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Background There is increasing evidence that dysregulation of polyunsaturated fatty acids (FAs) mediated membrane function plays a role in the pathophysiology of schizophrenia. Even though preclinical findings have supported the anti-inflammatory properties of omega-3 FAs on brain health, their biological roles as anti-inflammatory agents and their therapeutic role on clinical symptoms of psychosis risk are not well understood. In the current study, we investigated the relationship of erythrocyte omega-3 FAs with plasma immune markers in a clinical high risk for psychosis (CHR) sample. In addition, a mediation analysis was performed to examine whether previously reported associations between omega-3 FAs and clinical outcomes were mediated via plasma immune markers. Clinical outcomes for CHR participants in the NEURAPRO clinical trial were measured using the Brief Psychiatric Rating Scale (BPRS), Schedule for the Scale of Assessment of Negative Symptoms (SANS) and Social and Occupational Functioning Assessment Scale (SOFAS) scales. The erythrocyte omega-3 index [eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA)] and plasma concentrations of inflammatory markers were quantified at baseline (n = 268) and 6 month follow-up (n = 146) by gas chromatography and multiplex immunoassay, respectively. In linear regression models, the baseline plasma concentrations of Interleukin (IL)-15, Intercellular adhesion molecule (ICAM)-1 and Vascular cell adhesion molecule (VCAM)-1 were negatively associated with baseline omega-3 index. In addition, 6-month change in IL-12p40 and TNF-α showed a negative association with change in omega-3 index. In longitudinal analyses, the baseline and 6 month change in omega-3 index was negatively associated with VCAM-1 and TNF-α respectively at follow-up. Mediation analyses provided little evidence for mediating effects of plasma immune markers on the relationship between omega-3 FAs and clinical outcomes (psychotic symptoms and functioning) in CHR participants. Our results indicate a predominantly anti-inflammatory relationship of omega-3 FAs on plasma inflammatory status in CHR individuals, but this did not appear to convey clinical benefits at 6 month and 12 month follow-up. Both immune and non-immune biological effects of omega-3 FAs would be resourceful in understanding the clinical benefits of omega-3 FAs in CHR papulation.

Immune cell-type composition changes with age, potentially weakening the response to infectious diseases. Profiling epigenetics marks of immune cells can help us understand the relationship with disease severity. We therefore leveraged a targeted DNA methylation method to study the differences in a cohort of pneumonia patients (both COVID-19 positive and negative) and unaffected individuals from peripheral blood. This approach allowed us to predict the pneumonia diagnosis with high accuracy (AUC = 0.92), and the PCR positivity to the SARS-CoV-2 viral genome with moderate, albeit lower, accuracy (AUC = 0.77). We were also able to predict the severity of pneumonia (PORT score) with an R2 = 0.69. By estimating immune cellular frequency from DNA methylation data, patients under the age of 65 positive to the SARS-CoV-2 genome (as revealed by PCR) showed an increase in T cells, and specifically in CD8+ cells, compared to the negative control group. Conversely, we observed a decreased frequency of neutrophils in the positive compared to the negative group. No significant difference was found in patients over the age of 65. The results suggest that this DNA methylation-based approach can be used as a cost-effective and clinically useful biomarker platform for predicting pneumonias and their severity. © 2022 Informa UK Limited, trading as Taylor & Francis Group.

A wide range of diseases have been shown to be influenced by the accumulation of senescent cells, from fibrosis to diabetes, cancer, Alzheimer’s and other age-related pathologies. Consistent with this, clearance of senescent cells can prolong healthspan and lifespan in in vivo models. This provided a rationale for developing a new class of drugs, called senolytics, designed to selectively eliminate senescent cells in human tissues. The senolytics tested so far lack specificity and have significant off-target effects, suggesting that a targeted approach could be more clinically relevant. Here, we propose to use an extracellular epitope of B2M, a recently identified membrane marker of senescence, as a target for the specific delivery of toxic drugs into senescent cells. We show that an antibody–drug conjugate (ADC) against B2M clears senescent cells by releasing duocarmycin into them, while an isotype control ADC was not toxic for these cells. This effect was dependent on p53 expression and therefore more evident in stress-induced senescence. Non-senescent cells were not affected by either antibody, confirming the specificity of the treatment. Our results provide a proof-of-principle assessment of a novel approach for the specific elimination of senescent cells using a second generation targeted senolytic against proteins of their surfaceome, which could have clinical applications in pathological ageing and associated diseases.

Objective: The potential contribution of asymmetric dimethylarginine (ADMA) and high-sensitivity C reactive protein (hsCRP) to endothelial dysfunction in APS patients has not been studied in detail, until now. The study involved 105 APS patients (59 diagnosed with primary APS (PAPS) and 46 APS associated with systemic lupus erythematosus (SAPS)) who were compared to 40 controls. Endothelial dysfunction was assessed by measurement of flow-mediated dilatation (FMD) and glyceryl trinitrate dilatation (NMD) of the brachial artery. ADMA (micromol/L) was analyzed by ELISA. Results: FMD in patients with APS was significantly lower than that of the controls (p < 0.001), with no difference between the PAPS and the SAPS groups. ADMA and hsCRP concentrations were significantly higher in the patient cohort than in the control group (p < 0.001, p = 0.006, respectively), as was the case with the SAPS group as compared to the PAPS group (p < 0.001, p = 0.022, respectively). FMD impairment correlated to ADMA (ρ 0.472, p < 0.001) and to hsCRP (ρ 0.181, p = 0.033). In the regression model, the ADMA concentration confirmed the strength of its association (B 0.518, SE 0.183, Wald 8.041, p = 0.005, Exp(B) 1.679, 95% CI 1.174–2.402) to FMD impairment. The synergistic probability model of ADMA and hsCRP caused FMD impairment when the positivity of β2GPIIgG was added. ADMA may be used as a simple and low-cost tool for verifying the presence of endothelial dysfunction in APS patients. According to the results of the study, we could presume that hsCRP, together with aPL, has a preparatory effect on the endothelium in causing endothelial dysfunction.

Objectives: Advanced-stage biliary tract cancers (BTC) are rare malignancies with poor prognosis. There are few prospective trials, but several retrospective studies regarding treatment options. In this study, we aimed to investigate the role of systemic inflammatory parameters (SIP) and other possible independent factors that may affect survival and treatment approaches and to determine the benefit of later-line treatments in these patients. Methods: A total of 284 patients, initially diagnosed with advanced stage or progressed after curative treatment of BTC, from different oncology centers in Turkey were included in this retrospective study. The prognostic significance of clinicopathological factors, SIPs and treatment options was analyzed. Results: At a median follow-up of 13 months, the median progression-free survival (PFS) was 6.1 months (95% CI:5.51–6.82), and the median overall survival (OS) time was 16.8 months (95% CI: 13.9–19.6). Treatment choice (p

Coronavirus-related disease-2019 (COVID-19)-associated coagulopathy presents predominantly with thrombosis and leads to complications in close association with inflammatory process. Soluble endothelial protein C receptor (sEPCR), which is the soluble form of EPCR, reduces the anticoagulant and anti-inflammatory activity of activated protein C. The purpose of this study is to investigate the relationship between sEPCR and the laboratory parameters and thorax computed tomography (CT) findings in the course of COVID-19. Twenty-five laboratory-confirmed [reverse transcription-quantitative polimerase chain reaction (RT-qPCR) positive] and 24 clinically diagnosed (RT-qPCR negative) COVID-19 patients were enrolled in the study. Blood specimens were collected for sEPCR and haematological and biochemical parameter measurement. Thorax CT was performed to detect COVID-19 findings. These parameters from RT-qPCR positive and negative patients were then compared. Although there was no difference between the groups in terms of symptoms, the time between the onset of symptoms and the admission time was shorter in RT-qPCR positive group (P?=?0.000). sEPCR levels were significantly higher in the RT-qPCR positive group (P?=?0.011). Patients with ground-glass opacity and bilateral involvement on thorax CT have higher serum sEPCR levels (P?=?0.012 and 0.043, respectively). This study has shown for the first time that serum sEPCR levels, which is a member of coagulation cascade and has also been reported to be associated with inflammation, is higher in patients with positive RT-qPCR test and patients with GGO or bilateral involvement on thorax CT regardless of the PCR result. Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Context: The Corona Virus Disease 2019 (COVID-19) is a contagious disease caused by the novel Coronavirus (2019-nCoV) and was declared a pandemic disease by the World Health Organization (WHO) in March 2020. The nasopharyngeal and the oropharyngeal swabs are being taken during the screening procedure. However, the virus is also present in the oral bio-fluid and hence it could be a potential tool for screening COVID-19 cases. Aim: The aim of the present study was to test the accuracy of whole saliva as a diagnostic specimen in COVID-19. Settings and Design: This cross-sectional, analytical study was conducted on out-patients visiting the COVID-19 hospital. Methods and Material: The whole saliva and the nasopharyngeal/oropharyngeal samples from 309 COVID-19 suspected patients were collected and subjected to RT-PCR analysis. Statistical Analysis Used: The paired t test was used to compare the measured variables (CT values) between the saliva and the swab samples. The positive predictive value (PPV), negative predictive value (NPV), the sensitivity, and the specificity of the tests were calculated for the saliva sample. Results: The saliva and swab results revealed a similar result (ties) in 86.73% of the samples. The sensitivity and the specificity between the swab and saliva samples were 40% and 96.85%, respectively. The positive predictive value of the saliva sample was 73.3%. Conclusions: The sensitivity of whole saliva when compared to the swab samples is low. Large sample studies are needed to validate the role of saliva as a diagnostic tool in COVID-19.

