Reference Individuals Research Articles

Metabolic Dysfunction-Associated Steatotic Liver Disease and Pancreatic Disease-A Population-Based Nationwide Cohort and Sibling-Controlled Study.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to pancreatic diseases, but evidence from population-based studies with liver histology is lacking. In this population-based cohort including all Swedish adults (n=8563) with biopsy-proven MASLD, we aimed to investigate incidences of pancreatic diseases compared with matched reference individuals from the general population (n=38,858) and full siblings (n=6696). Using Cox proportional hazard models, we calculated multivariable adjusted hazard ratios (aHRs) and confidence intervals (CIs). We documented 359 incidents of pancreatic diseases in MASLD patients and 880 events in matched reference individuals, resulting in an incidence rate difference of 1.54 (95% CI, 1.25-1.84). The relative risk of pancreatic disease was highest in the first two years after MASLD diagnosis (aHR, 2.19 [95% CI, 1.92-2.50), but remained statistically significant increased even up to ten years [aHR, 1.60 (95% CI, 1.38-1.85)]. The most common pancreatic disease in individuals with MASLD was acute non-biliary pancreatitis (1.44 vs. 0.44 events/1000 PY), followed by chronic pancreatitis (0.54 vs. 0.12/1000 PY) and pancreatic cancer (0.88 vs. 0.47/1000 PY). We documented 130 versus 344 pancreas-related deaths among individuals with MASLD and their matched comparators, yielding an absolute risk difference of 0.51/1000 PY and an aHR of 2.41 (95%CI=1.95-2.97). The findings were consistent in sibling-controlled analyses with an aHR of 2.21 (95%CI=1.69-2.90). MASLD was associated with significantly higher rates of acute and chronic pancreatitis of predominantly non-biliary origin, as well as an increased risk of pancreatic cancer and pancreas-related mortality.

P1253 Temporal Trend of Opioid Prescriptions Among Adults with Ulcerative Colitis: A Nationwide Cohort Study in Sweden 2008-2021

Abstract Background The rising opioid misuse and related mortality led the US government to declare opioid use as a public health emergency in 2017 [1]. Population-based studies on opioid use in Ulcerative Colitis (UC) are scarce [2]. The aim of this study was to describe the time trend of opioid use among adults with UC compared to the general population in Sweden. Methods We conducted a nationwide cohort study including individuals aged ≥18 years with a UC diagnosis, identified via two ICD-10 code K51 registrations in the National Patient Register. Each patient with UC was matched with up to 10 reference individuals without inflammatory bowel disease (IBD) by birth year, sex, calendar year, and place of residence. Observation started on January 1, 2008, at age 18, or the date when the UC diagnosis definition was fulfilled (whichever came last) and ended at emigration, death, or December 31, 2021 (whichever came first). Data on opioid dispensations were obtained from the Prescribed Drug Register. Opioid use per calendar year was defined as ≥1dispensed opioid prescription. We categorized codeine combinations, tramadol, and dextropropoxifen opioids as weak and oxycodone, morphine, hydromorphone, fentanyl, buprenorphine, tapentadol, and petidine as strong. Annual prevalence estimates of opioid use were calculated, and joinpoint analysis was performed to explore the trend and to estimate annual percent change (APC) of opioids. Results The cohort included 59,983 patients with UC (47.4% female) and 539,505 reference individuals. Cancer diagnoses within two years prior to the index date were observed in 1.1% of UC patients and 0.7% of reference individuals, while psychiatric disorders were identified in 3.8% and 3.6%, respectively. During the observation period, UC patients had a higher prevalence of opioid use compared to reference individuals. The Joinpoint analysis revealed three distinct periods (Figure 1): slightly increasing from 2008-2014, followed by decreasing trends during 2015-2018 (APC: -2.45) and 2019–2021 (APC: -5.20). As shown in Figure 2, the prevalence of any annual opioid use among UC patients declined from 15.5% in 2008 (compared to 9.5% for reference individuals) to 13.0% in 2021 (8.0% for reference individuals). Conversely, strong opioid use among UC patients increased from 3.0% to 9.0% over the study period, compared to a rise from 1.0% to 4.0% among reference individuals. Conclusion Opioid use among UC patients in Sweden showed a modestly decreasing trend since 2015 similar to that in the general population. The main limitation of this research was the inability to account for illegal opioid use, which is likely to underestimate the use of opioids among the reference group.

