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The dynamic phase of preclinical Alzheimer's disease, as characterized by accumulating cortical amyloid-β, is a window of opportunity for amyloid-β-lowering therapies to have greater efficacy. Biomarkers that accurately predict amyloid-β accumulation may be of critical importance for participant inclusion in secondary prevention trials and thus enhance development of early Alzheimer's disease therapies. We compared the abilities of baseline plasma pTau181, pTau217 and amyloid-β PET load to predict future amyloid-β accumulation in asymptomatic elderly. In this longitudinal cohort study, baseline plasma pTau181 and pTau217 were quantified using single molecule array assays in cognitively unimpaired elderly selected from the community-recruited F-PACK cohort based on the availability of baseline plasma samples and longitudinal amyloid-β PET data (median time interval = 5 years, range 2-10 years). The predictive abilities of pTau181, pTau217 and PET-based amyloid-β measures for PET-based amyloid-β accumulation were investigated using receiver operating characteristic analyses, correlations and stepwise regression analyses. We included 75 F-PACK subjects (mean age = 70 years, 48% female), of which 16 were classified as amyloid-β accumulators [median (interquartile range) Centiloid rate of change = 3.42 (1.60) Centiloids/year). Plasma pTau181 [area under the curve (95% confidence interval) = 0.72 (0.59-0.86)] distinguished amyloid-β accumulators from non-accumulators with similar accuracy as pTau217 [area under the curve (95% confidence interval) = 0.75 (0.62-0.88) and amyloid-β PET [area under the curve (95% confidence interval) = 0.72 (0.56-0.87)]. Plasma pTau181 and pTau217 strongly correlated with each other ( r = 0.93, P false discovery rate < 0.001) and, together with amyloid-β PET, similarly correlated with amyloid-β rate of change ( r pTau181 = 0.33, r pTau217 = 0.36, r amyloid-β PET = 0.35, all P false discovery rate ≤ 0.01). Addition of plasma pTau181, plasma pTau217 or amyloid-β PET to a linear demographic model including age, sex and APOE-ε4 carriership similarly improved the prediction of amyloid-β accumulation (ΔAkaike information criterion ≤ 4.1). In a multimodal biomarker model including all three biomarkers, each biomarker lost their individual predictive ability. These findings indicate that plasma pTau181, plasma pTau217 and amyloid-β PET convey overlapping information and therefore predict the dynamic phase of asymptomatic amyloid-β accumulation with comparable performances. In clinical trial recruitment, confirmatory PET scans following blood-based prescreening might thus not provide additional value for detecting participants in these early disease stages who are destined to accumulate cortical amyloid-β. Given the moderate performances, future studies should investigate whether integrating plasma pTau species with other factors can improve performance and thus enhance clinical and research utility., Competing Interests: S.D.M., J.M.S., E.S.L., M.R., E.R.B., I.C., P.D., G.d.M. and K.P. report no disclosures. J.V. and E.S. are full-time paid employees, and EV is co-founder of ADx Neurosciences. K.V.L. has performed contract research through UZ/KU Leuven as principal investigator for GE Healthcare and received speaker fees from GE Healthcare. H.Z. has served at scientific advisory boards and/or as a consultant for AbbVie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, NervGen, Novo Nordisk, OptoCeutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave; has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). N.J.A. has given lectures in symposia sponsored by Eli Lilly, Roche Diagnostics and Quanterix. N.J.A. has declined paid opportunities from ALZpath. C.E.T. performed contract research for Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Grifols, Instant Nano Biosensors, Merck, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama and Vivoryon. She serves on editorial boards of Medidact Neurologie/Springer, Alzheimer’s Research and Therapy and Neurology: Neuroimmunology & Neuroinflammation. R.V.’s institution has had a clinical trial agreement for Phase 1 and 2 studies with GE Healthcare, which provided [18F]flutemetamol for this study., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Blood-based biomarkers have been extensively evaluated for their diagnostic potential in Alzheimer's disease. However, their relative prognostic and monitoring capabilities for cognitive decline, amyloid-β (Aβ) accumulation and grey matter loss in cognitively unimpaired elderly require further investigation over extended time periods. This prospective cohort study in cognitively unimpaired elderly [n = 185, mean age (range) = 69 (53-84) years, 48% female] examined the prognostic and monitoring capabilities of glial fibrillary acidic protein (GFAP), neurofilament light (NfL), Aβ1-42/Aβ1-40 and phosphorylated tau (pTau)181 through their quantification in serum. All participants underwent baseline Aβ-PET, MRI and blood sampling as well as 2-yearly cognitive testing. A subset additionally underwent Aβ-PET (n = 109), MRI (n = 106) and blood sampling (n = 110) during follow-up [median time interval (range) = 6.1 (1.3-11.0) years]. Matching plasma measurements were available for Aβ1-42/Aβ1-40 and pTau181 (both n = 140). Linear mixed-effects models showed that high serum GFAP and NfL predicted future cognitive decline in memory (βGFAP×Time = -0.021, PFDR = 0.007 and βNfL×Time = -0.031, PFDR = 0.002) and language (βGFAP×Time = -0.021, PFDR = 0.002 and βNfL×Time = -0.018, PFDR = 0.03) domains. Low serum Aβ1-42/Aβ1-40 equally but independently predicted memory decline (βAβ1-42/Aβ1-40×Time = -0.024, PFDR = 0.02). Whole-brain voxelwise analyses revealed that low Aβ1-42/Aβ1-40 predicted Aβ accumulation within the precuneus and frontal regions, high GFAP and NfL predicted grey matter loss within hippocampal regions and low Aβ1-42/Aβ1-40 predicted grey matter loss in lateral temporal regions. Serum GFAP, NfL and pTau181 increased over time, while Aβ1-42/Aβ1-40 decreased only in Aβ-PET-negative elderly. NfL increases associated with declining memory (βNfLchange×Time = -0.030, PFDR = 0.006) and language (βNfLchange×Time = -0.021, PFDR = 0.02) function and serum Aβ1-42/Aβ1-40 decreases associated with declining language function (βAβ1-42/Aβ1-40×Time = -0.020, PFDR = 0.04). GFAP increases associated with Aβ accumulation within the precuneus and NfL increases associated with grey matter loss. Baseline and longitudinal serum pTau181 only associated with Aβ accumulation in restricted occipital regions. In head-to-head comparisons, serum outperformed plasma Aβ1-42/Aβ1-40 (ΔAUC = 0.10, PDeLong, FDR = 0.04), while both plasma and serum pTau181 demonstrated poor performance to detect asymptomatic Aβ-PET positivity (AUC = 0.55 and 0.63, respectively). However, when measured with a more phospho-specific assay, plasma pTau181 detected Aβ-positivity with high performance (AUC = 0.82, PDeLong, FDR < 0.007). In conclusion, serum GFAP, NfL and Aβ1-42/Aβ1-40 are valuable prognostic and/or monitoring tools in asymptomatic stages providing complementary information in a time- and pathology-dependent manner., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Alzheimer's disease is one of the great challenges in the coming decades, and despite great efforts, a widely effective disease-modifying therapy in humans remains elusive. One particular promising non-pharmacological therapy that has received increased attention in recent years is based on the Gamma ENtrainment Using Sensory stimulation (GENUS), a high-frequency neural response elicited by a visual and/or auditory stimulus at 40 Hz. While this has shown to be effective in animal models, studies on human participants have reported varying success. The current work hypothesizes that the varying success in humans is due to differences in cognitive workload during the GENUS sessions., Methods: We recruited a cohort of 15 participants who underwent a scalp-EEG recording as well as one epilepsy patient who was implanted with 50 subdural surface electrodes over temporo-occipital and temporo-basal cortex and 14 depth contacts that targeted the hippocampus and insula. All participants completed several GENUS sessions, in each of which a different cognitive task was performed., Results: We found that the inclusion of a cognitive task during the GENUS session not only has a positive effect on the strength and extent of the gamma entrainment, but also promotes the propagation of gamma entrainment to additional neural areas including deep ones such as hippocampus which were not recruited when no cognitive task was required from the participants. The latter is of particular interest given that the hippocampal complex is considered to be one of the primary targets for AD therapies., Discussion: This work introduces a possible improvement strategy for GENUS therapy that might contribute to increasing the efficacy of the therapy or shortening the time needed for the positive outcome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Khachatryan, Wittevrongel, Reinartz, Dauwe, Carrette, Meurs, Van Roost, Boon and Van Hulle.)