Hepatocellular carcinoma (HCC) is known as the fifth most common cancer in the world for its poor prognosis. New diagnostic markers and treatments are urgent to discover. To evaluate the protein expression of Tropomyosin4 (TPM4) and investigate its prognostic value in HCC, we collected 110 patients with different degrees of HCC and 10 patients with normal hepatic tissues and performed immunohistochemistry. Western bot was used to evaluate the expression of TPM4 in three HCC cell lines (HepG2, Huh7, SMMC-7721) and normal liver cell line LO2, as well as 7 HCC tissues and 7 normal hepatic tissues. The results of TPM4 staining revealed that TPM4 expression in HCC was higher than that in normal hepatic tissues, which was positive in 51.8% (n=57) and negative in 48.2% (n=53) while in normal hepatic tissues positive staining was in 10% (n=1) and negative staining was in 90% (n=9) (P=0.011). And the expression of TPM4 was related to pT status, grade and stage (P

Bu çalışmada 22 yazar bulunmaktadır. Bu yazarlardan sadece Bursa Uludağ Üniversitesi mensuplarının girişleri yapılmıştır. In this review, we discuss recent publications on asthma and review the studies that have reported on the different aspects of the prevalence, risk factors and prevention, mechanisms, diagnosis, and treatment of asthma. Many risk and protective factors and molecular mechanisms are involved in the development of asthma. Emerging concepts and challenges in implementing the exposome paradigm and its application in allergic diseases and asthma are reviewed, including genetic and epigenetic factors, microbial dysbiosis, and environmental exposure, particularly to indoor and outdoor substances. The most relevant experimental studies further advancing the understanding of molecular and immune mechanisms with potential new targets for the development of therapeutics are discussed. A reliable diagnosis of asthma, disease endotyping, and monitoring its severity are of great importance in the management of asthma. Correct evaluation and management of asthma comorbidity/multimorbidity, including interaction with asthma phenotypes and its value for the precision medicine approach and validation of predictive biomarkers, are further detailed. Novel approaches and strategies in asthma treatment linked to mechanisms and endotypes of asthma, particularly biologicals, are critically appraised. Finally, due to the recent pandemics and its impact on patient management, we discuss the challenges, relationships, and molecular mechanisms between asthma, allergies, SARS-CoV-2, and COVID-19. Sanofi & Regeneron GlaxoSmithKline European Commission Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung Christine Kühne – Center for Allergy Research and Education

Neurotrophins have been proposed to be involved in biological mechanisms which might underlie different clinical outcomes in schizophrenia. The aims of the present study were to examine the BDNF/NGF plasma levels in a cohort of first-episode schizophrenia (FES) patients in remission as potential biological predictors of relapse; to study the associations between these neurotrophins and the symptomatology severity through different stages after a FES in two independent cohorts. 2EPs-Cohort: 69 first-episode in clinical remission were included. BDNF/NGF plasma levelsand symptom severity were measured at enrollment and at 3-year or at the time of the second episode/relapse. FLAMM-PEPs-Cohort: 65 first-episodes were also included. BDNF/NGF and symptom severity were obtained at enrollment and 2-year follow-up. Symptomatology was assessed with the Marder-PANSS-Factor scores. Plasma neurotrophins did not differ significantly over time and neither BDNF/NGF were predictors of relapse. Besides, in remission stages, baseline BDNF levels showed significant correlations with both positive and negative symptoms (p

©Copyright 2022 by Turkish Society of Hematology | Turkish Journal of Hematology, Published by Galenos Publishing HouseObjective: Multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM, are plasma cell neoplasms. The evolution of the treatment of MM in recent years has dramatically improved the outcome for these patients. Currently, multidisciplinary studies are being conducted to elucidate the etiopathogenesis of the disease and develop specific treatment agents and prognostic markers. The present study investigates the relationships between immunoexpression of CD138, Pan-Ras, CCL-3, DKK-1, and MUM-1 and disease progression in cases of MM and MGUS. Materials and Methods: Immunohistochemical staining for CD138, Pan-Ras, CCL-3, DKK-1, and MUM-1 were performed on bone marrow biopsy samples from 94 MM and 20 MGUS patients diagnosed between 2011 and 2018. Immunohistochemical results were examined semiquantitatively, and the associations between the immunohistochemical, clinical, and biochemical markers utilized for MM and MGUS patient staging were analyzed. Results: Pan-Ras, DKK-1, and MUM-1 staining results were significantly higher in MM compared to MGUS (p=0.005, 0.001, and 0.001, respectively). The mean CCL-3 expression in patients with MGUS was 23.15%, while it was 18.68% in cases of MM (p=0.413). CCL-3 expression was significantly higher in high-risk MGUS cases compared to other risk groups according to the Mayo Clinic Risk Stratification for MGUS. According to the International Staging System and the Revised International Staging System, CD138 expression was higher among stage II and stage III patients than stage I patients. Conclusion: Differences in Pan-Ras, MUM-1, DKK-1, and CCL-3 expressions between MM and MGUS suggest that these molecules may play a role in the progression of MGUS to MM. CCL-3, an immunohistochemical marker, may be predictive of MGUS progression, while CD138 is associated with more advanced stages of MM. Amaç: Multipl myelom (MM) ve MM’nin prekürsörü olan önemi belirsiz monoklonal gamopati (MGUS), plazma hücreli neoplazilerdir. Güncel çalışmalarda bu hastalıkların etiyopatogenezini aydınlatmak, spesifik tedavi ajanları ve prognostik belirteçler geliştirmek için multidisipliner çalışmalar yürütülmektedir. Çalışmamızda MM ve MGUS’lerde CD138, Pan-Ras, CCL-3, DKK-1 ve MUM1 immünoekspresyonun hastalık evreleriyle olan ilişkisini araştırmayı hedefledik. Gereç ve Yöntemler: 2011-2018 yılları arasında tanı alan 94 MM ve 20 MGUS olgusuna ait kemik iliği biyopsilerine, CD138, Pan-Ras, CCL-3, DKK-1, MUM-1 immünohistokimyasal (İHK) boyaması yapıldı. İHK sonuçları semi kantitatif olarak değerlendirildi ve MM ve MGUS olgularının hastalık evreleriyle olan ilişkileri değerlendirildi. Bulgular: Pan-Ras, DKK-1 ve MUM-1 immünoekspresyonu, MM’li olgularda MGUS’li olgulara göre anlamlı olarak daha yüksek saptandı (p=0,005, 0,001, ve 0,001, sırasıyla). MGUS olgularında ortalama CCL-3 immünoekspresyonu %23,15 iken, MM olgularında %18,68 idi (p=0,413). MGUS olgularında Mayo Klinik risk sınıflandırması (MCRS) modeline göre, yüksek riskli MGUS olgularında diğer risk gruplarına kıyasla CCL-3 ekspresyonu önemli ölçüde artmış olarak saptandı. CD138 ekspresyonu, ISS ve R-ISS sınıflama sistemlerine göre, evre 2 ve evre 3 hastalarda evre 1 hastalara göre artmış olarak tespit edildi. Sonuç: MM ve MGUS olgularında Pan-Ras, MUM-1, DKK-1 ve CCL-3 ekspresyonlarındaki farklılıklar, bu belirteçlerin MGUS-MM progresyonunda önemli roller üstlendiğini göstermektedir. Kemik iliği biyopsilerinde, kolay ve pratik bir şekilde, CCL-3 immün belirteci MGUS progresyonunda prediktif; CD138 ise MM olgularında ileri evre tayininde kullanılabilir. maç: Multipl myelom (MM) ve MM’nin prekürsörü olan önemi belirsiz monoklonal gamopati (MGUS), plazma hücreli neoplazilerdir. Güncel çalışmalarda bu hastalıkların etiyopatogenezini aydınlatmak, spesifik tedavi ajanları ve prognostik belirteçler geliştirmek için multidisipliner çalışmalar yürütülmektedir. Çalışmamızda MM ve MGUS’lerde CD138, Pan-Ras, CCL-3, DKK-1 ve MUM1 immünoekspresyonun hastalık evreleriyle olan ilişkisini araştırmayı hedefledik. Gereç ve Yöntemler: 2011-2018 yılları arasında tanı alan 94 MM ve 20 MGUS olgusuna ait kemik iliği biyopsilerine, CD138, Pan-Ras, CCL-3, DKK-1, MUM-1 immünohistokimyasal (İHK) boyaması yapıldı. İHK sonuçları semi kantitatif olarak değerlendirildi ve MM ve MGUS olgularının hastalık evreleriyle olan ilişkileri değerlendirildi. Bulgular: Pan-Ras, DKK-1 ve MUM-1 immünoekspresyonu, MM’li olgularda MGUS’li olgulara göre anlamlı olarak daha yüksek saptandı (p=0,005, 0,001, ve 0,001, sırasıyla). MGUS olgularında ortalama CCL-3 immünoekspresyonu %23,15 iken, MM olgularında %18,68 idi (p=0,413). MGUS olgularında Mayo Klinik risk sınıflandırması (MCRS) modeline göre, yüksek riskli MGUS olgularında diğer risk gruplarına kıyasla CCL-3 ekspresyonu önemli ölçüde artmış olarak saptandı. CD138 ekspresyonu, ISS ve R-ISS sınıflama sistemlerine göre, evre 2 ve evre 3 hastalarda evre 1 hastalara göre artmış olarak tespit edildi. Sonuç: MM ve MGUS olgularında Pan-Ras, MUM-1, DKK-1 ve CCL-3 ekspresyonlarındaki farklılıklar, bu belirteçlerin MGUS-MM progresyonunda önemli roller üstlendiğini göstermektedir. Kemik iliği biyopsilerinde, kolay ve pratik bir şekilde, CCL-3 immün belirteci MGUS progresyonunda prediktif; CD138 ise MM olgularında ileri evre tayininde kullanılabilir.

