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Background Biliary atresia (BA) is a rare disorder characterized by obstructive jaundice in infants, shortly after birth. Postoperatively, some patients exhibit portal hypertension and progressive liver fibrosis. Splenomegaly is a symptom of portal hypertension. We aimed to investigate splenomegaly as a marker for complications of portal hypertension and the relationship between splenomegaly and liver fibrosis in the long-term native liver (NL). Methods Between 1977 and 2018, 71 patients underwent hepaticojejunostomy. We included 54 patients (34 NL group, 20 liver transplant (LT) group) who fulfilled the eligibility criteria. Spleen volume (SV), total bile acids, hyaluronic acid, type IV collagen, and aspartate aminotransferase-to-platelet ratio index (APRi) were measured. Data were analyzed using Student's t-test, regression analysis, and receiver operating characteristic (ROC) curve analysis (P Results Total bile acids, hyaluronic acid, type IV collagen, and APRi increased in NL patients with a large SV at >25 years. SV and type IV collagen were correlated with NL for >25 years (r = 0.79 [P = 0.006], y = 1.1 - [0.03 × type IV collagen] [P = 0.008]). In the ROC curve analysis, the cutoff value for type IV collagen was 165 ng/mL (P = 0.07). Conclusions We suggest that SV as a prognostic index for End-Stage Liver Disease may be useful in biliary atresia. Long-term follow-up is necessary because the clinical course may be favorable in childhood but worsen during adulthood.

Background: Physical activity (PA) has substantial health benefits and is important in combatting chronic diseases, which have been associated with elevated levels of advanced glycation endproducts (AGEs). AGEs play a role in the aging process, and an association between PA and AGEs has been reported. We aimed to investigate the relationship between PA and AGE accumulation in a general population and in a population with chronic diseases.Methods: This large cross-sectional population study used data from adult participants in the LifeLines project, with participant information drawn from the LifeLines database as well data from patients with diabetes mellitus or renal and/or cardiovascular diseases. Tissue AGE accumulation was assessed non-invasively by skin-autofluorescence (SAF) using an AGE reader (DiagnOptics Technologies BV, Groningen, the Netherlands). PA was assessed using the short questionnaire to assess health-enhancing physical activity (SQUASH). Multivariate linear regression analyses were adjusted for age, body mass index, sex, and smoking status.Results: Data from 63,452 participants (general population n = 59,177, chronic disease n = 4275) were analyzed. The general population was significantly younger (43.58 +/- 11.77 years, mean +/- SD) and had significantly lower SAF (1.90 +/- 0.42 arbitrary units (AU)) compared to the population with chronic disease (age: 55.51 +/- 12.07 years; SAF: 2.27 +/- 0.51 AU). In the group with chronic disease, more hours of moderate to vigorous physical activities per week were associated with lower SAF (beta= -0.002, 95% confidence interval (95%CI): -0.002 to -0.001). For the general population, there was no association between hours of moderate to vigorous activity and SAF (beta= 3.2 x 10(-5), 95%CI: 0.000-0.001, p = 0.742). However, there was an association in the general population between total hours of PA per week and SAF (beta= 4.2 x 10(-4), 95%CI: 0.000-0.001, p < 0.001), but this association was not found in the chronic disease population (beta = -3.2 x 10(-4), 95%CI: -0.001 to 0.000, p = 0.347).Conclusion: Our study demonstrates that an inverse relationship exists between PA and AGE accumulation in the population with chronic disease. More hours of moderate to vigorous activity is associated with a significantly decreased SAF. More PA is associated with a lower SAF, even after adjusting for the established predictors (age, body mass index, smoking status, and sex). Our findings could help to promote health and prolong longevity.

Background Plasma neutrophil gelatinase-associated lipocalin (pNGAL) has been investigated extensively in acute kidney injury. This study investigated its pathophysiological significance and utility as marker for graft failure and mortality in stable kidney transplant recipients (KTR). Methods Baseline pNGAL was measured in 698 KTR (58% male, age 53 ± 13 years, estimated glomerular filtration rate 52.4 ± 20.4 mL/min/1.73 m2) at median 5.4 (interquartile range 1.8–12.0) years after transplantation, enrolled in the prospective TransplantLines Food and Nutrition Biobank and Cohort Study. Results pNGAL concentrations were higher in males, younger patients, patients with a deceased-donor kidney and higher serum creatinine. Independent of these, pNGAL was positively associated with urinary protein excretion, systemic inflammation parameters and calcineurin inhibitor use. During median follow-up of 5.3 (4.5–6.0) years, death-censored graft failure rates were 3.9%, 7.3% and 25.0% across increasing tertiles of pNGAL (Plog-rank Conclusions pNGAL is associated with parameters of kidney graft damage and with graft failure. The latter association is particularly present in KTR with pre-existent poor kidney function and proteinuria. Trial Registration: ClinicalTrials.gov NCT02811835.

Ruoran Wang,1 Min He,2 Jing Zhang,1 Shaobo Wang,3 Jianguo Xu1 1Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 2Department of Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, People’s Republic of China; 3Department of Infectious Diseases, Xi’an Hospital of Traditional Chinese Medicine, Xi’an, Shannxi Province, People’s Republic of ChinaCorrespondence: Jianguo XuDepartment of Neurosurgery, West China Hospital, Sichuan University, No. 37, Guoxue Alley, Chengdu, 610041, People’s Republic of ChinaEmail xujg@scu.edu.cnShaobo WangDepartment of Infectious Diseases, Xi’an Hospital of Traditional Chinese Medicine, No. 69, Fengcheng 8th Road, Xi’an, 710016, People’s Republic of ChinaEmail 1307799083@qq.comBackground: As an inflammation-based marker, red cell distribution width to platelet ratio (RPR) has been verified to be associated with disease severity and outcome in many clinical settings. We designed this study to evaluate the prognostic value of RPR in patients with traumatic brain injury (TBI).Methods: A total of 420 patients admitted with TBI were included in this study. Laboratory and clinical data were collected from an electronic medical record system. Univariate and multivariate logistic regression analyses were sequentially performed to discover risk factors of in-hospital mortality. Receiver operating characteristic (ROC) curves were drawn to confirm the predictive value of different markers including RPR in training set and testing set.Results: Non-survivors had higher level of RPR than survivors (P< 0.001). Logistic regression analysis showed that RPR was significantly associated with mortality even after adjusting for confounding factors (P< 0.001). The area under the ROC curve (AUC) value of Glasgow Coma Scale (GCS) for predicting mortality was 0.761 and 0775 in training set and testing set, respectively. And the constructed predictive model incorporating RPR had the highest AUC value of 0.858 and 0.884 in training set and testing set.Conclusion: RPR is significantly associated with mortality in TBI patients. Utilizing RPR to construct a predictive model is valuable to evaluate prognosis of TBI patients.Keywords: red cell distribution to platelet ratio, traumatic brain injury, prognosis, marker

Purpose Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours. Aims To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU. Methods A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan–Meier curves. Publication bias was assessed using funnel-plots and Egger’s test. Results 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage. Conclusions In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy.

Proximal urea cycle disorders (PUCDs) are not included in most newborn screening programs due to the lack of adequate markers to monitor. Failure to alter citrulline and glutamine levels, the prognostic markers commonly used, can results in high false negative. Therefore, new biomarkers, prognostic of PUCDs, are strongly desirable.We used tandem mass spectrometry to analyze blood spot from PUCDs patients during their follow up in our referral center focusing on glutamine to glutamate (Gln/Glu) ratio. We reanalyzed the same specimens of three patients after two months and the specimen of a new patient with suspicious of PUCD disorder.Specimens of our patients shown a significant elevation of the ratio Gln/Glu compared to that of a healthy population (p 0.05) as well as the specimens analyzed after two months, while the glutamine concentration dropped. New patient, showing high value of the ratio, was molecularly confirmed as PUCD patient. We further analyzed the blood spots from a neonatal population in order to fix a cut-off value and include it in a newborn screening panel.Our preliminary results suggest that the Gln/Glu ratio could be a very useful diagnostic marker, more stable over time than glutamine, which could improve the performance in early PUCDs identification.

