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Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but the mechanisms of Ab protection are incompletely understood. In this work, we used a variety of cell and animal model systems and showed that the cytosolic Ab receptor and E3 ligase TRIM21 (T21) could play a role in Ab protection against tau pathology. Tau-Ab complexes were internalized to the cytosol of neurons, which enabled T21 engagement and protection against seeded aggregation. Ab-mediated protection against tau pathology was lost in mice that lacked T21. Thus, the cytosolic compartment provides a site of immunotherapeutic protection, which may help in the design of Ab-based therapies in neurodegenerative disease.

Antibodies mediate the majority of their effects in the extracellular domain, or in intracellular compartments isolated from the cytosol. Under a growing list of circumstances, however, antibodies are found to gain access to the cytoplasm. Cytosolic immune complexes are bound by the atypical antibody receptor TRIM21, which mediates the rapid degradation of the immune complexes at the proteasome. These discoveries have informed the development of TRIM-Away, a technique to selectively deplete proteins using delivery of antibodies into cells. A range of related approaches that elicit selective protein degradation using intracellular constructs linking antibody fragments to degradative effector functions have also been developed. These methods hold promise for inducing the degradation of proteins as both research tools and as a novel therapeutic approach. Protein aggregates are a pathophysiological feature of neurodegenerative diseases and are considered to have a causal role in pathology. Immunotherapy is emerging as a promising route towards their selective targeting, and a role of antibodies in the cytosol has been demonstrated in cell-based assays. This review will explore the mechanisms by which therapeutic antibodies engage and eliminate intracellularly aggregated proteins. We will discuss how future developments in intracellular antibody technology may enhance the therapeutic potential of such antibody-derived therapies.

With the increased use of Internet resources, cyber attackers are using novel ways to attack the services of network. Thus network security is becoming inevitable part of the network system. In order to detect such attacks efficiently and effectively, robust IDS (Intrusion Detection System) is needed. An IDS is a tool that analyzes each and every packet deeply to detects malicious activity by monitoring a network or a system. The main purpose of IDS is to identify unwanted or abnormal action and to inform the network administrator about such actions. Thus, IDS is important tool for the network administrator to prevent the network from both known and unknown attacks that make the network resources more vulnerable. Machine learning methods can be used to employ efficient intrusion detection system (IDS). In this research work four machine learning methods were used namely RF (Random Forest), DT (Decision Tree), MLP (Multilayer perceptron) and SVM (Support Vector Machine) for classification of the data. NSL-KDD dataset was used for training and testing these various machine learning models. Feature selections were used to eliminate the irrelevant and unwanted features from the dataset. Therefore feature selection reduces the dimensionality of the dataset which in turn reduces the computational complexity. The proposed model’s output was evaluated using three feature subsets, randomly selected from the NSL-KDD dataset. The proposed method has a classification accuracy of more than 99 percent.

