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Internet of Things (IoT) has become a part of everyday life as well as industry and society. One of the main concerns of a mobile operator before implementing IoT in the mobile network is how much the IoT traffic will affect the performance of MBB users. In this paper, we present the simulation study that analyzes the impact of NB-IoT implementation on LTE MBB performance, based on one real network case considering the current status as well as the projected future traffic growth in the network.

The research objective was to investigate the influence of different pipe drainage systems on the concentration and quantity of atrazine leached in drainage water, as well as in surface (0-30 cm) and sub-surface (30-60 cm) soil horizons in the production of agricultural crops on drained Gleyic Podzoluvisol. Investigations involved four different variants of drainpipe spacing (15, 20, 25 and 30 m, i.e. four variants in four repetitions). In a particular trial year, the same crop was grown and the same agricultural practices applied in all trial variants. Maize was grown in the first two trial years and wheat in the last year. Soil and water samples were qualitatively and quantitatively analysed for the presence of atrazine by gas chromatography. Atrazine concentrations in drainage water ranged from those within the limits tolerated for drinking water (out of the growing season) up to 458 ng.dm-3. Maximum quantity of leached atrazine was recorded in 1998 (0.500 g.ha-1), namely, from atrazine application in May 1997 to March 1998 incl., 0.630 g.ha-1 or 0.052% of the initially added quantity was leached. Maximum atrazine concentration in the surface soil layer was recorded in traces or it was not recorded at all (0.013 mg.kg-1), whereas no atrazine was recorded in the subsurface layer during the trial period. Analysis of variance produced no statistically significant difference in the atrazine concentration and leaching in drainage water and in the surface soil layer between different variants of pipe drainpipe spacing.

Gut bacteria regulate brain pathology of Alzheimer's disease (AD) patients and animal models; however, the underlying mechanism remains unclear. In this study, 3-month-old APP-transgenic female mice with and without knock-out of Il-17a gene were treated with antibiotics-supplemented or normal drinking water for 2 months. The antibiotic treatment eradicated almost all intestinal bacteria, which led to a reduction in Il-17a-expressing CD4-positive T lymphocytes in the spleen and gut, and to a decrease in bacterial DNA in brain tissue. Depletion of gut bacteria inhibited inflammatory activation in both brain tissue and microglia, lowered cerebral Aβ levels, and promoted transcription of Arc gene in the brain of APP-transgenic mice, all of which effects were abolished by deficiency of Il-17a. As possible mechanisms regulating Aβ pathology, depletion of gut bacteria inhibited β-secretase activity and increased the expression of Abcb1 and Lrp1 in the brain or at the blood-brain barrier, which were also reversed by the absence of Il-17a. Interestingly, a crossbreeding experiment between APP-transgenic mice and Il-17a knockout mice further showed that deficiency of Il-17a had already increased Abcb1 and Lrp1 expression at the blood-brain barrier. Thus, depletion of gut bacteria attenuates inflammatory activation and amyloid pathology in APP-transgenic mice via Il-17a-involved signaling pathways. Our study contributes to a better understanding of the gut-brain axis in AD pathophysiology and highlights the therapeutic potential of Il-17a inhibition or specific depletion of gut bacteria that stimulate the development of Il-17a-expressing T cells.

