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Background/objectives: Cisplatin is part of the first-line treatment of advanced urothelial carcinoma. Cisplatin resistance is a major problem but may be overcome by combination treatments such as targeting epigenetic aberrances. Here, we investigated the effect of the class I HDACi entinostat and bromodomain inhibitors (BETis) on the potency of cisplatin in two pairs of sensitive and cisplatin-resistant bladder cancer cell lines. Cisplatin-resistant J82cisR and T24 LTT were 3.8- and 24-fold more resistant to cisplatin compared to the native cell lines J82 and T24. In addition, a hybrid compound (compound 20 ) comprising structural features of an HDACi and a BETi was investigated., Results: We found complete (J82cisR) or partial (T24 LTT) reversal of chemoresistance upon combination of entinostat, JQ1, and cisplatin. The same was found for the BETis JQ35 and OTX015, both in clinical trials, and for compound 20 . The combinations were highly synergistic (Chou Talalay analysis) and increased caspase-mediated apoptosis accompanied by enhanced expression of p21, Bim, and FOXO1. Notably, the combinations were at least 4-fold less toxic in non-cancer cell lines HBLAK and HEK293., Conclusions: The triple combination of entinostat, a BETi, and cisplatin is highly synergistic, reverses cisplatin resistance, and may thus serve as a novel therapeutic approach for bladder cancer.

Herein, we describe the design, synthesis, and biological evaluation of 15 Contilisant + Tubastatin A hybrids. These ligands are polyfunctionalized indole derivatives developed by juxtaposing selected pharmacophoric moieties of Contilisant and Tubastatin A to act as multifunctional ligands. Compounds 3 and 4 were identified as potent HDAC6 inhibitors (IC 50 = 0.012 μM and 0.035 μM, respectively), so they were further evaluated in Drosophila and human cell models of Parkinson's disease (PD). Both compounds attenuated PD-like phenotypes, such as motor defects, oxidative stress, and mitochondrial dysfunction in PD model flies. Ligands 3 and 4 were also studied in the transgenic Caenorhabditis elegans CL2006 model of Alzheimer's disease (AD). Both compounds were nontoxic, did not induce undesirable animal functional changes, inhibited age-related paralysis, and improved cognition in the thrashing assay. These results highlight 3 and 4 as novel multifunctional ligands that improve the features of PD and AD hallmarks in the respective animal models.

Apicidins are a class of naturally occurring cyclic tetrapeptides produced by few strains within the Fusarium genus. These secondary metabolites have gained significant attention due to their antiprotozoal activity through HDAC inhibition, thereby highlighting their potential for the treatment of malaria. Predominantly, apicidins have been isolated from Fusarium semitectum, offering a deep insight into the biosynthetic pathway responsible for their formation. A similar biosynthetic gene cluster has also been identified in the rice pathogenic fungus F. fujikuroi, leading the discovery of three additional apicidins through genetic manipulation. Routine mass spectrometric screening of these compound-producing strains revealed another metabolite structurally related to previously studied apicidins. By optimizing culture conditions and developing an effective isolation method, we obtained a highly pure substance, whose chemical structure was fully elucidated using NMR and HRMS fragmentation. Further studies were conducted to determine cytotoxicity, antimalarial activity, and HDAC inhibitory activity of this new secondary metabolite alongside the previously known apicidins. This work not only expands the apicidin class with a new member but also provides extensive insights and comparative analysis of apicidin-like substances produced by F. fujikuroi., (© 2024. The Author(s).)