P1221 Microscopic colitis and risk of venous thromboembolism: A nationwide matched cohort study

Abstract Background Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, have been associated with an increased risk of venous thromboembolism (VTE). However, data on VTE is lacking in large population-based cohorts of microscopic colitis (MC). We aimed to investigate the association between MC and VTE. Methods We included all Swedish adults (≥18 years) with MC without previous VTE (1990-2017, n=12,489, follow-up until 2021). MC and subtypes (collagenous colitis and lymphocytic colitis) were defined from prospectively recorded colorectal histopathology reports from all 28 pathology departments in Sweden. MC patients were matched for age, sex, calendar year and county of residence with up to five reference individuals (n=55,809) without MC or previous VTE from the general population. Sensitivity analyses included full sibling comparisons and stricter definition of VTE requiring a primary diagnosis of VTE. Incidence rates and multivariable-adjusted hazard ratios (aHRs) with 95% confidence interval (CI) were calculated using Cox proportional hazards modelling. Results Over a median of 10.0 years of follow-up, 755 (6.0%; 11.3/1000 person-years [95%CI 10.5-12.1]) VTE events occurred in individuals with MC and 2674 (4.8%; 8.6/1000 person-years [8.3-8.9]) in reference individuals. Individuals with MC had a higher overall relative risk of any VTE event compared with reference individuals (aHR 1.21 [1.11-1.32]), including higher risk of pulmonary embolism (aHR 1.23 [1.08-1.40]), deep vein thrombosis of the legs (aHR 1.16 [1.03-1.32), and other VTE events (aHR 1.31 [1.08-1.58]). Compared to full siblings, individuals with MC showed numerically, but statistically non-significant, higher relative risk of VTE (aHR 1.15 [0.98-1.35]). Restricting the outcome definition to VTE diagnoses recorded as the primary diagnosis, the estimate of any VTE event was similar for MC overall (aHR 1.26 [1.15-1.39]). In the stratified analyses of VTE there were no major differences in sex, age group, follow-up time, year of MC diagnosis, country of birth, and presence/absence of celiac disease diagnosis at the index date. Conclusion In this population-based study, individuals with MC had a 21% higher risk of VTE compared with reference individuals from the general population, equal to one extra VTE event for every 37 MC individuals followed for ten years.

P1087 Opioid Use Before and After Ulcerative Colitis Diagnosis: A Nationwide Cohort Study in Sweden 2006-2021

Abstract Background Opioid misuse has been declared in the US since 2017 [1]. Population-based studies to describe opioid use among adults with ulcerative colitis (UC) are scarce [2]. This study aimed to evaluate patterns of opioid use two years before and up to five years after UC diagnosis date among adults with UC compared to reference individuals in Sweden. Methods We conducted a nationwide cohort study including individuals aged ≥18 years with an incident UC diagnosis between 2008 and 2019, identified through two International Classification of Disease 10 code K51 recorded in the National Patient Register. Each patient with UC was matched with up to 10 reference individuals without inflammatory bowel disease (IBD) by birth year, sex, calendar year, and place of residence. Observation started on January 1, 2006, age 18, or 24 months before the first UC diagnosis date (index date), whichever came last, and ended at emigration, death, or December 31, 2021. Data on opioid dispensations were obtained from the Prescribed Drug Register. Opioid use was defined as ≥1 dispensed opioid prescription per six-months periods. We categorized opioids as weak (codeine combinations, tramadol, dextropropoxifen) and strong (oxycodone, morphine, hydromorphone, fentanyl, buprenorphine, tapentadol, petidine). Opioid use during 24 months before the index date was classified as non-use (no dispensations), intermittent use (≥1 dispensation in 1–3 of the four preceding six-month periods), or chronic use (≥1 dispensation in all four six-months periods). Mean daily doses (MDD) of opioids were calculated using oral morphine equivalents. Opioid use prevalence and MDDs were reported with 95% confidence intervals. Results The cohort included 20,265 patients with incident UC (48.7% female) and 185,973 reference individuals. At the index date, 2.4% of UC patients and 1.4% of reference individuals chronically used opioids, while 15.0% and 11.1% used opioids intermittently. Among patients with UC, opioid use increased right after the index date to 12.0% and stabilized at approximately 10% thereafter (Figure 1). The use of stronger opioids increased after diagnosis, while the use of weak opioids remained unchanged (data not shown). The MDD of opioids among patients with UC increased from 0.75 mg (0.60 mg in the reference group) at 18-24 months before the index date to 1.45 mg (0.65 mg in the reference group) at 54-60 months post-diagnosis. Conclusion Overall prevalence of opioid use among adults with UC increased only modestly following diagnosis, with a shift toward using stronger opioids. The main limitation of this research was the inability to account for illegal opioid use, which may result in underestimating the use of opioids among the reference group.

