Sex Differences in Subacute Blood Biomarker Levels and Associations With Post-Concussion Symptom Severity in Adolescents With Concussion

To compare brain injury biomarker release levels between two different cardiopulmonary bypass (CPB) flow rates in elective cardiac surgery and to explore differences in postoperative delirium between groups and associations between age, sex, CPB time, oxygen levels, and near-infrared spectroscopy, and biomarker levels. A randomized controlled substudy trial SETTING: Sahlgrenska University Hospital, Sweden PARTICIPANTS: Forty patients undergoing elective cardiac surgery with CPB INTERVENTION: Patients were assigned at random to either a standard (2.4 L/min/m2) or a high (2.9 L/min/m2) CPB flow rate. Glial fibrillary acidic protein, neurofilament light chain, total-tau, and phosphorylated-tau217 were sampled in plasma before anesthesia induction, after 60 minutes on CPB, and at 30 minutes, 24 hours, and 72 hours post-CPB. Mixed models for repeated measures were used to analyze differences in biomarker levels between groups and to assess relationships, which showed no differences between the 2 flow rate groups. There also was no difference in the occurrence of delirium between the 2 groups. Associations were found between age and increased neurofilament light chain levels. Female sex, oxygen delivery >330 mL/min/m2, and near-infrared spectroscopy level >60% were associated with lower biomarker levels. An increased flow rate did not have any significant effects on biomarker levels compared to a standard flow rate. Several associations were identified between treatment characteristics and biomarker levels. No difference in delirium was seen.

X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD. We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4-13 years) using Simoa®and Luminex® technologies. Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80-100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD. Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset. Austrian Science Fund, European Leukodystrophy Association.

Biomarkers of Inflammation and Oxidative Stress in HeartMate II vs HeartMate 3 Patients

The identification of biomarkers associated with major depressive disorder (MDD) holds great promise to develop an objective laboratory test. However, current biomarkers lack discriminative power due to the complex biological background, and not much is known about the influence of potential modifiers such as gender. We first performed a cross-sectional study on the discriminative power of biomarkers for MDD by investigating gender differences in biomarker levels. Out of 28 biomarkers, 21 biomarkers were significantly different between genders. Second, a novel statistical approach was applied to investigate the effect of gender on MDD disease classification using a panel of biomarkers. Eleven biomarkers were identified in men and eight in women, three of which were active in both genders. Gender stratification caused a (non-significant) increase of Area Under Curve (AUC) for men (AUC = 0.806) and women (AUC = 0.807) compared to non-stratification (AUC = 0.739). In conclusion, we have shown that there are differences in biomarker levels between men and women which may impact accurate disease classification of MDD when gender is not taken into account.

PurposeThe pathology of peri-implantitis is still not fully understood and there have been recent challenges to the consensus on its aetiology and pathology, especially in comparison with periodontitis. The assessment of biomarkers allows a comparison of the pathology of these diseases. The aim of this systematic review was to answer the research question: “Is there a difference in the biomarkers associated with peri-implantitis compared with periodontitis in adult humans?”MethodsElectronic databases were searched and screened, and a manual search was also undertaken. The inclusion criteria were adults with peri-implantitis who had been compared to adults with periodontitis with the outcome of biomarkers assessed via biopsies or crevicular fluid samples in primary or secondary care settings, as recorded in case-control, case series and retrospective, prospective and cross-sectional observational studies. Two reviewers independently screened titles and abstracts and assessed full text articles for eligibility and inclusion. Both reviewers independently extracted data and assessed risk of bias. Differences in biomarker levels were the primary outcome and a narrative review was undertaken due to the heterogeneity of studies.ResultsIn total, 2,374 articles were identified in the search, of which 111 full-text articles were assessed for eligibility and 13 were included in the qualitative synthesis. Five of the 13 included studies were deemed to be at high risk of bias, with the others having moderate risk. All studies were cross-sectional and performed at university hospitals. Nine of the 13 included studies found significant differences in the levels of biomarkers or their ratios between peri-implantitis and periodontitis. Four of the studies found no significant differences.ConclusionsWithin the limitations of the included studies, it appears that there may be a difference in biomarker levels and ratios between peri-implantitis and periodontitis, suggesting that these disease processes are somewhat distinct.