Aim: We recently proposed miR-142-3p as a molecular player in inflammatory synaptopathy, a new pathogenic hallmark of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE), that leads to neuronal loss independently of demyelination. MiR-142-3p seems to be unique among potential biomarker candidates in MS, since it is an inflammatory miRNA playing a dual role in the immune and central nervous systems. Here, we aimed to verify the impact of miR-142-3p circulating in the cerebrospinal fluid (CSF) of MS patients on clinical parameters, neuronal excitability and its potential interaction with disease modifying therapies (DMTs). Methods and Results: In a cohort of 151 MS patients, we found positive correlations between CSF miR-142-3p levels and clinical progression, IL-1β signalling as well as synaptic excitability measured by transcranial magnetic stimulation. Furthermore, therapy response of patients with ‘low miR-142-3p’ to dimethyl fumarate (DMF), an established disease-modifying treatment (DMT), was superior to that of patients with ‘high miR-142-3p’ levels. Accordingly, the EAE clinical course of heterozygous miR-142 mice was ameliorated by peripheral DMF treatment with a greater impact relative to their wild type littermates. In addition, a central protective effect of this drug was observed following intracerebroventricular and ex vivo acute treatments of EAE wild type mice, showing a rescue of miR-142-3p-dependent glutamatergic alterations. By means of electrophysiology, molecular and biochemical analysis, we suggest miR-142-3p as a molecular target of DMF. Conclusion: MiR-142-3p is a novel and potential negative prognostic CSF marker of MS and a promising tool for identifying personalised therapies.

Neutrophil-lymphocyte ratio (NLR) and C-reactive protein-albumin ratio (CAR) are simple and objective markers of inflammatory responses. However, there are no studies in the literature evaluating these two markers together in traumatic brain injury (TBI). Therefore, this study aimed to examine whether CAR or NLR is a better biomarker for predicting in-hospital mortality in patients with TBI. METHODS: A total of 257 consecutive patients admitted to the hospital between January 2016 and December 2021 were included in the study. The files of all patients aged >18 years with TBI were retrospectively reviewed. Clinical characteristics, Glasgow Coma Scale, and patient data during hospital stay were recorded. Definitive diagnosis was made using computed brain tomography. Routine blood tests were performed in the first 12-24 h of hospitalization. Laboratory results of patients with and without in-hospital mortality were comparatively analyzed. RESULTS: According to the Mann-Whitney U-test, median CRP, CAR, NLR, WBC, monocyte, neutrophil, RDW-CV, RDW-SD, and platelet values were significantly higher, whereas median albumin and RBC values were significantly lower in patients with in-hospital mortality. Student's t-test showed that the mean hemoglobin level was significantly lower in patients with in-hospital mortality compared to other patients. Univariate logistics regression model revealed that age, albumin, CRP, CAR, NLR, WBC, monocyte, neutrophil, RBC, RDW-CV, RDW-SD, and hemoglobin were the factors predicting mortality. However, in the multivariate logistic regression model, only age, albumin, CAR, and WBC were the factors predicting mortality. Areas under the curve were 0.891 for CAR (95% GA, 0.847-0.935), 0.759 for WBC (95% GA, 0.696-0.823), and 0.671 for NLR (95% GA, 0.598-0.744). CONCLUSION: The results of this study showed that CAR has better prognostic value than NLR in predicting in-hospital mortality in patients with TBI.

Objective: Second- and third-trimester SARS-CoV-2 infections may have an increased risk of obstetric complications. However, data on first-trimester infections are scarce. We sought to characterize the clinical and inflammatory presentations and pregnancy outcomes of first-trimester infections. Methods: A population-based multicenter study including 817 singleton pregnancies with SARS-CoV-2 serologic testing at 8-14 weeks between March and May 2020. Blood count, uterine artery Doppler, and pregnancy-associated plasma protein A (PAPP-A) were performed in all women. Placental growth factor (PlGF), soluble fms-like tyrosine kinase 1 (sFlt-1), IL-6, and ferritin were determined in positive women. Obstetric outcomes were evaluated. Results: The prevalence of first-trimester infection was 15.2% (n = 124). 72.6% of positive women were asymptomatic. Symptomatic women had higher rates of lymphopenia (1.91 × 109/L vs. 2.16 × 109/L, p = 0.017) and increased levels of IL-6 (9.1% vs. 1.2%, p = 0.051), but lower rates of decreased ferritin (6.3% vs. 19.8%, p = 0.015). PAPP-A was higher in symptomatic women compared with asymptomatic and negative women (1.44 [IQR 0.90-1.82] vs. 1.08 [IQR 0.66-1.61] p = 0.014, vs. 1.08 [IQR 0.77-1.55] p = 0.019, respectively). Obstetric outcomes were not increased. Conclusions: First-trimester SARS-CoV-2 infections are mostly asymptomatic, with a mild increase of inflammatory markers in symptomatic women. Obstetric complications were not increased, but PAPP-A levels were higher in symptomatic women. © 2022

BACKGROUND Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to >= 70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.)

