Systematic review and meta-analysis of the effect of adverse childhood experiences (ACEs) on brain-derived neurotrophic factor (BDNF) levels.

There is continued interest in identifying dysregulated biomarkers that mediate associations between adverse childhood experiences (ACEs) and negative long-term health outcomes. However, little is known regarding how ACE exposure modulates neural biomarkers to influence poorer health outcomes in ACE-exposed children. To address this, we performed a systematic review and meta-analysis of the impact of ACE exposure on Brain Derived Neurotrophic Factor (BDNF) levels - a neural biomarker involved in childhood and adult neurogenesis and long-term memory formation. Twenty-two studies were selected for inclusion within the systematic review, ten of which were included in meta-analysis. Most included studies retrospectively assessed impacts of childhood maltreatment in clinical populations. Sample size, BDNF protein levels in ACE-exposed and unexposed subjects, and standard deviations were extracted from ten publications to estimate the BDNF ratio of means (ROM) across exposure categories. Overall, no significant difference was found in BDNF protein levels between ACE-exposed and unexposed groups (ROM: 1.08; 95 % CI: 0.93-1.26). Age at sampling, analyte type (e.g., sera, plasma, blood), and categories of ACE exposure contributed to high between-study heterogeneity, some of which was minimized in subset-based analyses. These results support continued investigation into the impact of ACE exposure on neural biomarkers and highlight the potential importance of analyte type and timing of sample collection on study results.

Socioenvironmental Adversity and Adolescent Psychotic Experiences: Exploring Potential Mechanisms in a UK Longitudinal Cohort.

BACKGROUND AND HYPOTHESIS: Children exposed to socioenvironmental adversities (eg, urbanicity, pollution, neighborhood deprivation, crime, and family disadvantage) are more likely to subsequently develop subclinical psychotic experiences during adolescence (eg, hearing voices, paranoia). However, the pathways through which this occurs have not been previously investigated. We hypothesized that cognitive ability and inflammation would partly explain this association. STUDY DESIGN: Data were utilized from the Environmental-Risk Longitudinal Twin Study, a cohort of 2232 children born in 1994-1995 in England and Wales and followed to age 18. Socioenvironmental adversities were measured from birth to age 10 and classified into physical risk (defined by high urbanicity and air pollution) and socioeconomic risk (defined by high neighborhood deprivation, neighborhood disorder, and family disadvantage). Cognitive abilities (overall, crystallized, fluid, and working memory) were assessed at age 12; and inflammatory markers (C-reactive protein, interleukin-6, soluble urokinase plasminogen activator receptor) were measured at age 18 from blood samples. Participants were interviewed at age 18 regarding psychotic experiences. STUDY RESULTS: Higher physical risk and socioeconomic risk were associated with increased odds of psychotic experiences in adolescence. The largest mediation pathways were from socioeconomic risk via overall cognitive ability and crystallized ability, which accounted for ~11% and ~19% of the association with psychotic experiences, respectively. No statistically significant pathways were found via inflammatory markers in exploratory (partially cross-sectional) analyses. CONCLUSIONS: Cognitive ability, especially crystallized ability, may partly explain the association between childhood socioenvironmental adversity and adolescent psychotic experiences. Interventions to support cognitive development among children living in disadvantaged settings could buffer them against developing subclinical psychotic phenomena.

Childhood Adversity and Midlife Health: Shining a Light on the Black Box of Psychosocial Mechanisms.

Adverse childhood experiences (ACEs) are associated with poorer health, which has spurred public health efforts to reduce the number of adverse events children experience. Unfortunately, it is unlikely that all ACEs can be prevented. For adults who already experienced ACEs in childhood, what psychological, social, and behavioral intervention targets might reduce risk for negative health outcomes? To provide insight into the "black box" of psychosocial mechanisms linking ACEs to poor health, our study used data from the Dunedin Study, a longitudinal cohort assessed from birth to age 45. Mediation models (N = 859) were used to examine whether candidate psychosocial variables in adulthood explained the association between childhood ACEs and health in midlife. Potential psychosocial mediators included stressful life events, perceived stress, negative emotionality, and health behaviors. Children who experienced more ACEs had poorer health in midlife. They also had significantly more stressful life events, more perceived stress, more negative emotionality, and unhealthier behaviors as adults. These mediators were each independently associated with poorer health in midlife and statistically mediated the association between ACEs and midlife health. Health behaviors evidenced the strongest indirect effect from ACEs to midlife health. Together, these psychosocial mediators accounted for the association between ACEs in childhood and health three decades later. Public health efforts to mitigate the health consequences of ACEs could aim to reduce the stressful life events people experience, reduce negative emotionality, reduce perceived stress, or improve health behaviors among adults who experienced childhood adversity.