Gastric cancer remains among the deadliest neoplasms worldwide, with limited therapeutic options. Since efficacies of targeted therapies are unsatisfactory, drugs with broader mechanisms of action rather than a single oncogene inhibition are needed. Preclinical studies have identified histone deacetylases (HDAC) as potential therapeutic targets in gastric cancer. However, the mechanism(s) of action of HDAC inhibitors (HDACi) are only partially understood. This is particularly true with regard to ferroptosis as an emerging concept of cell death. In a panel of gastric cancer cell lines with different molecular characteristics, tumor cell inhibitory effects of different HDACi were studied. Lipid peroxidation levels were measured and proteome analysis was performed for the in-depth characterization of molecular alterations upon HDAC inhibition. HDACi effects on important ferroptosis genes were validated on the mRNA and protein level. Upon HDACi treatment, lipid peroxidation was found increased in all cell lines. Class I HDACi (VK1, entinostat) showed the same toxicity profile as the pan-HDACi vorinostat. Proteome analysis revealed significant and concordant alterations in the expression of proteins related to ferroptosis induction. Key enzymes like ACSL4, POR or SLC7A11 showed distinct alterations in their expression patterns, providing an explanation for the increased lipid peroxidation. Results were also confirmed in primary human gastric cancer tissue cultures as a relevant ex vivo model. We identify the induction of ferroptosis as new mechanism of action of class I HDACi in gastric cancer. Notably, these findings were independent of the genetic background of the cell lines, thus introducing HDAC inhibition as a more general therapeutic principle., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Declarations of interest: none. This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (DFG; AI 24/33-1 to A. A. and HA 7783/4-1 to F. K. H.), and by a grant from the Roland-Ernst-Stiftung für Gesundheitsforschung (Project 5/19 to A. A. and F. K. H.)., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Studies report an association between study conditions and student health outcomes. The aim was to investigate the influence of specific study-related demands and resources on self-assessed health., Method: Students of the Technical University of Dresden were surveyed online about their health and their studies. Referring to the Study Demands-Resources Model descriptive and regression analytic methods were applied., Results: 1,312 students were included in the analyses. About one-fifth of participants reported low life satisfaction and high exhaustion. Time and cognitive demands were associated with poorer health, social support and time margin in studies were linked to better health. This relationship was particularly evident with a combination of high demands and low resources., Conclusion: The results provide approaches for preventive measures to strengthen the health of students., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Background: Early mobilization is only carried out to a limited extent in the intensive care unit. To address this issue, the robotic assistance system VEMOTION® was developed to facilitate (early) mobilization measures more easily. This paper describes the first integration of robotic assistance systems in acute clinical intensive care units., Objective: Feasibility test of robotic assistance in early mobilization of intensive care patients in routine clinical practice., Setting: Two intensive care units guided by anesthesiology at a German university hospital., Participants: Patients who underwent elective surgery with postoperative treatment in the intensive care unit and had an estimated ventilation time over 48 h., Methods: Participants underwent robot-assisted mobilization, scheduled for twenty-minute sessions twice a day, ten times or one week, conducted by nursing staff under actual operational conditions on the units. No randomization or blinding took place. We assessed data regarding feasible cutoff points (in brackets): the possibility of enrollment (x ≥ 50 %), duration (pre- and post-setup (x ≤ 25 min), therapy duration (x = 20 min), and intervention-related parameters (number of mobilizing professionals (x ≤ 2), intensity of training, events that led to adverse events, errors or discontinuation). Mobilizing professionals rated each mobilization regarding their physical stress (x ≤ 3) and feasibility (x ≥ 4) on a 7 Point Likert Scale. An estimated sample size of at least twenty patients was calculated. We analyzed the data descriptively., Results: Within 6 months, we screened thirty-two patients for enrollment. 23 patients were included in the study and 16 underwent mobilization using robotic assistance, 7 dropped out (enrollment eligibility = 69 %). On average, 1.9 nurses were involved per therapy unit. Participants received 5.6 robot-assisted mobilizations in mean. Pre- and post-setup had a mean duration of 18 min, therapy a mean of 21 min. The robot-assisted mobilization was started after a median of 18 h after admission to the intensive care unit. We documented two adverse events (pain), twelve errors in handling, and seven unexpected events that led to interruptions or discontinuation. No serious adverse events occurred. The mobilizing nurses rated their physical stress as low (mean 2.0 ± 1.3) and the intervention as feasible (mean 5.3 ± 1.6)., Conclusions: Robot-assisted mobilization was feasible, but specific safety measures should be implemented to prevent errors. Robotic-assisted mobilization requires process adjustments and consideration of unit staffing levels, as the intervention does not save staff resources or time., Registration: clinicaltrials.org TRN: NCT05071248; Date: 2021/10/08; URL https://clinicaltrials.gov/ct2/show/NCT05071248., Tweetable Abstract: Robot-assisted early mobilization in intensive care patients is feasible and no adverse event occurred., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests. The company that manufactures the VEMOTION® system is part of the overall study consortium. However, it was not part of the clinical study or the analysis team., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background/aims: Ectasia of the cornea can occur decades after penetrating keratoplasty (PK), especially in keratoconus eyes. The purpose of this study was to characterise ectasia after PK by morphological findings in anterior segment optical coherence tomography (AS-OCT)., Methods: In this retrospective, single-centre case series, 50 eyes of 32 patients with a history of PK at an average of 25±10 years earlier were included. The eyes were classified either as ectatic (n=35) or as non-ectatic (n=15). The main parameters included central corneal thickness (CCT), lowest corneal thickness at the interface (LCTI), anterior chamber depth, graft-host interface angle at the thinnest point and host cornea-iris angle. Furthermore, steep and flat keratometry readings obtained by AS-OCT (CASIA-2, Tomey) and Scheimpflug tomography (Pentacam, Oculus) were assessed. OCT findings were correlated with clinical grading of ectasia., Results: There was a highly significant difference in LCTI, graft-host interface angle and anterior chamber depth (in pseudophakic eyes) between the groups. The ratio calculated by the quotient of LCTI divided by CCT was significantly lower in ectatic than non-ectatic eyes (p<0.001). In eyes with an LCTI/CCT ratio of ≤0.7, the OR for the occurrence of a clinical detectable ectasia was 2.4 (CI 1.5 to 3.7). Steep keratometry values were significantly higher in ectatic eyes., Conclusion: AS-OCT is a helpful tool to recognise and quantify ectasia in post-PK eyes objectively., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Histone deacetylases (HDACs) are a class of enzymes that cleave acyl groups from lysine residues of histone and non-histone proteins. There are 18 human HDAC isoforms with different cellular targets and functions. Among them, HDAC6 was found to be overexpressed in different types of cancer. However, when used in monotherapy, HDAC6 inhibition by selective inhibitors fails to show pronounced anti-cancer effects. The HDAC6 enzyme also addresses non-histone proteins like α-tubulin and cortactin, making it important for cell migration and angiogenesis. Recently, the NLRP3 inflammasome was identified as an important regulator of inflammation and immune responses and, importantly, HDAC6 is critically involved the activation of the inflammasome. We herein report the design, synthesis and biological evaluation of a library of selective HDAC6 inhibitors. Starting from the previously published crystal structure of MAIP-032 in complex with CD2 of zHDAC6, we performed docking studies to evaluate additional possible interactions of the cap group with the L1-loop pocket. Based on the results we synthesized 13 novel HDAC6 inhibitors via the Groebke-Blackburn-Bienaymé three component reaction as the key step. Compounds 8k (HDAC1 IC 50 : 5.87 μM; HDAC6 IC 50 : 0.024 μM; selectivity factor (SF 1/6 ): 245) and 8m (HDAC1 IC 50 : 3.07 μM; HDAC6 IC 50 : 0.026 μM; SF 1/6 : 118) emerged as the most potent and selective inhibitors of HDAC6 and outperformed the lead structure MAIP-032 (HDAC1 IC 50 : 2.20 μM; HDAC6 IC 50 : 0.058 μM; SF 1/6 : 38) both in terms of inhibitory potency and selectivity. Subsequent immunoblot analysis confirmed the high selectivity of 8k and 8m for HDAC6 in a cellular environment. While neither 8k and 8m nor the selectivity HDAC6 inhibitor tubastatin A showed antiproliferative effects in the U-87 MG glioblastoma cell line, compound 8m attenuated cell migration significantly in wound healing assays in U-87 MG cells. Moreover, in macrophages compounds 8k and 8m demonstrated significant inhibition of LPS-induced IL1B mRNA expression and TNF release. These findings suggest that our imidazo[1,2-a]pyridine-capped HDAC6 inhibitors may serve as promising candidates for the development of drugs to effectively treat NLRP3 inflammasome-driven inflammatory diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Biological trait analysis (BTA) is a valuable tool for evaluating changes in community diversity and its link to ecosystem processes as well as environmental and anthropogenic perturbations. Trait-based analytical techniques like BTA rely on standardised datasets of species traits. However, there are currently only a limited number of datasets available for marine macrobenthos that contain trait data across multiple taxonomic groups. Here, we present an open-access dataset of 16 traits for 235 macrozoobenthic species recorded throughout multiple sampling campaigns of the Dutch Wadden Sea; a dynamic soft bottom system where humans have long played a substantial role in shaping the coastal environment. The trait categories included in this dataset cover a variety of life history strategies that are tightly linked to ecosystem functioning and the resilience of communities to (anthropogenic) perturbations and can advance our understanding of environmental changes and human impacts on the functioning of soft bottom systems., (© 2023. The Author(s).)

