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Evidence-based design has been fundamental to designing healthcare environments for patient outcomes and experience, yet few studies have studied how design factors drive patient choice. 652 patients who recently received care at hospitals across the United States were administered an online discrete choice survey to investigate the factors playing into their choice between hypothetical hospitals. Discrete choice models are widely used to model patient preferences among treatment alternatives, but few studies have utilized this approach to investigate healthcare design alternatives. In the current study, respondents were asked to choose between hypothetical hospitals that differed in patient room design, window features of the room, appointment availability, distance from home, insurance coverage, and HCAHPS ratings. The results demonstrate that patient room design that allowed unobscured access to daylight and views through windows, in-network insurance coverage, closer distance from home, and one-star higher patient experience rating increased the likelihood of a patient's hospital choice. The study broadly explores discrete choice model's applicability to healthcare design and its ability to quantify patient perceptions with a metric meaningful for hospital administrators.

This study examined forces leading Korean cities to join the WHO Global Network of Age-Friendly Cities and Communities (AFCC) and implement the WHO guidelines, from the perspectives of multiple streams theory and policy transfer theory. We conducted interviews with stakeholders from six member cities and identified relevant themes using directed content analysis. Political motivation was the strongest factor in seeking Network membership, but the lack of political motivations after gaining membership resulted in lackluster local implementation efforts. The national capital cities may need to take a stronger leadership role to encourage the expansion of the WHO AFCC Network in Asia. [ABSTRACT FROM AUTHOR]

Growth arrest and DNA damage-inducible beta (GADD45b) plays a critical role in intracellular events such as cell growth and apoptosis. Although the functional study of GADD45b has been conducted, the mechanism for the transcriptional regulation of GADD45b is largely unknown. Due to the drastic induction of hepatic GADD45b mRNA by peroxisome proliferator-activated receptor alpha activation in wild-type mice, we investigated a key factor that affects the upregulation of GADD45b mRNA. Interestingly, we found that GADD45b-promoter luciferase activity was dramatically increased as the 5'-flanking regions were closer to the transcription start site in Hepa1c1c7 cells. Additionally, we found 2 E2F (E2F-myc activator/cell cycle regulator) binding motifs in the region (-150/-1) of the GADD45b promoter. Notably, E2F3 mRNA was significantly increased only in wild-type mice treated with WY-14643, a peroxisome proliferator-activated receptor alpha agonist, followed by the induction of GADD45b mRNA. Furthermore, gene functional studies and Chromatin Immunoprecipitation assays revealed that E2F3 could regulate the GADD45b gene via the E2F binding motif. Thus, we suggest that E2F3 may play a key role in regulating the GADD45b gene as a positive transcription factor., Competing Interests: Declaration of Competing Interests The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Object: We retrospectively analyzed clinical data to evaluate the safety and efficacy of single antiplatelet therapy (SAPT) after stent-assisted coil embolization (SAC) for ruptured cerebral aneurysms., Methods: In total, 176 stent-assisted coil embolization procedures were investigated. Among them, 77 ruptured and 99 unruptured aneurysms were grouped and compared respectively. In the ruptured group, only SAPT (aspirin) was administered after the procedure. Meanwhile, in the unruptured group, dual antiplatelet therapy (DAPT) (aspirin and clopidogrel) was administered before and after the procedure following standard guidelines. We compared both groups in regards to thromboembolic complications by analyzing post procedural diffusion-weighted images (DWI), hyperacute thrombosis during the procedure, and post-procedural symptoms., Results: The single antiplatelet therapy ruptured intracranial aneurysm (SAPT-RIA) group had 77 saccular aneurysms (62 ICA, 3 MCA, 4 ACA, 8 posterior circulation) with a mean diameter of 8.07 mm. The dual antiplatelet therapy unruptured intracranial aneurysm (DAPT-UIA) group had 99 aneurysms (81 ICA, 5 MCA, 3 ACA, 10 posterior circulation) with a mean diameter of 6.32 mm. DWI positivity rates were similar between groups, but hyperacute thrombosis was higher in the SAPT-RIA group (10.4%) compared to none in the DAPT-UIA group. Each group had one symptomatic complication., Conclusions: SAPT could be a viable option for the peri-procedural management of SAC in acutely ruptured cases.

Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges., Competing Interests: L.B-.L. and M.A.F. are inventors on a filed patent application covering the therapeutic use of the described compounds to block TRPM4. All other authors declare no conflicts of interest., (© 2024 The Author(s).)