A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease. Introduction Neurodegenerative diseases are typified by the accumulation of specific proteins into fibrillar assemblies. In around twenty distinct neurodegenerative diseases, including the most common, Alzheimer’s disease, the protein tau forms hyperphosphorylated, filamentous inclusions within the cytoplasm of neurons. Tau pathology can be a direct cause of neurodegeneration. For instance, human genetic studies reveal that around 50 distinct mutations in MAPT, the gene that encodes tau, cause inherited forms of dementia with evidence of tau filaments [1]. The origin of tau assemblies in the human brain remains uncertain. Cell-autonomous processes may lead to the spontaneous nucleation of oligomeric forms of tau within the cytoplasm of neurons. Some of these assemblies adopt filamentous conformations that are able to undergo extension by the addition of tau monomers to the filament ends. Over the past decade it has been postulated that, in addition to these cell-autonomous mechanisms, tau pathology may occur through a spreading or ‘prion-like’ mechanism [2]. Several lines of evidence demonstrate that assemblies of tau can be taken up into cells, whereupon they seed the conversion of native tau to the assembled state. Addition of tau assemblies to the exterior of cells, or the injection of tau assemblies into the brains of tau-transgenic and wildtype mice, can induce intracellular tau assembly in the recipient [3,4,5,6]. Population cross-sectional studies demonstrate that the appearance of tau pathology follows a predictable pattern over time and space in the human brain, potentially indicating spreading via a prion-like mechanism. Immunoreactivity to antibodies such as AT8, which detects tau that is phosphorylated at positions S202 and T205 [7], progresses in a manner that can be systematically categorised into stages according to anatomical distribution (Braak stages 0–VI) [8, 9]. In young adults, some AT8 immunoreactivity is observed in the vast majority of brains by the third decade of life. However, it is generally confined to neurons within the locus coeruleus (LC) in the brainstem (Braak pretangle stages 0 a–c and 1a,b). Subsequently, AT8 staining is observed in the entorhinal cortex (EC) and hippocampus (HC) (Braak stages I–II). Later stages are characterised by progressive dissemination and increasing density of staining in neocortical regions (Braak stages III–VI). These late stages are associated with severe disease and the overall burden of tau pathology negatively correlates with cognitive function [10]. Though intracranial challenge experiments demonstrate that seeded aggregation can in principle occur, they provide little insight as to whether physiological concentrations of extracellular tau species might support prion-like activity. The concentration of tau in wildtype mouse interstitial fluid (ISF) is around 50 ng/ml total tau (equivalent to ~ 1 nM tau monomer). Wildtype mouse ISF levels typically exceed cerebrospinal fluid (CSF) tau levels by around tenfold [11]. In humans between ages 21–50 years, CSF total tau is below 300 pg/ml increasing to 500 pg/ml over age 70 [12]—approximately 7–12 pM if considering the average mass of full length tau isoforms. Levels are increased 2–threefold in Alzheimer’s disease [13]. If a similar relationship between ISF and CSF tau concentration exists in humans as in mice, ISF tau levels are likely in the order of 100 pM, rising to 300 pM in Alzheimer’s disease. Intracranial injection experiments typically supply tau in the high micromolar range. Even if this were distributed broadly across the brain, micromolar concentrations would be exceeded and local concentration at the injection site may plausibly be 100-fold greater. Thus, intracranial injection experiments likely exceed physiological concentrations of extracellular tau by two to seven orders of magnitude. For classical infectious agents, infectivity is related to dose by a “one-hit” relationship wherein the amount of infectivity decreases linearly upon dilution until end-point [14]. This property is also evident in PrPSc prions, though it is complicated by the presence of multiple aggregation states and the size distribution of particles [15]. The relationship between dose and prion-like activity for tau has not been established. It is therefore currently not possible to reconcile high-dose challenge experiments with the low concentrations of tau observed in the extracellular spaces of the brain. To address this, we developed a model of seeded tau aggregation in mouse organotypic hippocampal slice cultures, allowing direct control of the concentration of tau neurons were exposed to. Brain slice cultures have been used for over 40 years [16], though developments in recent years have rendered them increasingly relevant for the study of neurodegenerative diseases [17,18,19,20,21]. We prepared slices from transgenic mice expressing human tau bearing the P301S mutation [22], which is causative of familial fronto-temporal dementia and displays accelerated fibrilisation compared to wildtype tau [23]. Using our system, we show that neurons within CA1 are preferentially susceptible to seeded aggregation, displaying intracellular hyperphosphorylated tau tangles. We find that seeding activity cannot be titrated down and only occurs at high concentrations of tau assemblies. The concentrations of tau assemblies required to initiate seeding in this model exceed reported physiological ranges of ISF and CSF tau. Our results imply that a model of tau spread via seeded aggregation requires these concentrations to be locally exceeded or requires other mechanisms not captured here to facilitate seeded aggregation. Results Sagittal hippocampal slices of ~ 300 µm thickness were prepared from homozygous P301S tau-transgenic mice at age 7 d, and cultured at the air–liquid interface on culture support membranes (Fig. 1a). Hippocampal structures are well developed at this age, yet the tissue exhibits plasticity that aids recovery from the slicing procedure [24]. We stained OHSCs with antibodies against markers of the major cell types of the brain: neurons (Map2), microglia (Iba1) and astrocytes (Gfap) (Fig. 1b). Similar to previous studies [20], neurons were found to maintain extensive arborisation with evidence of intact neuronal tracts. Microglia were observed with normal morphology with extensive processes, similar to quiescent cells in whole brains [25]. Astrocytes were also well represented throughout the cultures. Immunostaining for P301S tau revealed widespread expression in all regions of the hippocampus (Fig. 1c). After 5 weeks in culture no overt signs of tau pathology were apparent, as visualised by staining with AT8 (Fig. 1d). These results demonstrate that hippocampal architecture and cell types from P301S tau transgenic mice are maintained through the slicing and culture process. Importantly, they demonstrate that OHSCs from P301S tau transgenic mice do not undergo detectable spontaneous aggregation over this time period. Fig. 1 figure1 Organotypic hippocampal slice cultures (OHSCs) maintain cellular diversity and display no spontaneous tau pathology. a Schematic of the production of OHSCs. 300 µm thick sagittal slices are cut from brain hemispheres. The hippocampus is then dissected and cultured at the air–liquid interface on semi-permeable membranes with media supplied to the basal side of the membrane. b OHSCs from mice transgenic for P301S tau were fixed after 2 weeks in culture and stained for nuclei (DAPI), the neuronal marker Map2, the astrocyte marker Gfap, and the microglial marker Iba1. Scale bars, 50 µm. c OHSCs from P301S tau transgenic mice stain positive for human tau-specific antibody HT7 whereas OHSCs from WT mice do not. Scale bars, 250 µm and 25 µm. d OHSCs from P301S tau transgenic mice after 5 weeks in culture display only background levels of staining with the phospho-tau specific antibody AT8. Slices were stained with DAPI and Map2 as above and with pan-tau. Scale bars, 250 µm Full size image To investigate the response of slice cultures to challenge with tau assemblies, we prepared tau from two independent sources. First, we expressed the 0N4R isoform of tau bearing the P301S mutation in E. coli. Recombinant protein was incubated with heparin and, following a lag period, was found to give a fluorescent signal in the presence of thioflavin T, a dye whose fluorescence increases upon binding to β-sheet rich amyloid structures (Fig. 2a). Negative stain transmission electron microscopy revealed the presence of abundant filamentous structures (Fig. 2b). Second, we prepared the sarkosyl-insoluble (SI) fraction from aged P301S tau transgenic mice, a procedure that enriches insoluble tau species. Brain-derived assemblies were subjected to western blot, confirming the presence of hyperphosphorylated, insoluble tau (Fig. 2c). The samples were quantified using a dot-blot method using recombinant fibrillar tau as a standard (Additional file 1: Supplementary Fig. 1). Tau assemblies were added to HEK293 cells stably expressing 0N4R P301S tau-venus, a reporter cell line for seeded aggregation [26]. In this assay, transfection reagents are used to deliver tau assemblies into cells, whereupon tau-venus is observed to form puncta over 1–2 d. This aggregation was previously found to result in the accumulation of tau-venus in the sarkosyl-insoluble pellet [26]. In the present study, abundant venus-positive puncta were detected following challenge with recombinant fibrils or mouse brain derived tau (Fig. 2d). To investigate whether these seeded assemblies bore markers of tau hyperphosphorylation, we stained with the monoclonal antibody AT8 and AT100, which recognises tau phosphorylated at pT212 and pS214. These epitopes occur on tau filaments extracted from post-mortem tauopathy brains, including those from Alzheimer’s disease patients. We observed that challenge with recombinant tau assemblies resulted in colocalization between tau-venus puncta and AT8 or AT100 (Fig. 2e, f). We therefore concluded that our tau preparations contained species able to induce bona fide seeded aggregation in recipient cells. Fig. 2 figure2 Characterisation of seed competent tau assemblies. a Time course of recombinant P301S tau assembly, monitored by Thioflavin T fluorescence. b Representative transmission electron microscopy image of heparin assembled P301S tau. c Aged P301S tau transgenic mouse brain homogenate was immunoblotted for human tau (HT7 antibody) to detect transgenic tau and for cyclophilin B which served as a loading control. Presence of sarkosyl insoluble (SI) tau was confirmed with the HT7 antibody and AT100 (tau phosphorylated at pT212, pT214). Lanes represent preparations from different mice which were subsequently pooled. d Representative images from HEK293 cells expressing P301S tau-venus 48 h after challenge with either recombinant P301S tau assemblies or mouse SI tau in the presence of LF2000. e, f Tau-venus aggregates observed following challenge with tau assemblies stain with AT8 and AT100 demonstrating that the induced tau aggregates are phosphorylated. Scale bars, 20 µm Full size image To test whether OHSCs support seeded aggregation, we treated slices at DIV7 with recombinant tau assemblies or mouse brain derived sarkosyl insoluble (SI) tau. After three days a complete media change was performed to remove the tau, and the OHSCs were incubated for a further three weeks (Fig. 3a). Following treatment with tau assemblies, we observed pronounced AT8 staining, suggesting the presence of intracellular hyperphosphorylated tau structures (Fig. 3b, c). The addition of monomeric tau did not induce these same structures, indicating that the misfolded state of tau was responsible for seeded aggregation (Fig. 3b, d). Furthermore, addition of tau assemblies to OHSCs prepared from wildtype mice did not induce seeded aggregation suggesting that the transgenic P301S tau construct is responsible for the phenotype (Fig. 3b, c). The hyperphosphorylation of tau was accompanied by the accumulation of sarkosyl-insoluble species following seeding in P301S transgenic OHSCs but not in wildtype OHSCs (Fig. 3e, f) (Additional file 1: Supplementary Fig. 2). Whilst the human transgenic tau is therefore required for seeding to occur, we cannot exclude the possibility that endogenous mouse tau also contributes to aggregates in the transgenic slices since the AT8 epitope is identical between human and mouse tau. To test whether exogenously applied tau could be found within the slices, recombinant tau assemblies were supplied to the culture media of wildtype slices, beneath the membrane, for a period of three days. After this time, we observed human tau present in the slices by western blot, indicating the transfer of tau assemblies from the media to the slice (Fig. 3g) (Additional file 1: Supplementary Fig. 2). Taken together, these data demonstrate that exogenously supplied tau assemblies are taken up into OHSCs and can induce the formation of hyperphosphorylated, insoluble tau species. Fig. 3 figure3 Challenging OHSCs with exogenous tau assemblies induces seeded tau aggregation. a Timeline of organotypic hippocampal slice culture preparation and treatment. OHSCs were prepared from P7 pups. After 7 days in vitro (DIV), tau assemblies were added to the media and incubated for 3 days. A complete media change was carried out at the end of the seeding period (pink). At other times (green) 50% media changes were performed twice weekly until fixation at 28 days in vitro (DIV). b OHSCs derived from P301S tau transgenic mice were challenged with either 100 nM recombinant tau assemblies, 100 nM monomeric tau, 5 µL (~ 300 nM) of mouse brain origin sarkosyl insoluble (SI) tau or buffer only. WT OHSCs were challenged with 100 nM recombinant tau assemblies or buffer only. Scale bars, 50 µm. c Quantification of seeding levels in WT and P301S tau transgenic OHSCs, following addition of 100 nM recombinant tau assemblies or buffer only. d Levels of AT8 immunostaining following challenge of OHSCs with monomeric tau (Mono) or heparin assembled tau (Seed). e, f Levels of sarkosyl insoluble tau present in transgenic P301S (e) or WT (f) OHSCs with and without the addition of 100 nM recombinant tau assemblies. Data derived from Western blot, normalised to input levels of tau and loading control. g Levels of human tau (HT7) present in WT OHSCs after 3 days of exposure to 300 nM recombinant tau assemblies applied beneath the membrane. c and d, statistical significance determined by Kruskal–Wallis test by ranks and Dunn’s multiple comparisons test. e–g statistical significance determined by unpaired t-test. For panels c–f, data points represent individual fields of view from multiple slices derived from N = 3 mice per condition. ****P