Histone deacetylase 6 (HDAC6) is an important drug target in oncological and non-oncological diseases. Most available HDAC6 inhibitors (HDAC6i) utilize hydroxamic acids as a zinc-binding group, which limits therapeutic opportunities due to its genotoxic potential. Recently, difluoromethyl-1,3,4-oxadiazoles (DFMOs) were reported as potent and selective HDAC6i but their mode of inhibition remained enigmatic. Herein, we report that DFMOs act as mechanism-based and essentially irreversible HDAC6i. Biochemical data confirm that DFMO 6 is a tight-binding HDAC6i capable of inhibiting HDAC6 via a two-step slow-binding mechanism. Crystallographic and mechanistic experiments suggest that the attack of 6 by the zinc-bound water at the sp 2 carbon closest to the difluoromethyl moiety followed by a subsequent ring opening of the oxadiazole yields deprotonated difluoroacetylhydrazide 13 as active species. The strong anionic zinc coordination of 13 and the binding of the difluoromethyl moiety in the P571 pocket finally result in an essentially irreversible inhibition of HDAC6.

Purpose: The aim of the study was to evaluate whether the quantification of B-lines via lung ultrasound after lung transplantation is feasible and correlates with the diagnosis of primary graft dysfunction., Methods: Following lung transplantation, patients underwent daily lung ultrasound on postoperative days 1-3. B-lines were quantified by an ultrasound score based on the number of single and confluent B-lines per intercostal space, using a four-region protocol. The ultrasound score was correlated with the diagnosis of primary graft dysfunction. Furthermore, correlation analyses and receiver operating characteristics analyses taking into account ultrasound score, chest radiographs, and PaO2/FiO2 ratio were performed., Results: A total of 32 patients (91 ultrasound measurements) were included, whereby 10 were diagnosed with primary graft dysfunction. The median B-line score was 5 [IQR: 4, 8]. There was a significant correlation between B-line score and the diagnosis of primary graft dysfunction (r = 0.59, p < 0.001). A significant correlation could also be seen between chest X-rays and primary graft dysfunction (r = 0.34, p = 0.008), but the B-line score showed superiority over chest X-rays with respect to diagnosing primary graft dysfunction in the receiver operating characteristics curves with an area under the curve value of 0.921 versus 0.708. There was a significant negative correlation between B-line score and PaO2/FiO2 ratio (r = -0.41, p < 0.001), but not between chest X-rays and PaO2/FiO2 ratio (r = -0.14, p = 0.279)., Conclusion: The appearance of B-lines correlated well with primary graft dysfunction and outperformed chest radiographs., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Language has been used as a privileged window to investigate mental processes. More recently, descriptions of psychopathological symptoms have been analyzed with the help of natural language processing tools. An example is the study of speech organization using graph theoretical approaches that began approximately 10 years ago. After its application in different areas, there is a need to better characterize what aspects can be associated with typical and atypical behavior throughout the lifespan, given the variables related to aging as well as biological and social contexts. The precise quantification of mental processes assessed through language may allow us to disentangle biological/social markers by looking at naturalistic protocols in different contexts. In this review, we discuss 10 years of studies in which word recurrence graphs were adopted to characterize the chain of thoughts expressed by individuals while producing discourse. Initially developed to understand formal thought disorder in the context of psychotic syndromes, this line of research has been expanded to understand the atypical development in different stages of psychosis and differential diagnosis (such as dementia) as well as the typical development of thought organization in school-age children/teenagers in naturalistic and school-based protocols. We comment on the effects of environmental factors, such as education and reading habits (in monolingual and bilingual contexts), in clinical and nonclinical populations at different developmental stages (from childhood to older adulthood, considering aging effects on cognition). Looking toward the future, there is an opportunity to use word recurrence graphs to address complex questions that consider biological/social factors within a developmental perspective in typical and atypical contexts., (Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objectives: The present explorative study evaluates the question of media regulation in treatment and the question of psychoanalysts' experiences with digital crossings of boundaries. Methods: Using a self-constructed questionnaire, N = 50 completed questionnaires were distributed to psychoanalysts (age: M = 48,64, SD = 12,71; m = 44 %, f = 56 %) at the 51st IPA Congress held in July 2019 that were analyzed using aMann-Whitney U-test and Chi square test. Results: The majority of the psychoanalysts surveyed 68 %, (n = 34) do not regularly discuss the use ofmedia with their patients at the beginning of treatment, 28%(n = 14) of the analysts surveyed contacted their patients using digital media services without discussing this possibility of contact beforehand, 16 % (n = 8) contacted their patients at night, 46 %, n = 23 googled their patients and 24 %, (n = 12) secretly used a mobile phone during analysis. Conclusions: Due to the advancing technology of the health care system, further psychoanalytic research that accompanies the process of using media in treatment is necessary.