Recently approved anti-amyloid immunotherapies for Alzheimer's disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing., Competing Interests: Competing interests J.T. has served as a consultant for the Neurotorium educational platform, outside of the scope of the submitted work. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, 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 Cellectricon, Fujirebio, Alzecure, Biogen and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program (outside submitted work). O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. R.C.P. has consulted for Roche, Genentech, Eli Lilly, Eisai and Nestle, all outside the scope of the current work. M.S.-C. has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and Grifols S.L.; has given lectures in symposia sponsored by Roche Diagnostics, S.L.U and Roche Farma, S.A.; and was granted with a project funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC). A.P.P. has served at advisory boards for Schwabe Farma Iberica. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). S. Johnson has served at scientific advisory boards or as a consultant for ALZpath, Prothena, Roche Diagnostics, and Enigma. M.M.M. has served as a consultant and at advisory boards for Biogen, Eisai, Lilly, Merck, Roche, and Siemens Healthineers. P.R.-N. has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. A.A.-S. has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics and Siemens Healthineers. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: Blood-based disease staging across the Alzheimer's disease (AD) continuum holds the promise to identify individuals that profit from disease-modifying therapies. We set out to identify Braak V + (Braak V and/or VI) tau PET-positive individuals within amyloid-β (Aβ)-positive individuals using plasma biomarkers., Methods: In this cross-sectional study, we assessed 289 individuals from the TRIAD cohort and 306 individuals from the WRAP study across the AD continuum. The participants were evaluated by amyloid-PET with [ 18 F]AZD4694 or [ 11 C]PiB and tau-PET with [ 18 F]MK6240 and measured plasma levels included total tau, phospho-tau isoforms (pTau) pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers using different analytic platforms to predict Braak V + positivity in Aβ+ individuals., Findings: Highest associations with Braak V + tau positivity in Aβ+ individuals were found for plasma pTau-217+ Janssen (AUC [CI 95% ] = 0.97 [0.94, 1.0]) and ALZpath pTau-217 (AUC [CI 95% ] = 0.93 [0.86, 1.0]) in TRIAD. Plasma ALZpath pTau-217 separated Braak V + tau PET-positive individuals in the WRAP longitudinal study (AUC [CI 95% ] = 0.97 [0.94, 1.0])., Interpretation: Thus, we demonstrate that using adjusted cut-offs, plasma pTau-217 identifies individuals with later Braak stage tau accumulation which will be helpful to stratify patients for treatments and clinical studies., Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR) [MOP-11-51-31; RFN 152985, 159815, 162303], Canadian Consortium of Neurodegeneration and Aging (CCNA; MOP-11-51-31 -team 1), the Alzheimer's Association [NIRG-12-92090, NIRP-12-259245], Brain Canada Foundation (CFI Project 34874; 33397), the Fonds de Recherche du Québec-Santé (FRQS; Chercheur Boursier, 2020-VICO-279314). P.R-N and SG are members of the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging. Colin J. Adair Charitable Foundation., Competing Interests: Declaration of interests H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, 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, 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). K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for Biogen, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H.C.K and G.T.B receive salary and stock from Janssen R&D. All other authors declare no conflicts of interest. E.M.J. served on DSMB for the NIA study K01 AG073587. S.G. received consulting fees as a member of the scientific advisory boards in Abbvie, Alzheon, AmyriAD, Eisai, Enigma/Meilleur, Lilly, Okutsa, Novo Nordisk, TauRx, honoraria for educational videos from Lundbeck, reimbursement for AD/PD 2024 travel expenses by TauRx. S.G. is board member at the Sharon and Robert Francis Foundation, Toronto, Canada, and the Canadian Conference on Dementia (CCD). S.C.J. received payment for consulting Enigma Biomedical and consulted ALZpath without payment. T.J.B. received funding from NIH/NIA (R01AG080766), personal honoraria from the NIH, Intermountain Healthcare, reimbursements for travel by University College London, Alzheimer's Association, and NIH. J.T. served as a Consultant for the Neurotorium Educational platform and for Alzheon. P.V. received consulting fees from Eisai, Novo Nordisk, honoraria from Astra, support for travelling by Lilly, and participated on DMSB for the IntelGenxCorp. Y.T.W. has written an educational article for the Neurotorium Educational platform. P.R.N. received consulting fees from Novo Nordisk, Eisai, and honoraria for an academic talk from Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Mucosal-associated invariant T (MAIT) cells express semi-invariant T cell receptors (TCR) for recognizing bacterial and yeast antigens derived from riboflavin metabolites presented on the non-polymorphic MHC class I-related protein 1 (MR1). Neuroinflammation in multiple sclerosis (MS) is likely initiated by autoreactive T cells and perpetuated by infiltration of additional immune cells, but the precise role of MAIT cells in MS pathogenesis remains unknown. Here, we use experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and find an accumulation of MAIT cells in the inflamed central nervous system (CNS) enriched for MAIT17 (RORγt + ) and MAIT1/17 (T-bet + RORγt + ) subsets with inflammatory and protective features. Results from transcriptome profiling and Nur77GFP reporter mice show that these CNS MAIT cells are activated via cytokines and TCR. Blocking TCR activation with an anti-MR1 antibody exacerbates EAE, whereas enhancing TCR activation with the cognate antigen, 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil, ameliorates EAE severity, potentially via the induction of amphiregulin (AREG). In summary, our findings suggest that TCR-mediated MAIT cell activation is protective in CNS inflammation, likely involving an induction of AREG., (© 2024. The Author(s).)

Fermented and aged mountain-cultivated ginseng sprouts (FAMCGS) exhibit superior antioxidant and anti-inflammatory properties compared to mountain-cultivated ginseng sprouts (MCGS). However, the mechanisms behind these properties of FAMCGSE remain unclear. This study explores the anti-inflammatory effects of FAMCGS extract (FAMCGSE) on LPS-stimulated RAW 264.7 macrophages and the underlying mechanisms. The MTT assay confirmed that FAMCGSE (0 to 0.1%) maintained cell viability without inducing morphological changes. Pretreatment with FAMCGSE significantly mitigated LPS-induced morphological alterations dose-dependently. RT-PCR and Western blot analyses showed that FAMCGSE significantly reduced the mRNA and protein levels of proinflammatory mediators such as TNF-α, IL-1β, IL-6, iNOS, and COX-2. Additionally, FAMCGSE decreased the production of TNF-α, IL-1β, IL-6, nitric oxide, and PGE 2 in LPS-activated RAW264.7 cells. Mechanistically, FAMCGSE inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs; ERK, p38, and JNK) and prevented the LPS-induced nuclear translocation of NF-κB, with effects comparable to compound K (CK) or dexamethasone. Notably, FAMCGSE was particularly effective in inhibiting ERK and JNK activation, with less impact on p38, suggesting a specific inhibitory action on certain MAPK pathways. These findings highlight FAMCGSE's potential as an inhibitor of MAPK and NF-κB pathways, indicating that FAMCGSE, including its main component CK, may be a promising therapeutic agent for inflammation-related conditions., Competing Interests: The authors declare no conflicts of interest. The funding sponsors did not influence the study design, data collection, analysis, interpretation, manuscript writing, or publication of the results., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)

Aneurysmal subarachnoid haemorrhage (aSAH) can lead to complications such as acute hydrocephalic congestion. Treatment of this acute condition often includes establishing an external ventricular drainage (EVD). However, chronic hydrocephalus develops in some patients, who then require placement of a permanent ventriculoperitoneal (VP) shunt. The aim of this study was to employ recurrent neural network (RNN)-based machine learning techniques to identify patients who require VP shunt placement at an early stage. This retrospective single-centre study included all patients who were diagnosed with aSAH and treated in the intensive care unit (ICU) between November 2010 and May 2020 (n = 602). More than 120 parameters were analysed, including routine neurocritical care data, vital signs and blood gas analyses. Various machine learning techniques, including RNNs and gradient boosting machines, were evaluated for their ability to predict VP shunt dependency. VP-shunt dependency could be predicted using an RNN after just one day of ICU stay, with an AUC-ROC of 0.77 (CI: 0.75-0.79). The accuracy of the prediction improved after four days of observation (Day 4: AUC-ROC 0.81, CI: 0.79-0.84). At that point, the accuracy of the prediction was 76% (CI: 75.98-83.09%), with a sensitivity of 85% (CI: 83-88%) and a specificity of 74% (CI: 71-78%). RNN-based machine learning has the potential to predict VP shunt dependency on Day 4 after ictus in aSAH patients using routine data collected in the ICU. The use of machine learning may allow early identification of patients with specific therapeutic needs and accelerate the execution of required procedures., (© 2024. The Author(s).)