View the review history for Infectious mononucleosis in children and differences in biomarker levels and other features between disease caused by Epstein–Barr virus and other pathogens: a single-center retrospective study in China

Gastrin-17 (G-17), pepsinogen-1 (Pg1) and pepsinogen-2 (Pg2) reflect the functional state of gastric mucosa and are used for non-invasive diagnosis and screening of atrophic gastritis. The aim of the study was to clarify if erosive reflux disease (ERD) or non-ERD (NERD) can be distinguished from other dyspeptic conditions in patients, in a non-invasive manner using specific biomarkers. Levels of G-17, Pg1, and Pg2 were measured in 141 ERD patients (median age 48 years, males — 68), 122 NERD patients (median age 45 years, males — 32) and 410 control patients (median age 50 years, males — 97). Levels of biomarkers in ERD and NERD groups were compared to controls. Median levels of G-17 (1.94 vs 2.92 pmol/L, p = 0.036) and Pg2 (6.70 vs 7.79 µg/l, p = 0.046) were lower in the ERD group compared to control patients; no difference with respect to the control was found for the NERD group. After exclusion of the patients having at least one potential condition that might modify the levels of the biomarkers (gastric mucosa atrophy, Helicobacter pylori colonisation), no difference in levels of biomarkers was observed with respect to the control for both the ERD and NERD groups. G-17, Pg1, and Pg2 based tests cannot be used to distinguish ERD or NERD from other dyspeptic conditions in patients.

There is significant heterogeneity in outcomes following mild traumatic brain injury (mTBI). While several host factors (age, gender, and preinjury psychiatric history) have been investigated, the influence of preinjury psychological resilience and mood status in conjunction with mild TBI remains relatively unexplored. Euthymic mood and high resilience are potentially protective against anxiety and postconcussion symptoms, but their relative contributions are currently unknown. This prospective study obtained preinjury estimates of resilience and mood measures in addition to measures of anxiety (Acute Stress Disorder Scale and PTSD-Checklist-Civilian form) and postconcussion symptom severity (Rivermead Post Concussion Symptoms Questionnaire) <24 hours (Baseline), 1 week, and 1 month postinjury in patients with either mTBI (n=46) or a comparison group with orthopedic injuries not involving the head (OI, n=29). The groups did not differ on preinjury resilience or mood status at baseline, but differed significantly on measures of anxiety and postconcussion symptom severity at each subsequent study occasion. Multivariate linear regression analyses were conducted to determine if preinjury resilience and mood were significant contributors to anxiety and postconcussion symptoms during the first month postinjury after accounting for other known host factors (e.g., age at injury, gender, and education). Injury group and preinjury mood status were significant predictors for all three dependent variables at each study occasion (all p<0.007). Preinjury resilience showed a positive trend only for acute stress severity at baseline, but demonstrated significant prediction of all three dependent measures at one week and one month postinjury. These results suggest that preinjury depressed mood and resilience are significant contributors to the severity of postinjury anxiety and postconcussion symptoms, even after accounting for effects of other specific host factors.

Country-level differences in nicotine vaping products used and biomarkers of exposure among long-term e-cigarette users and dual users remain understudied. This cross-sectional study was conducted in 2014 in the United States (n = 166), United Kingdom (n = 129), and Poland (n = 161). We compared patterns of tobacco product use and nicotine and toxicant exposure among cigarette-only smokers (n = 127); e-cigarette-only users (n = 124); dual users of tobacco cigarettes and e-cigarettes (n = 95); and non-users (control group, n = 110) across three countries using mixed-effects linear regression. Compared with cigarette smokers, e-cigarette-only users had lower levels of toxicant biomarkers, but higher levels of nicotine biomarkers. Dual users had higher levels of toxicant biomarkers than e-cigarette-only users but similar levels to cigarette-only smokers. E-cigarette users in Poland, who overwhelmingly used refillable tank devices, exhibited greater levels of nicotine, and toxicant biomarkers relative to e-cigarette users in US/UK. Despite smoking fewer cigarettes, dual users from Poland exhibited similar levels of nicotine biomarkers compared with UK dual users, but higher than US dual users. Country-level differences in e-cigarette devices used and smoking behaviors (e.g., intensity) may contribute to differences in biomarker levels among users of the same products residing in different countries.