Summary: Maximum likelihood (ML) is a widely used phylogenetic inference method. ML implementations heavily rely on numerical optimization routines that use internal numerical thresholds to determine convergence. We systematically analyze the impact of these threshold settings on the log-likelihood and runtimes for ML tree inferences with RAxML-NG, IQ-TREE, and FastTree on empirical datasets. We provide empirical evidence that we can substantially accelerate tree inferences with RAxML-NG and IQ-TREE by changing the default values of two such numerical thresholds. At the same time, altering these settings does not significantly impact the quality of the inferred trees. We further show that increasing both thresholds accelerates the RAxML-NG bootstrap without influencing the resulting support values. For RAxML-NG, increasing the likelihood thresholds ϵ LnL and ϵ brlen to 10 and 10 3 , respectively, results in an average tree inference speedup of 1.9 ± 0.6 on Data collection 1 , 1.8 ± 1.1 on Data collection 2 , and 1.9 ± 0.8 on Data collection 2 for the RAxML-NG bootstrap compared to the runtime under the current default setting. Increasing the likelihood threshold ϵ LnL to 10 in IQ-TREE results in an average tree inference speedup of 1.3 ± 0.4 on Data collection 1 and 1.3 ± 0.9 on Data collection 2 ., Availability and Implementation: All MSAs we used for our analyses, as well as all results, are available for download at https://cme.h-its.org/exelixis/material/freeLunch&#95;data.tar.gz. Our data generation scripts are available at https://github.com/tschuelia/ml-numerical-analysis., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

Histone deacetylases (HDACs) play a key role in the control of transcription, cell proliferation, and migration. FDA-approved histone deacetylase inhibitors (HDACi) demonstrate clinical efficacy in the treatment of different T-cell lymphomas and multiple myeloma. However, due to unselective inhibition, they display a wide range of adverse effects. One approach to avoiding off-target effects is the use of prodrugs enabling a controlled release of the inhibitor in the target tissue. Herein, we describe the synthesis and biological evaluation of HDACi prodrugs with photo-cleavable protecting groups masking the zinc-binding group of the established HDACi DDK137 ( I ) and VK1 ( II ). Initial decaging experiments confirmed that the photocaged HDACi pc-I could be deprotected to its parent inhibitor I . In HDAC inhibition assays, pc-I displayed only low inhibitory activity against HDAC1 and HDAC6. After irradiation with light, the inhibitory activity of pc-I strongly increased. Subsequent MTT viability assays, whole-cell HDAC inhibition assays, and immunoblot analysis confirmed the inactivity of pc-I at the cellular level. Upon irradiation, pc-I demonstrated pronounced HDAC inhibitory and antiproliferative activities which were comparable to the parent inhibitor I . Additionally, only phototreated pc-I was able to induce apoptosis in Annexin V/PI and caspase-Glo 3/7 assays, making pc-I a valuable tool for the development of light-activatable HDACi.

Background: Early mobilization can help reduce severe side effects such as muscle atrophy that occur during hospitalization. However, due to time and staff shortages in intensive and critical care as well as safety risks for patients, it is often difficult to adhere to the recommended therapy time of twenty minutes twice a day. New robotic technologies might be one approach to achieve early mobilization effectively for patients and also relieve users from physical effort. Nevertheless, currently there is a lack of knowledge regarding the factors that are important for integrating of these technologies into complex treatment settings like intensive care units or rehabilitation units., Methods: European experts from science, technical development and end-users of robotic systems (n = 13) were interviewed using a semi-structured interview guideline to identify barriers and facilitating factors for the integration of robotic systems into daily clinical practice. They were asked about structural, personnel and environmental factors that had an impact on integration and how they had solved challenges. A latent content analysis was performed regarding the COREQ criteria., Results: We found relevant factors regarding the development, introduction, and routine of the robotic system. In this context, costs, process adjustments, a lack of exemptions, and a lack of support from the manufacturers/developers were identified as challenges. Easy handling, joint decision making between the end-users and the decision makers in the hospital, an accurate process design and the joint development of the robotic system of end-users and technical experts were found to be facilitating factors., Conclusion: The integration and preparation for the integration of robotic assistance systems into the inpatient setting is a complex intervention that involves many parties. This study provides evidence for hospitals or manufacturers to simplify the planning of integrations for permanent use., Trial Registration: DRKS-ID: DRKS00023848; registered 10/12/2020., (© 2023. The Author(s).)

Using a microwave-assisted protocol, we synthesized 16 peptoid-capped HDAC inhibitors (HDACi) with fluorinated linkers and identified two hit compounds. In biochemical and cellular assays, 10h stood out as a potent unselective HDACi with remarkable cytotoxic potential against different therapy-resistant leukemia cell lines. 10h demonstrated prominent antileukemic activity with low cytotoxic activity toward healthy cells. Moreover, 10h exhibited synergistic interactions with the DNA methyltransferase inhibitor decitabine in AML cell lines. The comparison of crystal structures of HDAC6 complexes with 10h and its nonfluorinated counterpart revealed a similar occupation of the L1 loop pocket but slight differences in zinc coordination. The substitution pattern of the acyl residue turned out to be crucial in terms of isoform selectivity. The introduction of an isopropyl group onto the phenyl ring provided the highly HDAC6-selective inhibitor 10p , which demonstrated moderate synergy with decitabine and exceeded the HDAC6 selectivity of tubastatin A.

Background: Early mobilization positively influences the outcome of critically ill patients, yet in clinical practice, the implementation is sometimes challenging. In this study, an adaptive robotic assistance system will be used for early mobilization in intensive care units. The study aims to evaluate the experience of the mobilizing professionals and the general feasibility of implementing robotic assistance for mobilization in intensive care as well as the effects on patient outcomes as a secondary outcome., Methods: The study is single-centric, prospective, and interventional and follows a longitudinal study design. To evaluate the feasibility of robotic-assisted early mobilization, the number of patients included, the number of performed VEM (very early mobilization) sessions, and the number and type of adverse events will be collected. The behavior and experience of mobilizing professionals will be evaluated using standardized observations (n > 90) and episodic interviews (n > 36) before implementation, shortly after, and in routine. Patient outcomes such as duration of mechanical ventilation, loss of muscle mass, and physical activity will be measured and compared with a historical patient population. Approximately 30 patients will be included., Discussion: The study will provide information about patient outcomes, feasibility, and the experience of mobilizing professionals. It will show whether robotic systems can increase the early mobilization frequency of critically ill patients. Within ICU structures, early mobilization as therapy could become more of a focus. Effects on the mobilizing professionals such as increased motivation, physical relief, or stress will be evaluated. In addition, this study will focus on whether current structures allow following the recommendation of mobilizing patients twice a day for at least 20 min., Trial Registration: ClinicalTrials.gov, NCT05071248 . Date: 2021/10/21., (© 2022. The Author(s).)