Autosomal recessive polycystic kidney disease (ARPKD) is characterized by bilateral fibrocystic changes resulting in pronounced kidney enlargement. Impairment of kidney function is highly variable and widely available prognostic markers are urgently needed as a base for clinical decision-making and future clinical trials. In this observational study we analyzed the longitudinal development of sonographic kidney measurements in a cohort of 456 ARPKD patients from the international registry study ARegPKD. We furthermore evaluated correlations of sonomorphometric findings and functional kidney disease with the aim to describe the natural disease course and to identify potential prognostic markers. Kidney pole-to-pole (PTP) length and estimated total kidney volume (eTKV) increase with growth throughout childhood and adolescence despite individual variability. Height-adjusted PTP length decreases over time, but such a trend cannot be seen for height-adjusted eTKV (haeTKV) where we even observed a slight mean linear increase of 4.5 ml/m per year during childhood and adolescence for the overall cohort. Patients with two null PKHD1 variants had larger first documented haeTKV values than children with missense variants (median (IQR) haeTKV 793 (450–1098) ml/m in Null/null, 403 (260–538) ml/m in Null/mis, 230 (169–357) ml/m in Mis/mis). In the overall cohort, estimated glomerular filtration rate decreases with increasing haeTKV (median (IQR) haeTKV 210 (150–267) ml/m in CKD stage 1, 472 (266–880) ml/m in stage 5 without kidney replacement therapy). Strikingly, there is a clear correlation between haeTKV in the first eighteen months of life and kidney survival in childhood and adolescence with ten-year kidney survival rates ranging from 20% in patients of the highest to 94% in the lowest quartile. Early childhood haeTKV may become an easily obtainable prognostic marker of kidney disease in ARPKD, e.g. for the identification of patients for clinical studies. © 2021, The Author(s)., ESPN 2014.2; PKD Foundation, PKDF; Bundesministerium für Bildung und Forschung, BMBF: 01GM1515, 01GM1903; Universität zu Köln, UoC; Marga und Walter Boll-Stiftung; Universitätsklinikum Köln, We thank the German Society for Pediatric Nephrology (GPN), the ESCAPE Network, and the European Society for Paediatric Nephrology (ESPN; Working Groups CAKUT and Inherited Renal Diseases) for their support. ML was supported by grants of the GPN, ESPN (Grant ESPN 2014.2), and the German PKD foundation. KB and ML were supported by the Medical Faculty of the University of Cologne (Koeln Fortune program), and the Marga and Walter Boll-Foundation. FS and ML are supported by the German Federal Ministry of Research and Education (BMBF grant 01GM1515 and 01GM1903). This work was generated within the European Reference Network for Rare Kidney Disorders (ERKNet).

To compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C), patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data. Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey who were followed for at least 6 months were included in the study. Demographic, clinical, and laboratory findings of all patients were analyzed. A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (8.2, 3, 12 years, respectively). Myalgia (39.6%), cardiac (50.6%), gastrointestinal (72.7%), and neurological (22.1%) involvements were more common in patients with MIS-C compared to others. MIS-C patients had lower levels of lymphocyte (950 vs 1700 cells/µl) and thrombocyte (173,000 vs 355,000 cells/µl) counts and higher pro-BNP (1108 vs 55 pg/ml) levels than KD. Ferritin levels were higher in patients with MIS-C compared to patients with KD while they were lower than patients with sJIA-MAS (440, 170, 10,442 ng/ml, respectively). Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS (p = 0.02) while they required intensive care unit admission more frequently (55 vs 8 patients, p < 0.001). The median MAS/sJIA score of MIS-C patients was ? 1.64 (? 5.23 to 9.68) and the median MAS/sJIA score of sJIA-MAS patients was ?2.81 ([? 3.79] to [? 1.27]). MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and sJIA-MAS. Definition of the differences and similarities between MIS-C and the other intense inflammatory syndromes of childhood such as KD and MAS will help the clinicians while making timely diagnosis. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Stunting, defined as height-for-age Z score equal to or lower than -2, is associated with increased childhood mortality, cognitive impairment, and chronic diseases. The aim of the study was to investigate the relationship between linear growth, intestinal damage, and systemic inflammation in infants at risk of stunting. We followed up 78 infants aged 5-12 months living in rural areas of Peru for 6 months. Blood samples for biomarkers of intestinal damage (intestinal fatty-acid-binding protein [I-FABP] and zonulin) and systemic inflammation (interleukin-1beta, interleukin-6, tumor necrosis factor alpha [TNF-alpha], soluble CD14, and lipopolysaccharide-binding protein [LBP]) and fecal samples for microbiome analysis were collected at baseline and closure of the study. The children's growth and health status were monitored through biweekly home visits by trained staff. Twenty-one percent of the children became stunted: compared with non-stunted children, they had worse nutritional parameters and higher levels of serum I-FABP at baseline. The likelihood of becoming stunted was strongly associated with an increase in sCD14 over time; LBP and TNF-alpha showed a trend toward increase in stunted children but not in controls. The fecal microbiota composition of stunted children had an increased beta diversity compared with that of healthy controls throughout the study. The relative abundance of Ruminococcus 1 and 2, Clostridium sensu stricto, and Collinsella increased in children becoming stunted but not in controls, whereas Providencia abundance decreased. In conclusion, stunting in our population was preceded by an increase in markers of enterocyte turnover and differences in the fecal microbiota and was associated with increasing levels of systemic inflammation markers.

Background Recent studies proposed the whole-blood based IFN-γ-release assay to study the antigen-specific SARS-CoV-2 response. Since the early prediction of disease progression could help to assess the optimal treatment strategies, an integrated knowledge of T-cell and antibody response lays the foundation to develop biomarkers monitoring the COVID-19. Whole-blood-platform tests based on the immune response detection to SARS-CoV2 peptides is a new approach to discriminate COVID-19-patients from uninfected-individuals and to evaluate the immunogenicity of vaccine candidates, monitoring the immune response in vaccine trial and supporting the serological diagnostics results. Here, we aimed to identify in the whole-blood-platform the best immunogenic viral antigen and the best immune biomarker to identify COVID-19-patients. Methods Whole-blood was overnight-stimulated with SARS-CoV-2 peptide pools of nucleoprotein-(NP) Membrane-, ORF3a- and Spike-protein. We evaluated: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL- 15, IL-17A, eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF, RANTES, TNF-α, VEGF. By a sparse partial least squares discriminant analysis we identified the most important soluble factors discriminating COVID-19- from NO-COVID-19-individuals. Results We identified a COVID-19 signature based on six immune factors: IFN-γ, IP-10 and IL-2 induced by Spike; RANTES and IP-10 induced by NP and IL-2 induced by ORF3a. We demonstrated that the test based on IP-10 induced by Spike had the highest AUC (0.85, p Conclusions We set-up a whole-blood assay identifying the best antigen to induce a T-cell response and the best biomarkers for SARS-CoV-2 infection evaluating patients with acute COVID-19 and recovered patients. We focused on IP-10, already described as a potential biomarker for other infectious disease such as tuberculosis and HCV. An additional application of this test is the evaluation of immune response in SARS-CoV-2 vaccine trials: the IP-10 detection may define the immunogenicity of a Spike-based vaccine, whereas the immune response to the virus may be evaluated detecting other soluble factors induced by other viral-antigens.

Background: Annexin A1 (AnxA1) is an important endogenous glucocoticoid protein that contributes to the suppression of inflammation by limiting the production of neutrophil and pro-inflammatory cytokines. This study aims to determine the clinical predictivity value of blood AnxA1 levels in patients with mild and severe–critical pneumonia induced by COVID-19. Methods: This study employed a prospective, case–control study design and was conducted at Ankara Training and Research hospital between 10 February 2021 and 15 March 2021. A total of 74 patients (42 of whom had moderate and 32 of whom had severe/critical cases of COVID-19 disease according to World Health Organization guidelines) and 50 nonsymptomatic healthy volunteers participated in the study. Blood samples were taken from patients at the time of hospital admission, after which serum was isolated. Following the isolation of serum, AnxA1 levels were evaluated using the enzyme-linked immunosorbent assay method. Results: The serum AnxA1 levels were measured as 25.5 (18.6-38.6) ng/ml in the control group, 21.2 (14.7-32) ng/ml in the moderate disease group, and 14.8 (9.7-26.8) ng/ml in the severe/critical disease group. Serum AnxA1 levels were significantly lower in the severe/critical disease group compared with the control and moderate disease groups (P =.01 and P =.0001, respectively). Using receiver operating characteristic analysis, a larger area under the curve (AUC) for the serum AnxA1 levels of the control group (AUC = 0.715, 95% CI = 0.626-0.803; P =.0001) was calculated compared with the COVID-19 patient group for the diagnosis of COVID-19 disease. The AnxA1 level was found to be 80% sensitive and 54.1% specific at a cut-off level of 18.5 ng/ml for the diagnosis of COVID-19 disease. Moreover, the AnxA1 level was found to be 69.8% sensitive and 58.1% specific at a cut-off level of 17.2 ng/ml in predicting the need for intensive care unit (ICU) treatment. Conclusion: AnxA1 levels may be a beneficial biomarker in the diagnosis of COVID-19 pneumonia and in predicting the need for ICU treatment in patients with COVID-19 pneumonia at the time of admission to the emergency department. © 2021 John Wiley & Sons Ltd

