Blood Levels Of Biomarkers Research Articles

AAV9-mediated Schwann cell-targeted gene therapy rescues a model of demyelinating neuropathy

Mutations in the GJB1 gene, encoding the gap junction (GJ) protein connexin32 (Cx32), cause X-linked Charcot-Marie-Tooth disease (CMT1X), an inherited demyelinating neuropathy. We developed a gene therapy approach for CMT1X using an AAV9 vector to deliver the GJB1/Cx32 gene under the myelin protein zero (Mpz) promoter for targeted expression in Schwann cells. Lumbar intrathecal injection of the AAV9-Mpz.GJB1 resulted in widespread biodistribution in the peripheral nervous system including lumbar roots, sciatic and femoral nerves, as well as in Cx32 expression in the paranodal non-compact myelin areas of myelinated fibers. A pre-, as well as post-onset treatment trial in Gjb1-null mice, demonstrated improved motor performance and sciatic nerve conduction velocities along with improved myelination and reduced inflammation in peripheral nerve tissues. Blood biomarker levels were also significantly ameliorated in treated mice. This study provides evidence that a clinically translatable AAV9-mediated gene therapy approach targeting Schwann cells could potentially treat CMT1X.

Association between periodontitis and severity of COVID-19 infection: A case-control study.

AimCOVID‐19 is associated with an exacerbated inflammatory response that can result in fatal outcomes. Systemic inflammation is also a main characteristic of periodontitis. Therefore, we investigated the association of periodontitis with COVID‐19 complications.Materials and MethodsA case–control study was performed using the national electronic health records of the State of Qatar between February and July 2020. Cases were defined as patients who suffered COVID‐19 complications (death, ICU admissions or assisted ventilation), and controls were COVID‐19 patients discharged without major complications. Periodontal conditions were assessed using dental radiographs from the same database. Associations between periodontitis and COVID 19 complications were analysed using logistic regression models adjusted for demographic, medical and behaviour factors.ResultsIn total, 568 patients were included. After adjusting for potential confounders, periodontitis was associated with COVID‐19 complication including death (OR = 8.81, 95% CI 1.00–77.7), ICU admission (OR = 3.54, 95% CI 1.39–9.05) and need for assisted ventilation (OR = 4.57, 95% CI 1.19–17.4). Similarly, blood levels of white blood cells, D‐dimer and C Reactive Protein were significantly higher in COVID‐19 patients with periodontitis.ConclusionPeriodontitis was associated with higher risk of ICU admission, need for assisted ventilation and death of COVID‐19 patients, and with increased blood levels of biomarkers linked to worse disease outcomes.

Interleukin-8 Levels in the Stratum Corneum as a Biomarker for Monitoring Therapeutic Effect in Atopic Dermatitis Patients

Introduction: The stratum corneum contains several growth factors and cytokines that are synthesized in keratinocytes. We previously reported that the amount of interleukin-8 in the stratum corneum (scIL-8) is related to the severity of local skin inflammation in atopic dermatitis (AD). However, it is unknown whether scIL-8 levels reflect pharmacologic responses to a therapeutic intervention in AD patients. Therefore, in this study, we aimed to investigate whether the improvement of dermatitis in AD is correlated with scIL-8 levels before and after topical corticosteroid treatment. Methods: Stratum corneum samples were collected from 22 AD patients using the noninvasive tape-stripping method before treatment, 2 weeks after topical treatment, and 4–6 weeks after treatment. Results: scIL-8 levels on the forearm reduced significantly from 790 ± 348 pg/mg before treatment to 163 ± 68 pg/mg 2 weeks after treatment and 100 ± 37 pg/mg 4–6 weeks after corticosteroid treatment. scIL-8 levels on the abdomen also reduced significantly from 902 ± 391 to 142 ± 38 pg/mg at the end of study. The reduction in scIL-8 levels was associated with the improvement in local skin severity in AD. We also found that scIL-8 levels, along with blood biomarker levels (serum thymus and activation-regulated chemokine, lactate dehydrogenase, and %eosinophil), decreased significantly after the treatment. Conclusion: The scIL-8 concentration decreases with improvements in skin symptoms in AD patients after topical corticosteroid treatment; thus, it may be a suitable biomarker for monitoring therapeutic effects in AD patients.