BACKGROUND Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients. METHODS In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.9±14.8 years). The assay was carried out on a total of 232 liquid biopsies collected at the same time as endomyocardial biopsy (EMB) during routine post-transplant follow-up. RESULTS Results show a significant increase of dd-cfDNA related to ischemia-reperfusion injury (2.22±2.09%) and to acute cellular rejection (1.71±3.10%) compared to stable conditions (0.43±1.04%, p < 0.0001). On the contrary, no increase was observed during infections or vascular complications, underlining the potential role of this biomarker for rejection monitoring. With a cut-off of 0.11%, the test showed 70.8% specificity (95% CI, 58.17% - 81.40%) and 64.2% sensitivity (95% CI, 49.80% - 76.86%) in discriminating acute rejection from no rejection. CONCLUSIONS These data demonstrate that this HLA mismatch-based droplet digital PCR method is effective for monitoring rejection in heart transplant recipients. Compared to next generation sequencing approaches, it is far more flexible, less expensive and provides faster results.

This review article is devoted to the main problems of early diagnostic and prognosis of non-muscle-invasive bladder cancer, which accounts for 75 % of all newly detected cases of bladder cancer according to statistics. Chromosomal disorders that have been detected in urothelial cells can lead to the development of non-muscle-invasive bladder cancer. The review highlights the main problems of existing diagnostic systems for bladder cancer, their disadvantage and limitations of use in practice. Special attention is given to tumor stem cells, which are actively involved in the development of relapses of malignant neoplasms, and, also play an important role in the development of chemo - and radioresistance of tumor cells. Their significance in the diagnosis, detection of disease recurrence and the possibility of using the data obtained to adjustment therapeutic methods of treatment in oncology is one of the main tasks in cancer pathology.

Background Esophageal cancer is one of the most common malignancies among Iranians and is categorized as adenocarcinoma and squamous cell carcinoma. Various environmental and genetic factors are involved in this malignancy. Despite the recent advances in therapeutic modalities there is still a noticeable mortality rate among such patients which can be related to the late diagnosis. Regarding high ratio of esophageal squamous cell carcinoma (ESCC) in Iran, therefore it is required to assess molecular biology of ESCC to introduce novel diagnostic markers. In present study we assessed the role of Maelstrom (MAEL) cancer testis gene in biology of ESCC among Iranian patients. Methods Forty-five freshly normal and tumor tissues were enrolled to evaluate the levels of MAEL mRNA expression using Real time polymerase chain reaction. Results MAEL under and over expressions were observed in 12 (26.7%) and 9 (20%) of patients, respectively. MAEL fold changes were ranged between -4.33 to -1.87 (mean SD: -2.90± 0.24) and 1.92 to 7.72 (mean SD: 3.97± 0.69) in under and over expressed cases, respectively. There was a significant association between stage and MAEL expression in which majority of MAEL over expressed tumors (8/9, 88.9%) were in stage I/II (pp=0.017). Moreover, there were significant correlations between MAEL expression, tumor size (p=0.028), and grade (p=0.003) among male patients. Conclusions Our data showed that the MAEL was mainly involved in primary stages of tumor progression and it has a declining expression levels toward the advanced stages and higher depth of tumor invasions. Therefore, MAEL can be efficiently introduced as an early detection marker among Iranian ESCC patients.

Background. In present days, much attention is paid to the study of the interrelation between the macrophage/hystiocytic microenvironment and the tumor substrate in lymphoproliferative disorders.Objective. The article is devoted to the morphometric and morphological assessment of CD163-positive macrophages in nodular sclerosis Hodgkin lymphoma.Materials and methods. Formalin fixed, paraffin-embedded (FFPE) lymph node samples of 45 patients were used for the study. To identify and visualize CD163-positive cells in the test material, an immunohistochemical staining method was used.Results. The study shows that the morphometric and morphological analysis of CD163-positive cells can be an effective and promising criterion for representing them as potential predictors of the disease course. Immunohistochemical study of 45 cases using the CD163 marker revealed a difference in the nature of macrophages localization in the lymph nodes nodules. The dependence of CD163-expressing cells number on the disease course was determined.Conclusion. The data obtained can be used to stratify patients with nodular sclerosis of classical Hodgkin lymphoma into risk groups and to determine personalized approaches to treatment. Immunohistochemical determination of the CD163 marker can be used in the complex diagnosis of the causes of refractoriness to the first and subsequent lines of therapy.

IntroductionThe aim of this randomized controlled experimental study was to evaluate the efficacy of potassium, pH and D-dimer levels in blood, as well as potassium and pH levels in peritoneal lavage fluid, in the early diagnosis of acute mesenteric ischemia.Material and methodsThis study was conducted at the Istanbul University Center of Experimental Medicine after having received approval from the Istanbul University animal testing ethics committee. Male albino Wistar rats (n = 24; 250 to 350 g) were divided into two control groups and two ischemic groups. Levels of potassium, pH, and D-dimer in blood and levels of potassium and pH in peritoneal lavage fluid were analyzed for 1 h and 2 h after the induced acute mesenteric ischemia procedure. The degree of ischemic injury was determined using the histopathological damage score in tissue samples taken from the terminal ileum.ResultsIschemic groups had statistically significant differences in potassium and pH in blood and peritoneal lavage fluid compared to non-ischemic groups (p < 0.05). There was no significant difference between control and ischemic groups in terms of D-dimer and histologic grading results after 1 h (p = 0.132, p = 0.475 respectively), while there was a significant difference between control and ischemic groups after 2 h (p < 0.05).ConclusionsThe levels of potassium, pH, and D-dimer could be useful in daily practice for the early diagnosis of acute mesenteric ischemia.

Background Patients with popliteal artery aneurysm (PA) often have multiple aneurysms, such as bilateral disease or a concomitant abdominal aortic aneurysm (AAA). microRNAs (miRs) are regulators of biological processes and have been investigated as biomarkers for AAA. The aim of this study was to explore if the presence of multiple aneurysms and/or location correlated with miR levels in blood. Methods Using quantitative polymerase chain reaction, 23 miRs were analyzed in plasma from 183 patients with PA. Results Fifteen of the miRs were associated with the number and/or location of aneurysms (1.3- to 2.1-fold changes). Levels of miR-93 (1.4-fold) and miR-215 (1.6- to 1.9-fold) were changed in all compared groups. MiR-24 and miR-23a were altered in those with AAA (1.4- and 1.5-fold, respectively) or bilateral PA (1.5- and 1.4-fold, respectively), compared with in those without. MiR-145 were significantly altered (1.7-fold) in those with isolated PA and AAA, whereas miR-326 were altered in those with bilateral (2.3-fold) and isolated PA (1.9-fold). Conclusions Different miRs seem to be important or to be markers for different subgroups of patients with PA. The identified miRs target vascular smooth muscle cell proliferation and vascular inflammation. Further studies are needed to increase the understanding of the pathogenesis of aneurysmal disease., Clinical Relevance Patients with popliteal artery aneurysm often have multiple aneurysms, such as bilateral disease or concomitant abdominal aortic aneurysms, but the molecular pathogenesis of the disease is not fully understood. MicroRNAs are important regulators of gene expression and biological processes and have recently been investigated as possible biomarkers for abdominal aortic aneurysm. This study identified 11 microRNAs that were altered in subgroups of patients with popliteal artery aneurysm, which could be important regulators to study in interventional studies.

Aim of the study P-selectin (CD62P) is a platelet activation marker that was claimed to mediate the accumulation of platelets induced by cholestasis. The nature of platelet dysfunction and hemostasis abnormalities in cholestatic liver disease needs to be more explored. The aim of this study was to assess platelet CD62P expression in cirrhotic patients with and without cholestasis, and to evaluate its relationship with a bleeding tendency. Material and methods 150 patients were included in this case-control study. Participants were divided into 84 patients with liver cirrhosis (group I), 44 of whom had cholestasis (Group Ia) and 40 patients were without cholestasis (group Ib); 36 patients who were cholestatic without liver cirrhosis (group II); and 30 healthy subjects who formed the control group (group III). Platelet CD62P expression was assessed by a flow cytometer. Results Platelets expressing CD62P were significantly increased in all patient groups compared to controls (p < 0.001). Platelets expressing CD62P were significantly increased in gastrointestinal (GIT) bleeders compared to non-bleeders in cirrhotic and cholestatic groups (p < 0.001 each). Among group I patients at cut-off > 12.4, up-regulation of platelet CD62P yielded 72% sensitivity and 44.1% specificity to discriminate bleeders from non-bleeders (p = 0.01), while among group II at cut-off > 12.9, it yielded 90% sensitivity and 80.8% specificity (p < 0.001). In cirrhotic patients, platelet CD62P expression was significantly increased in patients with an advanced Child-Pugh class (p < 0.001). Platelet expressing CD62P was shown as an independent risk factor for bleeding among cirrhotic cases with an odds ratio of 1.07 and CI 0.99-1.15. Conclusions Up-regulation of platelet CD62P expression can serve as a GIT bleeding predictor in liver cirrhosis.