Background: Early detection of individuals at risk for Alzheimer's disease (AD) is highly important. Amyloid accumulation is an early pathological AD event, but the genetic association with known AD risk variants beyond the APOE4 effect is largely unknown. We investigated the association between different AD polygenic risk scores (PRS) and amyloid accumulation in the Flemish Prevent AD Cohort KU Leuven (F-PACK)., Methods: We calculated PRS with and without the APOE region in 90 cognitively healthy F-PACK participants (baseline age 67.8 (52-80) years, 41 APOE4 carriers), with baseline and follow-up amyloid-PET (time interval 6.1 (3.4-10.9) years). Individuals were genotyped using Illumina GSA and imputed. PRS were calculated using three p-value thresholds (pT) for variant inclusion: 5 × 10 -8 , 1 × 10 -5 , and 0.1, based on the stage 1 summary statistics from Kunkle et al. (Nat Genet 51:414-30, 2019). Linear regression models determined if these PRS predicted amyloid accumulation., Results: A score based on PRS excluding the APOE region at pT = 5 × 10 -8 plus the weighted sum of the two major APOE variants (rs429358 and rs7412) was significantly associated with amyloid accumulation (p = 0.0126). The two major APOE variants were also significantly associated with amyloid accumulation (p = 0.0496). The other PRS were not significant., Conclusions: Specific PRS are associated with amyloid accumulation in the asymptomatic phase of AD., (© 2022. The Author(s).)

Purpose: End-of-life studies have validated the binary visual reads of 18 F-labeled amyloid PET tracers as an accurate tool for the presence or absence of increased neuritic amyloid plaque density. In this study, the performance of a support vector machine (SVM)-based classifier will be tested against pathological ground truths and its performance determined in cognitively healthy older adults., Methods: We applied SVM with a linear kernel to an 18 F-Flutemetamol end-of-life dataset to determine the regions with the highest feature weights in a data-driven manner and to compare between two different pathological ground truths: based on neuritic amyloid plaque density or on amyloid phases, respectively. We also trained and tested classifiers based on the 10% voxels with the highest amplitudes of feature weights for each of the two neuropathological ground truths. Next, we tested the classifiers' diagnostic performance in the asymptomatic Alzheimer's disease (AD) phase, a phase of interest for future drug development, in an independent dataset of cognitively intact older adults, the Flemish Prevent AD Cohort-KU Leuven (F-PACK). A regression analysis was conducted between the Centiloid (CL) value in a composite volume of interest (VOI), as index for amyloid load, and the distance to the hyperplane for each of the two classifiers, based on the two pathological ground truths. A receiver operating characteristic analysis was also performed to determine the CL threshold that optimally discriminates between neuritic amyloid plaque positivity versus negativity, or amyloid phase positivity versus negativity, within F-PACK., Results: The classifiers yielded adequate specificity and sensitivity within the end-of-life dataset (neuritic amyloid plaque density classifier: specificity of 90.2% and sensitivity of 83.7%; amyloid phase classifier: specificity of 98.4% and sensitivity of 84.0%). The regions with the highest feature weights corresponded to precuneus, caudate, anteromedial prefrontal, and also posterior inferior temporal and inferior parietal cortex. In the cognitively normal cohort, the correlation coefficient between CL and distance to the hyperplane was -0.66 for the classifier trained with neuritic amyloid plaque density, and -0.88 for the classifier trained with amyloid phases. This difference was significant. The optimal CL cut-off for discriminating positive versus negative scans was CL = 48-51 for the different classifiers (area under the curve (AUC) = 99.9%), except for the classifier trained with amyloid phases and based on the 10% voxels with highest feature weights. There the cut-off was CL = 26 (AUC = 99.5%), which closely matched the CL threshold for discriminating phases 0-2 from 3-5 based on the end-of-life dataset and the neuropathological ground truth., Discussion: Among a set of neuropathologically validated classifiers trained with end-of-life cases, transfer to a cognitively normal population works best for a classifier trained with amyloid phases and using only voxels with the highest amplitudes of feature weights., (© 2022. The Author(s).)

