The associations of socioeconomic position with structural brain damage and connectivity and cognitive functioning: The Maastricht Study.

BACKGROUND: Socioeconomic inequalities in cognitive impairment may partly act through structural brain damage and reduced connectivity. This study investigated the extent to which the association of early-life socioeconomic position (SEP) with later-life cognitive functioning is mediated by later-life SEP, and whether the associations of SEP with later-life cognitive functioning can be explained by structural brain damage and connectivity. METHODS: We used cross-sectional data from the Dutch population-based Maastricht Study (n = 4,839; mean age 59.2 ± 8.7 years, 49.8% women). Early-life SEP was assessed by self-reported poverty during childhood and parental education. Later-life SEP included education, occupation, and current household income. Participants underwent cognitive testing and 3-T magnetic resonance imaging to measure volumes of white matter hyperintensities, grey matter, white matter, cerebrospinal fluid, and structural connectivity. Multiple linear regression analyses tested the associations between SEP, markers of structural brain damage and connectivity, and cognitive functioning. Mediation was tested using structural equation modeling. RESULTS: Although there were direct associations between both indicators of SEP and later-life cognitive functioning, a large part of the association between early-life SEP and later-life cognitive functioning was explained by later-life SEP (72.2%). The extent to which structural brain damage or connectivity acted as mediators between SEP and cognitive functioning was small (up to 5.9%). CONCLUSIONS: We observed substantial SEP differences in later-life cognitive functioning. Associations of structural brain damage and connectivity with cognitive functioning were relatively small, and only marginally explained the SEP gradients in cognitive functioning.

The Impact of Childhood Adversity on Life Course Alcohol Use Patterns and Health Status Among People Living with HIV.

Adverse childhood experiences (ACEs) and financial hardship are associated with increased likelihood of heavier alcohol use and health challenges in adulthood among persons living with HIV (PWH). We examined whether retrospectively captured lifetime drinking trajectories are a pathway through which childhood hardships affect current health in a sample of 365 adult PWH. Childhood economic hardship and ACEs were used as main predictors. Measures of alcohol use included age at first drink and lifetime drinking trajectories. Health indicators included health-related quality of life, frailty, number of comorbidities, and symptoms of anxiety, depression, and post-traumatic stress disorder (PTSD). Structural equation modeling (SEM) was applied to estimate both direct and indirect pathways between childhood hardship and physical and mental health. Participants were mostly male; Black (84%); and averaged 48 years of age. SEM results supported both direct and indirect pathways between childhood experiences and adult health. ACEs were connected to physical health directly and mental health both directly and indirectly through age at first drink and drinking heaviness during ages 10-20. Childhood economic hardship related to mental health indirectly through higher drinking levels during ages 10-20. Childhood adverse experiences, economic hardship, and early drinking patterns appear to accumulate, resulting in later life physical and mental health concerns for PWH. Findings support taking a life course approach to health. This includes considering individual trauma histories in HIV care engagement and taking preventative approaches which support the economic and social well-being of vulnerable children to improve health in subsequent decades.

Brain structure and connectivity mediate the association between lifestyle and cognition: The Maastricht Study.

