Browsing by Subject "biomarkers"
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Item Open Access A Brief Chronicle of CD4 as a Biomarker for HIV/AIDS: A Tribute to the Memory of John L. Fahey.(For Immunopathol Dis Therap) Kagan, Jonathan M; Sanchez, Ana M; Landay, Alan; Denny, Thomas NFoundational cellular immunology research of the 1960s and 1970s, together with the advent of monoclonal antibodies and flow cytometry, provided the knowledge base and the technological capability that enabled the elucidation of the role of CD4 T cells in HIV infection. Research identifying the sources and magnitude of variation in CD4 measurements, standardized reagents and protocols, and the development of clinical flow cytometers all contributed to the feasibility of widespread CD4 testing. Cohort studies and clinical trials provided the context for establishing the utility of CD4 for prognosis in HIV-infected persons, initial assessment of in vivo antiretroviral drug activity, and as a surrogate marker for clinical outcome in antiretroviral therapeutic trials. Even with sensitive HIV viral load measurement, CD4 cell counting is still utilized in determining antiretroviral therapy eligibility and time to initiate therapy. New point of care technologies are helping both to lower the cost of CD4 testing and enable its use in HIV test and treat programs around the world.Item Open Access Apoptotic variants as predictors of risk of oropharyngeal cancer recurrence after definitive radiotherapy.(Int J Cancer, 2015-11-15) Zhang, Fenghua; Sturgis, Erich M; Sun, Yan; Zhang, Yang; Wei, Qingyi; Zhang, Caiyun; Zheng, Hongliang; Li, GuojunSingle nucleotide polymorphisms (SNPs) in the promoter region of FAS and FASLG may alter their transcriptional activity. Thus, we determined the associations between four FAS and FASLG promoter variants (FAS1377G>A, rs2234767; 670A>G, rs1800682; FASLG844T>C, rs763110 and 124A>G, rs5030772) and the risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP). We evaluated the associations between FAS and FASLG genetic variants and the risk of recurrence in a cohort of 1,008 patients. The log-rank test and multivariate Cox models were used to evaluate the associations. Compared with patients with common homozygous genotypes of FAS670 and FASLG844 polymorphisms, patients with variant genotypes had lower disease-free survival rates (log-rank p < 0.0001 and p < 0.0001, respectively) and an approximately threefold higher risk of SCCOP recurrence (HR, 3.2;95% CI, 2.2-4.6; and HR, 3.1; 95% CI, 2.2-4.4, respectively) after multivariate adjustment. Furthermore, among patients with HPV16-positive tumors, those with variant genotypes of these two polymorphisms had lower disease-free survival rates (log-rank, p < 0.0001 and p < 0.0001, respectively) and a higher recurrence risk than did patients with common homozygous genotypes (HR, 12.9; 95% CI, 3.8-43.6; and HR, 8.1; 95% CI, 3.6-18.6, respectively), whereas no significant associations were found for FAS1377 and FASLG124 polymorphisms. Our findings suggest that FAS670 and FASLG844 polymorphisms modulate the risk of recurrence of SCCOP, particularly in patients with HPV16-positive tumors. Larger studies are needed to validate these results.Item Open Access Collagen biomarkers for arthritis applications.(Biomark Insights, 2007-02-07) Birmingham, James D; Vilim, Vladimir; Kraus, Virginia BItem Open Access Country of residence is associated with distinct inflammatory biomarker signatures in HIV-infected patients.(J Virus Erad, 2017-01-01) Manion, Maura; Andrade, Bruno B; DerSimonian, Rebecca; Gu, Wenjuan; Rupert, Adam; Musselwhite, Laura W; Sierra-Madero, Juan G; Belaunzaran-Zamudio, Pablo F; Sanne, Ian; Lederman, Michael M; Sereti, IriniBACKGROUND: Inflammation and coagulation biomarkers are independent predictors of morbidity and mortality in HIV-infected patients. The impact of country of residence on these biomarkers is unknown and was investigated in persons at similar stages of HIV infection. METHODS: Cryopreserved plasma specimens were analysed from 267 ART-naive patients with CD4 cell counts <100 cells/μl from Mexico (n=124) and South Africa (n=143). Biomarkers were compared and dimension reduction analyses were performed to highlight biosignatures according to nationality, gender and tuberculosis co-infection. RESULTS: Mexican patients were significantly different from South Africans with regard to age, gender, CD4 cell count, haemoglobin, presence of AIDS-defining illness and prevalence of active tuberculosis. After adjusting for baseline characteristics, patients from Mexico had higher levels of IFN-γ, IL-8, and CXCL-10 whereas patients from South Africa had higher levels of fibrinogen, LTB4, P-selectin, protein S, and sCD40 ligand. The effect of country on the profile of biomarker expression was stronger than gender differences and tuberculosis co-infection. CONCLUSION: Inflammation and coagulation biomarkers vary significantly by country. Further studies are needed to evaluate how these differences may contribute to HIV pathogenesis and prognosis in diverse populations and how they can be accounted for in studies using biomarkers as surrogate end points.Item Open Access Cytokine biomarkers in tear film for primary open-angle glaucoma.