Improving risk indexes for Alzheimer's disease and related dementias for use in midlife.

Knowledge of a person's risk for Alzheimer's disease and related dementias (ADRDs) is required to triage candidates for preventive interventions, surveillance, and treatment trials. ADRD risk indexes exist for this purpose, but each includes only a subset of known risk factors. Information missing from published indexes could improve risk prediction. In the Dunedin Study of a population-representative New Zealand-based birth cohort followed to midlife (N = 938, 49.5% female), we compared associations of four leading risk indexes with midlife antecedents of ADRD against a novel benchmark index comprised of nearly all known ADRD risk factors, the Dunedin ADRD Risk Benchmark (DunedinARB). Existing indexes included the Cardiovascular Risk Factors, Aging, and Dementia index (CAIDE), LIfestyle for BRAin health index (LIBRA), Australian National University Alzheimer's Disease Risk Index (ANU-ADRI), and risks selected by the Lancet Commission on Dementia. The Dunedin benchmark was comprised of 48 separate indicators of risk organized into 10 conceptually distinct risk domains. Midlife antecedents of ADRD treated as outcome measures included age-45 measures of brain structural integrity [magnetic resonance imaging-assessed: (i) machine-learning-algorithm-estimated brain age, (ii) log-transformed volume of white matter hyperintensities, and (iii) mean grey matter volume of the hippocampus] and measures of brain functional integrity [(i) objective cognitive function assessed via the Wechsler Adult Intelligence Scale-IV, (ii) subjective problems in everyday cognitive function, and (iii) objective cognitive decline measured as residualized change in cognitive scores from childhood to midlife on matched Weschler Intelligence scales]. All indexes were quantitatively distributed and proved informative about midlife antecedents of ADRD, including algorithm-estimated brain age (ß's from 0.16 to 0.22), white matter hyperintensities volume (ß's from 0.16 to 0.19), hippocampal volume (ß's from -0.08 to -0.11), tested cognitive deficits (ß's from -0.36 to -0.49), everyday cognitive problems (ß's from 0.14 to 0.38), and longitudinal cognitive decline (ß's from -0.18 to -0.26). Existing indexes compared favourably to the comprehensive benchmark in their association with the brain structural integrity measures but were outperformed in their association with the functional integrity measures, particularly subjective cognitive problems and tested cognitive decline. Results indicated that existing indexes could be improved with targeted additions, particularly of measures assessing socioeconomic status, physical and sensory function, epigenetic aging, and subjective overall health. Existing premorbid ADRD risk indexes perform well in identifying linear gradients of risk among members of the general population at midlife, even when they include only a small subset of potential risk factors. They could be improved, however, with targeted additions to more holistically capture the different facets of risk for this multiply determined, age-related disease.

Longitudinal associations between adolescents' individualised risk for depression and inflammation in a UK cohort study.

Inflammation is associated with poor physical and mental health including major depressive disorder (MDD). Moreover, there is evidence that childhood adversity - a risk factor for MDD - becomes biologically embedded via elevated inflammation. However, the risk of developing MDD arises from multiple sources and yet there has been little investigation of the links between individuals' constellation of MDD risk and subsequent inflammation. We therefore examined associations between individual risk for MDD calculated in early adolescence and levels of inflammation six years later. We use data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative UK birth cohort of 2,232 children followed to age 18 with 93% retention. Participants' individual risk for developing future MDD was calculated at age 12 using a recently developed prediction model comprising multiple psychosocial factors. Plasma levels of three inflammation biomarkers were measured at age 18: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer biomarker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to reflect the level of systemic chronic inflammation. MDD risk scores calculated at age 12 were positively associated with levels of suPAR (but not CRP or IL-6) at age 18 after adjusting for key covariates (b = 1.70, 95% CI = 0.46 - 2.95, p = 0.007). Adolescents at high risk of MDD (risk scores ≥ 90th centile) had significantly higher mean levels of suPAR six years later than adolescents who had been identified as low risk (risk scores ≤ 10th centile) (b = 0.41, 95% CI = 0.18 - 0.64, p < 0.001). Findings support the notion that childhood psychosocial risk for MDD leads to increased levels of low-grade inflammation. If replicated in studies with repeated assessments of inflammation biomarkers throughout childhood and adolescence, these findings would support targeted interventions to reduce inflammation, as measured by suPAR, for adolescents at high risk of MDD to potentially prevent development of depression and physical health problems related to chronic inflammation.