Objective: Investigating the recurrence of high-risk non-muscle invasive bladder cancer patients with the phosphohistone H3 (PPH3), P53, and Ki-67 as a predictive markers. Materials and Methods: A total of 46 patients with high-risk non-muscle invasive bladder cancer patients were included. All the patients treated with bacillus Calmette-Guerin instillation. Patients were divided into two groups consisted of the with recurrence (group 1) and without recurrence (group 2). Assessment of mitotic cells only in metaphase that are stained with PPH3 immunhistochemically counted separately at 20 and 40 magnification in most intense areas under microscope. Immunhistochemically stained urothelial cells with P53 evaluation was based on 3 different scoring categories that are intense, extent, and the total score. Ki-67 immunhistochemical stained cells were calculated with ratio of counted positive stained cells in intense area to the total cells. Mann-Whitney U test was used. Results: There is no significant differences between the median value of PPH3 at 20 and 40 magnification in the two groups (p=0.620, p=0.241). P53 that was assessed with median values of the extent, intense, and total score had no significant findings between the two groups (p=0.377, p=0.102, p=0.380). Also, no significant results in median values of Ki-67 between the two groups found. Conclusion: These markers could not predict recurrence in our study, but in our opinion, significant results will be found if increasing case numbers and standard immunhistochemichal staining and assessment methods are used.

Background Bladder cancer (BCa) is the ninth frequent and 13th leading cause of cancer related deaths in the world which is mainly observed among men. There is a declining mortality rates in developed countries. Although, the majority of BCa patients present Non-Muscle-Invasive Bladder Cancer (NMIBC) tumors, only 30% of patients suffer from muscle invasion and distant metastases. Radical cystoprostatectomy, radiation, and chemotherapy have proven to be efficient in metastatic tumors. However, tumor relapse is observed in a noticeable ratio of patients following the chemotherapeutic treatment. Non-coding RNAs (ncRNAs) are important factors during tumor progression and chemo resistance which can be used as diagnostic and prognostic biomarkers of BCa. Main body In present review we summarized all of the lncRNAs and miRNAs associated with chemotherapeutic resistance in bladder tumor cells. Conclusions This review paves the way of introducing a prognostic panel of ncRNAs for the BCa patients which can be useful to select a proper drug based on the lncRNA profiles of patients to reduce the cytotoxic effects of chemotherapy in such patients.

Medulloblastoma (MB) is the first primary central nervous system cancer of infancy. During the last thirty years, there has been an evolution of its treatment: although chemotherapy and radiotherapy have improved the prognosis, surgery remains a determinant key-factor for therapeutic outcome. The search of an effective adjuvant treatment along with a reduced toxicity is difficult. Following treatment with surgery, chemotherapy and radiotherapy, the prognosis for infants and young children with MB is still unfavourable and burdened by an high risk of neurocognitive deficits. The biological features of MB are not fully characterized, but now there are important directions for research. Clinical and molecular prognostic markers can be used to create a disease risk classification. In our review we resume the main features of MB, including clinical, histopathologic and molecular aspects and discuss on the therapeutic options for its treatment.

Fecal calprotectin (FC) is a marker used for the differential diagnosis of inflammatory bowel disease (IBD). FC is also used to determine the effects of treatment and recurrence prediction because of its non-decomposition by bacteria, relative week stability at room temperature, and its uniform distribution within feces. Healthy male and female adults between the age of 30 and 80 living in Jeju were selected for this study. The FC concentration in the healthy control group (N=45) was distributed widely as 0∼545.9 μg/g and showed a significant difference with age in healthy adults. The FC concentration in adults over 70 years old (80.6 years on average) was 160.3 μg/g. The result is approximately 10 times higher than in adults below 50 years (44 years on average), with FC concentrations at 15.88 μg/g. Moreover, adults over 50 years, with an average age of 59.6, had FC concentrations of 35.46 μg/g, which were two times higher than the below 50-year-old group, confirming the significant correlation between age and FC concentration. As the FC test is a non-invasive and cost-effective objective marker in IBD tests, a suitable cut-off value is required for different ages. This study provides the baseline data for differential diagnoses.

BackgroundLower limb arterial calcification is a frequent, underestimated but serious complication of diabetes. The DIACART study is a prospective cohort study designed to evaluate the determinants of the progression of lower limb arterial calcification in 198 patients with type 2 diabetes.MethodsLower limb arterial calcification scores were determined by computed tomography at baseline and after a mean follow up of 31.20 ± 3.86 months. Serum RANKL (Receptor Activator of Nuclear factor kB Ligand) and bone remodeling, inflammatory and metabolic parameters were measured at baseline. The predictive effect of these markers on calcification progression was analyzed by a multivariate linear regression model.ResultsAt baseline, mean ± SD and median lower limb arterial calcification scores were, 2364 ± 5613 and 527 respectively and at the end of the study, 3739 ± 6886 and 1355 respectively. Using multivariate analysis, the progression of lower limb arterial log calcification score was found to be associated with (β coefficient [slope], 95% CI, p-value) baseline log(calcification score) (1.02, 1.00–1.04, p ConclusionIn patients with type 2 diabetes, lower limb arterial calcification is frequent and can progress rapidly. Circulating RANKL and triglycerides are independently associated with this progression. These results open new therapeutic perspectives in peripheral diabetic calcifying arteriopathy.Trial registrationNCT02431234

Background: Fragmented QRS (fQRS) on 12-lead electrocardiogram(ECG) is associated with scarred myocardium and adverse outcome. However, the data on gender differences in terms of its prevalence and prognostic value is sparse. The aim of this study was to evaluate whether gender differences in fQRS exist among subjects drawn from populations with different risk profiles. Methods: We analyzed fQRS from 12-lead ECG in 953 autopsy-confirmed victims of sudden cardiac death (SCD) (78% men; 67.0 +/- 11.4 yrs), 1900 coronary artery disease (CAD) patients with angiographically confirmed stenosis of >= 50% (70% men; 66.6 +/- 9.0 yrs, 43% with previous myocardial infarction [MI]), and in 10,904 adults drawn from the Finnish adult general population (52% men; 44.0 +/- 8.5 yrs). Results: Prevalence of fQRS was associated with older age, male sex and the history and severity of prior cardiac disease of subjects. Among the general population fQRS was more commonly found among men in comparison to women (20.5% vs. 14.8%, p

OBJECTIVES: The use of an anatomical side marker (ASM) on x-rays, be it digital or radio paque, is an important quality and safety concept within general radiology. Using radiopaque ASMs is best practice, and lack of any ASMs may have dire consequences in terms of patient safety. To date, there have been no systematic reviews investigating the use of ASMs in clinical practice. METHODS: A systematic search of electronic databases (CINAHL, the Cochrane Library, Medline, EMBASE, ERIC, and JBI) from inception to March 1, 2018, was undertaken. Gray literature searching (through Google) and pearling was conducted. Methodological quality was assessed using a modified version of the McMaster Critical Appraisal tool for quantitative studies. A customized data extraction tool was developed, which included characteristics of the studies. RESULTS: Of 624 studies, 7 studies met the eligibility criteria. Despite diverse study designs, collectively, the studies demonstrated that only a small number of x-rays did not include an ASM. On x-rays that did use a radiopaque ASM, most of them were positioned in the primary radiation field. A noticeable shift in practice from the use of radiopaque ASMs to digital ASM was also identified. Multifaceted barriers were reported for the use of ASM in routine clinical practice. CONCLUSIONS: Although missing ASMs on x-rays were a small feature, findings from this review highlight opportunities for improvement and a need to ameliorate barriers for ASM use. Refereed/Peer-reviewed