Evaluation of a new soluble transferrin receptor assay and comparison to three measurement procedures.

Soluble transferrin receptor (sTfR) is a useful marker in the differentiation of anemia. Clinical utility is limited by lack of standardization between measurement procedures and interpretative recommendations. Our objective was to evaluate the analytical performance of a research sTfR immunoturbidimetric assay (Alinity c, Abbott Diagnostics) and compare it to three established measurement procedures. Assay imprecision was assessed with 7 panels across the analytical measuring interval. 159 patient samples were measured across four instrument systems (Alinity c [Abbott Diagnostics], Tina-quant c502 [Roche Diagnostics], Quantex Biokit [Werfen], and ACCESS [Beckman Coulter]). Ferritin was also measured to calculate an sTfR/Log Ferritin ratio. Sera from 100 reference individuals were assayed for sTfR and ferritin (Alinity) for reference interval (RI) verification (sTfR) or establishment (sTfR index). Assay imprecision met defined goals. Method comparison between Alinity c and ACCESS sTfR assays showed good agreement (slope: 1.06, intercept: -0.12, r: 0.989). Comparisons across other assays demonstrated significant proportional bias with slopes ranging from 0.44 (Tina-quant c502, mean bias: -2.52mg/L) to 1.24 (Quantex Biokit, mean bias: 0.60mg/L). A proportional bias was observed between other instruments. While the sTfR RI was verified on the Alinity assay, agreement in interpretation (within vs outside RI) between Alinity and other platforms ranged from 74.2 to 80.5%. We report the first characterization of the performance of a research sTfR immunoturbidimetric assay (Alinity c, Abbott Diagnostics). Our findings emphasize the lack of harmonization between measurement procedures and result interpretation for sTfR and sTfR index, necessitating standardization efforts and clinical studies.

Reconstructing ancient Southern African mitochondrial genomes at Faraoskop

Twelve human skeletons, approximately 2000 years old, were recovered from the Faraoskop archaeological site in the Western Cape Province, South Africa (Manhire 1993). Several of the skeletons were well enough preserved to determine the osteological profiles (sex, age and stature etc.). Additionally, paleopathological and traumatic changes were observed on some of these skeletal remains. Given suggested context that these human remains were drawn from a single mortuary event, this paper investigates the possibility of familial relationships between the individuals by establishing maternal profiles from mitochondrial DNA. The mitochondrial DNA analysis resulted in the identification of four full genomes from the Faraoskop (FK) individuals and the two Khoesan pastoralist individuals chosen as reference samples for the analysis. Three other FK individuals provided partial genomes which could be assigned to incomplete haplotypes. Five individuals could not be sequenced due to poor DNA preservation. Molecular sex could be confirmed for five FK and two reference individuals, adding to the sex assessment from osteological data. All but one of the mitochondrial haplotypes were L0d1 or L0d2 which is consistent with mtDNA from living Khoesan populations in southern Africa. One individual (FK1) was L0f1, a haplotype which is not present southern African Khoesan, but is currently centred in Uganda and Tanzania. It is occasionally found amongst southern African Bantu speakers which suggests that the presence of L0f1 is a remnant of an earlier distribution which is now lost. The three L0 mitochondrial haplotypes from the six Faraoskop individuals (L0d1, L0d2, and L0f) suggest a diversity of maternal lineages compatible with the diversity of Khoesan groups but given the simultaneity of the burial, it is tempting to suggest that those with similar maternal haplotypes were closely related.

Establishment of reference intervals for estimated glomerular filtration rate in apparently healthy adults based on the full age spectrum equation: A single-centre study.