Risk of Malnutrition upon Admission and after Discharge in Acutely Admitted Older Medical Patients: A Prospective Observational Study.

There is a lack of knowledge about malnutrition and risk of malnutrition upon admission and after discharge in older medical patients. This study aimed to describe prevalence, risk factors, and screening tools for malnutrition in older medical patients. In a prospective observational study, malnutrition was evaluated in 128 older medical patients (≥65 years) using the Nutritional Risk Screening 2002 (NRS-2002), the Mini Nutritional Assessment-Short Form (MNA-SF) and the Eating Validation Scheme (EVS). The European Society of Clinical Nutrition (ESPEN) diagnostic criteria from 2015 were applied for diagnosis. Agreement between the screening tools was evaluated by kappa statistics. Risk factors for malnutrition included polypharmacy, dysphagia, depression, low functional capacity, eating-related problems and lowered cognitive function. Malnutrition or risk of malnutrition were prevalent at baseline (59-98%) and follow-up (30-88%). The baseline, follow-up and transitional agreements ranged from slight to moderate. NRS-2002 and MNA-SF yielded the highest agreement (kappa: 0.31 (95% Confidence Interval (CI) 0.18-0.44) to 0.57 (95%CI 0.42-0.72)). Prevalence of risk factors ranged from 17-68%. Applying ESPEN 2015 diagnostic criteria, 15% had malnutrition at baseline and 13% at follow-up. In conclusion, malnutrition, risk of malnutrition and risk factors hereof are prevalent in older medical patients. MNA-SF and NRS-2002 showed the highest agreement at baseline, follow-up, and transitionally.

Associations between childhood victimization, inflammatory biomarkers and psychotic phenomena in adolescence: A longitudinal cohort study.

Exposure to victimization in childhood has been linked to the development of psychosis. However, little is known about how childhood victimization is translated into biological risk for psychosis. One possibility is via increased inflammation. This study aimed to investigate the association between childhood victimization, psychotic experiences (PEs) in adolescence and inflammatory markers using data from a general population cohort. Participants were 1,419 British-born children followed from birth to age 18 years as part of the Environmental Risk Longitudinal Twin Study. Childhood victimization was measured prospectively using multiple sources from birth to age 12 years. PEs were assessed during private interviews with participants at age 18 years for the period since age 12. Plasma C-reactive protein (CRP), interleukin-6 (IL-6), and soluble urokinase plasminogen activator receptor (suPAR) levels were measured from plasma samples collected from participants at 18 years. Young people with both PEs and childhood victimization were more likely to belong to a group with elevated suPAR, CRP and IL-6 levels at 18 years of age (OR = 3.34, 95% CI 1.69-6.59, p = 0.001) than those with no childhood victimization and without PEs. However, this association was attenuated when adjusted for other risk factors for elevated inflammation at age 18 (OR = 1.94, 95% CI 0.94-4.04, p = 0.075). In contrast, presence of PEs without childhood victimization was not significantly associated with age-18 inflammatory markers and neither was childhood victimization without PEs (all p's greater than 0.05). The current study highlights that inflammatory dysregulation is mostly present in adolescents reporting PEs who also experienced childhood victimization, though this seemed to be largely due to concurrent inflammation-related risk factors.

Linking stressful life events and chronic inflammation using suPAR (soluble urokinase plasminogen activator receptor).

