To Örebro University

There is evidence that persistent dysregulation of the immune system caused by SARS-CoV-2 infection may increase susceptibility to other infections. Here, we assessed whether it is associated with subsequent diagnoses of infectious mononucleosis due to Epstein-Barr virus (EBV-IM). Residents of Sweden aged 3-100 years without a prior diagnosis of EBV-IM were followed between January 1, 2020, and November 30, 2022, comprising a total of 9 978 860 participants. Individuals were categorized into those without a COVID-19 diagnosis, those with a positive SARS-CoV-2 polymerase chain reaction (PCR) test only - less severe exposure, and those admitted to hospital with COVID-19 - more severe exposure. Cox regression was used to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the association between the exposure, modeled as a time-varying covariate, and EBV-IM occurrence. EBV-IM rates per 100 000 person-years and 95% CIs were 4.6 (4.4-4.9) for individuals not diagnosed with COVID-19, 7.8 (6.9-8.9) for those with a positive SARS-CoV-2 test only, and 10.5 (6.2-17.6) for patients admitted to hospital with COVID-19. HR and 95% CI were 1.61 (1.39-1.88) for people with a positive PCR test only and 5.71 (3.33-9.79) for those admitted to hospital with COVID-19 compared with people without a COVID-19 diagnosis, after adjustment for birth year, sex, Swedish healthcare region, region of birth, and Charlson comorbidity index. SARS-CoV-2 infection was associated with a subsequent raised risk of EBV-IM, including among those with less severe acute infection, signaling immune perturbation and the possibility of further delayed sequelae linked with EBV-IM.

As disease risk for many conditions can start earlier in life, an essential aspect of these studies was to take a life-course approach using Swedish national register data to identify whether infectious or other inflammatory exposures are associated with a raised risk of subsequently diagnosed neurological diseases, and infectious mononucleosis whichis a risk factor for subsequent neurological sequelae.

Study I investigated the risk of dementia at older ages associated with an atopic dermatitis diagnosis at around 18 years of age or at any point in life, using data from national Swedish registers. No association was found between atopic dermatitis and the risk of dementia among men or women.

Study II examined a potentially causal association between hospital-treated infections and the subsequent risk of Parkinson’s disease (PD). Hospital-treated gastrointestinal and respiratory infections at ages 21-30, but not at ages 31-40 years, were associated withan elevated risk of PD.

Study III examined whether a positive SARS-CoV-2 test only (less severe exposure) or hospital admission with COVID-19 (more severe exposure) could be a risk factor for demyelinating diseases of the central nervous system. Only the more severe exposure was associated with a raised risk of both multiple sclerosis (MS) and non-MS demyelinating diseases.

Study IV explored whether SARS-CoV-2 infection is associated with a heightened risk of subsequent infectious mononucleosis due to Epstein-Barr virus (EBV-IM). National registers in Sweden were used for this research, covering the entire population betweenthe ages of 3 and 100. Both a positive SARS-CoV-2 test only and hospital admission with COVID-19 were associated with a raised risk of subsequent EBV-IM. This suggests that the immune perturbation caused by COVID-19 increases the risk of a more substantial immune response against EBV, resulting in IM.

These studies indicate that infections occurring many years earlier in life may be aetiologically important in Parkinson’s disease and that the SARS-CoV-2 pandemic may be associated with conditions such as demyelinating diseases of the central nervous system and an increased risk of EBV-IM. Atopic dermatitis does not appear to be a risk factor for dementia.

A previous study indicated that atopic dermatitis (AD) was associated with better cognitive function in males during late adolescence. This association was examined among 2 021 369 males who had a medical examination and cognitive function testing during a military conscription assessment in late adolescence in Sweden. Sibling-comparison analysis to tackle confounding indicated that AD is associated with poorer cognitive function, suggesting AD in childhood is detrimental for the development of cognitive function.

