To Örebro University

Introduction & Objectives: Tobacco smoking and occupational exposure to carcinogens constitute well-established risk factors for bladder cancer (BC), while limited evidence suggest a possible effect of dietary factors and inflammation on BC risk. Dietary patterns with impact on systemic levels of inflammation have further been proposed and investigated as possible determinants of cancer risk. In this cohort study, we evaluated the association between the anti-inflammatory potential of diet and the risk of BC.

Materials & Methods: Using the Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research (SIMPLER), we identified a study population of N=79,292 men and women derived from the two original cohorts Cohort of Swedish Men (COSM, established in 1997) and Swedish Mammography Cohort (SMC, established in 1987). We used a 96-item food frequency questionnaire (FFQ), completed at baseline in 1997 and repeated in 2009, to calculate the Anti-Inflammatory Diet Index (AIDI) for all participants. AIDI is a previously developed, empirically derived composite measure of dietary anti-inflammatory potential, based on the food groups previously found to have the strongest association with levels of systemic inflammation. The index comprises 16 food groups: 11 with proposed anti-inflammatory and 5 with proposed pro-inflammatory potential. We used ICD-10 code C67 to identify incident BC cases op to year 2020 in the Swedish National Cancer Register, and we used baseline study questionnaire to assess covariates, including smoking status and socioeconomic measures. We further used Cox proportional hazards regression models to estimate unadjusted and multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between quartiles of AIDI in the population and later BC diagnosis – overall as well as with outcome separated into non-muscle invasive (NMIBC: Ta or T1 or CIS and N0, M0) and muscle invasive (MIBC: ≤T2 or N1 or M1) BC for cases occurring after year 2004.

Results: During follow-up until 2020, 1165 BC cases occurred, of which 249 were non-muscle invasive, 201 muscle invasive and 715 of unknown stage. Overall, we observed an inverse association between the highest quartile of AIDI (Q4 vs. Q1, representing most anti-inflammatory diet compared to most pro-inflammatory) and later BC diagnosis (multivariable-adjusted HR 0.74, 95% CI 0.61-0.89, p-trend: 0.01). When separating outcome by stage, we observed an association for MIBC (HR 0.35, 95% CI 0.22-0.57), but not for NMIBC (HR 0.86, 95% CI 0.57-1.28).

Conclusions: We observed an inverse association between a measure of dietary anti-inflammatory potential and BC risk, particularly the risk of MIBC. Our observations support a possible implication of the inflammatory potential of diet in BC development and the more pronounced association observed for MIBC may hint at a true biological association.

INTRODUCTION: A diet rich in fruits, vegetables, coffee, and tea, limited red meat, and moderate alcohol intake may reduce the risk of renal cell carcinoma (RCC). The anti-inflammatory potential of diet has been proposed as a mechanism influencing cancer risk. This study assessed the association between an anti-inflammatory diet and RCC risk.

METHODOLOGY: Data from two Swedish cohorts, the Swedish-Mammography-Cohort and the Cohort-of-Swedish-Men, were analysed. Dietary habits were assessed using a 96-item food frequency questionnaire. The Anti-Inflammatory Diet Index (AIDI), composed of 16 food groups (11 anti-inflammatory and 5 pro-inflammatory), was used to score dietary patterns. RCC cases were identified from the Swedish Cancer Register using ICD-10 codes, and Cox proportional hazards models were used to estimate hazard ratios based on AIDI quartiles.

RESULTS: Among 71,421 participants, 431 RCC cases were identified during a 19.7-year follow-up. Higher AIDI scores were associated with a lower RCC risk (HR for Q4 vs. Q1: 0.68, CI: 0.52-0.89). In sex-stratified analyses (p-for heterogeneity = 0.006), the association was stronger in among women (HR: 0.47, CI: 0.30-0.75) but less clear in among men (HR: 0.83, CI: 0.63-1.24).