SUMMARYTrim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.

Type A aortic dissections during pregnancy are rare but lethal events, with reported mortalities as high as 60%. Unique changes in hemodynamics, hormone-related alterations in aortic tissue, and preexisting risk factors place patients at an elevated risk for dissection. We report a successful repair of a Type A aortic dissection at 32 weeks of gestation, with excellent outcomes in both mother and child. This report highlights the importance of gestational age and multidisciplinary effort.

The processing of amyloid precursor protein (APP) to the neurotoxic pro-aggregatory Aβ peptide is controlled by the mechanisms that govern the trafficking and localisation of APP. We hypothesised that genes involved in endosomal protein sorting could play an important role in regulating APP processing and, therefore, analysed ~ 40 novel endosome-to-Golgi retrieval genes previously identified in a genome-wide siRNA screen. We report that phospholipase D3 (PLD3), a type II membrane protein, functions in endosomal protein sorting and plays an important role in regulating APP processing. PLD3 co-localises with APP in endosomes and loss of PLD3 function results in reduced endosomal tubules, impaired trafficking of several membrane proteins and reduced association of sortilin-like 1 with APP. Electronic supplementary material The online version of this article (10.1007/s00018-018-2752-9) contains supplementary material, which is available to authorized users.

Postoperative myocardial infarction remains a serious complication in cardiac surgery. The incidence and impact of this condition in acute type A aortic dissection are poorly understood.A total of 1445 patients with acute type A aortic dissection who underwent surgery were enrolled in the International Registry of Acute Aortic Dissection from 1996 to 2013. Individuals with preoperative myocardial infarction at hospital presentation and a history of myocardial infarction were excluded. Patients with postoperative myocardial infarction (n = 38, 2.6%) were compared with those without postoperative myocardial infarction (n = 1407, 97.4%).The postoperative myocardial infarction group was more often of white race (100% vs 90%, P = .043) with bicuspid aortic valve (15.6% vs 4.5%, P = .015). Imaging demonstrated more aortic root involvement (75.8% vs 49.5%, P = .003), pericardial effusion (65.5% vs 44.1%, P = .022), and coronary artery compromise (27.3% vs 10.2%, P = .022). Patients with postoperative myocardial infarction were more frequently hypotensive or in shock during surgery (42.9% vs 25.5%, P = .021). Patients with postoperative myocardial infarction were more likely to have undergone root replacement (54.5% vs 33.3%, P = .011), coronary artery bypass grafting (28.6% vs 7.4%, P .001), or aortic valve replacement (40.0% vs 23.8%, P = .027), and less likely to have had complete arch replacement (2.8% vs 14.0%, P = .050). Median circulatory arrest time was higher in postoperative myocardial infarction (60 vs 38 minutes, P = .024). In-hospital mortality (57.9% vs 16.3%, P .001) and Kaplan-Meier estimates of 5-year mortality (P = .007) were distinctly higher in postoperative myocardial infarction.Postoperative myocardial infarction is a devastating complication of type A aortic dissection repair. It is associated with bicuspid aortic valve, root involvement, pericardial effusion, and extent of surgical repair. Patients with postoperative myocardial infarction have higher serious postoperative complications, in-hospital mortality, and 5-year mortality rates than those without postoperative myocardial infarction.