Serious infections may result in greater risk of Parkinson's disease. However, high-quality cohort studies focusing on a potential causal role of different types and sites of infection are lacking. Gastrointestinal infections are of a particular interest due to growing evidence implicating gut dysbiosis in Parkinson's disease aetiology. This population-based cohort study used the Swedish Total Population Register to identify individuals born during 1944-77 and resident in Sweden between 1990 and 2018 (N = 3 698 319). Hospital-treated infections at ages 21-30 and 31-40 years were identified from the National Patient Register. Participants were followed to identify Parkinson's disease diagnoses from age 41 years up to December 31, 2018, when the oldest individual reached 75 years. Cox regression with a sibling comparison design to tackle familial genetic and environmental confounding was used to derive hazard ratios and 95% confidence intervals for each infection site, type, or any infections at ages 21-30 and 31-40 years. During a median follow-up of 15.4 years, 8815 unique Parkinson's disease diagnoses were accrued, with a crude rate of 17.3 (95% confidence interval 17.0, 17.7) per 100 000 person-years. After controlling for shared familial factors, hospital-treated gastrointestinal and respiratory infections between 21 and 30 years of age were associated with a greater risk of Parkinson's disease [hazard ratios 1.35 (95% confidence interval: 1.05, 1.75) and 1.45 (95% confidence interval: 1.08, 1.95), respectively]; no association was found for any infections at age 31-40 [hazard ratio 1.05 (95% confidence interval: 0.93, 1.19)]. After adjustment, no statistically significant associations were observed for other sites including genitourinary and skin. These findings suggest that hospital-treated infections of the gastrointestinal tract and lungs, both of which may have an influence on the gut microbiome, by age 30 years may be risk factors for Parkinson's disease.

Background: Viral infections, particularly Epstein-Barr virus (EBV), have been linked with risk of multiple sclerosis (MS). Given the evidence that SARS- CoV-2 infection can have consequences for the central nervous system (CNS) and autoimmune disorders, it might increase risk of MS and other demyelinating diseases of the CNS.

Objectives: We aimed to assess whether SARS- CoV-2 infection is associated with subsequent diagnoses of non-MS demyelinating CNS diseases, MS, and infectious mononucleosis (IM) due to EBV—an important MS risk factor.

Methods: All residents of Sweden aged 3–100 years were followed between 1st January 2020 and 30th November 2022, excluding those with demyelinating disease prior to 2020, resulting in 9,981,915 individuals. Exposure was classified as SARS- Cov-2 uninfected or infected, the latter divided by severity, and mod-elled as a time-varying covariate (uninfected, infection without hospital admission and infected with hospital admission). Cox regression assessed the risk of three separate outcomes: hospital-diagnosed non-MS demyelinating diseases; MS; and IM due t oEBV, adjusting for sex, year of birth (age), Charlson comorbidity index, healthcare region and country of birth.

Results: Hospital admission for COVID-19 was associated with raised risk of subsequent non-MS demyelinating disease. Rates per 100 000 person years (and 95% confidence intervals [CI]) were 3.8 (3.6– 4.1) among those without a COVID-19 diagnosis and 9.0 (5.1–15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio (aHR) and 95% CI of 2.31 (1.30– 4.10). Equivalent associations with MS were rates of 9.5 (9.1–9.9) and 21.0 (14.5–30.5) per 100,000, and an aHR of 2.48 (1.70–3.61). For subsequent IM due to EBV, hospital admission for COVID-19 was associated with a rate of 10.5 (6.2–17.8) per 100,000 compared with 4.7 (4.4–5.0) for those without COVID-19, and an aHR of 5.63 (3.29–9.66).

Conclusions: There was increased risk of CNS demyelinating diseases among people admitted to hospital for COVID-19. COVID-19 was also associated with a raised risk of IM due to EBV, an established risk factor for MS. It is possible that at least a proportion of these associations is due to surveillance or referral bias (due to a previous hospital admission for infection), so future research should continue to follow the population that had COVID-19 for development of MS and other demyelinating diseases, which can have long asymptomatic and prodromal phases.