(Clin Ophthalmol, 2017) Gupta, Divakar; Wen, Joanne C; Huebner, Janet L; Stinnett, Sandra; Kraus, Virginia B; Tseng, Henry C; Walsh, MollyPURPOSE: To determine the utility of tear film cytokines as biomarkers for early primary open-angle glaucoma (POAG). METHODS: Patients without POAG and eye drop-naïve patients with newly diagnosed POAG were recruited from an academic hospital-based glaucoma practice. Tear films of recruited patients were obtained and analyzed using a multiplex, high-sensitivity electrochemiluminescent enzyme-linked immunosorbent assay for proinflammatory cytokines (IFNγ, IL-10, IL-12p70, IL-13, IL-1β, IL-2, IL-4, IL-6, IL-8, and TNFα). RESULTS: Mean concentrations of tear film cytokines were lower in the glaucoma group for 8 of 10 cytokines tested. IL-12p70 (3.94±2.19 pg/mL in control vs 2.31±1.156 pg/mL in POAG;P=0.035) was significantly lower in the tear film of patients with newly diagnosed POAG. CONCLUSION: Proinflammatory cytokines were lower in eye drop-naïve newly diagnosed glaucoma patients. Tear film cytokine profiles may be used as biomarkers of early POAG.Item Open Access Evaluation of the prognostic value of GDF-15, ABC-AF-bleeding score and ABC-AF-death score in patients with atrial fibrillation across different geographical areas.(Open heart, 2021-03) Pol, Tymon; Hijazi, Ziad; Lindbäck, Johan; Alexander, John H; Bahit, M Cecilia; De Caterina, Raffaele; Eikelboom, JW; Ezekowitz, Michael D; Gersh, Bernard J; Granger, Christopher B; Hylek, Elaine M; Lopes, Renato; Siegbahn, Agneta; Wallentin, LarsObjectives
Growth differentiation factor 15 (GDF-15) is a biomarker independently associated with bleeding and death in anticoagulated patients with atrial fibrillation (AF). GDF-15 is also used as one component in the more precise biomarker-based ABC (age, biomarkers, clinical history)-AF-bleeding and ABC-AF-death risk scores. Data from large trials indicate a geographic variability in regard to overall outcomes, including bleeding and mortality risk. Our aim was to assess the consistency of the association between GDF-15, ABC-AF-bleeding score and ABC-AF-death score, with major bleeding and death, across world geographic regions.Methods
Data were available from 14 767 patients with AF from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial and 8651 patients with AF from the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial in this cohort study. GDF-15 was analysed from plasma samples obtained at randomisation. The geographical consistency of the associations between outcomes and GDF-15, ABC-AF-bleeding score and ABC-AF-death scores were assessed by Cox-regression models including interactions with predefined geographical region.Results
GDF-15 and the ABC-AF-bleeding score were associated with major bleeding in both trials across regions (p<0.0001). Similarly, GDF-15 and the ABC-AF-death score were associated with all-cause mortality in both trials across regions (p<0.0001). Overall, the association between GDF-15, the ABC-AF-bleeding score and ABC-AF-death risk score with major bleeding and death was consistent across regions in both ARISTOTLE and the RE-LY trial cohorts. The ABC-AF-bleeding and ABC-AF-death risk scores were consistent regarding discriminative ability when comparing geographic regions in both trial cohorts. The C-indices ranged from 0.649 to 0.760 for the ABC-AF-bleeding and from 0.677 to 0.806 for the ABC-AF-death score by different geographic regions.Conclusions
In patients with AF on anticoagulation, GDF-15 and the biomarker-based ABC-AF-bleeding and ABC-AF-death risk scores are consistently associated with respectively increased risk of major bleeding and death and have similar prognostic value across world geographic regions.Trial registration number
ClinicalTrials.gov Registry NCT00412984 and NCT00262600.Item Embargo Exploring the Utility of Silicone Wristbands for Monitoring Exposure to Chemicals Present in Personal Care Products with a Focus on Parabens(2024) Levasseur, Jessica LesaParabens are environmental phenols that are most commonly found in personal care products (PCPs) worldwide. Though used widely, there is some contradictory information and data in the peer reviewed literature regarding their safety. To support informed risk assessment, more detailed information on exposure, exposure sources, and behaviors that contribute to exposure are needed. Current approaches for assessing exposure to parabens typically utilize urine samples that may not reflect average chronic