In Alzheimer's disease (AD) brain, inflammatory activation regulates protein levels of amyloid-β-peptide (Aβ) and phosphorylated tau (p-tau), as well as neurodegeneration; however, the regulatory mechanisms remain unclear. We constructed APP- and tau-transgenic AD mice with deletion of IKKβ specifically in neurons, and observed that IKKβ deficiency reduced cerebral Aβ and p-tau, and modified inflammatory activation in both AD mice. However, neuronal deficiency of IKKβ decreased apoptosis and maintained synaptic proteins (e.g., PSD-95 and Munc18-1) in the brain and improved cognitive function only in APP-transgenic mice, but not in tau-transgenic mice. Additionally, IKKβ deficiency decreased BACE1 protein and activity in APP-transgenic mouse brain and cultured SH-SY5Y cells. IKKβ deficiency increased expression of PP2A catalytic subunit isoform A, an enzyme dephosphorylating cerebral p-tau, in the brain of tau-transgenic mice. Interestingly, deficiency of IKKβ in neurons enhanced autophagy as indicated by the increased ratio of LC3B-II/I in brains of both APP- and tau-transgenic mice. Thus, IKKβ deficiency in neurons ameliorates AD-associated pathology in APP- and tau-transgenic mice, perhaps by decreasing Aβ production, increasing p-tau dephosphorylation, and promoting autophagy-mediated degradation of BACE1 and p-tau aggregates in the brain. However, IKKβ deficiency differently protects neurons in APP- and tau-transgenic mice. Further studies are needed, particularly in the context of interaction between Aβ and p-tau, before IKKβ/NF-κB can be targeted for AD therapies., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: The aim of this study was to examine the influence of intraluminal thrombus (ILT) volume on the level of proteolytic activity and the content of abdominal aortic aneurysm (AAA) wall., Methods: The research was designed as a cross-sectional study at the Clinic for Vascular and Endovascular Surgery, Clinical Center of Serbia in the period from April 2017 to February 2018. During this period, a total of 155 patients with asymptomatic AAA underwent open surgical treatment and 50 were included in the study based on inclusion and exclusion criteria. Before surgery, patients included in the study were examined by MRI. During the operation, samples of ILT and AAA wall were taken for biochemical analysis., Results: A statistically significant correlation was found between the volume of the ILT and largest AAA diameter (ρ = 0.56; P < 0.001). The correlation of the ILT volume on the anterior wall and the concentration of MMP-9, MMP-2 and NE/ELA in the wall did not find statistical significance. Also, no statistically significant association was found between the volume of ILT and the concentration of ECM proteins (collagen type 3, elastin, proteoglycan) in the corresponding part of the wall. The association of ILT volume with MDA was also of no statistical significance. There was a positive statistical significance found in correlation of volume of ILT and catalase activity in the wall of AAA (ρ = 0.28, P = 0.049)., Conclusions: The volume of ILT in the aneurysmal sac seemed not to affect the level of proteolytic activity and the content of the aneurysm wall. However, a positive correlation was found between the ILT and the catalase activity. The effect of ILT on the aneurysm wall and its role in the progression of aneurysmal disease should be examined in future studies., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD), the most common cause of dementia in the elderly, is pathologically characterized by extracellular deposition of amyloid-β peptides (Aβ) and microglia-dominated inflammatory activation in the brain. p38α-MAPK is activated in both neurons and microglia. How p38α-MAPK in microglia contributes to AD pathogenesis remains unclear. In this study, we conditionally knocked out p38α-MAPK in all myeloid cells or specifically in microglia of APP-transgenic mice, and examined animals for AD-associated pathologies (i.e., cognitive deficits, Aβ pathology, and neuroinflammation) and individual microglia for their inflammatory activation and Aβ internalization at different disease stages (e.g., at 4 and 9 months of age). Our experiments showed that p38α-MAPK-deficient myeloid cells were more effective than p38α-MAPK-deficient microglia in reducing cerebral Aβ and neuronal impairment in APP-transgenic mice. Deficiency of p38α-MAPK in myeloid cells inhibited inflammatory activation of individual microglia at 4 months but enhanced it at 9 months. Inflammatory activation promoted microglial internalization of Aβ. Interestingly, p38α-MAPK-deficient myeloid cells reduced IL-17a-expressing CD4-positive lymphocytes in 9 but not 4-month-old APP-transgenic mice. By cross-breeding APP-transgenic mice with Il-17a-knockout mice, we observed that IL-17a deficiency potentially activated microglia and reduced Aβ deposition in the brain as shown in 9-month-old myeloid p38α-MAPK-deficient AD mice. Thus, p38α-MAPK deficiency in all myeloid cells, but not only in microglia, prevents AD progression. IL-17a-expressing lymphocytes may partially mediate the pathogenic role of p38α-MAPK in peripheral myeloid cells. Our study supports p38α-MAPK as a therapeutic target for AD patients., (© 2022 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Preoperative anxiety is associated with increased morbidity and/or mortality in surgical patients. This study investigated the incidence, predictors, and association of preoperative anxiety with postoperative complications in vascular surgery., Methods: Consecutive patients undergoing aortic, carotid, and peripheral artery surgery, under general and regional anesthesia, from February until October 2019 were included in a cross-sectional study. Anesthesiologists assessed preoperative anxiety using a validated Serbian version of the Amsterdam Preoperative Anxiety and Information Scale. Patients were divided into groups with low/high anxiety, both anesthesia- and surgery-related. Statistical analysis included multivariate linear logistic regression and point-biserial correlation., Results: Of 402 patients interviewed, 16 were excluded and one patient refused to participate (response rate 99.7%). Out of 385 patients included (age range 39-86 years), 62.3% had previous surgery. High-level anesthesia- and surgery-related anxieties were present in 31.2 and 43.4% of patients, respectively. Independent predictors of high-level anesthesia-related anxiety were having no children (OR = 0.443, 95% CI: 0.239-0.821, p = 0.01), personal bad experiences with anesthesia (OR = 2.294, 95% CI: 1.043-5.045, p = 0.039), and time since diagnosis for ≥ 4 months (OR = 1.634, 95% CI: 1.023-5.983, p = 0.04). The female sex independently predicted high-level surgery-related preoperative anxiety (OR = 2.387, 95% CI: 1.432-3.979, p = 0.001). High-level anesthesia-related anxiety correlated with postoperative mental disorders (r pb  = 0.193, p = 0.001) and pulmonary complications (r pb  = 0.104, p = 0.042). Postoperative nausea (r pb  = 0.111, p = 0.03) and postoperative mental disorders (r pb  = 0.160, p = 0.002) correlated with high-level surgery-related preoperative anxiety., Conclusions: Since preoperative anxiety affects the postoperative course and almost every third patient experiences anxiety preoperatively, routine screening might be recommended in vascular surgery., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

Background and Objectives: Despite the relatively large number of publications concerning the validation of these models, there is currently no solid evidence that they can be used with absolute precision to predict survival. The goal of this study is to identify preoperative factors that influenced 30-day mortality and to create a predictive model after open ruptured abdominal aortic aneurysm (RAAA) repair. Materials and Methods: This was a retrospective single-center cohort study derived from a prospective collected database, between 1 January 2009 and 2016. Multivariate logistic regression analysis was used to identify all significant predictive factors. Variables that were identified in the multivariate analysis were dichotomized at standard levels, and logistic regression was used for the analysis. To ensure that dichotomized variables were not overly simplistic, the C statistic was evaluated for both dichotomized and continuous models. Results: There were 500 patients with complete medical data included in the analysis during the study period. Of them, 37.6% were older than 74 years, and 83.8% were males. Multivariable logistic regression showed five variables that were predictive of mortality: age > 74 years (OR = 4.01, 95%CI 2.43−6.26), loss of consciousness (OR = 2.21, 95%CI 1.11−4.40), previous myocardial infarction (OR = 2.35, 95%CI 1.19−4.63), development of ventricular arrhythmia (OR = 4.54, 95%CI 1.75−11.78), and DAP < 60 mmHg (OR = 2.32, 95%CI 1.17−4.62). Assigning 1 point for each variable, patients were stratified according to the preoperative RAAA mortality risk score (range 0−5). Patients with 1 point suffered 15.3% mortality and 3 points 68.2% mortality, while all patients with 5 points died. Conclusions: This preoperative RAAA score identified risk factors readily assessed at the bedside and provides an accurate prediction of 30-day mortality after open repair of RAAA.

