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Symptoms in the urogenital organs are common in multiple system atrophy (MSA), also in the years preceding the MSA diagnosis. It is unknown how MSA is triggered and these observations in prodromal MSA led us to hypothesize that synucleinopathy could be triggered by infection of the genitourinary tract causing ɑ-synuclein (ɑSyn) to aggregate in peripheral nerves innervating these organs. As a first proof that peripheral infections could act as a trigger in MSA, this study focused on lower urinary tract infections (UTIs), given the relevance and high frequency of UTIs in prodromal MSA, although other types of infection might also be important triggers of MSA. We performed an epidemiological nested-case control study in the Danish population showing that UTIs are associated with future diagnosis of MSA several years after infection and that it impacts risk in both men and women. Bacterial infection of the urinary bladder triggers synucleinopathy in mice and we propose a novel role of ɑSyn in the innate immune system response to bacteria. Urinary tract infection with uropathogenic E. coli results in the de novo aggregation of ɑSyn during neutrophil infiltration. During the infection, ɑSyn is released extracellularly from neutrophils as part of their extracellular traps. Injection of MSA aggregates into the urinary bladder leads to motor deficits and propagation of ɑSyn pathology to the central nervous system in mice overexpressing oligodendroglial ɑSyn. Repeated UTIs lead to progressive development of synucleinopathy with oligodendroglial involvement in vivo. Our results link bacterial infections with synucleinopathy and show that a host response to environmental triggers can result in ɑSyn pathology that bears semblance to MSA. ispartof: ACTA NEUROPATHOLOGICA vol:145 issue:5 pages:541-559 ispartof: location:Germany status: published

Background: The underlying disease mechanisms of Parkinson’s disease (PD) are still unknown and knowledge about risk and prognostic factors is sparse. Objective: To examine the association between intelligence, education, body height, and body mass index (BMI) in young adulthood and risk of PD and subsequent survival. Methods: In total, 656,751 men born 1939–1959 with information from conscription examinations around age 19 years were followed for PD and mortality from 1977–2018 in Danish registries. Cox proportional hazard regression was used to conduct the analyses. Results: During follow-up, 5,264 (0.8%) men were diagnosed with PD. Higher intelligence, education, and body height conferred a higher hazard of PD, independent of age at disease onset. BMI above compared to below the mean (22.8 kg/m2) was associated with slightly higher hazard of late-onset PD (>60 years). During follow-up, 2,125 (40.5%) men with PD died, corresponding to a 2.55 (95% confidence interval:2.44–2.66) times higher mortality compared to men without PD. Intelligence was inversely associated with mortality in men with and without PD. Higher education and body height were also inversely associated with mortality in men without PD, whereas the estimates were less pronounced and imprecisely estimated for men with PD. Having an obese BMI was associated with higher mortality in men with PD. Conclusion: Intelligence, education, and body height in young adulthood are positively associated with risk of PD later in life among men. BMI above the mean only confer a higher risk for late-onset PD. For men diagnosed with PD, high intelligence is the only early life indicator associated with better survival, whereas obese BMI predicts poorer survival.

BACKGROUND: Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy.METHODS: In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration.FINDINGS: Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11).INTERPRETATION: Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications.FUNDING: None.

Background and Aims The aim of this study was to examine the risk of new-onset inflammatory bowel disease [IBD] following bariatric surgery. Methods We conducted a nationwide population-based prospective cohort study of the entire Danish population 18 to 60 years of age, alive, and residing in Denmark, from 1996 to 2018. Bariatric surgery was included as a time-dependent variable, and Cox proportional hazards regression models were used to estimate hazard ratios [HRs] of IBD. We used a model adjusting for age, sex, and birth cohort and a multifactor-adjusted model additionally including educational status and number of obesity-related comorbidities. Results We followed 3 917 843 individuals of whom 15 347 had a bariatric surgery, for development of new-onset IBD. During 106 420 person-years following bariatric surgery, 100 IBD events occurred [incidence rate 0.940/1000 person-years]. During 55 553 785 person-years without bariatric surgery, 35 294 events of IBD occurred [incidence rate 0.635/1000 person-years]. This corresponded to a multifactor-adjusted hazard ratio [HR] of 1.15 (95% confidence interval[CI], 0.94–1.40) for IBD. Multifactor-adjusted HRs of Crohn’s disease [CD] and ulcerative colitis [UC] were 1.85 [95% CI, 1.40–2.44] and 0.81 [95% CI, 0.61–1.08], respectively. Among women, the multifactor-adjusted HR for CD was 2.18 [95% CI, 1.64–2.90]. When limiting the study population to individuals with a diagnosis of overweight/obesity, bariatric surgery remained associated with increased risk of CD, multifactor-adjusted HR 1.59 [95% CI, 1.18–2.13]. Conclusions This nationwide cohort study shows that bariatric surgery is associated with increased risk of development of new-onset CD, but not of UC. The underlying mechanisms remain elusive.