CONCLUSION: These data suggest that adherence to an anti-inflammatory diet may confer a reduced risk for RCC, especially among women.

AIMS/HYPOTHESIS: The potential impact of childhood bereavement-a severe psychological stressor-on childhood type 1 diabetes development remains unclear. Here, we aimed to bridge this knowledge gap and assess whether bereavement characteristics influenced any impact.

METHODS: We conducted a register-based cohort study encompassing 3,598,159 children born in Sweden between 1987 and 2020. Childhood bereavement was defined as the death of a biological mother, father or sibling. Diagnosis of type 1 diabetes in childhood (<18 years) was ascertained through the National Patient Register. We applied a Cox proportional hazards regression model to investigate the impact of childhood bereavement on type 1 diabetes, while adjusting for potential confounders (including parental type 1 diabetes status, country of birth and demographic characteristics).

RESULTS: During follow-up, 86,226 children (2.4%) lost a family member, and 18,817 children (0.52%) were diagnosed with type 1 diabetes (median age at onset 9.1 years). We did not detect any overall association between childhood bereavement and type 1 diabetes (adjusted HR 1.04; 95% CI 0.93, 1.17). We found no influence of age at loss, cause of death, familial relationship to the deceased, and time since loss.

CONCLUSIONS/INTERPRETATION: In this large population-based Swedish study, we observed no evidence supporting a link between childhood bereavement and type 1 diabetes.

INTRODUCTION: Despite increasing numbers of working-age cancer survivors, evidence on their future work-related circumstances is limited. This study examined their future sick leave, disability pension, and unemployment benefits compared to matched cancer-free individuals.

METHODS: A matched cohort study was conducted using nationwide Swedish registers. In total, 94,411 individuals aged 25 to 59 years when diagnosed with incident cancer in 2001-2012 and who returned to work after cancer were compared with their matched cancer-free individuals (N = 354,814). Follow-up started from the year before cancer diagnosis and continued up to 14 years. Generalized estimating equations were used to calculate incidence rate ratios (IRR) and odds ratios for the difference between cancer survivors and matched cancer-free individuals.

RESULTS: Compared with cancer-free individuals, cancer survivors had six times higher sick-leave days per year after cancer (IRR 6.25 [95% CI, 5.97-6.54] for men; IRR, 5.51 [5.39-5.64] for women). This higher number of sick-leave days declined over time but a two-fold difference persisted. An approximate 1.5 times higher risk of receiving disability pension remained during follow-up. The unemployment days tended to be lower for cancer survivors (IRR, 0.84 [0.75-0.94] for men; IRR, 0.91 [0.86-0.96] for women). Risk of sick leave and disability pension was higher among those with leukemia, colorectal, and breast cancer than skin and genitourinary cancers.

CONCLUSIONS: Cancer survivors who returned to work experienced a high and persisting sick leave and disability pension for over a decade. Prolonged receipt of a high amount of benefits may have long-term adverse impacts on financial circumstances; more knowledge to promote the environment that encourages returning to and remaining in work is needed.

The European Union-sponsored ONCOBIOME network has spurred an international effort to identify and validate relevant gut microbiota-related biomarkers in oncology, generating a unique and publicly available microbiome resource. ONCOBIOME explores the effects of the microbiota on gut permeability and metabolism as well as on antimicrobial and antitumor immune responses. Methods for the diagnosis of gut dysbiosis have been developed based on oncomicrobiome signatures associated with the diagnosis, prognosis and treatment responses in patients with cancer. The mechanisms explaining how dysbiosis compromises natural or therapy-induced immunosurveillance have been explored. Through its integrative approach of leveraging multiple cohorts across populations, cancer types and stages, ONCOBIOME has laid the theoretical and practical foundations for the recognition of microbiota alterations as a hallmark of cancer. ONCOBIOME has launched microbiota-centered interventions and lobbies in favor of official guidelines for avoiding diet-induced or iatrogenic (for example, antibiotic- or proton pump inhibitor-induced) dysbiosis. Here, we review the key advances of the ONCOBIOME network and discuss the progress toward translating these into oncology clinical practice.