Stressful life events have been linked to declining health, and inflammation has been proposed as a physiological mechanism that might explain this association. Using 828 participants from the Dunedin Longitudinal Study, we tested whether people who experienced more stressful life events during adulthood would show elevated systemic inflammation when followed up in midlife, at age 45. We studied three inflammatory biomarkers: C-reactive protein (CRP), interleukin-6 (IL-6), and a newer biomarker, soluble urokinase plasminogen activator receptor (suPAR), which is thought to index systemic chronic inflammation. Stressful life events were not associated with CRP or IL-6. However, people who experienced more stressful life events from age 38 to 44 had elevated suPAR at age 45, and had significantly greater increases in suPAR from baseline to follow-up across the same period. When examining stressful life events across the lifespan, both adverse childhood experiences (ACEs) and adult stressful life events were independently associated with suPAR at age 45. ACEs moderated the association of adult stressful life events and suPAR at age 45-children with more ACEs showed higher suPAR levels after experiencing stressful life events as adults. The results suggest systemic chronic inflammation is one physiological mechanism that could link stressful life events and health, and support the use of suPAR as a useful biomarker for such research.

Patterns of Reliability: Assessing the Reproducibility and Integrity of DNA Methylation Measurement.

DNA methylation plays an important role in both normal human development and risk of disease. The most utilized method of assessing DNA methylation uses BeadChips, generating an epigenome-wide "snapshot" of >450,000 observations (probe measurements) per assay. However, the reliability of each of these measurements is not equal, and little consideration is paid to consequences for research. We correlated repeat measurements of the same DNA samples using the Illumina HumanMethylation450K and the Infinium MethylationEPIC BeadChips in 350 blood DNA samples. Probes that were reliably measured were more heritable and showed consistent associations with environmental exposures, gene expression, and greater cross-tissue concordance. Unreliable probes were less replicable and generated an unknown volume of false negatives. This serves as a lesson for working with DNA methylation data, but the lessons are equally applicable to working with other data: as we advance toward generating increasingly greater volumes of data, failure to document reliability risks harming reproducibility.

Soluble urokinase plasminogen activator receptor (suPAR) is lower in disease-free patients but cannot rule out incident disease in patients with suspected cancer.

BACKGROUND: Accurate first-line diagnostics are essential for early recognition of cancer but also to identify patients free of disease. The biomarker soluble urokinase plasminogen activator receptor (suPAR) is elevated in patients with cancer or non-malignant disease compared to disease-free patients. We tested if low suPAR could be used to identify disease-free patients in an accelerated cancer diagnostics program, including ruling out cancer. METHODS: Patients with serious nonspecific symptoms and signs of cancer (NSSC) were included at the Diagnostic Outpatient Clinic, Copenhagen University Hospital Hvidovre, Denmark. Data from a clinical examination, including blood tests and imaging, was combined with national registry data on diagnoses and mortality. The association between blood suPAR and the primary outcome of disease-free (i.e., absence of incident disease and mortality) within 1-year follow-up was analysed with logistic regression analysis. RESULTS: Of 1583 patients included, 349 (22.0%) were diagnosed with cancer, 837 (52.9%) with non-malignant disease, and 392 (25.8%) were disease-free within one year. Admission suPAR was significantly lower in disease-free patients compared to patients with cancer or non-malignant disease (P < 0.001), area under the curve 0.67 (95% confidence interval (CI): 0.64-0.70). The highest positive predictive value (PPV) for the outcome of disease-free was 0.55 (95% CI: 0.41-0.68) at a suPAR of 1.65 ng/mL. Patients who died had significantly higher suPAR compared to patients who survived in all disease subgroups. The AUC of suPAR for 1-year mortality was 0.80 (95% CI: 0.77-0.83). CONCLUSIONS: suPAR was significantly lower in disease-free individuals compared to patients with cancer or other conditions, but the PPV was not sufficiently high to terminate further clinical investigation with appropriate safety. Elevated suPAR may be a useful prognostic marker for adverse outcomes.

Association of Neighborhood Disadvantage in Childhood With DNA Methylation in Young Adulthood.

