Reykjavik Study using serum protein electrophoresis and FLC assessment. The median age was 78 years (range 67-93 years). The outcome was first incidence of lymphoproliferative disorder, denoting multiple myeloma, lymphoma, amyloidosis, lymphocytic leukemia, plasmacytoma, and Waldenström's macroglubulinemia. Information on outcomes was supplemented by cross-linkage to national registries, and median follow-up time was 8.8 years. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of lymphoproliferative disorders. Results were adjusted for serum albumin in categories (below 35 g/L, 35-40 g/L, or above 40 g/L), M-protein concentration (above or below 15 g/L), FLC ratio, levels of free light chains, use of statins, smoking status, renal function in categories, and M-protein isotype. The multivariate model was reduced in a step-wise manner to a final model with only significant covariates. Results During follow-up, 26 of 299 individuals with MGUS proceeded to develop a lymphoproliferative disorder, representing a cumulative risk of 8.7% and an annual risk of 1.0%. MM occurred in 17 of 218 individuals with non-IgM MGUS, representing a cumulative risk of 7.8% and an annual risk of 0.9%. In multivariate analysis, the final model contained serum albumin, M-protein concentration, and isotype A versus all other isotypes. Low serum albumin (HR = 6.3, 95% CI 1.0-40.6 for In a similar model for progression to multiple myeloma only, low serum albumin, high M-protein concentration, and isotype A were also significantly associated with risk of progression, although the impact of low serum albumin was greater (HR = 33.1, 95% CI 2.4-462.2 for When assigning a risk score for progression where 1 point each was assigned for isotype IgA, serum albumin 15 g/L, the HRs for individuals with 1 point was 3.9 (95% CI 1.6-9.9), and for 2 points 10.02 (95% CI 2.3-43.3). No individual had 3 points. For Kaplan-Meier estimates from risk scores, see Figure. Summary and conclusions In this large, population-based screening study, we found an annual risk of progression from MGUS to lymphoproliferative disease of 1%. Low serum albumin, high M-protein concentration, and M-protein isotype A were all independent risk factors for progression. Our results are in line with results from previous studies where a low serum albumin at MGUS diagnosis also has been associated with shorter survival and/or malignant transformation. Results from our study contradict previous studies that have pointed to skewed FLC ratio as an important risk factor for progression; in our study, a skewed FLC ratio was not significantly associated with risk of progression when adjusted for other covariates. The findings in our study suggest that serum albumin is important to take into account when assessing the risk of progression for individuals with MGUS. Figure 1 Kaplan-Meier estimates for risk of progression, by risk score. Figure 1. Kaplan-Meier estimates for risk of progression, by risk score. Disclosures Korde: Medscape: Honoraria. Landgren:Merck: Honoraria; Takeda: Honoraria; Amgen: Honoraria, Research Funding; Medscape Myeloma Program: Honoraria; BMS: Honoraria; Celgene: Honoraria, Research Funding.

Introduction: AL amyloidosis (AL) is a plasma cell disorder characterized by life-threatening vital organ dysfunction resulting in nearly a third of patients dying within the first year of diagnosis. The only available therapies are anti-plasma cell chemotherapy agents, which reduce the toxic and amyloidogenic immunoglobulin light chains. We have previously shown improved survival in multiple myeloma (MM) due to novel anti-plasma cell therapies. Studies from specialty amyloid centers have also shown improved survival in AL, but this has never been studied in a population-based setting. Methods: By using the nationwide Swedish Patient Registry we identified all individuals registered with AL amyloidosis (defined as more than one occurrence of the ICD-code E85.8 and E85.9) in Sweden 1995-2013. By using the Total Population Registry we identified four matched controls for each case of amyloidosis, matched by gender and year of birth, and the controls had to be alive at the time of diagnosis for the corresponding AL-amyloidosis case. By using the Cause of Death Registry we obtained information on date of death, with follow-up through 2013. Overall survival (OS) was analyzed using Kaplan-Meier method and Cox proportional model, adjusting for age, gender, and calendar period of diagnosis. The cohort was divided into 4 calendar periods to evaluate changes in overall survival (OS) over time. Results: We identified 1,430 AL patients; mean age at diagnosis of 66.3 years; male gender 58.5%. A diagnosis of MM was made in 10.7% of patients, 3.6% after the AL diagnosis (AL-MM) and 7.1% before the AL diagnosis (MM-AL). Compared to matched controls, AL patients in the entire cohort had a median OS of 1.72 years, median OS was not reached for controls (p Conclusions: In the first population-based study of outcomes in AL, based on almost 1,500 patients diagnosed during almost 20 years, we found that OS has improved over time. The most probable explanation is the availability of highly-effective anti-plasma cell agents and possibly improvement in supportive care. We have also demonstrated an improvement in early mortality in AL amyloidosis possibly due to earlier recognition of disease and prompt anti-plasma cell chemotherapy. This novel finding deserves further investigation. Figure 1 Figure 1. Disclosures Weiss: Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Cohen:Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Landgren:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria; Merck: Honoraria; Medscape Myeloma Program: Honoraria.