Demyelinating diseases including multiple sclerosis are associated with prior infectious exposures, so we assessed whether SARS-CoV-2 infection is associated with subsequent diagnoses of non-multiple sclerosis demyelinating diseases and multiple sclerosis. All residents of Sweden aged 3-100 years were followed between 1 January 2020 and 30 November 2022, excluding those with demyelinating disease prior to 2020, comprising 9 959 818 individuals divided into uninfected and those who were infected were categorized into those with and without hospital admission for the infection as a marker of infection severity. Cox regression assessed the risk of two separate outcomes: hospital diagnosed non-multiple sclerosis demyelinating diseases of the CNS and multiple sclerosis. The exposures were modelled as time-varying covariates (uninfected, infection without hospital admission and infected with hospital admission). Hospital admission for COVID-19 was associated with raised risk of subsequent non-multiple sclerosis demyelinating disease, but only 12 individuals had this outcome among the exposed, and of those, 7 has an unspecified demyelinating disease diagnosis. Rates per 100 000 person-years (and 95% confidence intervals) were 3.8 (3.6-4.1) among those without a COVID-19 diagnosis and 9.0 (5.1-15.9) among those admitted to hospital for COVID-19, with an adjusted hazard ratio and (and 95% confidence interval) of 2.35 (1.32-4.18, P = 0.004). Equivalent associations with multiple sclerosis (28 individuals had this outcome among the exposed) were rates of 9.5 (9.1-9.9) and 21.0 (14.5-30.5) and an adjusted hazard ratio of 2.48 (1.70-3.61, P < 0.001). Only a small number of non-multiple sclerosis demyelinating disease diagnoses were associated with hospital admission for COVID-19, and while the number with multiple sclerosis was somewhat higher, longer duration of follow-up will assist in identifying whether the associations are causal or due to shared susceptibility or surveillance bias, as these diseases can have long asymptomatic and prodromal phases.

BACKGROUND: Loneliness at older ages has been associated with higher morbidity and mortality. One of the risk factors for loneliness may be age-related decline in skeletal muscle strength, which may limit the possibilities for engagement in usual social activities and maintaining relationships. We aimed to identify if decrease in grip strength is an independent determinant of subsequent change in loneliness.

METHODS: Prospective cohort study of participants aged 50 years or older living in private households and provided data in the English Longitudinal Study of Ageing waves 2 (2004/2005), 4 (2008/2009) and 6 (2012/2013) (n=6118). We used fixed effects linear models to estimate β coefficients and 95% confidence intervals.

RESULTS: The adjusted estimates for a 5-kilogramme decrease in grip strength and loneliness score (ranging from 3 to 9) are β 0.04 and 95% CI -0.003 to 0.08 among men and β 0.03 and 95% CI -0.02 to 0.09 among women. In age-stratified analysis, a statistically significant association was observed among men below the age of 80 years (0.04, 0.0001 to 0.08) but not among older men (0.04, -0.28 to 0.35), and among women below the age of 80 years (0.03, -0.002 to 0.09) or above (-0.02, -0.32 to 0.28).

CONCLUSION: Muscle strength declines with age and may help explain the greater social isolation that occurs at older ages. Decline in strength was only independently associated with modestly increased loneliness among men younger than 80 years of age, indicating its limitation as a potential marker of loneliness risk.

Background: Atopic dermatitis is a chronic inflammatory skin disease and inflammation has been implicated in development of other chronic diseases, but few studies have examined the relationship with dementia.

Objectives: This study examines associations of atopic dermatitis (AD) and systemic inflammation in adolescence measured using erythrocyte sedimenta-tion rate (ESR), as well as AD diagnosed in adulthood, with dementia risk.

Methods: We used three Swedish register‐based cohorts. Cohort I (N= 795,680) comprised men, born in 1951–1968, who participated in themilitary conscription examinations with physician‐assessed AD and ESR; Cohort II (N= 1,757,600) included men and women, born in 1951–1968; and Cohort III (N= 3,988,783) included all individuals in Sweden, born in 1930–1968. We used Cox regression, estimating hazard ratios (HR), with thefollow‐up from 50 years of age to dementia diagnosis, date of emigration, death, or 31 December 2018, which ever occurred first. Further, we used asibling comparison design to adjust for unmeasured confounders shared among siblings.

