Systemic inflammation, lifestyle behaviours and dementia: A 10-year follow-up investigation.

Objectives: Lifestyle behaviours have been linked to dementia incidence, but their cumulative impact on dementia and the underlying mechanisms remain poorly understood. This study investigated the association of co-occurring lifestyle behaviours with dementia incidence and the mediating role of systemic inflammation in this association. Methods: The sample comprised 3131 participants (55.2% female) from the English Longitudinal Study of Ageing aged 52-92 years at baseline (2008/09). Self-reported baseline lifestyle behaviours (alcohol intake, fruit and vegetable consumption, smoking, physical activity, sleep duration, social engagement, and cognitive activity) were summed to derive an index of lifestyle behaviours, ranging from 0 to 7, with higher scores denoting a higher number of health-risk behaviours. Incident dementia cases (n = 130, 4.2%) were identified through doctor-diagnosed dementia, informant interviews, and health records between 2014/15 and 2018/19. Systemic inflammation was measured through fasting plasma concentrations of C-reactive protein in 2012/13. Results: Binary logistic regression models indicated that the odds of subsequent dementia increased by 1.19 for each additional health-risk behaviour (95% confidence intervals: 1.04, 1.37, p = 0.014) after adjusting for age, sex, ethnicity, wealth, education, marital status, body mass index, coronary heart disease, hypertension, stroke, and depression. However, this association was not mediated by C-reactive protein. Conclusions: Co-occurring health-risk behaviours were associated with higher dementia incidence up to 10 years later, underscoring the importance of modifying health-risk behaviours for the prevention of dementia. Systemic inflammation did not explain the association between behaviours and dementia.

Doctor's Orders-Why Radiologists Should Consider Adjusting Commercial Machine Learning Applications in Chest Radiography to Fit Their Specific Needs.

This retrospective study evaluated a commercial deep learning (DL) software for chest radiographs and explored its performance in different scenarios. A total of 477 patients (284 male, 193 female, mean age 61.4 (44.7-78.1) years) were included. For the reference standard, two radiologists performed independent readings on seven diseases, thus reporting 226 findings in 167 patients. An autonomous DL reading was performed separately and evaluated against the gold standard regarding accuracy, sensitivity and specificity using ROC analysis. The overall average AUC was 0.84 (95%-CI 0.76-0.92) with an optimized DL sensitivity of 85% and specificity of 75.4%. The best results were seen in pleural effusion with an AUC of 0.92 (0.885-0.955) and sensitivity and specificity of each 86.4%. The data also showed a significant influence of sex, age, and comorbidity on the level of agreement between gold standard and DL reading. About 40% of cases could be ruled out correctly when screening for only one specific disease with a sensitivity above 95% in the exploratory analysis. For the combined reading of all abnormalities at once, only marginal workload reduction could be achieved due to insufficient specificity. DL applications like this one bear the prospect of autonomous comprehensive reporting on chest radiographs but for now require human supervision. Radiologists need to consider possible bias in certain patient groups, e.g., elderly and women. By adjusting their threshold values, commercial DL applications could already be deployed for a variety of tasks, e.g., ruling out certain conditions in screening scenarios and offering high potential for workload reduction.

The mediating role of health behaviors in the association between depression, anxiety and cancer incidence: an individual participant data meta-analysis.

BACKGROUND: Although behavioral mechanisms in the association among depression, anxiety, and cancer are plausible, few studies have empirically studied mediation by health behaviors. We aimed to examine the mediating role of several health behaviors in the associations among depression, anxiety, and the incidence of various cancer types (overall, breast, prostate, lung, colorectal, smoking-related, and alcohol-related cancers). METHODS: Two-stage individual participant data meta-analyses were performed based on 18 cohorts within the Psychosocial Factors and Cancer Incidence consortium that had a measure of depression or anxiety (N = 319 613, cancer incidence = 25 803). Health behaviors included smoking, physical inactivity, alcohol use, body mass index (BMI), sedentary behavior, and sleep duration and quality. In stage one, path-specific regression estimates were obtained in each cohort. In stage two, cohort-specific estimates were pooled using random-effects multivariate meta-analysis, and natural indirect effects (i.e. mediating effects) were calculated as hazard ratios (HRs). RESULTS: Smoking (HRs range 1.04-1.10) and physical inactivity (HRs range 1.01-1.02) significantly mediated the associations among depression, anxiety, and lung cancer. Smoking was also a mediator for smoking-related cancers (HRs range 1.03-1.06). There was mediation by health behaviors, especially smoking, physical inactivity, alcohol use, and a higher BMI, in the associations among depression, anxiety, and overall cancer or other types of cancer, but effects were small (HRs generally below 1.01). CONCLUSIONS: Smoking constitutes a mediating pathway linking depression and anxiety to lung cancer and smoking-related cancers. Our findings underline the importance of smoking cessation interventions for persons with depression or anxiety.