Objective: Plasma phosphorylated-tau-181 (p-tau181) reliably detects clinical Alzheimer's disease (AD) as well as asymptomatic amyloid-β (Aβ) pathology, but is consistently quantified with assays using antibody AT270, which cross-reacts with p-tau175. This study investigates two novel phospho-specific assays for plasma p-tau181 and p-tau231 in clinical and asymptomatic AD., Methods: Plasma p-tau species were quantified with Simoa in 44 AD patients, 40 spouse controls and an independent cohort of 151 cognitively unimpaired (CU) elderly who underwent Aβ-PET. Simoa plasma Aβ42 measurements were available in a CU subset (N = 69). Receiver operating characteristics and Aβ-PET associations were used to evaluate biomarker validity., Results: The novel plasma p-tau181 and p-tau231 assays did not show cross-reactivity. Plasma p-tau181 accurately detected clinical AD (area under the curve (AUC) = 0.98, 95% CI 0.95-1.00) as well as asymptomatic Aβ pathology (AUC = 0.84, 95% CI 0.76-0.92), while plasma p-tau231 did not (AUC = 0.74, 95% CI 0.63-0.85 and 0.61, 95% CI 0.52-0.71, respectively). Plasma p-tau181, but not p-tau231, detected asymptomatic Aβ pathology more accurately than age, sex and APOE combined (AUC = 0.64). In asymptomatic elderly, correlations between plasma p-tau181 and Aβ pathology were observed throughout the cerebral cortex (ρ = 0.40, p < 0.0001), with focal associations within AD-vulnerable regions, particularly the precuneus. The plasma Aβ42/p-tau181 ratio did not reflect asymptomatic Aβ pathology better than p-tau181 alone., Interpretation: The novel plasma p-tau181 assay is an accurate tool to detect clinical as well as asymptomatic AD and provides a phospho-specific alternative to currently employed immunoassays., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Language dysfunction is common in Alzheimer's disease. There is increasing interest in the preclinical or asymptomatic phase of Alzheimer's disease. Here we examined in 35 cognitively intact older adults (age range 52-78 years at baseline, 17 male) in a longitudinal study design the association between accumulation of amyloid over a 5-6-year period, measured using PET, and functional changes in the language network measured over the same time period using task-related functional MRI. In the same participants, we also determined the association between the longitudinal functional MRI changes and a cross-sectional measure of tau load as measured with 18F-AV1451 PET. As predicted, the principal change occurred in posterior temporal cortex. In the cortex surrounding the right superior temporal sulcus, the response amplitude during the associative-semantic versus visuo-perceptual task increased over time as amyloid load accumulated (Pcorrected = 0.008). In a whole-brain voxel-wise analysis, amyloid accumulation was also associated with a decrease in response amplitude in the left inferior frontal sulcus (Pcorrected = 0.009) and the right dorsomedial prefrontal cortex (Pcorrected = 0.005). In cognitively intact older adults, cross-sectional tau load was not associated with longitudinal changes in functional MRI response amplitude. Our findings confirm the central role of the neocortex surrounding the posterior superior temporal sulcus as the area of predilection within the language network in the earliest stages of Alzheimer's disease. Amyloid accumulation has an impact on cognitive brain circuitry in the asymptomatic phase of Alzheimer's disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: A patent foramen ovale (PFO) has been associated with embolic strokes and transient ischemic attacks (TIAs). Catheter closure of PFO is effective in preventing recurrent events. Residual shunts and procedure or device related complications can occur, including atrial fibrillation and thrombus formation. This study examines the initial experience with a new PFO closure device, the IrisFIT PFO-Occluder (Lifetech Scientific, Shenzhen, China)., Methods: 95 patients with indications for PFO closure underwent percutaneous closure with the IrisFIT PFO-Occluder. The primary endpoint was the rate of accurate device placement with no/small residual shunt at 3 or 6 months follow-up. All patients underwent transoesophageal echocardiography (TEE) after 1 to 6 months. In case of a residual shunt, an additional TEE was performed after 12 months. Clinical follow-up was performed up to a mean of 33.1 ± 3.6 months., Results: The device was successfully implanted in 95 (100%) patients with no relevant procedural complications. At final TEE follow-up (7.6 ± 3.9 months) the effective closure rate was 96.8% with 1 moderate and 2 large residual shunts. There were 8 cases of new onset atrial fibrillation and 2 TIAs. There were no cases of device embolization or erosion., Conclusion: The IrisFIT occluder is a new PFO closure device with several advantages compared to other devices. In this small study cohort, technical success rate, closure rate and adverse event rate were comparable to other devices. The rate of new onset atrial fibrillation was higher in comparison to other studies and warrants further investigation., Competing Interests: Declaration of competing interest Kolja Sievert: none. Jiangtao Yu: BBraun, Boston Scientific, LifeTech. Stefan Bertog: none. Marius Hornung: none. Ralph Stephan von Bardeleben: none. Sameer Gafoor: none. Markus Reinartz: none. Predrag Matic: none. Ilona Hofmann: none. Iris Grunwald: none. Nalan Schnelle: none. Horst Sievert: 4tech Cardio, Abbott, Ablative Solutions, Ancora Heart, Bavaria Medizin Technologie GmbH, Bioventrix, Boston Scientific, Carag, Cardiac Dimensions, Celonova, Cibiem, CGuard, Comed B.V., Contego, CVRx, Edwards, Endologix, Hemoteq, InspireMD, Lifetech, Maquet Getinge Group, Medtronic, Mitralign, Nuomao Medtech, Occlutech, pfm Medical, Recor, Renal Guard, Rox Medical, Terumo, Vascular Dynamics, Vivasure Medical, Venus, Veryan., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: The aim of this registry was to evaluate the feasibility and safety of transcatheter tricuspid valve implantation (TTVI) in patients with extreme surgical risk., Background: Isolated tricuspid regurgitation (TR) surgery is associated with high in-hospital mortality., Methods: Thirty consecutive patients (mean age 75 ± 10 years; 56% women) from 10 institutions, with symptomatic functional TR, had institutional and notified body approval for compassionate use of the GATE TTVI system. Baseline, discharge, and 30-day follow-up echocardiographic data and procedural, in-hospital, and follow-up clinical outcomes were collected., Results: At baseline, all patients had multiple comorbidities, severe or greater TR, and reduced baseline right ventricular function. Technical success was achieved in 26 of 30 patients (87%). Device malpositioning occurred in 4 patients, with conversion to open heart surgery in 2 (5%). Of those who received the device, 100% had reductions in TR of ≥1, and 75% experienced reductions of ≥2 grades, resulting in 18 of 24 of patients (76%) with mild or less TR at discharge. All patients had mild or less central TR. There was continued improvement in TR grade between discharge and 30 days in 15 of 19 patients (79%). In-hospital mortality was 10%. At mean follow-up of 127 ± 82 days, 4 patients (13%) had died. Of patients alive at follow-up, 62% were in New York Heart Association functional class I or II, with no late device-related adverse events., Conclusions: Compassionate treatment of severe, symptomatic functional TR using a first-generation TTVI device is associated with significant reduction in TR and improvement in functional status with acceptable in-hospital mortality. Further studies are needed to determine the appropriate patient population and long-term outcomes with TTVI therapy., Competing Interests: Author Relationship With Industry Drs. Bartus and Rodés-Cabau are consultants for NaviGate Cardiac Structures. Dr. Hahn has received speaking fees from Boston Scientific, Baylis Medical, Edwards Lifesciences, and Medtronic; is an advisory board member for Abbott Structural, Edwards Lifesciences, Medtronic, NaviGate Cardiac Structures, and Philips Healthcare; holds equity in NaviGate Cardiac Structures; has received nonfinancial support from 3mensio; and is the chief scientific officer for the Echocardiography Core Laboratory at the Cardiovascular Research Foundation for multiple industry-sponsored trials, for which she receives no direct industry compensation. Dr. Latib is a consultant for Medtronic, Edwards Lifesciences, Abbott, and NeoChord. Dr. Navia is a consultant for NaviGate Cardiac Structures, with equity and royalties for inventor patents of the device. Dr. Sievert is a consultant for 4tech Cardio, Abbott, Ablative Solutions, Ancora Heart, Append Medical, Bavaria Medizin Technologie, BioVentrix, Boston Scientific, Carag, Cardiac Dimensions, Cardimed, CeloNova Biosciences, Comed, Contego, CVRx, Dinova, Edwards Lifesciences, Endologix, Hemoteq, Hangzhou Nuomao Medtech, Holistick Medical, Lifetech Scientific, Maquet Getinge Group, Medtronic, Mokita, Occlutech, ReCor Medical, Renal Guard, Terumo, Vascular Dynamics, Vectorious Medtech, Venock, Venus, and Vivasure Medical. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: During the process of decision-making for long-term care, clients are often dependent on informal support and available information about quality ratings of care services. However, clients do not take ratings into account when considering preferred care, and need assistance to understand their preferences. A tool to elicit preferences for long-term care could be beneficial. Therefore, the aim of this qualitative descriptive study is to understand the user requirements and develop a web-based preference elicitation tool for clients in need of long-term care., Methods: We applied a user-centred design in which end-users influence the development of the tool. The included end-users were clients, relatives, and healthcare professionals. Data collection took place between November 2017 and March 2018 by means of meetings with the development team consisting of four users, walkthrough interviews with 21 individual users, video-audio recordings, field notes, and observations during the use of the tool. Data were collected during three phases of iteration: Look and feel, Navigation, and Content. A deductive and inductive content analysis approach was used for data analysis., Results: The layout was considered accessible and easy during the Look and feel phase, and users asked for neutral images. Users found navigation easy, and expressed the need for concise and shorter text blocks. Users reached consensus about the categories of preferences, wished to adjust the content with propositions about well-being, and discussed linguistic difficulties., Conclusion: By incorporating the requirements of end-users, the user-centred design proved to be useful in progressing from the prototype to the finalized tool 'What matters to me'. This tool may assist the elicitation of client's preferences in their search for long-term care.