exposure due to their short half-lives in the body. Wearable sensors, such as the silicone wristband (SWB), hold promise for improving exposure research in this area, particularly for chemicals that are quickly metabolized in the body. The overarching goal of this dissertation was to determine if SWBs could be an effective tool for measuring individual level exposure to parabens as a result of PCP use. Four parabens are examined herein: methylparaben, ethylparaben, propylparaben, and butylparaben. These compounds are often measured in exposure measurement matrices as a proxy for PCP exposure. Current research suggests that SWBs integrate both inhalation and dermal routes of exposure, the two major exposure routes for parabens. This dissertation therefore set out to determine if SWBs could provide more precise measures of exposure compared to more traditional approaches that utilize house dust samples, hand wipes, or spot urine samples. Aim 1 of this thesis sought to investigate the relationships between environmental and biological samples for phenols, including parabens and triclosan, in the home environment . This involved analysis of paired house dust, hand wipes, children’s urine, and SWBs collected from children in North Carolina. Guardians of these children (aged 3-6 years) completed questionnaires on habits and behaviors. All questionnaires and samples were collected between 2014 and 2016. Positive correlations for methyl-, ethyl-, and propylparaben were observed frequently in all matrices investigated. Exposure measurements from the sampled abiotic matrices were significantly correlated to associated urinary biomarkers for these parabens , although correlations with urine were higher for hand wipes and SWBs compared to dust. Everyday lotion use was also associated with significantly higher levels of urinary paraben biomarkers in children. These results demonstrated that lotion is a predictor of paraben exposure in children, and that SWBs may be a suitable tool for assessing children’s exposure to both parabens and triclosan. Aim 2 was designed to determine if SWBs could provide a quantitative estimate of total paraben internal dose by comparing their predictive ability compared to a spot urine sample. Uptake of parabens onto SWBs was assessed by asking 10 adults from central North Carolina to wear five SWBs, with one removed each day over five days. 24-hour urine samples and random spot urine samples were also collected daily to evaluate paraben biomarkers of exposure for methyl-, ethyl-, propyl-, and butylparaben. The concentrations of parabens and triclosan in SWB and spot urine samples were compared to measures of the total mass excreted over five days. Results demonstrated that butylparaben had a significant and positive linear uptake over five days, while methyl- and ethylparaben displayed an apparent steady state concentration over five days. SWBs and spot urine samples were similarly correlated to total mass excreted for parabens. Due to the advantages of SWBs over spot urine samples, such as higher sensitivity (i.e. greater detection rates), reduced participant burden, and less dependency on the timing of sample collection, SWBs may be a more suitable tool for assessing exposure to PCPs. Lastly, Aim 3 investigated the sensitivity of SWBs in their ability to detect paraben exposures resulting from the use of a specific PCP (lotion) and whether concentrations observed in SWBs correlate with the total mass of parabens excreted in urine. To support this aim, 20 adults from central North Carolina were asked to participate for two, three-day periods over two weeks. Participants were asked to keep PCP use identical between the two periods, but during one period (randomized as first or second period per participant) participants were asked to apply one pump of a body lotion (containing a known about of parabens) to the arm on which they wore the wristband. During both periods, participants wore a single SWB and collected three 24-hour urine samples. Results demonstrate that wristbands were able to differentiate paraben exposure between Lotion and No Lotion periods as well as urinary biomarkers of exposure. This study provides evidence that SWBs can detect chemical exposures originating from use of PCPs, and suggest that SWBs are a promising and sensitive tool to capture differences in PCP use in individuals. Collectively, this dissertation provides evidence that SWBs are a promising method to measure exposure to chemicals found within PCPs. Accurate exposure classification is critical for both epidemiological studies of health effects and risk assessments used for chemical regulation. This dissertation supplies the first evidence that SWBs can be used to measure common exposures, such as those from PCPs like lotions, and that these measurements realistically correlate to common measurements of internal dose.