Impact of physical and sexual abuse on risk of hospitalisations for physical and mental illnesses: insights from two large prospective cohort studies.

Background: Physical abuse can lead to severe health consequences that extend beyond immediate harm. We explored the associations of physical abuse experienced during childhood and adulthood with a wide range of adult health conditions requiring hospital treatment. Methods: We utilised data from a sub-cohort of 157,366 UK Biobank participants (46.4% of the baseline population; age range 45-81; 89,101 women) and repeated analyses in an independent population of 85,929 adults from the Finnish Public Sector (FPS) study (age range 17-78; 68,544 women). Participants in both cohorts reported instances of physical and sexual abuse at study baseline. Follow-up included 77 common health conditions ascertained from linkage data to national hospital and mortality registries. Findings: Mean follow-up duration was 4.6 years (SD 0.14) in UK Biobank and 10.6 years (4.3) in FPS. Physical and sexual abuse was associated with 22 mental and physical health conditions. After multivariable adjustments, participants who experienced abuse during both early and later stages of life had a 2.12- (95% confidence interval 1.39-3.23) to 3.37-fold (1.52-7.45) increased risk of mental and behavioural disorders, a 1.46 (1.20-1.79) to 1.83 (1.05-3.20) times increased risk of metabolic, haematologic, and respiratory diseases, and a 1.24 (1.07-1.45) times higher risk of inflammatory diseases compared with non-exposed participants. The absolute risk difference between these groups was greatest for metabolic and haematologic conditions (rate 381 and risk difference 160 per 100,000 person-years). Frailty, comorbidities, and competing risk of death did not modify these associations, but the possibility of bias or residual confounding cannot be excluded. Interpretation: Repeated exposure to physical and sexual abuse amplifies the risk of hospitalisations from mental disorders and physical diseases spanning diverse organ systems. Addressing this issue may necessitate multifaceted strategies, including shifts in societal norms, legal measures, and increased healthcare provision for affected individuals and their families. Funding: Wellcome Trust, UK Medical Research Council, U.S. National Institute on Aging, Academy of Finland.

Depressive symptoms, socioeconomic position and mortality in older people living with and beyond cancer.

OBJECTIVE: Evidence shows that higher depressive symptoms are associated with mortality among people living with and beyond cancer (LWBC). However, prior studies have not accounted for a wider range of potential confounders, and no study has explored whether socioeconomic position (SEP) moderates the association. This study aimed to examine the association between depressive symptoms and mortality among people LWBC, and moderation by SEP. METHODS: Participants from the English Longitudinal Study of Ageing (ELSA), diagnosed with cancer and with a measure of depressive symptoms within four years following their diagnosis were included. Elevated depressive symptoms were indicated by a score of ≥3 on the 8-item Center for Epidemiologic Studies Depression Scale (CES-D). Cox regression models examined associations with all-cause mortality. Competing risk regression examined associations with cancer mortality. RESULTS: In 1352 people LWBC (mean age = 69.6 years), elevated depressive symptoms were associated with a 93% increased risk of all-cause mortality (95% CI: 1.52-2.45) within the first four years of follow-up, and 48% increased risk within a four to eight year follow-up (95% CI: 1.02-2.13) after multivariable adjustment. Elevated depressive symptoms were associated with a 38% increased risk of cancer mortality, but not after excluding people who died within one year after baseline assessments. There were no interactions between depressive symptoms and SEP. CONCLUSIONS: Elevated depressive symptoms are associated with a greater risk of all-cause mortality among people LWBC within an eight year follow-up period. Associations between depressive symptoms and cancer mortality might be due to reverse causality.

Cardiovascular Disease Events in Adults with a History of State Care in Childhood: Pooling of Unpublished Results from 9 Cohort Studies.