Aging and overweight increase the risk of developing type 2 diabetes mellitus. In this cross‐sectional study, we aimed to investigate the potential mediating role of T‐EMRA cells and inflammatory markers in the development of a decreased insulin sensitivity. A total of 134 healthy older volunteers were recruited (age 59.2 (SD 5.6) years). T cell subpopulations were analyzed by flow cytometry. Furthermore, body composition, HOMA‐IR, plasma tryptophan (Trp) metabolites, as well as cytokines and adipokines were determined. Using subgroup and covariance analyses, the influence of BMI on the parameters was evaluated. Moreover, correlation, multiple regression, and mediation analyses were performed. In the subgroup of participants with obesity, an increased proportion of CD8+EMRA cells and elevated concentrations of plasma kynurenine (KYN) were found compared to the lower‐weight subgroups. Linear regression analysis revealed that an elevated HOMA‐IR could be predicted by a higher proportion of CD8+EMRA cells and KYN levels. A mediation analysis showed a robust indirect effect of the Waist‐to‐hip ratio on HOMA‐IR mediated by CD8+EMRA cells. Thus, the deleterious effects of abdominal obesity on glucose metabolism might be mediated by CD8+EMRA cells in the elderly. Longitudinal studies should validate this assumption and analyze the suitability of CD8+EMRA cells as early predictors of incipient prediabetes. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

Objective Acute aortic dissection (AAD) is a common life-threatening cardiovascular disease. This retrospective study was conducted to analyze the plasma concentration of S100A1 and its diagnostic value for AAD through receiver operating characteristic (ROC) curve and logistic regression analyses. Methods Seventy-eight patients with AAD and 77 healthy controls were included, and the relevant clinical data for each group were collected. According to the Stanford classification, the AAD patients were divided into types A and B. The plasma levels of S100A1, D-dimer, hypersensitive C-reactive protein, and cardiac troponin T were detected by enzyme-linked immunosorbent assays. Results The S100A1 concentrations in the healthy control, Stanford A, and Stanford B groups were 0.7 ± 0.6, 4.9 ± 2.6, and 3.5 ± 2.2 ng/mL, respectively. The concentration of S100A1 was increased in patients with AAD complicated with aortic regurgitation, pericardial effusion, or in-hospital death. ROC curve analysis showed that the area under the curve was 0.89. Logistic regression analysis revealed that the S100A1 level was an important risk factor for the development of AAD. Conclusion Plasma S100A1 is significantly elevated in patients with AAD, and its concentration has potential clinical value for diagnosing AAD.

Background/Aim: Extracellular S100b effects are mediated by the receptor for advanced glycation end products (RAGE), which is the S100b membrane receptor. RAGE belongs to the immunoglobulin superfamily of cell surface molecules and serves as a multiligand receptor and is expressed in high abundance by alveolar type I (AT-I) cells in adult pulmonary tissue. This study aimed to provide an insight into the association between the severity of COVID- 19 disease and serum S100b levels during admission to the emergency department (ED). Patients and Methods: A total of 64 patients (34 mild cases; 30 severe cases) were diagnosed with COVID-19 pneumonia and 30 healthy volunteers were admitted to study. Serum S100b levels were measured by using enzymle linked immunoassay method from blood serum samples. Results: Serum S100b levels showed a significantly higher mean value in mild and severe disease cohorts than in healthy controls (p=0.036 and p=0.028 respectively). Receiver operating characteristic (ROC) analysis indicated greater area under the curve (AUC) for serum S100b levels of the COVID-19 patients (AUC=0.663, 95% CI=0.541-0.785; p=0.014). In addition, serum S100b concentration was measured as 151.7 ng/ml at 79.3% sensitivity and 51.7% specificity (p=0.014). Serum S100b protein levels can serve as a valuable clinical marker in establishing diagnosis of patients. Though not useful in identifying different stages of COVID-19 infection, serum S100b concentration along with other known markers can be utilized to reliably predict clinical severity along with other clinical parameters. © 2021 International Institute of Anticancer Research. All rights reserved.

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because symptoms are overshadowed by the intellectual disability associated with Down syndrome. In people with Down syndrome, fluid and imaging biomarkers have shown good diagnostic performances and a strikingly similar temporality of changes with respect to sporadic and autosomal dominant Alzheimer's disease. Most importantly, there are no treatments to prevent Alzheimer's disease, even though adults with Down syndrome could be an optimal population in whom to conduct Alzheimer's disease prevention trials. Unprecedented research activity in Down syndrome is rapidly changing this bleak scenario that will translate into disease-modifying therapies that could benefit other populations.

Osteocalcin (OC) is inversely related to body fat distribution and fasting glucose levels. We sought to observe the effect of OC on fat distribution and subclinical atherosclerosis as measured by carotid intima-media thickness (CIMT) in premenopausal obese women. In this prospective observational study, totally, 73 premenopausal obese women (aged 17-55 years) and 53 healthy women (aged 20-50 years) with normal weight were included as controls. Anthropometric measurements, total fat and fat ratio, insulin, fasting blood glucose, and OC levels were estimated. Ultrasonography was used to assess fat distribution, and fat thickness was measured in 4 regions. Subcutaneous fat (SCF), visceral fat (VF), and preperitoneal fat (PPF) thicknesses were considerably higher in obese subjects (p< 0.01) than healthy controls, while OC levels were significantly lower. No correlation was observed between OC levels and SCF, VF, or PPF. In a multiple regression analysis, OC was significantly positively associated with SCF (p=0.04, Beta=0.284). No associations were observed between OC levels and VF, PPF, or CIMT. A significant association was observed between parathyroid hormone (PTH) and VF (p=0.021, Beta=0.284), and vitamin D levels were inversely associated with VF (p=0.002, r=?0.366). OC levels were lower in premenopausal obese women than normal-weight healthy controls, but OC exhibited no correlation with VF or PPF, and only a weak positive association with SCF. Additionally, VF was positively correlated with PTH and inversely correlated with vitamin D. These results suggest that OC may be an early indicator of lipid accumulation in te subcutaneous area and development of atherosclerosis. © 2021, Acta Medica Okayama. All Rights Reserved.

Background and Aim: The prevalence and clinical significance of extrahepatic autoimmune diseases (EHAIDs) have not been evaluated in a large cohort of primary biliary cholangitis (PBC). Methods: The medical records of 1554 patients with PBC from 20 international centers were retrospectively reviewed. Development of decompensated cirrhosis (ascites, variceal bleeding, and/or hepatic encephalopathy) and hepatocellular carcinoma were considered clinical endpoints. Results: A total of 35 different EHAIDs were diagnosed in 440 (28.3%) patients with PBC. Patients with EHAIDs were more often female (92.5% vs 86.1%, P&nbsp

© Springer Nature Limited 2020, Bone is the most frequent site for metastasis for many cancers, notably for tumours originating in the breast and the prostate. Tumour cells can escape from the primary tumour site and colonize the bone microenvironment. Within the bone, these disseminated tumour cells, as well as those arising in the context of multiple myeloma, may assume a state of dormancy, remaining quiescent for years before resuming proliferation and causing overt metastasis, which causes bone destruction via activation of osteoclast-mediated osteolysis. This structural damage can lead to considerable morbidity, including pain, fractures and impaired quality of life. Although treatment of bone metastases and myeloma bone disease is rarely curative, disease control is often possible for many years through the use of systemic anticancer treatments on a background of multidisciplinary supportive care. This care should include bone-targeted agents to inhibit tumour-associated osteolysis and prevent skeletal morbidity as well as use of appropriate local treatments such as radiation therapy, orthopaedic surgery and specialist palliative care to minimize the impact of metastatic bone disease on physical functioning. In this Primer, we provide an overview of the clinical features, the pathophysiology and the specific treatment approaches to prevent and treat bone metastases from solid tumours as well as myeloma bone disease.

Background: Multiple system atrophy (MSA) is a fatal neurodegenerative disease that progresses very rapidly and has a poor prognosis. Some studies indicate that the level of inflammatory cytokines may be related to MSA. However, no consistent conclusion has been drawn yet. The purpose of our research is to perform a meta-analysis to investigate whether the level of inflammatory cytokines is altered in MSA. Methods: Case-control studies on inflammatory cytokine levels in MSA will be searched in the following 3 databases: PubMed, Embase, and Web of Science from the database start time to March 17, 2020. Two independent authors will conduct research selection, data extraction, and quality evaluation. Data synthesis, subgroup analysis, sensitivity analysis, and the meta-analysis will be performed using Stata15.0 software. Results: This study will provide a comprehensive review of all studies on inflammatory cytokine levels in MSA. Conclusion: To the best of our knowledge, this study will be the first meta-analysis that provides the quantitative evidence of inflammatory cytokine levels in MSA. Registration Number: INPLASY202060034.