Importance: Adults with obsessive-compulsive disorder (OCD) display perseverative behavior in stable environments but exhibit vacillating choice when payoffs are uncertain. These findings may be associated with intolerance of uncertainty and compulsive behaviors; however, little is known about the mechanisms underlying learning and decision-making in youths with OCD because research into this population has been limited., Objective: To investigate cognitive mechanisms associated with decision-making in youths with OCD by using executive functioning tasks and computational modeling., Design, Setting, and Participants: In this cross-sectional study, 50 youths with OCD (patients) and 53 healthy participants (controls) completed a probabilistic reversal learning (PRL) task between January 2014 and March 2020. A separate sample of 27 patients and 46 controls completed the Wisconsin Card Sorting Task (WCST) between January 2018 and November 2020. The study took place at the University of Cambridge in the UK., Main Outcomes and Measures: Decision-making mechanisms were studied by fitting hierarchical bayesian reinforcement learning models to the 2 data sets and comparing model parameters between participant groups. Model parameters included reward and punishment learning rates (feedback sensitivity), reinforcement sensitivity and decision consistency (exploitation), and stickiness (perseveration). Associations of receipt of serotonergic medication with performance were assessed., Results: In total, 50 patients (29 female patients [58%]; median age, 16.6 years [IQR, 15.3-18.0 years]) and 53 controls (30 female participants [57%]; median age, 16.4 years [IQR, 14.8-18.0 years]) completed the PRL task. A total of 27 patients (18 female patients [67%]; median age, 16.1 years [IQR, 15.2-17.2 years]) and 46 controls (28 female participants [61%]; median age, 17.2 [IQR, 16.3-17.6 years]) completed the WCST. During the reversal phase of the PRL task, patients made fewer correct responses (mean [SD] proportion: 0.83 [0.16] for controls and 0.61 [0.31] for patients; 95% CI, -1.31 to -0.64) and switched choices more often following false-negative feedback (mean [SD] proportion: 0.09 [0.16] for controls vs 0.27 [0.34] for patients; 95% CI, 0.60-1.26) and true-positive feedback (mean [SD] proportion: 0.93 [0.17] for controls vs 0.73 [0.34] for patients; 95% CI, -2.17 to -1.31). Computational modeling revealed that patients displayed enhanced reward learning rates (mean difference [MD], 0.21; 95% highest density interval [HDI], 0.04-0.38) but decreased punishment learning rates (MD, -0.29; 95% HDI, -0.39 to -0.18), reinforcement sensitivity (MD, -4.91; 95% HDI, -9.38 to -1.12), and stickiness (MD, -0.35; 95% HDI, -0.57 to -0.11) compared with controls. There were no group differences on standard WCST measures and computational model parameters. However, patients who received serotonergic medication showed slower response times (mean [SD], 1420.49 [279.71] milliseconds for controls, 1471.42 [212.81] milliseconds for patients who were unmedicated, and 1738.25 [349.23] milliseconds for patients who were medicated) (control vs medicated MD, -320.26 [95% CI, -547.00 to -88.68]) and increased unique errors (mean [SD] proportion: 0.001 [0.004] for controls, 0.002 [0.004] for patients who were unmedicated, and 0.008 [0.01] for patients who were medicated) (control vs medicated MD, -0.007 [95% CI, -3.14 to -0.36]) on the WCST., Conclusions and Relevance: The results of this cross-sectional study indicated that youths with OCD showed atypical probabilistic reversal learning but were generally unimpaired on the deterministic WCST, although unexpected results were observed for patients receiving serotonergic medication. These findings have implications for reframing the understanding of early-onset OCD as a disorder in which decision-making is associated with uncertainty in the environment, a potential target for therapeutic treatment. These results provide continuity with findings in adults with OCD.

Introduction: We present single-institution results of types I and II hybrid procedures for aortic arch disease with 30-day and long-term results and review of the literature., Materials and Methods: This is a retrospective study of all patients that underwent zone 0 endografting and open bypass from ascending aorta to the arch vessels at our institution between January 2013 and 2020. The following data for the systematic review were extracted from eligible studies: 30-day/in-hospital mortality, stroke rate, spinal cord ischemia (SCI) rate, renal failure requiring dialysis, development of retrograde dissection, early (<30 days) types I and III endoleak, follow-up length, late (>30 days) endoleak, and late (>30 days) mortality., Results: Twelve patients underwent hybrid aortic arch treatment in our institution. The most common aortic arch pathology was degenerative aortic aneurysm. The rate of retrograde dissection and SCI was 8.33%. Regarding the literature data, a total of 768 patients undergoing types I and II hybrid aortic arch debranching procedure. The pooled rate of 30-day/in-hospital mortality was 10.96% (95% confidence interval [CI], 8.21-14.06), SCI pooled rate was 2.91% (95% CI, 1.76%-4.33%), and retrograde dissection pooled rate was 3.22% (95% CI, 1.99-4.72)., Conclusion: Hybrid arch techniques provide safe alternative to open repair with acceptable short- and midterm results., (© 2021 Wiley Periodicals LLC.)