Background:The vast majority of chronic lymphocytic leukemia survivors experience late effect of treatment including cardiovascular events. These effects contribute most of the substantial effects excess mortality in patients with full or partial response to CLL treatment.Aims:We aimed to evaluate the impact of atorvastatin on galectin‐3 and VE‐cadherin, and cardiovascular risk in patients with chronic lymphocytic leukemia in remission.Methods:One hundred fifty seven out subjects with chronic lymphocytic leukemia in full or partial remission were enrolled in the study. Atorvastatin at doses 20 mg/d and 40 mg/d was prescribed for patients with hypercholesterinemia, dyslipidemia, coronary artery disease risk factors. Blood samples for biomarkers measurements were collected at the visit of inclusion into the study. Plasma levels of galectin‐3, and VE‐cadherin were measured by ELISA method at baseline and after 1 year of observation period.Results:Two hundred seventy cumulative clinical events occurred in 68 patients (43.3%) within the follow‐up, with their distribution being as follows: 12 deaths for cardiovascular reasons, 17 life‐threatening arrhythmias, 36 cardiac ischemic events, 9 strokes, 38 decompensated chronic heart failures, and 58 hospital admissions for cardiovascular reasons. Patients were divided to two groups depending on the atorvastatin treatment. At baseline there were no difference in levels of biomarkers between groups. In one year there were significant differences in levels of galectin‐3 (8,86 ± 5,62 ng/ml vs 16,74 ± 8,52 ng/ml; р = 0,035), VE‐cadherin (0,76 ± 0,64 ng/ml vs 2,19 ± 1,66 ng/ml; р = 0,046) in the group without atorvastatin treatment. The optimal cut‐off point of galectin‐3 level for distinguishing high cardiovascular risk patients from low risk ones was 11.75 ng/ml, with a sensitivity of 70.4% and a specificity of 96.8%; for VE‐cadherin – 0.53 ng/ml, with a sensitivity of 72.6% and a specificity of 95.2%. Combination of galectin‐3 and VE‐cadherin had high negative prognostic value (93.4%) for evaluation of cardiovascular events.Atorvastatin treatment were associated with decreasing of cumulative cardiovascular events with appearance of early differences between groups during 3 year observation time (long‐rank test, χ2 = 11,775, р = 0,001). During first year of observation event‐free survival were better for patients treated with atorvastatin 40 mg/d in comparing to patients treated with atorvastatin 20 mg/d (long‐rank test, χ2 = 6,147, р = 0,013).Summary/Conclusion:Among patients with chronic lymphocytic leukemia in remission galectin‐3 and VE‐cadherin are associated with increased risk of cardiovascular events within 3 year observation period. Atorvastatin prevents increasing of galectin‐3 and VE‐cadherin and reduces risk of cardiovascular events in this group of patients. It was proposed to prescribe atorvastatin to patients with level of galectin‐3 11.75 ng/ml or higher, and/or level of VE‐cadherin 0.53 mg/ml or higher for prevention of cardiovascular events during 3 year period.