Background: Individuals who were separated from their biological family and placed into the care of the state during childhood (out-of-home care) are more prone to developing selected physical and mental health problems in adulthood, however, their risk of cardiovascular disease (CVD) is uncertain. Accordingly, we pooled published and unpublished results from cohort studies of childhood care and adult CVD. Methods: We used two approaches to identifying relevant data on childhood care and adult CVD (PROSPERO registration CRD42021254665). First, to locate published studies, we searched PubMed (Medline) until November 2023. Second, with the aim of identifying unpublished studies with the potential to address the present research question, we scrutinised retrieved reviews of the impact of childhood state care on related adult health outcomes. All included studies were required to have prospective measurement of state care in childhood and a follow-up of CVD events in adulthood as the primary outcome (incident coronary heart disease and/or stroke). Collaborating investigators provided study-specific estimates which were aggregated using random-effects meta-analysis. The Newcastle-Ottawa Scale was used to assess individual study quality. Findings: Thirteen studies (2 published, 11 unpublished) met the inclusion criteria, and investigators from nine provided viable results, including updated analyses of the published studies. Studies comprised 611,601 individuals (301,129 women) from the US, UK, Sweden, Finland, and Australia. Relative to the unexposed, individuals with a care placement during childhood had a 50% greater risk of CVD in adulthood (summary rate ratio after basic adjustment [95% confidence interval]: 1.50 [1.22, 1.84]); range of study-specific estimates: 1.28 to 2.06; I2 = 69%, p = 0.001). This association was attenuated but persisted after multivariable adjustment for socioeconomic status in childhood (8 studies; 1.41 [1.15, 1.72]) and adulthood (9 studies, 1.28 [1.10, 1.50]). There was a suggestion of a stronger state care-CVD association in women. Interpretation: Our findings show that individuals with experience of state care in childhood have a moderately raised risk of CVD in adulthood. For timely prevention, clinicians and policy makers should be aware that people with a care history may need additional attention in risk factor management.

Psychosocial factors, health behaviors and risk of cancer incidence: Testing interaction and effect modification in an individual participant data meta-analysis.

Depression, anxiety and other psychosocial factors are hypothesized to be involved in cancer development. We examined whether psychosocial factors interact with or modify the effects of health behaviors, such as smoking and alcohol use, in relation to cancer incidence. Two-stage individual participant data meta-analyses were performed based on 22 cohorts of the PSYchosocial factors and CAncer (PSY-CA) study. We examined nine psychosocial factors (depression diagnosis, depression symptoms, anxiety diagnosis, anxiety symptoms, perceived social support, loss events, general distress, neuroticism, relationship status), seven health behaviors/behavior-related factors (smoking, alcohol use, physical activity, body mass index, sedentary behavior, sleep quality, sleep duration) and seven cancer outcomes (overall cancer, smoking-related, alcohol-related, breast, lung, prostate, colorectal). Effects of the psychosocial factor, health behavior and their product term on cancer incidence were estimated using Cox regression. We pooled cohort-specific estimates using multivariate random-effects meta-analyses. Additive and multiplicative interaction/effect modification was examined. This study involved 437,827 participants, 36,961 incident cancer diagnoses, and 4,749,481 person years of follow-up. Out of 744 combinations of psychosocial factors, health behaviors, and cancer outcomes, we found no evidence of interaction. Effect modification was found for some combinations, but there were no clear patterns for any particular factors or outcomes involved. In this first large study to systematically examine potential interaction and effect modification, we found no evidence for psychosocial factors to interact with or modify health behaviors in relation to cancer incidence. The behavioral risk profile for cancer incidence is similar in people with and without psychosocial stress.

Predicting long-term sickness absence with employee questionnaires and administrative records: a prospective cohort study of hospital employees.