Objective Chronic hepatitis C virus (HCV) infection is an important health problem that can cause liver cirrhosis and hepatocellular carcinoma. Recently, novel inflammatory markers from complete blood count have been used as a precursor of many clinical conditions. In this study, we investigated the role of hemogram parameters in predicting advanced liver fibrosis in chronic HCV patients. Methods Patients who underwent percutaneous liver biopsy due to chronic HCV infection between 01.01.2011 and 01.08.2019 were included in this study. Liver biopsies were evaluated according to Ishak method. Patients were classified into those with mild fibrosis (F = 3). Hemogram parameters of these groups were compared and their efficacy in predicting severe fibrosis was investigated. Results Of the 81 chronic HCV patients, 38 cases were in the mild fibrosis group and 43 cases were in the severe fibrosis group. Mean platelet volume, mean platelet volume to lymphocyte ratio, mean platelet volume to platelet ratio, and red cell distribution width to platelet ratio of the severe fibrosis group were significantly higher than those of the mild fibrosis group (P < 0.05 for all). In the ROC curve analysis, mean platelet volume to platelet ratio showed the biggest area under the curve in the prediction of advanced fibrosis. Conclusion Mean platelet volume to platelet ratio may be an easy and practical biomarker to gain a preliminary insight into advanced fibrosis in chronic HCV patients. WOS:000528610100009 2-s2.0-85081077302 PubMed: 31714386

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0-1312]) compared to patients carrying a T allele (median 0 [range 0-966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC. ispartof: SCIENTIFIC REPORTS vol:10 issue:1 ispartof: location:England status: published

Pain and emotional distress have a reciprocal relation. The amygdala has been implicated in emotional processing. The central nucleus of the amygdala (CeA) receives nociceptive information from the dorsal horn of spinal cord and is responsible for the central plasticity in chronic pain. Neuropathic pain is a type of severe chronic pain and can be strongly influenced by emotional components. Plastic changes in the CeA may play a key role in the development or maintenance or both of neuropathic pain. We studied the expression levels of proteins in the CeA of spinal nerve transection (SNT) model rats. Total tissue lysate proteins were separated by two-dimensional-gel electrophoresis (2D-PAGE). Gels from different time points were compared using Progenesis SameSpot software, and the spots with Fold Change greater than 2 were excised for protein identification by mass spectrometry. We identified more than 50 cytosolic proteins as significantly altered in their expression levels in the CeA of SNT rats, and most of these changes have been validated at mRNA levels by qRT-PCR. We also identified more than 40 membrane proteins as notably up- or down-regulated in the CeA of SNT model rats relative to a control using stable isotope dimethyl labeling nano-LC-MS/MS based proteomics and found that one such protein, doublecortin (DCX), a microtubule-associated protein expressed by neuronal precursor cells during development, is specifically localized in the membrane fraction without changes in total amount of the protein. Immunohistochemistry showed that doublecortin is expressed in processes in the CeA of rats 7 and 21 days after SNT surgery, suggesting that doublecortin is one of the proteins that may contribute to the plastic changes, namely, redevelopment or rewiring of neural networks, in the CeA in the neuropathic pain model. These dysregulated proteins may play roles in reciprocal relationships between pain and psychological distress in the amygdala and contribute to central sensitization. Data are available via ProteomeXchange with identifier PXD017473.

Myoepithelial tumors (MET) represent a clinicopathologically heterogeneous group of tumors, ranging from benign to highly aggressive lesions. Although MET arising in soft tissue, bone, or viscera share morphologic and immunophenotypic overlap with their salivary gland and cutaneous counterparts, there is still controversy regarding their genetic relationship. Half of MET of soft tissue and bone harbor EWSR1 or FUS related fusions, while MET arising in the salivary gland and skin often show PLAG1 and HMGA2 gene rearrangements. Regardless of the site of origin, the gold standard in diagnosing a MET relies on demonstrating its "myoepithelial immunophenotype" of positivity for EMA/CK and S100 protein or GFAP. However, the morphologic spectrum of MET in soft tissue and bone is quite broad and the above immunoprofile is nonspecific, being shared by other pathogenetically unrelated neoplasms. Moreover, rare MET lack a diagnostic immunoprofile but shows instead the characteristic gene fusions. In this study, we analyzed a large cohort of 66 MET with EWSR1 and FUS gene rearrangements spanning various clinical presentations, to better define their morphologic spectrum and establish relevant pathologic-molecular correlations. Genetic analysis was carried out by FISH for EWSR1/FUS rearrangements and potential partners, and/or by targeted RNA sequencing. Then, 82% showed EWSR1 rearrangement, while 18% had FUS abnormalities. EWSR1-POU5F1 occurred with predilection in malignant MET in children and young adults and these tumors had nested epithelioid morphology and clear cytoplasm. In contrast, EWSR1/FUS-PBX1/3 fusions were associated with benign and sclerotic spindle cell morphology. Tumors with EWSR1-KLF17 showed chordoma-like morphology. Our results demonstrate striking morphologic-molecular correlations in MET of bone, soft tissue and viscera, which might have implications in their clinical behavior.

Background: Sentinel lymph node (SLN) biopsy remains crucial for melanoma staging. The European Organisation for Research and Treatment of Cancer Melanoma Group recommends performing immunohistochemical stainings for reproducible identification of melanoma metastases. S100 protein (pS100) is a commonly used melanocytic antigen because of its high sensitivity in spite of relatively low specificity. SRY-related HMG-box 10 protein (SOX10) is a transcription factor characterising neural crest-derived cells. It is uniformly expressed mostly in the nuclei of melanocytes, neural, and myoepithelial cells. Pathologists sometimes prefer SOX10 as a melanoma marker, but it has not yet been investigated on a large-scale to confirm that it is reliable and recommendable for routine SLN evaluation. Methods: Four hundred one treatment-naïve lymph node (LN) metastatic melanomas were included in high-density tissue microarrays and were assessed for the presence of SOX10 and pS100 by immunohistochemistry. The slides were digitalised, shared and evaluated by a panel of experienced melanoma pathologists. Results: The vast majority of melanomas were double-positive for pS100 and SOX10 (93.2%); a small percentage of the cases (3.9%) were double-negative melanomas. Discordance between the two markers was observed: 1.9% pS100(−)/SOX10(+) and 0.75% pS100(+)/SOX10(−). SOX10 was not expressed by immune cell types in the LN, resulting in a less controversial interpretation of the staining. Conclusions: SOX10 is as equally specific as pS100 for the detection of melanoma metastases in LNs. The interpretation of SOX10 staining is highly reproducible among different centres and different pathologists because of the absence of staining of immune cells.

Background: Carotid restenosis following carotid endarterectomy (CEA) has a cumulative risk at 5-years up to 32%, which may impact the well-being of patients following CEA. Haematological parameters in the standard complete blood cell count (CBC) are emerging as potential biomarkers, but their application in CEA is scarce. The primary aim of this study was to investigate haematological markers for restenosis following CEA. The secondary aim was to characterize clinical risk factors for restenosis. Methods: From January 2012 to January 2019, 151 patients who underwent CEA under regional anaesthesia due to carotid stenosis were selected from a prospectively maintained cohort database. Patients were included if a preoperative CBC was available in the 2 weeks preceding CEA. Multivariable analysis was performed alongside propensity score matching (PSM) analysis, using the preoperative CEA parameters, to reduce confounding factors between categories. Results: The study group comprised 28 patients who developed carotid restenosis. The remaining 123 patients without restenosis composed the control group. Mean age of the patients did not differ significantly between groups (70.25 +/- 8.05 vs. 70.32 +/- 9.61 YO, P = 0.973), neither did gender (male gender 89.3% vs. 78.9%, P = 0.206). Regarding haematological parameters, only MPV remained statistically significant within multivariable analysis (1.855, aOR [1.174-2.931], P = 0.008), a result supported by PSM analysis (2.072, aOR [1.036-4.147], P = 0.042). Conclusions: MPV was able to predict restenosis 2 years after CEA. Thus, MPV can be incorporated into score calculations to identify patients at greater risk of restenosis, who could benefit from specific monitoring during follow-up. While results are promising, more research is necessary to corroborate them. info:eu-repo/semantics/publishedVersion

Globally, different diagnostic tests of urinary tract infection (UTI) are in clinical practices. A reliable test can increase the efficiency of the healthcare system, especially in a developing country like Nepal, reducing cost and time. Thus, we accessed the possibility of pyuria detected by microscopic urinalysis as a marker of pediatric UTI. The prospective study was conducted fromJuly2014 to January 2015 at Alka hospital, Lalitpur. Microscopic urinalysis of 353clean-catch urine samples was done by the wet mount method, followed by urine culture by a semi-quantitative method. We confirmed 64 (18.1%) UTI cases by culture, the gold standard for UTI diagnosis. Fever was the most common clinical manifestation in UTI cases. The sensitivity, specificity, positive predictive value and negative predictive value of pyuria detected by microscopic urinalysis to identify UTI were 50%, 70.9%, 27.6% and 86.5% respectively. In 318 febrile cases, the sensitivity, specificity, positive predictive value and negative predictive value of pyuria detected by microscopic urinalysis to identify UTI were 73.2%, 72.6%, 28.3% and 94.8% respectively. The findings suggest pyuria detected by microscopic urinalysis as not a worth while marker of pediatric UTI. But it is a trust worthy marker in febrile pediatric cases.