Results: Cohort I: 1466 dementia events were accrued during follow‐up of 7.8 years, with a crude rate of 21.6 [95% confidence interval (CI): 20.6, 22.8] per 100,000 person‐years. Cohort II: 3549 dementia events were accrued duringfollow‐up of 7.4 years, with a crude rate of 23.7 (95% CI: 22.9, 24.5) per 100,000 person‐years. Cohort III: 120,303 dementia events were accrued during follow‐up of 23.7 years, with a crude rate of 180.3 (95% CI: 179.3, 181.3) per 100,000 person‐years. In multivariable analysis using Cohort I, there was no association between AD and dementia [HR 0.68 (95% CI 0.32, 1.43)], norwith moderate [HR 0.71 (95% CI: 0.46, 1.10)] or high [HR 1.23 (95% CI: 0.87, 1.75)] ESR. AD was not associated with dementia risk in Cohort II [HR 1.28(0.97, 1.71)] or Cohort III [HR 1.01 (0.92, 1.11)].

Conclusions: AD was not associated with dementia risk, neither was systemic inflammation measured by ESR in adolescence.

Chrono-nutrition is an emerging research field in nutritional epidemiology that encompasses 3 dimensions of eating behavior: timing, frequency, and regularity. To date, few studies have investigated how an individual's circadian typology, i.e., one's chronotype, affects the association between chrono-nutrition and cardiometabolic health. This review sets the directions for future research by providing a narrative overview of recent epidemiologic research on chronotype, its determinants, and its association with dietary intake and cardiometabolic health. Limited research was found on the association between chronotype and dietary intake in infants, children, and older adults. Moreover, most of the evidence in adolescents and adults was restricted to cross-sectional surveys with few longitudinal cohorts simultaneously collecting data on chronotype and dietary intake. There was a gap in the research concerning the association between chronotype and the 3 dimensions of chrono-nutrition. Whether chronotype modifies the association between diet and cardiometabolic health outcomes remains to be elucidated. In conclusion, further research is required to understand the interplay between chronotype, chrono-nutrition, and cardiometabolic health outcomes.

Loneliness has been associated with adverse health outcomes, including age-related diseases with an inflammatory etiology such as cardiovascular disease. We aimed to identify potential biological pathways linking loneliness with morbidity and mortality by examining associations of loneliness with biomarkers. Participants in the English Longitudinal Study of Ageing (n = 3239) aged 50 years or older with an average age of 64 years, provided data in waves 4 (2008/2009) and 6 (2012/2013). Linear regression conditional change models had three outcomes: C reactive protein (CRP) measured in mg/L (log transformed), fibrinogen in g/L and ferritin in g/dL. In men, the onset of loneliness indicated by answering 'no' at wave 4 and 'yes' at wave 6 to question "Much of the time during the past week, you felt lonely?" was associated with a statistically significant increase in levels of CRP (β = 0.36, 95% confidence interval (0.09 to 0.62)), plasma fibrinogen (0.18 (0.04 to 0.31)) and ferritin (41.04 (6.58 to 75.50)), after full adjustment. A statistically significant increase in CRP in men was also observed for onset of loneliness assessed with the question "How often do you feel lonely?" (0.20 (0.03 to 0.38)). These associations were not mediated by depressive symptoms. Persistent loneliness (loneliness experienced at both baseline and follow-up) assessed using the University of California Los Angeles (UCLA) loneliness scale was associated with an increase in CRP (0.11 (0.004 to 0.22)) among men. Associations of the two latter loneliness measures with fibrinogen and ferritin were mainly null. Among women, the only statistically significant association was for persistent loneliness (loneliness at both waves) identified by question "Much of the time during the past week, you felt lonely?" with a reduction in levels of ferritin (-20.62 (-39.78 to -1.46)). Men may be more susceptible to loneliness-associated disease risks signaled by biological changes, including systemic inflammation. Combined social and targeted medical interventions may help to reduce health risks associated with loneliness.