OBJECTIVE: This study aimed to compare the utility of risk estimation derived from questionnaires and administrative records in predicting long-term sickness absence among shift workers. METHODS: This prospective cohort study comprised 3197 shift-working hospital employees (mean age 44.5 years, 88.0% women) who responded to a brief 8-item questionnaire on work disability risk factors and were linked to 28 variables on their working hour and workplace characteristics obtained from administrative registries at study baseline. The primary outcome was the first sickness absence lasting ≥90 days during a 4-year follow-up. RESULTS: The C-index of 0.73 [95% confidence interval (CI) 0.70-0.77] for a questionnaire-only based prediction model, 0.71 (95% CI 0.67-0.75) for an administrative records-only model, and 0.79 (95% CI 0.76-0.82) for a model combining variables from both data sources indicated good discriminatory ability. For a 5%-estimated risk as a threshold for positive test results, the detection rates were 76%, 74%, and 75% and the false positive rates were 40%, 45% and 34% for the three models. For a 20%-risk threshold, the corresponding detection rates were 14%, 8%, and 27% and the false positive rates were 2%, 2%, and 4%. To detect one true positive case with these models, the number of false positive cases accompanied varied between 7 and 10 using the 5%-estimated risk, and between 2 and 3 using the 20%-estimated risk cut-off. The pattern of results was similar using 30-day sickness absence as the outcome. CONCLUSIONS: The best predictive performance was reached with a model including both questionnaire responses and administrative records. Prediction was almost as accurate with models using only variables from one of these data sources. Further research is needed to examine the generalizability of these findings.

Obesity and psychological distress.

The relationship between high body weight and mental health has been studied for several decades. Improvements in the quality of epidemiological, mechanistic and psychological research have brought greater consistency to our understanding of the links. Large-scale population-based epidemiological research has established that high body weight is associated with poorer mental health, particularly depression and subclinical depressive symptoms. There is some evidence for bidirectional relationships, but the most convincing findings are that greater body weight leads to psychological distress rather than the reverse. Particular symptoms of depression and distress may be specifically related to greater body weight. The psychological stress induced by weight stigma and discrimination contributes to psychological distress, and may in turn handicap efforts at weight control. Heightened systemic inflammation and dysregulation of the hypothalamic-pituitary-adrenal axis are biological mechanisms that mediate in part the relationship of greater body weight with poorer mental health. Changing negative societal attitudes to high body weights would improve the wellbeing of people living with obesity, and promote more effective weight-inclusive attitudes and behaviours in society at large, particularly in healthcare settings. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: Prospective cohort study.

BACKGROUND: While systemic inflammation has been implicated in the etiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS), a condition with high case-fatality, is untested. Accordingly, we quantified the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with subsequent ALS occurrence. METHODS: We used data from UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centers between 2006 and 2010. Venous blood was collected at baseline in the full cohort and assayed for CRP, and repeat measurement was made 3-7 years later in a representative subgroup (N = 14,514) enabling correction for regression dilution. ALS was ascertained via national hospitalization and mortality registries until 2021. We computed multivariable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles. RESULTS: In an analytical sample of 400,884 initially ALS-free individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalizations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviors, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalizations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend ≤ 0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalizations (1.37; 1.05, 1.76). CONCLUSIONS: Higher levels of CRP, a blood-based biomarker widely captured in clinical practice, is associated with moderately increased future risk of amyotrophic lateral sclerosis.

Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis.

BACKGROUND: Depression and anxiety have long been hypothesized to be related to an increased cancer risk. Despite the great amount of research that has been conducted, findings are inconclusive. To provide a stronger basis for addressing the associations between depression, anxiety, and the incidence of various cancer types (overall, breast, lung, prostate, colorectal, alcohol-related, and smoking-related cancers), individual participant data (IPD) meta-analyses were performed within the Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. METHODS: The PSY-CA consortium includes data from 18 cohorts with measures of depression or anxiety (up to N = 319,613; cancer incidences, 25,803; person-years of follow-up, 3,254,714). Both symptoms and a diagnosis of depression and anxiety were examined as predictors of future cancer risk. Two-stage IPD meta-analyses were run, first by using Cox regression models in each cohort (stage 1), and then by aggregating the results in random-effects meta-analyses (stage 2). RESULTS: No associations were found between depression or anxiety and overall, breast, prostate, colorectal, and alcohol-related cancers. Depression and anxiety (symptoms and diagnoses) were associated with the incidence of lung cancer and smoking-related cancers (hazard ratios [HRs], 1.06-1.60). However, these associations were substantially attenuated when additionally adjusting for known risk factors including smoking, alcohol use, and body mass index (HRs, 1.04-1.23). CONCLUSIONS: Depression and anxiety are not related to increased risk for most cancer outcomes, except for lung and smoking-related cancers. This study shows that key covariates are likely to explain the relationship between depression, anxiety, and lung and smoking-related cancers. PREREGISTRATION NUMBER: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=157677.

Suicide and depression in former contact sports participants: population-based cohort study, systematic review, and meta-analysis.