IMPORTANCE: Childhood bereavement increases the risk of common psychiatric disorders later in life. However, the role of stress resilience in this association remains underexplored.

OBJECTIVE: To assess whether stress resilience mediates the association between childhood bereavement and psychiatric disorder risk in adulthood.

DESIGN, SETTING, AND PARTICIPANTS: Three matched cohort studies were performed using data recorded in the Swedish Military Conscription Register. Individuals with childhood loss of either a parent or a sibling (19 162 participants), a parent (16 247 participants), or a sibling (3023 participants) due to death from 1987 to 2020, together with 10 unexposed individuals per exposed individual, were matched on sex, birth year, and county of birth. All participants had available stress resilience measure at conscription. Data were analyzed from February to December 2024.

EXPOSURES: Childhood bereavement was ascertained from the Swedish Multi-Generation and Causes of Death Registers.

MAIN OUTCOMES AND MEASURES: Incident diagnosis of depression, anxiety, substance use disorder, and stress-related disorder was ascertained from the Swedish Patient Register. Cox models were used to estimate the association between childhood bereavement and risk of postconscription psychiatric disorders after multivariable adjustment. Causal mediation analysis was conducted to examine if stress resilience measured at conscription mediated this association.

RESULTS: Among 1 733 085 conscripted individuals (median [IQR] age at conscription 18.2 [18.0-18.5] years; 1 707 960 [98.5%] male), the median (IQR) age of individuals exposed to loss of either a parent or a sibling, parent, or sibling was 13.4 (9.6-15.8), 13.7 (10.4-15.9), and 10.7 (5.5-14.9) years, respectively. The crude incidence rate of any psychiatric disorder was 7.9, 8.1, and 6.6 per 1000 person-years among the 3 groups (5.3, 5.8, and 5.5 per 1000 person-years among the respective unexposed groups). A positive association was noted for loss of either a parent or a sibling (HRs ranged from 1.13; 95% CI, 1.06-1.20 for anxiety to 1.31; 95% CI, 1.23-1.40 for substance abuse disorder) and loss of a parent (HRs ranged from 1.10; 95% CI, 1.01-1.20 for stress-related disorders to 1.19; 95% CI, 1.12-1.27 for depression). For loss of a sibling, the statistically significant associations were for any common psychiatric disorder (HR, 1.12; 95% CI, 1.00-1.25) and stress-related disorders (1.27; 95% CI, 1.04-1.55). Stress resilience partially mediated the associations (proportions for loss of either a parent or a sibling ranged from 10.6%-19.4%, for a parent ranged from 15.6%-21.7%, and for a sibling ranged from 6.2% for stress-related disorders to 18.4% for any common psychiatric disorder).

CONCLUSIONS AND RELEVANCE: In this cohort study of a nationwide Swedish sample, altered stress resilience was found to be one mechanism through which childhood bereavement is associated with risk of psychiatric disorders later in life.

IMPORTANCE: Exposure to adverse childhood experiences (ACEs) has consistently been associated with multiple negative mental health outcomes extending into adulthood. However, given that ACEs and psychiatric disorders cluster within families, it remains to be comprehensively assessed to what extent familial confounding contributes to associations between ACEs and clinically confirmed adult psychiatric disorders.

OBJECTIVE: To investigate whether associations between ACEs and adult mental health outcomes remain after adjusting for familial (genetic and environmental) confounding.

DESIGN, SETTING, AND PARTICIPANTS: This Swedish twin cohort study used a discordant twin pair design based on monozygotic (MZ) and dizygotic (DZ) twins. A total of 25 252 adult twins (aged 18-47 years) from the Swedish Twin Registry born between 1959 and 1998 were followed up from age 19 years until 2016, with a maximum follow-up time of 39 years. Data were analyzed from April 2022 to November 2023.

