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Anne L Meulenbroek,1 Miriam C Faes,2 Stefanie R van Mil,1 MG Buimer,1 Hans GW de Groot,1 Eelco J Veen,1 Gwan H Ho,1 Leandra JM Boonman-de Winter,3,4 Jolanda de Vries,5,6 Rebecca van Gorkom,1 Fleur Toonders,1 Rene van Alphen,7 Karolien van Overveld,8 Nathalie Verbogt,1 Ewout W Steyerberg,9 Lijckle van der Laan1,10 1Department of Surgery, Amphia Hospital, Breda, the Netherlands; 2Department of Geriatrics, Amphia Hospital, Breda, the Netherlands; 3Department of Scientific Research, Amphia Hospital, Breda, the Netherlands; 4Admiraal de Ruyter Ziekenhuis, Goes, the Netherlands; 5Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands; 6Board, Admiraal de Ruyter Hospital, Goes, the Netherlands; 7Department of Physical Therapy, Amphia Hospital, Breda, the Netherlands; 8Department of Dieticians, Amphia Hospital, Breda, the Netherlands; 9Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands; 10Department of Cardiovascular Science, University Hospitals Leuven, Leuven, BelgiumCorrespondence: Anne L Meulenbroek, Department of Surgery, Amphia Hospital, Molengracht 21, Breda, 4818 CK, the Netherlands, Tel +31 76 595 3157, Fax +31 76 595 3818, Email AMeulenbroek1@amphia.nlObjective: Chronic limb threatening ischemia is the final stage of peripheral arterial disease. Current treatment is based on revascularization to preserve the leg. In the older, hospitalized chronic limb threatening ischemia patient, delirium is a frequent and severe complication after revascularization. Delirium leads to an increased length of hospital stay, a higher mortality rate and a decrease in quality of life. Currently, no specific guidelines to prevent delirium in chronic limb threatening ischemia patients exist. We aim to evaluate the effect of a multicomponent, multidisciplinary prehabilitation program on the incidence of delirium in chronic limb threatening ischemia patients ≥ 65 years.Design: A prospective observational cohort study to investigate the effects of the program on the incidence of delirium will be performed in a large teaching hospital in the Netherlands. This manuscript describes the design of the study and the content of this specific prehabilitation program.Methods: Chronic limb threatening ischemia patients ≥ 65 years that require revascularization will participate in the program. This program focuses on optimizing the patient’s overall health and includes delirium risk assessment, nutritional optimization, home-based physical therapy, iron infusion in case of anaemia and a comprehensive geriatric assessment in case of frailty. The primary outcome is the incidence of delirium. Secondary outcomes include quality of life, amputation-free survival, length of hospital stay and mortality. Exclusion criteria are the requirement of acute treatment or patients who are mentally incompetent to understand the procedures of the study or to complete questionnaires. A historical cohort from the same hospital is used as a control group.Discussion: This study will clarify the effect of a prehabilitation program on delirium incidence in chronic limb threatening ischemia patients. New insights will be obtained on optimizing a patient’s preoperative mental and physical condition to prevent postoperative complications, including delirium.Trial: This protocol is registered at the Netherlands National Trial Register (NTR) number: NL9380.Keywords: chronic limb threatening ischemia, vascular surgical procedures, delirium, delirium/prevention and control, prehabilitation

Chloé ML Peters,1 Paul Lodder,2,3 Jolanda de Vries,2,4 Stijn L Steunenberg,1 Eelco J Veen,1 Hans GW de Groot,1 Gwan H Ho,1 Lijckle van der Laan1,5 1Department of Surgery, Amphia Hospital, Breda, The Netherlands; 2Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands; 3Department of Methodology and Statistics, Tilburg University, Tilburg, The Netherlands; 4Department of Medical Psychology, Elisabeth-TweeSteden Hospital Tilburg University, Tilburg, The Netherlands; 5Department of Cardiovascular Science, UZ Leuven - University Hospitals, Leuven, BelgiumCorrespondence: Lijckle van der LaanAmphia Hospital, Molengracht 21, Breda, CK 4818, the NetherlandsTel +31 76 595 5000Email lvanderlaan@amphia.nlPurpose: In elderly patients with chronic limb-threatening ischemia (CLTI), there is little scientific understanding of the long-term changes of quality of life (QoL) and health status (HS) after treatment. The primary goal of this study was to provide long-term QoL and HS results for elderly CLTI patients after therapy. Treatments consisted of endovascular revascularization, surgical revascularization, or conservative treatment. Furthermore, the aim of this study was to identify the distinctive trajectories of QoL and HS.Patients and Methods: CLTI patients aged ≥ 70 years were included in a prospective observational cohort study with a two-year follow-up. The WHOQOL-BREF was used to asses QoL. The 12-Item Short Form Health Survey was used to measure HS. The QoL and HS scores were compared to the scores in the general elderly Dutch population. Latent class trajectory analysis was used.Results: A total of 195 patients were included in this study. After two years, in all treatment groups patients showed significantly higher physical QoL score compared to baseline and there was no significant difference with the corresponding values in the elderly Dutch population. In the latent class trajectory analysis, there were no overlapping risk factors for poorer QoL or HS.Conclusion: This study shows that QoL levels in surviving elderly CLTI patients in the long-term do not differ from the corresponding values for elderly in the general population. There were no disparities in sociodemographic, clinical and treatment characteristics associated with poorer QoL and HS. This study was carried out to encourage further analysis of the influence of biopsychosocial characteristics on QoL and HS in elderly CLTI patients.Keywords: quality of life, health status, peripheral arterial disease, frail elderly, chronic limb-threatening ischemia