Background Monoclonal gammopathy of undetermined significance (MGUS) is a precursor condition to multiple myeloma (MM) and other lymphoproliferative disorders. Patients with MM have an increased risk of venous and arterial thrombosis. Results from previous studies have also shown an increased risk of thrombosis in MGUS. However, these studies have been performed on clinically established cohorts, and no previous study has examined the risk of thrombosis in light chain MGUS (LC-MGUS). Methods We performed a population-based study on the longitudinal cohort of the AGES-Reykjavik Study, consisting of 5,764 elderly Icelandic men and women. Through screening all participants with free light chain analysis and serum protein electrophoresis, MGUS and LC-MGUS were identified in 299 and 52 individuals, respectively. The outcome was first incidence/occurrence of venous or arterial thrombosis, as diagnosis or as cause of death. Information on outcomes was supplemented by health care records, available from nine years prior to study baseline and for a median follow-up time of 8.8 years. Through logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to evaluate history of arterial and venous thrombosis, respectively, at study baseline. A Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% CIs for the risk of first incidence of thrombosis during follow-up. Results A history of any thrombosis during the nine years prior to diagnosis was present in 30 (10.0%) of individuals with MGUS, 13 (25.0%) of individuals with LC-MGUS, and 643 (12.0%) of individuals without MGUS. In a model adjusting for age, sex, smoking, serum cholesterol levels, diabetes, hypertension, and family history of thrombosis, the odds of having had a thrombosis was not significantly different for neither MGUS (OR = 0.75, 95% CI 0.50-1.12) nor LC-MGUS (OR = 1.81, 0.92-3.58), compared to those without MGUS. During a median follow-up time of 8.8 years, 80 (26.8%) of individuals with MGUS, 14 (26.9%) of individuals with LC-MGUS, and 1,344 (25.0%) of individuals without MGUS were diagnosed with thrombosis. Individuals with MGUS and with LC-MGUS had no increased risk of arterial thrombosis, when adjusted for age, sex, cholesterol, diabetes, hypertension, smoking, and family history of thrombosis (HR 1.04, 0.82-1.32). Similarly, no increased risk was found in MGUS or LC-MGUS for venous thrombosis, in a model adjusted for age, sex, body mass index, and previous or current cancer (HR 0.89, 0.41-1.89). Excluding individuals with a diagnosis of thrombosis occurring before baseline, or adjusting for a personal history of thrombosis, did not affect the results. Summary and conclusions In this large, population-based, screening cohort study, we found no increased risk of arterial or venous thrombosis in MGUS. A history of thrombosis was more common in individuals with LC-MGUS, which might be an effect of higher age in LC-MGUS individuals. To our knowledge, this is the first study to investigate risk of thrombosis in LC-MGUS. The results from our screened study contradict previous findings from clinically established cohorts. Future work is needed to better understand observed differences between studies and across populations. For example, potential underlying factors may include aggregation of underlying comorbidities in clinically diagnosed MGUS patients, and biological variations (shared germline genetic susceptibility) by ethnic groups. Table. Risk of thrombosis in individuals with MGUS and LC-MGUS, compared to individuals without MGUS. MGUS LC-MGUS No MGUS No. HR (95% CI) No. HR (95% CI) No. HR (95% CI) Any thrombosis* 80 (26.76%) 1.01 (0.80-1.26) 14 (26.92%) 1.13 (0.80-1.26) 1,344 (25.02%) 1.00 (Reference) Arterial thrombosis† 76 (25.42%) 1.04 (0.82-1.32) 14 (26.92%) 1.16 (0.67-2.01) 1,240 (23.08%) 1.00 (Reference) Venous thrombosis†† 7 (2.34%) 0.89 (0.41-1.89) 0 (0.0%) - 151 (2.81%) 1.00 (Reference) *Results adjusted for age and sex. † Results adjusted for age, sex, smoking, hypertension, cholesterol, diabetes, and family history of arterial thrombosis. †† Results adjusted for age, sex, body mass index, and previous or current cancer. MGUS: monoclonal gammopathy of undetermined significance, LC-MGUS: light-chain monoclonal gammopathy of undetermined significance. HR: hazard ratio, CI: confidence interval. Disclosures Landgren: Celgene: Consultancy; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Consultancy; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; BMJ Publishing: Honoraria; Onyx: Consultancy; Medscape: Consultancy.