Effects of pre-analytical procedures on blood biomarkers for Alzheimer's pathophysiology, glial activation, and neurodegeneration.

IntroductionWe tested how tube types (ethylenediaminetetraacetic acid [EDTA], serum, lithium heparin [LiHep], and citrate) and freeze–thaw cycles affect levels of blood biomarkers for Alzheimer's disease (AD) pathophysiology, glial activation, and neuronal injury.MethodsAmyloid beta (Aβ)42, Aβ40, phosphorylated tau181 (p‐tau181), glial fibrillary acidic protein, total tau (t‐tau), neurofilament light, and phosphorylated neurofilament heavy protein were measured using single molecule arrays.ResultsLiHep demonstrated the highest mean value for all biomarkers. Tube types were highly correlated for most biomarkers (r > 0.95) but gave significantly different absolute concentrations. Weaker correlations between tube types were found for Aβ42/40 (r = 0.63–0.86) and serum t‐tau (r = 0.46–0.64). Freeze–thaw cycles highly influenced levels of serum Aβ and t‐tau (P < .0001), and minor decreases in EDTA Aβ40 and EDTA p‐tau181 were found after freeze–thaw cycle 4 (P < .05).DiscussionThe same tube type should be used in research studies on blood biomarkers. Individual concentration cut‐offs are needed for each tube type in all tested biomarkers despite being highly correlated. Serum should be avoided for Aβ42, Aβ40, and t‐tau. Freeze–thaw cycles > 3 should be avoided for p‐tau181.

Frailty and aging-associated syndromes in lung transplant candidates and recipients.

Many lung transplant candidates and recipients are older and frailer compared to previous eras. Older patients are at increased risk for pre- and posttransplant mortality, but this risk is not explained by numerical age alone. This manuscript represents the product of the American Society of Transplantation (AST) conference on frailty. Experts in the field reviewed the latest published research on assessment of elderly and frail lung transplant candidates. Physical frailty, often defined as slowness, weakness, low physical activity, shrinking, and exhaustion, and frailty evaluation is an important tool for evaluation of age-associated dysfunction. Another approach is assessment by cumulative deficits, and both types of frailty are common in lung transplant candidates. Frailty is associated with death or delisting before transplant, and may be associated with posttransplant mortality. Sarcopenia, cognitive dysfunction, depression, and nutrition are other important components for patient evaluation. Aging-associated inflammation, telomere dysfunction, and adaptive immune system senescence may also contribute to frailty. Developing tools for frailty assessment and interventions holds promise for improving patient outcomes before and after lung transplantation.

A risk score based on pediatric sequential organ failure assessment predicts 90-day mortality in children with Klebsiella pneumoniae bloodstream infection