Item Open Access Heterogeneity of glycan biomarker clusters as an indicator of recurrence in pancreatic cancer.(Frontiers in oncology, 2023-01) Wisniewski, Luke; Braak, Samuel; Klamer, Zachary; Gao, ChongFeng; Shi, Chanjuan; Allen, Peter; Haab, Brian BIntroduction
Outcomes following tumor resection vary dramatically among patients with pancreatic ductal adenocarcinoma (PDAC). A challenge in defining predictive biomarkers is to discern within the complex tumor tissue the specific subpopulations and relationships that drive recurrence. Multiplexed immunofluorescence is valuable for such studies when supplied with markers of relevant subpopulations and analysis methods to sort out the intra-tumor relationships that are informative of tumor behavior. We hypothesized that the glycan biomarkers CA19-9 and STRA, which detect separate subpopulations of cancer cells, define intra-tumoral features associated with recurrence.Methods
We probed this question using automated signal thresholding and spatial cluster analysis applied to the immunofluorescence images of the STRA and CA19-9 glycan biomarkers in whole-block sections of PDAC tumors collected from curative resections.Results
The tumors (N = 22) displayed extreme diversity between them in the amounts of the glycans and in the levels of spatial clustering, but neither the amounts nor the clusters of the individual and combined glycans associated with recurrence. The combined glycans, however, marked divergent types of spatial clusters, alternatively only STRA, only CA19-9, or both. The co-occurrence of more than one cluster type within a tumor associated significantly with disease recurrence, in contrast to the independent occurrence of each type of cluster. In addition, intra-tumoral regions with heterogeneity in biomarker clusters spatially aligned with pathology-confirmed cancer cells, whereas regions with homogeneous biomarker clusters aligned with various non-cancer cells.Conclusion
Thus, the STRA and CA19-9 glycans are markers of distinct and co-occurring subpopulations of cancer cells that in combination are associated with recurrence. Furthermore, automated signal thresholding and spatial clustering provides a tool for quantifying intra-tumoral subpopulations that are informative of outcome.Item Open Access High-sensitivity troponin assays: evidence, indications, and reasonable use.(J Am Heart Assoc, 2014-01-27) Sherwood, Matthew W; Kristin Newby, LItem Open Access Initial displacement of the intra-articular surface after articular fracture correlates with PTA in C57BL/6 mice but not "superhealer" MRL/MpJ mice.(Journal of orthopaedic research : official publication of the Orthopaedic Research Society, 2021-09) Vovos, Tyler J; Furman, Bridgette D; Huebner, Janet L; Kimmerling, Kelly A; Utturkar, Gangadhar M; Green, Cynthia L; Kraus, Virginia B; Guilak, Farshid; Olson, Steven APosttraumatic arthritis (PTA) occurs commonly after articular fracture and may arise, in part, from joint surface incongruity after injury. MRL/MpJ (MRL) "super-healer" mice are protected from PTA compared to C57BL/6 (B6) mice following articular fracture. However, the relationship between the initial displacement of the articular surface, biologic response, and susceptibility to PTA after fracture remains unclear. The objective of this study was to assess whether joint incongruity after articular fracture, as measured by in vivo micro-computed tomography (microCT), could predict pathomechanisms of PTA in mice. B6 and MRL mice (n = 12/strain) received a closed articular fracture (fx) of the left tibial plateau. Articular incongruity was quantified as bone surface deviations (BSD) for each in vivo microCT scan obtained from pre-fx to 8 weeks post-fx, followed by histologic assessment of arthritis. Serum concentrations of bone formation (PINP) and bone resorption (CTX-I) biomarkers were quantified longitudinally. Both strains showed increases in surface incongruity over time, as measured by increases in BSD. In B6 mice, acute surface incongruity was significantly correlated to the severity of PTA (R 2 = 0.988; p = .0006), but not in MRL mice (R 2 = 0.224; p = .220). PINP concentrations significantly decreased immediately post-fx in B6 mice (p = .023) but not in MRL mice, indicating higher bone synthesis in MRL mice. MRL/MpJ mice demonstrate a unique biologic response to articular fracture such that the observed articular bone surface displacement does not correlate with the severity of subsequent