Identifying gender and age-related eGFR trends is crucial for precise renal function assessment. This study aims to analyse eGFR distribution with the full age spectrum (FAS) equation and establish reference intervals based on gender and age in a single-centre cohort. Following the inclusion and exclusion criteria outlined in this study, a total of 24,024 reference individuals were ultimately selected. Using the approach recommended by the CLSI C28-A3 guidelines, we assessed the distribution of eGFR across different gender and age groups. The two-sided nonparametric method (P2.5-P97.5) was applied to establish the eGFR reference intervals for a healthy Chinese population. The eGFR levels in healthy adults exhibited a non-normally distributed pattern. Notably, there were significant differences in eGFR levels between males and females, with females showing a notably higher eGFR level than males. Additionally, eGFR levels demonstrated significant variations across different age groups within both male and female cohorts. As age increased, eGFR showed a significant decline, except in individuals aged 20-29 and 30-39 years. Therefore, reference intervals for eGFR were created based on both gender and age. We established the reference interval for eGFR using the FAS equation, drawing from a large sample population at a single centre. This establishes a potential framework for evaluating renal function in healthy individuals and for diagnosing and treating kidney-related diseases.

An observational post-authorization study to assess the effectiveness of a single dose Ad26.COV2.S for the prevention of COVID-19 using real-world data.

The goal of this FDA-committed, post authorization study was to assess the real-world effectiveness of Ad26.COV2.S in preventing observed COVID-19 disease in individuals in the United States interacting with the healthcare system who were vaccinated according to the national immunization recommendations. The study cohort consisted of individuals ≥18 years in the U.S. between March 1, 2021 and July 31, 2022. Two exposure groups were considered: those who received a single dose of COVID-19 Ad26.COV2.S vaccine and individuals who were unvaccinated. Individuals eligible for the referent group, defined as those who were unvaccinated, were identified through exact matching on age, sex, location, and Gagne comorbidity score. Propensity-score (PS) matched Cox proportional hazards models were used to evaluate COVID-19 related outcomes. A total of 478,162 vaccinated, and 1,897,759 risk set sampled (RSS) and PS-matched unvaccinated referent individuals were included. The vaccine effectiveness (VE) against any observed COVID-19 disease was 20% (95% CI, 19 to 21%). VE increased as the outcome severity increased. The VE against COVID-19 related hospitalizations was 43% (95% CI, 40 to 45%). VE was highest, 53% (95% CI, 42 to 61%), against all-cause mortality temporally associated with COVID-19. The results of subgroup analyses generally showed a similar pattern as the main analyses with VE increasing in parallel with seriousness of outcomes, albeit with lower VE in groups thought to be at higher risk of COVID-19. This population-representative cohort study in U.S. clinical practice showed that a single dose of Ad26.COV2.S is effective for at least 12 months against several COVID-19 related outcomes. Individuals who were vaccinated with a single dose of Ad26.COV2.S were at lower risk for developing COVID-19, for being hospitalized for COVID-19, and for all-cause mortality temporally associated with COVID-19 compared to unvaccinated individuals in the U.S. during Alpha, Delta, and Omicron BA.1, BA.2, BA.212.1, and BA.5 variants circulation.

Risk of Cancer Diagnosis in Patients With Eosinophilic Esophagitis Using a Nationwide Swedish Population Cohort.

Eosinophilic esophagitis (EoE) is a chronic, inflammatory disease of the esophagus. Chronic inflammation has been linked to cancer development. We aimed to study the potential association between EoE and later cancer diagnosis. In this nationwide population-based cohort study, we identified 1580 individuals with EoE diagnosed between 1990-2017 through Sweden's 28 pathology departments. Up to five general population reference individuals were matched on age and sex (n=7533). A Cox regression analysis estimated adjusted hazard ratios (aHRs) for cancer up until December 31, 2020. To reduce potential intrafamilial confounding, we also compared EoE individuals with their unaffected siblings. During a median follow-up of 7years, 47 individuals with EoE (3.9/1000person-years) developed cancer versus 183 (3.2/1000person-years) reference individuals. This corresponded to a non-significant aHR of 1.11 (95% CI=0.80-1.53). Incidence rates were independent of budesonide and proton-pump inhibitor use. Individuals with EoE however did have an increased risk of esophageal cancer where two EoE versus one reference individual were diagnosed (aHR=25.20; 95% CI=2.28-278.80), and also Barrett's esophagus risk was also increased in EoE (HR=18.18; 95% CI=6.75-48.95). Non-esophageal gastrointestinal (GI) cancer occurred in 11 EoE versus 24 reference individuals: aHR=2.03 (95% CI=0.99-4.18). We found no increased risk of cancers from the skin (EoE n=10), lung (n=0), breast (n=4), or blood (n=0). Sibling analyses supported these findings. We did not find any overall association between EoE and cancer development. EoE was associated with esophageal cancer, but this was very rare with wide confidence interval and few cases therefore we urge caution with generalization of these findings.