EXPOSURES: A total of 7 ACEs, including family violence, emotional abuse or neglect, physical neglect, physical abuse, sexual abuse, rape, and hate crime, were assessed with items from the Life Stressor Checklist-Revised in a web-based survey.

MAIN OUTCOMES AND MEASURES: Adult (ages >18 years) clinical diagnosis of psychiatric disorders (ie, depressive, anxiety, alcohol or drug misuse, or stress-related disorders) were obtained from the Swedish National Patient Register.

RESULTS: Of 25 252 twins included in the study (15 038 female [59.6%]; mean [SD] age at ACE assessment, 29.9 [8.7] years), 9751 individuals (38.6%) reported exposure to at least 1 ACE. A greater number of ACEs was associated with increased odds of any psychiatric disorder in the full cohort (odds ratio [OR] per additional ACE, 1.52; 95% CI, 1.48-1.57). The association remained but ORs per additional ACE were attenuated in DZ (1.29; 95% CI, 1.14-1.47) and MZ (1.20; 95% CI, 1.02-1.40) twin pairs. Individuals who were exposed to sexual abuse compared with those who were not exposed had increased odds of any clinically confirmed psychiatric disorder in all comparisons: full cohort (OR, 3.09; 95% CI, 2.68-3.56), DZ twin pairs (OR, 2.10; 95% CI, 1.33-3.32), and MZ twin pairs (1.80; 95% CI, 1.04-3.11).

CONCLUSIONS AND RELEVANCE: This study found that associations between ACEs and adult mental health outcomes remained after controlling for shared genetic and environmental factors, which was particularly evident after multiple ACEs or sexual abuse. These findings suggest that targeted interventions may be associated with reduced risks of future psychopathology.

OBJECTIVE: The majority of patients hospitalized for treatment of a manic episode are readmitted within 2 years despite maintenance treatment. Electroconvulsive therapy (ECT) has been associated with lower rehospitalization rates in some psychiatric conditions, but its association with readmission after a manic episode has not been investigated. Therefore, the aim of this study was to determine whether the time to readmission in patients with mania treated with ECT was longer than in patients not treated with ECT and whether there were subgroups of patients that benefited more.

METHODS: This was a nationwide register-based, observational study. All patients diagnosed with bipolar disorder, manic episode, admitted to any hospital in Sweden between 2012 and 2021 were included. Patients contributed data to the study for every admission. All admissions were followed up until psychiatric readmission, death, or the end of the study (December 31, 2021). Association between ECT and time to readmission was analyzed. A paired samples model was performed for 377 patients with at least two admissions for mania, treated with ECT at one admission and without ECT at the other admission. Times to readmission were analyzed.

RESULTS: A total of 12,337 admissions were included; mean (SD) age 47.7 (17.2), 5443 (44.1%) men. Readmission rate within 1 year was 54.6%. ECT was administered in 902 (7.3%) admissions. Within 30 days after admission, 182 out of 894 (20.4%) patients treated with ECT versus 2105 out of 11,305 (18.6%) patients treated without ECT were readmitted. There was no association between ECT and time to readmission (aHR 1.00, 95% CI 0.86-1.16, p = 0.992) in the model with all admissions. The paired samples model included 754 admissions (377 patients), mean (SD) age during admission without ECT was 45.6 (16.5), and with ECT 46.6 (16.4), 147 (39.0%) were men. In that model, readmission rate within 30 days for treatment with ECT was 19.0%, and for treatments without ECT, 24.1% (aHR 0.75, 95% CI 0.55-1.02, p = 0.067).

CONCLUSION: Readmission rates after inpatient treatment of mania were high. ECT was not significantly associated with longer time to readmission, but there was a trend toward a protective effect of ECT when admissions with and without ECT were compared within the same patients.