PTA. Clinical Relevance: Identifying therapies to enhance acute biologic repair following articular fracture may mitigate the risk of articular surface displacement for PTA.Item Open Access Preclinical and Early Osteoarthritis(2023) Kraus, VirginiaThe term early osteoarthritis (OA) is often used to refer to mild or moderately severe radiographic OA. More recently, the term early OA has been used to refer to preradiographic or even earlier phases of disease. Diagnosis of OA in its early preradiographic stages could improve the likelihood of disease modification and thereby reduce medical costs, morbidity, and disability. The advent of sensitive imaging techniques has provided concrete evidence for joint structural abnormalities predating the quintessential radiographic changes we associate with OA. However, conventional OA risk factors function poorly for detection of preclinical and early OA. Therefore, it is currently difficult to define asymptomatic early stage (preclinical) OA in the absence of imaging abnormalities. Because not all radiographic OA progresses to a severe grade of disease or results in joint replacement, by inference, likely not all preclinical or preradiographic OA is expected to progress to early OA and more advanced stages of disease. The trajectory from preclinical to preradiographic to radiographic OA is influenced by the robustness of the endogenous cartilage repair responses, that vary by joint site, and genetic polymorphisms of growth factors implicated in OA susceptibility. The paradigm of joint tissue and biomarker alterations after joint injury is expected to provide a scenario for developing diagnostic algorithms for the early detection of idiopathic OA.Item Open Access Predictors of Stress-Delta High-Sensitivity Troponin T in Emergency Department Patients Undergoing Stress Testing.(Cureus, 2022-09) White, Emily J; Susman, Stephen J; Bouffler, Andrew; Leahy, J Clancy; Griffin, S Michelle; Christenson, Robert; Newby, L Kristin; Gordee, Alexander; Kuchibhatla, Maragatha; Limkakeng, Alexander TBackground and objective Elevations in high-sensitivity troponin T (hs-TnT) are frequently observed following extreme physical exercise. In light of this, we sought to determine whether specific clinical characteristics are associated with this phenomenon in patients undergoing cardiac exercise tolerance testing (ETT). Methods We conducted a retrospective analysis of a prospectively collected biospecimen repository of 257 patients undergoing a stress echocardiogram for possible acute coronary syndrome (ACS). Ischemic electrocardiogram (ECG) changes during ETT and the presence or absence of ischemia on imaging were determined by a board-licensed cardiologist. N-terminal pro-brain natriuretic peptide (NT-proBNP) and hs-TnT assays were obtained immediately before and two hours following ETT. We developed linear regression models including several clinical characteristics to predict two-hour stress-delta hs-TnT. Variable selection was performed using the least absolute shrinkage and selection operator (LASSO). Results The mean age of the patients was 52 years [standard deviation (SD): 11.4]; 125 (48.6%) of them were men, and 88 (34.2%) were African-American. Twenty-two patients (8.6%) had ischemia evident on echocardiography, and 31 (12.1%) had ischemic ECG changes during exercise. The mean baseline hs-TnT was 5.6 ng/L (SD: 6.4) and the mean two-hour hs-TnT was 7.1 ng/L (SD: 10.2). Age and ischemic ECG changes were associated with two-hour stress-delta hs-TnT values. Conclusions Based on our findings, ischemic changes in stress ECG and age were associated with an increase in hs-TnT levels following exercise during a stress echo.Item Open Access Prognostic significance of a complement factor H autoantibody in early stage NSCLC.(Cancer biomarkers : section A of Disease markers, 2022-01-14) Gottlin, Elizabeth B; Campa, Michael J; Gandhi, Rikesh; Bushey, Ryan T; Herndon Nd, James E; Patz, Edward FBiomarkers that predict which patients with early stage NSCLC will develop recurrent disease would be of clinical value. We previously discovered that an autoantibody to a complement regulatory protein, complement factor H (CFH), is associated with early stage, non-recurrent NSCLC, and hypothesized that the anti-CFH antibody inhibits metastasis. The primary objective of this study was to evaluate the anti-CFH antibody as a prognostic marker for recurrence in stage I NSCLC. A secondary objective was to determine if changes in