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Background Ideal cardiovascular health (CVH) can be assessed by 7 metrics: smoking, body mass index, physical activity, diet, hypertension, dyslipidemia and diabetes, proposed by the American Heart Association. We examined the association of ideal CVH metrics with risk of all-cause, CVD and non-CVD death in a large cohort. Methods A total of 29,557 participants in the Swedish National March Cohort were included in this study. We ascertained 3,799 deaths during a median follow-up of 19 years. Cox regression models were used to estimate hazard ratios with 95% confidence intervals (95% CIs) of the association between CVH metrics with risk of death. Laplace regression was used to estimate 25th, 50th and 75th percentiles of age at death. Results Compared with those having 6-7 ideal CVH metrics, participants with 0-2 ideal metrics had 107% (95% CI = 46-192%) excess risk of all-cause, 224% (95% CI = 72-509%) excess risk of CVD and 108% (31-231%) excess risk of non-CVD death. The median age at death among those with 6-7 vs. 0-2 ideal metrics was extended by 4.2 years for all-causes, 5.8 years for CVD and 2.9 years for non-CVD, respectively. The observed associations were stronger among females than males. Conclusions The strong inverse association between number of ideal CVH metrics and risk of death supports the application of the proposed seven metrics for individual risk assessment and general health promotion.

Both short (< 6 hr) and long (> 8 hr) sleep are associated with increased mortality. We here investigated whether the association between sleep duration and all-cause, cardiovascular disease and cancer mortality differs between men and women. A cohort of 34,311 participants (mean age and standard deviation = 50.5 ± 15.5 years, 65% women), with detailed assessment of sleep at baseline and up to 20.5 years of follow-up (18 years for cause-specific mortality), was analysed using Cox proportional hazards model to estimate HRs with 95% confidence intervals. After adjustment for covariates, all-cause, cardiovascular disease and cancer mortalities were increased for both < 5 hr and ≥ 9 hr sleep durations (with 6 hr as reference). For all-cause mortality, women who slept < 5 hr had a hazard ratio = 1.54 (95% confidence interval = 1.32–1.80), while the corresponding hazard ratio was 1.05 (95% confidence interval = 0.88–1.27) for men, the interaction being significant (p < 0.05). For cardiovascular disease mortality, exclusion of the first 2 years of exposure, as well as competing risk analysis eliminated the originally significant interaction. Cancer mortality did not show any significant interaction. Survival analysis of the difference between the reference duration (6 hr) and the short duration (< 5 hr) during follow-up showed a gradually steeper reduction of survival time for women than for men for all-cause mortality. We also observed that the lowest cancer mortality appeared for the 5-hr sleep duration. In conclusion, the pattern of association between short sleep duration and all-cause mortality differed between women and men, and the difference between men and women increased with follow-up time., The present study was supported by The Tercentenary Fund of Bank of Sweden. Ylva Trolle Lagerros was supported by Region Stockholm (clinical research appointment).

PURPOSE: To assess whether androgens play a role in explaining the sex related differences in the incidence of colorectal cancer (CRC). METHODS: A nationwide matched cohort study was conducted employing the Prostate Cancer data Base Sweden (PCBaSe) 4.0 during the study period 2006-2016. Prostate cancer (PC) patients receiving androgen deprivation therapy (ADT) were treated as exposed. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed group. All were followed until a diagnosis of CRC, death, emigration, or end of the study period. The risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men was calculated using a flexible parametric survival model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: There was an increased risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men (HR 1.27 [95% CI 1.15-1.41]), in particular an increased risk of adenocarcinoma of the colon (HR 1.33 [95% CI 1.17-1.51]) and more specifically an increased risk of adenocarcinoma of the distal colon (HR 1.53 [95% CI 1.26-1.85]). Examination of latency effects yielded significantly decreased HRs over time for CRC (p = 0.049 for trend). CONCLUSIONS: This population-based study found an increased risk of CRC among PC patients exposed to ADT, specifically adenocarcinoma of the distal colon, which indicates an increased association between ADT (PC + ADT) and CRC but not a positive dose-response trend questioning a true causal effect.

PURPOSE: To assess whether androgens play a role in explaining the sex related differences in the incidence of colorectal cancer (CRC). METHODS: A nationwide matched cohort study was conducted employing the Prostate Cancer data Base Sweden (PCBaSe) 4.0 during the study period 2006-2016. Prostate cancer (PC) patients receiving androgen deprivation therapy (ADT) were treated as exposed. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed group. All were followed until a diagnosis of CRC, death, emigration, or end of the study period. The risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men was calculated using a flexible parametric survival model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: There was an increased risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men (HR 1.27 [95% CI 1.15-1.41]), in particular an increased risk of adenocarcinoma of the colon (HR 1.33 [95% CI 1.17-1.51]) and more specifically an increased risk of adenocarcinoma of the distal colon (HR 1.53 [95% CI 1.26-1.85]). Examination of latency effects yielded significantly decreased HRs over time for CRC (p = 0.049 for trend). CONCLUSIONS: This population-based study found an increased risk of CRC among PC patients exposed to ADT, specifically adenocarcinoma of the distal colon, which indicates an increased association between ADT (PC + ADT) and CRC but not a positive dose-response trend questioning a true causal effect.

Objective: Given the importance of sleep in maintaining neurocognitive health, both sleep duration and quality might be component causes of dementia. However, the possible role of insomnia symptoms as risk factors for dementia remain uncertain. Methods: We prospectively studied 22,078 participants in the Swedish National March Cohort who were free from dementia and stroke at baseline. Occurrence of dementia was documented by national registers during a median follow-up period of 19.2 years. Insomnia symptoms and sleep duration were ascertained by Karolinska Sleep Questionnaire. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Compared to participants without insomnia at baseline, those who reported any insomnia symptom experienced a greater incidence of dementia during follow-up (HR 1.08, 95% CI: 1.03, 1.35). Difficulty initiating sleep versus non insomnia (HR 1.24, 95% CI: 1.02, 1.52), but not difficulty maintaining sleep or early morning awakening was associated with an increased risk of dementia. Short sleep duration was associated with increased risk of dementia (6 h vs. 8 h, HR 1.29, 95% CI: 1.11-1.51; 5 h vs. 8 h, HR 1.26, 95% CI: 1.00-1.57). Stratified analyses suggested that insomnia symptoms increased the risk of dementia only amongst participants with =7 h sleep (vs. non-insomnia HR 1.24, 95% CI: 1.00-1.54, P=0.05), but not amongst short sleepers (<7 h). Short sleep duration also did not further inflate the risk of dementia amongst insomniacs. Conclusion: Insomnia and short sleep duration increase the risk of dementia amongst middle-aged to older adults., This research was supported by ZJU 100 Young Professor Project (X.T.), Åke Wiberg Foundation (X.T., M19–0266), Fredrik and Ingrid Thuring Foundation (X.T., 2019–00488) and Region Stockholm Clinical Research Appointment (Y.T.L.), the Swedish Research Council (HX.W., 2018–02998), and the Swedish Research Council for Health, Working life, and Welfare (HX.W., 2019–01120, 2020–00313).