Growing evidence indicates that innate immune molecules regulate microglial activation in Alzheimer's disease (AD); however, their effects on amyloid pathology and neurodegeneration remain inconclusive. Here, we conditionally deleted one allele of myd88 gene specifically in microglia in APP/PS1-transgenic mice by 6 months and analyzed AD-associated pathologies by 9 months. We observed that heterozygous deletion of myd88 gene in microglia decreased cerebral amyloid β (Aβ) load and improved cognitive function of AD mice, which was correlated with reduced number of microglia in the brain and inhibited transcription of inflammatory genes, for example, tnf-α and il-1β, in both brain tissues and individual microglia. To investigate mechanisms underlying the pathological improvement, we observed that haploinsufficiency of MyD88 increased microglial recruitment toward Aβ deposits, which might facilitate Aβ clearance. Microglia with haploinsufficient expression of MyD88 also increased vasculature in the brain of APP/PS1-transgenic mice, which was associated with up-regulated transcription of osteopontin and insulin-like growth factor genes in microglia. Moreover, MyD88-haploinsufficient microglia elevated protein levels of LRP1 in cerebral capillaries of APP/PS1-transgenic mice. Cell culture experiments further showed that treatments with interleukin-1β decreased LRP1 expression in pericytes. In summary, haploinsufficiency of MyD88 in microglia at a late disease stage attenuates pro-inflammatory activation and amyloid pathology, prevents the impairment of microvasculature and perhaps also protects LRP1-mediated Aβ clearance in the brain of APP/PS1-transgenic mice, all of which improves neuronal function of AD mice., (© 2021 The Authors. GLIA published by Wiley Periodicals LLC.)

Amyloid β peptide (Aβ) is the major pathogenic molecule in Alzheimer's disease (AD). BACE1 enzyme is essential for the generation of Aβ. Deficiency of p38α-MAPK in neurons increases lysosomal degradation of BACE1 and decreases Aβ deposition in the brain of APP-transgenic mice. However, the mechanisms mediating effects of p38α-MAPK are largely unknown. In this study, we used APP-transgenic mice and cultured neurons and observed that deletion of p38α-MAPK specifically in neurons decreased phosphorylation of Snapin at serine, increased retrograde transportation of BACE1 in axons and reduced BACE1 at synaptic terminals, which suggests that p38α-MAPK deficiency promotes axonal transportation of BACE1 from its predominant locations, axonal terminals, to lysosomes in the cell body. In vitro kinase assay revealed that p38α-MAPK directly phosphorylates Snapin. By further performing mass spectrometry analysis and site-directed mutagenic experiments in SH-SY5Y cell lines, we identified serine residue 112 as a p38α-MAPK-phosphorylating site on Snapin. Replacement of serine 112 with alanine did abolish p38α-MAPK knockdown-induced reduction of BACE1 activity and protein level, and transportation to lysosomes in SH-SY5Y cells. Taken together, our study suggests that activation of p38α-MAPK phosphorylates Snapin and inhibits the retrograde transportation of BACE1 in axons, which might exaggerate amyloid pathology in AD brain., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Transit time flow meter (TTFM) allows quick and accurate intraoperative graft assessment. The main study goal is to evaluate the influence of graft flow measurements on long-term clinical outcomes in patients with chronic limb-threatening ischemia (CLTI) undergoing bellow the knee (BTK) vein bypass surgery., Methods: Between January 1st, 1999 and January 1st, 2006, 976 CLTI consecutive patients underwent lower extremity bypass surgery. When applying the exclusion criteria, 249 patients were included in the final analysis. Control measurements were performed at the end of the procedure. Patients were divided according to the mean (more/less than 100 ml/min) and diastolic graft flow (more/less than 40 ml/min) values in four groups. The primary endpoints were a major adverse limb event (male) and primary graft patency., Results: After the median follow-up of 68 months, a group with the mean graft flow below 100 ml/min and the diastolic graft flow below 40 ml/min had the highest rates of male (χ 2  = 36.60, DF = 1, P < 0.01, log-rank test) and the worst primary graft patency (χ 2  = 53.05, DF = 1, P < 0.01, log-rank test)., Conclusion: In patients with CLTI undergoing BTK vein bypass surgery, TTFM parameters, especially combined impact of mean graft flow less than 100 ml/min and diastolic graft flow less than 40 ml/min, were associated with an increased risk of poor long-term male and primary graft patency.

Background : Main objective of this study was to evaluate the influence of statins and/or acetylsalicylic acid on biochemical characteristics of abdominal aortic aneurysm (AAA) wall and intraluminal thrombus (ILT). Patients and methods : Fifty patients with asymptomatic infrarenal AAA were analyzed using magnetic resonance imaging on T1w sequence. Relative ILT signal intensity (SI) was determined as a ratio between ILT and psoas muscle SI. Samples containing the full ILT thickness and aneurysm wall were harvested from the anterior surface at the level of the maximal diameter. The concentration of enzymes such as matrix metalloproteinase (MMP) 9, MMP2 and neutrophil elastase (NE/ELA) were analyzed in ILT and AAA wall; while collagen type III, elastin and proteoglycan 4 were analyzed in harvested AAA wall. Oxidative stress in the AAA wall was assessed by catalase and malondialdehyde activity in tissue samples. Results : Relative ILT signal intensity (1.09 ± 0.41 vs 0.89 ± 0.21, p = 0.013) were higher in non-statin than in statin group. Patients who were taking aspirin had lower relative ILT area (0.89 ± 0.19 vs 1.13. ± 0.44, p = 0.016), and lower relative ILT signal intensity (0.85 [0.73-1.07] vs 1.01 [0.84-1.19], p = 0.021) compared to non-aspirin group. There were higher concentrations of elastin in AAA wall among patients taking both of aspirin and statins (1.21 [0.77-3.02] vs 0.78 (0.49-1.05) ng/ml, p = 0.044) than in patients who did not take both of these drugs. Conclusions : Relative ILT SI was lower in patients taking statin and aspirin. Combination of antiplatelet therapy and statins was associated with higher elastin concentrations in AAA wall.