The exoerythrocytic stage of Plasmodium infection is a critical window for prophylactic intervention. Using genome-wide dual RNA sequencing of flow-sorted infected and uninfected hepatoma cells we show that the human mucosal immunity gene, mucin-13 (MUC13), is strongly upregulated during Plasmodium exoerythrocytic hepatic-stage infection. We confirm MUC13 transcript increases in hepatoma cell lines and primary hepatocytes. In immunofluorescence assays, host MUC13 protein expression distinguishes infected cells from adjacent uninfected cells and shows similar colocalization with parasite biomarkers such as UIS4 and HSP70. We further show that localization patterns are species independent, marking both P. berghei and P. vivax infected cells, and that MUC13 can be used to identify compounds that inhibit parasite replication in hepatocytes. This data provides insights into host-parasite interactions in Plasmodium infection, and demonstrates that a component of host mucosal immunity is reprogrammed during the progression of infection., Host-parasite interactions during the exoerythrocytic stage of Plasmodium infection remains poorly understood. Using dual RNA-Seq, the authors show that human mucosal immunity protein mucin-13 is upregulated during Plasmodium hepatic-stage infection and marks infected cells independent of tested Plasmodium species.

Background: The incidence of atherosclerotic cardiovascular diseases, which constitute an important disease group, is expected to rise with increasing life expectancy. The aim of this study was to investigate the predictive values of triglyceride/HDL cholesterol (TG/HDL-C) ratio and whole blood viscosity on possible severe carotid or peripheral arterial disease in patients who were admitted to our clinic and scheduled for coronary artery bypass graft (CABG) surgery. Methods: This study retrospectively examined 299 patients who were admitted to our clinic and scheduled for CABG between August 1, 2015, and August 1, 2019. Patients with severe carotid or peripheral arterial disease were included in group 2; those in whom peripheral arterial disease and stenosis were not detected were included in group 1. Results: Group 1 consisted of 255 patients, mean (+/- standard deviation) age 58.1 +/- 8.9 years; the 44 patients in group 2 had a mean age of 64.1 +/- 10.6 years (P = .018). The incidence of diabetes mellitus and tobacco use were significantly higher in group 2 (P < .001 and P = .034, respectively). Triglyceride values, TG/HDL-C, and whole blood viscosity at high and low shear rates were significantly higher in group 2 (P = .017, P < .001, P < .001, and P < .001, respectively). Receiver operator characteristic analysis revealed that the cutoff value of TG/HDL-C was 3.2 with 77% sensitivity and 72% specificity; that of high-shear-rate viscosity was 16.1 with 73% sensitivity and 69% specificity; and that of low-shear-rate viscosity was 59.2 with 70% sensitivity and 63% specificity. Conclusion: It is possible to predict severe additional arterial diseases in patients scheduled for CABG with whole blood viscosity and TG/HDL-C ratios, both of which can be obtained with simple blood tests.

Background/Aim: A novel human coronavirus, named SARS-COV-2, has recently caused thousands of deaths all around the world. Endoplasmic reticulum (ER) stress plays an important role in the development of diseases. Patients and Methods: We aimed to to investigate the relationship between ER stress markers in patients infected with SARS-COV-2 and patients with pneumonia. A total of 9 patients (4 patients diagnosed with pneumonia and 5 patients diagnosed with SARS-COV-2 infection) who admitted to the emergency Department with symptoms of pneumonia and SARS-COV-2 were included in the study. A total of 18 healthy individuals without any known chronic or acute disease and drug use were included as the healthy control group. Serum human glucose regulated protein 78 (GRP78), serum human C/EBP homologous protein (CHOP) and serum human phospho extracellular signal regulated kinase (PERK) levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: GRP78 levels were found to be significantly higher in SARS-COV-2 positive cases compared to individuals in other groups. Serum GRP- 78 level median value was statistically significantly higher in SARS-COV-2-positive group compared to the other groups (p=0.0003). Serum PERK level was statistically significantly higher in SARS-COV-2-positive pneumonia cases (p=0.046). Conclusion: An association was shown between GRP78 and SARS-COV-2 infection. Although a small number of patients was investigated, these results will be important and guide future treatments of SARS-COV-2. © 2020 International Institute of Anticancer Research. All rights reserved.

SUMMARY Recently, studies have reported that inflammatory response and elevated platelet counts are associated with several cancers. In the present study, we aimed to evaluate hemocytometer parameters in differentiating adrenal adenoma and carcinoma, and the prognostic utility of hemocytometer parameters in adrenocortical carcinoma (ACC). We included 30 patients with nonfunctional adrenal adenoma and 13 patients with ACC having undergone surgery between 2005 and 2017 and followed up postoperatively at our centre. The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), red blood cell distribution width (RDW), mean platelet volume (MPV) and plateletcrit (PCT) were evaluated preoperatively in all patients included in the study. There was a significant difference between the adrenal adenoma and ACC groups in terms of neutrophil and lymphocyte counts, NLR and PLR. There was no significant difference between the two groups in terms of platelet count and MPV, but PCT levels were significantly lower in ACC group. There was no statistically significant difference between recurrent and/or metastasis positive patients and negative ones according to NLR, PLR, RDW and MPV. There was a statistically significant difference in RDW levels and tumor diameter between the groups. Our study is the first to evaluate hemocytometer parameters in differentiating adrenal adenomas and carcinomas, and also in the prognosis of ACC. The present study suggested that the hemocytometer parameters may be a marker in the differential diagnosis of adrenal adenomas and carcinomas. However, our study also showed that these parameters had no prognostic value in ACC.

Background MAGE‐A genes belong to the cancer/testis antigens family. The prognostic significance of MAGE‐A expression in the peripheral blood of patients with lung cancer is unknown. Therefore, this study evaluated the expression and possible prognostic significance of MAGE‐A in the peripheral blood of patients with lung cancer. Methods In this study, we detected MAGE‐A gene expression in the peripheral blood of 150 patients with lung cancer and 30 healthy donors using multiplex semi‐nested PCR and analyzed their correlation with clinicopathological risk factors. Results MAGE‐A expression was associated with factors indicating poor prognosis. The expression of MAGE‐A and each individual MAGE‐A gene were also associated with low overall survival in patients with lung cancer. Conclusion The expression of MAGE‐A genes in peripheral blood may act as a poor prognostic marker in patients with lung cancer.

Background/Aims: The metabolic features of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. The expression of glycolytic enzyme enolase 2 (ENO2) was found to be closely associated with the clinical features of acute lymphoblastic leukemia (ALL) patients, but its functions remain unclear in ALL. Methods: We evaluated the association between ENO2 mRNA expression in bone marrow mononuclear cells (BM-MNCs) and the efficacy of chemotherapy, and further explored the function of ENO2 in ALL. The molecular mechanisms of ENO2 expression and its effects on cell growth, glycolysis and glucocorticoid resistance were explored by Cell Counting Kit-8, glucose-consumption assay, Quantitative RT-PCR, Western blotting and in vivo tumorigenesis in NOD/SCID mice. Results: The results showed that ENO2 mRNA expression in BM-MNCs was significantly decreased when patients completed induction chemotherapy and reached complete remission (CR). ENO2 mRNA expression was increased when patients suffered relapse. Functional studies demonstrated that ENO2 promoted cell growth, glycolysis, and glucocorticoid resistance, all of which were effectively inhibited when ENO2 was silenced with shRNAs. Further studies revealed that ENO2 up-regulated various glycolysis-related genes and enhanced Akt activity with subsequent glycogen synthase kinase3β (GSK-3β) phosphorylation, inducing cell proliferation and glycolysis. The combination of silencing ENO2 and 2-deoxyglucose (2-DG) synergistically inhibited leukemia cell survival. Conclusions: These results indicate that ENO2 may be a biological marker for monitoring chemotherapeutic efficacy and relapse in ALL. ENO2 may provide a potential therapeutic strategy for ALL.

Objective: In studies on the relationship between amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) concentration and height velocity in children, CNP has been implicated as an emerging new growth marker during childhood. It has been reported that besides its well-studied role in growth, plasma CNP levels are reduced in overweight and/or obese adolescents, suggesting CNP as a potential biomarker in childhood obesity. The primary goal of this study was to test this hypothesis in a Turkish population. Methods: Consent was taken from 317 children [ages 0-18 (158 girls, 159 boys)] and their parents. All subjects were physically examined; anthropometric measurements were obtained. Body mass index was calculated. During routine blood work, 1 mL extra blood was taken. Plasma NT-proCNP concentration was measured by enzyme-linked immunosorbent assay. Results: Results confirmed the previously described relationship between plasma NT-proCNP concentration and growth velocity. Plasma NT-proCNP concentration showed a negative correlation with age, weight, and height in children. Gender was not a factor that alters the age-dependent plasma NT-proCNP concentration until puberty. Conclusion: Unlike previous reports, plasma NT-proCNP concentration of overweight/obese children was not significantly lower than that of children with normal weight in age groups analyzed in a Turkish population. Thus, it is too early to conclude that CNP is a potential biomarker in childhood obesity. Further studies are necessary to address this question. © 2017 by Turkish Pediatric Endocrinology and Diabetes Society.

