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Context: Whether biochemical remission normalizes life expectancy in Cushings disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status., Funding agencies: Medical Research Council of Southeast SwedenUK Research & Innovation (UKRI)Medical Research Council UK (MRC) [FORSS-930862]

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) has been associated with spondyloarthritis (SpA), but population-based estimates are scarce. Here we compare the occurrence of SpA before and after a diagnosis of IBD to the general population, overall and by IBD subtype and age. METHODS: We used a nationwide register-based cohort study of 39,203 patients diagnosed with IBD during 2006-2016, identified from Swedish registers and gastrointestinal biopsy data, and 390,490 matched reference individuals from the general population. Conditional logistic regression models were used to estimate odds ratios (ORs) for a prior (prevalent) SpA diagnosis and conditional Cox regression to calculate hazard ratios (HRs) for a subsequent (incident) SpA diagnosis in IBD patients. RESULTS: IBD patients were more likely to have prevalent SpA at IBD diagnosis (2.5%) compared to reference individuals (0.7%) with an OR of 3.48 (95%CI:3.23-3.75). They also more often received an incident diagnosis of SpA; during 23,341,934 person-years of follow-up in IBD patients, there were 1,030 SpA events (5.0/1,000 person-years) compared to 1,524 SpA events in the reference group (0.72/1,000 person-years), corresponding to an HR of 7.15 (95%CI:6.60-7.75). In subgroup analyses, associations were most pronounced among patients with Crohn's disease [(OR=5.20; 95%CI:4.59-5.89), and (HR=10.55; 95%CI:9.16-12.15)] and paediatric onset IBD [(OR=3.63; 95%CI:2.35-5.59) and (HR=15.03; 95%CI:11.01-20.53)]. CONCLUSION: IBD patients more frequently experience SpA both before and after the diagnosis of IBD compared to the general population, supporting evidence of a shared pathophysiology. The variation in SpA comorbidity across IBD subtypes and age-groups, calls for targeted approaches to facilitate timely diagnosis and intervention., Funding agency:Orebro University Hospital Research Foundation OLL-936004 OLL-890291 OLL-790011 OLL-723021

Objective: To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden. Design and methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019. Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85-1.33) nor between 2001 and2011, SMR: 0.87 (0.61-1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively. Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

Purpose: The Swedish National Patient Register (NPR) is often used in observational studies of childhood-onset inflammatory bowel disease (IBD) (<18 years of age) and its subtypes, but the validity of previously used register-based algorithms for capturing childhood-onset IBD has never been examined. Methods: We identified a random sample of 233 individuals with at least two first ever diagnostic listings of IBD in the NPR between 2002 and 2014. We calculated the test characteristics for different register-based definitions of IBD and its subtypes using the Copenhagen criteria and the revised Porto criteria as gold standard, both based on medical chart review. We made assumptions of the occurrence of undiagnosed IBD in the general child population based on available literature. Results: Out of 233 individuals with at least two diagnostic listings of IBD, 216 had true IBD, resulting in a positive predictive value (PPV) = 93% (95% confidence interval (CI) 89–96), sensitivity = 88% (95% CI 83–92), specificity = 100% (95% CI 100–100), and negative predictive value (NPV) = 100% (95% CI 100–100). The PPV for the NPR-based definitions of IBD subtypes at time of first IBD diagnosis and at end of follow-up were 78% (95% CI 69–86) and 88% (95% CI 80–94), respectively, for Crohn’s disease and 74% (95% CI 63–83) and 71% (95% CI 60–80), respectively, for ulcerative colitis. Conclusion: The validity of register-based definitions of childhood-onset IBD in the Swedish NPR is high and can be used to identify patients in observational research.

BACKGROUND: Previous research indicates that the increased relative risk of colorectal cancer (CRC) in inflammatory bowel disease (IBD) is limited to young-onset IBD. AIM: To estimate risks of incident CRC and death from CRC in elderly-onset IBD METHODS: Patients diagnosed with IBD at age ≥ 60 years between 1969 and 2017 were identified using Danish and Swedish National Patient Registers and histopathology data. We linked data to Cancer and Causes of Death Registers and used Cox regression to estimate hazard ratios (HRs) for CRC diagnosis and death compared to matched (by sex, age, and region) IBD-free individuals. RESULTS: Among 7869 patients with Crohn's disease followed for 54,220 person-years, and 21,224 patients with ulcerative colitis (UC) followed for 142,635 person-years, 2.10% and 1.90% were diagnosed with CRC, compared to 2.26% and 2.34% of reference individuals (median follow-up 6 and 7 years). The incidence of CRC was elevated during the first year after IBD diagnosis: 4.36 (95% CI = 3.33-5.71) in Crohn's disease and 2.48 (95% CI = 2.03-3.02) in UC, but decreased after the first year of follow-up: 0.69 (95% CI = 0.56-0.86) and 0.78 (95% CI = 0.69-0.88). Once diagnosed with CRC, the risk of CRC death was similar for IBD patients and the general population. CONCLUSION: The excess risk of CRC in elderly-onset IBD was probably due to bias and not observed beyond the first year. From 2010, the HR for CRC diagnosis more than 1 year after initial IBD diagnosis was lower than in the largely unscreened reference population, supporting the benefit of endoscopic screening and surveillance in patients with IBD., Funding agencies:Bengt Ihres FoundationDanish Cancer Association Independent Research Fund Denmark