Background: The aim of this study was to assess safety, efficacy, and clinical outcome of the IrisFIT PFO Closure System (Lifetech Scientific) for transcatheter closure of patent foramen ovale (PFO) in patients with a history of cryptogenic stroke, transient ischemic attack (TIA), or peripheral embolization., Patients and Methods: We report the results of 60 consecutive patients undergoing PFO closure with the IrisFIT occluder for secondary prevention of paradoxical embolization. All cases were analyzed for periprocedural and device-related adverse events up to 12 months after implantation. In addition, the patients were evaluated for complete defect closure with transesophageal echocardiography (TEE) after 1 month, 6 months, and (if indicated) 12 months. Mean patient age was 53 ± 14 years and 37 patients (62%) were males. All patients had a history of at least 1 cryptogenic stroke, TIA, or peripheral embolization., Results: Technical success was achieved in all 60 procedures. The mean procedure time was 28 ± 11 minutes. There were no periprocedural or device-related complications up to 12 months after the implant. Successful defect closure at 6 months post device implantation was achieved in 56 cases (93.3%). Within 12 months of follow-up, 2 patients had recurrent TIAs, both with complete PFO sealing at the last TEE prior to the event., Conclusion: The IrisFIT PFO Closure System can be used safely and with high technical success for secondary prevention of cryptogenic stroke or peripheral embolization.