Background: Former participants in sports characterised by low intensity repetitive head impact appear to have elevated rates of later dementia, but links with other psychological health outcomes such as depression and suicide are uncertain. We quantified the occurrence of these endpoints in former contact sports athletes against general population controls using new data from a cohort study and a meta-analysis. Methods: The cohort study comprised 2004 retired male athletes, who had competed internationally as amateurs for Finland across a range of sports, and 1385 general population controls. All study members were linked to mortality and hospitalisation registries. In the PROSPERO-registered systematic review (CRD42022352780), we searched PubMed and Embase to October 31 2022 for cohort studies that reported standard estimates of association and precision. Study-specific estimates were aggregated in a random-effect meta-analysis. The Newcastle-Ottawa Scale was used to appraise the quality of each study. Findings: In survival analyses of the Finnish cohort data, former boxers (depression: hazard ratio 1.43 [95% CI 0.73, 2.78]; suicide: 1.75 [0.64, 4.38]), Olympic-style wrestlers (depression: 0.94 [0.44, 2.00]; suicide: 1.60 [0.64, 3.99]), and soccer players (depression: 0.62 [0.26, 1.48]; suicide: 0.50 [0.11, 2.16]) did not have statistically higher rates of major depressive disorder or suicide at follow-up relative to controls. In the systematic review, 7 cohort studies met inclusion criteria. After aggregating results with the Finnish cohort, retired soccer players appeared to have a lower risk of depression (summary risk ratio: 0.71 [0.54, 0.93]) relative to general population controls, while the rate of suicide was statistically the same across groups (0.70 [0.40, 1.23]). Past participation in American football seemed to be associated with some protection against suicide (0.58 [0.43, 0.80]) but there were insufficient studies of depression in this sport to facilitate aggregation. The aggregation of results from the soccer and American football studies showed directionally consistent relationships and there was no indication of inter-study heterogeneity (I2 = 0%). Interpretation: Based on a small cluster of studies exclusively comprising men, retired soccer players had a lower rate of later depression and former American football players had a lower risk of suicide relative to comparator groups. Whether these findings are generalisable to women requires testing. Funding: The preparation of this manuscript was unfunded.

Dementia in former amateur and professional contact sports participants: population-based cohort study, systematic review, and meta-analysis.

Background: Although there is growing evidence that former professional athletes from sports characterised by repetitive head impact subsequently experience an elevated risk of dementia, the occurrence of this disorder in retired amateurs, who represent a larger population, is uncertain. The present meta-analysis integrates new results from individual-participant analyses of a cohort study of former amateur contact sports participants into a systematic review of existing studies of retired professionals and amateurs. Methods: The cohort study comprised 2005 male retired amateur athletes who had competed internationally for Finland (1920-1965) and a general population comparison group of 1386 age-equivalent men. Dementia occurrence was ascertained from linked national mortality and hospital records. For the PROSPERO-registered (CRD42022352780) systematic review, we searched PubMed and Embase from their inception to April 2023, including cohort studies published in English that reported standard estimates of association and variance. Study-specific estimates were aggregated using random-effect meta-analysis. An adapted Cochrane Risk of Bias Tool was used to assess study quality. Findings: In the cohort study, up to 46 years of health surveillance of 3391 men gave rise to 406 dementia cases (265 Alzheimer's disease). After adjustment for covariates, former boxers experienced elevated rates of dementia (hazard ratio: 3.60 [95% CI 2.46, 5.28]) and Alzheimer's disease (4.10 [2.55, 6.61]) relative to general population controls. Associations were of lower magnitude in retired wrestlers (dementia: 1.51 [0.98, 2.34]; Alzheimer's disease: 2.11 [1.28, 3.48]) and soccer players (dementia: 1.55 [1.00, 2.41]; Alzheimer's disease: 2.07 [1.23, 3.46]), with some estimates including unity. The systematic review identified 827 potentially eligible published articles, of which 9 met our inclusion criteria. These few retrieved studies all sampled men and the majority were of moderate quality. In sport-specific analyses according to playing level, there was a marked difference in dementia rates in onetime professional American football players (2 studies; summary risk ratio: 2.96 [95% CI 1.66, 5.30]) relative to amateurs in whom there was no suggestion of an association (2 studies; 0.90 [0.52, 1.56]). For soccer players, while dementia occurrence was raised in both erstwhile professionals (2 studies; 3.61 [2.92, 4.45]) and amateurs (1 study; 1.60 [1.11, 2.30]) there was again a suggestion of a risk differential. The only studies of boxers comprised former amateurs in whom there was a tripling in the rates of dementia (2 studies; 3.14 [95% CI 1.72, 5.74]) and Alzheimer's disease (2 studies; 3.07 [1.01, 9.38]) at follow-up compared to controls. Interpretation: Based on a small number of studies exclusively sampling men, former amateur participants in soccer, boxing, and wrestling appeared to experience an elevated risk of dementia relative to the general population. Where data allowed comparison, there was a suggestion that risks were greater amongst retired professionals relative to amateurs in the sports of soccer and American football. Whether these findings are generalisable to the contact sports not featured, and to women, warrants examination. Funding: This work was unfunded.