Importance: DNA methylation has been proposed as an epigenetic mechanism by which the childhood neighborhood environment may have implications for the genome that compromise adult health. Objective: To ascertain whether childhood neighborhood socioeconomic disadvantage is associated with differences in DNA methylation by age 18 years. Design, Setting, and Participants: This longitudinal cohort study analyzed data from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally representative birth cohort of children born between 1994 and 1995 in England and Wales and followed up from age 5 to 18 years. Data analysis was performed from March 15, 2019, to June 30, 2019. Exposures: High-resolution neighborhood data (indexing deprivation, dilapidation, disconnection, and dangerousness) collected across childhood. Main Outcomes and Measures: DNA methylation in whole blood was drawn at age 18 years. Associations between neighborhood socioeconomic disadvantage and methylation were tested using 3 prespecified approaches: (1) testing probes annotated to candidate genes involved in biological responses to growing up in socioeconomically disadvantaged neighborhoods and investigated in previous epigenetic research (stress reactivity-related and inflammation-related genes), (2) polyepigenetic scores indexing differential methylation in phenotypes associated with growing up in disadvantaged neighborhoods (obesity, inflammation, and smoking), and (3) a theory-free epigenome-wide association study. Results: A total of 1619 participants (806 female individuals [50%]) had complete neighborhood and DNA methylation data. Children raised in socioeconomically disadvantaged neighborhoods exhibited differential DNA methylation in genes involved in inflammation (ß = 0.12; 95% CI, 0.06-0.19; P < .001) and smoking (ß = 0.18; 95% CI, 0.11-0.25; P < .001) but not obesity (ß = 0.05; 95% CI, -0.01 to 0.11; P = .12). An epigenome-wide association study identified multiple CpG sites at an arraywide significance level of P < 1.16 × 10-7 in genes involved in the metabolism of hydrocarbons. Associations between neighborhood disadvantage and methylation were small but robust to family-level socioeconomic factors and to individual-level tobacco smoking. Conclusions and Relevance: Children raised in more socioeconomically disadvantaged neighborhoods appeared to enter young adulthood epigenetically distinct from their less disadvantaged peers. This finding suggests that epigenetic regulation may be a mechanism by which the childhood neighborhood environment alters adult health.

High suPAR and Low Blood Eosinophil Count are Risk Factors for Hospital Readmission and Mortality in Patients with COPD.

Introduction: The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with increased mortality in chronic obstructive pulmonary disease (COPD), while elevated blood eosinophils have been associated with better survival. We hypothesized that suPAR and blood eosinophil count are independent risk factors for readmission and mortality after an acute admission in patients with COPD. Methods: This retrospective cohort study comprised 4022 patients with prevalent COPD acutely admitted to Hvidovre Hospital, Denmark. Irrespective of cause of admission, suPAR and blood eosinophils were measured, and patients were followed up to 365 days. Associations with 365-day respiratory readmission, all-cause readmission and all-cause mortality were investigated by Cox regression analyses adjusted for age, sex, Charlson score and C-reactive protein. Results: suPAR was significantly elevated in patients who later experienced readmission or died. At 365 days, hazard ratios (HRs) for all-cause readmission and mortality reached 1.61 (95% CI 1.40-1.85; p<0.0001) and 3.40 (95% CI 2.64-4.39; p<0.0001), respectively, for COPD patients in the fourth suPAR quartile compared to patients in the first suPAR quartile. High blood eosinophils (>300 cells/µL) were associated with lower risk of mortality (HR 0.49, 95% CI 0.39-0.62; p<0.0001) compared with patients with <150 cells/µL. When stratifying patients by suPAR quartiles and blood eosinophil counts, the highest relative mortality rate was found in patients belonging to both the fourth suPAR quartile and the low blood eosinophil (<150 cells/µL) group. Conclusion: In this cohort of COPD patients acutely admitted to a hospital, elevated suPAR concentrations were associated with both higher risk of all-cause readmission and mortality, whereas higher blood eosinophil count was associated with lower risk of mortality.

Adolescents' perceptions of family social status correlate with health and life chances: A twin difference longitudinal cohort study.

Children from lower-income households are at increased risk for poor health, educational failure, and behavioral problems. This social gradient is one of the most reproduced findings in health and social science. How people view their position in social hierarchies also signals poor health. However, when adolescents' views of their social position begin to independently relate to well-being is currently unknown. A cotwin design was leveraged to test whether adolescents with identical family backgrounds, but who viewed their family's social status as higher than their same-aged and sex sibling, experienced better well-being in early and late adolescence. Participants were members of the Environmental Risk Longitudinal Twin Study, a representative cohort of British twins (n = 2,232) followed across the first 2 decades of life. By late adolescence, perceptions of subjective family social status (SFSS) robustly correlated with multiple indicators of health and well-being, including depression; anxiety; conduct problems; marijuana use; optimism; not in education, employment, or training (NEET) status; and crime. Findings held controlling for objective socioeconomic status both statistically and by cotwin design after accounting for measures of childhood intelligence (IQ), negative affect, and prior mental health risk and when self-report, informant report, and administrative data were used. Little support was found for the biological embedding of adolescents' perceptions of familial social status as indexed by inflammatory biomarkers or cognitive tests in late adolescence or for SFSS in early adolescence as a robust correlate of well-being or predictor of future problems. Future experimental studies are required to test whether altering adolescents' subjective social status will lead to improved well-being and social mobility.