Ovarian cysts are linked to hormone imbalances and altered gene expressions, but the connection between cysts and ion channel expression is understudied. This study explored the role of TWIK-related acid-sensitive K + (TASK) channels in bovine ovarian cyst formation. The ovarian follicles were split into small (5 to 10 mm in diameter) and large (>25 mm in diameter) groups. Among the measured K + , Na + , and Cl - concentrations in follicular fluid (FF) obtained from small-sized follicles (SFs) and large-sized follicles (LFs), the K + concentration was significantly lower in LFFF. Quantitative PCR, Western blot, and immunocytochemistry data revealed that TASK-3 expression levels significantly decreased by approximately 50% in LFs and granulosa cells obtained from LFs (LFGCs) compared to the corresponding controls. The TASK-3 protein was localized to the plasma membranes of GCs. The diameters of LFGCs were larger than those of SFGCs. The cell swelling response to exposure to a hypotonic solution (200 mOsm/L) was highly reduced in TASK-3-overexpressing cells compared to vector-transfected cells. TASK-3-knockdown cells showed arrested growth. Senescence markers were detected in LFGCs and TASK-3-knockdown cells. These findings suggest that reduced TASK-3 expression in LFs is associated with the inhibition of GC growth, leading to senescence and cyst formation.

Mangifera indica L., a member of the Anacardiaceae family, is widely cultivated across the globe. The leaves of M. indica are renowned for their medicinal properties, attributed to the abundance of bioactive compounds. This study investigated the effects of mango leaf extract on oxidative stress in HeLa cells. Notably, the n-hexane fraction (MLHx) significantly enhanced antioxidant response element (ARE)-luciferase activity at a concentration of 100 µg/mL, surpassing other fractions. MLHx also promoted the expression of HO-1 mRNA by increasing nuclear NRF2 levels. The molecular mechanism of MLHx involves increased phosphorylation of ERK1/2 and stabilization of NRF2. Bioactivity-guided isolation resulted in the identification of six oxylipins: 13(R)-hydroxy-octadeca-(9Z,11E,15Z)-trienoic acid ( C-1 ), 9(R)-hydroxy-octadeca-(10E,12Z,15Z)-trienoic acid ( C-2 ), 13(R)-hydroxy-(9Z,11E)-octadecadienoic acid ( C-3 ), 9(R)-hydroxy-(10E,12Z)-octadecadienoic acid ( C-4 ), 9-oxo-(10E,12E)-octadecadienoic acid ( C-5 ), and 9-oxo-(10E,12Z)-octadecadienoic acid ( C-6 ). These structures were elucidated using comprehensive spectroscopic techniques, including MS and 1H NMR. Additionally, compounds C-7 (9-oxo-(10E,12Z,15Z)-octadecatrienoic acid) and 8 (13-oxo-(9E,11E)-octadecadienoic acid) were characterized by LC-MS/MS mass fragmentation. This study reports the isolation of compounds 1-6 from M. indica for the first time. When tested for their effect on NRF2 activity in HeLa cells, compounds 3 , 5 , and 6 showed strong stimulation of ARE-luciferase activity in a dose-dependent manner.

Objective: Reconstruction methods, including stent-assisted coiling, multiple telescopic stents, and flow diverters, are preferred modalities for the treatment of unruptured vertebral artery dissecting aneurysms (VADAs). We aimed to compare the clinical outcomes between two reconstructive flow diversion techniques: single flow diverter (FD) device and multiple telescopic stenting (TS)., Methods: We retrospectively reviewed the clinical data of 39 patients with unruptured VADAs. Of these, 17 patients were treated with multiple TS and 22 with a single FD device. Aneurysm characteristics and clinical outcomes were compared between the two groups., Results: All aneurysms included in this study successfully achieved flow diversion, regardless of the treatment modality and duration. However, the mean procedure duration to complete the diversion was shorter in the FD group. Subgroup analysis in TS group showed that there were no significant clinical differences between the low-profile visualized intraluminal support and Enterprise stents, except for the mean procedure duration., Conclusions: Both the single FD and multiple TS methods showed excellent angiographic and clinical outcomes in the treatment of unruptured VADAs. However, single FD required a shorter procedure duration and was associated with faster achievement of complete flow diversion.

Introduction: Endovascular thrombectomy stands as a pivotal component in the standard care for patients experiencing acute ischemic stroke with large vessel occlusion. Subsequent care for patients often extends to a neurological intensive care unit. While fluid management is integral to intensive care, the association between early fluid balance and neurological and functional outcomes post-thrombectomy has not yet been thoroughly investigated., Methods: In a retrospective analysis of an observational, single-center study spanning from 2015 to 2021 at the University Medical Center Hamburg-Eppendorf, Germany, we enrolled stroke patients who underwent thrombectomy and received subsequent treatment in the ICU. Unfavorable functional and neurological outcome was defined as a mRS > 2 on day 90 after admission (mRS d90) or NIHSS > 5 at discharge, respectively. A multivariate regression model, adjusting for confounders, utilized the average fluid balance in the first 5 days to predict outcomes. Patients were dichotomized by their average fluid balance (>1 L vs <1 L) within the first 5 days, and a multivariate mRS d90 shift analysis was conducted after adjusting for covariates., Results: Between 2015 and 2021, 1252 patients underwent thrombectomy, and 553 patients met the inclusion criteria (299 women [54%]). Unfavorable functional outcome was significantly associated with a higher daily average fluid balance in the first 5 days in the ICU (mRS d90 ⩽ 2: 0.3 ± 0.5 L, mRS d90 > 2: 0.7 ± 0.7 L, p  = 0.02). The same association was observed for the NIHSS at discharge (NIHSS ⩽ 5: 0.3 ± 0.5 L; NIHSS > 5: 0.6 ± 0.6 L; p  = 0.03). The mRS d90 shift analysis revealed significance for patients with an average fluid balance <1 L for better functional outcomes (adjusted odds ratio [AOR] 2.17; 95% confidence interval [CI] 1.54-3.07; p  < 0.01)., Discussion: Fluid retention in post-thrombectomy stroke patients in the ICU is associated with poorer functional and neurological outcomes. Consequently, fluid retention emerges as an additional potential predictor for post-intervention stroke outcomes. Our findings provide an initial indication that preventing excessive fluid retention in stroke patients after endovascular thrombectomy could be beneficial for both functional and neurological recovery. Therefore, fluid retention might be an element to consider in optimizing fluid management for stroke patients., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors declare no competing interests and no conflict of interest. M.F. receives financial support from the External Research Program, Medtronic GmbH, unrelated to this work. CG reports personal fees from Amgen, Boehringer Ingelheim, Daiichi Sankyo, Abbott, Prediction Biosciences, Novartis, and Bayer outside the submitted work.