Objective Thoracic endovascular aortic repair is the standard of care for acute complicated type B aortic dissections, but long-term single-device outcomes are limited. Methods Fifty patients were treated with the Valiant Captivia thoracic stent graft (Medtronic Inc, Santa Rosa, Calif) for acute complicated type B aortic dissections in this prospective, nonrandomized Dissection Trial. All-cause mortality, secondary procedures, and serious adverse events were assessed, and a core lab evaluated images for aortic remodeling. Results Compliance for both clinical and imaging follow-up was 78% (18 out of 23) for the available patients at 5 years. Notable baseline characteristics were 86% of patients (43 out of 50) had malperfusion, 20% (10 out of 50) had ruptures, and 94% (46 out of 49) had DeBakey class IIIB dissections. The 5-year freedom from dissection-related mortality, secondary procedures related to the dissection, and endoleaks was 83%, 86%, and 85%, respectively. After 5 years, 89% of patients (16 out of 18) had a completely thrombosed false lumen in the stented segment of the aorta and the true lumen diameter over the length of stent graft was stable or increased for 94% of patients (16 out of 17) while the false lumen diameter was stable or decreased in 77% (13 out of 17) after 5 years. Conclusions In the Dissection Trial, patients experienced positive and sustained measures of aortic remodeling. Survival outcomes, need for secondary procedures, and adverse event rates were consistent with previous thoracic endovascular aortic repair studies. Although limitations exist with the follow-up compliance, the Valiant Captivia thoracic stent graft system was effective in the long-term management of acute complicated type B aortic dissections in this patient population with a challenging condition.

Background: Individuals with type 2 diabetes mellitus are at increased risk for heart failure (HF), particularly those with coexisting atherosclerotic cardiovascular disease and/or kidney disease. Some but not all dipeptidyl peptidase-4 inhibitors have been associated with increased HF risk. We performed secondary analyses of HF and related outcomes with the dipeptidyl peptidase-4 inhibitor linagliptin versus placebo in CARMELINA (The Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), a cardiovascular outcomes trial that enrolled participants with type 2 diabetes mellitus and atherosclerotic cardiovascular disease and/or kidney disease. Methods: Participants in 27 countries with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease were randomized 1:1 to receive once daily oral linagliptin 5 mg or placebo, on top of standard of care. All hospitalization for HF (hHF), cardiovascular outcomes, and deaths were prospectively captured and centrally adjudicated. In prespecified and post hoc analyses of HF and related events, Cox proportional hazards models adjusting for region and baseline history of HF were used. Recurrent hHF events were analyzed using a negative binomial model. In a subset of participants with left ventricular ejection fraction captured within the year before randomization, HF-related outcomes were assessed in subgroups stratified by left ventricular ejection fraction > or 50%. Results: CARMELINA enrolled 6979 participants (mean age, 65.9 years; estimated glomerular filtration rate, mL/min per 1.73m(2); hemoglobin A1c, 8.0%; 62.9% men; diabetes mellitus duration, 14.8 years), including 1873 (26.8%) with a history of HF at baseline. Median follow-up was 2.2 years. Linagliptin versus placebo did not affect the incidence of hHF (209/3494 [6.0%] versus 226/3485 [6.5%], respectively; hazard ratio [HR], 0.90; 95% CI, 0.74-1.08), the composite of cardiovascular death/hHF (HR, 0.94; 95% CI, 0.82-1.08), or risk for recurrent hHF events (326 versus 359 events, respectively; rate ratio, 0.94; 95% CI, 0.75-1.20). There was no heterogeneity of linagliptin effects on hHF by history of HF at baseline, baseline estimated glomerular filtration rate or urine albumin-creatinine ratio, or prerandomization left ventricular ejection fraction. Conclusions: In a large, international cardiovascular outcome trial in participants with type 2 diabetes mellitus and concomitant atherosclerotic cardiovascular disease and/or kidney disease, linagliptin did not affect the risk of hHF or other selected HF-related outcomes, including among participants with and without a history of HF, across the spectrum of kidney disease, and independent of previous left ventricular ejection fraction. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01897532.

IMPORTANCE Type 2 diabetes is associated with increased cardiovascular (CV) risk. Prior trials have demonstrated CV safety of 3 dipeptidyl peptidase 4 (DPP-4) inhibitors but have included limited numbers of patients with high CV risk and chronic kidney disease. OBJECTIVE To evaluate the effect of linagliptin, a selective DPP-4 inhibitor, on CV outcomes and kidney outcomes in patients with type 2 diabetes at high risk of CV and kidney events. DESIGN, SETTING, AND PARTICIPANTS Randomized, placebo-controlled, multicenter noninferiority trial conducted from August 2013 to August 2016 at 605 clinic sites in 27 countries among adults with type 2 diabetes, hemoglobin A(1c) of 6.5% to 10.0%, high CV risk (history of vascular disease and urine-albumin creatinine ratio [UACR] > 200mg/g), and high renal risk (reduced eGFR and micro-or macroalbuminuria). Participants with end-stage renal disease (ESRD) were excluded. Final follow-up occurred on January 18, 2018. INTERVENTIONS Patients were randomized to receive linagliptin, 5 mg once daily (n = 3494), or placebo once daily (n = 3485) added to usual care. Other glucose-lowering medications or insulin could be added based on clinical need and local clinical guidelines. MAIN OUTCOMES AND MEASURES Primary outcomewas time to first occurrence of the composite of CV death, nonfatalmyocardial infarction, or nonfatal stroke. Criteria for noninferiority of linagliptin vs placebo was defined by the upper limit of the 2-sided 95% CI for the hazard ratio (HR) of linagliptin relative to placebo being less than 1.3. Secondary outcome was time to first occurrence of adjudicated death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline. RESULTS Of 6991 enrollees, 6979 (mean age, 65.9 years; eGFR, 54.6 mL/min/1.73m2; 80.1% with UACR > 30mg/g) received at least 1 dose of study medication and 98.7% completed the study. During a median follow-up of 2.2 years, the primary outcome occurred in 434 of 3494 (12.4%) and 420 of 3485 (12.1%) in the linagliptin and placebo groups, respectively, (absolute incidence rate difference, 0.13 [95% CI,-0.63 to 0.90] per 100 person-years) (HR, 1.02; 95% CI, 0.89-1.17; P