Objectives: The aim of this study was to evaluate the technical and clinical success of acute stroke interventions performed in our interventional cardiology center., Background: Dedicated interventional stroke centers remain limited. Interventional cardiologists have established networks of catheterization laboratories and the necessary infrastructure to provide around the clock interventional therapy. These networks may also provide the currently lacking universal rapid access to prompt stroke intervention., Methods: Between July 2012 and July 2018, 70 consecutive patients underwent acute stroke intervention for large-vessel occlusions. Seventeen patients (24%) had tandem or multiple vessel occlusions. The majority (n = 63, 90%) were admitted via our local stroke unit, and 7 (10%) patients were transferred from other regional referral centers., Results: In 43 (61%) patients, systemic fibrinolytic therapy was started after baseline imaging. Mean time between symptom onset and arrival to the cath lab was 138 min; mean door-to-vascular access time was 64 min; mean time between cath lab activation and its operational readiness was 13 min. In all cases, access to supra-aortic vessels was achieved. Mean time between femoral arterial puncture and lesion crossing was 26 min. Stent implantation for extracranial stenosis or dissection was performed in 14 (20%) cases. Thrombectomy of intracranial occlusions was done with a stent retriever (n = 64, 91%) or an aspiration system (n = 14, 20%). In 20 (28%) cases, a combination of techniques was used. Recanalization was technically successful (Thrombolysis In Cerebral Infarction flow grade 2b or 3) in 65 (93%) patients. The 30-day mortality was 18% (n = 13). Favorable clinical outcome, defined as a modified Rankin Scale score of 0 to 2, was achieved in 61% at 3-month follow-up., Conclusions: Acute stroke interventions can be performed safely and with high technical and clinical success by experienced interventional cardiologists., (Copyright © 2019. Published by Elsevier Inc.)

One of the hallmarks of Alzheimer's disease is the presence of extracellular diffuse and fibrillar plaques predominantly consisting of the amyloid-β (Aβ) peptide. Apolipoprotein E (ApoE) influences the deposition of amyloid pathology through affecting the clearance and aggregation of monomeric Aβ in the brain. In addition to influencing Aβ metabolism, increasing evidence suggests that apoE influences microglial function in neurodegenerative diseases. Here, we characterize the impact that apoE has on amyloid pathology and the innate immune response in APPPS1ΔE9 and APPPS1-21 transgenic mice. We report that Apoe deficiency reduced fibrillar plaque deposition, consistent with previous studies. However, fibrillar plaques in Apoe -deficient mice exhibited a striking reduction in plaque compaction. Hyperspectral fluorescent imaging using luminescent conjugated oligothiophenes identified distinct Aβ morphotypes in Apoe -deficient mice. We also observed a significant reduction in fibrillar plaque-associated microgliosis and activated microglial gene expression in Apoe -deficient mice, along with significant increases in dystrophic neurites around fibrillar plaques. Our results suggest that apoE is critical in stimulating the innate immune response to amyloid pathology., (© 2018 Ulrich et al.)

Background  The ongoing technical advances in development of new implantable cardioverter defibrillator (ICD) systems led some investigators to question the routine use of intraoperative defibrillation testing (DT). Therefore, we evaluated retrospectively in a multicenter study effectiveness, safety, and usefulness of intraoperative DT on unbiased large patient population. Methods  Data from 4,572 consecutive patients undergoing any ICD intervention were retrospectively analyzed. Besides efficacy of DT, risk factors for DT failure were identified in a multiple logistic regression analysis. Results  Overall 5,483 shock data from 4,532 patients were available. Not tested for medical reasons were 13.5%. DT-associated complications were not noted. Primary DT effectiveness was 95.8%, whereas 4.2% were ineffective. Optimization (51.6% increase of DT energy, 10.1% subcutaneous lead array (SQ array), 2% generator exchange, 4.8% lead reposition, 9.3% lead exchange, and 22.2% change of shock parameters) led to successful DT in 152 patients (96.2%). Subanalyses and logistic regression identified implantation of generator in any other position than left subpectoral, age, body mass index and left ventricular ejection fraction as independent predictors for primary DT failure. Conclusion  The number of patients, including those undergoing generator exchange, system upgrade, or system revision, with inappropriate intraoperative testshock is relatively high. The results of recent prospective clinical trials can be extrapolated only on first ICD implantations with high-energy generators. For patients undergoing subcutaneous ICD implantation, right-sided implantation, patients with channelopathies and hypertrophic cardiomyopathy, as well as for procedures on already implanted ICD systems, the intraoperative DT might still be recommended., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: General anesthesia is known to be associated with an increased risk for complications, especially in elderly and multi-morbid patients, the primary target population of the MitraClip(®) technique. The aim is to assess whether general anesthesia and even conscious sedation can be avoided during the MitraClip(®) procedure., Methods: A total of 91 consecutive patients who underwent MitraClip(®) implantation [median 77 years, (IQR 72-83), 40 % female] were retrospectively analyzed. The first 26 patients were treated in general anesthesia. Afterwards, local anesthesia was chosen as primary anesthetic approach. Altogether, 28 (31 %) patients received general anesthesia, local anesthesia was performed in 35 (38 %) patients with sedation and in 28 (31 %) patients without sedation., Results: The respective patient groups were similar regarding their baseline characteristics. Procedural success (successful implantation of at least one clip and post-procedure MR grade ≤2) was achieved in 89 % with no difference between the groups (93 % in general anesthesia, 89 % in local anesthesia with sedation, 86 % in local anesthesia without sedation, p = ns). No difference regarding hospital complications was noted. Local anesthesia with and without sedation was associated with less necessity for ICU/IMC stay (100 % in general anesthesia, 14 % in local anesthesia with sedation, 14 % in local anesthesia without sedation; p < 0.0001). One-year estimated survival was not significantly different among the groups (63, 82 and 75 %; p = ns)., Conclusions: Transcatheter mitral valve repair with the MitraClip(®) can be performed without general anesthesia and even without conscious sedation with similar procedural success and complication rates.