Abnormal routine blood tests as predictors of mortality in acutely admitted patients.

BACKGROUND: This study aimed to improve early risk stratification in the emergency department by creating a simple blood test score based on routine biomarkers and assess its predictive ability for 30-day mortality of acutely admitted patients. METHODS: This was a secondary analysis of data from the TRIAGE II study. It included unselected acutely admitted medical and surgical patients, who had albumin, C-reactive protein, creatinine, haemoglobin, leukocytes, potassium, sodium and thrombocytes levels analysed upon admission. Patients were classified according to the number of biomarker results outside the reference range into four risk groups termed "very low", "low", "intermediate", and "high" with 0-1, 2-3, 4-5 and 6-8 abnormal biomarker results, respectively. Logistic regression was used to calculate odds ratios for 30-day mortality and receiver operating characteristic was used to test the discriminative value. The primary analysis was done in patients triaged with ADAPT (Adaptive Process Triage). Subsequently, we analysed two other cohorts of acutely admitted patients. RESULTS: The TRIAGE II cohort included 17,058 eligible patients, 30-day mortality was 5.2%. The primary analysis included 7782 patients. Logistic regression adjusted for age and sex showed an OR of 24.1 (95% CI 14.9-41.0) between the very low- and the high-risk group. The area under the curve (AUC) was 0.79 (95% CI 0.76-0.81) for the blood test score in predicting 30-day mortality. The subsequent analyses confirmed the results. CONCLUSIONS: A blood test score based on number of routine biomarkers with an abnormal result was a predictor of 30-day mortality in acutely admitted patients.

The biomarkers suPAR and blood eosinophils are associated with hospital readmissions and mortality in asthma - a retrospective cohort study.

INTRODUCTION: Prognostic biomarkers in asthma are needed. The biomarker soluble urokinase plasminogen activator receptor (suPAR) has been associated with asthma control and with prognosis in acutely admitted medical patients. We investigated if suPAR and blood eosinophil counts at the time of admission for asthma are associated with readmission and mortality. METHODS: Our cohort comprised 1341 patients (median age 45.3, IQR 30.1-63.1) acutely admitted with a diagnosis of asthma to Hvidovre Hospital, Denmark (November 2013 to March 2017). Patients had suPAR and blood eosinophils measured at admission. Outcomes were 365-day readmission and all-cause mortality. Logistic regression analysis adjusted for age, sex, C-reactive protein, and Charlson comorbidity score was used to assess the association of the two biomarkers with readmission and all-cause mortality. RESULTS: Compared to event-free patients, patients who were either readmitted (n = 452, 42.3%) or died (n = 57, 5.3%) had significantly higher suPAR concentrations (p < 0.0001) and lower eosinophil counts (p = 0.0031) at admission. The highest odds of readmission or mortality were observed for patients in either the 4th suPAR quartile (p < 0.0001) or with eosinophil counts < 150 cells/µL at admission. Increasing levels of suPAR were associated with 365-day readmission (OR 1.3 [1.0-1.6]; p = 0.05) and mortality (OR 2.9 [1.7-5.1]; p = 0.0002). Eosinophil count > 300 cells/µL was significantly associated with lower odds of readmission (OR 0.64 [0.5-0.9]; p = 0.005) and lower mortality (OR 0.7 [0.6-0.9]; p = 0.0007). CONCLUSIONS: In patients acutely admitted with asthma, elevated suPAR concentrations together with blood eosinophil count < 150 cells/µL at the time of hospital admission were associated with both 365-day all-cause readmission and mortality.

Early Discharge from the Emergency Department Based on Soluble Urokinase Plasminogen Activator Receptor (suPAR) Levels: A TRIAGE III Substudy.