PURPOSE: To assess whether androgens play a role in explaining the sex related differences in the incidence of colorectal cancer (CRC). METHODS: A nationwide matched cohort study was conducted employing the Prostate Cancer data Base Sweden (PCBaSe) 4.0 during the study period 2006-2016. Prostate cancer (PC) patients receiving androgen deprivation therapy (ADT) were treated as exposed. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed group. All were followed until a diagnosis of CRC, death, emigration, or end of the study period. The risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men was calculated using a flexible parametric survival model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: There was an increased risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men (HR 1.27 [95% CI 1.15-1.41]), in particular an increased risk of adenocarcinoma of the colon (HR 1.33 [95% CI 1.17-1.51]) and more specifically an increased risk of adenocarcinoma of the distal colon (HR 1.53 [95% CI 1.26-1.85]). Examination of latency effects yielded significantly decreased HRs over time for CRC (p = 0.049 for trend). CONCLUSIONS: This population-based study found an increased risk of CRC among PC patients exposed to ADT, specifically adenocarcinoma of the distal colon, which indicates an increased association between ADT (PC + ADT) and CRC but not a positive dose-response trend questioning a true causal effect.

PURPOSE: To assess whether androgens play a role in explaining the sex related differences in the incidence of colorectal cancer (CRC). METHODS: A nationwide matched cohort study was conducted employing the Prostate Cancer data Base Sweden (PCBaSe) 4.0 during the study period 2006-2016. Prostate cancer (PC) patients receiving androgen deprivation therapy (ADT) were treated as exposed. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed group. All were followed until a diagnosis of CRC, death, emigration, or end of the study period. The risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men was calculated using a flexible parametric survival model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: There was an increased risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men (HR 1.27 [95% CI 1.15-1.41]), in particular an increased risk of adenocarcinoma of the colon (HR 1.33 [95% CI 1.17-1.51]) and more specifically an increased risk of adenocarcinoma of the distal colon (HR 1.53 [95% CI 1.26-1.85]). Examination of latency effects yielded significantly decreased HRs over time for CRC (p = 0.049 for trend). CONCLUSIONS: This population-based study found an increased risk of CRC among PC patients exposed to ADT, specifically adenocarcinoma of the distal colon, which indicates an increased association between ADT (PC + ADT) and CRC but not a positive dose-response trend questioning a true causal effect.

Wuqing Huang,1,&ast; Ruimei Feng,1,&ast; Xin Xu,1,&ast; Mingyang Ma,1 Jun Chen,1 Junzhuo Wang,1 Zhijian Hu,1,2 Shanshan Du,1 Weimin Ye1– 3 1Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 2Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, People’s Republic of China; 3Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden&ast;These authors contributed equally to this workCorrespondence: Weimin Ye; Shanshan Du, Fujian Medical University, No. 1, Xue Yuan Road, University Town, Fuzhou City, Fujian Province, 350108, People’s Republic of China, Tel +86 591 2286 2023, Fax +86 591 2286 2510, Email ywm@fjmu.edu.cn; dushanshan1007@163.comBackground: Emerging data suggest that the interpretation of the association between obesity and lipids appears to be oversimplified. This study aimed to quantify the complex relationships between anthropometric indices and lipid profile.Methods: This is a cross-sectional study including 9620 participants in Southern China. Anthropometric indices included the indices of general obesity (ie, body mass index (BMI)) and central obesity (ie, waist circumference (WC) and waist-to-hip ratio (WHR)). Lipids included low-density lipoprotein cholesterol (LDLc) and atherogenic lipids (ie, high-density lipoprotein cholesterol (HDLc), triglycerides (TG) and TG/HDLc ratio). LOESS regression and general linear model were the main statistical methods.Results: Almost all associations between anthropometric indices and lipids were lost in obese adults. The loss of association occurred quicker with LDLc than that with atherogenic lipids; the break point for the association loss was at BMI of 24 kg/m2 with LDLc (Slope Below break-point = 1.81, P< 0.001; Slope Above break-point = 0.29, P=0.121), while at 28 kg/m2 with HDLC (Slope Below break-point

BACKGROUND: Dysbiosis of the oral mycobiome has been linked to some diseases, including cancers. However, the role of oral fungal communities in nasopharyngeal carcinoma (NPC) carcinogenesis has not previously been investigated. METHODS: We characterized the oral salivary fungal mycobiome in 476 untreated incident NPC patients and 537 population-based controls using fungal internal transcribed spacer (ITS)-2 sequencing. The relationship between oral fungal mycobiome and the risk of NPC was assessed through bioinformatic and biostatistical analyses. FINDINGS: We found that lower fungal alpha diversity was associated with an increased odds of NPC [lower vs. higher: observed features (adjusted odds ratio [OR] = 5.81, 95% confidence interval [CI] = 3.60-9.38); Simpson diversity (1.53, 1.03-2.29); Shannon diversity (2.03, 1.35-3.04)]. We also observed a significant difference in global fungal community patterns between cases and controls based on Bray-Curtis dissimilarity (P < 0.001). Carriage of oral fungal species, specifically, Saccharomyces cerevisiae, Candida tropicalis, Lodderomyces elongisporus, Candida albicans, and Fusarium poae, was associated with significantly higher odds of NPC, with ORs ranging from 1.56 to 4.66. Individuals with both low fungal and low bacterial alpha diversity had a profoundly elevated risk of NPC. INTERPRETATION: Our results suggest that dysbiosis in the oral mycobiome, characterized by a loss of fungal community diversity and overgrowth of several fungal organisms, is associated with a substantially increased risk of NPC. FUNDING: This work was funded by the US National Institutes of Health, the Swedish Research Council, the High-level Talents Research Start-up Project of Fujian Medical University, and the China Scholarship Council.