Aims: To evaluate the safety and feasibility of transcatheter aortic valve implantation (TAVI) via femoral access under local anesthesia only (without concomitant sedation) as the initial strategy., Methods and Results: Patients undergoing planned transfemoral TAVI without routine general anesthesia between May 2005 and December 2013 were identified. Baseline characteristics, procedural outcomes, and a 30-day clinical follow-up were obtained. A total of 215 patients underwent TAVI with local anesthesia only as the initial strategy (LA group). Of these patients, 40 (18.6%) received additional sedation (LAS group) during the procedure due to inadequate pain control or agitation and 7 patients (3.3%) underwent conversion to general anesthesia (GA group). TAVI was successfully performed in 211 cases (98.2%). When 30-day outcomes for patients requiring only local anesthesia were compared with patients requiring additional sedation, there was a significantly longer duration of Intensive Care Unit (ICU) stay in the group with additional sedation (LAS, 5.0 days [range, 3.0-6.0 days] vs LA 3 days [range, 2.0-5.0 days]; P=.02) and general anesthesia (GA 7.0 days [range, 2.5-18.0 days] vs LA 3 days [range, 2.0-5.0]; P=.04)., Conclusion: Our study suggests that TAVI with LA only as the initial strategy is a feasible alternative to GA, with potential benefit of this strategy over using routine concomitant sedation. LA only may be considered a primary option in many patients.

Objectives: The purpose of this study is to determine feasibility, safety, and effectiveness of the "shape-the-sheath" method in left atrial appendage closure., Background: LAA occlusion is often a difficult procedure, due to not just the learning curve but also the three-dimensional variable nature of the left atrial appendage. Multiple sheaths have been created for various takeoffs. The purpose of this article is to show the feasibility of the "shape-the-sheath" method in left atrial appendage closure., Methods: Ten consecutive patients undergoing LAA occlusion without the "shape-the-sheath" method were compared to 10 consecutive patients undergoing LAA occlusion with the "shape-the-sheath" method using the Amplatzer Cardiac Plug (ACP) system and the Amplatzer TorqVue 45×45 sheath., Results: The "shape-the-sheath" method resulted in significant decreases in fluoroscopy time (7.2±3.0 min vs. 13.7±6.7 min, P<0.05), number of partial recaptures (0% vs. 50%, P<0.05), with a trend toward decrease in the number of complete recaptures (0 vs. 40%, P=0.09) compared to conventional sheath use., Conclusions: Shaping-the-sheath is a simple, elegant way to help conform delivery systems to better access the LAA and ensure stable position. Further experience with this procedure optimization step is warranted., (© 2015 Wiley Periodicals, Inc.)

Structural heart disease requires a coordinated effort to join echocardiographic and fluoroscopic data. Various methods have been used, including echocardiography, CT, and MRI. We report on the use of EchoNavigator (Philips Inc., Amsterdam, Netherlands), a novel echocardiographic-fluoroscopic fusion system. This new system allows real-time integration and marking of important structures that track on fluoroscopy even with movement of the C-arm. In this article, we describe potential uses for this system in respect to transseptal puncture and left atrial appendage closure., (© 2015, Wiley Periodicals, Inc.)

Heart failure is a growing epidemic, with more patients living longer and suffering from this disease. There is a growing segment of patients who have persistent symptoms despite pharmacologic therapy. In an era when transplants are rare, the need for devices and interventions that can assist ventricular function is paramount. This review goes through the devices used in heart failure, including left ventricular reconstruction, aortic counterpulsation, short-term mechanical circulatory support, long-term mechanical circulatory support, and right heart interventions.

The protein kinase AKT is a central kinase in the heart and has a major impact on growth/hypertrophy, survival/apoptosis, and metabolism. To gain more insight into AKT isoform-specific signaling at the molecular level, we investigated the phosphoproteome of HL-1 cardiomyocytes carrying AKT1 or AKT2 isoform-specific knock down, respectively. We combined stable isotope labeling with high resolution mass spectrometry and identified 377 regulated phosphopeptides. Although AKT1 is expressed at 4-fold higher levels, insulin stimulation mainly activated AKT2, which might in part rely on a preferred interaction of AKT2 with the mammalian target of rapamycin complex 2. In line with this result, the highest number of regulated phosphopeptides was identified in the AKT2 knock down cells. Isoform-specific regulation of AKT targets not previously described could be observed, and specific regulation of indirect target sites allows a deeper insight into affected biological processes. In the myocardial context, we identified many phosphosites supporting a connection of AKT to excitation-contraction coupling. Phosphoproteins identified included L-type calcium channel, ryanodine receptor, junctophilin, histidine-rich calcium binding protein, phospholamban, heat shock protein beta-6, and Ca²⁺/calmodulin-dependent kinase II. In conclusion, AKT isoform-specific knock down combined with quantitative phosphoproteomics provided a powerful strategy to unravel AKT isoform-specific signaling.