OBJECTIVE: Using biomarkers for early and accurate identification of patients at low risk of serious illness may improve the flow in the emergency department (ED) by classifying these patients as nonurgent or even suitable for discharge. A potential biomarker for this purpose is soluble urokinase plasminogen activator receptor (suPAR). We hypothesized that availability of suPAR might lead to a higher proportion of early discharges. DESIGN: A substudy of the interventional TRIAGE III trial, comparing patients with a valid suPAR measurement at admission to those without. The primary endpoint was the proportion of patients discharged alive from the ED within 24 hours. Secondary outcomes were length of hospital stay, readmissions, and mortality within 30 days. SETTING: EDs at two university hospitals in the Capital Region of Denmark. PARTICIPANTS: 16,801 acutely admitted patients were included. MEASUREMENTS AND MAIN RESULTS: The suPAR level was available in 7,905 patients (suPAR group), but not in 8,896 (control group). The proportion of patients who were discharged within 24 hours of admittance was significantly higher in the suPAR group compared to the control group (50.2% (3,966 patients) vs. 48.6% (4,317 patients), P = 0.04). Furthermore, the mean length of hospital stay in the suPAR group was significantly shorter compared to that in the control group (4.3 days (SD 7.4) vs. 4.6 days (SD 9.4), P = 0.04). In contrast, the readmission rate within 30 days was significantly higher in the suPAR group (10.6% (839 patients) vs. 8.8% (785 patients), P < 0.001). Among patients discharged within 24 hours, there was no significant difference in the readmission rate or mortality within 30 days. Readmission occurred in 8.5% (336 patients) vs. 7.7% (331 patients) (P = 0.18) and mortality in 1.3% (52 patients) vs. 1.8% (77 patients) (P = 0.08) for the suPAR group and control group, respectively. CONCLUSION: These post hoc analyses demonstrate that the availability of the prognostic biomarker suPAR was associated with a higher proportion of discharge within 24 hours and reduced length of stay, but more readmissions. In patients discharged within 24 hours, there was no difference in readmission or mortality. TRIAL REGISTRATION OF THE MAIN TRIAL: This trial is registered with NCT02643459.

Availability of suPAR in emergency departments may improve risk stratification: a secondary analysis of the TRIAGE III trial.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a prognostic and nonspecific biomarker associated with short-term mortality in emergency department (ED) patients. Therefore, the blood level of suPAR might be usable for identification of patients at high- and low risk, shortly after arrival at the ED. Here, we investigate the value of adding suPAR to triage and how this may impact on risk stratification regarding mortality. METHODS: The analyses were performed on the TRIAGE III cohort. Patients were triaged in four groups: Red, Orange, Yellow, and Green. Outcome was all-cause mortality within seven days. Discriminative abilities of triage and suPAR on mortality were assessed using the area under the curve (AUC) for receiver operating characteristics (ROC) curves. A suPAR cut-off value was generated using the Youden's index. Patients were subsequently reclassified one triage level up if the suPAR level was above this cut-off and one level down if the suPAR level was below that value. RESULTS: The study included 4420 patients with an available triage category and suPAR measurement. suPAR was significantly better in predicting mortality than triage; AUC (95% confidence interval): 0.85 (0.80-0.89) vs. 0.71 (0.64-0.78), P < 0.001. Combining suPAR and triage yielded an AUC of 0.87 (0.82-0-93). The Youden's cut-off of suPAR was 5.9 ng/mL and reclassified triage using this value resulted in a more accurate risk stratification regarding hospital admission and mortality. CONCLUSION: Addition of suPAR to triage potentially improves prediction of short-term mortality. Measurement of suPAR in relation to the triage process may allow a more accurate identification of ED patients at risk. TRIAL REGISTRATION: Clinicaltrials.gov , NCT02643459. Registered 31 December 2015. https://clinicaltrials.gov/ct2/show/NCT02643459?cond=NCT02643459&rank=1 .

Soluble urokinase plasminogen activator receptor is linearly associated with dietary quality and predicts mortality.