BACKGROUND: Several psychiatric disorders have been associated with increased risk of cardiovascular disease (CVD), however, the role of familial factors and the main disease trajectories remain unknown. METHODS: In this longitudinal cohort study, we identified a cohort of 900,240 patients newly diagnosed with psychiatric disorders during January 1, 1987 and December 31, 2016, their 1,002,888 unaffected full siblings, and 1:10 age- and sex-matched reference population from nationwide medical records in Sweden, who had no prior diagnosis of CVD at enrolment. We used flexible parametric models to determine the time-varying association between first-onset psychiatric disorders and incident CVD and CVD death, comparing rates of CVD among patients with psychiatric disorders to the rates of unaffected siblings and matched reference population. We also used disease trajectory analysis to identify main disease trajectories linking psychiatric disorders to CVD. Identified associations and disease trajectories of the Swedish cohort were validated in a similar cohort from nationwide medical records in Denmark (N = 875,634 patients, same criteria during January 1, 1969 and December 31, 2016) and in Estonian cohorts from the Estonian Biobank (N = 30,656 patients, same criteria during January 1, 2006 and December 31, 2020), respectively. FINDINGS: During up to 30 years of follow-up of the Swedish cohort, the crude incidence rate of CVD was 9.7, 7.4 and 7.0 per 1000 person-years among patients with psychiatric disorders, their unaffected siblings, and the matched reference population. Compared with their siblings, patients with psychiatric disorders experienced higher rates of CVD during the first year after diagnosis (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.79-1.98) and thereafter (1.37; 95% CI, 1.34-1.39). Similar rate increases were noted when comparing with the matched reference population. These results were replicated in the Danish cohort. We identified seve, Funding agencies:European Research Council Consolidator grant 726413Icelandic Research fundUS NIMH R01 MH123724Outstanding Clinical Discipline Project of Shanghai Pudong PWYgy2021-02Fundamental Research Funds for the Central UniversitiesSouth-East Regional Health Authority 2017-112 2022-073 Stiftelsen Kristian Gerhard Jebsen SKGJ-MED-008 SKGJ-MED-021 EEA-RO-NO-2018-0535

IMPORTANCE: There is emerging evidence that spouses of patients with cancer may have a higher prevalence of mental illness, but these studies have been limited by pre-post designs, focus on a single mental illness, and short follow-up periods. OBJECTIVES: To assess the overall burden of psychiatric disorders among spouses of patients with cancer vs spouses of individuals without cancer and to describe possible changes in this burden over time. DESIGN, SETTING, AND PARTICIPANTS: This population based cohort study included spouses of patients with cancer (diagnosed 1986-2016 in Denmark and 1973-2014 in Sweden; exposed group) and spouses of individuals without cancer (unexposed group). Members of the unexposed group were individually matched to individuals in the exposed group on the year of birth, sex, and country. Spouses with and without preexisting psychiatric morbidity were analyzed separately. Data analysis was performed between May 2021 and January 2022. EXPOSURES: Being spouse to a patient with cancer. MAIN OUTCOMES AND MEASURES: The main outcome was a clinical diagnosis of psychiatric disorders through hospital-based inpatient or outpatient care. Flexible parametric models and Cox models were fitted to estimate hazard ratios (HRs) with 95% CIs, adjusted for sex, age and year at cohort entry, country, household income, and cancer history. RESULTS: Among 546 321 spouses in the exposed group and 2 731 574 in the unexposed group who had no preexisting psychiatry morbidity, 46.0% were male participants, with a median (IQR) age at cohort entry of 60 (51-68) years. During follow-up (median, 8.4 vs 7.6 years), the incidence rate of first-onset psychiatric disorders was 6.8 and 5.9 per 1000 person-years for the exposed and unexposed groups, respectively (37 830 spouses of patients with cancer [6.9%]; 153 607 of spouses of individuals without cancer [5.6%]). Risk of first-onset psychiatric disorders increased by 30% (adjusted HR, 1.30; 95% CI, 1.25-1.34) during the firs, Funding agencies:China Scholarship Council 201806240005 201700260291 201700260276Independent Research Fund Denmark DFF-6110-00019B DFF-9039-00010B 1030-00012BNordic Cancer Union R275-A15770 R278-A15877Karen Elise Jensens Fond

PURPOSE: To assess whether androgens play a role in explaining the sex related differences in the incidence of colorectal cancer (CRC). METHODS: A nationwide matched cohort study was conducted employing the Prostate Cancer data Base Sweden (PCBaSe) 4.0 during the study period 2006-2016. Prostate cancer (PC) patients receiving androgen deprivation therapy (ADT) were treated as exposed. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed group. All were followed until a diagnosis of CRC, death, emigration, or end of the study period. The risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men was calculated using a flexible parametric survival model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: There was an increased risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men (HR 1.27 [95% CI 1.15-1.41]), in particular an increased risk of adenocarcinoma of the colon (HR 1.33 [95% CI 1.17-1.51]) and more specifically an increased risk of adenocarcinoma of the distal colon (HR 1.53 [95% CI 1.26-1.85]). Examination of latency effects yielded significantly decreased HRs over time for CRC (p = 0.049 for trend). CONCLUSIONS: This population-based study found an increased risk of CRC among PC patients exposed to ADT, specifically adenocarcinoma of the distal colon, which indicates an increased association between ADT (PC + ADT) and CRC but not a positive dose-response trend questioning a true causal effect.

Background: Following progressive aging of the population worldwide, the prevalence of Parkinson disease is expected to increase in the next decades. Primary prevention of the disease is hampered by limited knowledge of preventable causes. Recent evidence regarding diet and Parkinson disease is inconsistent and suggests that dietary habits such as fat intake may have a role in the etiology. Objective: To investigate the association between intake of total and specific types of fat with the incidence of Parkinson disease. Methods: Participants from the Swedish National March Cohort were prospectively followed-up from 1997 to 2016. Dietary intake was assessed at baseline using a validated food frequency questionnaire. Food items intake was used to estimate fat intake, i.e. the exposure variable, using the Swedish Food Composition Database. Total, saturated, monounsaturated and polyunsaturated fat intake were categorized into quartiles. Parkinson disease incidence was ascertained through linkages to Swedish population-based registers. Cox proportional hazards regression models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI) of the association between fat intake from total or specific types of fats and the incidence of Parkinson disease. The lowest intake category was used as reference. Isocaloric substitution models were also fitted to investigate substitution effects by replacing energy from fat intake with other macronutrients or specific types of fat. Results: 41,597 participants were followed up for an average of 17.6 years. Among them, 465 developed Parkinson disease. After adjusting for potential confounders, the highest quartile of saturated fat intake was associated with a 41% increased risk of Parkinson disease compared to the lowest quartile (HR Q4 vs. Q1: 1.41; 95% CI: 1.04–1.90; p for trend: 0.03). Total, monounsaturated or polyunsaturated fat intake were not significantly associated with Parkinson disease. The isocaloric substit