Novel trisubstituted ethylenes, alkyl and alkoxy ring-disubstituted propyl 2-cyano-3-phenyl-2-propenoates, RPhCH˭C(CN)CO2C3H7 (where R is 2,3-dimethyl, 2,5-dimethyl, 2,6-dimethyl, 3,4-dimethyl, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy 3,4-dimethoxy, 3,5-dimethoxy) were prepared and copolymerized with styrene. The monomers were synthesized by the piperidine catalyzed Knoevenagel condensation of ring-substituted benzaldehydes and propyl cyanoacetate and characterized by CHN elemental analysis, IR, 1H- and 13C-NMR. All the ethylenes were copolymerized with styrene (M1) in solution with radical initiation (ABCN) at 70°C. The composition of the copolymers was calculated from nitrogen analysis, and the structures were analyzed by IR, 1H and 13C-NMR, GPC, DSC, and TGA. Decomposition of the copolymers in nitrogen occurred in two steps, first in the 200–500°C range with residue (0.6–5.0% wt.), which then decomposed in the 500–800°C range.

Background The risk of periprocedural stroke after thoracic endovascular aortic repair (TEVAR) ranges from 3% to 8%. Although cerebral embolic protection devices (CEPD) are widely utilized in transcatheter aortic valve replacement, there are currently no Food and Drug Administration approved CEPDs for use in TEVAR. We report our initial experience with the off-label use of a dual-filter CEPD in patients undergoing TEVAR. Methods Two patients at high risk for embolic stroke underwent TEVAR for descending thoracic aortic aneurysms (DTAAs) at a single institution. A dual-filter CEPD (Sentinel; Boston Scientific, Marlborough, MA) was used in an off-label fashion in both cases. Patient 1 was a 62-year-old woman with a 6.2-cm DTAA, extending from the left subclavian artery (LSCA) to the diaphragm (Zones 3–5) and associated with extensive atherosclerotic disease of the aortic arch. Patient 2 was a 78-year-old woman with a 6.3-cm DTAA, extending from the LSCA (Zone 2) to the sixth intercostal space (Zone 4) with associated mural thrombus. Given the proximity of the aneurysm to the LSCA, a left carotid–subclavian bypass was performed for planned LSCA coverage. Results Through a percutaneous right radial artery approach using a 6F sheath, the Sentinel dual-filter CEPD was delivered over a 0.014″ guidewire into the thoracic aorta. Under fluoroscopic guidance, the 2 filters were sequentially deployed in the innominate and left common carotid arteries, respectively. Appropriately sized devices were successfully delivered and deployed in the proximal and distal landing zones, respectively. Two devices were used for each patient. Completion angiograms showed successful exclusion of the DTAAs in both cases, without evidence of endoleak. The CEPD filters were retrieved in standard fashion without difficulty. Pathology demonstrated successful capture of embolic debris and fibrin clot in both patients. Neither patient exhibited neurological deficits or device-related complications. Both patients remained neurologically intact at 1- and 2-month follow-up, respectively. Surveillance angiograms revealed successful exclusion of the aneurysm without any evidence of endoleak. Conclusions We report the novel off-label use of a dual-filter CEPD in 2 patients undergoing TEVAR. Pathological confirmation of embolic debris in the filters makes this a potential tool for stroke prevention during TEVAR in high-risk patients.

Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key “safety net” in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible “safety net” for these immunocompromised hosts.

The retromer complex is a vital component of the endosomal protein sorting machinery necessary for sorting into both the endosome-to-Golgi retrieval pathway and also the endosome-to-cell-surface recycling pathway. Retromer mediates cargo selection through a trimeric complex comprising VPS35, VPS29 and VPS26, which is recruited to endosomes by binding to Rab7a and Snx3. Retromer function is linked to two distinct neurodegenerative diseases, Parkinson's disease and Alzheimer's disease and modulating retromer function has been proposed as an avenue to explore for a putative therapy in these conditions. We hypothesised that activating Rab7a to promote the recruitment of retromer to endosomes could positively modulate its activity. Here, we show that inhibition of the GTPase activating protein TBC1D5 can enhance Rab7a activation and lead to a gain of function for retromer., Highlighted Article: Enhancement of retromer complex function through inhibition of TBC1D5, a Rab GTPase-activating protein for Rab7a, leads to a gain of function for retromer-mediated endosomal sorting.

The retromer complex is a vital component of the endosomal protein sorting machinery being necessary for sorting into both the endosome-to-Golgi retrieval pathway and also the endosome-to-cell-surface recycling pathway. Retromer mediates cargo selection through a trimeric complex comprising VPS35, VPS29 and VPS26 which is recruited to endosomes by binding to Rab7a and Snx3. Retromer function is linked to two distinct neurodegenerative diseases, Parkinson’s disease and Alzheimer’s disease and modulating retromer function has been proposed as an avenue to explore for a putative therapy in these conditions. We hypothesised that activating Rab7a to promote the recruitment of retromer to endosomes could positively modulate its activity and here we show that inhibition of the GTPase activating protein, TBC1D5, can enhance Rab7a activation and lead to a gain-of-function for retromer.

Abdominal and thoracoabdominal aortic aneurysms are life-threatening diseases that are a frequent cause of death throughout the world. The etiology, risk factors, and indications for treatment are discussed. The history and outstanding results achieved with open surgical treatment utilizing modern practices are reviewed. The indications, techniques, outcomes, and complications of endovascular therapy, which has radically transformed the treatment approach to aortic disease, are evaluated in detail. Finally, novel approaches, including combined hybrid surgical and endovascular treatment, and new technologies, including branched and fenestrated stent grafts for the treatment of complex aortic pathology, are examined.