Chloé ML Peters,1 Jolanda de Vries,2,3 Eelco J Veen,1 Hans GW de Groot,1 Gwan H Ho,1 Paul Lodder,2,4 Stijn L Steunenberg,1 Lijckle van der Laan11Department of Surgery, Amphia Hospital, Breda, The Netherlands; 2Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands; 3Department of Medical Psychology, Elisabeth-Tweesteden Hospital (ETZ), Tilburg, The Netherlands; 4Department of Methodology and Statistics, Tilburg University, Tilburg, The NetherlandsPurpose: Despite high amputation rates, data on patient-reported outcomes is scarce in the elderly population with critical limb ischemia. The aim of this study was to provide mortality rates and long-term changes of the following patient-reported outcomes in elderly critical limb ischemia amputees: quality of life (QoL), health status (HS), and symptoms of depression.Patients and methods: In this prospective observational cohort study, amputated critical limb ischemia patients ≥70 years were included. The follow-up period was two years. Within the follow-up period patients completed the following questionnaires: the World Health Organization Quality Of Life -abbreviated version of the WHOQOL 100 (WHOQOL-BREF), the 12-Item Short Form Health Survey, and the Center for Epidemiological Studies Depression Scale.Results : A total of 49 elderly patients with critical limb ischemia had undergone major limb amputation within two years after inclusion. In these patients, the one-year mortality rate was 39% and the two-year mortality rate was 55%. The physical QoL was the only domain of the WHOQOL-BREF that improved significantly across time after amputation (p≤0.001). In the long-term, there was no difference in the ability to enjoy life (p=0.380) or the satisfaction in performing daily living activities (p=0.231) compared to the scores of the general elderly population. After amputation, the physical HS domain (p≤0.001) and the mental HS domain (p=0.002) improved. In the first year, amputees experienced less symptoms of depression (p=0.004).Conclusion: Elderly critical limb ischemia amputees are a fragile population with high mortality rates. Their QoL and HS increased after major limb amputation as compared to the baseline situation and they experienced less symptoms of depression. Moreover, our results show that, in the long-term, major limb amputation in the elderly patients with critical limb ischemia shows an acceptable QoL, which, in some aspects, is comparable to the QoL of their peers. These results can improve the shared-decision making process that does not delay the timing of major limb amputation.Keywords: amputation, critical limb ischemia, frail elderly, health status, quality of life

Stijn L Steunenberg,1 Jolanda de Vries,2,3 Jelle W Raats,1 Nathalie Verbogt,1 Paul Lodder,2,4 Geert-Jan van Eijck,5 Eelco J Veen,1 Hans GW de Groot,1 Gwan H Ho,1 Lijckle van der Laan11Department of Surgery, Amphia Hospital, Breda, The Netherlands; 2Department of Medical and Clinical Psychology, Tilburg University, Tilburg, The Netherlands; 3Department of Medical Psychology, ETZ, Tilburg, The Netherlands; 4Department of Methodology and Statistics, Tilburg University, Tilburg, The Netherlands; 5Department of Surgery, Bravis Hospital, Roosendaal, The NetherlandsIntroduction: Critical limb ischemia (CLI) patients are often of advanced age with reduced health status (HS) and quality of life (QoL) at baseline. Physical health is considered as the most affected domain due to reduced mobility and ischemic pain. QoL and HS are often used interchangeably in the current literature. HS refers to objectively perceived physical, psychological, and social functioning and in assessing QoL, change is measured subjectively and can only be determined by the individual since it concerns patients’ evaluation of their functioning. It is important to distinguish between QoL and HS, especially in the concept of shared decision-making when the opinion of the patient is key. Goal of this study was to examine and compare QoL and HS in elderly CLI patients in relation to the used therapy, with a special interest in conservatively treated patients.Methods: Patients suffering from CLI and ≥70 years old were included in a prospective study with a follow-up period of 1 year. Patients were divided into three groups; endovascular revascularization, surgical revascularization, and conservative therapy. The WHOQoL-Bref was used to determine QoL, and the 12-Item Short Form Health Survey was used to evaluate HS at baseline, 5–7 days, 6 weeks, 6 months, and 1 year.Results: Physical QoL of endovascularly and surgically treated patients showed immediate significant improvement during follow-up in contrast to delayed increased physical HS at 6 weeks and 6 months (P