Objectives: Timely diagnosis of Alzheimer's disease (AD) is critical for appropriate treatment/patient management. Cerebrospinal fluid (CSF) biomarker analysis is often used to aid diagnosis. We assessed analytical performance of second-generation (Gen II) Elecsys ® CSF immunoassays (Roche Diagnostics International Ltd), and adjusted existing cut-offs, to evaluate their potential utility in clinical routine., Methods: Analytical performance was assessed using CSF samples measured with Elecsys CSF Gen II immunoassays on cobas e analyzers. Aβ42 Gen I/Gen II immunoassay method comparisons were performed (Passing-Bablok regression). Cut-off values were adjusted using estimated bias in biomarker levels between BioFINDER protocol aliquots/Gen I immunoassays and Gen II protocol aliquots/immunoassays. Distribution of Gen II immunoassay values was evaluated in AD, mild cognitive impairment (MCI), and cognitively normal cohorts; percentage observations outside the measuring range were derived., Results: The Gen II immunoassays demonstrated good analytical performance, including repeatability, intermediate precision, lot-to-lot agreement (Pearson's r: ≥0.999), and platform agreement (Pearson's r: ≥0.995). Aβ42 Gen I/Gen II immunoassay measurements were strongly correlated (Pearson's r: 0.985-0.999). Aβ42 Gen II immunoassay cut-offs were adjusted to 1,030 and 800 ng/L, and pTau181/Aβ42 ratio cut-offs to 0.023 and 0.029, for Gen II and I protocols, respectively. No observations were below the lower limit of the measuring range; above the upper limit, there were none from the AD cohort, and 2.6 and 6.8% from the MCI and cognitively normal cohorts, respectively., Conclusions: Our findings suggest that the Gen II immunoassays have potential utility in clinical routine to aid diagnosis of AD., (© 2022 the author(s), published by De Gruyter, Berlin/Boston.)

The targeted degradation of histone deacetylase 6 (HDAC6) by heterobifunctional degraders constitutes a promising approach to treat HDAC6-driven diseases. Previous HDAC6 selective degraders utilised a hydroxamic acid as a zinc-binding group (ZBG) which features mutagenic and genotoxic potential. Here we report the development of a new class of selective HDAC6 degraders based on a difluoromethyl-1,3,4-oxadiazole warhead as ZBG.

Purpose: The purpose of this study was to obtain insight into cellular processes after CyPass microstent implantation into the supraciliary space. With this knowledge, we expected to find some reason for surgical failure., Methods: Nine CyPass microstents of 8 patients with primary open-angle glaucoma (n = 1), pseudoexfoliation glaucoma (n = 5), uveitic glaucoma (n = 1), and posttraumatic open-angle glaucoma (n = 1) were explanted due to recurrence of IOP elevation, corneal decompensation, or persistent hypotony. The explants were processed for light and transmission electron microscopy., Results: Fibrotic material, consisting of collagen fibrils, microfibrils, pseudoexfoliation fibrils produced by activated fibroblasts, was detected in the stent lumen of 4/5 pseudoexfoliation glaucoma patients and also in posttraumatic open-angle glaucoma. Fibrotic material was also present on the outer surface and within fenestrations of the majority of stents. Complete absence of fibrotic reaction was noticed in 3 of 9 microstents., Conclusion: Although MIGS is known to be less invasive than conventional surgery, implants placed in the suprachoroidal space may be adversely affected by a fibrotic tissue reaction resulting in implant failure. Understanding mechanisms and risk factors leading to fibrotic scarring following antiglaucomatous surgery may help to develop novel strategies that improve surgical outcome., (© 2022. The Author(s).)

Constant exposure of the airways to inhaled pathogens requires efficient early immune responses protecting against infections. How bacteria on the epithelial surface are detected and first-line protective mechanisms are initiated are not well understood. We have recently shown that tracheal brush cells (BCs) express functional taste receptors. Here we report that bitter taste signaling in murine BCs induces neurogenic inflammation. We demonstrate that BC signaling stimulates adjacent sensory nerve endings in the trachea to release the neuropeptides CGRP and substance P that mediate plasma extravasation, neutrophil recruitment, and diapedesis. Moreover, we show that bitter tasting quorum-sensing molecules from Pseudomonas aeruginosa activate tracheal BCs. BC signaling depends on the key taste transduction gene Trpm5, triggers secretion of immune mediators, among them the most abundant member of the complement system, and is needed to combat P. aeruginosa infections. Our data provide functional insight into first-line defense mechanisms against bacterial infections of the lung.

Pseudoexfoliation (PEX) syndrome, a stress-induced fibrotic matrix process, is the most common recognizable cause of open-angle glaucoma worldwide. The recent identification of PEX-associated gene variants uncovered the vitamin A metabolic pathway as a factor influencing the risk of disease. In this study, we analyzed the role of the retinoic acid (RA) signaling pathway in the PEX-associated matrix metabolism and evaluated its targeting as a potential candidate for an anti-fibrotic intervention. We provided evidence that decreased expression levels of RA pathway components and diminished RA signaling activity occur in an antagonistic crosstalk with TGF-β1/Smad signaling in ocular tissues and cells from PEX patients when compared with age-matched controls. Genetic and pharmacologic modes of RA pathway inhibition induced the expression and production of PEX-associated matrix components by disease-relevant cell culture models in vitro. Conversely, RA signaling pathway activation by natural and synthetic retinoids was able to suppress PEX-associated matrix production and formation of microfibrillar networks via antagonization of Smad-dependent TGF-β1 signaling. The findings indicate that deficient RA signaling in conjunction with hyperactivated TGF-β1/Smad signaling is a driver of PEX-associated fibrosis, and that restoration of RA signaling may be a promising strategy for anti-fibrotic intervention in patients with PEX syndrome and glaucoma.