Butterfly Transforms for Efficient Representation of Spatially Variant Point Spread Functions in Bayesian Imaging.

Bayesian imaging algorithms are becoming increasingly important in, e.g., astronomy, medicine and biology. Given that many of these algorithms compute iterative solutions to high-dimensional inverse problems, the efficiency and accuracy of the instrument response representation are of high importance for the imaging process. For efficiency reasons, point spread functions, which make up a large fraction of the response functions of telescopes and microscopes, are usually assumed to be spatially invariant in a given field of view and can thus be represented by a convolution. For many instruments, this assumption does not hold and degrades the accuracy of the instrument representation. Here, we discuss the application of butterfly transforms, which are linear neural network structures whose sizes scale sub-quadratically with the number of data points. Butterfly transforms are efficient by design, since they are inspired by the structure of the Cooley-Tukey fast Fourier transform. In this work, we combine them in several ways into butterfly networks, compare the different architectures with respect to their performance and identify a representation that is suitable for the efficient representation of a synthetic spatially variant point spread function up to a 1% error. Furthermore, we show its application in a short synthetic example.

Association Between Depression and Physical Conditions Requiring Hospitalization.

Importance: Depression is associated with an increased risk of physical illness, but the most common causes of hospitalization among people with depression are unclear. Objective: To examine the association of depression with an array of physical conditions requiring hospital treatment. Design, Setting, and Participants: In this outcomewide prospective multicohort study, primary analysis was based on data from the UK Biobank, a population-based study in the United Kingdom. Analyses were repeated in an independent data set of 2 cohorts in Finland, a population-based study and an occupational cohort. Data analysis was conducted between April and September 2022. Exposures: Self-reported depression, recurrent severe major depression, recurrent moderate major depression, and a single major depressive episode. Main Outcomes and Measures: A total of 77 common health conditions ascertained from linkage data to national hospital and mortality registries. Results: The analytical sample of UK Biobank participants consisted of 130 652 individuals (71 565 women [54.8%]; 59 087 men [45.2%]; mean [SD] age at baseline, 63.3 [7.8] years). The pooled data from the Finnish replication cohorts included 109 781 participants (82 921 women [78.6%]; 26 860 men [21.4%]; mean [SD] age, 42 [10.8] years). In the main analysis, severe/moderately severe depression was associated with the incidence of 29 nonoverlapping conditions requiring hospital treatment during a 5-year follow-up. Twenty-five of these associations remained after adjustment for confounders and multiple testing (adjusted hazard ratio [HR] range, 1.52-23.03) and were confirmed in the analysis of the Finnish cohorts. These included sleep disorders (HR, 5.97; 95% CI, 3.27-10.89), diabetes (HR, 5.15; 95% CI, 2.52-10.50), ischemic heart disease (HR, 1.76; 95% CI, 1.36-2.29), chronic obstructive bronchitis (HR, 4.11; 95% CI, 2.56-6.60), bacterial infections (HR, 2.52; 95% CI, 1.99-3.19), back pain (HR, 3.99; 95% CI, 2.96-5.38), and osteoarthritis (HR, 1.80; 95% CI, 1.46-2.20). The highest cumulative incidence was observed for endocrine and related internal organ diseases (245 per 1000 persons with depression; risk difference relative to unaffected individuals: 9.8%), musculoskeletal diseases (91 per 1000 persons; risk difference, 3.7%), and diseases of the circulatory system and blood (86 per 1000 persons; risk difference, 3.9%). The cumulative incidence was lower for hospital-treated mental, behavioral, and neurological disorders (20 in 1000 persons; risk difference, 1.7%). Depression was also associated with disease progression in people with prevalent heart disease or diabetes, and for 12 conditions, there was evidence of a bidirectional relationship. Conclusions and Relevance: In this study, the most common causes of hospitalization in people with depression were endocrine, musculoskeletal, and vascular diseases, not psychiatric disorders. These findings suggest that depression should be considered as a target for the prevention of physical and mental disease.