BACKGROUND: Alcohol consumption is a frequently studied risk factor for chronic diseases, but many studies are hampered by self-report of alcohol consumption. The urinary metabolite ethyl glucuronide (EtG), reflecting alcohol consumption during the past 72 h, is a promising objective marker, but population data are lacking. OBJECTIVE: The objective of this study was to assess the reliability of EtG as a marker for habitual alcohol consumption compared with self-report and other biomarkers in the general population. METHODS: Among 6211 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, EtG concentrations were measured in 24-h urine samples. EtG was considered positive when concentrations were ≥100 ng/mL. Habitual alcohol consumption was self-reported by questionnaire (categories: no/almost never, 1-4 units per month, 2-7 units per week, 1-3 units per day or ≥4 units per day). Plasma HDL cholesterol concentration, erythrocyte mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT) were determined as indirect biomarkers of alcohol consumption. Sensitivity, specificity, positive and negative predictive value, and proportions of agreement between reported consumption and EtG were calculated. To test the agreement of EtG concentration and alcohol consumption in categories, linear regression analysis was performed. In addition, the association between EtG concentrations and indirect biomarkers was analyzed. RESULTS: Mean age was 53.7 y, and 52.9% of participants men. Of the self-reported abstainers, 92.3% had an EtG concentration

BackgroundBladder cancer lacks useful and robust prognostic markers to stratify patients at risk. Our study is to identify a robust prognostic marker for bladder cancer.MethodsThe transcriptome and clinical data of bladder cancer were downloaded from multiple databases. We searched for genes with robust prognosis by Kaplan-Meier analysis of the whole genome. CIBERSORT and TIMER algorithm was used to calculate the degree of immune cell infiltration.ResultsWe identified OLFML2B as a robust prognostic marker for bladder cancer in five cohorts. Kaplan-Meier analysis showed that patients with a high level of OLFML2B expression had a poor prognosis. The expression of OLFML2B increased with the increase of stage and grade. We found that patients with high expression of OLFML2B still had a poor prognosis in two small bladder cancer cohorts. OLFML2B also has the prognostic ability in ten other tumors, and the prognosis is poor in high expression. The correlation analysis between OLFML2B and immune cells showed that it was positively correlated with the degree of macrophage infiltration and highly co-expressed with tumor-associated macrophage markers. Finally, the Wound-healing assay and Colony formation assay results showed that the migration and proliferation ability of bladder cancer cell lines decreased after the knockdown of OLFML2B.ConclusionsIn summary, OLFML2B is a robust risk prognostic marker, and it can help patients with bladder cancer improve individualized treatment.

Objective: This study demonstrates a novel method for pulse arrival time (PAT) segmentation into cardiac isovolumic contraction (IVC) and vascular pulse transit time to approximate central pulse wave velocity (PWV). Methods: 10 subjects (38 +/- 10 years, 121 +/- 12 mmHg SBP) ranging from normotension to hypertension were repeatedly measured at rest and with induced changes in blood pressure (BP), and thus PWV. ECG was recorded simultaneously with ultrasound-based carotid distension waveforms, a photoplethysmography-based peripheral waveform, noninvasive continuous and intermittent cuff BP. Central PAT was segmented into cardiac and vascular time intervals using a fiducial point in the carotid distension waveform that reflects the IVC onset. Central and peripheral PWVs were computed from (segmented) intervals and estimated arterial path lengths. Correlations with Bramwell-Hill PWV, systolic and diastolic BP (SBP/DBP) were analyzed by linear regression. Results: Central PWV explained more than twice the variability (R-2) in Bramwell-Hill PWV compared to peripheral PWV (0.56 vs. 0.27). SBP estimated from central PWV undercuts the IEEE mean absolute deviation threshold of 5 mmHg, significantly lower than peripheral PWV or PAT (4.2 vs. 7.1 vs. 10.1 mmHg). Conclusion: Cardiac IVC onset signaled in carotid distension waveforms enables PAT segmentation to obtain unbiased vascular pulse transit time. Corresponding PWV estimates provide the basis for single-site assessment of central arterial stiffness, confirmed by significant correlations with Bramwell-Hill PWV and SBP. Significance: In a small-scale cohort, we present proof-of-concept for a novel method to estimate central PWV and BP, bearing potential to improve the practicality of cardiovascular risk assessment in clinical routines.

High circulating dephosphorylated (dp) uncarboxylated (uc) matrix Gla protein (MGP) and uc osteocalcin (OC) concentrations are regarded as markers of vitamin K-deficiency. However, because MGP and OC are small molecules, they may potentially pass the glomerulus, and their blood concentrations may strongly depend on kidney function. However, many studies with vitamin K-status parameters do not structurally adjust for baseline kidney function, and detailed studies on kidney function-dependence of vitamin K-status markers are lacking. We therefore measured plasma dp-ucMGP using a chemiluminescent assay in 578 kidney transplant recipients (41% females, age 56 ± 13y, 7.5 (3.2 to 13.7)y after transplantation, eGFR 49 ± 17 ml/min/1.73m2) participating in the prospective TransplantLines Cohort Studies. Additionally, dp-carboxylated MGP, ucOC and carboxylated OC were measured using ELISA in plasma of a subgroup of 60 participants. Finally, dp-ucMGP was measured in a separate cohort of 124 kidney transplant recipients before and three months after kidney transplantation. Dp-ucMGP positively correlated with creatinine, cystatin C, and negatively with eGFR (Spearman’s ρ 0.54, 0.60, and -0.54, respectively, p &lt, 0.001 for all), and each 10 mL/min/1.73m2 increase in eGFR was associated with a 14.0% lower dp-ucMGP. Additionally, dp-ucMGP strongly declined after kidney transplantation (pretransplantation: 1252 (868 to 1744) pmol/L to posttransplantation: 609 (451 to 914) pmol/L, p &lt, 0.001). Proportions of dp-ucMGP over total MGP and ucOC over total OC were not associated with eGFR. This study highlights that dp-ucMGP is strongly associated with kidney function, and that levels strongly decrease after kidney transplantation. We therefore propose adequate adjustment for kidney function, or the use of kidney function-independent parameters such as proportion of uncarboxylated MGP or OC in the assessment of vitamin K-status in clinical practice and research.

Oxidized low-density lipoproteins play an important role in tissue pathology. In this study, we report a sensitive novel enzyme-linked immunosorbent assay for the detection of malondialdehyde-modified low-density lipoprotein (MDA-LDL), a key component of oxidized LDL. The assay is capable of measuring a variable presence of MDA-LDL within human plasma and serum. We demonstrate the robust nature of the assay on samples stored for over 20 months, as well as high inter-operator reproducibility (r = 0.74, p &lt, 0.0001). The assay was capable of detecting dynamic changes in patient blood samples after coronary artery bypass graft surgery, indicating synthesis or release of MDA-LDL with the oxidative stress of surgery, followed by homeostatic clearance. This robust, sensitive and specific assay for circulating MDA-LDL will serve as a valuable translational tool for the improved detection of oxidative forms of LDL in response to a range of physiological or pathological stimuli, with potential clinical applicability.