Life-course exposure to risk and protective factors impacts brain macro- and micro-structure, which in turn affects cognition. The concept of brain-age gap assesses brain health by comparing an individual's neuroimaging-based predicted age with their calendar age. A higher BAG implies accelerated brain ageing and is expected to be associated with worse cognition. In this study, we comprehensively modelled mutual associations between brain health and lifestyle factors, brain age and cognition in a large, middle-aged population. For this study, cognitive test scores, lifestyle and 3T MRI data for n = 4881 participants [mean age (± SD) = 59.2 (±8.6), 50.1% male] were available from The Maastricht Study, a population-based cohort study with extensive phenotyping. Whole-brain volumes (grey matter, cerebrospinal fluid and white matter hyperintensity), cerebral microbleeds and structural white matter connectivity were calculated. Lifestyle factors were combined into an adapted LIfestyle for BRAin health weighted sum score, with higher score indicating greater dementia risk. Cognition was calculated by averaging z-scores across three cognitive domains (memory, information processing speed and executive function and attention). Brain-age gap was calculated by comparing calendar age to predictions from a neuroimaging-based multivariable regression model. Paths between LIfestyle for BRAin health tertiles, brain-age gap and cognitive function were tested using linear regression and structural equation modelling, adjusting for sociodemographic and clinical confounders. The results show that cerebrospinal fluid, grey matter, white matter hyperintensity and cerebral microbleeds best predicted brain-age gap (R 2 = 0.455, root mean squared error = 6.44). In regression analysis, higher LIfestyle for BRAin health scores (greater dementia risk) were associated with higher brain-age gap (standardized regression coefficient ß = 0.126, P < 0.001) and worse cognition (ß = -0.046, P = 0.013), while higher brain-age gap was associated with worse cognition (ß=-0.163, P < 0.001). In mediation analysis, 24.7% of the total difference in cognition between the highest and lowest LIfestyle for BRAin health tertile was mediated by brain-age gap (ß indirect = -0.049, P < 0.001; ß total = -0.198, P < 0.001) and an additional 3.8% was mediated via connectivity (ß indirect = -0.006, P < 0.001; ß total = -0.150, P < 0.001). Findings suggest that associations between health- and lifestyle-based risk/protective factors (LIfestyle for BRAin health) and cognition can be partially explained by structural brain health markers (brain-age gap) and white matter connectivity markers. Lifestyle interventions targeted at high-risk individuals in mid-to-late life may be effective in promoting and preserving cognitive function in the general public.

Longitudinal associations of plasma kynurenines and ratios with fatigue and quality of life in colorectal cancer survivors up to 12 months post-treatment.

Fatigue is prevalent in colorectal cancer (CRC) survivors, impacting their health-related quality of life (HRQoL). Inflammation-induced activation of the kynurenine pathway may play a role in cancer-related fatigue and HRQoL, but evidence is scarce. Therefore, we aimed to investigate longitudinal associations of plasma tryptophan, kynurenines, and ratios with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Repeated measurements at 6 weeks, 6 months, and 12 months post-treatment were performed in 249 stage I-III CRC survivors. Plasma tryptophan and eight kynurenines were analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). Fatigue and HRQoL outcomes were evaluated using validated questionnaires. Confounder-adjusted linear mixed models were conducted to analyze longitudinal associations, with false discovery rate (FDR) correction. Higher tryptophan (Trp), kynurenic acid (KA), and xanthurenic acid (XA) concentrations, as well as a higher kynurenic acid-to-quinolinic acid ratio (KA/QA), were associated with less fatigue and better functioning, while a higher kynurenine-to-tryptophan ratio (KTR) and 3-hydroxykynurenine ratio (HKr) were associated with more fatigue and worse functioning. Finally, higher KA and XA concentrations and a higher KA/QA ratio were associated with a higher overall HRQoL summary score, while a higher HKr was associated with a lower overall HRQoL summary score. In conclusion, we observed that tryptophan and several kynurenines were longitudinally associated with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Future research is needed to validate our findings and explore the potential of the kynurenine pathway as intervention target for reducing fatigue and enhancing HRQoL after CRC treatment.

Associations of between- and within-day patterns of physical activity accumulation with arterial stiffness and indices of microvascular health-Evidence from The Maastricht study.