The disruption of astrocytic catabolic processes contributes to the impairment of amyloid-β (Aβ) clearance, neuroinflammatory signaling, and the loss of synaptic contacts in late-onset Alzheimer's disease (AD). While it is known that the posttranslational modifications of Aβ have significant implications on biophysical properties of the peptides, their consequences for clearance impairment are not well understood. It was previously shown that N-terminally pyroglutamylated Aβ3(pE)-42, a significant constituent of amyloid plaques, is efficiently taken up by astrocytes, leading to the release of pro-inflammatory cytokine tumor necrosis factor α and synapse loss. Here we report that Aβ3(pE)-42, but not Aβ1-42, gradually accumulates within the astrocytic endolysosomal system, disrupting this catabolic pathway and inducing the formation of heteromorphous vacuoles. This accumulation alters lysosomal kinetics, lysosome-dependent calcium signaling, and upregulates the lysosomal stress response. These changes correlate with the upregulation of glial fibrillary acidic protein (GFAP) and increased activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Treatment with a lysosomal protease inhibitor, E-64, rescues GFAP upregulation, NF-κB activation, and synapse loss, indicating that abnormal lysosomal protease activity is upstream of pro-inflammatory signaling and related synapse loss. Collectively, our data suggest that Aβ3(pE)-42-induced disruption of the astrocytic endolysosomal system leads to cytoplasmic leakage of lysosomal proteases, promoting pro-inflammatory signaling and synapse loss, hallmarks of AD-pathology., (© 2024 The Authors. GLIA published by Wiley Periodicals LLC.)

Inflammation-induced neurodegeneration is a defining feature of multiple sclerosis (MS), yet the underlying mechanisms remain unclear. By dissecting the neuronal inflammatory stress response, we discovered that neurons in MS and its mouse model induce the stimulator of interferon genes (STING). However, activation of neuronal STING requires its detachment from the stromal interaction molecule 1 (STIM1), a process triggered by glutamate excitotoxicity. This detachment initiates non-canonical STING signaling, which leads to autophagic degradation of glutathione peroxidase 4 (GPX4), essential for neuronal redox homeostasis and thereby inducing ferroptosis. Both genetic and pharmacological interventions that target STING in neurons protect against inflammation-induced neurodegeneration. Our findings position STING as a central regulator of the detrimental neuronal inflammatory stress response, integrating inflammation with glutamate signaling to cause neuronal cell death, and present it as a tractable target for treating neurodegeneration in MS., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pulmonary disorders affect 40%-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragm muscle weakness. Increased intradiaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs) - mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing the effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1-knockout (Thbs1-/-) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGF-β-related expression signatures and augmentation of a Thy1-expressing subpopulation previously linked to type 2 diabetes. Despite similar weight gain, Thbs1-/- mice were protected from these transcriptomic changes and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1-/- diaphragms maintained normal contractile force and motion after DIO challenge. THBS1 is therefore a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition and a potential therapeutic target in obesity-associated respiratory dysfunction.

Chronic low-grade inflammation and neuronal deregulation are two components of a smoldering disease activity that drives the progression of disability in people with multiple sclerosis (MS). Although several therapies exist to dampen the acute inflammation that drives MS relapses, therapeutic options to halt chronic disability progression are a major unmet clinical need. The development of such therapies is hindered by our limited understanding of the neuron-intrinsic determinants of resilience or vulnerability to inflammation. In this Review, we provide a neuron-centric overview of recent advances in deciphering neuronal response patterns that drive the pathology of MS. We describe the inflammatory CNS environment that initiates neurotoxicity by imposing ion imbalance, excitotoxicity and oxidative stress, and by direct neuro-immune interactions, which collectively lead to mitochondrial dysfunction and epigenetic dysregulation. The neuronal demise is further amplified by breakdown of neuronal transport, accumulation of cytosolic proteins and activation of cell death pathways. Continuous neuronal damage perpetuates CNS inflammation by activating surrounding glia cells and by directly exerting toxicity on neighbouring neurons. Further, we explore strategies to overcome neuronal deregulation in MS and compile a selection of neuronal actuators shown to impact neurodegeneration in preclinical studies. We conclude by discussing the therapeutic potential of targeting such neuronal actuators in MS, including some that have already been tested in interventional clinical trials., (© 2024. Springer Nature Limited.)

Acute lung injury (ALI) is a condition associated with acute respiratory failure, resulting in significant morbidity and mortality. It involves cellular changes such as disruption of the alveolar-capillary membrane, excessive neutrophil migration, and release of inflammatory mediators. Broncho-Vaxom ® (BV), a lyophilized product containing cell membrane components derived from eight bacteria commonly found in the respiratory tract, is known for its potential to reduce viral and bacterial lung infections. However, the specific effect of BV on ALI has not been clearly defined. This study explored the preventive effects of BV and its underlying mechanisms in a lipopolysaccharide (LPS)-induced ALI mouse model. Oral BV (1 mg/kg) gavage was administered one hour before the intratracheal injection of LPS to evaluate its preventive effect on the ALI model. The pre-administration of BV significantly mitigates inflammatory parameters, including the production of inflammatory mediators, macrophage infiltration, and NF-κB activation in lung tissue, and the increase in inflammatory cells in bronchoalveolar lavage fluid (BALF). Moreover, BV (3 μg/mL) pretreatment reduced the expression of M1 macrophage markers, interleukins (IL-1β, IL-6), tumor necrosis factor α, and cyclooxygenase-2, which are activated by LPS, in both mouse alveolar macrophage MH-S cells and human macrophage THP-1 cells. These findings showed that BV exhibits anti-inflammatory effects by suppressing inflammatory mediators through the NF-κB pathway, suggesting its potential to attenuate bronchial and pulmonary inflammation.

A disturbed balance between excitation and inhibition (E/I balance) is increasingly recognized as a key driver of neurodegeneration in multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system. To understand how chronic hyperexcitability contributes to neuronal loss in MS, we transcriptionally profiled neurons from mice lacking inhibitory metabotropic glutamate signaling with shifted E/I balance and increased vulnerability to inflammation-induced neurodegeneration. This revealed a prominent induction of the nuclear receptor NR4A2 in neurons. Mechanistically, NR4A2 increased susceptibility to excitotoxicity by stimulating continuous VGF secretion leading to glycolysis-dependent neuronal cell death. Extending these findings to people with MS (pwMS), we observed increased VGF levels in serum and brain biopsies. Notably, neuron-specific deletion of Vgf in a mouse model of MS ameliorated neurodegeneration. These findings underscore the detrimental effect of a persistent metabolic shift driven by excitatory activity as a fundamental mechanism in inflammation-induced neurodegeneration.