Sanne Klaphake,1,2 Kevin de Leur,1 Paul GH Mulder,1,3 Gwan H Ho,1 Hans G de Groot,1 Eelco J Veen,1 Hence JM Verhagen,2 Lijckle van der Laan1 1Department of Surgery, Amphia Hospital, Breda, 2Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, 3Amphia Academy, Amphia Hospital, Breda, the Netherlands Background: Owing to the aging population, the number of elderly patients with critical limb ischemia (CLI) has increased. The consequence of amputation is immense. However, at the moment, information about the mortality after amputation in the elderly vascular patients is unknown. For this reason, this study evaluated mortality rates and patient-related factors associated with mortality after a major amputation in elderly patients with CLI.Methods: From 2006 to 2013, we included patients aged >70 years who were treated for chronic CLI by primary or secondary major amputation within or after 3 months of initial therapy (revascularization or conservative management). Outcome measurements were mortality after major amputation and factors associated with mortality (age, comorbidity and timing of amputation).Results: In total, 168/651 patients (178 legs; 26%) underwent a major amputation. Patients were stratified by age: 70–80 years (n=86) and >80 years (n=82). Overall mortality after major amputation was 44%, 66% and 85% after 1, 3 and 5 years, respectively. The 6-month and 1-year mortality in patients aged 80 years or older was, respectively, 59% or 63% after a secondary amputation 3 months. Per year of age, the mortality rate increased by 4% (P=0.005). No significant difference in mortality after major amputation was found in the presence of comorbidity or according to Rutherford classification.Conclusion: Despite developments in the treatment of CLI by revascularization, amputation rates remain high and are associated with tremendous mortality rates. Secondary amputation after a failed attempt of revascularization causes a higher mortality. Further research concerning timing of amputation and patient-related outcome is needed to evaluate if selected patients might benefit from primary amputation. Keywords: peripheral arterial disease, aged, limb ischemia, primary amputation, octogenarians, patient selection

Jelle W Raats,1 Hans C Flu,1 Gwan H Ho,1 Eelco J Veen,1 Louwerens D Vos,2 Ewout W Steyerberg,3 Lijckle van der Laan1 1Department of Surgery, Amphia Hospital, Breda, 2Department of Radiology, Amphia Hospital, Breda, 3Department of Public Health, Erasmus MC, Rotterdam, the Netherlands Background: Despite advances in operative repair, ruptured abdominal aortic aneurysm (rAAA) remains associated with high mortality and morbidity rates, especially in elderly patients. The purpose of this study was to evaluate the outcomes of emergency endovascular aneurysm repair (eEVAR), conventional open repair (OPEN), and conservative treatment in elderly patients with rAAA.Methods: We conducted a retrospective study of all rAAA patients treated with OPEN or eEVAR between January 2005 and December 2011 in the vascular surgery department at Amphia Hospital, the Netherlands. The outcome in patients treated for rAAA by eEVAR or OPEN repair was investigated. Special attention was paid to patients who were admitted and did not receive operative intervention due to serious comorbidity, extremely advanced age, or poor physical condition. We calculated the 30-day rAAA-related mortality for all rAAA patients admitted to our hospital.Results: Twelve patients did not receive operative emergency repair due to extreme fragility (mean age 87 years, median time to mortality 27 hours). Twenty-three patients had eEVAR and 82 had OPEN surgery. The 30-day mortality rate in operated patients was 30% (7/23) in the eEVAR group versus 26% (21/82) in the OPEN group (P=0.64). No difference in mortality was noted between eEVAR and OPEN over 5 years of follow-up. There were more cardiac adverse events in the OPEN group (n=25, 31%) than in the eEVAR group (n=2, 9%; P=0.035). Reintervention after discharge was more frequent in patients who received eEVAR (35%) than in patients who had OPEN (6%, P

In this work, the phase evolution during calcinations of aBaTiO3 and TiO2 mixture was investigated. Based on the observations, a model for the reaction sequence ofthe phases was proposed and a modified process was suggested, namely to synthesizeBa2Ti9O20 materialsutilizing a BaTi4O9 and BaTi5O11 mixture,instead of a BaTiO3 and TiO2 mixture, as starting materials. The phase transformation kinetics isthus greatly enhanced by this process. While the reaction of the2BaTiO3+7TiO2 mixture requires1100 °C/4 h to transform completelyinto the Ba2Ti9O20 Hollandite-likephase, it needs only 1000 °C/4 hto fulfil the phase transformation process in theBaTi5O11+BaTi4O9 mixture.The BaTi5O11+BaTi4O9 mixture also leads to higher sinterability and more uniform granular structure, as compared to the2BaTiO3+7TiO2 mixture, when these powder mixtures were densified by a direct sinteringprocess. Furthermore, local microwave dielectric properties measuredby an evanescent microwave probe (EMP) reveals that the grains ofBa2Ti9O20 materialsprepared from the BaTi5O11+BaTi4O9 mixture possess larger dielectric constant than2BaTiO3+7TiO2 derived ones,indicating that the BaTi5O11+BaTi4O9 mixture has higher reactivity for the formation of theBa2Ti9O20 Hollandite-like phase. [ABSTRACT FROM AUTHOR]