While physical activity (PA) is understood to promote vascular health, little is known about whether the daily and weekly patterns of PA accumulation associate with vascular health. Accelerometer-derived (activPAL3) 6- or 7-day stepping was analyzed for 6430 participants in The Maastricht Study (50.4% women; 22.4% Type 2 diabetes mellitus (T2DM)). Multivariable regression models examined associations between stepping metrics (average step count, and time spent slower and faster paced stepping) with arterial stiffness (measured as carotid-femoral pulse wave velocity (cfPWV)), and several indices of microvascular health (heat-induced skin hyperemia, retinal vessel reactivity and diameter), adjusting for confounders and moderators. PA pattern metrics were added to the regression models to identify associations with vascular health beyond that of stepping metrics. Analyses were stratified by T2DM status if an interaction effect was present. Average step count and time spent faster paced stepping was associated with better vascular health, and the association was stronger in those with compared to those without T2DM. In fully adjusted models a higher step count inter-daily stability was associated with a higher (worse) cfPWV in those without T2DM (std ß = 0.04, p = 0.007) and retinal venular diameter in the whole cohort (std ß = 0.07, p = 0.002). A higher within-day variability in faster paced stepping was associated with a lower (worse) heat-induced skin hyperemia in those with T2DM (std ß = -0.31, p = 0.008). Above and beyond PA volume, the daily and weekly patterns in which PA was accumulated were additionally associated with improved macro- and microvascular health, which may have implications for the prevention of vascular disease.

Longitudinal associations of diurnal rest-activity rhythms with fatigue, insomnia, and health-related quality of life in survivors of colorectal cancer up to 5 years post-treatment.

BACKGROUND: There is a growing population of survivors of colorectal cancer (CRC). Fatigue and insomnia are common symptoms after CRC, negatively influencing health-related quality of life (HRQoL). Besides increasing physical activity and decreasing sedentary behavior, the timing and patterns of physical activity and rest over the 24-h day (i.e. diurnal rest-activity rhythms) could also play a role in alleviating these symptoms and improving HRQoL. We investigated longitudinal associations of the diurnal rest-activity rhythm (RAR) with fatigue, insomnia, and HRQoL in survivors of CRC. METHODS: In a prospective cohort study among survivors of stage I-III CRC, 5 repeated measurements were performed from 6 weeks up to 5 years post-treatment. Parameters of RAR, including mesor, amplitude, acrophase, circadian quotient, dichotomy index, and 24-h autocorrelation coefficient, were assessed by a custom MATLAB program using data from tri-axial accelerometers worn on the upper thigh for 7 consecutive days. Fatigue, insomnia, and HRQoL were measured by validated questionnaires. Confounder-adjusted linear mixed models were applied to analyze longitudinal associations of RAR with fatigue, insomnia, and HRQoL from 6 weeks until 5 years post-treatment. Additionally, intra-individual and inter-individual associations over time were separated. RESULTS: Data were available from 289 survivors of CRC. All RAR parameters except for 24-h autocorrelation increased from 6 weeks to 6 months post-treatment, after which they remained relatively stable. A higher mesor, amplitude, circadian quotient, dichotomy index, and 24-h autocorrelation were statistically significantly associated with less fatigue and better HRQoL over time. A higher amplitude and circadian quotient were associated with lower insomnia. Most of these associations appeared driven by both within-person changes over time and between-person differences in RAR parameters. No significant associations were observed for acrophase. CONCLUSIONS: In the first five years after CRC treatment, adhering to a generally more active (mesor) and consistent (24-h autocorrelation) RAR, with a pronounced peak activity (amplitude) and a marked difference between daytime and nighttime activity (dichotomy index) was found to be associated with lower fatigue, lower insomnia, and a better HRQoL. Future intervention studies are needed to investigate if restoring RAR among survivors of CRC could help to alleviate symptoms of fatigue and insomnia while enhancing their HRQoL. TRIAL REGISTRATION: EnCoRe study NL6904 ( https://www.onderzoekmetmensen.nl/ ).

Association of kidney function with physical performance: the Maastricht study.