Objectives The majority of lung cancer cases are of advanced stage and diagnosis is usually made using minimally invasive small biopsies and cytological specimens. The WHO 2015 classification recommends limiting immunocytochemistry (ICC) to lung cancer typing and molecular testing drives for personalised therapies. An algorithm using Bayes' theorem could be useful for defining antibody profiles. This study aims to assess the impact of different antibody profiles for cytological samples on the accuracy of lung cancer typing with a large-scale Bayesian analysis. Methods A retrospective examination of 3419 consecutive smears and/or cytospins diagnosed over 2011-2016 found 1960 primary lung cancer tumours: 972 adenocarcinomas (ADC), 256 squamous carcinomas (SQC), 268 neuroendocrine tumours (NET), and 464 non-small cell cancer-not otherwise specified (NSCC-NOS). The a priori and a posteriori probabilities, before and after ICC using antibodies singly or in combination, were calculated for different lung cancer types. Results TTF-1 or CK7 alone improved the a posteriori probabilities of correct cytological typing for ADC to 86.5% and 95.8%, respectively. For SQC, using p40 ( increment Np63) or CK5/6 together with CK5/14 led to comparable results (78.3% and 90.3%). With synaptophysin or CD56 alone, improvements in a posteriori probabilities to 87.5 and 90.3% for the correct recognition of NET could be achieved. Conclusions Based on morphological and clinical data, the use of two antibodies appears sufficient for reliable detection of the different lung cancer types. This applies to diagnoses that were finalised following ICC both on a clinical or cytological basis and on a histological basis. WOS:000699409600001 2-s2.0-85115704631 PubMed: 34402101

Simple Summary Breast cancer is the most common cancer among women. It is estimated that 2.3 million new cases of BC are diagnosed globally each year. Based on mRNA gene expression levels, BC can be divided into molecular subtypes that provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. This review addresses the overview on the BC epidemiology, risk factors, classification with an emphasis on molecular types, prognostic biomarkers, as well as possible treatment modalities. Abstract Breast cancer (BC) is the most frequently diagnosed cancer in women worldwide with more than 2 million new cases in 2020. Its incidence and death rates have increased over the last three decades due to the change in risk factor profiles, better cancer registration, and cancer detection. The number of risk factors of BC is significant and includes both the modifiable factors and non-modifiable factors. Currently, about 80% of patients with BC are individuals aged >50. Survival depends on both stage and molecular subtype. Invasive BCs comprise wide spectrum tumors that show a variation concerning their clinical presentation, behavior, and morphology. Based on mRNA gene expression levels, BC can be divided into molecular subtypes (Luminal A, Luminal B, HER2-enriched, and basal-like). The molecular subtypes provide insights into new treatment strategies and patient stratifications that impact the management of BC patients. The eighth edition of TNM classification outlines a new staging system for BC that, in addition to anatomical features, acknowledges biological factors. Treatment of breast cancer is complex and involves a combination of different modalities including surgery, radiotherapy, chemotherapy, hormonal therapy, or biological therapies delivered in diverse sequences.

Objective Synovitis is a joint disease that seriously affects patient quality of life, but there are currently no diagnostic markers. The albumin to fibrinogen ratio (AFR) and monocyte to lymphocyte ratio (MLR) are non-invasive and cost-effective markers for various systemic inflammatory diseases. However, these markers have not yet been investigated for synovitis. This cross-sectional study evaluated the predictive ability of AFR and MLR in patients with non-specific knee synovitis. Methods One hundred fifty-five patients with knee synovitis and 108 healthy control patients were enrolled. Patient characteristics, blood parameters, AFRs, and MLRs were assessed, and the diagnostic value of these factors was determined. Results Among 125 patients included, patients with synovitis had a lower AFR and higher MLR than control subjects. The diagnostic values of AFR and MLR were 0.86 and 0.84, respectively, and higher compared with other parameters by receiver operating characteristic curve assessments. Additionally, MLR was negatively correlated with AFR. Late-stage patients showed significantly lower AFRs and significantly higher MLRs than early-stage patients. Binary logistic regression analyses indicated that AFR was an independent predictor for synovitis severity. Conclusions The AFR and MLR had high diagnostic value for knee synovitis. The AFR was an independent predictor for synovitis severity.

Background Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has emerged in 2019 and caused a global pandemic in 2020, manifesting in the coronavirus disease 2019 (COVID-19). The majority of patients exhibit a mild form of the disease with no major complications; however, moderate to severe and fatal cases are of public health concerns. Predicting the potential prognosis of COVID-19 could assist healthcare workers in managing cases and controlling the pandemic in an effective way. Therefore, the objectives of the study were to search for biomarkers associated with COVID-19 mortality and predictors of the overall survival (OS). Methods Here, clinical data of 6026 adult COVID-19 patients admitted to two large centers in Saudi Arabia (Riyadh and Hafar Al-Batin cities) between April and June 2020 were retrospectively analysed. Results More than 23% of the study subjects with available data have died, enabling the prediction of mortality in our cohort. Markers that were significantly associated with mortality in this study were older age, increased d-dimer in the blood, higher counts of WBCs, higher percentage of neutrophil, and a higher chest X-ray (CXR) score. The CXR scores were also positively associated with age, d-dimer, WBC count, and percentage of neutrophil. This supports the utility of CXR scores in the absence of blood testing. Predicting mortality based on Ct values of RT-PCR was not successful, necessitating a more quantitative RT-PCR to determine virus quantity in samples. Our work has also identified age, d-dimer concentration, leukocyte parameters and CXR score to be prognostic markers of the OS of COVID-19 patients. Conclusion Overall, this retrospective study on hospitalised cohort of COVID-19 patients presents that age, haematological, and radiological data at the time of diagnosis are of value and could be used to guide better clinical management of COVID-19 patients.

Background There is an unmet need for noninvasive imaging markers that can help identify the aggressive subtype(s) of pancreatic ductal adenocarcinoma (PDAC) at diagnosis and at an earlier time point, and evaluate the efficacy of therapy prior to tumor reduction. In the past few years, there have been two major developments with potential for a significant impact in establishing imaging biomarkers for PDAC and pancreatic cancer premalignancy: (1) hyperpolarized metabolic (HP)-magnetic resonance (MR), which increases the sensitivity of conventional MR by over 10,000-fold, enabling real-time metabolic measurements; and (2) applications of artificial intelligence (AI). Objective Our objective of this review was to discuss these two exciting but independent developments (HP-MR and AI) in the realm of PDAC imaging and detection from the available literature to date. Methods A systematic review following the PRISMA extension for Scoping Reviews (PRISMA-ScR) guidelines was performed. Studies addressing the utilization of HP-MR and/or AI for early detection, assessment of aggressiveness, and interrogating the early efficacy of therapy in patients with PDAC cited in recent clinical guidelines were extracted from the PubMed and Google Scholar databases. The studies were reviewed following predefined exclusion and inclusion criteria, and grouped based on the utilization of HP-MR and/or AI in PDAC diagnosis. Results Part of the goal of this review was to highlight the knowledge gap of early detection in pancreatic cancer by any imaging modality, and to emphasize how AI and HP-MR can address this critical gap. We reviewed every paper published on HP-MR applications in PDAC, including six preclinical studies and one clinical trial. We also reviewed several HP-MR–related articles describing new probes with many functional applications in PDAC. On the AI side, we reviewed all existing papers that met our inclusion criteria on AI applications for evaluating computed tomography (CT) and MR images in PDAC. With the emergence of AI and its unique capability to learn across multimodal data, along with sensitive metabolic imaging using HP-MR, this knowledge gap in PDAC can be adequately addressed. CT is an accessible and widespread imaging modality worldwide as it is affordable; because of this reason alone, most of the data discussed are based on CT imaging datasets. Although there were relatively few MR-related papers included in this review, we believe that with rapid adoption of MR imaging and HP-MR, more clinical data on pancreatic cancer imaging will be available in the near future. Conclusions Integration of AI, HP-MR, and multimodal imaging information in pancreatic cancer may lead to the development of real-time biomarkers of early detection, assessing aggressiveness, and interrogating early efficacy of therapy in PDAC.

Background Elevated peripheral levels of different cytokines and chemokines in subjects with Alzheimer's disease (AD), as compared with healthy controls (HC), have emphasized the role of inflammation in such a disease. Considering the cross-talking between the central nervous system and the periphery, the inflammatory analytes may provide utility as biomarkers to identify AD at earlier stages. Objective Using an advanced statistical approach, we can discriminate the interactive network of cytokines/chemokines and propose a useful tool to follow the progression and evolution of AD, also in light of sex differences. Methods A cohort of 289 old-age subjects was screened for cytokine and chemokine profiling, measured in plasma, after a thorough clinical and neuropsychological evaluation. A custom algorithm based on Fisher linear discriminant analysis was applied to ascertain a classification signature able to discriminate HC from mild cognitive impairment (MCI) and AD. Results We observed that a joint expression of three proteins (a "signature" composed by IFN-α2, IL-1α, TNFα) can discriminate HC from AD with an accuracy of 65.24%. Using this signature on MCI samples, 84.93% of them were classified as "non-HC". Stratifying MCI samples by sex, we observed that 87.23% of women were classified as "non-HC", and only 57.69% of males. Indeed, in a scatter plot of IFN-α2 and IL-1α, the HC group was better separated from MCI and AD in women as compared with men. Conclusion These findings suggest that AD is accompanied by a peripheral inflammatory response that can already be present in MCI subjects, thus providing a mean for detecting this at-risk status and allow an anticipated intervention.