In Singapore, breast cancer is the leading cancer among other cancers in women. Being a multicultural society, the needs, concerns and coping strategies of women with breast cancer vary compared to women in other parts of the world. Therefore this study aims to identify the needs and concern of local women with breast cancer over the period of their illness. One hundred women newly diagnosed with breast cancer were recruited into the study. Ninety two of them agreed to the first interview (preoperative), 83 proceeded to the second interview (third month after surgery and undergoing treatment) and 62 completed the third Interview (9 month after surgery and had completed treatment). At the first interview, 68 patients were scheduled for simple mastectomy axillary clearance (SMAC) and 24 patients were for wide excision axillary clearance (WEAC). Fifty one percent of them were concerned about disease spread, outcome of surgery and postoperative recovery with no statistical significance between the 2 groups. Eleven percent of them said that they needed educational support on wound care and rehabilitation and further information on recovery. At the second interview, 65 patients were from the SMAC group while 18 patients were from the WEAC group. Fifty percent of them said that their main support (family support) were their spouses and children. For professional support, 63% of them identified the Breast Care Nurse and the clinic nurses as their main source of educational and emotional support. Forty six percent specified the need for more information on understanding adjuvant therapy and its side effects. At the third interview, 44 patients were from the SMAC group and 18 from the WEAC group. Those who had received adjuvant treatment made up 27.9% while 46% were on no treatment or only on 5-year oral Tamoxifen. Forty seven percent were relieved that the treatment was over, 40% were worried about recurrence after treatment and 60% of them wanted continual support and education on prevention of disease towards achieving total recovery. The study had shown that there was a need for patient education and emotional support during the treatment period, especially during chemotherapy and radiotherapy. During the initial counselling, many patients were unable to specify their concerns and needs or the need for continual support. The results also identified the specific areas regarding patient information, education and support that needed further exploration. [ABSTRACT FROM AUTHOR]

The HUGO Pan-Asian SNP consortium conducted the largest survey to date of human genetic diversity among Asians by sampling 1,719 unrelated individuals among 71 populations from China, India, Indonesia, Japan, Malaysia, the Philippines, Singapore, South Korea, Taiwan, and Thailand. We have constructed a database (PanSNPdb), which contains these data and various new analyses of them. PanSNPdb is a research resource in the analysis of the population structure of Asian peoples, including linkage disequilibrium patterns, haplotype distributions, and copy number variations. Furthermore, PanSNPdb provides an interactive comparison with other SNP and CNV databases, including HapMap3, JSNP, dbSNP and DGV and thus provides a comprehensive resource of human genetic diversity. The information is accessible via a widely accepted graphical interface used in many genetic variation databases. Unrestricted access to PanSNPdb and any associated files is available at: http://www4a.biotec.or.th/PASNP.

Background: Tetratricopeptide repeat domain 9A (TTC9A) protein is a recently identified protein which contains three tetratricopeptide repeats (TPRs) on its C-terminus. In our previous studies, we have shown that TTC9A was a hormonally-regulated gene in breast cancer cells. In this study, we found that TTC9A was over-expressed in breast cancer tissues compared with the adjacent controls (P < 0.00001), suggesting it might be involved in the breast cancer development process. The aim of the current study was to further elucidate the function of TTC9A.Methods: Breast samples from 25 patients including the malignant breast tissues and the adjacent normal tissues were processed for Southern blot analysis. Yeast-two-hybrid assay, GST pull-down assay and co-immunoprecipitation were used to identify and verify the interaction between TTC9A and other proteins.Results: Tropomyosin Tm5NM-1 was identified as one of the TTC9A partner proteins. The interaction between TTC9A and Tm5NM-1 was further confirmed by GST pull-down assay and co-immunoprecipitation in mammalian cells. TTC9A domains required for the interaction were also characterized in this study. The results suggested that the first TPR domain and the linker fragment between the first two TPR domains of TTC9A were important for the interaction with Tm5NM-1 and the second and the third TPR might play an inhibitory role.Conclusion: Since the primary function of tropomyosin is to stabilize actin filament, its interaction with TTC9A may play a role in cell shape and motility. In our previous results, we have found that progesterone-induced TTC9A expression was associated with increased cell motility and cell spreading. We speculate that TTC9A acts as a chaperone protein to facilitate the function of tropomyosins in stabilizing microfilament and it may play a role in cancer cell invasion and metastasis. [ABSTRACT FROM AUTHOR]

When used to edit genomes, Cas9 nucleases produce targeted double-strand breaks in DNA. Subsequent DNA-repair pathways can induce large genomic deletions (larger than 100 bp), which constrains the applicability of genome editing. Here we show that Cas9-mediated double-strand breaks induce large deletions at varying frequencies in cancer cell lines, human embryonic stem cells and human primary T cells, and that most deletions are produced by two repair pathways: end resection and DNA-polymerase theta-mediated end joining. These findings required the optimization of long-range amplicon sequencing, the development of a k-mer alignment algorithm for the simultaneous analysis of large DNA deletions and small DNA alterations, and the use of CRISPR-interference screening. Despite leveraging mutated Cas9 nickases that produce single-strand breaks, base editors and prime editors also generated large deletions, yet at approximately 20-fold lower frequency than Cas9. We provide strategies for the mitigation of such deletions., (© 2024. The Author(s).)