BackgroundKlebsiella pneumoniae bloodstream infection (Kp-BSI) is a serious threat to pediatric patients. The objective of this study was to explore the risk factors, validate the prediction efficiency of pediatric Sequential Organ Failure Assessment (SOFA) and establish better early predictors of mortality in pediatric patients with Kp-BSI.MethodsAll children diagnosed with Kp-BSI were included in this retrospective cohort study from January 2009 to June 2019. Basic characteristics, symptoms and physical examinations, treatments, laboratory statistics, and SOFA at the onset of Kp-BSI were recorded. The Cox proportional hazard model and receiver operating characteristic curves were used to assess the association between the variables and the 90-day mortality and their predictive value. DeLong’s test of receiver operating characteristic curves and integrated discrimination improvement index were used to determine the improvement in predictive capacity of the modified SOFA models. A predictive score was developed using multivariate logistic regression.ResultsOf the 146 children enrolled, 33 (22.6%) patients died within 90 days. Hospitalization in the last 6 months, intra-abdominal source of infection, presence of organ failure, and altered levels of blood biomarkers, including C-reactive protein, albumin, and lactate were significant risk factors for 90-day mortality. The area under the curve (AUC) of SOFA for predicting 90-day mortality was 0.80 (95% CI 0.71–0.89). Moreover, we found that a prediction model combining SOFA with two other parameters, namely hospitalization in the last 6 months and intra-abdominal source of infection, was better at predicting mortality (AUC = 0.89, 95% CI 0.82–0.96; sensitivity = 0.86; specificity = 0.84). According to this novel risk model, we defined three statistically different groups: low-risk, medium-risk and high-risk groups, with an observed 90-day mortality of 5.4, 35.7, and 72.0%, respectively. With reference to the low-risk patients, the medium-risk and high-risk groups had a higher mortality, with hazard ratios of 8.36 (95% CI 3.60–27.83) and 20.27 (95% CI 7.47–54.95), respectively.ConclusionsThe modified SOFA may be better than the original score to predict 90-day mortality in pediatric patients with Kp-BSI. Future prospective studies are required to validate this novel scoring system in external cohorts.

Association Between Proteomic Blood Biomarkers and DTI/NODDI Metrics in Adolescent Football Players: A Pilot Study.

While neuroimaging and blood biomarker have been two of the most active areas of research in the neurotrauma community, these fields rarely intersect to delineate subconcussive brain injury. The aim of the study was to examine the association between diffusion MRI techniques [diffusion tensor imaging (DTI) and neurite orientation/dispersion density imaging (NODDI)] and brain-injury blood biomarker levels [tau, neurofilament-light (NfL), glial-fibrillary-acidic-protein (GFAP)] in high-school football players at their baseline, aiming to detect cumulative neuronal damage from prior seasons. Twenty-five football players were enrolled in the study. MRI measures and blood samples were obtained during preseason data collection. The whole-brain, tract-based spatial statistics was conducted for six diffusion metrics: fractional anisotropy (FA), mean diffusivity (MD), axial/radial diffusivity (AD, RD), neurite density index (NDI), and orientation dispersion index (ODI). Five players were ineligible for MRIs, and three serum samples were excluded due to hemolysis, resulting in 17 completed set of diffusion metrics and blood biomarker levels for association analysis. Our permutation-based regression model revealed that serum tau levels were significantly associated with MD and NDI in various axonal tracts; specifically, elevated serum tau levels correlated to elevated MD (p = 0.0044) and reduced NDI (p = 0.016) in the corpus callosum and surrounding white matter tracts (e.g., longitudinal fasciculus). Additionally, there was a negative association between NfL and ODI in the focal area of the longitudinal fasciculus. Our data suggest that high school football players may develop axonal microstructural abnormality in the corpus callosum and surrounding white matter tracts, such as longitudinal fasciculus. A future study is warranted to determine the longitudinal multimodal relationship in response to repetitive exposure to sports-related head impacts.

Human Biomonitoring in the Oil Shale Industry Area in Estonia-Overview of Earlier Programmes and Future Perspectives.