Background Evidence supports the existence of different subphenotypes in systemic lupus erythematosus (SLE) and the pivotal role of cytokines and autoantibodies, which interact in a highly complex network. Thus, understanding how these complex nonlinear processes are connected and observed in real-life settings is a major challenge. Cluster approaches may assist in the identification of these subphenotypes, which represent such a phenomenon, and may contribute to the development of personalized medicine. Therefore, the relationship between autoantibody and cytokine clusters in SLE was analyzed. Methods This was an exploratory study in which 67 consecutive women with established SLE were assessed. Clinical characteristics including disease activity, a 14-autoantibody profile, and a panel of 15 serum cytokines were measured simultaneously. Mixed-cluster methodology and bivariate analyses were used to define autoantibody and cytokine clusters and to identify associations between them and related variables. Results First, three clusters of autoantibodies were defined: (1) neutral, (2) antiphospholipid antibodies (APLA)-dominant, and (3) anti-dsDNA/ENA-dominant. Second, eight cytokines showed levels above the threshold thus making possible to find 4 clusters: (1) neutral, (2) chemotactic, (3) G-CSF dominant, and (4) IFNα/Pro-inflammatory. Furthermore, the disease activity was associated with cytokine clusters, which, in turn, were associated with autoantibody clusters. Finally, when all biomarkers were included, three clusters were found: (1) neutral, (2) chemotactic/APLA, and (3) IFN/dsDNA, which were also associated with disease activity. Conclusion These results support the existence of three SLE cytokine-autoantibody driven subphenotypes. They encourage the practice of personalized medicine, and support proof-of-concept studies. Electronic supplementary material The online version of this article (10.1186/s12967-017-1345-y) contains supplementary material, which is available to authorized users.

Background and Aim Muscular fitness and an adherence to the Southern European Atlantic Diet (SEADiet) have been inversely associated with cardiometabolic risk. Our aim was to assess the independent and combined associations of muscular fitness and adherence to the SEADiet on cardiometabolic risk in adolescents. Methods and Results A total of 467 Portuguese adolescents (275 girls) participated in this cross-sectional study. Sum of the Z-Scores of Curl-Up and Push-Up tests was used to create a muscular fitness score. Adherence to SEADiet was obtained using a food frequency questionnaire. A cardiometabolic risk score was computed from sum of Z-score of triglycerides, systolic blood pressure, total cholesterol/HDL ratio, HOMA-IR and waist circumference. Adolescents with low muscular fitness and low adherence to the SEADiet had the poorest cardiovascular profile F(5, 452) = 5.074 (p and lt; 0.001) and the highest odds of having a high cardiometabolic risk score (OR = 4.5; 95% CI: 2.1–14) when compared to those with High muscular fitness/High adherence to the SEADiet after adjustments for age, sex, pubertal stage, socioeconomic status, total energy intake, low-energy reporter and cardiorespiratory fitness. Conclusions Our findings seem suggest that improving muscular fitness as well as an adherence to the SEADiet could be an important strategy to reduce clustered cardiometabolic risk in youth. © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University

Aim: To investigate both maternal and umbilical cord adropin levels in patients with preeclampsia and the possible relations with its severity and perinatal outcomes. Materials and methods: In this study, a total of 38 preeclamptic and 40 age-matched healthy pregnant women between January and June 2016 were included. Serum and cord adropin levels were measured using an enzyme-linked immunosorbent assay (ELISA). Results: The maternal and umbilical cord adropin levels were significantly lower in the preeclamptic group compared to controls [71.19±22.21 vs. 100.76±27.02 ng/L and 92.39 (59.77:129.89) vs. 106.20 (74.42:208.02) ng/L, P Conclusion: The present study is the first to demonstrate a significant association between maternal and umbilical adropin levels and the presence and severity of preeclampsia. Adropin might be a useful parameter for predicting the presence and severity of preeclampsia.

Background and aims Studies in the paediatric population have shown inconsistent associations between cardiorespiratory fitness and inflammation independently of adiposity. The purpose of this study was (i) to analyse the combined association of cardiorespiratory fitness and adiposity with high-sensitivity C-reactive protein (hs-CRP), and (ii) to determine whether adiposity acts as a mediator on the association between cardiorespiratory fitness and hs-CRP in children and adolescents. Methods and results This cross-sectional study included 935 (54.7% girls) healthy children and adolescents from Bogotá, Colombia. The 20 m shuttle run test was used to estimate cardiorespiratory fitness. We assessed the following adiposity parameters: body mass index, waist circumference, and fat mass index and the sum of subscapular and triceps skinfold thickness. High sensitivity assays were used to obtain hs-CRP. Linear regression models were fitted for mediation analyses examined whether the association between cardiorespiratory fitness and hs-CRP was mediated by each of adiposity parameters according to Baron and Kenny procedures. Lower levels of hs-CRP were associated with the best schoolchildren profiles (high cardiorespiratory fitness + low adiposity) (p for trend and #x003C;0.001 in the four adiposity parameters), compared with unfit and overweight (low cardiorespiratory fitness + high adiposity) counterparts. Linear regression models suggest a full mediation of adiposity on the association between cardiorespiratory fitness and hs-CRP levels. Conclusions Our findings seem to emphasize the importance of obesity prevention in childhood, suggesting that having high levels of cardiorespiratory fitness may not counteract the negative consequences ascribed to adiposity on hs-CRP. © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University

Purpose Overexpression of Caveolin-1 has been associated with cancer growth, migration, and metastases in several malignancies, but only few data are available on its role in bladder cancer (BCa). The aim of this study is to validate Caveolin-1 as a prognosticator of recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS) in a large cohort of patients treated with radical cystectomy (RC) for BCa. Methods Caveolin-1 expression was evaluated by immunochemistry on a tissue microarray from 424 patients treated with RC for UCB at a single institution. Caveolin-1 was considered overexpressed when at least 50% of the tumor cells stained positively. Univariable and multivariable Cox proportional hazards regression models were used to assess the association of Caveolin-1 expression with RFS, OS, and CSS. Results Overexpression of Caveolin-1 was observed in 116 (27.4%) patients and was associated with lymph node metastasis ( P = 0.003). Median follow-up for patients alive at last follow-up was 129 months (interquartile range [IQR]: 82–178). Patients with overexpression of Caveolin-1 had significant worse RFS, OS, and CSS compared to those with normal expression (log-rank test, P = 0.008, P = 0.001, and P = 0.005, respectively). At multivariable analyses that adjusted for the effects of standard clinicopathologic features, Caveolin-1 remained associated with OS (hazard ratio = 1.47, P = 0.002) and CSS (hazard ratio = 1.42, P = 0.03). Conversely, no association with RFS was found ( P = 0.1). Addition of Caveolin-1 in a model for prediction of survival did not improve the accuracy of the prognostic model. Actually, C-index did not differ among models with or without Caveolin-1 (0.72 for a model predicting RFS, 0.65 for OS, and 0.71 for CSS). Conclusions Caveolin-1 is overexpressed in one-third of patients with BCa treated with RC. Overexpression of Caveolin-1 is significantly associated with OS and CSS, but not with RFS, in patients with BCa treated with RC. However, it is not clinically useful as it does not improve upon the predictive accuracy of survival achieved by pathologic variables alone.

Aims/Introduction To establish that the ficolin-3/adiponectin ratio is a predictor for gestational diabetes mellitus (GDM) and was eligible for screening tests for GDM. Materials and Methods A prospective cohort study of 86 pregnant women who developed GDM and 273 normal glucose tolerance (NGT) participants was performed. Maternal serum ficolin-3, adiponectin levels were investigated at 16–18 weeks gestation using ELISA. Results Compared to the NGT group, the GDM group showed significantly higher levels of ficolin-3 and the ratio of ficolin-3/adiponectin; and decreased levels of adiponectin between 16 to 18 weeks of gestation (P < 0.05 or P < 0.01). The cut-off values for the ratio of ficolin-3/adiponectin (≥1.06; sensitivity: 90.9%, specificity: 96.5%) to discriminate the pregnant women who developed GDM from the nondiabetic cases were identified using receiver operating characteristic (ROC) analysis. Using binary logistic regression analysis, ficolin-3, retinol-binding protein-4 (RBP-4) and adiponectin, but not C-reactive protein (CRP), triglyceride and free fatty acids (FFAs) were demonstrated as predictive factors for GDM. Conclusions The ratio of ficolin-3/adiponectin at 16–18 weeks gestation was changed in pregnant women who subsequently develop GDM and may provide effective early predicting and screening for GDM This article is protected by copyright. All rights reserved.