Probiotics exert various effects on the body and provide different health benefits. Previous reports have demonstrated that the P8 protein (P8), isolated from Lactobacillus rhamnosus , has anticancer properties. However, its efficacy in stem cells and normal cells has not been reported. In this study, the effect of P8 on cell proliferation and wound healing was evaluated, investigating its underlying mechanism. Based on scratch assay results, we demonstrated that P8 treatment significantly increases wound healing by activating the cell cycle and promoting stem cell stemness. Cellular mechanisms were further investigated by culturing stem cells in a medium containing Lactobacillus-derived P8 protein, revealing its promotion of cell proliferation and migration. Also, it is found that P8 enhances the expression of stemness markers, such as OCT4 and SOX2 , along with activation of the mitogen-activated protein kinase (MAPK) signaling and Hippo pathways. These results indicate that P8 can promote cell growth by increasing stem cell proliferation, migration, and stemness in a manner associated with MAPK and Hippo signaling, which could contribute to the increased wound healing after P8 treatment. Furthermore, P8 could promote wound healing in keratinocytes by activating the MAPK signaling pathways. These results suggest that P8 might be a promising candidate to enhance stem cell culture efficiency by activating cell proliferation, and enhance therapeutic effects in skin diseases.

Aggressive solid malignancies, including pancreatic ductal adenocarcinoma (PDAC), can exploit lysosomal exocytosis to modify the tumor microenvironment, enhance motility, and promote invasiveness. However, the molecular pathways through which lysosomal functions are co-opted in malignant cells remain poorly understood. In this study, we demonstrate that inositol polyphosphate 4-phosphatase, Type II (INPP4B) overexpression in PDAC is associated with PDAC progression. We show that INPP4B overexpression promotes peripheral dispersion and exocytosis of lysosomes resulting in increased migratory and invasive potential of PDAC cells. Mechanistically, INPP4B overexpression drives the generation of PtdIns(3,5)P2 on lysosomes in a PIKfyve-dependent manner, which directs TRPML-1 to trigger the release of calcium ions (Ca2+). Our findings offer a molecular understanding of the prognostic significance of INPP4B overexpression in PDAC through the discovery of a novel oncogenic signaling axis that orchestrates migratory and invasive properties of PDAC via the regulation of lysosomal phosphoinositide homeostasis., (© 2024 Saffi et al.)

Intra-neuronal accumulation of hyper-phosphorylated tau as neurofibrillary tangles (NFT) is a hallmark of Alzheimer's disease (AD). To prevent the aggregation of phosphorylated tau in neurons, decreasing the phosphorylated tau protein levels is important. Here, we examined the biological effects of rottlerin, a phytochemical compound extracted from the Kamala tree, Mallotus philippinensis, on phosphorylated tau levels. Notably, rottlerin decreased the levels of intracellular phosphorylated and total tau. A marked increase in the LC3-II, a hallmark of autophagy, was observed in these cells, indicating that rottlerin strongly induced autophagy. Interestingly, rottlerin induced the phosphorylation of Raptor at S792 through the activation of adenosine-monophosphate activated-protein kinase (AMPK), which likely inhibits the mammalian target of rapamycin complex 1 (mTORC1), thus resulting in the activation of transcription factor EB (TFEB), a master regulator of autophagy. In addition, nuclear factor erythroid 2-related factor 2 (Nrf2) activity increased in the presence of rottlerin. The decrease of phosphorylated tau levels in the presence of rottlerin was ameliorated by the knockdown of TFEB and partially attenuated by the knockout of the Nrf2 gene. Taken together, rottlerin likely enhances the degradation of phosphorylated tau through autophagy activated by TFEB and Nrf2. Thus, our results suggest that a natural compound rottlerin could be used as a preventive and therapeutic drug for AD., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The developed magnetic resonance electrical properties tomography (MREPT) techniques visualize the internal conductivity distribution at Larmor frequency by measuring the B1 transceive phase data. In biological tissues, electrical conductivity is influenced by ion concentrations and mobility. To visualize the anisotropic conductivity tensor of biological tissues, we use the Einstein-Smoluchowski equation, which links the diffusion coefficient to particle mobility. By assuming a correlation between ion mobility and water diffusivity, we aim to decompose the internal isotropic conductivity at Larmor frequency into anisotropic conductivity tensors within the intra- and extra-neurite compartments. The multi-compartment spherical mean technique (MC-SMT), utilizing both high and low b-value diffusion-weighted imaging (DWI) data, characterizes the diffusion of water molecules within and across the intra- and extra-neurite compartments by analyzing the microstructural intricacies and the foundational architectural arrangement of the brain's tissues. By analyzing the relationships between the measured DWI data, the microscopic diffusion signal, and the fiber orientation distribution function, we predict the DWI data for the intra- and extra-neurite compartments using spherical harmonic decomposition. Using the predicted DWI data for the intra- and extra-neurite compartments, we develop a conductivity tensor imaging method that operates specifically within the separated compartments. Human brain experiments, involving four healthy volunteers and a brain tumor patient, were performed to assess and confirm the reliability of the proposed method., Competing Interests: Declaration of competing interest The authors have no conflict of interest to report., (Copyright © 2024. Published by Elsevier Inc.)

Base editors (BEs) have emerged as a powerful tool for gene correction with high activity. However, bystander base editing, a byproduct of BEs, presents challenges for precise editing. Here, we investigated the effects of bystander edits on phenotypic restoration in the context of Leber congenital amaurosis (LCA), a hereditary retinal disorder, as a therapeutic model. We observed that in rd12 of LCA model mice, the highest editing activity version of an adenine base editors (ABEs), ABE8e, generated substantial bystander editing, resulting in missense mutations despite RPE65 expression, preventing restoration of visual function. Through AlphaFold-based mutational scanning and molecular dynamics simulations, we identified that the ABE8e-driven L43P mutation disrupts RPE65 structure and function. Our findings underscore the need for more stringent requirements in developing precise BEs for future clinical applications.