Data analysis and knowledge discovery has become more and more important in biology and medicine with the increasing complexity of biological datasets, but the necessarily sophisticated programming skills and in-depth understanding of algorithms needed pose barriers to most biologists and clinicians to perform such research. We have developed a modular open-source software, SIMON, to facilitate the application of 180+ state-of-the-art machine-learning algorithms to high-dimensional biomedical data. With an easy-to-use graphical user interface, standardized pipelines, and automated approach for machine learning and other statistical analysis methods, SIMON helps to identify optimal algorithms and provides a resource that empowers non-technical and technical researchers to identify crucial patterns in biomedical data., Competing Interests: The authors declare no competing interests., (© 2020 The Authors.)

Alzheimer's disease (AD) is the leading cause of dementia with very limited therapeutic options. Amyloid β (Aβ) and phosphorylated Tau (p-Tau) are key pathogenic molecules in AD. P38α-MAPK is specifically activated in AD lesion sites. However, its effects on AD pathogenesis, especially on p-Tau-associated brain pathology, and the underlying molecular mechanisms remain unclear. We mated human APP-transgenic mice and human P301S Tau-transgenic mice with mapk14-floxed and neuron-specific Cre-knock-in mice. We observed that deletion of p38α-MAPK specifically in neurons improves the cognitive function of both 9-month-old APP and Tau-transgenic AD mice, which is associated with decreased Aβ and p-Tau load in the brain. We further used next-generation sequencing to analyze the gene transcription in brains of p38α-MAPK deficient and wild-type APP-transgenic mice, which indicated that deletion of p38α-MAPK regulates the transcription of calcium homeostasis-related genes, especially downregulates the expression of grin2a, a gene encoding NMDAR subunit NR2A. Cell culture experiments further verified that deletion of p38α-MAPK inhibits NMDA-triggered calcium influx and neuronal apoptosis. Our systemic studies of AD pathogenic mechanisms using both APP- and Tau-transgenic mice suggested that deletion of neuronal p38α-MAPK attenuates AD-associated brain pathology and protects neurons in AD pathogenesis. This study supports p38α-MAPK as a novel target for AD therapy., (© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Machine learning has the potential to identify novel biological factors underlying successful antibody responses to influenza vaccines. The first attempts have revealed a high level of complexity in establishing influenza immunity, and many different cellular and molecular components are involved. Of note is that the previously identified correlates of protection fail to account for the majority of individual responses across different age groups and influenza seasons. Challenges remain from the small sample sizes in most studies and from often limited data sets, such as transcriptomic data. Here we report the creation of a unified database, FluPRINT, to enable large-scale studies exploring the cellular and molecular underpinnings of successful antibody responses to influenza vaccines. Over 3,000 parameters were considered, including serological responses to influenza strains, serum cytokines, cell phenotypes, and cytokine stimulations. FluPRINT, facilitates the application of machine learning algorithms for data mining. The data are publicly available and represent a resource to uncover new markers and mechanisms that are important for influenza vaccine immunogenicity.

Machine learning holds considerable promise for understanding complex biological processes such as vaccine responses. Capturing interindividual variability is essential to increase the statistical power necessary for building more accurate predictive models. However, available approaches have difficulty coping with incomplete datasets which is often the case when combining studies. Additionally, there are hundreds of algorithms available and no simple way to find the optimal one. In this study, we developed Sequential Iterative Modeling "OverNight" (SIMON), an automated machine learning system that compares results from 128 different algorithms and is particularly suitable for datasets containing many missing values. We applied SIMON to data from five clinical studies of seasonal influenza vaccination. The results reveal previously unrecognized CD4 + and CD8 + T cell subsets strongly associated with a robust Ab response to influenza Ags. These results demonstrate that SIMON can greatly speed up the choice of analysis modalities. Hence, it is a highly useful approach for data-driven hypothesis generation from disparate clinical datasets. Our strategy could be used to gain biological insight from ever-expanding heterogeneous datasets that are publicly available., (Copyright © 2019 by The American Association of Immunologists, Inc.)