BACKGROUND: Kidney failure has been associated with decreased physical capacity, although evidence regarding the physical performance of individuals with earlier stages of chronic kidney disease (CKD) remains limited. METHODS: Cross-sectional data were derived from the prospective, population-based Maastricht Study. Multivariate linear regression models were fitted to assess the association of estimated glomerular filtration rate (eGFR) and albuminuria categories with physical performance test outcomes. RESULTS: Overall, 7396 participants were included. Compared to eGFR 60-90 ml/min/1.73 m2, values < 60 ml/min/1.73 m2 were associated with significantly shorter 6-min walk distance (ß: - 13.04 m, 95% confidence intervals-CI - 19.95; - 6.13), worse timed chair rise stand test time (ß: 0.91 s, 95% CI 0.36; 1.47), lower maximal grip (ß: - 0.83 kg, 95% CI - 1.50; - 0.15) and elbow flexion (ß: - 3.64 Nm, 95% CI - 7.11; - 0.16) strength. Additionally, eGFR > 90 ml/min/1.73 m2 was linked to significantly shorter 6-min walk distance (ß: - 6.13 m, 95% CI - 9.44; - 2.82). Urinary albumin excretion > 30 mg/24 h was associated with shorter 6-min walk distance (ß: - 12.48 m, 95% CI - 18.28; - 6.68), worse timed chair rise stand test time (ß: 0.51 s, 95% CI 0.11; 1.06), lower maximal grip (ß: - 1.34 kg, 95% CI - 1.91; - 0.76) and elbow flexion strength (ß: - 3.31 Nm, 95% CI - 5.80; - 0.82). CONCLUSIONS: Reduced eGFR and higher albuminuria levels were associated with worse physical performance, especially shorter 6-min walk distance and lower muscle strength. The relationship between eGFR and physical function was non-linear, with also high eGFR values being associated with worse performance, especially in the six-minute walk test.

EPAS1 expression contributes to maintenance of the primordial follicle pool in the mouse ovary.

Oxygen availability can have profound effects on cell fate decisions and survival, in part by regulating expression of hypoxia-inducible factors (HIFs). In the ovary, HIF expression has been characterised in granulosa cells, however, any requirement in oocytes remains relatively undefined. Here we developed a Hif2a/Epas1 germline-specific knockout mouse line in which females were fertile, however produced 40% fewer pups than controls. No defects in follicle development were detected, and quality of MII oocytes was normal, as per assessments of viability, intracellular reactive oxygen species, and spindle parameters. However, a significant diminishment of the primordial follicle pool was evident in cKO females that was attributed to accelerated follicle loss from postnatal day 6 onwards, potentially via disruption of the autophagy pathway. These data demonstrate the importance of HIF signalling in oocytes, particularly at the primordial follicle stage, and lend to the importance of controlling oxygen tension in the development of in vitro growth and maturation approaches for assisted reproduction.

Associations of 24 h time-use compositions of sitting, standing, physical activity and sleeping with optimal cardiometabolic risk and glycaemic control: The Maastricht Study.

AIMS/HYPOTHESIS: The associations of sitting, standing, physical activity and sleep with cardiometabolic health and glycaemic control markers are interrelated. We aimed to identify 24 h time-use compositions associated with optimal metabolic and glycaemic control and determine whether these varied by diabetes status. METHODS: Thigh-worn activPAL data from 2388 participants aged 40-75 years (48.7% female; mean age 60.1 [SD = 8.1] years; n=684 with type 2 diabetes) in The Maastricht Study were examined. Compositional isometric log ratios were generated from mean 24 h time use (sitting, standing, light-intensity physical activity [LPA], moderate-to-vigorous physical activity [MVPA] and sleeping) and regressed with outcomes of waist circumference, fasting plasma glucose (FPG), 2 h plasma glucose, HbA1c, the Matsuda index expressed as z scores, and with a clustered cardiometabolic risk score. Overall analyses were adjusted for demographics, smoking, dietary intake and diabetes status, and interaction by diabetes status was examined separately. The estimated difference when substituting 30 min of one behaviour with another was determined with isotemporal substitution. To identify optimal time use, all combinations of 24 h compositions possible within the study footprint (1st-99th percentile of each behaviour) were investigated to determine those cross-sectionally associated with the most-optimal outcome (top 5%) for each outcome measure. RESULTS: Compositions lower in sitting time and with greater standing time, physical activity and sleeping had the most beneficial associations with outcomes. Associations were stronger in participants with type 2 diabetes (p<0.05 for interactions), with larger estimated benefits for waist circumference, FPG and HbA1c when sitting was replaced by LPA or MVPA in those with type 2 diabetes vs the overall sample. The mean (range) optimal compositions of 24 h time use, considering all outcomes, were 6 h (range 5 h 40 min-7 h 10 min) for sitting, 5 h 10 min (4 h 10 min-6 h 10 min) for standing, 2 h 10 min (2 h-2 h 20 min) for LPA, 2 h 10 min (1 h 40 min-2 h 20 min) for MVPA and 8 h 20 min (7 h 30 min-9 h) for sleeping. CONCLUSIONS/INTERPRETATION: Shorter sitting time and more time spent standing, undergoing physical activity and sleeping are associated with preferable cardiometabolic health. The substitutions of behavioural time use were significantly stronger in their associations with glycaemic control in those with type 2 diabetes compared with those with normoglycaemic metabolism, especially when sitting time was balanced with greater physical activity.