Background Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening complication of pregnancy. There is limited data regarding the predictors of persistent left ventricular (LV) systolic dysfunction. Recently, monocyte-to-high density lipoprotein (HDL) cholesterol ratio (MHR) has emerged as a novel indicator of inflammation and oxidative stress. We aimed to assess the predictive value of MHR on LV recovery in patients with PPCM. Methods A total of 64 patients with PPCM who admitted to our tertiary reference hospital between 2009 and 2017 were retrospectively analyzed in this study. Demographic and clinical data, laboratory parameters and echocardiographic findings were recorded. The duration of follow-up was at least 12 months after diagnosis for all participants. Recovery of LV systolic function was defined as the presence of LV ejection fraction (LV EF) > 45%. Univariate analysis was used to determine the significant predictors of persistent LV systolic dysfunction (non-recovery). A receiver operating characteristic (ROC) curve was used to establish the cut-off values for predictors. Results The mean follow-up duration was 72.1 ± 5.5 months. Of the 64 patients, 35 (55%) had persistent LVSD at their last follow-up while 29 (45%) showed LV EF improvement. The baseline MHR levels were significantly higher in the non-recovery group (P

Background and objective Early diagnosis of malignant pleural mesothelioma (MPM) is the key point of its treatment. The main problem is the precise diagnosis of mesothelioma and its differentiation from metastatic lung adenocarcinoma. Mesothelioma exhibits complex immunohistochemical characteristics. The aim of this study was to study hybrid immunohistochemistry in the differential diagnosis of primary malignant pleural effusion from metastatic pulmonary cancers. Material and methods Twenty tissue samples in paraffin blocks from the pathology department of Imam Reza Hospital in Tabriz whose pathology reports cited mesothelioma or metastatic lung adenocarcinomas, were included in the studies. These tissues were deemed appropriate for IHC in terms of tissue quality and quantity. They were studied and evaluated for pathological markers. Results In patients with adenocarcinoma CK7 in 100% of patients (13 patients), TTF1 in 61.5% of patients (8 patients) and CEA in 53.8% of patients (7 patients) were positive, but HBME1 and Calretinin were negative for all patients. In patients with mesothelioma, HBME1 and Calretinin were positive in 100% of patients (7 patients) and TTF1, CEA and CK7 were negative. Conclusion The results of this study showed that CEA, CK7, TTF1, Calretinin and HBME1 are suitable criteria for differentiating between metastatic lung adenocarcinoma and mesothelioma, and can differentiate the mesothelioma and adenocarcinoma with high accuracy.

Equine Glandular Gastric Disease (EGGD) is a common disease in sport horses. This disease might be associated with usage of nonsteroidal anti-inflammatory drugs (NSAIDs) for treating inflammatory diseases. Although gastroscopy has been an effective method for diagnosis, but a less invasive, and inexpensive method is preferred. This study used proteomic technology to identify candidate serum proteins that might be used as markers of NSAIDs induced EGGD. Five Thoroughbred horses were given high doses of NSAID, phenylbutazone to treat lameness. The experiment was divided into three periods: (i) Pre-EGGD period, (ii) during EGGD period, and (iii) Post-EGGD period. Gastroscopy were used to diagnose EGGD, serum was collected to perform gel electrophoresis (1D SDS-PAGE) and mass spectrometry (LC-MS) in order to identify serum proteins in each group. The candidate serum proteins were computationally predicted for the interaction between phenylbutazone and proteins, tissue specific expression, and association to gastric ulceration. After EGGD induction, all horses showed clinical signs of colic with marked congestion and erosion appearing in the mucosa of the glandular stomach whereas no change was observed in the mucosa of non-glandular stomach. Our proteomic results identified 14 proteins that might be used as EGGD markers. These proteins were highly expressed in the glandular stomach and some proteins were associated with phenylbutazone or ulcer development. However, confirmation of these candidate marker proteins is required with specific antibodies in the larger horse population before they can be considered for application in the field.

WOS:000462934300005 PubMed ID: 30249941 Aim: Peripheral artery disease (PAD) is a manifestation of atherosclerosis with poor prognosis. It is generally complicated by vascular calcification, which is located either in the intima as patchy infiltrates; or circumferentially in the media, also known as medial arterial calcification (MAC). Obstructive PAD is reflected by low ankle-brachial index (ABI 1.4). Considering the increase in cardiovascular mortality at both ends of the ABI spectrum, this study aimed to explore the underlying pathology through cytokines with established prognostic significance; namely pentraxin-3(PTX3), high sensitivity C-reactive protein (hsCRP), copeptin, soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), NT-proBNP, and neopterin. Methods: We categorized 180 patients with previous multivessel coronary artery bypass grafting surgery into three groups based on their ABI measurements; 60 patients with ABI 1.4 constituted the "PAD," "normal," "MAC" groups, respectively. The circulating levels of the biochemical markers were determined. Results: In the PAD group, the cytokine levels with predominantly proatherogenic actions such as PTX3, hsCRP, copeptin, and sTREM-1 were increased and these cytokine levels declined as the ABI increased. In the MAC group, the cytokine concentrations with pleiotropic actions such as NT-proBNP and neopterin increased and; NT-proBNP and neopterin concentrations decreased as ABI decreased. The linear regression analysis revealed that neopterin (beta = 0.72), PTX3 (beta = -0.32), and copeptin (beta = -0.48) were independent predictors of ABI. Conclusions: These findings suggest that different inflammatory pathways influence the pathology at the opposing ends of the ABI spectrum. Consequently, we suggest that PTX3, copeptin, and neopterin are promising biomarkers for future research. Scientific Research Projects of Namik Kemal University [NKUBAP.02, 16.043] This study was funded by the Scientific Research Projects of Namik Kemal University (NKUBAP.02.GA.16.043).

Background Fetal growth restriction is, despite advances in neonatal care and uptake of antenatal ultrasound scanning, still a major cause of perinatal morbidity. Neonates with birth weight > 10th percentile are assumed to be appropriate-for-gestational-age (AGA), although many are at increased risk of perinatal morbidity, because of undetected mild restriction of growth potential. We hypothesized that within AGA neonates, reduced fetal growth velocities are associated with adverse neonatal outcome. Methods A retrospective cohort study of singleton pregnancies, in the Maastricht University Medical Centre (MUMC) between 2010 and 2016. Women had two fetal biometry scans (18–22 weeks and 30–34 weeks of gestational age) and delivered a newborn with a birth weight between the 10th–80th percentile. Differences in growth velocities of the abdominal circumference (AC), biparietal diameter (BPD), head circumference (HC) and femur length (FL) were compared between the suboptimal AGA (sAGA) (birth weight centiles 10–50) and optimal AGA (oAGA) (birth weight centiles 50–80) group. We assessed the association between velocities and neonatal outcomes. Results We included 934 singleton pregnancies. In the suboptimal AGA group, fetal growth velocities were lower (in mm/week): AC 10.72 ± 1.00 vs 11.23 ± 1.00 (p

Introduction: Endocan and endoglin have been shown to play a role in angiogenesis. Aberrant excessive angiogenesis is a main factor in the development of diabetic nephropathy. In this study we evaluated endocan and endoglin levels in diabetes patients with and without albuminuria and compared them with healthy subjects. Therefore we aimed at gaining a better understanding of the role of angiogenesis in diabetic nephropathy and to assess the predictive role of endocan and endoglin as markers of diabetic nephropathy progression. Material and methods: Ninety-six type 2 diabetes patients were classified according to their 24-hour urinary albumin excretion rate. Forty type 2 diabetes patients with normoalbuminuria (urinary albumin excretion < 30 mg/day), 56 type 2 diabetes patients with diabetic nephropathy (with a urinary albumin excretion >= 30 mg/day) and 35 healthy non-diabetic control subjects were included. Their anthropometric features, arterial blood pressures, fasting glucose, glycated hemoglobin, urea, creatinine, lipids, endocan and endoglin levels were measured and compared to each other. Results: Endocan and endoglin levels of diabetics patients were higher than those of the controls. In comparison of endocan and endoglin levels of diabetic nephropathy patients with controls, p-values were < 0.001 and 0.002 respectively. In comparison of normoalbuminuric diabetic patients with controls, p-values were 0.001 and 0.017 respectively. Endocan levels of diabetic nephropathy cases were higher than those of normoalbuminuric patients (p = 0.011) but there was no statistically significant difference in endoglin levels between them (p = 0.822). Conclusions: Endocan might be a more reliable marker of diabetic nephropathy development than endoglin.