A cancer diagnosis is part of a complex stochastic process, which involves patient's characteristics, diagnosing methods, an initial assessment of cancer progression, treatments and a certain outcome of interest. To evaluate the performance of diagnoses, one needs not only a consistent estimation of the causal effect under a specified regime of diagnoses and treatments but also reliable confidence interval, P-value and hypothesis testing of the causal effect. In this article, we identify causal effects under various regimes of diagnoses and treatments by the point effects of diagnoses and treatments and thus are able to estimate and test these causal effects by estimating and testing point effects in the familiar framework of single-point causal inference. Specifically, using data from a Swedish prognosis study of stomach cancer, we estimate and test the causal effects on cancer survival under various regimes of diagnosing and treating hospitals including the optimal regime. We also estimate and test the modification of the causal effect by age. With its simple setting, one can readily extend the example to a large variety of settings in the area of cancer diagnosis: different personal characteristics such as family history, different diagnosing procedures such as multistage screening, and different cancer outcomes such as cancer progression.

A cancer diagnosis is part of a complex stochastic process, which involves patient's characteristics, diagnosing methods, an initial assessment of cancer progression, treatments and a certain outcome of interest. To evaluate the performance of diagnoses, one needs not only a consistent estimation of the causal effect under a specified regime of diagnoses and treatments but also reliable confidence interval, P-value and hypothesis testing of the causal effect. In this article, we identify causal effects under various regimes of diagnoses and treatments by the point effects of diagnoses and treatments and thus are able to estimate and test these causal effects by estimating and testing point effects in the familiar framework of single-point causal inference. Specifically, using data from a Swedish prognosis study of stomach cancer, we estimate and test the causal effects on cancer survival under various regimes of diagnosing and treating hospitals including the optimal regime. We also estimate and test the modification of the causal effect by age. With its simple setting, one can readily extend the example to a large variety of settings in the area of cancer diagnosis: different personal characteristics such as family history, different diagnosing procedures such as multistage screening, and different cancer outcomes such as cancer progression.

BackgroundHelicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status.MethodsA pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted.ResultsThe OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology.ConclusionThe NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

Background: Over 20 susceptibility single-nucleotide poly-morphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability.Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach.Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

Background: The association between cardiovascular disease (CVD) and selected psychiatric disorders has frequently been suggested while the potential role of familial factors and comorbidities in such association has rarely been investigated. Methods: We identified 869 056 patients newly diagnosed with CVD from 1987 to 2016 in Sweden with no history of psychiatric disorders, and 910 178 full siblings of these patients as well as 10 individually age- and sex-matched unrelated population controls (N=8 690 560). Adjusting for multiple comorbid conditions, we used flexible parametric models and Cox models to estimate the association of CVD with risk of all subsequent psychiatric disorders, comparing rates of first incident psychiatric disorder among CVD patients with rates among unaffected full siblings and population controls. Results: The median age at diagnosis was 60 years for patients with CVD and 59.2% were male. During up to thirty years of follow-up, the crude incidence rates of psychiatric disorder were 7.1, 4.6 and 4.0 per 1000 person-years for patients with CVD, their siblings and population controls. In the sibling comparison, we observed an increased risk of psychiatric disorder during the first year after CVD diagnosis (hazard ratio [HR], 2.74; 95% confidence interval [CI], 2.62-2.87) and thereafter (1.45; 95% CI, 1.42-1.48). Increased risks were observed for all types of psychiatric disorders and among all diagnoses of CVD. We observed similar associations in the population comparison. CVD patients who developed a comorbid psychiatric disorder during the first year after diagnosis were at elevated risk of subsequent CVD death compared to patients without such comorbidity (HR 1.55; 95% CI 1.44-1.67). Conclusions: Patients diagnosed with CVD are at an elevated risk for subsequent psychiatric disorders independent of shared familial factors and comorbid conditions. Comorbid psychiatric disorders in patients with CVD are associated with higher risk of cardiov, Funding agencies:Grant of Excellence, Icelandic Research Fund CoMorMent,847776European Research Council (ERC) European Commission 163362-51United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) D0886501 R01 MH123724

Background: Experimental observations have suggested a role of infection in the etiology of neurodegenerative disease. In human studies, however, it is difficult to disentangle whether infection is a risk factor or rather a comorbidity or secondary event of neurodegenerative disease. To this end, we examined the risk of 3 most common neurodegenerative diseases in relation to previous inpatient or outpatient episodes of hospital-treated infections. Methods and findings: We performed a nested case-control study based on several national registers in Sweden. Cases were individuals newly diagnosed with Alzheimer's disease (AD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS) during 1970 to 2016 in Sweden, identified from the National Patient Register. For each case, 5 controls individually matched to the case on sex and year of birth were randomly selected from the general population. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) with adjustment for potential confounders, including sex, year of birth, area of residence, educational attainment, family history of neurodegenerative disease, and Charlson comorbidity index. Infections experienced within 5 years before diagnosis of neurodegenerative disease were excluded to reduce the influence of surveillance bias and reverse causation. The analysis included 291,941 AD cases (median age at diagnosis: 76.2 years; male: 46.6%), 103,919 PD cases (74.3; 55.1%), and 10,161 ALS cases (69.3; 56.8%). A hospital-treated infection 5 or more years earlier was associated with an increased risk of AD (OR = 1.16, 95% CI: 1.15 to 1.18, P < 0.001) and PD (OR = 1.04, 95% CI: 1.02 to 1.06, P < 0.001). Similar results were observed for bacterial, viral, and other infections and among different sites of infection including gastrointestinal and genitourinary infections. Multiple infections before age 40 conveyed the greatest risk of AD (OR = 2.62, 95% CI: 2.52 to, Funding agencies:Joint Program on Neurodegenerative Diseases (JPND) 2021-00696China Scholarship Council