Background: During warfarin treatment rapid fluctuations occur in the traditional prothrombin time (PT) as a result of the short half-life of factor (F) VII which has little effect on the antithrombotic activity of warfarin, contrary to FII and FX. Such confounding INR fluctuations influence dosing and, hence also the variability of FII and FX. The new Fiix-PT measures only the activity of the longer half-life FII and FX leading to less variability of anticoagulation as shown in the Fiix-trial. Objectives: To assess if stability of warfarin anticoagulation monitored by PT and Fiix-PT was affected differently by gender. Methods: This study is a subgroup analysis of the prospective, randomized, double-blind Fiix-trial. A subgroup of 815 atrial fibrillation patients on long-term warfarin monitored with Fiix-PT (Fiix-warfarin patients) or PT (PT-warfarin patients) were assessed in an intention-to-monitor manner by comparing surrogate anticoagulation indicators such as dose and dose frequency, time in therapeutic range (TTR, Rosendaal method) and variance growth rate of the INR (VGR; an indicator of INR fluctuation size). Results: Baseline parameters between the 396 Fiix-warfarin and 419 PT-warfarin patients did not differ. The median observation time was 1.4 years. Fiix-warfarin patients had more tests within therapeutic range (66% vs 63%, p=0.0019) and fewer tests below range (19% vs 21%, p=0.0061) than PT-warfarin patients. The test-in-range improvement observed with Fiix-warfarin over that with PT-warfarin was mainly explained by an improvement observed in women, i.e. the fraction of monitoring tests within range was higher (64% vs 59%, p=0.0001) and the fraction below range was lower (20% vs 24%, p=0.0002) in women on Fiix-warfarin. Likewise, with Fiix-warfarin TTR was higher (81% compared with 79%) and this was mainly explained by higher TTR in women on Fiix-warfarin (80%) than in women on PT-warfarin (75%; p=0.0401). Little difference was observed in TTR in men. The INR varied less with Fiix-warfarin than with PT-warfarin (VGRB1 0.20 vs 0.24, p=0.0810). There was significantly more variation in VGR in women than in men. Thus, Fiix-warfarin men vs women had a VGRB1 of 0.18 vs 0.25, p=0.0372, and PT-warfarin men vs women had VGRB1 0.21 vs 0.30, p=0.0056. A trend for fewer annual dose changes with Fiix-warfarin than with PT-warfarin was observed (5.6 vs 6.2 annually, p=0.0822) and this was mainly explained by 20% fewer annual dose changes with Fiix-warfarin than with PT-warfarin in women (6.0 vs 7.4, p=0.0342). Also, there were fewer dose changes per monitoring test in Fiix warfarin women (0.27 vs 0.32, p=0.0292). Finally, women treated with Fiix-warfarin used a lower median daily warfarin dose than women treated with PT-warfarin (3.4 vs 4.2 mg, p=0.0029). Conclusions: Monitoring warfarin with the Fiix-PT improved the stability of warfarin anticoagulation and reduced the daily dose significantly in women. A non-significant but consistent smaller effect in the same direction was seen in men. Disclosures Gudmundsdottir: Fiix Diagnostics Ltd.: Equity Ownership, Patents & Royalties: Patent pending for Fiix prothrombin time. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: Patent pending status for Fiix prothrombin time.

Introduction: Anticoagulation with vitamin K antagonists (VKA) requires monitoring of their effect, traditionally with the prothrombin time (PT) that is affected by VKA influence on coagulation factors (F) II, VII and X. Rapid fluctuations in factor VII, which has a short half-life, contribute to the PT (INR) variation but not to the antithrombotic effect that depends mainly on reductions of FII and FX. This was lately confirmed by the Fiix-trial that showed that monitoring warfarin with Fiix-PT (affected only by FII and FX) improved anticoagulation stability. Here, we assessed anticoagulation variability in relation to the occurrence of thromboembolism and bleeding in patients monitored with Fiix-PT or PT. Methods and materials: This is a subgroup analysis of the Fiix-trial, a single-center, double blind, prospective, randomized controlled clinical trial, comparing outcomes in patients in whom warfarin was monitored with either Fiix-PT/Fiix-INR (Fiix-warfarin patients) or PT/INR (PT-warfarin patients). Patients on warfarin, 18 years and older, with target INR range of 2.0 - 3.0, were randomized and assessed for occurrence of clinically relevant vascular events (CRVE), i.e. thromboembolism (TE), major bleedings (MB) and other non-major clinically relevant bleedings. Using an intention-to-monitor method, we assessed test parameters, dosing, time in range (TTR) and the variance growth rate (VGR) of the INR (an INR fluctuation index) in relation to occurrence of CRVE. Results: The median observation time was 1.4 years in 572 patients managed with Fiix-warfarin and 571 with PT-warfarin. CRVE occurred in 115 Fiix-warfarin patients and 132 PT-warfarin patients (PNI=0.0066). MB and TE occurred in 19 vs. 21 (PNI=0.0142) and 10 vs. 19 (PNI=0.0002) patients, respectively. There were 11,026 monitoring tests in the Fiix-arm and 11,499 in the PT-arm. Patients suffering CRVE had significantly more frequent monitoring tests and shorter intervals between tests than those without. Patients with CRVE also had significantly greater dose changes (p Conclusions: Fiix-warfarin is a more stable anticoagulant than PT-warfarin. The significantly lower INR variation in Fiix-warfarin patients with TE is in agreement with the reduced long-term thromboembolism observed in the Fiix-trial. Monitoring warfarin with the Fiix-PT (Fiix-INR) instead of the PT (INR) and paying particular attention to patients demonstrating anticoagulation instability could improve the clinical outcome of patients on warfarin further. Disclosures Gudmundsdottir: Fiix Diagnostics Ltd.: Equity Ownership, Patents & Royalties: Patent pending for Fiix prothrombin time. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, Patents & Royalties: Patent pending status for Fiix prothrombin time.