Chronic inflammation is associated with disease risk and mortality in the general population. Soluble urokinase plasminogen activator receptor (suPAR) is a stable marker of chronic inflammation, and a higher serum-concentration of suPAR is found in individuals with an unhealthy lifestyle such as smoking. This article investigates the association between suPAR and dietary quality measured with the dietary quality score (DQS). The DQS is an index of the overall quality of an individual's dietary habits assessed through a self-administered FFQ. Furthermore, this article investigates the association of both suPAR and the DQS with CVD risk and mortality in the general Danish population. We analysed 5347 individuals aged 30-60 years from the Danish Inter99 study cohort. Multiple linear regression analyses showed a linear inverse association between the DQS and suPAR (P=0·0005). Cox regression analyses showed an 18 (95 % CI 9, 26) % increase in the risk of death from any cause with each 1 ng/ml increase in suPAR. We found no significant association between the DQS and the mortality (hazard ratio: 1·16, 95 % CI 0·79, 1·69). All analyses were adjusted for demographics and lifestyle factors. The association between the DQS and suPAR on the one hand and suPAR and mortality on the other supports the argument that low dietary quality may constitute a health risk through its influence on chronic inflammation. Future research should examine whether suPAR is modifiable through changes in dietary habits.

Combining National Early Warning Score With Soluble Urokinase Plasminogen Activator Receptor (suPAR) Improves Risk Prediction in Acute Medical Patients: A Registry-Based Cohort Study.

OBJECTIVES: Soluble urokinase plasminogen activator receptor is a prognostic biomarker associated with critical illness, disease progression, and risk of mortality. We aimed to evaluate whether soluble urokinase plasminogen activator receptor adds prognostic value to a vital sign-based score for clinical monitoring of patient risk (National Early Warning Score) in acute medical patients. DESIGN: Registry-based observational cohort study of consecutively admitted acute medical patients. SETTING: The Acute Medical Unit, Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark. PATIENTS: Acute medical patients admitted between November 18, 2013, and September 30, 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 17,312 included patients, admission National Early Warning Score was available for 16,244 (93.8%). During follow-up, 587 patients (3.4%) died in-hospital, 859 (5.0%) within 30 days, and 1,367 (7.9%) within 90 days. High soluble urokinase plasminogen activator receptor was significantly associated with in-hospital-, 30-day-, and 90-day mortality within all National Early Warning Score groups, in particular in patients with a low National Early Warning Score; for 30-day mortality, mortality rate ratios ranged from 3.45 (95% CI, 2.91-4.10) for patients with National Early Warning Score 0-1, to 1.86 (95% CI, 1.47-2.34) for patients with National Early Warning Score greater than or equal to 9 for every doubling in soluble urokinase plasminogen activator receptor (log2-transformed). Combining National Early Warning Score, age, and sex with soluble urokinase plasminogen activator receptor improved prediction of in-hospital-, 30-day-, and 90-day mortality, increasing the area under the curve (95% CI) for 30-day mortality from 0.86 (0.85-0.87) to 0.90 (0.89-0.91), p value of less than 0.0001, with a negative predictive value of 99.0%. CONCLUSIONS: The addition of soluble urokinase plasminogen activator receptor to National Early Warning Score significantly improved risk prediction of both low- and high-risk acute medical patients. Patients with low National Early Warning Score but elevated soluble urokinase plasminogen activator receptor had mortality risks comparable to that of patients with higher National Early Warning Score.

Soluble urokinase plasminogen activator receptor predicts mortality in exacerbated COPD.

BACKGROUND: The inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) is elevated in severe acute and chronic medical conditions and has been associated with short-term mortality. The role of suPAR in predicting risk of death following an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) has never been studied. We hypothesized that increased suPAR is an independent predictor of short-term mortality in patients admitted to hospital with COPD or acute respiratory failure. METHODS: This retrospective cohort study from a university hospital in the Capital Region of Denmark included 2838 acutely admitted medical patients with COPD as primary (AECOPD) or secondary diagnosis, who had plasma suPAR measured at the time of admission between November 18th, 2013 to September 30th, 2015 and followed until December 31st, 2015. Primary outcomes were 30- and 90-days all-cause mortality. Association of suPAR and mortality was investigated by Cox regression analyses adjusted for age, sex, CRP values and Charlson comorbidity index. RESULTS: For patients with AECOPD or underlying COPD, median suPAR levels were significantly higher among patients who died within 30 days compared with those who survived (5.7 ng/ml (IQR 3.8-8.1) vs. 3.6 ng/ml (2.7-5.1), P < 0.0001). Increasing suPAR levels independently predicted 30-day mortality in patients with COPD with a hazard ratio of 2.0 (95% CI 1.7-2.4) but not respiratory failure. CONCLUSIONS: In this large group of acutely admitted patients with COPD, elevated suPAR levels were associated with increased risk of mortality. The study supports the value of suPAR as a marker of poor prognosis.