Background: Eosinophilic gastrointestinal disorders (EGIDs) include inflammatory conditions with enteric infiltration of eosinophils and resulting symptoms. This study aims to examine a population-based sample of patients for prevalence, mortality, and cancer risk in EGIDs distal to the esophagus. Methods: Nationwide, population-based cohort study. EGID was identified through relevant biopsy codes from Sweden's all 28 pathology departments through the ESPRESSO cohort. Individuals with EGID were then matched to general population reference individuals with similar age and sex. Study participants were linked to Swedish healthcare registers. Through Cox regression, we calculated adjusted hazard ratios (aHRs) adjusting for sex, age, county, calendar period, and education. Results: In total, 2429 patients (56% female) were found to have EGID distal to the esophagus, representing a prevalence of about 1/4800 in the Swedish population. Mean age was 44 years with 11% children at the time of diagnosis. Mortality was increased 17% in patients with EGIDs compared to reference individuals (aHR = 1.17; 95%CI = 1.04-1.33). Excess mortality was seen in gastric and small bowel eosinophilic disease, but not colonic disease (aHR = 1.81; 95%CI = 1.32-2.48, aHR = 1.50; 95%CI = 1.18-1.89, and aHR = 0.99; 95%CI = 0.85-1.16, respectively). Cause specific mortality was driven by cancer-related death (aHR = 1.33; 95%CI = 1.05-1.69). However, this study failed to show an increase in incident cancers (aHR = 1.14; 95%CI = 0.96-1.35). Comparison of EGID individuals with their siblings yielded similar aHRs. Conclusions: This study found an increased risk of death in patients with EGIDs distal to the esophagus, with cancer death driving the increase. Proximal gut disease seems to confer the greatest risk. There was no increase in incident cancers.

A cancer diagnosis is part of a complex stochastic process, which involves patient's characteristics, diagnosing methods, an initial assessment of cancer progression, treatments and a certain outcome of interest. To evaluate the performance of diagnoses, one needs not only a consistent estimation of the causal effect under a specified regime of diagnoses and treatments but also reliable confidence interval, P-value and hypothesis testing of the causal effect. In this article, we identify causal effects under various regimes of diagnoses and treatments by the point effects of diagnoses and treatments and thus are able to estimate and test these causal effects by estimating and testing point effects in the familiar framework of single-point causal inference. Specifically, using data from a Swedish prognosis study of stomach cancer, we estimate and test the causal effects on cancer survival under various regimes of diagnosing and treating hospitals including the optimal regime. We also estimate and test the modification of the causal effect by age. With its simple setting, one can readily extend the example to a large variety of settings in the area of cancer diagnosis: different personal characteristics such as family history, different diagnosing procedures such as multistage screening, and different cancer outcomes such as cancer progression.

A cancer diagnosis is part of a complex stochastic process, which involves patient's characteristics, diagnosing methods, an initial assessment of cancer progression, treatments and a certain outcome of interest. To evaluate the performance of diagnoses, one needs not only a consistent estimation of the causal effect under a specified regime of diagnoses and treatments but also reliable confidence interval, P-value and hypothesis testing of the causal effect. In this article, we identify causal effects under various regimes of diagnoses and treatments by the point effects of diagnoses and treatments and thus are able to estimate and test these causal effects by estimating and testing point effects in the familiar framework of single-point causal inference. Specifically, using data from a Swedish prognosis study of stomach cancer, we estimate and test the causal effects on cancer survival under various regimes of diagnosing and treating hospitals including the optimal regime. We also estimate and test the modification of the causal effect by age. With its simple setting, one can readily extend the example to a large variety of settings in the area of cancer diagnosis: different personal characteristics such as family history, different diagnosing procedures such as multistage screening, and different cancer outcomes such as cancer progression.

A cancer diagnosis is part of a complex stochastic process, which involves patient's characteristics, diagnosing methods, an initial assessment of cancer progression, treatments and a certain outcome of interest. To evaluate the performance of diagnoses, one needs not only a consistent estimation of the causal effect under a specified regime of diagnoses and treatments but also reliable confidence interval, P-value and hypothesis testing of the causal effect. In this article, we identify causal effects under various regimes of diagnoses and treatments by the point effects of diagnoses and treatments and thus are able to estimate and test these causal effects by estimating and testing point effects in the familiar framework of single-point causal inference. Specifically, using data from a Swedish prognosis study of stomach cancer, we estimate and test the causal effects on cancer survival under various regimes of diagnosing and treating hospitals including the optimal regime. We also estimate and test the modification of the causal effect by age. With its simple setting, one can readily extend the example to a large variety of settings in the area of cancer diagnosis: different personal characteristics such as family history, different diagnosing procedures such as multistage screening, and different cancer outcomes such as cancer progression.

Background: The poor survival of patients with gastroesophageal cancers may improve if additional esophageal precursor lesions to Barrett's esophagus and squamous dysplasia are identified. We estimated the risk for gastroesophageal cancers among patients with various histopathological abnormalities in the esophagus, including Barrett's esophagus, subdivided by histopathological types. Methods: Histopathology data from esophageal biopsies obtained 1979-2014 were linked with several national population-based registers in Sweden. Patients were followed from 2 years after the first biopsy date until cancer, death, emigration, esophagectomy/gastrectomy or end of follow-up, 31st of December 2016, whichever came first. We estimated standardized incidence ratios (SIRs) as measures of relative risk with the Swedish general population as reference. Results: In total 367 esophageal adenocarcinoma (EAC) cases were ascertained during 831,394 person-years of follow-up. The incidence rate (IR) for EAC was 0.1 per 1000 person-years for normal morphology, 0.2-0.5 for inflammatory changes, and 0.8-2.9 for metaplasia. The IR was 1.0 per 1000 person-years (95% confidence interval 0.7-1.3) among patients with non-dysplastic intestinal metaplasia, 0.9 (0.8-1.1) in non-dysplastic gastric/glandular metaplasia and 2.9 (2.0-4.2) among columnar metaplasia patients with low-grade dysplasia. The SIRs were 11.7 (95% confidence interval 8.6-15.5), 12.0 (10.0-14.2) and 30.2 (20.5-42.8), respectively. The SIRs for gastric cardia adenocarcinoma (GCA) were moderately elevated. Conclusions: For the first time, we demonstrate that patients with esophageal inflammatory and other metaplastic abnormalities than Barrett's esophagus have an increased risk of EAC and GCA compared to the general population. Moreover, patients with different histopathologic subtypes of Barrett's esophagus have a comparable risk for EAC., Funding agency:Karolinska Institutet MD/PhD programme