Multiple myeloma (MM) is consistently preceded by the precursor state, monoclonal gammopathy of undetermined significance (MGUS). The average annual risk of progression from MGUS to multiple myeloma is 0.5% to 1.0%. Current guidelines suggest life-long clinical follow-up of individuals diagnosed as having MGUS depending on risk stratification. The impact of diagnosing and conducting clinical follow-up of MGUS on MM survival is unclear.To estimate the impact of prior knowledge of MGUS diagnosis and comorbidities on MM survival.We conducted a population-based study including all patients with MM (MM patients) diagnosed in Sweden (n = 14,798) from 1976 to 2005 (with follow-up until 2007); 394 (2.7%) had previously been diagnosed as having MGUS. Information on comorbidities was gathered for all patients. We calculated survival rates from the time of MM diagnosis, comparing patients with vs those without prior knowledge of MGUS. Using Cox proportional hazards models, we calculated hazard ratios (HRs) and 95% CIs for risk factors for death. χ2 Tests were used to evaluate differences in comorbidities.Prior knowledge of MGUS among MM patients. In a subanalysis, monoclonal (M)-protein concentration and type were used as exposure.Risk of death and comorbidities.Patients with MM with prior knowledge of MGUS had significantly (HR, 0.86; 95% CI, 0.77-0.96; P .01) better overall survival (median survival, 2.8 years) than MM patients without prior knowledge of MGUS (median survival, 2.1 years), although MM patients with (vs without) prior knowledge of MGUS had more comorbidities (P .001). Among MM patients with prior knowledge of MGUS, low M-protein concentration (0.5 g/dL) at MGUS diagnosis was associated with poorer MM survival (HR, 1.86; 95% CI, 1.13-3.04; P = .01).Patients with MM with prior knowledge of MGUS had better MM survival, suggesting that earlier treatment of MM leads to better survival. The observation that a low M-protein concentration at MGUS diagnosis was associated with poorer MM survival may reflect less frequent clinical follow-up. Our observations stress the importance of clinical follow-up in patients with MGUS, regardless of risk stratification.

Background Nearly all multiple myelomas (MM) are preceded by the premalignant state, monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic condition that needs no treatment. The etiology of MGUS and MM is to a large extent unknown. Two studies on the association between obesity and MGUS have been conducted with conflicting results, despite a reported association between obesity and MM. The aim of this study was to determine if obesity is associated with an increased risk of MGUS and light-chain MGUS (LC-MGUS) in a population-based screened cohort of individuals above the age of 65 years using extensive number of markers for current and early life obesity. Methods This study was based on participants from the Age, Gene/Environment Susceptibility – Reykjavik Study (AGES-RS), which is a continuation of the Reykjavik Study, a population-based study performed by the Icelandic Heart Association. In 1967, the Reykjavik Study began recruiting a sample of over 30,000 residents of Reykjavik from the 1907-1935 birth cohorts. In 2002, the AGES-RS began recruiting 5,764 of the surviving members. Serum protein electrophoresis (SPEP) and serum free light-chain assay were performed on all subjects. Obesity measures were performed at baseline, and participants were additionally asked about their weight at the age of 25 years. The measures at baseline included were weight (kg), body mass index (BMI) (kg/m2), percent body fat, fat (kg), and fat-free mass (kg) from bioimpedance, total body fat area (cm2), visceral and subcutaneous fat area (cm2), and waist circumference (cm). The association with MGUS and LC-MGUS was analyzed using logistic regression and adjustment was made for age and sex. Cox proportional-hazard regression was performed to test whether obesity was a risk factor for progression from MGUS to MM and lymphoproliferative diseases. Results A total of 304 (5.3%) MGUS cases and 118 participants (2.1%) with LC-MGUS were identified. No association was found between any of the obesity markers and MGUS (Table). A statistically significant positive association was found between obesity (BMI ≥ 30 kg/m2) at study baseline and LC-MGUS (Table). Weak but statistically significant association was found between LC-MGUS and BMI at baseline, weight, max weight, percent body fat, fat in kg, fat-free mass, and waist circumference (Table). No association was found on risk of MGUS using joint effect of early adulthood BMI and BMI at study entry. Analysis on the effect of the obesity markers on the progression from MGUS to MM and