Phosphoproteomic analysis of the adaption of epididymal epithelial cells to corticosterone challenge.

BACKGROUND: The epididymis has long been of interest owing to its role in promoting the functional maturation of the male germline. More recent evidence has also implicated the epididymis as an important sensory tissue responsible for remodeling of the sperm epigenome, both under physiological conditions and in response to diverse forms of environmental stress. Despite this knowledge, the intricacies of the molecular pathways involved in regulating the adaptation of epididymal tissue to paternal stressors remains to be fully resolved. OBJECTIVE: The overall objective of this study was to investigate the direct impact of corticosterone challenge on a tractable epididymal epithelial cell line (i.e., mECap18 cells), in terms of driving adaptation of the cellular proteome and phosphoproteome signaling networks. MATERIALS AND METHODS: The newly developed phosphoproteomic platform EasyPhos coupled with sequencing via an Orbitrap Exploris 480 mass spectrometer, was applied to survey global changes in the mECap18 cell (phospho)proteome resulting from sub-chronic (10-day) corticosterone challenge. RESULTS: The imposed corticosterone exposure regimen elicited relatively subtle modifications of the global mECap18 proteome (i.e., only 73 out of 4171 [∼1.8%] proteins displayed altered abundance). By contrast, ∼15% of the mECap18 phosphoproteome was substantially altered following corticosterone challenge. In silico analysis of the corresponding parent proteins revealed an activation of pathways linked to DNA damage repair and oxidative stress responses as well as a reciprocal inhibition of pathways associated with organismal death. Corticosterone challenge also induced the phosphorylation of several proteins linked to the biogenesis of microRNAs. Accordingly, orthogonal validation strategies confirmed an increase in DNA damage, which was ameliorated upon selective kinase inhibition, and an altered abundance profile of a subset of microRNAs in corticosterone-treated cells. CONCLUSIONS: Together, these data confirm that epididymal epithelial cells are reactive to corticosterone challenge, and that their response is tightly coupled to the opposing action of cellular kinases and phosphatases.

Caregiver burden and impact on COVID-19 patient participation and quality of life one year after ICU discharge - A prospective cohort study.

OBJECTIVES: to investigate changes in caregiver strain, mental health complaints and QoL in caregivers of COVID-19 ICU survivors in the first year after discharge, and their associations with patients' participation and quality of life. METHODS: Post-ICU COVID-19 survivors, needing inpatient rehabilitation and their informal caregivers were included. Caregiver self-administered questionnaires included quality of life, self-rated health, caregiver strain, anxiety and depression symptoms, post-traumatic stress and coping style. Patients' participation in society was assessed and quality of life. RESULTS: 67 patients (78% male) and 57 caregivers (23.6% male) were included. Three months post-ICU, caregivers experienced caregiver strain (32%), anxiety (41%), depressive symptoms (16%) and PTSD (24%). One year post-ICU, rates decreased, still being 11%, 26%, 10% and 5%, respectively. Caregiver anxiety symptoms and self-rated health at three months were associated with worse patient levels of participation and quality of life one year after ICU discharge (p < 0.05). CONCLUSIONS: COVID-19 caregivers experience high levels of mental health complaints one year after a patient's ICU discharge. Furthermore, our results indicate that patient participation levels and quality of life one year after ICU discharge may be negatively associated by caregiver complaints. PRACTICAL IMPLICATIONS: Counselling and routine assessment of emotional complaints and unmet needs of the informal caregiver should be incorporated and addressed in the rehabilitation treatment of (COVID-19) post-ICU patients.