BACKGROUND: It has been repeatedly shown that men infected by SARS-CoV-2 face a twofold higher likelihood of dying, being hospitalized or admitted to the intensive care unit compared to women, despite taking into account relevant confounders. It has been hypothesized that these discrepancies are related to sex steroid hormone differences with estrogens being negatively correlated with disease severity. The objective of this study was therefore to evaluate COVID-19-related mortality and morbidity among peri- and postmenopausal women in relation to estrogen-containing menopause hormonal treatments (MHT).

METHODS: This is a national register-based matched cohort study performed in Sweden between January 1 to December 31, 2020. Study participants comprised women over the age of 53 years residing in Sweden. Exposure was defined as prescriptions of local estrogens, systemic estrogens with and without progestogens, progestogens alone, or tibolone. MHT users were then compared with a matched cohort of non-users. The primary outcome consisted of COVID-19 mortality, whereas the secondary outcomes included inpatient hospitalizations/outpatient visits and confirmed SARS-CoV-2 infection. Multivariable adjusted Cox regression-derived hazard ratios (HRs) were calculated.

RESULTS: Use of systemic estrogens alone is associated with increased COVID-19 mortality among older women (aHR 4.73, 1.22 to 18.32), but the association is no longer significant when discontinuation of estrogen use is accounted for. An increased risk for COVID-19 infection is further observed for women using combined systemic estrogens and progestogens (aHR 1.06, 1.00 to 1.13) or tibolone (aHR 1.21, 1.01 to 1.45). Use of local estrogens is associated with an increased risk for COVID-19-related death (aHR 2.02,1.45 to 2.81) as well as for all secondary outcomes.

CONCLUSIONS: Systemic or local use of estrogens does not decrease COVID-19 morbidity and mortality to premenopausal background levels. Excess risk for COVID-19 morbidity and mortality was noted among older women and those discontinuing systemic estrogens. Higher risk for death was also noted among women using local estrogens, for which non-causal mechanisms such as confounding by comorbidity or frailty seem to be the most plausible underlying explanations.

TRIAL REGISTRATION DETAILS: Not applicable.

BACKGROUND: Helicobacter pylori (H. pylori) is an established gastric carcinogen, also associated with an increased risk of colorectal cancer. Therefore, we suspected that H. pylori eradication lowers the risk of colorectal cancer.

MATERIAL AND METHODS: We assessed if H. pylori eradication therapy is associated with a reduced risk of colorectal adenocarcinoma in a population-based nationwide cohort study. This study included all Swedish adults with at least one recorded H. pylori eradication episode between July 2005 and December 2012, based on the high-quality Swedish health registries. Colorectal adenocarcinoma risks were compared to the Swedish background population, presented as standardized incidence ratios (SIRs) and 95% confidence intervals (CIs), accounting for age, sex, calendar period, tumor location (left or right sided), stage, and number of eradication episodes, from 1 year after eradication and onward.

RESULTS: Among 80,381 individuals receiving H. pylori eradication therapy (average follow-up 4.1 years), 282 were diagnosed with colorectal cancer (97.2% adenocarcinoma). Overall, H. pylori eradication was associated with an elevated risk of colorectal adenocarcinoma (SIR 1.27, 95% CI: 1.12-1.43). The colorectal adenocarcinoma risk was increased 1-2 years after eradication (SIR 1.42, 95% CI: 1.17-1.72), then decreased 2-4 years (SIR 0.80, 95% CI: 0.65-0.98) and 4-6 years (SIR 0.76, 95% CI: 0.57-0.99), yet not ≥ 6 years (SIR 1.36, 95% CI: 0.78-2.21) after eradication compared to the general population. Overall, right-sided (SIR 1.47, 95% CI: 1.21-1.76) and left-sided (SIR 1.35, 95% CI: 1.09-1.67) colon adenocarcinomas risks were higher among eradicated individuals than the general population.

CONCLUSION: H. pylori eradication was not associated with a clear and consistent reduction of colorectal cancer in our Swedish cohort.