Blunt abdominal aortic injuries are extremely rare, diagnosed in less than 0.05% of all trauma admissions. Aortic injury caused by a seat belt during a car accident is often referred as "seat-belt aorta". We present a case of an 18-year-old woman, restrained back passenger involved in a vehicular collision, sustaining vertebral column and multiple rib fractures, mesenterium and colonic injury, and infrarenal aortic contusion with localized dissection and partial thrombosis., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Acute lower limb ischaemia (ALI) is the sudden onset of decreased arterial perfusion with imminent threat to limb viability. Contrast induced acute kidney injury (CI-AKI) is one of the complications that increases mortality in patients who undergo contrast imaging in coronary procedures. The goal of this study is to evaluate the impact of chronic kidney disease (CKD) and CI-AKI on long-term clinical outcomes in patients with ALI undergoing lower limb revascularisation., Methods: A total 1017 consecutive patients with acute lower limb ischaemia who were admitted between July 1, 2006, and January 1, 2017, were retrospectively reviewed. Patients who had end stage renal disease, those who had end stage heart and malignant disease and died within 7 days of limb revascularisation, and those who did not undergo angiography were excluded. Thus 546 patients were included in the final analysis. Patients were classified as with or without CKD and were then subdivided according to the presence or absence of the development of CI-AKI, defined as an increase in serum creatinine of ≥0.5 mg/dL or by ≥25% from the baseline value within the first 72 h after contrast exposure. The primary end point was all cause mortality and secondary major adverse limb event (MALE)., Results: Both CKD and CI-AKI were associated with the highest rate of all cause mortality (chi square = 55.77, d.f. = 1, p < .01, log rank test) and MALE (chi square = 79.07, d.f. = 1, p < .01, log rank test). The presence of CKD and CI-AKI were significant risk factors associated with long-term all cause mortality (HR = 2.61, p < .01) and MALE (HR = 2.87, p < .01)., Conclusion: In patients with ALI undergoing lower limb revascularisation, both CKD and CI-AKI were significantly associated with poor long-term outcomes compared with either CKD or CI-AKI alone. Further studies are required to assess this association and to confirm the combined effect of CKD and CI-AKI on long-term clinical outcomes., (Copyright © 2018 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

In this study, a reevaluation of the in vivo release phases from long-release PLGA-based microspheres is presented, leading to a better characterization of the plasma concentrations/time profile. Microspheres were designed for intramuscular injection releasing a cyclic somatostatin analog over 70 days. Clinical study was performed in 64 healthy subjects receiving a subcutaneous dose of an immediate release solution as reference formulation and an intramuscular injection of microspheres as test formulation. The in vivo input curve was obtained by numerical deconvolution. Results showed that double Weibull function could not fit correctly the tri-phasic (burst, lag, and erosion) in vivo input profile typical for PLGA-based formulations, due to a change in the drug release trend in the terminal phase. Triple Weibull showed a significant improvement in the curve fitting, each term being assigned to one of the following phases: initial (burst/lag), erosion, and terminal phase of drug release. The existence of the additional terminal phase was confirmed by a mechanistic approach as well, which denoted that this phase was, most probably, a consequence of the release mechanism change from erosion to diffusion controlled. The same model demonstrated that the burst release was as well influenced by the polymer swelling, while currently existing theories state that the burst phase is mainly determined by the dissolution of immediately available drug substance and diffusion through surface related pores., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-β (Aβ) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aβ and p-Tau are two major pathogenic molecules with tau acting downstream to Aβ to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3β. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

The volume state of dialysis patients is important in guiding the dialysis process. Volume overload in these patients is associated with inflammation. The objectives of the present study were to assess the body composition of patients on hemodialysis; to determine the concentrations of B-type natriuretic peptide (BNP) in plasma and evaluate the association of BNP concentrations with volume overload; to determine the concentrations of C-reactive protein (CRP), albumin and superoxide dismutase (SOD) activities as indicators of inflammatory or antioxidant processes. The study included 79 maintenance hemodialysis patients. Assessment of body compartments was carried out using a body composition monitor (BCM). After BCM measurements, blood samples were taken from the patients for laboratory tests. There were 40 (50.6%) volume-overloaded patients (relative overhydration >15%). These patients had a higher prevalence of arterial hypertension (P < 0.05), significantly higher concentrations of BNP (P = 0.01), lower body mass index (P < 0.05) and lower fat tissue index (P < 0.05). There was a positive correlation between plasma BNP and CRP concentrations (ρ = 0.231; P < 0.05), and a negative correlation between (log) BNP and albumin (r = -0.021; P < 0.05), as well as (log) CRP and albumin concentrations (r = -3; P < 0.01). SOD activity was positively correlated with albumin concentrations (r = 0.254; P < 0.05). The concentrations of BNP in this study were associated with volume overload and inflammatory markers. Patients with a higher albumin concentration had higher SOD activity., (© 2017 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

Purpose: Open lung strategy during ARDS aims to decrease the ventilator-induced lung injury by minimizing the atelectrauma and stress/strain maldistribution. We aim to assess how much of the lung is opened and kept open within the limits of mechanical ventilation considered safe (i.e., plateau pressure 30 cmH 2 O, PEEP 15 cmH 2 O)., Methods: Prospective study from two university hospitals. Thirty-three ARDS patients (5 mild, 10 moderate, 9 severe without extracorporeal support, ECMO, and 9 severe with it) underwent two low-dose end-expiratory CT scans at PEEP 5 and 15 cmH 2 O and four end-inspiratory CT scans (from 19 to 40 cmH 2 O). Recruitment was defined as the fraction of lung tissue which regained inflation. The atelectrauma was estimated as the difference between the intratidal tissue collapse at 5 and 15 cmH 2 O PEEP. Lung ventilation inhomogeneities were estimated as the ratio of inflation between neighboring lung units., Results: The lung tissue which is opened between 30 and 45 cmH 2 O (i.e., always closed at plateau 30 cmH 2 O) was 10 ± 29, 54 ± 86, 162 ± 92, and 185 ± 134 g in mild, moderate, and severe ARDS without and with ECMO, respectively (p < 0.05 mild versus severe without or with ECMO). The intratidal collapses were similar at PEEP 5 and 15 cmH 2 O (63 ± 26 vs 39 ± 32 g in mild ARDS, p = 0.23; 92 ± 53 vs 78 ± 142 g in moderate ARDS, p = 0.76; 110 ± 91 vs 89 ± 93, p = 0.57 in severe ARDS without ECMO; 135 ± 100 vs 104 ± 80, p = 0.32 in severe ARDS with ECMO). Increasing the applied airway pressure up to 45 cmH 2 O decreased the lung inhomogeneity slightly (but significantly) in mild and moderate ARDS, but not in severe ARDS., Conclusions: Data show that the prerequisites of the open lung strategy are not satisfied using PEEP up to 15 cmH 2 O and plateau pressure up to 30 cmH 2 O. For an effective open lung strategy, higher pressures are required. Therefore, risks of atelectrauma must be weighted versus risks of volutrauma., Trial Registration: Clinicaltrials.gov identifier: NCT01670747 ( www.clinicaltrials.gov ).