Stem cells derived from human orbicularis oculi muscle (hOOM) are a valuable resource for cell therapy. However, when stem cells are continuously cultured, their abilities tend to deteriorate over time. One method to address this issue is to use basic fibroblast growth factor (bFGF) to maintain the stem cell functionality. The limitation is that bFGF is unstable under mammalian cell culture conditions with a half-life of only 8 hours, which poses a significant challenge to the production and maintenance of high-quality stem cells. In this study, we used thermostable bFGF (TS-bFGF) and demonstrated that hOOM-derived stem cells cultured with TS-bFGF exhibited superior proliferation, stem cell function, reduced reactive oxygen species, and cellular senescence delay effect compared to cells cultured with wild-type bFGF. Considering the pivotal role of stem cells in broad ranges of applications such as regenerative medicine and cultured meat, we anticipate that TS-bFGF, owing to its thermostability and long-lasting properties, will contribute significantly to the acquisition of high-quality stem cells.

Objective: Elderly patients with Chronic Limb Threatening Ischemia (CLTI) undergoing revascularization are prone to delirium and prolonged hospitalization. Preoperative prehabilitation may prevent delirium and reduce the length of stay. This study investigates the effect of multimodal prehabilitation on delirium incidence in elderly CLTI patients undergoing revascularization., Methods: A comparative observational cohort study conducted in a large teaching hospital (intervention cohort n=101, retrospective control cohort n=207) and a university hospital (prospective control cohort n=48) from 2020 to 2023. Patients aged ≥ 65 years undergoing revascularization were included, with acute treatment or severe cognitive impairment as exclusion criteria. The three-week prehabilitation program included screening of general health and presence of delirium risk factors by a vascular nurse practitioner, screening and provision of personalized, home-based exercises by a physiotherapist, provision of nutritional advice by a dietician, and if indicated comprehensive geriatric assessment by a geriatrician, assessment of self-reliance and home situation by a prearranged homecare nurse, guidance and support for smoking cessation by a quit smoking coach, and anaemia treatment. Primary outcome was 30-day delirium incidence, analysed using regression models adjusting for potential confounders (age, physical impairment, history of delirium, preoperative anaemia and revascularization type). Secondary outcomes were length of stay, postoperative complications, 30-day mortality, and patient experiences., Results: Median age (IQR) was 76 years (71-82). Delirium incidence was lower in the prehabilitation cohort (n=2/101, 2%) compared to controls (n=23/255, 9%; OR=0.21, 95%CI 0.05-0.89, p=.04). Adjusted analysis showed a non-significant delirium reduction (OR=0.28, 95%CI 0.06-1.3, p=.097). The prehabilitation cohort had a significantly shorter length of stay (2 [1-5] vs 4 [2-9] days; p=<.001), and fewer minor complications (14% vs 26%, p=.01). No differences were present in major complications and 30-day mortality. Patients reported high compliance and satisfaction (median score 8/10, IQR 7-9)., Conclusions: Prehabilitation among elderly CLTI patients is safe and has the potential to yield multiple beneficial effects on general outcomes following revascularization, while also achieving high levels of patient satisfaction. Further validation and considering implementation in surgical settings is recommended., (Copyright © 2024. Published by Elsevier Inc.)

Defects in wide bandgap materials have emerged as promising candidates for solid-state quantum optical technologies. Electrical excitation of single emitters may lead to scalable on-chip devices and therefore is highly sought after. However, most wide bandgap materials are not amenable to efficient doping, posing challenges for electrical excitation and on-chip integration. Here, we demonstrate narrowband electroluminescence from visible and near-infrared color centers in hexagonal boron nitride (hBN). We harness van der Waals tunnel junctions of graphene-hBN-graphene. Charge carriers are electrically injected into hBN, exciting localized defects that emit nonclassical light, as characterized by the second order correlation measurement. Remarkably, the devices operate at room temperature and produce robust, narrowband emission spanning from visible to the near-infrared. Our work marks an important milestone in vdW materials and their promising attributes for integrated quantum technologies and on-chip photonic circuits.