Background: Differences in immune responses between women and men are leading to a strong sex bias in the incidence of autoimmune diseases that predominantly affect women, such as multiple sclerosis (MS). MS manifests in more than twice as many women, making sex one of the most important risk factor. However, it is incompletely understood which genes contribute to sex differences in autoimmune incidence. To address that, we conducted a gene expression analysis in female and male human spleen and identified the transmembrane protein CD99 as one of the most significantly differentially expressed genes with marked increase in men. CD99 has been reported to participate in immune cell transmigration and T cell regulation, but sex-specific implications have not been comprehensively investigated., Methods: In this study, we conducted a gene expression analysis in female and male human spleen using the Genotype-Tissue Expression (GTEx) project dataset to identify differentially expressed genes between women and men. After successful validation on protein level of human immune cell subsets, we assessed hormonal regulation of CD99 as well as its implication on T cell regulation in primary human T cells and Jurkat T cells. In addition, we performed in vivo assays in wildtype mice and in Cd99-deficient mice to further analyze functional consequences of differential CD99 expression., Results: Here, we found higher CD99 gene expression in male human spleens compared to females and confirmed this expression difference on protein level on the surface of T cells and pDCs. Androgens are likely dispensable as the cause shown by in vitro assays and ex vivo analysis of trans men samples. In cerebrospinal fluid, CD99 was higher on T cells compared to blood. Of note, male MS patients had lower CD99 levels on CD4 + T cells in the CSF, unlike controls. By contrast, both sexes had similar CD99 expression in mice and Cd99-deficient mice showed equal susceptibility to experimental autoimmune encephalomyelitis compared to wildtypes. Functionally, CD99 increased upon human T cell activation and inhibited T cell proliferation after blockade. Accordingly, CD99-deficient Jurkat T cells showed decreased cell proliferation and cluster formation, rescued by CD99 reintroduction., Conclusions: Our results demonstrate that CD99 is sex-specifically regulated in healthy individuals and MS patients and that it is involved in T cell costimulation in humans but not in mice. CD99 could potentially contribute to MS incidence and susceptibility in a sex-specific manner., (© 2024. The Author(s).)

Introduction: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers., Methods: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [ 18 F]AZD4694 and tau-PET with [ 18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals., Results: Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau-217 (AUC [CI 95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI 95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI 95%  = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity., Discussion: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice., Highlights: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau 181 , p-tau 217 and p-tau 231 with established immunoassay techniques., Methods: We measured p-tau 181 , p-tau 217 and p-tau 231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau 181 , p-tau 217 and p-tau 231 . P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity., Results: Mass spectrometry and immunoassays of p-tau 217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau 181 and p-tau 231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays., Conclusions: Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification., (© 2023. The Author(s).)

Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears., Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages., Results: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss., Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation., (© 2023. The Author(s).)

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, the roll-out of vaccines and therapeutic agents, as well as the emergence of novel SARS-CoV-2 variants, have shown significant effects on disease severity., Methods: Patients hospitalized at our center between January 2020 and April 2022 were attributed to subgroups depending on which SARS-CoV-2 variant was predominantly circulating in Germany: (i) Wild-type: January 1, 2020, to March 7, 2021, (ii) Alpha variant: August 3, 2021, to June 27, 2021, (iii) Delta variant: June 28, 2021, to December 26, 2021, and (iv) Omicron variant: December 27, 2021, to April 30, 2022., Results: Between January 2020 and April 2022, 1500 patients with SARS-CoV-2 infections were admitted to the University Medical Center Hamburg-Eppendorf. The rate of patients who were admitted to the intensive care unit (ICU) decreased from 31.2% (n = 223) in the wild-type group, 28.5% (n = 72) in the Alpha variant group, 18.8% (n = 67) in the Delta variant group, and 13.4% (n = 135) in the Omicron variant group. Also, in-hospital mortality decreased from 20.6% (n = 111) in the wild-type group, 17.5% (n = 30) in the Alpha variant group, 16.8% (n = 33) in the Delta variant group, and 6.6% (n = 39) in the Omicron variant group. The median duration of hospitalization was similar in all subgroups and ranged between 11 and 15 days throughout the pandemic., Conclusions: In-hospital mortality and rate of ICU admission among hospitalized COVID-19 patients steadily decreased throughout the pandemic. However, the practically unchanged duration of hospitalization demonstrates the persistent burden of COVID-19 on the healthcare system., Competing Interests: Declaration of Competing Interest S. Kluge received research support from Cytosorbents and Daiichi Sankyo. He also received lecture fees from ADVITOS, Biotest, Daiichi Sankyo, Fresenius Medical Care, Gilead, Mitsubishi Tanabe Pharma, MSD, Pfizer and Zoll. He received consultant fees from Fresenius, Gilead, MSD and Pfizer., (Copyright © 2023. Published by Elsevier Ltd.)

Migratory dendritic cells (migDCs) continuously patrol tissues and are activated by injury and inflammation. Extracellular adenosine triphosphate (ATP) is released by damaged cells or actively secreted during inflammation and increases migDC motility. However, the underlying molecular mechanisms by which ATP accelerates migDC migration is not understood. Here, we show that migDCs can be distinguished from other DC subsets and immune cells by their expression of the voltage-gated calcium channel subunit β3 (Cavβ3; CACNB3), which exclusively facilitates ATP-dependent migration in vitro and during tissue damage in vivo. By contrast, CACNB3 does not regulate lipopolysaccharide-dependent migration. Mechanistically, CACNB3 regulates ATP-dependent inositol 1,4,5-trisphophate receptor-controlled calcium release from the endoplasmic reticulum. This, in turn, is required for ATP-mediated suppression of adhesion molecules, their detachment, and initiation of migDC migration. Thus, Cacnb3 -deficient migDCs have an impaired migration after ATP exposure. In summary, we identified CACNB3 as a master regulator of ATP-dependent migDC migration that controls tissue-specific immunological responses during injury and inflammation.

Dysautonomia has substantially impacted acute COVID-19 severity as well as symptom burden after recovery from COVID-19 (long COVID), yet the underlying causes remain unknown. Here, we hypothesized that vagus nerves are affected in COVID-19 which might contribute to autonomic dysfunction. We performed a histopathological characterization of postmortem vagus nerves from COVID-19 patients and controls, and detected SARS-CoV-2 RNA together with inflammatory cell infiltration composed primarily of monocytes. Furthermore, we performed RNA sequencing which revealed a strong inflammatory response of neurons, endothelial cells, and Schwann cells which correlated with SARS-CoV-2 RNA load. Lastly, we screened a clinical cohort of 323 patients to detect a clinical phenotype of vagus nerve affection and found a decreased respiratory rate in non-survivors of critical COVID-19. Our data suggest that SARS-CoV-2 induces vagus nerve inflammation followed by autonomic dysfunction which contributes to critical disease courses and might contribute to dysautonomia observed in long COVID., (© 2023. The Author(s).)

Pulmonary disorders impact 40-80% of individuals with obesity. Respiratory muscle dysfunction is linked to these conditions; however, its pathophysiology remains largely undefined. Mice subjected to diet-induced obesity (DIO) develop diaphragmatic weakness. Increased intra-diaphragmatic adiposity and extracellular matrix (ECM) content correlate with reductions in contractile force. Thrombospondin-1 (THBS1) is an obesity-associated matricellular protein linked with muscular damage in genetic myopathies. THBS1 induces proliferation of fibro-adipogenic progenitors (FAPs)-mesenchymal cells that differentiate into adipocytes and fibroblasts. We hypothesized that THBS1 drives FAP-mediated diaphragm remodeling and contractile dysfunction in DIO. We tested this by comparing effects of dietary challenge on diaphragms of wild-type (WT) and Thbs1 knockout ( Thbs1 -/- ) mice. Bulk and single-cell transcriptomics demonstrated DIO-induced stromal expansion in WT diaphragms. Diaphragm FAPs displayed upregulation of ECM and TGFβ-related expression signatures, and augmentation of a Thy1 -expressing sub-population previously linked to type 2 diabetes. Despite similar weight gain, Thbs1 -/- mice were protected from these transcriptomic changes, and from obesity-induced increases in diaphragm adiposity and ECM deposition. Unlike WT controls, Thbs1 -/- diaphragms maintained normal contractile force and motion after DIO challenge. These findings establish THBS1 as a necessary mediator of diaphragm stromal remodeling and contractile dysfunction in overnutrition, and potential therapeutic target in obesity-associated respiratory dysfunction.