Herein we report the structure-activity and structure-physicochemical property relationships of a series of class I selective ortho-aminoanilides targeting the "foot-pocket" in HDAC1&2. To balance the structural benefits and the physicochemical disadvantages of these substances, we started with a set of HDACi related to tacedinaline (CI-994) and evaluated their solubility, lipophilicity (log D 7.4 ) and inhibition of selected HDAC isoforms. Subsequently, we selected the most promising "capless" HDACi and transferred its ZBG to our previously published scaffold featuring a peptoid-based cap group. The resulting hit compound 10 c (LSH-A54) showed favorable physicochemical properties and is a potent, selective HDAC1/2 inhibitor. The following evaluation of its slow binding properties revealed that LSH-A54 binds tightly to HDAC1 in an induced-fit mechanism. The potent HDAC1/2 inhibitory properties were reflected by attenuated cell migration in a modified wound healing assay and reduced cell viability in a clonogenic survival assay in selected breast cancer cell lines., (© 2022 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

The degree of acetylation of lysine residues on histones influences the accessibility of DNA and, furthermore, the gene expression. Histone deacetylases (HDACs) are overexpressed in various tumour diseases, resulting in the interest in HDAC inhibitors for cancer therapy. The aim of this work is the development of a novel 18F-labelled HDAC1/2-specific inhibitor with a benzamide-based zinc-binding group to visualize these enzymes in brain tumours by positron emission tomography (PET). BA3, exhibiting high inhibitory potency for HDAC1 (IC50 = 4.8 nM) and HDAC2 (IC50 = 39.9 nM), and specificity towards HDAC3 and HDAC6 (specificity ratios >230 and >2080, respectively), was selected for radiofluorination. The two-step one-pot radiosynthesis of [18F]BA3 was performed in a TRACERlab FX2 N radiosynthesizer by a nucleophilic aliphatic substitution reaction. The automated radiosynthesis of [18F]BA3 resulted in a radiochemical yield of 1%, a radiochemical purity of >96% and a molar activity between 21 and 51 GBq/µmol (n = 5, EOS). For the characterization of BA3, in vitro and in vivo experiments were carried out. The results of these pharmacological and pharmacokinetic studies indicate a suitable inhibitory potency of BA3, whereas the applicability for non-invasive imaging of HDAC1/2 by PET requires further optimization of the properties of this compound.

Acute cardiovascular exercise (aCE) seems to be a promising strategy to improve motor performance and learning. However, results are heterogeneous, and the related neurophysiological mechanisms are not well understood. Oscillatory brain activitiy, such as task-related power (TRPow) in the alpha and beta frequencies, are known neural signatures of motor activity. Here, we tested the effects of aCE on motor performance and learning, along with corresponding modulations in EEG TRPow over the sensorimotor cortex. Forty-five right-handed participants (aged 18-34 years) practiced a visuomotor force-matching (FM) task after either high-intensity (HEG), low-intensity (LEG), or no exercise (control group, CG). Motor performance was assessed immediately, 15 min, 30 min, and 24 h after aCE/control. EEG was measured during the FM task. Results of frequentist and Bayesian statistics revealed that high- and low-intensity aCE had no effect at the behavioral level, adding to the previous mixed results. Interestingly, EEG analyses showed an effect of aCE on the ipsilateral sensorimotor cortex, with a stronger decrease in β-TRPow 15 min after exercise in both groups compared to the CG. Overall, aCE applied before motor practice increased ipsilateral sensorimotor activity, while motor learning was not affected; it remains to be seen whether aCE might affect motor learning in the long run.

Motivation: Phylogenetic trees are now routinely inferred on large scale high performance computing systems with thousands of cores as the parallel scalability of phylogenetic inference tools has improved over the past years to cope with the molecular data avalanche. Thus, the parallel fault tolerance of phylogenetic inference tools has become a relevant challenge. To this end, we explore parallel fault tolerance mechanisms and algorithms, the software modifications required and the performance penalties induced via enabling parallel fault tolerance by example of RAxML-NG, the successor of the widely used RAxML tool for maximum likelihood-based phylogenetic tree inference., Results: We find that the slowdown induced by the necessary additional recovery mechanisms in RAxML-NG is on average 1.00 ± 0.04. The overall slowdown by using these recovery mechanisms in conjunction with a fault-tolerant Message Passing Interface implementation amounts to on average 1.7 ± 0.6 for large empirical datasets. Via failure simulations, we show that RAxML-NG can successfully recover from multiple simultaneous failures, subsequent failures, failures during recovery and failures during checkpointing. Recoveries are automatic and transparent to the user., Availability and Implementation: The modified fault-tolerant RAxML-NG code is available under GNU GPL at https://github.com/lukashuebner/ft-raxml-ng., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2021. Published by Oxford University Press.)

Multitarget drugs are an emerging alternative to combination therapies. In three iterative cycles of design, synthesis, and biological evaluation, we developed a novel type of potent hybrid inhibitors of bromodomain, and extra-terminal (BET) proteins and histone deacetylases (HDACs) based on the BET inhibitor XD14 and well-established HDAC inhibitors. The most promising new hybrids, 49 and 61 , displayed submicromolar inhibitory activity against HDAC1-3 and 6, and BRD4(1), and possess potent antileukemia activity. 49 induced apoptosis more effectively than the combination of ricolinostat and birabresib (1:1). The most balanced dual inhibitor, 61 , induced significantly more apoptosis than the related control compounds 62 (no BRD4(1) affinity) and 63 (no HDAC inhibition) as well as the 1:1 combination of both. Additionally, 61 was well tolerated in an in vivo zebrafish toxicity model. Overall, our data suggest an advantage of dual HDAC/BET inhibitors over the combination of two single targeted compounds.