Artiklen sætter fokus på faglige og etiske overvejelser i forbindelse med brugen af algoritmer baseret på maskinlæring til understøttelse af de beslutninger, socialrådgivere træffer i arbejdet med børn og familiers trivsel. Artiklen tager udgangspunkt i et igangværende forskningsprojekt ’Underretninger i Fokus’. Målet med projektet er, ved hjælp af maskinlæringsmetoder, at udvikle og afprøve en beslutningsstøttemodel. Artiklen diskuterer potentialer og bekymringer ved brugen af beslutningsstøttemodellen i socialt arbejde med børn og familier.

In this article we analyse and discuss how research on inclusion and children at risk can contribute to a more varied and nuanced language on well-being of children. We investigate central concepts relating to inclusion and children at risk and their implications for the language of the professions, i.e. the way the professionals understand and work with children’s well-being. We argue that both fields can benefit from each other’s language and primary focus thus it together with children and families becomes possible to meet in joined effort towards children’s well-being in and across day-care, school and home.

ObjectiveIn Guinea-Bissau, West Africa, we observed that having a smallpox vaccination scar was associated with lower HIV-1 prevalence, more strongly for women than men. If this represents a causal effect, the female/male HIV-1 prevalence ratio would increase for birth cohorts no longer receiving smallpox vaccination due to the phase-out of this vaccine.DesignAn ecological design using HIV surveys and information about smallpox vaccination coverage.SettingUrban and rural Guinea-Bissau.ParticipantsParticipants in HIV surveys were grouped into an age group with decreasing smallpox vaccination coverage (15–34 years) and an age group with steady smallpox vaccination coverage (≥35 years).InterventionsThe exposure of interest was the phase-out of the smallpox vaccine in Guinea-Bissau.Primary and secondary outcome measuresHIV-1 prevalence.ResultsAt both sites, the female/male HIV-1 prevalence ratio increased by calendar time for the age group with decreasing smallpox vaccination coverage; the combined female/male HIV-1 prevalence ratio among people aged 15–34 years was 1.00 (95% CI 0.17 to 5.99) in 1987–1990, 1.16 (95% CI 0.69 to 1.93) in 1996–1997, 2.32 (95% CI 1.51 to 3.56) in 2006–2007 (p value for no trend=0.04). There was no increase in the female-to-male HIV-1 prevalence ratio for the age group >35 years with steady smallpox vaccination coverage; 1.93 (95% CI 0.40 to 9.25) in 1987–1990, 1.32 (95% CI 0.83 to 2.10) in 1996–1997, 0.81 (95% CI 0.56 to 1.16) in 2006–2007 (p value for no trend=0.07).ConclusionsThus, data was compatible with the deduction that the phase-out of smallpox vaccination may have increased the susceptibility to HIV-1 relatively more for women than men. Hence, phasing out smallpox vaccination may have contributed to the global increase in the female/male HIV-1 prevalence ratio among young individuals. Due to the potential fallacies of ecological studies, the results should be interpreted carefully, and this hypothesis needs further assessment. If the hypothesis is true, studies of smallpox vaccination could inform HIV-1 vaccine research.