Ida-Viru County, in Eastern Estonia, features industrially contaminated sites–where oil shale has been mined and used for electricity generation, and shale oil extraction. Higher prevalence of respiratory and cardiovascular disease has been found in the region due to high quantities of air pollution. Within the framework of “Studies of the health impact of the oil shale sector—SOHOS,” this analysis aimed to map earlier human biomonitoring (HBM) studies and identify the suitable biomarkers for upcoming HBM in Estonia. Altogether, three studies have been conducted among residents: first, among adults in the 1980's; second, among children in the 1990's; and third, among employees, with a focus on workers and miners in the oil shale chemistry industry in the late 1990's and 2000's. In some of those studies, increased levels of biomarkers in blood and urine (heavy metals, 1-OHP) have appeared; nevertheless, in last 20 years, there has been no population-wide HBM in Estonia. According to air pollution monitoring and emission analysis, the pollutants of concern are benzene, PM10, PM2.5, and PAHs. In general, there is a decreasing trend in air pollutant levels, with the exception of a slight increase in 2018. One of the aims of HBM is to be analyzed if this trend can be identified in HBM, using similar biomarkers as applied earlier. The future perspective HBM could be divided into two Tiers. Tier 1 should focus on exposure biomarkers as heavy metals, PAH, and BTEX metabolites and Tier 2, in later stage, on effect biomarkers as Ox LDL, TBARS, etc.

ADHD May Associate With Reduced Tolerance to Acute Subconcussive Head Impacts: A Pilot Case-Control Intervention Study

Objective: To test our hypothesis that individuals with ADHD would exhibit reduced resiliency to subconcussive head impacts induced by ten soccer headings. Method: We conducted a case-control intervention study in 51 adults (20.6 ± 1.7 years old). Cognitive assessment, using ImPACT, and plasma levels of neurofilament-light (NF-L), Tau, glial-fibrillary-acidic protein (GFAP), and ubiquitin-C-terminal hydrolase-L1 (UCH-L1) were measured. Results: Ten controlled soccer headings demonstrated ADHD-specific transient declines in verbal memory function. Ten headings also blunted learning effects in visual memory function in the ADHD group while the non-ADHD counterparts improved both verbal and visual memory functions even after ten headings. Blood biomarker levels of the ADHD group were sensitive to the stress induced by ten headings, where plasma GFAP and UCH-L1 levels acutely increased after 10 headings. Variance in ADHD-specific verbal memory decline was correlated with increased levels of plasma GFAP in the ADHD group. Conclusions: These data suggest that ADHD may reduce brain tolerance to repetitive subconcussive head impacts.

MiR-155, miR-191, and miR-494 as diagnostic biomarkers for oral squamous cell carcinoma and the effects of Avastin on these biomarkers.

ObjectivesOral squamous cell carcinoma (OSCC) is one of the most common types of head and neck cancer. MicroRNAs, as new biomarkers, are recommended for diagnosis and treatment of different types of cancers. Bevacizumab, sold under the trade name Avastin, is a humanized whole monoclonal antibody that targets and blocks VEGF-A (vascular endothelial growth factor A; angiogenesis) and oncogenic signaling pathways.Materials and MethodsThis study comprised 50 cases suffering from OSCC and 50 healthy participants. Peripheral blood samples were collected in glass test tubes, and RNA extraction was started immediately. Expression levels of miR-155, miR-191, and miR-494 biomarkers in the peripheral blood of OSCC-affected individuals and healthy volunteers in vivo were evaluated using real-time PCR. The influence of Avastin on the expression levels of the aforementioned biomarkers in vitro and in the HN5 cell line was also investigated.ResultsExpression levels of miR-155, miR-191, and miR-494 in the peripheral blood of individuals affected by OSCC were higher than in those who were healthy. Moreover, Avastin at a concentration of 400 µM caused a decrease in the expression levels of the three biomarkers and a 1.5-fold, 3.5-fold, and 4-fold increase in apoptosis in the test samples compared to the controls in the HN5 cell line after 24, 48, and 72 hours, respectively.ConclusionThe findings of this study demonstrate that overexpression of miR-155, miR-191, and miR-494 is associated with OSCC, and Avastin is able to regulate and downregulate the expression of those biomarkers and increase apoptosis in cancerous cells in the HN5 cell line

High-Intensity Interval Cycle Ergometer Training in Parkinson's Disease: Protocol for Identifying Individual Response Patterns Using a Single-Subject Research Design.