Small cell lung carcinomas (SCLCs) represent highly aggressive tumors with an overall five-year survival rate in the range of 5 to 10%. Here, we show that four out of five SCLC cell lines reversibly develop a neuron-like phenotype on extracellular matrix constituents such as fibronectin, laminin or thrombospondin upon staurosporine treatment in an RGD/integrin-mediated manner. Neurite-like processes extend rapidly with an average speed of 10 µm per hour. Depending on the cell line, staurosporine treatment affects either cell cycle arrest in G2/M phase or induction of polyploidy. Neuron-like conversion, although not accompanied by alterations in the expression pattern of a panel of neuroendocrine genes, leads to changes in protein expression as determined by two-dimensional gel electrophoresis. It is likely that SCLC cells already harbour the complete molecular repertoire to convert into a neuron-like phenotype. More extensive studies are needed to evaluate whether the conversion potential of SCLC cells is suitable for therapeutic interventions.

AKT2 is one of the three isoforms of the protein kinase AKT being involved in the modulation of cellular metabolism. Since protein-protein interactions are one possibility to convey specificity in signal transduction, we performed AKT2-protein interaction analysis to elucidate their relevance for AKT2-dependent cellular functions. We identified heat shock protein 90 kDa (HSP90), Cdc37, heat shock protein 70 kDa (HSP70), 78 kDa glucose regulated protein (GRP78), tubulin, GAPDH, α-enolase and elongation factor 2 (EF2) as AKT2-interacting proteins by a combination of tandem affinity purification and mass spectrometry in HEK293T cells. Quantitative MS-analysis using stable isotope labeling by amino acids in cell culture (SILAC) revealed that only HSP90 and Cdc37 interact stably with AKT2, whereas the other proteins interact with low affinity with AKT2. The interactions of AKT2 with α-enolase and EF2 were further analyzed in order to uncover the functional relevance of these newly discovered binding partners. Despite the interaction of AKT2 and α-enolase, which was additionally validated by proximity ligation assay (PLA), no significant impact of AKT on α-enolase activity was detected in activity measurements. AKT stimulation via insulin and/or inhibition with the ATP-competitive inhibitor CCT128930 did not alter enzymatic activity of α-enolase. Interestingly, the direct interaction of AKT2 and EF2 was found to be dynamically regulated in embryonic rat cardiomyocytes. Treatment with the PI3-kinase inhibitor LY294002 before stimulation with several hormones stabilized the complex, whereas stimulation alone led to complex dissociation which was analyzed in situ with PLA. Taken together, these findings point to new aspects of AKT2-mediated signal transduction in protein synthesis and glucose metabolism.

Endothelial nitric oxide synthase (NOS)3-derived nitric oxide (NO) modulates inotropic response and diastolic interval for optimal cardiac performance under non-inflammatory conditions. In sepsis, excessive NO production plays a key role in severe hypotension and myocardial dysfunction. We aimed to determine the role of NOS3 on myocardial performance, NO production, and time course of sepsis development. NOS3(-/-) and C57BL/6 wildtype mice were rendered septic by cecum ligation and puncture (CLP). Cardiac function was analyzed by serial echocardiography, in vivo pressure and isolated heart measurements. Cardiac output (CO) increased to 160 % of baseline at 10 h after sepsis induction followed by a decline to 63 % of baseline after 18 h in wildtype mice. CO was unaltered in septic NOS3(-/-) mice. Despite the hyperdynamic state, cardiac function and mean arterial pressure were impaired in septic wildtype as early as 6 h post CLP. At 12 h, cardiac function in septic wildtype was refractory to catecholamines in vivo and respective isolated hearts showed impaired pressure development and limited coronary flow reserve. Hemodynamics remained stable in NOS3(-/-) mice leading to significant survival benefit. Unselective NOS inhibition in septic NOS3(-/-) mice diminished this survival benefit. Plasma NO( x )- and local myocardial NO( x )- and NO levels (via NO spin trapping) demonstrated enhanced NO( x )- and bioactive NO levels in septic wildtype as compared to NOS3(-/-) mice. Significant contribution by inducible NOS (NOS2) during this early phase of sepsis was excluded. Our data suggest that NOS3 relevantly contributes to bioactive NO pool in developing sepsis resulting in impaired cardiac contractility.

Background: Human beta-defensins (hBDs) and the C-C chemokine ligand 20 (CCL20) produced by gingival epithelial cells (GECs) and fibroblasts (HGFs) are antimicrobial peptides (AMPs) that play an important role in innate immunity. The aim of this study was to determine the differential immune response of GECs and HGFs to the oral commensal Streptococcus gordonii (SG) and the pathogen Porphyromonas gingivalis (PG)., Material and Methods: In addition to the analysis of gingival biopsies, primary GECs and HGFs were exposed to SG and/or PG, and expression of various AMPs and pro-inflammatory mediators was studied by real-time PCR and ELISA., Results: Gene expression of AMPs was detected in gingival connective tissue. Both SG and PG induced the mRNA-expression of hBD-2 and hBD-3 in GECs as well as HGFs after 24 h (p < 0.05). In HGFs, the commensal bacterium SG stimulated the mRNAs of hBD-3 and CCL20 after 24 h (p < 0.05), while not in GECs. In GECs, the inductive effect of PG on the mRNA-expression of hBD-2 was amplified when cells were first exposed to commensal SG (for 1 h) prior to stimulation with PG (SG-PG; p < 0.05)., Conclusion: Our data indicate that cell-bacteria interactions and/or bacteria-bacteria cross-talk may have an impact on AMP-regulation in gingiva., (© 2012 John Wiley & Sons A/S.)