Intronic Variants in the MSH2 (rs2303426 and rs10179950) and PMS2 (rs2286681 and rs62456178) Genes Are Not Associated with Colorectal Cancer in Mexican Patients.

In the origin and development of colorectal cancer (CRC), a global public health problem, a dysfunction mismatch repair system appears to be a key factor. The objective was to determine the association of intronic variants in the MSH2 and PMS2 genes with CRC in Mexican patients. Blood samples of 143 CRC patients and 146 reference individuals were genotyped through TaqMan® Genotyping Assays. Genotypic and allelic frequencies were determined by direct counting. To compare genotypic and allelic distributions, the chi-square test was used. For the association analysis, the risks of alleles and genotypes were estimated by odds ratio with 95% confidence intervals. Haplogroups were inferred with a Bayesian algorithm. Linkage disequilibrium was measured using D' and r2 with Arlequin v3.5.2. The in silico analysis was carried out using the SpliceAI, UCSC, JASPAR and TRRUST platforms. All statistical analyses were performed with SPSS v29.0.2.0. In the CRC group, the mean age was 58.2 ± 14.7 years and 60.8% were men. No variant was associated with CRC or implicated in gene post-replicative processing. Linkage disequilibrium was observed for loci rs2303426 and rs10179950 in MSH2 and for loci rs2286681 and rs62456178 in PMS2. The genotypic and allelic frequencies of the four variants are reported for the first time in Mexican patients with CRC. No association was found between gene variants and risk for CRC but there was a strong linkage disequilibrium between the loci of both MSH2 and PMS2 genes. None of the variants showed a possible repercussion on splicing.

Burden of disease and cost of illness of infants less than 6 months of age hospitalised with respiratory syncytial virus in Denmark – a 10-year national register-based study

BackgroundRespiratory syncytial virus (RSV) is the most common cause of hospitalisation in infants aged ≤ 6 months in Western countries. Nearly 1,500 infants under six months of age are hospitalised with RSV annually in Denmark. This nationwide study describes the healthcare resource utilisation and costs related to RSV hospitalisation in this vulnerable age group.MethodsRSV cases were identified in the Danish National Patient Register. Infants were included if they at the age of 0–5 months had a (1) respiratory related hospital admission (duration > 12 h), (2) within 10 days of a positive RSV test, (3) between January 2013 and December 2022. Each case was matched with five individuals never diagnosed with RSV on age, sex, region of residence, birth (pre/full term), number of siblings < 7 years old, and parents’ education. An episode of RSV was defined as the seven days prior to hospitalisation to 30 days after initial hospitalisation. Study outcomes included contacts with hospital and primary care, and total healthcare costs defined as the sum cost of hospital care, primary care, and prescription medicine. Cost and contacts attributable to RSV was calculated in a diff-in-diff framework, as the difference between case and reference group.ResultsThe study population comprised of 8,428 RSV cases and 41,725 reference individuals. Cases generated 1.58 (p < 0.001) attributable inpatient contacts, 0.84 (p < 0.001) outpatient contacts, and 1.19 (p < 0.001) primary care contacts during their RSV episode. An additional 0.6 (p < 0.001) inpatient, 1.08 (p < 0.001) outpatient and 2.42 (p < 0.001) primary care contacts were attributed to RSV in the year following the RSV episode. Total cost of an RSV episode was EUR 2,997 (p < 0.001) with an additional EUR 1,428 (p < 0.001) in the following year.ConclusionRSV hospitalisations of infants are associated with substantial healthcare utilisation and costs. The same pattern was observed in the year following the RSV episode. If the new RSV prevention options are introduced nationwide, the overall burden of RSV is expected to be substantially reduced in the future.