Trimethylamine N-oxide (TMAO), a novel cardiovascular (CV) disease and mortality risk marker, is a gut microbiota-derived metabolite as well. Recently, plasma concentrations of branched-chain amino acids (BCAA) have been reported to be affected by microbiota. The association of plasma TMAO with CV mortality in Type 2 Diabetes (T2D) and its determinants are still incompletely described. We evaluated the association between plasma BCAA and TMAO, and the association of TMAO with CV mortality in T2D individuals. We used data of 595 participants (mean age 69.5 years) from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort were analyzed. Plasma TMAO and BCAA were measured with nuclear magnetic resonance spectroscopy. CV mortality risk was estimated using multivariable-adjusted Cox regression models. Cross-sectionally, TMAO was independently associated with BCAA standardized (Std) β = 0.18 (95% Confidence Interval (CI) 0.09, 0.27), p &lt, 0.001. During a median follow-up of 10 years, 113 CV deaths were recorded. In Cox regression analyses, adjusted for multiple clinical and laboratory variables including BCAA, TMAO was independently associated with CV mortality: adjusted hazard ratio (adjHR) 1.93 (95% CI 1.11, 3.34), p = 0.02 (for the highest vs. the lowest tertile of the TMAO distribution). The same was true for analyses with TMAO as continuous variable: adjHR 1.32 (95% CI 1.07, 1.63), p = 0.01 (per 1 SD increase). In contrast, BCAAs were not associated with increased CV mortality. In conclusion, higher plasma TMAO but not BCAA concentrations are associated with an increased risk of CV mortality in individuals with T2D, independent of clinical and biochemical risk markers.

BackgroundStroke is the second leading cause of death worldwide. If risk of stroke could be evaluated early or even at a preclinical stage, the mortality rate could be reduced dramatically. However, the identified genetic factors only account for 5–10% of the risk of stroke. Studies on the risk factors of stroke are urgently needed. We investigated the correlation between blood-based β-actin (ACTB) methylation and the risk of stroke in a prospective nested case-control study.MethodsThe methylation level of ACTB was quantitatively determined by mass spectrometry in 139 stroke cases who developed stroke within 2 years after recruitment and 147 age- and sex-matched controls who remained stroke-free in a median follow-up of 2.71 years.ResultsWe observed a highly significant correlation between hypomethylation of one CpG site of ACTB and increased risk of stroke in an onset-time-dependent manner (for onset time ≤ 1.5 years: odds ratio (OR) per + 10% methylation = 0.76, P = 0.001; for onset time ≤ 1.32 years: OR per + 10% methylation = 0.59, P = 7.82 × 10–7; for onset time ≤ 1 year: OR per + 10% methylation = 0.43, P = 3.00 × 10–6), and the increased cumulative incidence of stroke (log-rank P = 3.13 × 10–7). Neighboring CpG sites showed an inverse correlation with age and drinking status in controls (P < 0.05) but not in stroke cases.ConclusionWe firstly reported the blood-based ACTB methylation as a marker for the risk evaluation and preclinical detection of stroke, which can be further modified by age and drinking.

Reliable protein markers for pre-diabetes in humans are not clinically available. In order to identify novel and reliable protein markers for pre-diabetes in humans, healthy volunteers and patients diagnosed with pre-diabetes and stroke were recruited for blood collection. Blood samples were collected from healthy and pre-diabetic subjects 12 h after fasting. BMI was calculated from body weight and height. Fasting blood glucose (FBG), glycated hemoglobin (HbA1C), triglyceride (TG), total cholesterol, high-density lipoprotein, low-density lipoprotein (LDL), insulin and albumin were assayed by automated clinical laboratory methods. We used a quantitative proteomics approach to identify 1074 proteins from the sera of pre-diabetic and healthy subjects. Among them, 500 proteins were then selected using Mascot analysis scores. Further, 70 out of 500 proteins were selected via volcano plot analysis according to their statistical significance and average relative protein ratio. Eventually, 7 serum proteins were singled out as candidate markers for pre-diabetes due to their diabetic relevance and statistical significance. Immunoblotting data demonstrated that laminin subunit alpha 2 (LAMA2), mixed-lineage leukemia 4 (MLL4), and plexin domain containing 2 (PLXDC2) were expressed in pre-diabetic patients but not healthy volunteers. Receiver operating characteristic curve analysis indicated that the combination of the three proteins has greater diagnostic efficacy than any individual protein. Thus, LAMA2, MLL4 and PLXDC2 are novel and reliable serum protein markers for pre-diabetic diagnosis in humans.

Angiotensin-converting enzyme (ACE)/Angiotensin (Ang) II pathway has crucial regulatory effects on circulatory hemostasis and immune responses. This pathway has a major role in the development of acute lung injury and acute respiratory distress syndrome (ARDS), which is a devastating complication of SARS-CoV-2 infection. The aim of this study is to investigate the serum ACE activity and its correlation with clinical features and the disease severity in patients with COVID-19. Patients with confirmed COVID-19 by detecting SARS-CoV-2 nucleic acid RT-PCR were included in the study. Demographic data, clinical features, laboratory and radiologic investigations were recorded. Patients were classified by disease severity; asymptomatic, mild, and severe pneumonia. The serum ACE activity was evaluated with an autoanalyzer based on a spectrophotometric method. Fifty-five patients (50.9% female) and 18 healthy subjects (33.3 % female) were enrolled in the study. The median age of patients was 40 years, ranging from 22 to 81 years. Eighteen healthy subjects were served as the control group. The baseline characteristics were comparable between groups. The median serum ACE activity of patients and controls (38.00 [IQR 21] U/L and 32.00 [IQR 24] U/L, respectively) and of between patients grouped by disease severity (38.5 [IQR 19], 36 [IQR 25], and 38 [IQR 22] U/L, asymptomatic, mild and severe pneumonia group, respectively) were similar. There was no correlation between the serum ACE activity and conventional inflammatory markers. In this study, we did not find an association between serum ACE activity and COVID-19 and serum ACE activity on admission did not reflect disease severity.

BackgroundThe medical home (MH) model has been promoted by both the federal and state governments in the United States in recent years. To ascertain American children’s MH status, many studies have relied on a large set of survey items, posing a considerable burden on their parents. We aimed to identify individual survey items or domains that best predict MH status for children and use them to develop brief markers of MH status. We also examined whether the identified items differed by status of special health care needs and by racial/ethnic group.MethodUsing the 9-year data from Medical Expenditure Panel Survey, we examined associations between children’s MH status and individual survey items or domains. We randomly split the data into two halves with the first half (training sample,n = 8611) used to identify promising items, and the second half (validation sample,n = 8779) used to calculate all statistical measures. After discovering significant predictors of children’s MH status, we incorporated them into several brief markers of MH status. We also conducted stratified analyses by status of special health care needs and by racial/ethnic group.ResultsLess than half (48.7%) of the 8779 study children had a MH. The accessibility domain has stronger association with children’s MH status (specificity = 0.84, sensitivity = 1, Kappa = 0.83) than other domains. The top two items with the strongest association with MH status asked about after-hours primary care access, including doctors’ office hours at night or on the weekend and children’s difficulty accessing care after hours. Both belong to the accessibility domain and are one of several reliable markers for children’s MH status. While each of the two items did not differ significantly by status of special health care needs, there were considerable disparities across racial/ethnic groups with Latino children lagging behind other children.ConclusionAccessibility, especially the ability to access health care after regular office hours, appears to be the major predictor of having a MH among children. The ongoing efforts to promote the MH model need to target improving accessibility of health care after regular hours for children overall and especially for Latino children.