Diseases of the thoracic and thoracoabdominal aorta are a leading cause of death. Thoracic endovascular aortic repair (TEVAR) for the treatment of acute aortic syndromes including thoracic aortic aneurysms, dissections, intramural hematomas, and traumatic aortic injury is evaluated in detail. The indications for treatment and complications associated with the procedure are reviewed. The endovascular technique and tools necessary to perform the procedure including the specific guidewires, catheters, and sheaths required, as well as appropriate imaging modalities are described. The use of hybrid surgical and endovascular techniques in addition to fenestrated and branched stent grafts to treat complex pathology in the aortic arch and thoracoabdominal aorta is also discussed. Finally, future trends in TEVAR including treatment of ascending aorta pathologies are introduced.

Background The impact of antimicrobial stewardship programs (ASPs) depends on physician perception of antimicrobial stewardship and institutional antibiotic prescribing culture. At Rush University Medical Center (RUMC), we conducted an antimicrobial stewardship study targeting inpatient levofloxacin (FQ) use and assessed rates of implementation of recommendations (IORs) by general medicine (GM), vs. surgical services (SS) (general surgery, urology, orthopedics and neurosurgery), vs. transplant surgery-immunocompromised host (T-ICH) teams when made by either infectious disease pharmacists (IDPharmD) or infectious disease fellows (IDMDF). Methods Between August 13, 2018 and January 15, 2019 at RUMC, IDPharmDs reviewed 251 inpatients on FQ, and made ASP recommendations on 36 (14%) that were communicated via telephone. No scripted discussion or note was utilized. From January 15, 2019 to April 19, 2019, an IDMDF reviewed 207 inpatients on FQ, and made ASP recommendations on 47 (22%). IDMDF’s recommendations were communicated via a scripted discussion describing the role of ASP, highlighting the importance of optimizing FQ use due to toxicity, low rates of RUMC’s FQ susceptibilities and to decrease rates of resistance. Telephone recommendations were made to the primary team house staff or attending followed by a templated electronic note left in the medical chart. Rates of IORs were assessed during each period and by each group. Results In 20 out of 83 recommendations (24%), no antibiotic was indicated (Figure 1). GM teams had the highest overall (IDPharmD + IDMDF) IOR (76%), compared with 40% IOR for both SS and T-ICH groups. For all groups, the scripted IDMDF recommendations had higher IOR compared with the nonscripted IDPharmD recommendations (GM 89% vs. 61%; SS 50% vs. 29%; T-ICH 50% vs. 0%). Conclusion ASP interventions using scripted discussions and notes by an IDMDF were more effective than nonscripted IDPharmD interventions across all service lines. Both interventions were less successful with SS or T-ICH compared with GM services. These findings demonstrate the need for further research to understand the importance of scripted vs. nonscripted communication methods by pharmacists and ID physicians, and to develop alternative communication models for nongeneral medicine service providers. Disclosures All authors: No reported disclosures.

Visceral ischemic syndromes are rare but catastrophic disorders. In acute presentations, treatment modalities include thrombolytic therapy, open surgical revascularization and percutaneous endovascular therapy. Endovascular therapy has become the most commonly utilized treatment option for chronic mesenteric ischemia and should be considered the first line of therapy for patients with anatomically suitable lesions or excessive open surgical risk. Open surgical revascularization has been associated with outstanding long-term outcomes. The various surgical and endovascular techniques and their associated outcomes for the treatment of mesenteric ischemic syndromes are reviewed in detail.

Thoracic endovascular aortic repair has become an attractive alternative treatment option for thoracic aortic disease. New devices and advanced image-guided procedures are continuously expanding the indications. This article focuses on technical aspects of transapical stent graft deployment for ascending aortic pathologies. With improving device technology, diverse available stent grafts, and imaging modalities, thoracic endovascular aortic repair has become safer and holds promising potential to expand treatment options, especially for high-risk patients requiring ascending aorta treatment.

Background In January 2019, the Clinical and Laboratory Standards Institute (CLSI) lowered breakpoints of fluoroquinolones (FQ) for Enterobacteriaceae (EB)and Pseudomonas aeruginosa (PsAr). Automated commercial antimicrobial susceptibility testing (cAST) can only report levofloxacin MIC ≤1 μg/mL according to 2018 breakpoints. Updated panels will not be available until FDA approval. Laboratories and antimicrobial stewardship programs (ASP) must decide how to implement the adoption of new FQ breakpoints. Methods All microbiologic isolates of EB or PsAr were collected March 11, 2019–March 22, 2019. Manual E-tests and cAST by Microscan were performed for levofloxacin. Susceptible or non-susceptible (NS) isolates to levofloxacin were identified using 2018 and 2019 CLSI breakpoints [Table1]. Data were analyzed by Microsoft Excel and SPSS. Results 159 isolates were analyzed. Isolates were predominantly from urine (78%) and females (68%). E.coli was the most frequently identified organism (40%) [Figure 1]. Application of new breakpoints changed 7% of EB (P = 0.083) and 16% of PsAr (P = 0.238) from susceptible to NS. [Figure 2] PsAr had higher rates of FQ NS compared with EB with new breakpoints (37% vs. 22%, P = 0.132, not shown). Non-urine and inpatient isolates had decreased susceptibility of ≥10% (P = 0.168 and 0.117). Lack of other resistance mechanism (ESBL, CRE, MDRO) was associated with a change in susceptibility (P = 0.036). Diagnosis of active cancer or immunosuppression (IS) was strongly associated with FQ NS by new breakpoints (P = 0.019, not shown). Patients with cancer or IS had the largest decrease in susceptibility (18%, P = 0.069) with application of new breakpoints. [Table 2]. Conclusion Updated CLSI FQ breakpoints resulted in trends of increased resistance. PsAr, non-urine and inpatient isolates were disproportionately affected. Implementation of manual MIC determination from select clinical isolates may be useful until approval of updated cAST. Diagnosis of cancer or IS was associated with FQ NS by new breakpoints. Restriction of FQ for empiric use may be considered, particularly in patients with cancer or IS. Larger studies are needed to determine the long-term effects of adjusted FQ breakpoints, but are anticipated to have significant impacts on ASP. Disclosures All authors: No reported disclosures.