antibody serum level one year after resection were associated with recurrence. Anti-CFH antibody was measured in the sera of 157 stage I NSCLC patients designated as a prognostic cohort: 61% whose cancers did not recur, and 39% whose cancers recurred following resection. Impact of anti-CFH antibody positivity on time to recurrence was assessed using a competing risk analysis. Anti-CFH antibody levels were measured before resection and one year after resection in an independent temporal cohort of 47 antibody-positive stage I NSCLC patients: 60% whose cancers did not recur and 40% whose cancers recurred following resection. The non-recurrent and recurrent groups were compared with respect to the one-year percent change in antibody level. In the prognostic cohort, the 60-month cumulative incidence of recurrence was 40% and 22% among antibody negative and positive patients, respectively; this difference was significant (Gray's test, P= 0.0425). In the temporal cohort, the antibody persisted in the serum at one year post-tumor resection. The change in antibody levels over the one year period was not statistically different between the non-recurrent and recurrent groups (Wilcoxon two-sample test, P= 0.4670). The anti-CFH autoantibody may be a useful prognostic marker signifying non-recurrence in early stage NSCLC patients. However, change in the level of this antibody in antibody-positive patients one year after resection had no association with recurrence.Item Open Access Provocative biomarker stress test: stress-delta N-terminal pro-B type natriuretic peptide.(Open Heart, 2018-01) Limkakeng, Alexander T; Leahy, J Clancy; Griffin, S Michelle; Lokhnygina, Yuliya; Jaffa, Elias; Christenson, Robert H; Newby, L KristinObjective:Stress testing is commonly performed in emergency department (ED) patients with suspected acute coronary syndrome (ACS). We hypothesised that changes in N-terminal pro-B type natriuretic peptide (NT-proBNP) concentrations from baseline to post-stress testing (stress-delta values) differentiate patients with ischaemic stress tests from controls. Methods:We prospectively enrolled 320 adult patients with suspected ACS in an ED-based observation unit who were undergoing exercise stress echocardiography. We measured plasma NT-proBNP concentrations at baseline and at 2 and 4 hours post-stress and compared stress-delta NT-proBNP between patients with abnormal stress tests versus controls using non-parametric statistics (Wilcoxon test) due to skew. We calculated the diagnostic test characteristics of stress-delta NT-proBNP for myocardial ischaemia on imaging. Results:Among 320 participants, the median age was 51 (IQR 44-59) years, 147 (45.9%) were men, and 122 (38.1%) were African-American. Twenty-six (8.1%) had myocardial ischaemia. Static and stress-deltas NT-proBNP differed at all time points between groups. The median stress-deltas at 2 hours were 10.4 (IQR 6.0-51.7) ng/L vs 1.7 (IQR -0.4 to 8.7) ng/L, and at 4 hours were 14.8 (IQR 5.0-22.3) ng/L vs 1.0 (-2.0 to 10.3) ng/L for patients with ischaemia versus those without. Areas under the receiver operating curves were 0.716 and 0.719 for 2-hour and 4-hour stress-deltas, respectively. After adjusting for baseline NT-proBNP levels, the 4-hour stress-delta NT-proBNP remained significantly different between the groups (p=0.009). Conclusion:Among patients with ischaemic stress tests, static and 4-hour stress-delta NT-proBNP values were significantly higher. Further study is needed to determine if stress-delta NT-proBNP is a useful adjunct to stress testing.Item Open Access Stress-delta B-type Natriuretic Peptide Levels as a Test for Inducible Myocardial Ischemia: A Systematic Review and Meta-Analysis.(Cureus, 2020-03-02) Kheang, Sopagna; Rodrigues, Clarissa G; Vissoci, Joao Ricardo N; Hassan, Almujtaba; Muller, Christian; Muller, Deborah; Limkakeng, Alexander TBackground Cardiac ischemia induces myocardial dysfunction and ventricular wall stretch, which causes the release of B-type natriuretic peptide (BNP) into the bloodstream. However, it is unclear whether inducible ischemia produces a significant change in BNP levels ("stress delta-BNP"). The objective of this study was to determine the utility of stress-delta BNP levels and its precursor NT-proBNP for detecting inducible myocardial ischemia during cardiac stress testing. Methods We conducted a systematic review and meta-analysis. We searched PubMed, EMBASE, Web of Science, Cumulative Index of Nursing and Allied