Although there is a clear relationship between family history (FH) and the risk of gastric cancer (GC), quantification is still needed in relation to different histological types and anatomical sites, and in strata of covariates. The objective was to analyze the risk of GC according to first-degree FH in a uniquely large epidemiological consortium of GC. This investigation includes 5946 cases and 12,776 controls from 17 studies of the Stomach Cancer Pooling (StoP) Project consortium. Summary odds ratios (OR) and the corresponding 95% confidence intervals (CIs) were calculated by pooling study-specific ORs using fixed-effect model meta-analysis techniques. Stratified analyses were carried out by sex, age, tumor location and histological type, smoking habit, socioeconomic status, alcohol intake and fruit consumption. The pooled OR for GC was 1.84 (95% CI: 1.64-2.04; I2 = 6.1%, P heterogeneity = 0.383) in subjects with vs. those without first-degree relatives with GC. No significant differences were observed among subgroups of sex, age, geographic area or study period. Associations tended to be stronger for non-cardia (OR = 1.82; 95% CI: 1.59-2.05 for subjects with FH) than for cardia GC (OR = 1.38; 95% CI: 0.98-1.77), and for the intestinal (OR = 1.92; 95% CI: 1.62-2.23) than for the diffuse histotype (OR = 1.62; 95% CI: 1.28-1.96). This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype. Considering these findings, accounting for the presence of FH to carry out correct prevention and diagnosis measures is of the utmost importance.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS metaanalysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Previous Mendelian randomization (MR) studies on 25-hydroxyvitamin D (25(OH)D) and cancer have typically adopted a handful of variants and found no relationship between 25(OH)D and cancer; however, issues of horizontal pleiotropy cannot be reliably addressed. Using a larger set of variants associated with 25(OH)D (74 SNPs, up from 6 previously), we perform a unified MR analysis to re-evaluate the relationship between 25(OH)D and ten cancers. Our findings are broadly consistent with previous MR studies indicating no relationship, apart from ovarian cancers (OR 0.89; 95% C.I: 0.82 to 0.96 per 1 SD change in 25(OH)D concentration) and basal cell carcinoma (OR 1.16; 95% C.I.: 1.04 to 1.28). However, after adjustment for pigmentation related variables in a multivariable MR framework, the BCC findings were attenuated. Here we report that lower 25(OH)D is unlikely to be a causal risk factor for most cancers, with our study providing more precise confidence intervals than previously possible.

Previous work has shown that both long and short sleep duration is associated with increased mortality, with lowest risk around 7 hr. This has had widespread impact on views on the optimal sleep duration. However, age, being employed/retired, and blue-/white-collar status, may influence the time available for sleep and thus, confound the association. We investigated the role of these factors on the association between sleep duration and mortality. We used employed and retired participants (N = 25,430) from the Swedish National March Cohort and Cox proportional hazards regression to model the shape of the association. We found a significant U-shaped association in a multivariable model with a hazard ratio (HR) of 1.24 (95% confidence interval [CI] 1.10, 1.39) for <5-hr sleep duration, and a HR of 1.30 (95% CI 1.12, 1.51) for >= 9-hr sleep duration, with the lowest HR for 7 hr, but with a span of low HRs from 5 to 8 hr. Unadjusted values showed a pronounced U-shape. Adjusting for age accounted for most of the attenuation in the multivariable model. Stratification into five age groups showed a significant U-shape only in those aged >60.3 years at baseline. The shape of the association did not differ between blue-/white-collar workers, nor between employed and retired groups. We conclude that the U-shaped association between sleep duration and mortality is present only in older individuals.

Although there is a clear relationship between family history (FH) and the risk of gastric cancer (GC), quantification is still needed in relation to different histological types and anatomical sites, and in strata of covariates. The objective was to analyze the risk of GC according to first-degree FH in a uniquely large epidemiological consortium of GC. This investigation includes 5946 cases and 12,776 controls from 17 studies of the Stomach Cancer Pooling (StoP) Project consortium. Summary odds ratios (OR) and the corresponding 95% confidence intervals (CIs) were calculated by pooling study-specific ORs using fixed-effect model meta-analysis techniques. Stratified analyses were carried out by sex, age, tumor location and histological type, smoking habit, socioeconomic status, alcohol intake and fruit consumption. The pooled OR for GC was 1.84 (95% CI: 1.64-2.04; I2 = 6.1%, P heterogeneity = 0.383) in subjects with vs. those without first-degree relatives with GC. No significant differences were observed among subgroups of sex, age, geographic area or study period. Associations tended to be stronger for non-cardia (OR = 1.82; 95% CI: 1.59-2.05 for subjects with FH) than for cardia GC (OR = 1.38; 95% CI: 0.98-1.77), and for the intestinal (OR = 1.92; 95% CI: 1.62-2.23) than for the diffuse histotype (OR = 1.62; 95% CI: 1.28-1.96). This analysis confirms the effect of FH on the risk of GC, reporting an approximately doubled risk, and provides further quantification of the risk of GC according to the subsite and histotype. Considering these findings, accounting for the presence of FH to carry out correct prevention and diagnosis measures is of the utmost importance.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Study objectives: The relationship between insomnia and suicide risk is not completely understood. We aimed to investigate the influence of insomnia on suicide risk, taking both sleep duration and depression into consideration. Methods: The present study is based on a Swedish prospective cohort study of 38,786 participants with a mean follow-up time of 19.2 years. Cox proportional hazards models with attained age as time-scale were used to estimate hazard ratios (HRs) of death by suicide with 95% confidence intervals (CI) for participants categorized by frequency of insomnia symptoms. Causal mediation analysis was performed to assess to what extent the relationship between insomnia and suicide risk is mediated by depression. Results: Insomnia was only associated with suicide risk among short sleepers, whereas no significant association was observed among those who slept 7 h/night or more. The total effect of insomnia in the context of short sleep on suicide risk, expressed on the HR scale, was 2.85 (95% CI 1.42-5.74). The direct effect was 2.25 (95% CI 1.12-4.54) and the indirect effect, mediated by depression, was 1.27 (95% CI 1.05-1.53). Of the total effect, 32% was mediated by depression. The association between insomnia and suicide risk became more pronounced with decreasing depressive symptoms (p value for trend <0.05). Conclusions: Insomnia in the context of short sleep increases suicide risk, both directly and indirectly by affecting the risk of depression. Abnormalities of sleep duration and insomnia symptoms should be evaluated when assessing suicide risk.