Acute type A aortic dissection is a potentially lethal condition which requires immediate diagnostic and therapeutic intervention. Open surgical repair remains the standard of care as survival rates continue to improve in the modern surgical era. Unfortunately, up to twenty percent of patients are denied surgical therapy because they are deemed medically unfit to undergo open repair. The application of thoracic endovascular aortic repair (TEVAR) has changed the treatment paradigm for aortic disease involving the descending thoracic aorta and may be a viable rescue option for patients with type A dissection who are not eligible for open surgical repair. New endovascular devices and advanced image-guided procedures are continually evolving. This article summarizes the pathology of aortic dissection and focuses on currently available endovascular solutions for transapical and transfemoral stent graft deployment for acute aortic dissection involving the ascending aorta for selected patients who are ineligible for open surgical repair.

ObjectivePerioperative infection of an aortic graft is one of the most devastating complications of vascular surgery, with a mortality rate of 10% to 30%. The rate of amputation of the lower limbs is generally >25%, depending on the graft material, the location of the graft and infection, and the bacterial virulence. In vitro studies suggest that an antibiotic-impregnated graft may help prevent perioperative graft infection. In a pilot animal study, we tested a locally developed technique of bonding Dacron aortic grafts with three antimicrobial agents to evaluate the ensuing synergistic preventive effect on direct perioperative bacterial contamination.MethodsWe surgically implanted a 6-mm vascular knitted Dacron graft in the infrarenal abdominal aorta of six Sinclair miniature pigs. Two pigs received unbonded, uninoculated grafts; two received unbonded, inoculated grafts; and two received inoculated grafts that were bonded with chlorhexidine, rifampin, and minocycline. Before implantation, the two bonded grafts and the two unbonded grafts were immersed for 15 minutes in a 2-mL bacterial solution containing 1 to 2 × 107 colony-forming units (CFU)/mL of Staphylococcus aureus (ATCC 29213). Two weeks after graft implantation, the pigs were euthanized, and the grafts were surgically excised for clinical, microbiologic, and histopathologic study.ResultsThe two bonded grafts treated with S aureus showed no bacterial growth upon explant, whereas the two unbonded grafts treated with S aureus had high bacterial counts (6.25 × 106 and 1.38 × 107 CFU/graft). The two control grafts (unbonded and untreated) showed bacterial growth (1.8 × 103 and 7.27 × 103 CFU/graft) that presumably reflected direct, accidental perioperative bacterial contamination; S cohnii ssp urealyticus and S chromogenes, but not S aureus, were isolated. The histopathologic and clinical data confirmed the microbiologic findings. Only pigs that received unbonded grafts showed histopathologic evidence of a perigraft abscess.ConclusionsOur results suggest that bonding aortic grafts with this triple antimicrobial combination is a promising method of reducing graft infection resulting from direct postoperative bacterial contamination for at least 2 weeks. Further studies are needed to explore the ability of this novel graft to combat one of the most feared complications in vascular surgery.Clinical RelevanceThis study introduces a novel bonded Dacron aortic graft for the prevention of perioperative aortic graft infection. The quantitative results of our experimental studies showed that the bonding of three antimicrobial agents (rifampin, minocycline, and chlorhexidine) to aortic grafts nearly prevented aortic graft infection by synergistically prolonging antistaphylococcal activity. Use of an antibiotic-bonded prosthetic graft with antistaphylococcal activity should be considered in patients who have arterial infections caused by Staphylococcus aureus. After the preventive effect of this graft and its safety have been further assessed, its use may be recommended for the in situ replacement of infected grafts and possibly for routine primary cases, especially in immunocompromised patients, patients with hostile abdomen, and patients undergoing redo procedures.

The retromer complex is a key element of the endosomal protein sorting machinery that is conserved through evolution and has been shown to play a role in diseases such as Alzheimer’s disease and Parkinson’s disease. Through sorting various membrane proteins (cargo), the function of retromer complex has been linked to physiological processes such as lysosome biogenesis, autophagy, down regulation of signalling receptors and cell spreading. The cargo-selective trimer of retromer recognises membrane proteins and sorts them into two distinct pathways; endosome-to-Golgi retrieval and endosome-to-cell surface recycling and additionally the cargo-selective trimer functions as a hub to recruit accessory proteins to endosomes where they may regulate and/or facilitate retromer-mediated endosomal proteins sorting. Unstructured domains present in cargo proteins or accessory factors play key roles in both these aspects of retromer function and will be discussed in this review.

We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.

Stroke is a devastating complication of thoracic endovascular aortic repair (TEVAR). Whether left subclavian artery (LSA) coverage and LSA revascularization affect stroke rate is debated. Whether patients with aneurysms or dissections undergoing TEVAR have higher stroke rates is also debated. We report a systematic review of 63 studies comprising more than 3,000 patients. We conclude that stroke risk after TEVAR is increased by LSA coverage, and that LSA revascularization reduces stroke risk. LSA revascularization may lower the rate of posterior stroke. TEVAR for aneurysm is associated with increased stroke risk compared to TEVAR for dissection.

Summary Thoracic endovascular aortic repair (TEVAR) has become an attractive alternative treatment option for thoracic aortic disease. New devices and advanced image-guided procedures are continuously expanding the indications. This article focuses on currently available endovascular solutions for thoracic aortic disease and future ‘all endovascular’ directions of TEVAR. Currently available endovascular solutions, such as hybrid operations, chimney stent grafting and transapical stent graft deployment, for ascending aortic pathologies are presented. Additionally, the impact of upcoming new technologies, such as endovascular treatment of Stanford Type A dissections of the ascending aorta, is elaborated. With improving device technology, diverse available stent grafts and imaging modalities, TEVAR has become safer and holds promising potential to expand treatment options, especially for the ascending aorta and the aortic arch.