lymphoproliferative diseases showed no association. Conclusion In this large population-based cross-sectional study aimed at evaluating the association between obesity and MGUS and LC-MGUS, we found obesity (BMI ≥ 30 kg/m2) to be associated with 2-fold excess risk for LC-MGUS. An association was additionally found between several of the obesity markers used and LC-MGUS. Future studies are needed to clarify underlying mechanisms for this finding. However, we did not find an association between any of the obesity markers and MGUS. Taken together, we were unable to confirm the previously reported association between MGUS and obesity. Abstract 5706. Table: Obesity and risk of MGUS or light-chain MGUS (LC-MGUS) No MGUS MGUS LC-MGUS No MGUS vs. MGUS OR* (95%CI) No MGUS vs. LC MGUS OR* (95%CI) BMI (n) *Adjusted for age and sex Disclosures No relevant conflicts of interest to declare.

Introduction: Experiments suggest that the anticoagulation effect of warfarin is mainly influenced by a reduction in coagulation factor (F) II and X activity and that FVII may have relatively little effect. Due to the short half-life of FVII but its strong influence on the prothrombin time (PT), monitoring warfarin using PT may therefore confound warfarin dosing. The Fiix-prothrombin time is specially designed to circumvent measuring FVII activity and is only sensitive to the activity of FII and FX in the sample. The Fiix-trial was a single center randomized prospective and blinded non-inferiority clinical trial that examined monitoring warfarin with the Fiix-PT compared to the PT. Methods: All community dwelling patients 18 years and older with an INR target of 2-3 managed by our center´s anticoagulation management service were eligible for participation. A PT ratio adapted for thromboplastin sensitivity (INR) was calculated for both tests and results were reported by the laboratory as R-INR (“research INR”) to the dosing staff that was blinded to each patient´s test method. Warfarin dosing was software assisted using the DAWN anticoagulation software. Protocols designed for monitoring with PT were used, including a recommended maximum six week interval between tests. The major efficacy endpoint was fatal and non-fatal thromboembolism (TE) rate and the major safety endpoint was major bleeding per patient year (ppy). Surrogate efficacy parameters included number of tests, tests in range, time within target range 2-3 (TTR), monitoring test interval and dose adjustment rate. Results: After exclusion of 4 patients in each group, 573 patients were evaluable in the Fiix-PT arm and 575 in the control arm. About 69% had atrial fibrillation (AF) and 21% had venous thromboembolism (TE). The median monitoring time was 1.7 (IQR 1.1-1.9) years per patient in both study arms. The TE rate was similar in the first six months but thereafter the event curves diverged (Figure 1) and therefore we specially examined events occuring after six months in a secondary analysis. In the primary analysis of events during days 1-720, the TE rate ppy was 1.2% in the Fiix-arm vs 2.3% in controls (-48%, p = 0.09) demonstrating at least non-inferiority of Fiix-PT monitoring compared to the PT in reducing TE. The major bleeding rate did not differ; 2.2% and 2.5%, respectively (p = n.s., non-inferior). In the secondary analysis, after excluding the first six observation months, the Fiix-PT lead to a superior long-term reduction in TE (1.1% vs 2.2% annual rate, -50%, p = 0.03) with major bleeding rate of 1.5% vs 2.3% respectively (p = 0.8). A subanalysis of patients with AF yielded similar results. The intracranial hemorrhage (ICH)/intracerebral hemorrhage rate was 0.26%/0.13% ppy in the Fiix-arm and 0.64%/0.38% ppy in the PT-arm. In the first six months the test volume was the same in both arms but therafter a 5.8% reduction occurred in the Fiix-arm. The dose adjustment rate was reduced 12% overall and 18% during long term monitoring (4.1 vs 5.0 ppy, p = 0.01). At six month intervals, the median percent TTR was 84.9 (79.9-86.7) in the Fiix-arm vs 80.3 (78.5-81.3%) in the PT-arm. Figure 1 Figure 1. Conclusion: Monitoring warfarin with Fiix-PT is non-inferior and possibly superior to the PT in reducing long-term recurrent TE. Bleeding is not increased despite omitting FVII activity in the monitoring test. With the Fiix-PT, the warfarin effect fluctuates less than with standard PT as manifested by a higher TTR and reduced dose-adjustment need. Overall, the results suggest that the fluctuation typically observed during warfarin treatment is partly caused by the traditional prothrombin time itself. Disclosures Onundarson: Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Gudmundsdottir:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.