Background: People with Parkinson's disease (PD) experience not only motor problems but also non-motor problems that seriously impede their daily functioning and quality of life. The current pharmacologic treatment of PD is symptomatic, and alternative rehabilitation treatments, which preferably also have a disease-modifying effect and promote neuroplasticity, are needed. Recent studies suggest that high-intensity interval training (HIIT) is promising for promoting neuroplasticity in human PD, with short training time and reduced burden. Biomarkers for neuroplasticity such as brain-derived neurotrophic factor (BDNF) and neurodegeneration (including neurofilament NfL and α-synuclein) may play a role, but their response to HIIT is not well-investigated.Objectives: The aims of this study were (1) to study the effects of 4 weeks of HIIT compared with 4 weeks of continuous aerobic exercise on motor and non-motor outcomes of PD and (2) to investigate the association between HIIT, motor/non-motor performances changes, and blood biomarker levels for neuroplasticity and neurodegeneration.Study Design: Single-subject research design with alternating treatment setup (ABACA) and frequent repeated measurements was used. Each participant received different intervention conditions (B/C) interspersed with baseline periods (A, i.e., ABACA or ACABA), and frequent repeated assessment of outcome measures is done to quantify within-subject, individual response patterns with sufficient power for data analysis. Blood samples were collected once a week in the baseline and training phases (A1 and B/C) and once every 2 weeks in the washout phases (A2 and A3).Intervention: Four subjects with PD on stable dopaminergic medication, two in Hoehn–Yahr stage 1–2, and two in Hoehn–Yahr stage 2.5–3 followed an ABACA or ACABA schedule, consisting of blocks with 30-min sessions of “B” (HIIT) or 50-min sessions of “C” [continuous aerobic exercise (CAE)] 3×/week for 4 weeks, separated by baseline “A” periods of 8 weeks for a total duration of 28 weeks.Outcome Measures: Outcome measures include disease status [Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS)], blood biomarkers (BDNF, Nfl, and α-synuclein), measures for functional mobility (including an activity tracker), and activities of daily living, as well as cognition, mood, biorhythm (sleeping problems), and quality of life.Data Analysis: Visual analysis of trends in level, slope, and variability in response patterns was carried out, confirmed by longitudinal regression analysis with phase (ABACA) as the independent variable.

Prognostic value of pretreatment inflammatory markers in variant histologies of the bladder: is inflammation linked to survival after radical cystectomy?

To investigate differences in standard preoperative inflammatory markers in patients with urothelial carcinoma (UC) and variant histologies undergoing radical cystectomy (RC) and determine its impact on survival. Patients undergoing RC at an academic high-volume center were retrospectively analyzed. Preoperatively taken CRP, leukocytes, hemoglobin (Hb), and thrombocytes were analyzed as routine inflammatory biomarkers. Log-rank tests and Kruskal-Wallis analysis were used to calculate for differences in survival and in blood levels of biomarkers. 886 patients with complete follow-up and UC or variant histology underwent RC at our institution between 2004 and 2019. Although variant histology presents with significantly higher t stage than UC, cancer-specific survival (CSS) of UC (1-year-CSS: 93%) is not significantly different to variant histology of UC with squamous differentiation (UCSD, 1-year-CSS: 81%), squamous cell carcinoma (SCC, 1-year-CSS: 82%), and adenocarcinoma (AC, 1-year-CSS: 81%). In UC, alterations in all biomarkers except leukocytes beyond routine cut-off values were associated with poor survival (p < 0.01), whereas Hb beyond cut-off values are associated with poor prognosis in SCC (p < 0.05). CRP levels are significantly elevated in UCSD and SCC at time of surgery compared to UC (p < 0.05). Inflammatory biomarkers reveal distinctive patterns across UC and variant histologies of bladder cancer. As inflammation might play an important role in cancer progression, further research is warranted to understand those molecular mechanisms and their potential therapeutic impact in variant histology of bladder cancer.

Periodized versus non-periodized swimming training with equal total training load: Physiological, molecular and performance adaptations in Wistar rats.