Epigenetic, transcriptional, and functional characterization of myeloid cells in familial Mediterranean fever.

Familial Mediterranean fever (FMF) is a periodic fever syndrome caused by variation in MEFV. FMF is known for IL-1ß dysregulation, but the innate immune landscape of this disease has not been comprehensively described. Therefore, we studied circulating inflammatory proteins, and the function of monocytes and (albeit less extensively) neutrophils in treated FMF patients in remission. We found that monocyte IL-1ß and IL-6 production was enhanced upon stimulation, in concordance with alterations in the plasma inflammatory proteome. We did not observe changes in neutrophil functional assays. Subtle differences in chromatin accessibility and transcriptomics in our small patient cohort further argued for monocyte dysregulation. Together, these observations suggest that the MEFV-mutation-mediated primary immune dysregulation in monocytes leads to chronic inflammation that is subsequently associated with counterregulatory epigenetic/transcriptional changes reminiscent of tolerance. These data increase our understanding of the innate immune changes in FMF, aiding future management of chronic inflammation in these patients.

Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

BACKGROUND: Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. METHODS: Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010-2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). RESULTS: After a median follow-up of 7.0 years (range 1.0-11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [s.d.]: 0.89 [95% confidence interval (CI) 0.83-0.96] and 0.93 [0.86-0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d.: 1.10 [1.01-1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69-0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07-1.43]). CONCLUSIONS: These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms.

Longitudinal associations of plasma kynurenines and ratios with anxiety and depression scores in colorectal cancer survivors up to 12 months post-treatment.

INTRODUCTION: Colorectal cancer (CRC) survivors often experience neuropsychological symptoms, including anxiety and depression. Mounting evidence suggests a role for the kynurenine pathway in these symptoms due to potential neuroprotective and neurotoxic roles of involved metabolites. However, evidence remains inconclusive and insufficient in cancer survivors. Thus, we aimed to explore longitudinal associations of plasma tryptophan, kynurenines, and their established ratios with anxiety and depression in CRC survivors up to 12 months post-treatment. METHODS: In 249 stage I-III CRC survivors, blood samples were collected at 6 weeks, 6 months, and 12 months post-treatment to analyze plasma concentrations of tryptophan and kynurenines using liquid-chromatography tandem-mass spectrometry (LC/MS-MS). At the same timepoints, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Confounder-adjusted linear mixed models were used to analyze longitudinal associations. Sensitivity analyses with false discovery rate (FDR) correction were conducted to adjust for multiple testing. RESULTS: Higher plasma tryptophan concentrations were associated with lower depression scores (ß as change in depression score per 1 SD increase in the ln-transformed kynurenine concentration: -0.31; 95%CI: -0.56,-0.05), and higher plasma 3-hydroxyanthranilic acid concentrations with lower anxiety scores (-0.26; -0.52,-0.01). A higher 3-hydroxykynurenine ratio (HKr; the ratio of 3-hydroxykynurenine to the sum of kynurenic acid, xanthurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid) was associated with higher depression scores (0.34; 0.04,0.63) and higher total anxiety and depression scores (0.53; 0.02,1.04). Overall associations appeared to be mainly driven by inter-individual associations, which were statistically significant for tryptophan with depression (-0.60; -1.12,-0.09), xanthurenic acid with total anxiety and depression (-1.04; -1.99,-0.10), anxiety (-0.51; -1.01,-0.01), and depression (-0.56; -1.08,-0.05), and kynurenic-acid-to-quinolinic-acid ratio with depression (-0.47; -0.93,-0.01). In sensitivity analyses, associations did not remain statistically significant after FDR adjustment. CONCLUSION: We observed that plasma concentrations of tryptophan, 3-hydroxyanthranilic acid, xanthurenic acid, 3-hydroxykynurenine ratio, and kynurenic-acid-to-quinolinic-acid ratio tended to be longitudinally associated with anxiety and depression in CRC survivors up to 12 months post-treatment. Future studies are warranted to further elucidate the association of plasma kynurenines with anxiety and depression.