Background & Aims The intestine regulates glucose homeostasis, but it is not clear whether chronic intestinal inflammation affects risk for type 2 diabetes. We investigated the long-term risk of type 2 diabetes in patients with inflammatory bowel diseases (IBD) in a nationwide cohort study in Denmark. Methods In a nationwide population-based cohort of 6,028,844 persons in Denmark, we compared data from individuals with a diagnosis of IBD (Crohn’s disease [CD] or ulcerative colitis UC]) with data from individuals from the general population from 1977 through 2014. Persons with type 2 diabetes were identified in the National Patient Register. Risk is presented as standardized incidence ratios (SIR) with 95% CIs. Results During 736,072 person-years of follow-up, 3436 patients with IBD developed type 2 diabetes vs 2224 expected (SIR, 1.54; 95% CI, 1.49–1.60). The risk was significantly increased in patients with UC (SIR, 1.54; 95% CI, 1.48–1.60), in patients with CD (SIR, 1.57; 95% CI, 1.47–1.67), in women (SIR, 1.51; 95% CI, 1.44–1.59), and in men (SIR, 1.57; 95% CI, 1.50–1.65). The risk was highest the first year after a diagnosis of IBD (SIR, 4.48; 95% CI, 4.16–4.83), but remained increased for 20 or more years following the diagnosis (SIR, 1.26; 95% CI, 1.16–1.38). The increased risk could not be accounted for by frequency of health care contacts or corticosteroid exposure. Patients who received a diagnosis of IBD from 2003 through 2014 (SIR, 1.79; 95% CI, 1.67–1.91) had a significantly higher risk of type 2 diabetes than patients who received a diagnosis of IBD from 1977 through 1988 (SIR, 1.47; 95% CI, 1.39–1.56) or 1989 through 2002 (SIR, 1.48; 95% CI, 1.41–1.56) (P Conclusions In a population-based cohort study, we found an increased risk of type 2 diabetes in patients with UC or CD, with highest risk estimates from 2003 through 2014, compared with earlier years. Studies are needed to determine the effects of IBD treatment on risk of type 2 diabetes.

Dr Weimers and colleagues have drawn attention1 to the possibility that our recently published observation of an association between IBD and Parkinson’s disease (PD) in a nationwide Danish cohort study2 may reflect surveillance bias. In a recently published Swedish cohort study, Dr Weimers and colleagues found that adjusting for number of healthcare visits during follow-up of patients with IBD attenuated the risk of developing PD markedly.3 They also found that the risk of future PD was …

ObjectiveIntestinal inflammation has been suggested to play a role in development of Parkinson’s disease (PD) and multiple system atrophy (MSA). To test the hypothesis that IBD is associated with risk of PD and MSA, we performed a nationwide population-based cohort study.DesignThe cohort consisted of all individuals diagnosed with IBD in Denmark during 1977–2014 (n=76 477) and non-IBD individuals from the general population, who were comparable in terms of gender, age and vital status (n=7 548 259). All cohort members were followed from IBD diagnosis/index date to occurrence of PD and MSA (according to the Danish National Patient Register).ResultsPatients with IBD had a 22% increased risk of PD as compared with non-IBD individuals (HR=1.22; 95% CI 1.09 to 1.35). The increased risk was present independently of age at IBD diagnosis, gender or length of follow-up. The overall incidence of MSA was low in our study, and the regression analysis suggested a tendency towards higher risk of developing MSA in patients with IBD as compared with non-IBD individuals (HR=1.41; 95% CI 0.82 to 2.44). Estimates were similar for women and men. The increased risk of parkinsonism was significantly higher among patients with UC (HR=1.35; 95% CI 1.20 to 1.52) and not significantly different among patients with Crohn’s disease (HR=1.12; 95% CI 0.89 to 1.40).ConclusionsThis nationwide, unselected, cohort study shows a significant association between IBD and later occurrence of PD, which is consistent with recent basic scientific findings of a potential role of GI inflammation in development of parkinsonian disorders.

Background The live smallpox and Bacillus Calmette-Guérin (BCG) vaccinations have been associated with better adult survival in both Guinea-Bissau and Denmark. In Guinea-Bissau, human immunodeficiency virus (HIV)-1 became an important cause of death after smallpox vaccination was phased out globally in 1980. We hypothesised that smallpox and BCG vaccinations were associated with a lower prevalence of HIV-1 infection, and we tested this hypothesis in both Guinea-Bissau and Denmark. Methods We conducted 2 studies: (1) a cross-sectional study of HIV infection and vaccination scars in Guinea-Bissau including 1751 individuals and (2) a case-base study with a background population of 46239 individuals in Denmark. In Guinea-Bissau, HIV-1 transmission was almost exclusively sexually transmitted. In Denmark, we excluded intravenous drug users. Data were analyzed using logistic regression. Results Bacillus Calmette-Guérin and/or smallpox vaccination compared with neither of these vaccines was associated with an adjusted odds ratio (aOR) for HIV-1 of 0.62 (95% confidence interval [CI], 0.36–1.07) in Guinea-Bissau and 0.70 (95% CI, 0.43–1.15) in Denmark. We combined the results from both settings in a meta-analysis (aOR = 0.66; 95% CI, 0.46–0.96). Data from Guinea-Bissau indicated a stronger effect of multiple smallpox vaccination scars (aOR = 0.27; 95% CI, 0.10–0.75) as follows: women, aOR = 0.18 (95% CI, 0.05–0.64); men, aOR = 0.52 (95% CI, 0.12–2.33); sex-differential effect, P = .29. Conclusions The studies from Guinea-Bissau and Denmark, 2 very different settings, both suggest that the BCG and smallpox vaccines could be associated with a decreased risk of sexually transmitted HIV-1. It might be informative to pursue this observation and explore possible protective mechanisms as part of the search for an HIV-1 vaccine.

Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries. The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines. In a background cohort (N=47,622) from the Copenhagen School Health Records Register, cases of leukaemia (N=20) and lymphoma (N=51) were identified through the Danish Cancer Registry. The vaccination status of the cases was compared with the vaccination status of a 5% random sample (N=2073) of the background cohort and analysed in a case-cohort design. BCG vaccination reduced the risk of lymphomas (HR=0.49 (95% CI: 0.26-0.93)), whereas smallpox vaccination did not (HR=1.32 (0.56-3.08)). With the small number of leukaemia cases, the analysis of leukaemia had limited power (BCG vaccination HR=0.81 (0.31-2.16); smallpox vaccination HR=1.32 (0.49-3.53)). The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas.

BACKGROUND:: Childhood immunology has been suggested to play a role in development of inflammatory bowel disease (IBD) based on the studies of childhood vaccinations, infections, and treatment with antibiotics. Bacille Calmette-Guerin (BCG) and smallpox vaccinations were gradually phased-out in Denmark for children born between 1965 and 1976, hence allowing the study of subsequent risk of Crohn's disease and ulcerative colitis in a unique prospective design. METHODS:: The Copenhagen School Health Records Register contains detailed documentation of vaccination. Among the background cohort of individuals born between 1965 and 1976 (N = 47,622), cases with Crohn's disease (n = 218) and ulcerative colitis (n = 256) were identified through linkage to the Danish National Patient Registry. The vaccination status of the cases was compared with that of a subcohort (n = 5741) of the background cohort and analyzed in a case-cohort design. RESULTS:: No difference in risk of IBD was observed between individuals vaccinated and unvaccinated with BCG (hazard ratio = 0.95; 95% confidence interval, 0.75-1.19) or smallpox vaccine (hazard ratio = 1.01; 95% confidence interval, 0.77-1.32). This was also the case for Crohn's disease and ulcerative colitis separately. However, BCG given before 4 months of age may decrease the risk of IBD (hazard ratio = 0.43; 95% confidence interval, 0.20-0.93). CONCLUSIONS:: This prospective long-term case-cohort study shows that BCG and smallpox vaccination do not cause IBD later in life. These findings are important for the etiological understanding of IBD and of clinical importance because BCG is still one of the most commonly used childhood vaccinations, smallpox vaccine has been reintroduced in the U.S. military, and both vaccines may be used as vectors in new vaccines. (Less)

BACKGROUND: There is growing evidence from observational studies and randomized trials in low-income countries that vaccinations have non-specific effects. Administration of live vaccines reduces overall child morbidity and mortality, presumably due to protection against non-targeted infections. In Denmark, the live vaccine against smallpox was phased out in the 1970s due to the eradication of smallpox. We used the phasing-out period to investigate the effect of smallpox vaccination on the risk of hospitalization for infections. METHODS: From the Copenhagen School Health Records Register, a cohort of 4048 individuals was sampled, of whom 3559 had information about receiving or not receiving smallpox vaccination. Infectious disease hospitalizations were identified in the Danish National Patient Register. RESULTS: During 87 228 person-years of follow-up, 1440 infectious disease hospitalizations occurred. Smallpox-vaccinated individuals had a reduced risk of all-cause infectious disease hospitalization compared with smallpox-unvaccinated individuals [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.72-0.98]. The reduced risk of hospitalizations was seen for most subgroups of infectious diseases. The effect may have been most pronounced after early smallpox vaccination (vaccination age