Background Multiple myeloma (MM) and its precursor state monoclonal gammopathy of undetermined significance (MGUS) are two plasma cell dyscrasias whose etiology is largely unknown. Autoimmune disorders (AI) include a variety of conditions, and a history of AI has been found to increase the risk of several malignancies. A personal history of AI is associated with a significantly increased risk of MGUS and to some extent MM. History of AI is a predictor of poor survival in the general population. Aims The aim of the study was to determine whether a personal history of AI has an impact on survival in MM and MGUS. Methods Using national Swedish registries we identified 2,719 patients with MM, diagnosed between January 1, 2000, and December 31, 2006, and 4,276 patients with MGUS, diagnosed between January 1, 1988, and December 31, 2006, as well as 28,063 matched control subjects. Through the Swedish Inpatient Registry and Cause of Death Registry, we obtained information on previous AI and on survival, respectively, in patients and controls. We calculated hazard ratios (HR) and 95% confidence intervals (CI). We used the Kaplan-Meier method with log-rank test and Cox proportional hazards model to compare outcome among patients and controls with and without AI. We performed sub-group analyses on seven specific AI conditions; rheumatoid arthritis, pernicious anemia, chronic rheumatic heart disease, ulcerative colitis, polymyalgia rheumatica, giant cell arteritis, and psoriasis. We also performed analyses by M-protein concentration and M-protein isotype (MGUS only). Results A history of AI was found in 232 MM patients (9%) and in 822 MM controls (8%). Compared to controls with no history of AI, male and female controls with a history of AI had a significantly 2.1-fold increased (95% CI 1.7-2.4, and 95% CI 1.7-2.5, respectively) risk of dying (Figure 1). In patients with MM and a prior history of AI, compared to MM patients with no history of AI, the risk of dying was significantly increased in females (HR=1.5, 95% CI 1.2-2.0) and in males (HR=1.3, 95% CI 1.0-1.7). The increased risk of dying after a prior AI was greater in MM patients than in controls for the specific AI conditions rheumatoid arthritis (HR=1.8, 95% CI 1.2-2.5 for controls, HR=1.9, 95% CI 1.3-2.9 for MM patients) and giant cell arteritis (HR=1.9, 95% CI 1.1-3.5 for controls, HR=4.1, 95% CI 1.3-12.7 for MM patients). For the other specific conditions analyzed, the increased risk of dying after a prior AI was smaller in MM patients than in controls. A history of AI was found in 570 MGUS patients (13%) and in 1,312 MGUS controls (8%). Compared to controls with no history of AI, male and female controls with a history of AI had a 1.8-fold (95% CI 1.7-2.1) and a 2.4-fold (95% CI 2.2-2.7) increased risk of dying, respectively (Figure 2). In patients with MGUS and a prior history of AI, compared to MGUS patients with no history of AI, the risk of dying was significantly increased in males (HR=1.3, 95% CI 1.1-1.6) and in females (HR=1.9, 95% CI 1.6-2.3). The increased risk of dying after a prior AI was greater in MGUS patients than in controls for the specific AI condition ulcerative colitis (HR= 1.2, 95% CI 0.6-2.5 for controls, HR=2.6, 95% CI 1.4-5.1 for MGUS patients). For the other specific conditions analyzed, the increased risk of dying after a prior AI was smaller in MGUS patients than in controls. In patients with MGUS, the effect of a history of AI on survival was not statistically different by isotype (IgA, IgG, or IgM), or by M-protein concentration (above/below 2.0 g/dl) at MGUS diagnosis. Conclusions In this large, population-based study aimed at evaluating the influence of a history of AI on survival in MM and in MGUS, we found AI to be a risk factor for survival in both conditions. However, a prior AI was a stronger predictor of survival in individuals without MM or MGUS. For certain AI conditions a history of AI had a greater impact on survival in MM or MGUS patients than in the general population. More attention should be paid to comorbidity as a prognostic factor in MM, and to the need for tailoring therapy according to comorbidity. Disclosures: No relevant conflicts of interest to declare.