Research has found that service members (SMs) with mild traumatic brain injury (mTBI) and co-occurring bodily injuries endorse lower chronic postconcussive symptom severity than SMs with mTBI and no bodily injuries. Investigations were conducted with primarily post–9/11 war-era SMs with blast injuries. The current study explores these findings in a cohort of more heterogeneous and recently evaluated military SM. Possible reasons suggested for the earlier findings include SMs with bodily injuries report fewer postconcussive symptoms due to (1) focusing attention on extra-cranial injuries and associated pain; (2) receiving more interpersonal and medical support, lowering distress; (3) using analgesics such as morphine or opioids; or (4) experiencing delayed postconcussive symptoms. The current investigation evaluates each of these hypothesized reasons for the earlier findings and the generalizability of the findings to a more recent sample. Data were extracted from 165 SMs in a TBI repository at a U.S. military medical center. All participants reported a history of an mTBI, confirmed by a clinical interview to meet Veterans Affairs and Department of Defense criteria. Other bodily injuries received at the time of the mTBI were documented with the Abbreviated Injury Scale (AIS). Multiple regression models evaluated the ability of the four hypothesized mechanisms to predict postconcussive symptom severity, measured by the Neurobehavioral Symptom Inventory. SMs with bodily injuries (n = 48) reported nonsignificantly lower postconcussive symptoms than SMs with no bodily injuries (n = 117). The level of subjective pain was a determinant of postconcussive symptom severity among SMs with a history of mTBI, with or without associated bodily injuries. Social support was a weaker negative predictor of postconcussive symptoms among SMs with no associated bodily injuries.

Obesity and insulin resistance (IR) predispose to type 2 diabetes mellitus. Yet only half of obese adolescents have IR and far fewer progress to type 2 diabetes mellitus. We hypothesized that amino acid and fatty acid metabolites may serve as biomarkers or determinants of IR in obese teens. Fasting blood samples were analyzed by tandem mass spectrometry in 82 obese adolescents. A principal components analysis and multiple linear regression models were used to correlate metabolic components with surrogate measures of IR: homeostasis model assessment index of insulin resistance (HOMA-IR), adiponectin, and triglyceride (TG) to high-density lipoprotein (HDL) ratio. Branched-chain amino acid (BCAA) levels and products of BCAA catabolism were higher (P < .01) in males than females with comparable body mass index (BMI) z-score. In multivariate analyses, HOMA-IR in males correlated positively with BMI z-score and a metabolic signature containing BCAA, uric acid, and long-chain acylcarnitines and negatively with byproducts of complete fatty acid oxidation (R(2) = 0.659, P < .0001). In contrast, only BMI z-score correlated with HOMA-IR in females. Adiponectin correlated inversely with BCAA and uric acid (R(2) = 0.268, P = .0212) in males but not females. TG to HDL ratio correlated with BMI z-score and the BCAA signature in females but not males. BCAA levels and byproducts of BCAA catabolism are higher in obese teenage boys than girls of comparable BMI z-score. A metabolic signature comprising BCAA and uric acid correlates positively with HOMA-IR in males and TG to HDL ratio in females and inversely with adiponectin in males but not females. Likewise, byproducts of fatty acid oxidation associate inversely with HOMA-IR in males but not females. Our findings underscore the roles of sex differences in metabolic function and outcomes in pediatric obesity.

Purpose Enteroviruses (EV) comprises many different types and are the most common cause of aseptic meningitis. How the virus affects the brain including potential differences between types are largely unknown. Measuring biomarkers in CSF is a tool to estimate brain damage caused by CNS infections. Methods A retrospective study was performed in samples from 38 patients with acute neurological manifestations and positive CSF-EV RNA (n = 37) or serum-IgM (n = 1). The EV in 17 samples were typed by sequencing. The biomarkers neurofilament light (NFL), glial fibrillary acidic protein (GFAP), S-100B protein, amyloid-β (Aβ) 40 and Aβ42, total-tau (T-tau) and phosphorylated tau (P-tau) were measured and compared with data derived from a control group (n = 19). Results There were no increased levels of GFAP (p ≤ 0.1) nor NFL (p ≤ 0.1) in the CSF of patients with EV meningitis (n = 38) compared with controls. However, we found decreased levels of Aβ42 (p < 0.001), Aβ40 (p < 0.001), T-tau (p ≥ 0.01), P-tau (p ≤ 0.001) and S-100B (p ≤ 0.001). E30 (n = 9) and CVB5 (n = 6) were the most frequent EV-types identified, but no differences in biomarker levels or other clinical parameters were found between the infecting virus type. Seven patients who were followed for longer than one month reported remaining cognitive impairment, although no correlations with biomarker concentrations were observed. Conclusion There are no indication of neuronal or astrocyte damage in patients with EV meningitis. Yet, decreased concentrations of Aβ40, Aβ42, P-tau and T-tau were shown, a finding of unknown importance. Cognitive impairment after acute disease occurs, but with only a limited number of patients analysed, no conclusion can be drawn concerning any association with biomarker levels or EV types.