Background and Purpose: This study aimed to investigate if pre-existing neurological conditions, such as dementia and a history of cerebrovascular disease, increase the risk of severe outcomes including death, intensive care unit (ICU) admission and vascular events in patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in 2022, when Omicron was the predominant variant., Methods: A retrospective analysis was conducted of all patients with SARS-CoV-2 infection, confirmed by polymerase chain reaction test, admitted to the University Medical Center Hamburg-Eppendorf from 20 December 2021 until 15 August 2022. In all, 1249 patients were included in the study. In-hospital mortality was 3.8% and the ICU admission rate was 9.9%. Ninety-three patients with chronic cerebrovascular disease and 36 patients with pre-existing all-cause dementia were identified and propensity score matching by age, sex, comorbidities, vaccination status and dexamethasone treatment was performed in a 1:4 ratio with patients without the respective precondition using nearest neighbor matching., Results: Analysis revealed that neither pre-existing cerebrovascular disease nor all-cause dementia increased mortality or the risk for ICU admission. All-cause dementia in the medical history also had no effect on vascular complications under investigation. In contrast, an increased odds ratio for both pulmonary artery embolism and secondary cerebrovascular events was observed in patients with pre-existing chronic cerebrovascular disease and myocardial infarction in the medical history., Conclusion: These findings suggest that patients with pre-existing cerebrovascular disease and myocardial infarction in their medical history may be particularly susceptible to vascular complications following SARS-CoV-2 infection with presumed Omicron variant., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Unpredictable vegetative deteriorations made the treatment of patients with acute COVID-19 on intensive care unit particularly challenging during the first waves of the pandemic. Clinical correlates of dysautonomia and their impact on the disease course in critically ill COVID-19 patients are unknown., Methods: We retrospectively analyzed data collected during a single-center observational study (March 2020-November 2021) which was performed at the University Medical Center Hamburg-Eppendorf, a large tertiary medical center in Germany. All patients admitted to ICU due to acute COVID-19 disease during the study period were included (n = 361). Heart rate variability (HRV) and blood pressure variability (BPV) per day were used as clinical surrogates of dysautonomia and compared between survivors and non-survivors at different time points after admission. Intraindividual correlation of vital signs with laboratory parameters were calculated and corrected for age, sex and disease severity., Results: Patients who deceased in ICU had a longer stay (median days ± IQR, survivors 11.0 ± 27.3, non-survivors 14.1 ± 18.7, P = 0.85), in contrast time spent under invasive ventilation was not significantly different (median hours ± IQR, survivors 322 ± 782, non-survivors 286 ± 434, P = 0.29). Reduced HRV and BPV predicted lethal outcome in patients staying on ICU longer than 10 days after adjustment for age, sex, and disease severity. Accordingly, HRV was significantly less correlated with inflammatory markers (e.g. CRP and Procalcitonin) and blood carbon dioxide in non-survivors in comparison to survivors indicating uncoupling between autonomic function and inflammation in non-survivors., Conclusions: Our study suggests autonomic dysfunction as a contributor to mortality in critically ill COVID-19 patients during the first waves of the pandemic. Serving as a surrogate for disease progression, these findings could contribute to the clinical management of COVID-19 patients admitted to the ICU. Furthermore, the suggested measure of dysautonomia and correlation with other laboratory parameters is non-invasive, simple, and cost-effective and should be evaluated as an additional outcome parameter in septic patients treated in the ICU in the future., (© 2023. The Author(s).)

Persistent somatic and neuropsychiatric symptoms have been frequently described in patients after infection with severe acute respiratory syndrome coronavirus 2 even after a benign clinical course of the acute infection during the early phases of the coronavirus severe acute respiratory syndrome coronavirus 2 pandemic and are part of Long COVID. The Omicron variant emerged in November 2021 and has rapidly become predominant due to its high infectivity and suboptimal vaccine cross-protection. The frequency of neuropsychiatric post-acute sequelae after infection with the severe acute respiratory syndrome coronavirus 2 Omicron and adequate vaccination status is not known. Here, we aimed to characterize post-acute symptoms in individuals with asymptomatic or mildly symptomatic breakthrough infection with severe acute respiratory syndrome coronavirus 2. These individuals had either proven infection with the Omicron variant ( n = 157) or their infection occurred in 2022 where Omicron was the predominant variant of severe acute respiratory syndrome coronavirus 2 in Germany ( n = 107). This monocentric cross-sectional study was conducted at the University Medical Center Hamburg-Eppendorf between 11 February 2022 and 11 April 2022. We employed questionnaires addressing self-reported somatic symptom burden (Somatic Symptom Scale 8) and neuropsychiatric symptoms including mood (Patient Health Questionnaire 2), anxiety (Generalized Anxiety Disorder 7), attention (Mindful Attention Awareness Scale) and fatigue (Fatigue Assessment Scale) in a cohort of hospital workers. Scores were compared between 175 individuals less than 4 weeks after positive testing for severe acute respiratory syndrome coronavirus 2, 88 individuals more than 4 weeks after positive testing and 87 severe acute respiratory syndrome coronavirus 2 uninfected controls. The majority ( n = 313; 89.5%) of included individuals were vaccinated at least three times. After recovery from infection, no significant differences in scores assessing neuropsychiatric and somatic symptoms were detected between the three groups (severe acute respiratory syndrome coronavirus 2 uninfected controls, individuals less and more than 4 weeks after positive testing) independent of age, sex, preconditions and vaccination status. In addition, self-reported symptom burden did not significantly correlate with the number of vaccinations against severe acute respiratory syndrome coronavirus 2, time from recovery or the number of infections. Notably, in all three groups, the mean scores for each item of our questionnaire lay below the pathological threshold. Our data show that persistent neuropsychiatric and somatic symptoms after recovery from severe acute respiratory syndrome coronavirus 2 infection in fully vaccinated hospital workers do not occur more frequently than that in uninfected individuals. This will guide healthcare professionals in the clinical management of patients after recovery from breakthrough infections with severe acute respiratory syndrome coronavirus 2., Competing Interests: The authors declare no competing interests and no conflict of interest. MAF received honoraria for consultation and travel expenses from Biogen, Merck KGaA, Novartis and Roche unrelated to this work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Synaptic dysfunction caused by soluble β-amyloid peptide (Aβ) is a hallmark of early-stage Alzheimer's disease (AD), and is tightly linked to cognitive decline. By yet unknown mechanisms, Aβ suppresses the transcriptional activity of cAMP-responsive element-binding protein (CREB), a master regulator of cell survival and plasticity-related gene expression. Here, we report that Aβ elicits nucleocytoplasmic trafficking of Jacob, a protein that connects a NMDA-receptor-derived signalosome to CREB, in AD patient brains and mouse hippocampal neurons. Aβ-regulated trafficking of Jacob induces transcriptional inactivation of CREB leading to impairment and loss of synapses in mouse models of AD. The small chemical compound Nitarsone selectively hinders the assembly of a Jacob/LIM-only 4 (LMO4)/ Protein phosphatase 1 (PP1) signalosome and thereby restores CREB transcriptional activity. Nitarsone prevents impairment of synaptic plasticity as well as cognitive decline in mouse models of AD. Collectively, the data suggest targeting Jacob protein-induced CREB shutoff as a therapeutic avenue against early synaptic dysfunction in AD., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