Objective: Previous studies investigating the association between nightmares and suicide have yielded different results. We aimed to investigate whether nightmares, directly or indirectly, influence the incidence of suicide. Methods: We used a prospective cohort study, based on 40,902 participants with a mean follow-up duration of 19.0 years. Cox proportional hazards models with attained age as time-scale were fitted to estimate hazard ratios (HR) of suicide with 95% confidence intervals (CI) as a function of the presence or absence of depression and nightmares. Mediation analysis was used to asses to what extent the relationship between nightmares and the incidence rate of suicide could be mediated by depression. Results: No association was observed between nightmares and the incidence of suicide among participants without depression. Compared with non-depressed participants without nightmares, the incidence of suicide among participants with a diagnosis of depression was similar among those with and without nightmares (HR 12.3, 95% CI 5.55-27.2 versus HR 13.2, 95% CI 7.25-24.1). The mediation analysis revealed no significant effects of nightmares on suicide incidence. However, the incidence of depression during follow-up was higher among those who suffered from nightmares than among those who did not (p < 0.001). Conclusions: Our findings indicate that nightmares have no influence on the incidence rate of suicide, but may reflect pre-existing depression. This is supported by a recent discovery of a strong genetic correlation of nightmares with depressive disorders, with no evidence that nightmares would predispose to psychiatric illness or psychological problems. Interventions targeting both depression and nightmares, when these conditions co-occur, may provide additional therapeutic benefit.

Objective Several, but not all studies, have shown a dose-dependent inverse association with alcohol consumption and rheumatoid arthritis (RA), whereas smoking is an established risk factor for RA. We aimed to study the association between alcohol consumption and RA incidence and investigate a potential interaction between alcohol and smoking habits, regarding RA incidence. Methods We used a prospective cohort study, based on 41 068 participants with detailed assessment of alcohol intake, smoking and potential confounders at baseline in 1997. We ascertained a total of 577 incident cases of RA during a mean of 17.7 years of follow-up through linkage to nationwide and essentially complete databases. Multivariate Cox proportional hazards models were used to estimate HR with 95% CI. Interaction on the additive scale between alcohol and smoking was estimated by calculating the attributable proportion due to interaction (AP). Results Overall, alcohol consumption was associated with a 30% reduced incidence of RA (HR 0.69, 95% CI 0.55 to 0.86) with a dose-response relationship (p value for trend <0.001) which remained significant after stratification by age and smoking habits. The positive association between smoking and RA incidence was reduced with increasing alcohol consumption (p value for trend <0.001). A synergistic effect was observed between alcohol and smoking (AP 0.40, 95% CI 0.15 to 0.64), indicating that 40% of the cases among the double exposed are due to the interaction per se. Conclusions Our findings suggest an inverse association between alcohol consumption and RA incidence, and a synergistic effect between alcohol and smoking.

Motivation Full length, high resolution 16s rRNA marker gene sequencing has been challenging historically. Short amplicons provide high accuracy reads with widely available equipment, at the cost of taxonomic resolution. One recent proposal has been to reconstruct multiple amplicons along the full-length marker gene, however no barcode-free computationally tractable approach for this is available. To address this gap, we present Sidle (SMURF Implementation Done to acceLerate Efficiency), an implementation of the Short MUltiple Reads Framework algorithm with a novel tree building approach to reconstruct rRNA genes from individually amplified regions. Results Using simulated and real data, we compared Sidle to two other approaches of leveraging multiple gene region data. We found that Sidle had the least bias in non-phylogenetic alpha diversity, feature-based measures of beta diversity, and the reconstruction of individual clades. With a curated database, Sidle also provided the most precise species-level resolution. Availability and Implementation Sidle is available under a BSD 3 license from https://github.com/jwdebelius/q2-sidle

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Genome-wide association studies (GWAS) of esophageal adenocarcinoma (EAC) and its precursor, Barrett's esophagus (BE), have uncovered significant genetic components of risk, but most heritability remains unexplained. Targeted assessment of genetic variation in biologically relevant pathways using novel analytical approaches may identify missed susceptibility signals. Central obesity, a key BE/EAC risk factor, is linked to systemic inflammation, altered hormonal signaling and insulin-like growth factor (IGF) axis dysfunction. Here, we assessed IGF-related genetic variation and risk of BE and EAC. Principal component analysis was employed to evaluate pathway-level and gene-level associations with BE/EAC, using genotypes for 270 single-nucleotide polymorphisms (SNPs) in or near 12 IGF-related genes, ascertained from 3295 BE cases, 2515 EAC cases and 3207 controls in the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) GWAS. Gene-level signals were assessed using Multi-marker Analysis of GenoMic Annotation (MAGMA) and SNP summary statistics from BEACON and an expanded GWAS meta-analysis (6167 BE cases, 4112 EAC cases, 17 159 controls). Global variation in the IGF pathway was associated with risk of BE (P = 0.0015). Gene-level associations with BE were observed for GHR (growth hormone receptor; P = 0.00046, false discovery rate q = 0.0056) and IGF1R (IGF1 receptor; P = 0.0090, q = 0.0542). These gene-level signals remained significant at q < 0.1 when assessed using data from the largest available BE/EAC GWAS metaanalysis. No significant associations were observed for EAC. This study represents the most comprehensive evaluation to date of inherited genetic variation in the IGF pathway and BE/EAC risk, providing novel evidence that variation in two genes encoding cell-surface receptors, GHR and IGF1R, may influence risk of BE.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance. Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants. Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E−06 in 1D approach and a Local Moran’s Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8—a lncRNA associated with pancreatic carcinogenesis—with a lowest p value = 6.91E−05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1—a major regulator of the ER stress and unfolded protein responses in acinar cells—identified by 3D; all of them with a strong in silico functional support. Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

The aim of this study was to explore the male predominance in esophageal and gastric adenocarcinoma by evaluating the preventive potential of androgen deprivation therapy (ADT). This matched cohort study was based on a national Swedish database of prostate cancer patients in 2006-2013. Prostate cancer patients receiving ADT were the exposed group. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed control group. The participants were followed until a diagnosis of esophageal or gastric cancer, death, emigration, or end of the study period. The risk of esophageal adenocarcinoma, cardia gastric adenocarcinoma, non-cardia gastric adenocarcinoma, and esophageal squamous-cell carcinoma among ADT-exposed compared to unexposed was calculated by multivariable Cox proportional hazard regression. The hazard ratios (HRs) and 95% confidence intervals (CIs) were adjusted for confounders. There was a risk reduction of non-cardia gastric adenocarcinoma among ADT-users compared to non-users (HR 0.49 [95% CI 0.24-0.98]). No such decreased risk was found for esophageal adenocarcinoma (HR 1.17 [95% CI 0.60-2.32]), cardia gastric adenocarcinoma (HR 0.99 [95% CI 0.40-2.46]), or esophageal squamous cell carcinoma (HR 0.99 [95% CI 0.31-3.13]). This study indicates that androgen deprivation therapy decreases the risk of non-cardia gastric adenocarcinoma, while no decreased risk was found for esophageal adenocarcinoma, cardia gastric adenocarcinoma, or esophageal squamous-cell carcinoma.