The risk of cancer in pediatric-onset immune-mediated inflammatory diseases – A nationwide study

Background and objectivesAdult-onset immune-mediated inflammatory disease (IMID) increases the risk of several cancers. However, data on pediatric-onset IMID (pIMID) remains scarce. We estimated the long-term cancer risk in pIMID and the association between medical treatment and specific cancers. MethodsWe used the nationwide Danish health registers to identify pIMID patients diagnosed from Jan 1, 1980 to Dec 31, 2018. Patients were matched with ten reference individuals based on age, sex, and residence. The primary exposure was pIMID, including autoimmune hepatitis, primary sclerosing cholangitis, Crohn's disease, ulcerative colitis, juvenile idiopathic arthritis, systemic lupus erythematosus, vasculitis, and connective tissue disease. Secondary exposures were immunomodulators and tumor necrosis factor-α antagonists (anti-TNFα). The primary outcome was cancer. Estimates are presented as hazard ratios adjusted for family income at diagnosis (AHR). ResultsWe included 12,664 pIMID patients and 109,274 reference individuals. Median follow-up time was 10.6 (interquartile range: 5.4–17.7) years for patients and 10.2 (interquartile range: 5.2–17.3) years for reference individuals. Patients with pIMID had a twofold higher cancer risk (AHR 2.2 [95 % confidence interval (CI): 1.8–2.6]) compared with reference individuals. Thiopurine treatment was associated with a higher risk of lymphoma (AHR 6.1 [95%CI: 2.2–16.8]) and skin cancer (AHR 6.1 [95%CI: 2.4–15.4]). Anti-TNFα treatment was associated with a higher risk of lymphoma (AHR 4.9 [95%CI: 1.1–22.6]). ConclusionsWe found an increased cancer risk in patients with pIMID followed into adulthood. Additionally, thiopurines and anti-TNFα were associated with increased lymphoma and skin cancer risks. This highlights the importance of individualized immunotherapy and cancer surveillance.

Risk of depression in patients with atopic dermatitis: An updated systematic review and meta-analysis of children, adolescent and adult groups.

Atopic dermatitis is a popular allergy disease among children, adolescents and adults. The risk of depression in patients with atopic dermatitis can be evaluated using an updated systemic review and meta-analysis of observational and cross-sectional studies. The log odds ratio (OR) was transformed using the OR and 95% confidence interval (CI) to assess the risk of depression in patients with atopic dermatitis across the children, adolescent and adult groups. After a restricted selection, 39 studies of 234 306 patients with atopic dermatitis and 10 935 459 reference individuals were enrolled. The focused outcome was the OR and 95% CI of depression risk in each included study, assigned according to the age for the children, adolescent and adult groups. In adult patients with atopic dermatitis, a significantly higher risk of depression was observed. In addition, the similar significantly higher risk of depression was observed in children and adolescent patients with atopic dermatitis, respectively. However, the significantly high heterogeneity was observed across children, adolescent and adult groups. In the current meta-analysis, the patients with atopic dermatitis had a higher risk of depression across the children, adolescent and adult groups, respectively. However, substantial heterogeneity should be considered during the interpretation of our meta-analysis results.

Calcium kinetic rates in Caucasian males and females from birth to adulthood

Calcium plays an important role in bone physiology and its kinetics change over lifetime. The analysis of calcium deposition and release through stable isotope techniques has guided recommendations on nutritional uptake for overall health. In addition, calcium kinetics have great relevance for toxicokinetic studies of bone-seeking elements (e.g, aluminium and lead) since these elements use common uptake and release pathways. While the impact of many factors on calcium kinetics have been investigated individually, a consolidated age- and sex-dependent kinetic description amenable for toxicokinetic modeling, however, is still lacking. Motivated by this need, we systematically reviewed the existing literature on calcium kinetics and assembled a large and consistent dataset. Then, building on the work of O'Flaherty in the 1990s, we formulated age- and sex-dependent functions describing calcium deposition, release, net retention, and mass. This description represents the current knowledge on calcium kinetics in a reference individual of Caucasians as most data was from this population.

Bidirectional association between inflammatory bowel disease and type 1 diabetes: a nationwide matched cohort and case-control study