This study investigated the effect of non-periodized training performed at 80, 100 and 120% of the anaerobic threshold intensity (AnT) and a linear periodized training model adapted for swimming rats on the gene expression of monocarboxylate transporters 1 and 4 (MCT1 and 4, in soleus and gastrocnemius muscles), protein contents, blood biomarkers, tissue glycogen, body mass, and aerobic and anaerobic capacities. Sixty Wistar rats were randomly divided into 6 groups (n = 10 per group): a baseline (BL; euthanized before training period), a control group (GC; not exercised during the training period), three groups exercised at intensities equivalent to 80, 100 and 120% of the AnT (G80, G100 and G120, respectively) at the equal workload and a linear periodized training group (GPE). Each training program lasted 12 weeks subdivided into three periods: basic mesocycle (6 weeks), specific mesocycle (5 weeks) and taper (1 week). Although G80, G100 and G120 groups were submitted to monotony workload (i.e. non-modulation at intensity or volume throughout the training program), rodents were evaluated during the same experimental timepoints as GPE to be able comparisons. Our main results showed that all training programs were capable to minimize the aerobic capacity decrease promoted by age, which were compared to control group. Rats trained in periodization model had reduced levels of lipid blood biomarkers and increased hepatic glycogen stores compared to all other trained groups. At the molecular level, only expressions of MCT1 in the muscle were modified by different training regimens, with MCT1 mRNA increasing in rats trained at lower intensities (G80), and MCT1 protein content showed higher values in non-periodized groups compared to pre-training and GPE. Here, training at different intensities but at same total workload promoted similar adaptations in rats. Nevertheless, our results suggested that periodized training seems to be optimize the physiological responses of rats.

Влияние курса нейромодуляции на профиль нейротрофических факторов у пациентов с хроническими нарушениями сознания

Transcranial magnetic stimulation (TMS) is one of rehabilitation approaches for patients with chronic disorders of consciousness (DOC). The aim of our study was to assess neurotrophic factors and the changes of those after TMS course in patients with chronic DOC. We enrolled 26 patients with chronic DOC of various etiology and 21 heathy volunteers. Blood serum and cerebrospinal fluid (CSF) were collected from all patients before and after the TMS course, the levels of BDNF, NSE, NGF, РDGF, GDNF and NT3 were assessed in the biomaterial. The blood BDNF, NSE, PDGF, GDNF and NT3 in patients with chronic DOC were higher compared to healthy volunteers (p &lt; 0.05). We found no correlations between the type of DOC and neurotrophic factors concentrations in blood and CSF. The CSF level of BDNF in patients after traumatic brain injury (TBI) was higher compared to patients with non-traumatic chronic DOC (p &lt; 0.05). We also found the increase of CSF BDNF after the TMS course in patients after TBI (p &lt; 0.05). No other significant differences between groups and another blood and cerebrospinal fluid biomarker levels were detected. Thus, the serum BDNF, NSE, PDGF, GDNF and NT3 levels in patients with chronic DOC were higher compared to healthy volunteers. The BDNF level in CSF was higher in patients with traumatic DOC, and it also increased after the course of high-frequency TMS in this group. This fact may indicate the long-term neuronal plasticity processes in patients after TBI, as well as more favorable rehabilitation prognosis.

Serum-neuroproteins, near-infrared spectroscopy, and cognitive outcome after beach-chair shoulder surgery: Observational cohort study analyses.