Background In recent decades, millions of refugees and migrants have fled wars and sought asylum in Europe. The aim of this study was to quantify the risk of mortality and major diseases among migrants during the 1991–2001 Balkan wars to Sweden in comparison to other European migrants to Sweden during the same period. Methods and findings We conducted a register-based cohort study of 104,770 migrants to Sweden from the former Yugoslavia during the Balkan wars and 147,430 migrants to Sweden from 24 other European countries during the same period (1991–2001). Inpatient and specialized outpatient diagnoses of cardiovascular disease (CVD), cancer, and psychiatric disorders were obtained from the Swedish National Patient Register and the Swedish Cancer Register, and mortality data from the Swedish Cause of Death Register. Adjusting for individual-level data on sociodemographic characteristics and emigration country smoking prevalence, we used Cox regressions to contrast risks of health outcomes for migrants of the Balkan wars and other European migrants. During an average of 12.26 years of follow-up, being a migrant of the Balkan wars was associated with an elevated risk of being diagnosed with CVD (HR 1.39, 95% CI 1.34–1.43, p < 0.001) and dying from CVD (HR 1.45, 95% CI 1.29–1.62, p < 0.001), as well as being diagnosed with cancer (HR 1.16, 95% CI 1.08–1.24, p < 0.001) and dying from cancer (HR 1.27, 95% CI 1.15–1.41, p < 0.001), compared to other European migrants. Being a migrant of the Balkan wars was also associated with a greater overall risk of being diagnosed with a psychiatric disorder (HR 1.19, 95% CI 1.14–1.23, p < 0.001), particularly post-traumatic stress disorder (HR 9.33, 95% CI 7.96–10.94, p < 0.001), while being associated with a reduced risk of suicide (HR 0.68, 95% CI 0.48–0.96, p = 0.030) and suicide attempt (HR 0.57, 95% CI 0.51–0.65, p < 0.001). Later time period of migration and not having any first-degree relatives in Sweden

Low socioeconomic position (SEP) is a strong risk factor for incidence and premature mortality from several cancers. Our study aimed at quantifying the association between SEP and gastric cancer (GC) risk through an individual participant data meta-analysis within the "Stomach cancer Pooling (StoP) Project". Educational level and household income were used as proxies for the SEP. We estimated pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) across levels of education and household income by pooling study-specific ORs through random-effects meta-analytic models. The relative index of inequality (RII) was also computed. A total of 9,773 GC cases and 24,373 controls from 25 studies from Europe, Asia and America were included. The pooled OR for the highest compared to the lowest level of education was 0.60 (95% CI, 0.44-0.84), while the pooled RII was 0.45 (95% CI, 0.29-0.69). A strong inverse association was observed both for noncardia (OR 0.39, 95% CI, 0.22-0.70) and cardia GC (OR 0.47, 95% CI, 0.22-0.99). The relation was stronger among H. pylori negative subjects (RII 0.14, 95% CI, 0.04-0.48) as compared to H. pylori positive ones (RII 0.29, 95% CI, 0.10-0.84), in the absence of a significant interaction (p = 0.28). The highest household income category showed a pooled OR of 0.65 (95% CI, 0.48-0.89), while the corresponding RII was 0.40 (95% CI, 0.22-0.72). Our collaborative pooled-analysis showed a strong inverse relationship between SEP indicators and GC risk. Our data call for public health interventions to reduce GC risk among the more vulnerable groups of the population. What's new? Gastric cancer is associated with low socioeconomic position but the precise impact of education on gastric cancer risk needs to be quantified. Here the authors provide an updated quantification through the analysis of the Stomach cancer Pooling (StoP) Project, a large international consortium of case-control studies. They observe a similar to 40% decrea

Background In recent decades, millions of refugees and migrants have fled wars and sought asylum in Europe. The aim of this study was to quantify the risk of mortality and major diseases among migrants during the 1991–2001 Balkan wars to Sweden in comparison to other European migrants to Sweden during the same period. Methods and findings We conducted a register-based cohort study of 104,770 migrants to Sweden from the former Yugoslavia during the Balkan wars and 147,430 migrants to Sweden from 24 other European countries during the same period (1991–2001). Inpatient and specialized outpatient diagnoses of cardiovascular disease (CVD), cancer, and psychiatric disorders were obtained from the Swedish National Patient Register and the Swedish Cancer Register, and mortality data from the Swedish Cause of Death Register. Adjusting for individual-level data on sociodemographic characteristics and emigration country smoking prevalence, we used Cox regressions to contrast risks of health outcomes for migrants of the Balkan wars and other European migrants. During an average of 12.26 years of follow-up, being a migrant of the Balkan wars was associated with an elevated risk of being diagnosed with CVD (HR 1.39, 95% CI 1.34–1.43, p < 0.001) and dying from CVD (HR 1.45, 95% CI 1.29–1.62, p < 0.001), as well as being diagnosed with cancer (HR 1.16, 95% CI 1.08–1.24, p < 0.001) and dying from cancer (HR 1.27, 95% CI 1.15–1.41, p < 0.001), compared to other European migrants. Being a migrant of the Balkan wars was also associated with a greater overall risk of being diagnosed with a psychiatric disorder (HR 1.19, 95% CI 1.14–1.23, p < 0.001), particularly post-traumatic stress disorder (HR 9.33, 95% CI 7.96–10.94, p < 0.001), while being associated with a reduced risk of suicide (HR 0.68, 95% CI 0.48–0.96, p = 0.030) and suicide attempt (HR 0.57, 95% CI 0.51–0.65, p < 0.001). Later time period of migration and not having any first-degree relatives in Sweden