Alzheimer's disease (AD) is characterized by intracellular neurofibrillary tangles. The primary component, hyperphosphorylated Tau (p-Tau), contributes to neuronal death. Recent studies have shown that autophagy efficiently degrades p-Tau, but the mechanisms modulating autophagy and subsequent p-Tau clearance in AD remain unclear. In our study, we first analyzed the relationship between the inflammatory activation and autophagy in brains derived from aged mice and LPS-injected inflammatory mouse models. We found that inflammatory activation was essential for activation of autophagy in the brain, which was neuronal ATG5-dependent. Next, we found that autophagy in cultured neurons was enhanced by LPS treatment of cocultured macrophages. In further experiments designed to provoke chronic mild stimulation of TLR4 without inducing obvious neuroinflammation, we gave repeated LPS injections (i.p., 0.15 mg/kg, weekly for 3 mo) to transgenic mice overexpressing human Tau mutant (P301S) in neurons. We observed significant enhancement of neuronal autophagy, which was associated with a reduction of cerebral p-Tau proteins and improved cognitive function. In summary, these results show that neuroinflammation promotes neuronal autophagy and that chronic mild TLR4 stimulation attenuates AD-related tauopathy, likely by activating neuronal autophagy. Our study displays the beneficial face of neuroinflammation and suggests a possible role in the treatment of AD patients., (Copyright © 2016 by The American Association of Immunologists, Inc.)

The objective of this study was development of accelerated in vitro release method for peptide loaded PLGA microspheres using flow-through apparatus and assessment of the effect of dissolution parameters (pH, temperature, medium composition) on drug release rate and mechanism. Accelerated release conditions were set as pH 2 and 45°C, in phosphate buffer saline (PBS) 0.02M. When the pH was changed from 2 to 4, diffusion controlled phases (burst and lag) were not affected, while release rate during erosion phase decreased two-fold due to slower ester bonds hydrolyses. Decreasing temperature from 45°C to 40°C, release rate showed three-fold deceleration without significant change in release mechanism. Effect of medium composition on drug release was tested in PBS 0.01M (200 mOsm/kg) and PBS 0.01M with glucose (380 mOsm/kg). Buffer concentration significantly affected drug release rate and mechanism due to the change in osmotic pressure, while ionic strength did not have any effect on peptide release. Furthermore, dialysis sac and sample-and-separate techniques were used, in order to evaluate significance of dissolution technique choice on the release process. After fitting obtained data to different mathematical models, flow-through method was confirmed as the most appropriate for accelerated in vitro dissolution testing for a given formulation., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Blunt injuries of the supra-aortic branches are rare entity, and majority of patients die before arrival at the hospital. Those who arrive alive require complex and fast procedure that requires sternotomy. We report 3 successfully managed cases., Case Reports: We report 3 patients with injury of supra-aortic branches. One was treated urgently due to longitudinal rupture on the posterior wall of innominate artery after car accident, and another 2 had chronic false aneurysm located at the very orifice of the right subclavian and left common carotid artery. In first and second patient bypass grafting with a hand-made, Y-shaped, 8-mm Dacron graft from the ascending aorta to the right common carotid and proximal right subclavian artery were performed, whereas in last 1 bypass grafting from the ascending aorta to the cervical part of the left common carotid artery was performed. In our facility, there were no possibilities for any endovascular treatment., Conclusions: When endovascular technology is not available, open surgical repair of blunt injuries of supra-aortic vessels can be performed without complications. No matter to that, endovascular and hybrid procedures should be considered whenever possible., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Amyloid β (Aβ) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in Aβ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases Aβ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38α MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38α MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated Aβ generation in the AD mouse brain. Inhibition of p38α MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38α MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38α MAPK plays a critical role in the regulation of BACE1 degradation and Aβ generation in AD pathogenesis., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)