Health Literature (CINAHL), and Ovid. Studies examining the changes in levels of BNP and its precursor, N-terminal pro-B-type natriuretic peptide (NT-proBNP), after an exercise cardiac stress test were included. Two reviewers independently analyzed titles and abstracts. Abstracts that did not provide enough information regarding eligibility criteria were kept for full-text evaluation. The same two reviewers also performed data extraction for analyses. Any disagreement was resolved by a consensus and, if it persisted, by a third reviewer adjudication. We report the median and mean values in studies in the order of sample size. Results A total of 15 studies met the inclusion criteria. Nine studies reported results in medians and six studies reported results in means. Of the nine studies, five assessed BNP alone, three assessed NT-proBNP, and one assessed both. Due to the non-normal distribution of results in these studies, they could not be meta-analyzed. Of the six studies that reported results in means, three assessed BNP and three assessed NT-proBNP. The standardized difference between normal and ischemic patients' stress-delta BNP values was -0.39 (95% confidence interval (CI): -0.61; -0.17) in a fixed-effects model and -0.73 (95% CI: -1.72; 0.28) in the random-effects model with high heterogeneity (I^2 = 94%, Q test P = 0.001). For NT-proBNP, the meta-analysis model showed no significant difference between the stress-delta test for ischemic and normal patients (standardized mean difference (SMD): -0.02, 95% CI: -0.31; 0.28). Patients without inducible ischemia appeared to have a lower baseline BNP and NT-proBNP compared to patients with inducible ischemia by stress testing. Although some studies report higher stress-delta BNP in the ischemic group, this pattern was not seen consistently across studies. There was high heterogeneity across studies which was not robust to sensitivity analysis. A random-effects model failed to find statistically significant differences in stress-delta BNP or NT-proBNP. Conclusions We failed to find a relationship between stress-delta BNP or NT-proBNP and the presence or absence of ischemia. This may be due to high heterogeneity in the underlying studies.Item Open Access Tryptophan Metabolism and Neurodegeneration: Longitudinal Associations of Kynurenine Pathway Metabolites with Cognitive Performance and Plasma Alzheimer's Disease and Related Dementias Biomarkers in the Duke Physical Performance Across the LifeSpan Study.(Journal of Alzheimer's disease : JAD, 2022-12) Parker, Daniel C; Kraus, William E; Whitson, Heather E; Kraus, Virginia B; Smith, Patrick J; Cohen, Harvey Jay; Pieper, Carl F; Faldowski, Richard A; Hall, Katherine S; Huebner, Janet L; Ilkayeva, Olga R; Bain, James R; Newby, L Kristin; Huffman, Kim MBackground
The kynurenine pathway (KP) comprises a family of tryptophan-derived metabolites that some studies have reported are associated with poorer cognitive performance and an increased risk of Alzheimer's disease and related dementias (ADRD).Objective
The objective of this study was to determine the associations of plasma KP metabolites (kynurenine [KYN], kynurenic acid [KA], and tryptophan [TRP]) with a panel of plasma ADRD biomarkers (Aβ42/ β40 ratio, pTau-181, glial fibrillary acidic protein [GFAP], and neurofilament light [NfL]) and cognitive performance in a subset of older adults drawn from the Duke Physical Performance Across the LifeSpan (PALS) study.Methods
The Montreal Cognitive Assessment (MoCA) was used to assess cognitive performance. We used multivariate multiple regression to evaluate associations of the KYN/TRP and KA/KYN ratios with MoCA score and plasma ADRD biomarkers at baseline and over two years (n = 301; Age = 74.8±8.7).Results
Over two years, an increasing KYN/TRP ratio was associated with increasing plasma concentrations of plasma p-Tau181 (β= 6.151; 95% CI [0.29, 12.01]; p = 0.040), GFAP (β= 11.12; 95% CI [1.73, 20.51]; p = 0.020), and NfL (β= 11.13; 95% CI [2.745, 19.52]; p = 0.009), but not MoCA score or the Aβ42/Aβ40 ratio. There were no significant associations of KA/KYN with MoCA score or plasma ADRD biomarkers.Conclusion
Our findings provide evidence that greater concentrations of KP metabolites are associated longitudinally over two years with greater biomarker evidence of neurofibrillary tau pathology (pTau-181), neuroinflammation (GFAP), and neurodegeneration (NfL), suggesting that dysregulated KP metabolism may play a role in ADRD pathogenesis.