Background: Alzheimer's disease and its complications are the leading cause of death in adults with Down syndrome. Studies have assessed Alzheimer's disease in individuals with Down syndrome, but the natural history of biomarker changes in Down syndrome has not been established. We characterised the order and timing of changes in biomarkers of Alzheimer's disease in a population of adults with Down syndrome. Methods: We did a dual-centre cross-sectional study of adults with Down syndrome recruited through a population-based health plan in Barcelona (Spain) and through services for people with intellectual disabilities in Cambridge (UK). Cognitive impairment in participants with Down syndrome was classified with the Cambridge Cognitive Examination for Older Adults with Down Syndrome (CAMCOG-DS). Only participants with mild or moderate disability were included who had at least one of the following Alzheimer's disease measures: apolipoprotein E allele carrier status; plasma concentrations of amyloid ß peptides 1–42 and 1–40 and their ratio (Aß1–42/1–40), total tau protein, and neurofilament light chain (NFL); tau phosphorylated at threonine 181 (p-tau), and NFL in cerebrospinal fluid (CSF); and one or more of PET with 18F-fluorodeoxyglucose, PET with amyloid tracers, and MRI. Cognitively healthy euploid controls aged up to 75 years who had no biomarker abnormalities were recruited from the Sant Pau Initiative on Neurodegeneration. We used a first-order locally estimated scatterplot smoothing curve to determine the order and age at onset of the biomarker changes, and the lowest ages at the divergence with 95% CIs are also reported where appropriate. Findings: Between Feb 1, 2013, and June 28, 2019 (Barcelona), and between June 1, 2009, and Dec 31, 2014 (Cambridge), we included 388 participants with Down syndrome (257 [66%] asymptomatic, 48 [12%] with prodromal Alzheimer's disease, and 83 [21%] with Alzheimer's disease dementia) and 242 euploid controls. CSF Aß1–42/1–40 and plasma NFL values changed in individuals with Down syndrome as early as the third decade of life, and amyloid PET uptake changed in the fourth decade. 18F-fluorodeoxyglucose PET and CSF p-tau changes occurred later in the fourth decade of life, followed by hippocampal atrophy and changes in cognition in the fifth decade of life. Prodromal Alzheimer's disease was diagnosed at a median age of 50·2 years (IQR 47·5–54·1), and Alzheimer's disease dementia at 53·7 years (49·5–57·2). Symptomatic Alzheimer's disease prevalence increased with age in individuals with Down syndrome, reaching 90–100% in the seventh decade of life. Interpretation: Alzheimer's disease in individuals with Down syndrome has a long preclinical phase in which biomarkers follow a predictable order of changes over more than two decades. The similarities with sporadic and autosomal dominant Alzheimer's disease and the prevalence of Down syndrome make this population a suitable target for Alzheimer's disease preventive treatments. Funding: Instituto de Salud Carlos III, Fundació Bancaria La Caixa, Fundació La Marató de TV3, Medical Research Council, and National Institutes of Health. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high‐fat diet (HFD)‐induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno‐associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD‐induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9‐hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD‐induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans., We thank Gloria González‐Aseguinolaza for kindly supplying the EalbAATp promoter. Financial support statement: This study was supported by the Ministry of Spain (MINECO) (SAF2014‐52223‐C2‐1‐R to DS, SAF2017‐83813‐C3‐1‐R to DS and LH, SAF2017‐82813‐C3‐3R to NC co‐financed by the European Regional Development Fund [ERDF], a doctoral fellowship to JFM, and a Juan de la Cierva—Incorporación research fellowship [IJCI‐2016‐28313] to PM and DS), the Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN) (CB06/03/0001 to DS), the Government of Catalonia (2014SGR465 to DS), Instituto de Salud Carlos III (FISPI18/01584 to VL‐C, FIS‐PI17/00412 to RB, FIS PI18/01484 to SA and FIS17/01455 to DS‐I, Miguel Servet Fund CP15/00106 to DS‐I and Rio Hortega grant (CM19/00039) to CM) and co‐financed by the European Regional Development Fund (ERDF), Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) to JC‐EG, the Fundació La Marató de TV3 (201627‐30 to DS and 201627‐31 to NC), the European Foundation for the Study of Diabetes (EFSD)/Lilly and EFSD/Janssen‐Rising Star and L'Oréal‐UNESCO “For Women in Science” research fellowships to LH, a doctoral fellowship from the Ciência sem Fronteiras‐CNPq (237976/2012‐9) to MW. Figure 4F was created with BioRender.com.

Background: The studies have reported that mean platelet volume may be a marker in the discrimination of upper and lower urinary tract infections. We investigated whether the mean platelet volume was a reliable indicator in upper and lower urinary tract infections. Methods: One hundred and eighty-two patients between the ages of 1 month and 14 years who were diagnosed with urinary tract infection were included in this study. The mean platelet volume values, clinical and other laboratory characteristics of the groups were compared. The discriminative ability of each biomarker for patients with UUTI was evaluated by drawing receiver operating characteristic (ROC) curves for the biomarkers. All values of p < 0.05 were considered statistically significant. Results: The leukocyte count, C-reactive protein, and erythrocyte sedimentation rates of the patients with upper urinary tract infection were significantly higher than the patients with lower urinary tract infections (p < 0.001). However, there was no statistically significant difference in terms of the mean platelet volume values between patients with upper and lower urinary tract infection ([7.2 (1.3) vs. 7.2 (1.6) fL]; p = 0.79, respectively). The value of the area under the curve of MPV's p-value was > 0.05. However, p-values of CRP and ESR were significant in ROC analysis. Conclusions: Our study showed that there was no significant difference in the mean platelet volume values between patients with upper and lower urinary tract infections. The use of mean platelet volume as an indicator of upper urinary tract infection is controversial. © 2020 Verlag Klinisches Labor GmbH. All rights reserved.

The accuracy of risk prediction for coronary artery disease can be improved with the use of novel molecular or genetic biomarkers. In this study, we investigated the difference of five selected microRNAs (miR or miRNA) in patients with coronary artery disease (CAD) and controls, assessed by coronary angiography. The study population consisted of 85 subjects, aged between 18 and 75 years and underwent invasive coronary angiography. Subjects with more than 30% stenosis in at least one coronary artery, patients with a history of prior percutaneous coronary intervention or coronary by-pass surgery were allocated to the patient group; whereas the subjects without at least 30% stenosis consisted the control group. Groups were similar in age, presence of hypertension, and smoking status. However, the proportion of males and subjects taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta blockers, nitrates, and statins were higher in the patient group. miR-221 and miR-155 were downregulated (P = .02 and .001, respectively), while miR-21 levels were significantly increased (P = .003) in the patient group compared to controls. Changes in miR-145 and miR-126 did not reach statistical significance (P > .05). miRNA- 21, miR-155, and miR-221 were differentially expressed between the patients and controls. miRNAs are promising biomarkers for CAD diagnosis, however, this requires further research with larger groups. C1 [Sanlialp, Musa] Tavas State Hosp, Dept Cardiol, Denizli, Turkey. [Dodurga, Yavuz; Secme, Mucahit] Pamukkale Univ, Sch Med, Dept Med Biol & Genet, Denizli, Turkey. [Uludag, Burcu] Dr Suat Seren Chest Hosp, Dept Cardiol, Izmir, Turkey. [Alihanoglu, Yusuf, I] Denizli Cerrahi Hosp, Dept Cardiol, Denizli, Turkey. [Enli, Yasar; Bostanci, Hayrani Eren] Pamukkale Univ, Fac Med, Dept Biochem, Denizli, Turkey. [Sanlialp, Sara Cetin] Servergazi State Hosp, Dept Cardiol, Denizli, Turkey. [Tok, Ozge Ozden] Bahcelievler Mem Hosp, Dept Cardiol, Istanbul, Turkey. [Kaftan, Asuman; Kilic, Ismail Dogu] Pamukkale Univ Hosp, Dept Cardiol, TR-20160 Denizli, Turkey.