A 26-year-old male presented to the emergency center having been shot in the neck. Multislice computed tomography angiography revealed injury of the right internal carotid artery at level of the carotid bifurcation with hematoma and injury of right internal jugular vein. Under general anesthesia, transposition of internal carotid artery to external carotid artery, with ligation of internal jugular vein, was successfully performed. This case emphasizes the value of "old fashion" surgical treatment in modern endovascular age., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We present an interesting case of a patient with spinal cord ischemia presented with physical and angiographic findings of acute right leg ischemia 6 days after abdominal aortic aneurysm open repair. After unsuccessful transpopliteal thrombectomy, patient was treated with spinal cord drainage. Cause of this complication might be ischemic lumbal plexopathy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The concentrations of trace metals (Fe, Zn, Mn, Ni, Cu, Co and Cr) were determined for the first time in Mediterranean blue mussels (Mytilus galloprovincialis) and surface sediments. The mussel and sediment samples were collected from five sites on the Montenegrin coastal area (southeastern Adriatic Sea) in the fall of 2005 and 2006. The collected samples were digested with a microwave digestion system. The maximum Fe, Zn, Mn, Ni, Cu, Co and Cr mean concentrations in the mussel samples were 603.0, 345.0, 85.0, 18.9, 17.2, 9.1 and 4.2mg/kg of sample dry weight, respectively. The maximum Fe, Mn, Cr, Ni, Zn, Cu and Co concentrations in the sediment samples were 40867, 943.0, 382.0, 336.0, 67.2, 24.8 and 16.9mg/kg of sample dry weight, respectively. A correlation between the metal levels found in the mussel soft tissues with those found in sediments, for both 2005 and 2006, could be established, except for the levels of Zn observed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The major molecular risk factor for Alzheimer disease so far identified is the amyloidogenic peptide Abeta(42). In addition, growing evidence suggests a role of cholesterol in Alzheimer disease pathology and Abeta generation. However, the cellular mechanism of lipid-dependent Abeta production remains unclear. Here we describe that the two enzymatic activities responsible for Abeta production, beta-secretase and gamma-secretase, are inhibited in parallel by cholesterol reduction. Importantly, our data indicate that cholesterol depletion within the cellular context inhibits both secretases additively and independently from each other. This is unexpected because the beta-secretase beta-site amyloid precursor protein cleaving enzyme and the presenilin-containing gamma-secretase complex are structurally different from each other, and these enzymes are apparently located in different subcellular compartments. The parallel and additive inhibition has obvious consequences for therapeutic research and may indicate an intrinsic cross-talk between Alzheimer disease-related amyloid precursor protein processing, amyloid precursor protein function, and lipid biology.

Purpose: To determine the frequency of neuron specific enolase (NSE) tissue expression and its possible influence on survival of patients treated for advanced non small cell lung cancer (NSCLC)., Patients and Methods: We studied 158 patients with histological diagnosis of NSCLC (stage III/IV). Combined chemoradiotherapy was used in stage III disease (without pleural effusion), whereas chemotherapy only was used in stage III (with pleural effusion) as well as in stage IV disease. Immunohistochemical analysis of NSE expression was determined using antibodies to NSE (DAKO, Den). One- and 2-year overall survival were assessed., Results: 45 (28.5%) patients had positive NSE expression. The most frequent NSE expression was seen in 6/9 (66.7%) patients with large cell carcinoma and in 23/50 (46%) with adenocarcinoma. One- and 2-year survival rates were 70% and 30% in the group of patients with positive NSE expression compared to 26% and 3% in the group with negative NSE expression (p=0.000). The median survival time was 16.4 vs. 11.4 months in the groups of patients with and without NSE expression, respectively (p < 0.001). One-and 2-year survival rate was higher in NSCLC patients with more than 50% of NSE positive cancer cells (p=0.0004 and 0.000, respectively)., Conclusion: A total of 28.5% of advanced NSCLC patients had positive NSE expression. Median 1- and 2-year survival time was significantly longer in patients with positive NSE expression.

Giant cell fibroblastoma (GCF) is a rare type of fibroblastic tumor, first described as a juvenile form of dermatofibrosarcoma. Although recurrences are common after local surgical resection, metastasis is not reported.We report a case of a 4-year-old boy with giant cell fibroblastoma, in which the neoplasm was characterized histologically by a proliferation of spindle-shaped cells intermixed with pseudovascular channels called "angiectold spaces". The spaces were lined by large cells with pleomorphic nuclei intermixed with multinucleated cells. Immunohistochemically, the tumor stained diffusely for vimentin and CD34, but negative for S 100 protein. Since the initial description in 1982, less than 100 cases of GCF have been reported. This patient's presentation is particularly interesting because present the first case reported in Bosnia and Herzegovina.

We investigated whether the direct fXa inhibitor tick anticoagulant peptide (TAP) can be N-terminally coupled to a clot-targeting, single-chain antibody specific for fibrin (scFv(59D8)). Due to its unique position at the convergence point of the intrinsic and extrinsic pathways early in the coagulation cascade, factor Xa (fXa) represents an attractive therapeutic target. In contrast to indirect inhibitors, direct fXa inhibitors effectively inhibit clot-bound and prothrombinase-associated fXa. Targeting of direct fXa inhibitors to clots promises to enhance local anticoagulative potency and to reduce systemic anticoagulation which potentially results in less bleeding complications.TAP is a highly potent fXa inhibitor. Since its N-terminus is essential for anti-fXa activity, it was a challenging question, whether TAP will be active as a N-terminally coupled fusion molecule. Two step affinity chromatography with Ni(2+) and beta(15-22)-peptide of human fibrin results in a pure 36 kDa protein, which was tested for its targeting function and anti-fXa activity. The recombinant fusion did not destroy the function of the fusion partners. Antibody binding function was on a par with the parent molecule. TAP activity was partially reduced, arguing that a free N-terminus is not required for anti-fXa activity, but is important for maximal potency. In human whole blood clots, scFv(59D8)-TAP revealed anticoagulative properties at concentrations (200 to 500 nM) where non-targeted TAP did not reveal anticoagulative activity at all. In summary, scFv(59D8)-TAP constitutes a promising new anticoagulant with fibrin-targeted factor Xa inhibition. The production in E. coli and the established purification methods are a solid basis for a modern, large scale production at low cost and reproducible activity.