Systemic inflammation and subsequent risk of amyotrophic lateral sclerosis: prospective cohort study.

Importance: While systemic inflammation has been implicated in the aetiology of selected neurodegenerative disorders, its role in the development of amyotrophic lateral sclerosis (ALS) is untested. Objective: To quantify the relationship of C-reactive protein (CRP), an acute-phase reactant and marker of systemic inflammation, with ALS occurrence. Design Setting Participants: UK Biobank, a prospective cohort study of 502,649 participants who were aged 37 to 73 years when examined at research centres between 2006 and 2010. Exposure: Venous blood was collected at baseline in the full cohort and assayed for CRP. Repeat measurement was made 3-7 years later in a representative subgroup (N=14,514) enabling correction for regression dilution. Main Outcomes and Measures: ALS as ascertained via national hospitalisation and mortality registries. We computed multi-variable hazard ratios with accompanying 95% confidence intervals for log-transformed CRP expressed as standard deviation and tertiles. Results: In an analytical sample of 400,884 individuals (218,203 women), a mean follow-up of 12 years gave rise to 231 hospitalisations and 223 deaths ascribed to ALS. After adjustment for covariates which included health behaviours, comorbidity, and socio-economic status, a one standard deviation higher log-CRP was associated with elevated rates of both ALS mortality (hazard ratios; 95% confidence intervals: 1.32; 1.13, 1.53) and hospitalisations (1.20; 1.00, 1.39). There was evidence of dose-response effects across tertiles of CRP for both outcomes (p for trend≤0.05). Correction for regression dilution led to a strengthening of the relationship with CRP for both mortality (1.62; 1.27, 2.08) and hospitalisations (1.37; 1.05, 1.76) ascribed to ALS. Conclusions and Relevance: Higher levels of CRP, a blood-based biomarker widely captured in clinical practice, were associated with a higher subsequent risk of ALS. Key Points: Question: Is C-reactive protein (CRP), a marker of systemic inflammation widely used in clinical practice, associated with later risk of amyotrophic lateral sclerosis (ALS)?Findings: Following 11 years disease surveillance in 400,884 individuals (218,203 women), after adjustment for covariates and correction for regression dilution, a one standard deviation higher CRP levels were associations with both mortality (hazard ratio; 95% confidence interval: 1.62; 1.27, 2.08) and hospitalisations (1.37; 1.05, 1.76) ascribed to ALS.Meaning: In the present study, CRP has a dose-response relationship with the risk of later ALS.

Excess body weight and specific types of depressive symptoms: Is there a mediating role of systemic low-grade inflammation?

OBJECTIVES: Obesity is associated with an increased risk of depression. Systemic low-grade inflammation, a plausible consequence of obesity, has also been linked to depression. However, the potential mediating effects of systemic low-grade inflammation on the association between excess body weight and specific symptom domains of depression remain uncertain. This study examined whether systemic low-grade inflammation mediated the associations of excess body weight (overweight and obesity) with subsequent overall, cognitive-affective, and somatic depressive symptoms. DESIGN: This study used a prospective cohort design. METHODS: The final analytical sample included 4,942 adults aged ≥50 years drawn from the English Longitudinal Study of Ageing (ELSA). Body mass index (BMI) and covariates were ascertained at baseline (wave 4, 2008/09). Continuous BMI scores were divided into four categories: 'normal weight' (18.5 ≤ BMI <25 kg/m2); 'overweight' (25 ≤ BMI <30 kg/m2); 'obesity' (BMI ≥30 kg/m2); in addition to 'excess body weight' ('overweight' and 'obesity' combined). Covariates included sociodemographic variables, behavioural factors, and chronic physical conditions. Serum concentrations of CRP were measured at wave 6 (2012/13). Depressive symptoms were assessed at baseline and ten years later (wave 9, 2018/19), using the 8-item Centre for Epidemiological Studies Depression (CES-D) Scale. Two symptom domains were constructed, distinguishing between cognitive-affective (depressed mood, loneliness, sadness, enjoyment in life, and happiness) and somatic (sleep problems, low energy levels, and fatigue) symptoms. Mediation analyses were performed to examine whether CRP statistically mediated the associations between BMI categories and depressive symptoms. RESULTS: In multivariable-adjusted analyses, excess body weight was associated with elevated somatic (OR = 1.231, 95% CI: 1.029, 1.473), but not cognitive-affective or overall depressive symptoms at follow-up. Higher CRP was associated with elevated somatic (OR = 1.156, 95% CI: 1.061, 1.259), but not cognitive-affective or overall depressive symptoms. CRP acted as a partial mediator (14.92%) of the association between excess body weight and elevated somatic, but not cognitive-affective, or overall depressive symptoms. CONCLUSION: Systemic low-grade inflammation may partially explain the association of excess body weight with somatic depressive symptoms, but not the associations with cognitive-affective or overall depressive symptoms.