Dietary intake of dicarbonyl compounds and changes in body weight over time in a large cohort of European adults.

Dicarbonyl compounds are highly reactive precursors of advanced glycation end products (AGE), produced endogenously, present in certain foods and formed during food processing. AGE contribute to the development of adverse metabolic outcomes, but health effects of dietary dicarbonyls are largely unexplored. We investigated associations between three dietary dicarbonyl compounds, methylglyoxal (MGO), glyoxal (GO) and 3-deoxyglucosone (3-DG), and body weight changes in European adults. Dicarbonyl intakes were estimated using food composition database from 263 095 European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home in Relation to Anthropometry participants with two body weight assessments (median follow-up time = 5·4 years). Associations between dicarbonyls and 5-year body-weight changes were estimated using mixed linear regression models. Stratified analyses by sex, age and baseline BMI were performed. Risk of becoming overweight/obese was assessed using multivariable-adjusted logistic regression. MGO intake was associated with 5-year body-weight gain of 0·089 kg (per 1-sd increase, 95 % CI 0·072, 0·107). 3-DG was inversely associated with body-weight change (-0·076 kg, -0·094, -0·058). No significant association was observed for GO (0·018 kg, -0·002, 0·037). In stratified analyses, GO was associated with body-weight gain among women and older participants (above median of 52·4 years). MGO was associated with higher body-weight gain among older participants. 3-DG was inversely associated with body-weight gain among younger and normal-weight participants. MGO was associated with a higher risk of becoming overweight/obese, while inverse associations were observed for 3-DG. No associations were observed for GO with overweight/obesity. Dietary dicarbonyls are inconsistently associated with body weight change among European adults. Further research is needed to clarify the role of these food components in overweight and obesity, their underlying mechanisms and potential public health implications.

Common and distinct metabolomic markers related to immune aging in Western European and East African populations.

In old age, impaired immunity causes high susceptibility to infections and cancer, higher morbidity and mortality, and poorer vaccination efficiency. Many factors, such as genetics, diet, and lifestyle, impact aging. This study aimed to investigate how immune responses change with age in healthy Dutch and Tanzanian individuals and identify common metabolites associated with an aged immune profile. We performed untargeted metabolomics from plasma to identify age-associated metabolites, and we correlated their concentrations with ex-vivo cytokine production by immune cells, DNA methylation-based epigenetic aging, and telomere length. Innate immune responses were impacted differently by age in Dutch and Tanzanian cohorts. Age-related decline in steroid hormone precursors common in both populations was associated with higher systemic inflammation and lower cytokine responses. Hippurate and 2-phenylacetamide, commonly more abundant in older individuals, were negatively correlated with cytokine responses and telomere length and positively correlated with epigenetic aging. Lastly, we identified several metabolites that might contribute to the stronger decline in innate immunity with age in Tanzanians. The shared metabolomic signatures of the two cohorts suggest common mechanisms of immune aging, revealing metabolites with potential contributions. These findings also reflect genetic or environmental effects on circulating metabolites that modulate immune responses.

Similar long-term outcomes for venous, bovine pericardial, and polyester patches for primary carotid endarterectomy.