Psoriasis is a common chronic inflammatory disease in which keratinocytes proliferate abnormally due to excessive immune action. Psoriasis can be associated with various comorbidities and has a significant impact on health-related quality of life. Although many systemic treatments, including biologic agents, have been developed, topical treatment remains the main option for psoriasis management. Consequently, there is an urgent need to develop topical treatments with minimal side effects and high efficacy. Mesenchymal stem cells (MSCs) exhibit excellent immune regulation, anti-inflammatory activities, and therapeutic effects, and MSC-derived extracellular vesicles (EVs) can serve as crucial mediators of functional transfer from MSCs. Therefore, this study aimed to develop a safe and easy-to-use emulsion cream for treating psoriasis using MSC conditioned media (CM) containing EVs. We developed an enhanced Wharton's jelly MSC (WJ-MSC) culture method through a three-dimensional (3D) culture containing exogenous transforming growth factor-β3. Using the 3D culture system, we obtained CM from WJ-MSCs, which yielded a higher EV production compared to that of conventional WJ-MSC culture methods, and investigated the effect of EV-enriched 3D-WJ-MSC-CM cream on psoriasis-related inflammation. Administration of the EV-enriched 3D-WJ-MSC-CM cream significantly reduced erythema, thickness, and scaling of skin lesions, alleviated imiquimod-induced psoriasiform lesions in mice, and ameliorated histopathological changes in mouse skin. The upregulated mRNA expression of inflammatory cytokines, including IL-17a, IL-22, IL-23, and IL-36, decreased in the lesions. In conclusion, we present here a new topical treatment for psoriasis using an MSC EV-enriched cream.

Targeting altered expression and/or activity of GABA (γ-aminobutyric acid) transporters (GATs) provide therapeutic benefit for age-related impairments, including cognitive dysfunction. However, the mechanisms underlying the transcriptional regulation of GATs are unknown. In the present study, we demonstrated that the stimulator of interferon genes (STING) upregulates GAT1 and GAT3 expression in the brain, which resulted in cognitive dysfunction. Genetic and pharmacological intervention of STING suppressed the expression of both GAT1 and GAT3, increased the ambient GABA concentration, and therefore, enhanced tonic GABA A inhibition of principal hippocampal neurons, resulting in spatial learning and working memory deficits in mice in a type I interferon-independent manner. Stimulation of the STING→GAT pathway efficiently restored cognitive dysfunction in STING-deficient mice models. Our study uncovered for the first time that the STING signaling pathway regulates GAT expression in a cell autonomous manner and therefore could be a novel target for GABAergic cognitive deficits., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

The skin is an essential organ that protects the body from external aggressions; therefore, damage from various wounds can significantly impair its function, and effective methods for regenerating and restoring its barrier function are crucial. This study aimed to mass-produce wound-healing exosomes using a fragment of the fibroblast growth factor 2 (FGF2)-derived peptide (FP2) to enhance cell proliferation and exosome production. Our experiments demonstrated increased cell proliferation when Wharton's jelly mesenchymal stem cells (WJ MSCs) were coated with FP2. Exosomes from FP2-coated WJ MSCs were analyzed using nanoparticle-tracking analysis, transmission electron microscopy, and Western blotting. Subsequently, fibroblasts were treated with these exosomes, and their viability and migration effects were compared. Anti-inflammatory effects were also evaluated by inducing pro-inflammatory factors in RAW264.7 cells. The treatment of fibroblasts with FP2-coated WJ MSC-derived exosomes (FP2-exo) increased the expression of FGF2, confirming their wound-healing effect in vivo. Overall, the results of this study highlight the significant impact of FP2 on the proliferation of WJ MSCs and the anti-inflammatory and wound-healing effects of exosomes, suggesting potential applications beyond wound healing.

Background: To evaluate the patient-perceived satisfaction and feasibility of a personalized eHealth application (app) for abdominal aortic aneurysm (AAA) patients undergoing surgery., Methods: Patients were offered to download the app prior to undergoing AAA surgery, in a prospective single-center cohort study, using a mixed-methods sequential explanatory design. It offers information via the timely delivery of push notifications with text, images, and videos. The information includes chapters regarding the AAA, surgical techniques (endovascular aneurysm repair and open surgical repair), and perioperative lifestyle advice, such as physical exercise programmes, healthy and protein rich diet, geriatric care, and to stop smoking or drinking alcohol., Results: The app was installed by 59/65 patients (91%). After installation, 6 patients deactivated the app (10%). The mean age was 74 years (SD = 7), and 85% of patients were male. The app was opened a median of 67 times (interquartile range [IQR] 33-127) and with a median time interval of 50 hours (IQR 28-74). Overall, 90% (53/59) completed a satisfaction questionnaire. On a numeric rating scale from 0 to 10, the median scored satisfaction for guidance was 8 (IQR 6-8), provided information was 8 (IQR 6-8), usefulness was 7 (IQR 6-8.5), and for recommending it to others it was 8 (IQR 6-9). Using purposeful sampling, 7 patients underwent a semistructured interview on the user-experience of the app. They described experiencing positive changes to lifestyle habits and appreciating the ability to share it with loved ones or informal caregivers. Several areas of improvement were reported., Conclusions: The personalized eHealth app is feasible in older AAA patients and is valued as a useful supplement to the standard of care. We argue that the app aids in managing a prehabilitation program, aids in the digital transformation of healthcare, and thereby decreases the workload of hospital staff., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Many studies have been conducted on the use of ultra-small iron oxide nanoparticles (USIONs) (d < 3 nm) as potential positive magnetic resonance imaging (MRI)-contrast agents (CAs); however, there is dearth of research on clustered USIONs. In this study, nearly monodispersed clustered USIONs were synthesized using a simple two-step one-pot polyol method. First, USIONs (d = 2.7 nm) were synthesized, and clustered USIONs (d = 27.9 nm) were subsequently synthesized through multiple cross-linking of USIONs with poly(acrylic acid-co-maleic acid) (PAAMA) polymers with many -COOH groups. The clustered PAAMA-USIONs exhibited very weak ferromagnetism owing to the magnetic interaction between superparamagnetic USIONs; this was evidenced by their appreciable r 1 = 3.9 s ‒1 mM ‒1 and high r 2 /r 1 ratio of 14.6. Their ability to function as a dual-modal T 1 /T 2 MRI-CA in T 1 -weighted MRI was demonstrated when they simultaneously exhibited positive and negative contrasts in T 1 -weighted MRI of tumor model mice after intravenous injection. They displayed positive contrasts at the kidneys, bladder, heart, and aorta and negative contrasts at the liver and tumor.&#xD., (© 2024 IOP Publishing Ltd. All rights, including for text and data mining, AI training, and similar technologies, are reserved.)