Background A recent prospective cancer screening trial including over 77,000 individuals followed-up for over 10 years shows that multiple myeloma (MM) is consistently preceded by a precursor state, monoclonal gammopathy of undetermined significance (MGUS). Clinically, most newly diagnosed MM patients are unaware of their prior MGUS state. Importantly, among individuals diagnosed with MGUS, only a small proportion will develop MM or a related malignancy during their lifespan. Current clinical guidelines suggest lifelong, annual monitoring of individuals diagnosed with MGUSto detect progression to MM or related disorders. At this time, the impact of annual monitoring on the outcome of patients who eventually develop MM is unknown. In addition, as MGUS is usually diagnosed during work-up for another disorder, the impact of comorbidity in MM patients with prior knowledge of MGUS is unknown. We assessed the impact of prior knowledge of MGUS in relation to MM survival. Patients and Methods The study cohort consisted of 14,798 individuals diagnosed with MM in Sweden 1976-2005, with follow-up until 2007. A total of 394 patients had previously been diagnosed with MGUS. Patients diagnosed with MM were identified through the Swedish Cancer Register. MM patients with prior knowledge of MGUS were identified from a nationwide MGUS cohort which was established from in and out-patient units from major hospital-based hematology/oncology centers in Sweden. Details of sex, date of birth, date of diagnosis, type and concentration of M-protein at MGUS diagnosis, and comorbidities (autoimmune diseases, infections, other malignant diseases, ischemic heart diseases, heart failure, cerebrovascular diseases, chronic lung diseases and renal diseases) were gathered for all patients. Survival rate from time of MM diagnosis comparing patients with and without prior knowledge of MGUS was calculated with a Kaplan Meier method. Risk factors for death were analysed in a Cox proportional hazards model where relative risks (RR) and 95% confidence intervals (CIs) were calculated. A Chi-square test was used to evaluate whether there was a significant difference in comorbidities. Results MM patients with prior knowledge of MGUS had significantly (RR = 0.86; CI = 0.77-0.96) better survival (median = 2.8 years; 95% CI = 2.6-3.3) than MM patients without prior knowledge of MGUS (median = 2.1 years; 95% CI = 2.1-2.2; Figure). Older age at diagnosis (RR = 1.04; 95% CI = 1.04-1.05) was associated with an inferior survival, whereas female sex and recent year at diagnosis were related to improved survival: RR = 0.86 (CI = 0.83-0.89) and 0.95 (CI = 0.95-0.95), respectively. There was no difference in survival comparing MGUS patients with high (>1.5 g/dL) versus low ( Autoimmune diseases (p Conclusions Based almost 15,000 MM patients diagnosed in Sweden between 1976 and 2005, for the first time, we found that prior knowledge of MGUS is associated with better survival (median overall survival 2.8 versus 2.1 years). Given patterns of co-morbidities, the observed survival difference is likely a reflection of the fact that MGUS patients are evaluated more often for signs of MM progression and may be diagnosed/treated at an earlier stage. The finding that low-risk MGUS patients that develop MM had a shorter survival rate is interesting and may be due to less intense monitoring and needs to be studied further. Our observations raise the question whether screening for MGUS, e.g., above the age of 50, could translate into earlier detection/treatment of MM (“early myeloma“) and lead to better survival. Future prospective studies are needed to explore these findings further. Disclosures: Turesson: Celgene Corp: Honoraria.

Introduction Multiple myeloma (MM) is characterized by the proliferation of plasma cells in the bone marrow and a secretion of monoclonal immunoglobulins. Survival in MM is very variable and multiple factors are known to influence prognosis such as age, ISS stage, and genetic abnormalities. Fibrosis can be found in the bone marrow of MM patients but the literature reporting the incidence of fibrosis and its effect on prognosis is very limited. The purpose of this study was to estimate the incidence of bone marrow fibrosis in MM patients and its effect on survival. Materials and methods Data was collected at the Karolinska University Hospital in Solna, Sweden and information obtained from the hospital's records. We gathered information on all patients diagnosed with MM between 2003 and 2011. All bone marrow reports were reviewed and the presence of bone marrow fibrosis (evaluated using reticulin staining) at diagnosis was recorded. Fibrosis was graded as 1 (mild), 2 (significant) and 3 (advanced), in accordance with WHO 2008 criteria. Patients with fibrosis were paired with patients without fibrosis (matched by sex, birth year, and year of diagnosis). Survival comparing MM patients with and without fibrosis was evaluated using Kaplan-Meier estimate and Cox regression model. Results A total of 586 individuals, 327 males and 259 females, were diagnosed with MM at the Karolinska University Hospital, Solna during 2003 – 2011. Evidence of bone marrow fibrosis was noted in 223 (38%) patients at diagnosis, and 175 had fibrosis grade 1, 33 grade 2, and 15 grade 3. No significant difference was observed between males (N = 135) and females (N = 88) (p = 0.085). Mean age at diagnosis was significantly lower for patients with fibrosis (67.1 years) than in patients without fibrosis (69.7 years) (p = 0.013). Compared with paired patients without fibrosis (N = 217), patients with fibrosis had significantly worse survival (Figure), being 5.0 years vs. 4.4 years, respectively (relative risk (RR)=1.3, 95% confidence interval (CI) 1.00-1.70; p= 0.049). The difference was greatest in male patients and patients younger than 65 years at diagnosis. Survival was worse in patients with advanced fibrosis, 4.5 (95% CI 3.6-6.4) years for grade 1 fibrosis, and 3.0 (95% CI 1.6-NA) years for higher degree of fibrosis. Conclusion In this study, based on almost 600 patients with MM we show that bone marrow fibrosis is common at diagnosis (38%). Importantly, our findings show that the presence of fibrosis was associated with inferior survival. More studies are needed regarding the underlying causes for these findings, including treatment response, treatment-related complications and relation to other known prognostic factors. Disclosures: No relevant conflicts of interest to declare.