In vitro data suggest the monoclonal antibody sotrovimab may have lost inhibitory capability against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant. We aimed to provide real-life data on clinical outcomes in hospitalized patients. We retrospectively analyzed patients who were treated at the University Medical Center Hamburg-Eppendorf, Germany, between December 2021 and June 2022. Out of all 1,254 patients, 185 were treated with sotrovimab: 147 patients received sotrovimab monotherapy, and 38 received combination treatment with sotrovimab and remdesivir. We compared in-hospital mortality for the different treatment regimens for patients treated on regular wards and the intensive care unit separately and performed propensity score matching by age, sex, comorbidities, immunosuppression, and additional dexamethasone treatment to select patients who did not receive antiviral treatment for comparison. No difference in in-hospital mortality was observed between any of the treatment groups and the respective control groups. These findings underline that sotrovimab adds no clinical benefit for hospitalized patients with SARS-CoV-2 Omicron variant infections. IMPORTANCE This study shows that among hospitalized patients with SARS-CoV-2 Omicron variant infection at risk of disease progression, treatment with sotrovimab alone or in combination with remdesivir did not decrease in-hospital mortality. These real-world clinical findings in combination with previous in vitro data about lacking neutralizing activity of sotrovimab against SARS-CoV-2 Omicron variant do not support sotrovimab as a treatment option in these patients.

The accurate assessment of cerebrospinal fluid opening pressure during spinal puncture provides important medical information in diagnosis, prognosis and therapy of several neurological conditions. However, purpose-specific spinal needle choice is debated. While atraumatic needles are associated with lower incidence of post-puncture headache and re-hospitalisation, some clinicians believe that they lack in accuracy of CSF opening pressure assessment. Our primary objective was to investigate different needle types on correctly assessing CSF opening pressure. We compared typical clinically utilised traumatic (0.9 mm outer diameter) and atraumatic (0.7 mm; 0.45 mm) spinal needles with regards to the assessment of the opening pressure in an experimental spinal puncture model testing experimental and cerebrospinal fluids in predefined pressures. Our goal was to measure the time until indicated pressure levels were correctly shown. Atraumatic needles of at least 0.7 mm diameter had a similar accuracy as traumatic needles without significant differences in time-to-equilibrium. These results were independent of protein and glucose concentration and the presence of haemoglobin. This study demonstrates that atraumatic needles can be used to accurately measure CSF opening pressure. This knowledge might guide clinicians in their choice of needle and help to reduce post-puncture headaches and re-hospitalisation., (© 2022. The Author(s).)

The association between asthma and oxidative stress remains controversial. Oxidative stress-induced ferroptosis has not been extensively studied in asthma models. This study was performed to investigate the anti-asthmatic and anti-ferroptotic effects of fermented and aged ginseng sprouts (FAGS) with enhanced antioxidant activity and its main component, compound K (CK), in a mouse model of ovalbumin (OVA)-induced allergic asthma. The experimental asthma model was sensitized and challenged with OVA. During the challenge period, two different concentrations of FAGS and CK were administered via oral gavage. Asthmatic parameters were analyzed in bronchoalveolar lavage fluid (BALF), blood, and lung tissue. CK, among the ginsenosides analyzed, was highly increased in FAGS compared with GS. Asthma parameters, such as Th2 cytokine and IgE production, mast cell activation, goblet cell hyperplasia, hyperresponsiveness, and inflammation, were dramatically increased in the OVA group. Oxidation and ferroptosis markers were increased in the OVA group. The asthma parameters and ferroptosis markers were markedly decreased in the OVA + FAGS and OVA + CK groups. These results showed that FAGS and CK alleviated asthma parameters in an allergic asthma mouse model by inhibiting inflammation and ferroptosis. Our findings suggest that FAGS and CK could be used as potential treatments for allergic asthma.

Neuroinflammation leads to neuronal stress responses that contribute to neuronal dysfunction and loss. However, treatments that stabilize neurons and prevent their destruction are still lacking. Here, we identify the histone methyltransferase G9a as a druggable epigenetic regulator of neuronal vulnerability to inflammation. In murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS), we found that the G9a-catalyzed repressive epigenetic mark H3K9me2 was robustly induced by neuroinflammation. G9a activity repressed anti-ferroptotic genes, diminished intracellular glutathione levels, and triggered the iron-dependent programmed cell death pathway ferroptosis. Conversely, pharmacological treatment of EAE mice with a G9a inhibitor restored anti-ferroptotic gene expression, reduced inflammation-induced neuronal loss, and improved clinical outcome. Similarly, neuronal anti-ferroptotic gene expression was reduced in MS brain tissue and was boosted by G9a inhibition in human neuronal cultures. This study identifies G9a as a critical transcriptional enhancer of neuronal ferroptosis and potential therapeutic target to counteract inflammation-induced neurodegeneration.

Purpose: This study aimed to describe clinical nurses' lived experiences of workplace verbal violence through qualitative research using descriptive phenomenology., Methods: Six female Korean nurses who had less than 5 years of clinical experience and had experienced verbal violence in the workplace within the past year participated in the study. Data were collected through one-on-one in-depth interviews with the participants and analyzed using Colaizzi's phenomenological method., Results: A total of 27 codes, eight themes, and four theme clusters were derived from the participants' statements. The four theme clusters of the clinical nurses' experiences of verbal violence in the workplace were as follows: "tip of the iceberg," "beyond me and my control," "fear and resignation," and "personal burden." The participants recognized that nurses experienced verbal violence daily, and that the causes of and responses to verbal violence were determined by external situational factors rather than nurses' individual problems. This suggests that nurses felt that they had no choice but to personally cope with verbal violence and bear the consequences due to systematic indifference and silence about verbal violence experienced by clinical nurses., Conclusion: The findings show that verbal violence was pervasive and unmerited, yet often endured at the cost of a personal burden to nurses. A clear definition of verbal violence and education for employees are needed, and a reporting system should be established to report all forms of violence regardless of the severity of the incident., Competing Interests: Conflict of interest The authors declared no conflict of interest., (Copyright © 2022 Korean Society of Women Health Nursing.)