Numerous studies covering some aspects of SARS-CoV-2 data analyses are being published on a daily basis, including a regularly updated phylogeny on nextstrain.org. Here, we review the difficulties of inferring reliable phylogenies by example of a data snapshot comprising a quality-filtered subset of 8,736 out of all 16,453 virus sequences available on May 5, 2020 from gisaid.org. We find that it is difficult to infer a reliable phylogeny on these data due to the large number of sequences in conjunction with the low number of mutations. We further find that rooting the inferred phylogeny with some degree of confidence either via the bat and pangolin outgroups or by applying novel computational methods on the ingroup phylogeny does not appear to be credible. Finally, an automatic classification of the current sequences into subclasses using the mPTP tool for molecular species delimitation is also, as might be expected, not possible, as the sequences are too closely related. We conclude that, although the application of phylogenetic methods to disentangle the evolution and spread of COVID-19 provides some insight, results of phylogenetic analyses, in particular those conducted under the default settings of current phylogenetic inference tools, as well as downstream analyses on the inferred phylogenies, should be considered and interpreted with extreme caution., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.)

Applications of laser-plasma accelerators demand low energy spread beams and high-efficiency operation. Achieving both requires flattening the accelerating fields by controlled beam loading of the plasma wave. Here, we optimize the generation of an electron bunch via localized ionization injection, such that the combination of injected current profile and averaged acceleration dynamics results in optimal beam loading conditions. This enables the reproducible production of 1.2% rms energy spread bunches with 282 MeV and 44 pC at an estimated energy-transfer efficiency of ∼19%. We correlate shot-to-shot variations to reveal the phase space dynamics and train a neural network that predicts the beam quality as a function of the drive laser.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Generating high-quality laser-plasma accelerated electron beams requires carefully balancing a plethora of physical effects and is therefore challenging-both conceptually and in experiments. Here, we use Bayesian optimization of key laser and plasma parameters to flatten the longitudinal phase space of an ionization-injected electron bunch via optimal beam loading. We first study the concept with particle-in-cell simulations and then demonstrate it in experiments. Starting from an arbitrary set point, the plasma accelerator autonomously tunes the beam energy spread to the subpercent level at 254 MeV and 4.7  pC/MeV spectral density. Finally, we study a robust regime, which improves the stability of the laser-plasma accelerator and delivers sub-five-percent rms energy spread beams for 90% of all shots.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Particularly during the early and middle stages of the COVID-19 pandemic, a population's compliance with precautionary measures (e.g., hygiene rules, smart working, travel restrictions, and quarantine) is paramount in preventing the virus from spreading. Objective: The investigation and documentation of different socio-demographic and personality-specific factors in regards to preventative measures and consequent specific health behaviors during the COVID-19 pandemic, based on the Health Belief Model. Method: An online survey was conducted on N = 3,006 individuals living in Germany and Austria during the early stages of lockdown. The questionnaire consisted of a self-administered section, exploring the dimensions posited in the Health Belief Model: perceived severity, perceived susceptibility, perceived barriers, perceived benefits of health-promoting measures, and engagement in health-promoting behaviors. Additionally, the following standardized scales were used to record personality determinants: the Stress Coping Style Questionnaire SVF 78 to evaluate coping and processing strategies in stressful circumstances, the Positive and Negative Affect Schedule (PANAS) to assess the emotional state induced by the coronavirus crisis, the UI-18 scale to diagnose the intolerance of uncertainty, and the State-Trait Anxiety Inventory (STAI) to assess anxiety. Results: In line with the Health Belief model, four groups were created based on perceived susceptibility and engagement in health-promoting behaviors, and consequently studied in relation to personality determinants. Those four groups differed significantly in regards to almost all personality dimensions ( p ≤ 0.005). Group 1 ( n = 450) shows a reduced engagement with protective measures and displays underestimation of the COVID-19-pandemic. Group 2 ( n = 984) displays many positive personality variables and high compliance with protective measures. Group 3 ( n = 468) perceives the subjective risk of disease as high, but high emotional discomfort and stress caused by the protective measures leads to the activation of a complex fear defense. Group 4 ( n = 1,004) is highly anxious and therefore compliant. Conclusion: This typification has implications for establishing the appropriate support systems. This is particularly important to encourage compliance with preventive regulations within the groups, which showed poor abidance for several reasons. For Group 1, further education on the realistic threat and efficient protective measures is as central as the fostering of empathy for others; with its resource-conscious exemplary behavior Group 2 could be used as a positive social role model. Group 3 would benefit from promoting self-care, while Group 4 requires information on psychosocial assistance availability in order to mitigate the high stress to which the group members are subjected., 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 © 2021 Eichenberg, Grossfurthner, Andrich, Hübner, Kietaibl and Holocher-Benetka.)

Empathy refers to the ability to understand the emotions of others. It encompasses a cognitive component of decoding a mental state, and an affective component that relates to an emotional response. Deficits in empathy have been associated with social dysfunction in depression. It is further assumed that impairments are aggravated when depression takes a chronic course. Existing evidence in the literature, however, is scarce and heterogeneous. The present study investigated empathy in patients with persistent and recurrent depression as well as in healthy controls (N = 102). Empathy measurements included both self-report (Interpersonal Reactivity Index, IRI) as well as a laboratory task (Multifaceted Empathy Task, MET). A mixed model analyses of covariance, which accounted for differences in executive functioning, found no evidence for impaired cognitive empathy in depression. All three groups performed equally well in understanding mental states. However, both IRI and MET confirmed the hypothesis of significant deficits in affective empathy. Patients reported higher personal distress than controls, and showed lower affective responses towards positive emotions in others. There was no difference between patient groups. Childhood maltreatment was further related to reduced affective empathy. The present results contribute to our understanding of social dysfunction in depression, since loss of emotional reactivity to the feelings of others is considered to reduce the desire to engage in social interaction, thus leading to isolation and aggravation of depression., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

There is increasing evidence that histone deacetylase (HDAC) inhibitors can (re)sensitize cancer cells for chemotherapeutics via "epigenetic priming". In this work, we describe the synthesis of a series of class I-selective HDAC inhibitors with 2-aminoanilides as zinc-binding groups. Several of the synthesized compounds revealed potent inhibition of the class I HDAC isoforms HDAC1, HDAC2, and/or HDAC3 and promising antiproliferative effects in the human ovarian cancer cell line A2780 and the human squamous carcinoma cell line Cal27. Selected compounds were investigated in a cellular model of platinum resistance. In particular, compound 2a revealed potent chemosensitizing properties and full reversal of cisplatin resistance in Cal27CisR cells. This effect is related to a synergistic increase in caspase 3/7 activation and induction of apoptosis. Thus, this work demonstrates that pan-HDAC inhibition or dual class I/class IIb inhibition is not required for full reversal of cisplatin resistance.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

It remains controversial whether aging influences motor learning and whether physiological factors, such as local strength or fitness, are associated with fine motor performance and learning in older adults (OA). OA ( n  = 51) and young adults (YA, n  = 31) performed a short-term motor learning session using a precision grip force modulation task. The rate of improvement of OA compared with YA was steeper with respect to performance variability and temporal precision. Both age groups showed positive transfer during an unpracticed variant of the force modulation task. Local muscle strength (pinch and grip strength) and high cardiovascular fitness positively predicted fine motor performance, whereas initial performance, muscle strength, and motor fitness (heterogeneous motor test battery) negatively predicted rate of improvement. Analyses indicated potentials, but also limits of plasticity for OA.