To the editor: Myeloproliferative neoplasms (MPNs) show a familial aggregation whereby first-degree relatives of MPN patients have a 5 to 7 times higher risk of developing MPNs.[1][1],[2][2] MPN patients have a reduced life expectancy as compared with the general population,[3][3] but there is

To determine the proportion of patients with gastroesophageal reflux disease who are on proton pump inhibitors (PPIs) who could reduce their prior dosage by half, and identify predictors of successful step-down.Appropriate hypergastrinemia results from gastric acid inhibition. A gender difference in fasting gastrin with higher levels among women than among men on long-term PPI therapy has been demonstrated.Patients with endoscopically verified erosive esophagitis on long-term PPI therapy were randomized double blindly to step down their dose by half or continue with the same dose for 8 weeks. Fasting gastrin levels were measured before and after treatment. The primary endpoint was successful step-down throughout the study period.Overall, 100 patients were randomized, 49 (24 females) to continue with the same dose as before and 51 (25 females) to step down. Female patients had higher gastrin levels compared with male patients: 78 pg/mL (IQR, 50 to 99) versus 50 pg/mL (IQR, 36 to 74) (P=0.007). Among those randomized to the step-down intervention only 3/25 (12%) women failed to complete the 2 months of lower-dose therapy versus 9/25 (36%) men (P=0.09). Female gender (P=0.048) was the strongest predictor for successful step-down (odds ratio=1.27; 95% CI, 1.01-1.60). The chance of failing to maintain symptom control was twice as high in the reduction group (24%) as compared with the control group (13%) (P=0.2).Female patients on long-term PPI therapy were 3 times more likely to tolerate half of their prior dose. Female gender had higher probability for successful step-down. These results indicate that women with gastroesophageal reflux disease might manage with lower doses of PPIs as compared with men.European Clinical Trial Database (https://eudract.ema.europa.eu/), number 2013-002067-26.

Background Infections are a major cause of morbidity and mortality in patients with hematologic malignancies. However, largely due to the rarity of Waldenström’s macroglobulinemia (WM)/lymphoplasmacytic lymphoma (LPL), the literature on infectious morbidity is limited. Using population-based data from Sweden, we estimated the risk of bacterial and viral infections among 2,608 LPL/WM patients compared to 10,433 matched controls. Patients and Methods We identified all WM/LPL patients diagnosed 1980-2005 in the nationwide Swedish Cancer and Patient Registries, as well as a national network database including all major hematology/oncology centers; duplicate records were removed. Follow-up time was up to 2006. For each WM/LPL patient, four population-based controls (matched by age, sex, and county of residence) were identified randomly from the Swedish population database. Information on type of infection and date of infection was obtained from the Patient Registry which captures information on all individual patient-based discharge diagnosis from inpatient (since 1964) and outpatient care (since 2000). Through linkage to the nationwide Cause of Death Registry, we identified dates of death for WM/LPL patients and controls. Cox proportional hazard models were used to estimate the overall risk of infections. Models were adjusted for sex, age, and calendar period. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for individual infections. Results Overall, WM/LPL patients had a 3.4-fold (95% CI=3.1-3.6) elevated risk of developing any infection than controls (Figure). Compared to controls, the risk of developing bacterial and viral infections was 3.2-fold (95%; CI=2.9-3.5) and 6.0-fold (95% CI=4.9-7.3) higher, respectively. More specifically, WM/LPL patients had an increased risk (p Discussion In this large population-based study including over 2,600 WM/LPL patients and 10,000 matched controls, we found that bacterial and viral infections represent a major threat to WM/LPL patients. This was particularly true during the first years following diagnosis. Importantly, the risk of infections increased in more recent years. The effects on infectious complications due to novel drugs in the treatment of WM/LPL need to be better defined and trials on prophylactic measures are needed. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.