Co-occurrence of inflammatory bowel disease (IBD) and type 1 diabetes (T1D) has been linked to poor clinical outcomes, but evidence on their bidirectional associations remain scarce. This study aims to investigate their bidirectional associations. A nationwide matched cohort and case-control study with IBD patients identified between 1987 and 2017. The cohort study included 20,314 IBD patients (≤28 years; Crohn's disease [CD, n=7277], ulcerative colitis [UC, n=10,112], and IBD-unclassified [IBD-U, n=2925]) and 99,200 individually matched reference individuals, with a follow-up until December 2021. The case-control study enrolled 87,001 IBD patients (no age restriction) and 431,054 matched controls. We estimated adjusted hazard ratio (aHR) of incident T1D in the cohort study with flexible parametric survival model and adjusted odds ratio (aOR) of having a prior T1D in the case-control study with conditional logistic regression model, with 95% confidence intervals (CI). During a median follow-up of 14 years, 116 IBD patients and 353 reference individuals developed T1D. Patients with IBD had a higher hazard of developing T1D (aHR=1.58 [95% CI=1.27-1.95]). The hazard was increased in UC (aHR=2.02 [1.51-2.70]) but not in CD or IBD-U. In the case-control study, a total of 1018 (1.2%) IBD patients and 3496 (0.8%) controls had been previously diagnosed with T1D. IBD patients had higher odds of having prior T1D (aOR=1.36 [1.26-1.46]). Such positive association was observed in all IBD subtypes. The sibling comparison analyses showed similar associations between IBD and T1D (aHR=1.44 [0.97-2.15] and aOR=1.32 [1.18-1.49]). Patients with IBD had a moderately increased hazard of developing T1D and higher odds of having prior T1D. Their bidirectional associations may be partially independent of shared familial factors. European Crohn's and Colitis Organisation, Stiftelsen Professor Nanna Svartz Fond, SSMF (project#: PG-23-0315-H-02), Ruth and Richard Julin Foundation; and FORTE (project#: 2016-00424).

Reference Intervals Revisited: A Novel Model for Population-Based Reference Intervals, Using a Small Sample Size and Biological Variation Data.

Conventional population-based reference intervals (popRIs) are established on the ranking of single measurement results from at least 120 reference individuals. In this study, we aimed to explore a new model for popRIs, utilizing biological variation (BV) data to define the reference interval (RI) limits and compared BV-based popRI from different sample sizes with previously published conventional popRIs from the same population. The model is based on defining the population set point (PSP) from single-measurement results of a group of reference individuals and using the total variation around the PSP, derived from the combination of BV and analytical variation, to define the RI limits. Using data from 143 reference individuals for 48 clinical chemistry and hematology measurands, BV-based popRIs were calculated for different sample sizes (n = 16, n = 30, and n = 120) and considered acceptable if they covered 90% of the population. In addition, simulation studies were performed to estimate the minimum number of required reference individuals. The median ratio of the BV-based to conventional RI ranges was 0.98. The BV-based popRIs calculated from the different samples were similar, and most met the coverage criterion. For 25 measurands ≤16 reference individuals and for 23 measurands >16 reference individuals were required to estimate the PSP. The BV-based popRI model delivered robust RIs for most of the included measurands. This new model requires a smaller group of reference individuals than the conventional popRI model and can be implemented if reliable BV data are available.

Diverticular disease and risk of incident major adverse cardiovascular events: A nationwide matched cohort study.

An increased risk of cardiovascular disease (CVD) has been reported in patients with diverticular disease (DD). However, there are knowledge gaps about specific risks of each major adverse cardiovascular event (MACE) component. This nationwide cohort study included Swedish adults with DD (1987-2017, N=52,468) without previous CVD. DD was defined through ICD codes in the National Patient Register and colorectal histopathology reports from the ESPRESSO study. DD cases were matched by age, sex, calendar year and county of residence to ≤5 population reference individuals (N=194,525). Multivariable-adjusted hazard ratios (aHRs) for MACE up until December 2021 were calculated using stratified Cox proportional hazard models. Median age at DD diagnosis was 62 years and 61% were females. During a median follow-up of 8.6 years, 16,147 incident MACE occurred in individuals with DD, and 48,134 in reference individuals (incidence rates (IRs)=61.4 vs. 43.8/1,000 person-years) corresponding to an aHR of 1.24 (95%CI=1.22-1.27), equivalent to one extra case of MACE for every 6 DD patients followed for 10 years. The risk was increased for ischemic heart disease (IR=27.9 vs. 18.6; aHR=1.36, 95%CI=1.32-1.40), congestive heart failure (IR=23.2 vs. 15.8; aHR=1.26, 95%CI=1.22-1.31), and stroke (IR=18.0 vs. 13.7; aHR=1.15, 95%CI=1.11-1.19). DD was not associated with cardiovascular mortality (IR=18.9 vs. 15.3; aHR=1.01, 95%CI=0.98-1.05). Results remained robust in sibling-controlled analyses. Patients with DD had a 24% increased risk of MACE compared with reference individuals, but no increased cardiovascular mortality. Future research should confirm these data and examine underlying mechanisms and shared risk factors between DD and CVD.