Cerebral hypoxia may occur during surgery but currently used cerebral oxygenation saturation (rSO2) monitors remain controversial with respect to improving clinical outcome. Novel neuroprotein biomarkers are potentially released into systemic circulation and combined with near-infrared spectroscopy (NIRS) could clarify the presence of per-operative cerebral hypoxia. We investigated changes to serum-neuroprotein concentrations post-surgically, paired with NIRS and cognitive outcome, in patients operated in the beach chair position (BCP). A prospective cohort in 28 shoulder surgery patients placed in the BCP. Blood samples were collected before induction of anaesthesia, and 2hours and 3-5days post-operatively. We analysed blood levels of biomarkers including tau and neurofilament light (NFL). We post hoc assessed the cross-wise relationship between biomarker levels and post-surgical changes in cognitive function and intraoperatively monitored rSO2 from NIRS. Serum-NFL decreased from 24.2pg/mL to 21.5 (P=.02) 2hours post-operatively, then increased to 27.7pg/mL on day 3-5 (P=.03). Conversely, s-tau increased from 0.77pg/mL to 0.98 (2h), then decreased to 0.81 on day 3-5 (P=.08). In 14/28 patients, episodic rSO2 below 55% occurred, and the duration<55% was correlated to change in s-tau (P<.05). The cognitive function z-score at 1week and 3 mo. correlated to the change in tau (P=.01), but not to NFL. Some biomarkers were significantly changed with surgery in the beach chair position. The change was at some points associated to post-operative cognitive decline, and to intraoperative low rSO2. (237).

Abstract CT287: CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC)

Abstract Background: In the CANTOS study, treatment with canakinumab (selective IL-1β inhibitor) was associated with reduced incidence and mortality of NSCLC in patients with stable post-myocardial infarction who had elevated high-sensitivity C-reactive protein (hs-CRP) levels. The results provided a rationale to investigate the therapeutic role of canakinumab in NSCLC. Methods: The phase III, multicenter, randomized, double-blind, placebo-controlled CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult patients with completely resected NSCLC. Patients with AJCC/UICC v.8 stages II-IIIA and IIIB (T&amp;gt;5 cm, N2), any histology, completely resected (R0) NSCLC who have completed adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiation therapy (if applicable) are eligible. Patients must not have had prior neoadjuvant chemotherapy or neoadjuvant radiotherapy. Patients (~1500) are randomized 1:1 to receive canakinumab (200 mg Q3W, SC) or placebo (Q3W, SC) for 18 cycles or until NSCLC disease recurrence as determined by investigator, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, start of a new antineoplastic therapy, death, or loss to follow-up. Randomization is stratified by AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T&amp;gt;5 cm, N2 disease), tumor histology (squamous vs non-squamous), and region (western Europe and North America vs eastern Asia vs rest of the world). Primary objective is disease-free survival (DFS) per local investigator assessment. Secondary objectives are overall survival (OS), lung cancer specific survival, safety, pharmacokinetics, immunogenicity, and patient reported outcomes. Adult patients with stage IIA-IIIA, IIIB (N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker sub-study to understand how resection surgery may impact biomarkers involved in the IL-1β inflammatory pathway as well as mutations present in blood. For all patients participating into the sub-study, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed at pre- and post-surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamics [PD] biomarkers). For patients who will also enroll into the main study, possible associations between pre- and post-surgery biomarker levels with canakinumab efficacy will be determined (endpoint: DFS and OS by hs-CRP and other PD biomarkers). The CANOPY-A study is currently enrolling. As of Jan 13, 2020, there are 307 study locations. Citation Format: Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz Kowalski, Shun Lu, Luis Paz-Ares, David R. Spigel, Alexander Spira, Michael Thomas, Mimi Leung, Jason Baum, Zewen Zhu, Bijoyesh Mookerjee, James Chih-Hsin Yang. CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT287.

Results from the TRIBE-AKI Study found associations between post-operative blood biomarkers and risk of chronic kidney disease after cardiac surgery

Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort -TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m2, we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m2, we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro-B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery.

Evolution of blood biomarker levels following percutaneous atrial septal defect closure in adults.