Causal, Bayesian, & non-parametric modeling of the SARS-CoV-2 viral load distribution vs. patient's age.

The viral load of patients infected with SARS-CoV-2 varies on logarithmic scales and possibly with age. Controversial claims have been made in the literature regarding whether the viral load distribution actually depends on the age of the patients. Such a dependence would have implications for the COVID-19 spreading mechanism, the age-dependent immune system reaction, and thus for policymaking. We hereby develop a method to analyze viral-load distribution data as a function of the patients' age within a flexible, non-parametric, hierarchical, Bayesian, and causal model. The causal nature of the developed reconstruction additionally allows to test for bias in the data. This could be due to, e.g., bias in patient-testing and data collection or systematic errors in the measurement of the viral load. We perform these tests by calculating the Bayesian evidence for each implied possible causal direction. The possibility of testing for bias in data collection and identifying causal directions can be very useful in other contexts as well. For this reason we make our model freely available. When applied to publicly available age and SARS-CoV-2 viral load data, we find a statistically significant increase in the viral load with age, but only for one of the two analyzed datasets. If we consider this dataset, and based on the current understanding of viral load's impact on patients' infectivity, we expect a non-negligible difference in the infectivity of different age groups. This difference is nonetheless too small to justify considering any age group as noninfectious.

Overweight, obesity, and individual symptoms of depression: A multicohort study with replication in UK Biobank.

OBJECTIVES: Obesity is associated with increased risk of depression, but the extent to which this association is symptom-specific is unknown. We examined the associations of overweight and obesity with individual depressive symptoms. METHODS: We pooled data from 15 population-based cohorts comprising 57,532 individuals aged 18 to 100 years at study entry. Primary analyses were replicated in an independent cohort, the UK Biobank study (n = 122,341, age range 38 to 72). Height and weight were assessed at baseline and body mass index (BMI) was computed. Using validated self-report measures, 24 depressive symptoms were ascertained once in 16 cross-sectional, and twice in 7 prospective cohort studies (mean follow-up 3.2 years). RESULTS: In the pooled analysis of the primary cohorts, 22,045 (38.3 %) participants were overweight (BMI between 25 and 29.9 kg/m2), 12,025 (20.9 %) class I obese (BMI between 30 and 34.9 kg/m2), 7,467 (13.0 %) class II-III obese (BMI ≥ 35 kg/m2); and 7,046 (12.3 %) were classified as depressed. After multivariable adjustment, obesity class I was cross-sectionally associated with 1.11-fold (95 % confidence interval 1.01-1.22), and obesity class II-III with 1.31-fold (1.16-1.49) higher odds of overall depression. In symptom-specific analyses, robust associations were apparent for 4 of the 24 depressive symptoms ('could not get going/lack of energy', 'little interest in doing things', 'feeling bad about yourself, and 'feeling depressed'), with confounder-adjusted odds ratios of having 3 or 4 of these symptoms being 1.32 (1.10-1.57) for individuals with obesity class I, and 1.70 (1.34-2.14) for those with obesity class II-III. Elevated C-reactive protein and 21 obesity-related diseases explained 23 %-31 % of these associations. Symptom-specific associations were confirmed in longitudinal analyses where obesity preceded symptom onset, were stronger in women compared with men, and were replicated in UK Biobank. CONCLUSIONS: Obesity is associated with a distinct set of depressive symptoms. These associations are partially explained by systemic inflammation and obesity-related morbidity. Awareness of this obesity-related symptom profile and its underlying biological correlates may inform better targeted treatments for comorbid obesity and depression.