Background: Dysregulation of microRNA (miRNA) expression is regularly found in various types of cancer and contributes to tumorigenic processes. However, little is known about miRNA expression in non-melanoma skin cancer in which a pathogenic role of beta human papillomaviruses (HPV) is discussed. A carcinogenic potential of beta HPV8 could be demonstrated in a transgenic mouse model, expressing all early genes of HPV8 (HPV8-CER). A single UVA/B-dose induced oncogene expression and led to papilloma growth within three weeks., Objective: Expression of miRNAs and their targets during HPV8-mediated tumor formation in mice., Methods: Skin of untreated or UV-irradiated wild-type and HPV8-CER mice was analyzed for miRNA expression and localization by qPCR and in situ hybridization. MiRNA target protein expression was analyzed by immunohistochemical staining., Results: Early steps in skin tumor formation in HPV8-CER mice were associated with an upregulation of the oncogenic miRNA-17-5p, -21 and -106a and a downregulation of the tumor-suppressive miRNA-155 and -206, which could be demonstrated by qPCR and in situ hybridization. The respective targets of miRNA-21 and -106a, the tumor suppressors PTEN, PDCD4 and Rb with their pivotal role in cell cycle regulation, apoptosis and proliferation were found to be downregulated., Conclusion: This is the first report demonstrating that a cutaneous HPV type deregulates the expression of miRNAs. These deregulations are closely related to the UV-induced upregulation of HPV8 oncogene levels, which suggest a direct or indirect HPV8-specific effect on miRNA expression. These data presume that HPV8 interferes with the miRNA mediated gene regulation to induce tumorigenesis., (Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: The role of iNOS induction in the context of cardiac hypertrophy and heart failure is still not fully understood. We have used transgenic mice with cardiac specific overexpression of iNOS (tg-iNOS) to investigate the consequences of high level NO formation on cardiac function in vivo and the response to chronic pressure overload. Conductance manometry was used to analyze cardiac function of wild type (WT) and tg-iNOS mice under basal conditions and β-adrenergic stimulation. To investigate the influence of iNOS on cardiac function in hypertrophied hearts, transversal aortic constriction was performed. Despite a high level of cardiac NO formation tg-iNOS mice showed almost normal LV function under basal conditions. The cardiac response to β-adrenergic stimulation, however, was completely abolished. Acute NOS inhibition led to an instantaneous recovery of the inotropic response to catecholamines in tg-iNOS mice. Chronic pressure overload induced a similar extent of cardiac hypertrophy in WT and tg-iNOS hearts. LV function, however, was more compromised in tg-iNOS hearts as revealed by a decreased contractility and cardiac output., In Conclusion: a high level of cardiac NO formation does not induce heart failure per se but severely enhances the functional depression in response to pressure overload. This effect could be due to the tonic impairment of the cardiac β-adrenergic response., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Epidemiological studies have indicated a relationship between coronary heart disease (CHD) and periodontitis. Recently, CDKN2BAS was reported as a shared genetic risk factor of CHD and aggressive periodontitis (AgP), but the causative variant has remained unknown. To identify and validate risk variants in different European populations, we first explored 150 kb of the genetic region of CDKN2BAS including the adjacent genes CDKN2A and CDKN2B, covering 51 tagging single nucleotide polymorphisms (tagSNPs) in AgP and chronic periodontitis (CP) in individuals of Dutch origin (n=313). In a second step, we tested the significant SNP associations in an independent AgP and CP population of German origin (n=1264). For the tagSNPs rs1360590, rs3217992, and rs518394, we could validate the associations with AgP before and after adjustment for the covariates smoking, gender and diabetes, with SNP rs3217992 being the most significant (OR 1.48, 95% CI 1.19 to 1.85; p=0.0004). We further showed in vivo gene expression of CDKN2BAS, CDKN2A, CDKN2B, and CDK4 in healthy and inflamed gingival epithelium (GE) and connective tissue (CT), and detected a significantly higher expression of CDKN2BAS in healthy CT compared to GE (p=0.004). After 24 h of stimulation with Porphyromonas gingivalis in Streptococcus gordonii pre-treated gingival fibroblast (HGF) and cultured gingival epithelial cells (GECs), we observed a 25-fold and fourfold increase of CDKN2BAS gene expression in HGFs (p=0.003) and GECs (p=0.004), respectively. Considering the global importance of CDKN2BAS in the disease risk of CHD, this observation supports the theory of inflammatory components in the disease physiology of CHD.

Background: Sublingual immunotherapy (SLIT) is safe and effective as treatment of allergic rhinitis and mild asthma. Oral mucosal Langerhans cells (oLCs) play a central role. However, little is known about allergen binding by oLCs during mucosal allergen resorption and its impact on oLC functions., Objective: Binding of Phl p 5 to oLCs was studied in a standardized ex vivo model to investigate mechanisms important for SLIT., Methods: Human oral mucosal biopsies were incubated with the grass pollen allergen Phl p 5. Migration, binding of Phl p 5, phenotype and cytokine production, and T-cell priming of Phl p 5-binding oLCs were analyzed., Results: Significant uptake required more than 5 minutes, and dose-dependent binding of Phl p 5 to oLCs was saturated at 100 microg/mL Phl p 5. Furthermore, Phl p 5 significantly increased the migratory capacity of oLCs but attenuated their maturation and strongly promoted the release of TGF-beta1 and IL-10 by oLCs themselves as well as by cocultured T cells., Conclusion: Oral mucosal Langerhans cells bind Phlp5 in a dose-dependent and time-dependent manner, leading to an increased production of tolerogenic cytokines and an enhanced migratory capacity but decelerated maturation of oLCs., (Copyright (c) 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Multifunctional nanocarriers for amino functional targets with a high density of accessible binding sites are obtained in a single polymerization step by grafting from copolymerization of an active ester monomer from superparamagnetic cores. As a result of the brush-like structure of the highly dispersed shell, the nano-objects exhibit an available capture capacity for amines that is found to be up to 2 orders of magnitude higher than for commercial magnetic beads, and the functional brush shell can serve as a template for many types of pendant functional groups and molecules. As comonomer, oligo(ethylene glycol) methacrylate allows for excellent water solubility at room temperature, biocompatibility, and thermoflocculation. We demonstrate the biorelated applicability of the hybrid nanoparticles by two different approaches. In the first approach, the immobilization of trypsin to the core-shell nanoparticles results in highly active, nanoparticulate biocatalysts that can easily be separated magnetically. Second, we demonstrate that the obtained nanoparticles are suitable for the effective labeling of cell membranes, opening a novel pathway for the easy and effective isolation of membrane proteins.