Moderate intensity cardiovascular exercise appears to provide a low-cost "intervention" on neurocognitive processes such as attentional control, yet the effects vary depending, for example, on cognitive task, time of testing, or exercise intensity. However, while a number of studies show that brief bouts of acute exercise can modulate behavioral indices of cognitive control, relatively few studies have attempted to identify the brain activity associated with these changes immediately following exercise. Here, we tested 11 young adults in a crossover design with a Flanker task at rest and immediately (within 2-3 minutes) following 20 minutes of acute exercise at 60% of the individual VO 2 max. In order to prevent delayed exercise effects that might confound or dilute immediate effects, a short version of the Flanker task (8 minutes) was chosen and an EEG was recorded simultaneously. The N2 and P3 ERP components were analyzed in addition to accuracy and response time. The N2 reflects conflict resolution, and the P3 has been linked to stimulus evaluation processes. No effect of exercise was found for behavioral data but P3 peak latencies were shorter following exercise as compared to rest. The N2 amplitude data suggest that exercise seems to prevent a decline in resources of attentional control over time. These data indicate that acute exercise, at a moderate intensity level, speeds up neural processing of attentional control by modulating stimulus evaluation processes immediately following exercise and that exercise helps maintain a steady level of neurocognitive resources.

Background: Various types of robots have already been successfully used in medical care, and the use of new technologies is also playing an increasing role in the area of sexuality. Sex robots are marketed as advanced sex toys and sex dolls with artificial intelligence. Only a few considerations about the therapeutic use of sex robots in sexual therapy are debated in expert discussions., Objective: The aim of this study was to conduct a first exploratory survey on the attitudes of sex therapists and physicians toward the therapeutic benefits of sex robots., Methods: This study comprised a quantitative online survey and a qualitative interview study. A self-constructed questionnaire was used to survey the general attitudes of sex therapists and physicians regarding the benefits of sex robots in therapy. The qualitative study was designed to gain in-depth insight into the participants' beliefs and attitudes. Therefore, semistructured interviews were conducted. The quantitative data were evaluated by statistical analysis, and the interviews were transcribed and analyzed by using a grounded theory approach., Results: A total of 72 sex therapists and physicians completed our self-constructed questionnaire (response rate 15%, 72/480). Only a few respondents (11%, 8/72) said that the use of sex robots was not conceivable for them, and almost half of all therapists and physicians could imagine recommending sex robots in therapy (45%, 33/72). The attitude toward sex robots as a therapeutic tool was very heterogeneous, with gender (P=.006), age (P=.03), and occupational differences (P=.05); female therapists, older therapists, and psychologists (in contrast to physicians) were more critical toward the therapeutic use of sex robots. The analysis of the 5 interviews identified 3 high-level core themes that were representative of the participants' responses: (1) the importance of the personal definition of sex robots for the assessment of their therapeutic benefits, (2) therapeutic benefits and dangers of sex robots, and (3) considerations on the quality of human-robot sexuality. Initial insights into the possible therapeutic use of sex robots in different disorders (eg, sexual dysfunction or pedophilia) and situations were gained from the perspective of sex therapists., Conclusions: The results of this study provide a first overview of the potential therapeutic use of sex robots. Moral, ethical, and treatment-related issues in this context are still unresolved and need to be further researched. We suggest integrating the topic into the training of sex therapists to form opinions beyond media images and to show therapy possibilities. Scientists engaged in sexual research should be involved in the development of sex robots to design robots with positive effects on sexual education, sexual therapy, sexual counseling, and sexual well-being for interested groups., (©Christiane Eichenberg, Marwa Khamis, Lisa Hübner. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 20.08.2019.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Four-dimensional (4D) flow magnetic resonance imaging (MRI) sequences with advanced parallel imaging have the potential to reduce scan time with equivalent image quality and accuracy compared with standard two-dimensional (2D) flow MRI. We compared 4D flow to standard 2D flow sequences using a constant and pulsatile flow phantom at 3 T., Methods: Two accelerated 4D flow sequences (GRAPPA2 and k-t-GRAPPA5) were evaluated regarding the concordance of flow volumes, flow velocities, and reproducibility as well as dependency on measuring plane and velocity encoding (V enc ). The calculated flow volumes and peak velocities of the phantom were used as reference standard. Flow analysis was performed using the custom-made software "Bloodline"., Results: No significant differences in flow volume were found between the 2D, both 4D flow MRI sequences, and the pump reference (p = 0.994) or flow velocities (p = 0.998) in continuous and pulsatile flow. An excellent correlation (R = 0.99-1.0) with a reference standard and excellent reproducibility of measurements (R = 0.99) was achieved for all sequences. A V enc overestimated by up to two times had no impact on flow measurements. However, misaligned measuring planes led to an increasing underestimation of flow volume and mean velocity in 2D flow accuracy, while both 4D flow measurements were not affected. Scan time was significantly shorter for k-t-GRAPPA5 (1:54 ± 0:01 min, mean ± standard deviation) compared to GRAPPA2 (3:56 ± 0:02 min) (p = 0.002)., Conclusions: Both 4D flow sequences demonstrated equal agreement with 2D flow measurements, without impact of V enc overestimation and plane misalignment. The highly accelerated k-t-GRAPPA5 sequence yielded results similar to those of GRAPPA2.