Thiopurines and the Risk of Cancer in Patients With Inflammatory Bowel Disease and Reference Individuals Without Inflammatory Bowel Disease – A Danish Nationwide Cohort Study (1996-2018)

Thiopurine therapy is a cornerstone in the treatment of inflammatory bowel disease (IBD). We aimed to assess the effect of thiopurines on cancer risk in IBD according to drug exposure and age. Danish national registers were used to identify incident IBD patients, exposure to drugs and status of cancers, in 1996-2018. Cox regressions were used to compare cancer risks in IBD and non-IBD individuals and to assess IBD patients' cumulative drug exposure and the association to first cancer, excluding non-melanoma skin cancer. We followed 43,419 IBD patients for a median of 8.2 years (IQR:3.7-14.2) after IBD diagnosis. Cancer was reported in 3,128 (7.2%) IBD patients. The risk of cancer was increased in IBD patients in all age categories compared to non-IBD individuals (<50 years (aHR: 1.59 (95%CI: 1.43-1.77)), 50-65 years (aHR: 1.31 (95%CI: (1.19-1.44)), and >65 years (aHR: 1.14 (95%CI: 1.05-1.24)). Monotherapy and combination therapy were associated with cancer (aHR:1.36 (95%CI:1.17-1.57) and (aHR:2.49 (95%CI:1.64-3.78), respectively) compared to unexposed IBD patients. Among elderly (>65 years), the aHR was 2.79 (95%CI:1.24-6.28) in those receiving combination therapy. In patients discontinuing thiopurines, aHRs returned to the level of unexposed (aHR:0.89 (95%CI:0.78-1.01)). The aHR was positively associated with cumulative thiopurine exposure and in patients with >5 years of exposure, reaching aHR 1.36 (95%CI:1.15-1.61). Thiopurines were associated with increased hazard of cancer, especially when used in combination therapy in the elderly. The hazard increased by 36% when patients were exposed to thiopurines for more than five years. Reassuringly, the hazard returned to baseline after discontinuation of thiopurines.

When do entrepreneurs and employees consider reversing career choices to manage regrets?

ABSTRACT We examine when employees consider becoming entrepreneurs and vice versa out of career choice regret. We collected data on 724 entrepreneurs and 721 employees and applied PLS-SEM to test a new conceptual model made of simple and double moderating effects. We report that individuals consider reversing career choices to manage regrets when: (1) the foregone career is accessible and resistance to change does not prevail; (2) it is not yet too late to do so; (3) they never tried the forgone option or, mistakenly or strategically, gave up on it; (4) the decision can benefit from genuine social support and approval of referent individuals; and (5) can advance valued active goals. We do not only test the regret regulation theory but also offer new areas in which it might be clarified and extended in line with the post-decision regret management strategies. The policy implications of the findings are discussed.

Psychiatric Disorders Among 5,800 Patients With Microscopic Colitis: A Nationwide Population-Based Matched Cohort Study.

Microscopic colitis (MC) is an inflammatory condition of the large intestine. Primarily diagnosed in middle-aged and older adults, the incidence of the disease has increased markedly during the past few decades. While MC is associated with a reduced quality of life, large-scale studies on the association with future psychiatric disorders are lacking. We conducted a nationwide matched cohort study in Sweden from 2006 to 2021. Through a nationwide histopathology database (the Epidemiology Strengthened by histoPathology Reports in Sweden study), we identified 5,816 patients with a colorectal biopsy consistent with MC. These patients were matched with 21,509 reference individuals from the general population all of whom with no previous record of psychiatric disorders. From 2006 to 2021, 519 patients with MC (median age 64.4 years [interquartile range = 49.5-73.3]) and 1,313 reference individuals were diagnosed with psychiatric disorders (9.9 vs 6.5 events per 1,000 person-years), corresponding to 1 extra case of psychiatric disorder in 29 patients with MC over 10 years. After adjustments, the hazard ratio for psychiatric disorders was 1.57 (95% confidence interval = 1.42-1.74). We found significantly elevated estimates up to 10 years after MC diagnosis and a trend toward higher risk with increasing age. Specifically, we observed increased risks for unipolar depression, anxiety disorders, stress-related disorders, substance abuse, and suicide attempts. In sibling-controlled analysis, the adjusted hazard ratio was 1.76 (95% confidence interval = 1.44-2.15). Patients with MC are at increased risk of incident psychiatric disorders compared with the general population.