We sought to assess the effects of percutaneous atrial septal defect (ASD) closure on blood biomarker levels that possibly reflect reverse cardiac remodeling. Therefore, this study investigated temporal changes in six blood biomarkers following percutaneous ASD closure in adults. In this prospective observational cohort study, adults with ASD type II scheduled for percutaneous closure were included (2012-2016). NT-proBNP, high-sensitive troponin-T (hs-TnT), high-sensitive C-reactive protein (hs-CRP), red blood cell distribution width (RDW), growth differentiation factor-15 (GDF-15) and galectin-3 were measured one day prior to ASD closure and one day, three months and one year post ASD closure, and changes were evaluated using paired T-tests. Echocardiographic measurements were obtained. Fifty patients were included (median age 50years, 62% women, 32% NYHA II). At baseline, biomarker levels were elevated in a substantial number of patients; NT-proBNP n=22 (45%), hs-TnT n=6 (13%) hs-CRP n=19 (40%), galectin-3 n=5 (11%) and GDF n=10 (23%). One day after ASD closure, significant increases of hs-TnT (median change (Δ)=12ng/L), hs-CRP (Δ=1.9mg/L), GDF-15(Δ=129pg/mL) and RDW (Δ=0.1%) were observed, and a decrease in galectin-3 (Δ=-1.0ng/mL). Consequently, 92% had at least one abnormal biomarker directly after closure. At three months biomarker levels returned to baseline, and while echocardiographic measures 1year post closure were indicative of reverse cardiac remodeling, biomarker levels did not further decrease. Percutaneous ASD closure in adults leads to a direct increase in most blood biomarkers, in particular hs-CRP and hs-TnT. After three months, biomarkers returned to baseline levels and remained stable up to one year.

Effects of Rapid Recovery on Alcohol Hangover Severity: A Double-Blind, Placebo-Controlled, Randomized, Balanced Crossover Trial.

The aim of this study was to evaluate the efficacy of putative hangover treatment, Rapid Recovery, in mitigating alcohol hangover (AH) symptom severity. Using a double-blind, randomized, placebo-controlled, balanced crossover design, 20 participants attended the laboratory for two evenings of alcohol consumption, each followed by morning assessments of AH severity. Participants were administered Rapid Recovery and placebo on separate visits. In the first testing visit, participants self-administered alcoholic beverages of their choice, to a maximum of 1.3 g/kg alcohol. Drinking patterns were recorded and replicated in the second evening testing visit. In the morning visits, AH severity was assessed using questionnaires measuring AH symptom severity and sleep quality, computerized assessments of cognitive functioning as well as levels of blood biomarkers of liver function (gamma-glutamyl transferase (GGT)) and inflammation (high-sensitive C-reactive protein (hs-CRP)). There were no differences in the blood alcohol concentrations (BAC) obtained in the Rapid Recovery (mean = 0.096%) and placebo (mean = 0.097%) conditions. Participants reported significantly greater sleep problems in the Rapid Recovery compared to placebo condition, although this difference was no longer significant following Bonferroni’s correction. There were no other significant differences between Rapid Recovery and placebo. These data suggest that Rapid Recovery has no significant effect on alcohol hangover nor on associated biomarkers.

Increased levels of the cardiovascular disease risk biomarkers GDF15 and myostatin in patients with chronic lymphocytic leukemia

Individuals suffering from cancer, including hematological malignancies, are at increased risk of cardiovascular disease (CVD). Elevated levels of several biomarkers in blood are associated with an increased risk of CVD. The aim of this study was to investigate whether a subset of such CVD risk biomarkers was elevated in patients with untreated chronic lymphocytic leukemia (CLL). Blood plasma and serum from 139 CLL patients and 71 healthy age-matched controls were analyzed for 11 proposed CVD risk biomarkers. The CLL cohort displayed a more heterogeneous pattern of biomarker expression compared to controls. The majority, eight out of 11, analyzed CVD risk biomarkers differed significantly in concentrations between CLL patients and controls. Increased levels of the biomarkers GDF15 and myostatin have not previously been reported in CLL. Further prospective studies are warranted to investigate whether these biomarkers predict future cardiovascular events in patients with CLL.