BACKGROUND: Currently, the type of patch used for carotid endarterectomy closure depends on the preference of the operating surgeon. Various materials are available, including autologous venous patches, bovine pericardial patches (BPP), and synthetic patches. The purpose of this study was to compare the long-term outcomes. METHODS: All patients who underwent primary carotid endarterectomy with patch angioplasty using a venous, bovine, or polyester patch between 2010 and 2020 at two high-volume medical centers were included in this retrospective analysis on largely prospectively collected data. Study endpoints included long-term ipsilateral transient ischemic attack or cerebrovascular accident, restenosis, reintervention, and all-cause mortality. Cox proportional hazard models were fitted to assess the effect of patch type to each outcome. RESULTS: In total, 1481 CEAs were performed with a follow-up of 32 (13-65) months. Venous patch was used in 309 patients (20.9%), BPP in 1000 patients (67.5%), and polyester patch in 172 patients (11.6%). A preoperative symptomatic carotid artery stenosis of >50% was observed in 91.9% (n = 284) of the patients who received a venous patch, 92.1% (n = 921) of the patients who received BPP, and 90.7% (n = 156) of the patients who received a polyester patch (p = 0.799). Only in selected patients with an asymptomatic stenosis of >70% surgery was considered. Multivariable analyses showed no significant differences between the three patch types regarding long-term outcomes after adjusting for confounders. CONCLUSIONS: In patients undergoing primary carotid endarterectomy, the use of venous, bovine pericardial, or polyester patches seems equally safe and durable in terms of comparability in long-term outcomes.

Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study.

AIMS/HYPOTHESIS: Type 2 diabetes is a highly heterogeneous disease for which new subgroups ('clusters') have been proposed based on disease severity: moderate age-related diabetes (MARD), moderate obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD). It is unknown how disease severity is reflected in terms of quality of life in these clusters. Therefore, we aimed to investigate the cluster characteristics and cluster-wise evolution of quality of life in the previously defined clusters of type 2 diabetes. METHODS: We included individuals with type 2 diabetes from the Maastricht Study, who were allocated to clusters based on a nearest centroid approach. We used logistic regression to evaluate the cluster-wise association with diabetes-related complications. We plotted the evolution of HbA1c levels over time and used Kaplan-Meier curves and Cox regression to evaluate the cluster-wise time to reach adequate glycaemic control. Quality of life based on the Short Form 36 (SF-36) was also plotted over time and adjusted for age and sex using generalised estimating equations. The follow-up time was 7 years. Analyses were performed separately for people with newly diagnosed and already diagnosed type 2 diabetes. RESULTS: We included 127 newly diagnosed and 585 already diagnosed individuals. Already diagnosed people in the SIDD cluster were less likely to reach glycaemic control than people in the other clusters, with an HR compared with MARD of 0.31 (95% CI 0.22, 0.43). There were few differences in the mental component score of the SF-36 in both newly and already diagnosed individuals. In both groups, the MARD cluster had a higher physical component score of the SF-36 than the other clusters, and the MOD cluster scored similarly to the SIDD and SIRD clusters. CONCLUSIONS/INTERPRETATION: Disease severity suggested by the clusters of type 2 diabetes is not entirely reflected in quality of life. In particular, the MOD cluster does not appear to be moderate in terms of quality of life. Use of the suggested cluster names in practice should be carefully considered, as the non-neutral nomenclature may affect disease perception in individuals with type 2 diabetes and their healthcare providers.

BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination.

Bacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against non-tuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.

Multi-omics analysis of innate and adaptive responses to BCG vaccination reveals epigenetic cell states that predict trained immunity.

Immune responses are tightly regulated yet highly variable between individuals. To investigate human population variation of trained immunity, we immunized healthy individuals with Bacillus Calmette-Guérin (BCG). This live-attenuated vaccine induces not only an adaptive immune response against tuberculosis but also triggers innate immune activation and memory that are indicative of trained immunity. We established personal immune profiles and chromatin accessibility maps over a 90-day time course of BCG vaccination in 323 individuals. Our analysis uncovered genetic and epigenetic predictors of baseline immunity and immune response. BCG vaccination enhanced the innate immune response specifically in individuals with a dormant immune state at baseline, rather than providing a general boost of innate immunity. This study advances our understanding of BCG's heterologous immune-stimulatory effects and trained immunity in humans. Furthermore, it highlights the value of epigenetic cell states for connecting immune function with genotype and the environment.