Through linkage of data from Danish and Swedish national registers we identified 6937 patients with childhood (<18 years)-onset Crohn disease (CD), 8514 patients with childhood-onset ulcerative colitis (UC) and up to 10 times as many matched (sex, age, residence) reference individuals 1969-2017. During follow-up to a median age of 27 (interquartile range = 21-39) years, 25 (0.36%) CD patients were diagnosed with colorectal cancer (CRC) versus 43 (0.06%) reference individuals, and 113 (1.33%) UC patients versus 45 (0.05%) reference individuals. The hazard ratio (HR) for CRC was 6.46 (95% CI = 3.95-10.6) in CD and 32.5 (95% CI = 23.0-45.9) in UC and increased with decreasing age at diagnosis. The HR for CRC was increased for all phenotypes, but with higher estimates for colonic CD [17.9 (95% CI = 7.43-43.3)] and UC with extensive/pancolitis [36.3 (95% CI = 22.8-57.8)]. The relative risk of CRC was increased for all phenotypes of childhood-onset inflammatory bowel disease. Age at onset may be considered an additional risk factor when implementing surveillance programs., Funding agencies:Bengt Ihre Research Foundation Bengt Ihre Research FellowshipYoung Scholar Award from the Strategic Research Area Epidemiology Program at Karolinska InstitutetIndependent Research Fund Denmark Danish Cancer AssociationRegional Agreement on Medical Training and Clinical Research between Stockholm County Council

Objective: To assess absolute and relative risks of serious infections (resulting in inpatient care) in children with inflammatory bowel disease (IBD) compared with the general population. Study design: We identified children (<18 years of age) with a first diagnosis of IBD in the Swedish nationwide health registry (2002-2017; n = 5767) and individuals from the general population matched for sex, age, calendar year, and place of residence (reference group; n = 58 418). Hazard ratios (HRs) for serious infections were estimated using Cox regression separately in children with ulcerative colitis (n = 2287), Crohn's disease (n = 2365), and IBD unclassified (n = 1115). Results: During 17 408 person-years of follow-up, 672 serious infections (38.6/1000 person-years) occurred among the children with IBD compared with 778 serious infections in the reference group (4.0/1000 person-years; adjusted HR (95% CI), 9.46 [8.53-10.5]). HRs were increased for children with ulcerative colitis 8.48 (7.21-9.98), Crohn's disease 9.30 (7.86-11.0), and IBD unclassified 12.1 (9.66-16.1). HRs were highest in the first year of follow-up (HR = 12.6 [10.7-14.9]), then decreasing to a 4.8-fold increased risk beyond 10 years of follow-up. Particularly high HRs were also seen in children with IBD undergoing surgery. Apart from a high relative risk of gastrointestinal infections resulting in hospitalization, children with IBD were also at an increased risk of opportunistic infections (HR = 11.8 [6.17-22.5]). Conclusions: Children with IBD have an increased risk of serious infection requiring hospitalization compared with the general population., Funding agencies:Strategic Research Area Epidemiology program at Karolinska InstitutetRegional Agreement on Medical Training and Clinical Research between Stockholm County CouncilMag-tarmfondenBengt Ihre foundationJanssen CorporationJohnson & Johnson USAJanssen Biotech IncFerring Pharmaceuticals

Background/Aim: The main objective of this study was to evaluate if there was an increased incidence of brain tumours between years 1980-2012, a time period when mobile phone usage has increased substantially. Materials and Methods: From the Swedish Cancer Registry, cases of meningiomas, low-grade gliomas (LGG) and high-grade gliomas (HGG) were identified in patients between 1980-2012. Direct age-standardised incidence rates were used to calculate incidence trends over time. Results: A total of 13,441 cases of meningiomas, 12,259 cases of high-grade gliomas and 4,555 cases of LGG were reported to the register during the study period. The results suggest that there may be a negative development in the trend for LGG of -0,016 cases per 100,000 and year, corresponding to a mean reduction of approximately 1% per year. Conclusion: The present study was not able to demonstrate an increased incidence of glioma during the past 30 years in Sweden.

New data show a continuously increased five-year survival for almost all analyzed cancer diagnoses since 1990. It has to be emphasized that the figures are uncertain due to the limited number of patients. The variation is huge and the greatest improvements are seen not least among the three major tumor diseases (breast, colorectal and prostate cancer), where the society, industry and research bodies made the biggest investments over the years. The causes of improved survival can be sought in several areas, such as earlier detection and better treatments. In addition to survival estimates, it is also always of importance to consider aspects around patient related outcome, such as quality of life.

In this paper we fit non-linear models. We build Threshold Autoregressive (TAR) and Generalized Autoregressive Conditional Heteroskedasticity (GARCH) models and estimate the parameters associated to the models, e.g. the threshold for the TAR model. The TAR and the GARCH model concept are applied to simulated data and to three empirical datasets, two River flow time series and one Blowfly data set. We observe significant non-linear effects from the tests for the three empirical time series. Two different TAR models fit to the Blowfly data. We fit ultimately TAR models to the river data sets. The fitted AR-GARCH model does not give satisfactory results for the three empirical data sets.