BackgroundTwenty to thirty percent of persons with Trypanosoma cruzi infection eventually develop cardiomyopathy. If an early indicator were to be identified and validated in longitudinal studies, this could enable treatment to be prioritized for those at highest risk. We evaluated cardiac and extracellular matrix remodeling markers across cardiac stages in T. cruzi infected (Tc+) and uninfected (Tc−) individuals.MethodsParticipants were recruited in a public hospital in Santa Cruz, Bolivia and assigned cardiac severity stages by electrocardiogram and echocardiogram. BNP, NTproBNP, CKMB, troponin I, MMP-2, MMP-9, TIMP-1, TIMP-2, TGFb1, and TGFb2 were measured in specimens from 265 individuals using multiplex bead systems. Biomarker levels were compared between Tc+ and Tc− groups, and across cardiac stages. Receivers operating characteristic (ROC) curves were created; for markers with area under curve>0.60, logistic regression was performed.ResultsAnalyses stratified by cardiac stage showed no significant differences in biomarker levels by Tc infection status. Among Tc+ individuals, those with cardiac insufficiency had higher levels of BNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 than those with normal ejection fraction and left ventricular diameter. No individual marker distinguished between the two earliest Tc+ stages, but in ROC-based analyses, MMP-2/MMP-9 ratio was significantly higher in those with than those without ECG abnormalities.ConclusionsBNP, NTproBNP, troponin I, MMP-2, TIMP-1, and TIMP-2 levels rose with increasing severity stage but did not distinguish between Chagas cardiomyopathy and other cardiomyopathies. Among Tc+ individuals without cardiac insufficiency, only the MMP-2/MMP-9 ratio differed between those with and without ECG changes.

To investigate risk factors that can help identify the possibility of pregnancy loss in threatened late miscarriage (TLM) patients with and without spontaneous uterine contractions. Amniotic immune biomarkers (IL2β receptor, IL6, IL8, IL10, IL1β, and TNFα) were assayed, and "sludge" was assessed. Patients without intrauterine infections were treated and followed up until delivery, and pregnancy outcomes were recorded. The two groups were compared for the differences in biomarker levels and "sludge," and the independent associations of biomarkers, "sludge," and other maternal factors with late miscarriage were investigated. The amniotic levels of IL2βR, IL8, and TNFα were higher in the group with contractions (P<.05). When considered alone, each of the six biomarkers was significantly associated with late miscarriage in the no-contractions group and four of these (IL8, IL10, IL1β, and TNFα) in the contractions group (P<.05). Biomarker levels were correlated, and in multivariate Cox regression analysis, there was an independent effect only for IL8 in the no-contractions group (HR=18.16, 95% CI: 5.75-57.43) and TNFα in the contractions group (HR=4.11, 95% CI: 1.68-10.08). For patients with contractions, IL10, IL8, and IL1β were different in those with and without "sludge," but no such difference was seen in the no-contractions group. For TLM patients without intrauterine infections, amniotic immune biomarkers differ between patients with different symptoms, not only for their levels but also for the impact of these biomarkers on the risk of late miscarriage. These findings suggest that the symptoms of TLM should be considered in the study of miscarriage risk.