Garlic, a once-a-year crop, is mass-produced in a single event. Most of the garlic harvested during the year, unless consumed or processed immediately, should be stored. Stored raw garlic (SRG) can be used to make black garlic (BG) via aging, and storage may affect the properties and quality of the BG compared with the use of raw garlic that has not been stored. This study was performed to identify the effect of long-term storage of raw garlic on the quality of BG products. SRG was aged for 21 days at 40-86 °C for BG production. Moisture content and pH gradually decreased with the aging period. Total phenolic, total flavonoid, and fructose contents were significantly increased during the aging period. Compared with non-stored raw garlic (NSRG), alliin and S-allylcysteine (SAC) contents were 1.7-fold and 5.9-fold higher in SRG, respectively, and γ-glutamyl-S-allylcysteine (γ-GSAC) content was 2.8-fold lower in SRG. The contents of alliin and γ-GSAC reduced as the aging period of SRG and NSRG progressed. However, the SAC content of NSRG increased with aging, but the SAC content of SRG decreased or increased slightly with extended aging. The antioxidant activity was also higher in BG made from NSRG rather than SRG. These results show that the SAC content is relatively low in BG manufactured from SRG compared with NSRG. Our findings suggest that it is necessary to establish an aging method suitable for SRG in BG production with high SAC content, a representative indicator of BG.

Our previous study showed that oyster hydrolysate (OH) protected against the liver damage caused by a single instance of ethanol (EtOH) binge drinking. Oyster broth concentrate (OBC) was discovered in the process of searching for a different substance derived from oysters ( Crassostrea gigas ) with economic value. OBC is a by-product of boiling oysters at 95°C for 3 min. In this study, we investigated the effects of OBC and its major component taurine on blood and liver tissues obtained from a single-EtOH-binge-drinking mouse model. The preadministration of OBC enhanced EtOH metabolism by increasing the activities of alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and catalase. In addition, the preadministration of OBC reduced cytochrome P450 2E1 (CYP2E1) activity, reactive oxygen species (ROS) generation, Ca 2+ concentrations, apoptotic signals, and inflammatory mediators in liver tissues. The reduction of apoptotic and inflammatory signals by OBC resulted from the downregulation of endoplasmic reticulum (ER) stress molecules and NF-κB activity. Taurine administration showed similar effects to OBC. These results show that OBC protected against acute EtOH-induced liver damage through the action of taurine. Our findings suggest that OBC could be an economically valuable substance and a functional food with hepatoprotective effects., Competing Interests: The authors declare no conflicts of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of the data; in the writing of the manuscript; or in the decision to publish the results., (© 2022 The Authors. Food Science & Nutrition published by Wiley Periodicals LLC.)

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Models created by the intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN) have been widely used to study the pathogenesis of human acute liver failure (ALF) and drug development. Our previous study reported that oyster (Crassostrea gigas) hydrolysate (OH) had a hepatoprotective effect in LPS/D-GalN-injected mice. This study was performed to identify the hepatoprotective effect of the tyrosine-alanine (YA) peptide, the main component of OH, in a LPS/D-GalN-injected ALF mice model. We analyzed the effect of YA on previously known mechanisms of hepatocellular injury in the model. LPS/D-GalN-injected mice showed inflammatory, apoptotic, ferroptotic, and pyroptotic liver injury. The pre-administration of YA (10 mg/kg or 50 mg/kg) significantly reduced the liver damage factors. The hepatoprotective effect of YA was higher in the 50 mg/kg YA pre-administered group than in the 10 mg/kg YA pre-administered group. These results showed that YA had a hepatoprotective effect by reducing inflammation, apoptosis, ferroptosis, and pyroptosis in the LPS/D-GalN-injected ALF mouse model. We suggest that YA can be used as a functional peptide for the prevention of acute liver injury.

Background: Cystic fibrosis (CF) patients present with a variety of symptoms, including mood and cognition deficits, in addition to classical respiratory, and autonomic issues. This suggests that brain injury, which can be examined with non-invasive magnetic resonance imaging (MRI), is a manifestation of this condition. However, brain tissue integrity in sites that regulate cognitive, autonomic, respiratory, and mood functions in CF patients is unclear. Our aim was to assess regional brain changes using high-resolution T1-weighted images based gray matter (GM) density and T2-relaxometry procedures in CF over control subjects., Methods: We acquired high-resolution T1-weighted images and proton-density (PD) and T2-weighted images from 5 CF and 15 control subjects using a 3.0-Tesla MRI. High-resolution T1-weighted images were partitioned to GM-tissue type, normalized to a common space, and smoothed. Using PD- and T2-weighted images, whole-brain T2-relaxation maps were calculated, normalized, and smoothed. The smoothed GM-density and T2-relaxation maps were compared voxel-by-voxel between groups using analysis of covariance (covariates, age and sex; SPM12, p < 0.001)., Results: Significantly increased GM-density, indicating tissues injury, emerged in multiple brain regions, including the cerebellum, hippocampus, amygdala, basal forebrain, insula, and frontal and prefrontal cortices. Various brain areas showed significantly reduced T2-relaxation values in CF subjects, indicating predominant acute tissue changes, in the cerebellum, cerebellar tonsil, prefrontal and frontal cortices, insula, and corpus callosum., Conclusions: Cystic fibrosis subjects show predominant acute tissue changes in areas that control mood, cognition, respiratory, and autonomic functions and suggests that tissue changes may contribute to symptoms resulting from ongoing hypoxia accompanying the condition., (© 2021. The Author(s).)

COVID-19 is a respiratory tract infection that can affect multiple organ systems. Predicting the severity and clinical outcome of individual patients is a major unmet clinical need that remains challenging due to intra- and inter-patient variability. Here, we longitudinally profiled and integrated more than 150 clinical, laboratory, and immunological parameters of 173 patients with mild to fatal COVID-19. Using systems biology, we detected progressive dysregulation of multiple parameters indicative of organ damage that correlated with disease severity, particularly affecting kidneys, hepatobiliary system, and immune landscape. By performing unsupervised clustering and trajectory analysis, we identified T and B cell depletion as early indicators of a complicated disease course. In addition, markers of hepatobiliary damage emerged as robust predictor of lethal outcome in critically ill patients. This allowed us to propose a novel clinical CO VID-19 S everi T y (COST) score that distinguishes complicated disease trajectories and predicts lethal outcome in critically ill patients., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)