In earlier studies of multiple-degree-of-freedom (MDOF) systems, an impact had always been assumed to affect the velocity of the lumped mass at the point of impact. Experiments show that the velocities of all points in a continuous system are influenced by the impact of the damper. In this study, the stead7-state behavior of an impact-damped beam is modeled by applying conservation of momentum between .the tmpact damper and the modal masses of the beam. Friction and gravity are considered for the case of honzontal and vertical motions, respectively. The impact damper exhibits a wide range of impact patterns and its optimum behavior occurs at two impacts per cycle. Three types of impact are identified for the case of two impacts per cycle, one of which expands the limit cycle of the system and therefore is detrimental.. Within limi~s, the effectiveness of the impact damper improves with an increase in its mass, with a decrease In the coeffictent of restitution, and when it is at a point of large amplitude. An optimum gap exists for each of the first three modes of vibrations. The damper expands the limit cycle of the system at higher excitation amplitudes. The phenomena of bouncedown and stuck impacts are shown to exist in continuous systems. as previously suggested (Masri 1973b). Therefore, there is a need to understand the particle's motion, at varying parame­ ters, as it travels between the container's boundaries to explore the potential of the impact damper fully. Studies mentioned above were very crucial in the develop­ ment of the theory presented in this paper, though limited in their scope. This study employs the consistent mass matrix to develop a finite-element model of a continuous beam, thus considering rotational and translational inertia at the nodes. The response of the system between impacts is obtained through the mode-superposition method. It is assumed, as had been suggested by Masri (1970), that the impact occurs during an infinitesimal period and that the displacement of the system does not change immediately before and after the impact. Pre­ vious experimental work shows that the duration of impact is indeed infinitesimal (Akl and Butt 1994). Momentum and res­ titution equations in terms of the principal coordinates are used to model the behavior of the impacting mass and the oscillat­ ing system. By using principal coordinates, we can determine the velocity of the system at all the nodes simultaneously after each impact without oversimplifying the model. The exact time of impact is determined by employing an optimization algorithm. Eventually, frequency response functions are ob­ tained by transforming the time domain data to the frequency domain by performing fast Fourier transforms (Weaver 1989).

Statistical analysis of the phenomenon of impact damping is performed on 60 steady-state vibration tests of a flexible beam to relate the system's modal damping to system parameters. Compared with other measures of effectiveness of the impact damper, modal damping ratios are useful in predicting the response of continuous systems under arbitrary forcing functions. Contour plots show that the modal damping ratio is nonlinearly dependent on the damper's mass and gap. However, these are not the only parameters that control the effectiveness of the impact damper. Multiple nonlinear regression analysis of the data is used to test the dependence of the system's modal damping on a number of parameters. It is hypothesized that the system's parameters are the mass and gap of the impact damper, the excitation frequency, the peak of the frequency response function, and the modal amplitude at the location of the impact damper. Multiple nonlinear regression analysis shows the validity of the hypothesis and the ability of the derived formula to predict the modal damping ratio of the beam.

Human memory is an important concept in cognitive psychology and neuroscience. Our brain is actively engaged in functions of learning and memorization. Generally, human memory has been classified into 2 groups: short-term/working memory, and long-term memory. Using different memory paradigms and brain mapping techniques, psychologists and neuroscientists have identified 3 memory processes: encoding, retention, and recall. These processes have been studied using EEG and functional MRI (fMRI) in cognitive and neuroscience research. This study reviews previous research reported for human memory processes, particularly brain behavior in memory retention and recall processes with the use of EEG and fMRI. We discuss issues and challenges related to memory research with EEG and fMRI techniques.

Objective Pseudoaneurysm (PSA) formation is a complication of hemodialysis access. Open repair requires PSA resection, interposition graft placement, and insertion of a catheter as a bridge. Endovascular stent graft repair is an alternative that permits immediate use of the access site. The objective of this study was to determine the efficacy of stent grafts for repair of arteriovenous fistula and arteriovenous graft PSA. Methods A retrospective review of medical records from October 2007 to March 2011 revealed 24 patients with a PSA who underwent endovascular repair using a stent graft. Indications for repair included PSA with symptoms (n = 11), PSA with skin erosion (n = 8), PSA with failed hemodialysis (n = 3), and PSA after balloon angioplasty of a stenosis (n = 2). Outcome measures were technical success, 30-day and 180-day patency, secondary interventions, and complications. All the statistical analyses were conducted by using software SAS 9.1 (SAS, SAS Institute, Gary, NC). Results Twenty-seven self-expanding stent grafts (Viabahn, W. L. Gore, n=25; Fluency, Bard, n=2) were used to treat hemodialysis access (arteriovenous graft, n=13; arteriovenous fistula, n=11) PSA in 24 patients (16 females; mean age, 55.7 years; mean body mass index, 28.4; mean PSA diameter, 19.5 mm). Comorbidities included hypertension (n = 22; 91.7%), diabetes mellitus (n = 8; 33.3%), and coronary artery disease (n = 4; 16.67%). The median time from access creation to repair was 455 days. The technical success rate was 100%. Balloon angioplasty of an outflow stenosis was performed in 56% of stent grafts. The 30- and 180-day patency rate was 100% and 69.2%, respectively. Three secondary interventions were performed for treatment of unrelated stenosis. Treatment failure occurred in five (18.5%) stent grafts due to infection (n = 3) and thrombosis (n = 2). Treatment of PSA with skin erosion was associated with failure due to infection (odds ratio, 5.0; 95% confidence interval, .38, 66.01). The remaining 22 (81.5%) stent grafts remain patent. The mean follow-up time was 268.9 days (median, 97.5). Conclusions Endovascular therapy is an effective and durable treatment option for patients with dialysis access PSAs. This technique permits immediate use of the hemodialysis access site as well as identification and treatment of associated stenosis. It may be considered as an alternative to open repair in patients who are anatomically suitable candidates.

Pulmonary vein thrombosis following lung transplantation is an infrequently reported and often fatal vascular complication. Two cases of early pulmonary vein thrombosis following single lung transplantation are described. Both patients underwent surgical thrombectomy and anastomotic reconstruction following institution of cardiopulmonary bypass, but died of multiorgan failure within 5 days of diagnosis. The efficacy of transesophageal echocardiography as a diagnostic modality, as well as medical and surgical management strategies for thrombectomy, are discussed.

A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease.

Funder: Wellcome Trust; doi: http://dx.doi.org/10.13039/100004440, Funder: DRI, Funder: Medical Research Council; doi: http://dx.doi.org/10.13039/501100000265, Funder: Takeda Pharmaceuticals U.S.A.; doi: http://dx.doi.org/10.13039/100007723, A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease.

Additional file 1: Supplementary Figures.

Additional file 1: Supplementary Figures.