Background/aims: Shifts in the gut microbiota and metabolites are interrelated with liver cirrhosis progression and complications. However, causal relationships have not been evaluated comprehensively. Here, we identified complication-dependent gut microbiota and metabolic signatures in patients with liver cirrhosis., Methods: Microbiome taxonomic profiling was performed on 194 stool samples (52 controls and 142 cirrhosis patients) via V3-V4 16S rRNA sequencing. Next, 51 samples (17 controls and 34 cirrhosis patients) were selected for fecal metabolite profiling via gas chromatography mass spectrometry and liquid chromatography coupled to time-of-flight mass spectrometry. Correlation analyses were performed targeting the gut-microbiota, metabolites, clinical parameters, and presence of complications (varices, ascites, peritonitis, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, and deceased)., Results: Veillonella bacteria, Ruminococcus gnavus, and Streptococcus pneumoniae are cirrhosis-related microbiotas compared with control group. Bacteroides ovatus, Clostridium symbiosum, Emergencia timonensis, Fusobacterium varium, and Hungatella&#95;uc were associated with complications in the cirrhosis group. The areas under the receiver operating characteristic curve (AUROCs) for the diagnosis of cirrhosis, encephalopathy, hepatorenal syndrome, and deceased were 0.863, 0.733, 0.71, and 0.69, respectively. The AUROCs of mixed microbial species for the diagnosis of cirrhosis and complication were 0.808 and 0.847, respectively. According to the metabolic profile, 5 increased fecal metabolites in patients with cirrhosis were biomarkers (AUROC >0.880) for the diagnosis of cirrhosis and complications. Clinical markers were significantly correlated with the gut microbiota and metabolites., Conclusion: Cirrhosis-dependent gut microbiota and metabolites present unique signatures that can be used as noninvasive biomarkers for the diagnosis of cirrhosis and its complications.

Sensory abnormalities are observed in ~90% of individuals with autism spectrum disorders (ASD), but the underlying mechanisms are poorly understood. GluN2B, an NMDA receptor subunit that regulates long-term depression and circuit refinement during brain development, has been strongly implicated in ASD, but whether GRIN2B mutations lead to sensory abnormalities remains unclear. Here, we report that Grin2b-mutant mice show behavioral sensory hypersensitivity and brain hyperconnectivity associated with the anterior cingulate cortex (ACC). Grin2b-mutant mice with a patient-derived C456Y mutation (Grin2b C456Y/+ ) show sensory hypersensitivity to mechanical, thermal, and electrical stimuli through supraspinal mechanisms. c-fos and functional magnetic resonance imaging indicate that the ACC is hyperactive and hyperconnected with other brain regions under baseline and stimulation conditions. ACC pyramidal neurons show increased excitatory synaptic transmission. Chemogenetic inhibition of ACC pyramidal neurons normalizes ACC hyperconnectivity and sensory hypersensitivity. These results suggest that GluN2B critically regulates ASD-related cortical connectivity and sensory brain functions., (© 2024. The Author(s).)

Electrochemical carbon dioxide reduction reaction (ECO 2 RR) is a promising approach to synthesize fuels and value-added chemical feedstocks while reducing atmospheric CO 2 levels. Here, high surface area cerium and sulfur-doped hierarchical bismuth oxide nanosheets (Ce@S-Bi 2 O 3 ) are develpoed by a solvothermal method. The resulting Ce@S-Bi 2 O 3 electrocatalyst shows a maximum formate Faradaic efficiency (FE) of 92.5% and a current density of 42.09 mA cm -2 at -1.16 V versus RHE using a traditional H-cell system. Furthermore, using a three-chamber gas diffusion electrode (GDE) reactor, a maximum formate FE of 85% is achieved in a wide range of applied potentials (-0.86 to -1.36 V vs RHE) using Ce@S-Bi 2 O 3 . The density functional theory (DFT) results show that doping of Ce and S in Bi 2 O 3 enhances formate production by weakening the OH* and H* species. Moreover, DFT calculations reveal that *OCHO is a dominant pathway on Ce@S-Bi 2 O 3 that leads to efficient formate production. This study opens up new avenues for designing metal and element-doped electrocatalysts to improve the catalytic activity and selectivity for ECO 2 RR., (© 2024 Wiley‐VCH GmbH.)

Background and Aims: The rapid urease test (RUT) is widely used to detect Helicobacter pylori infection; however, it is not preferred as a monitoring strategy after eradication owing to its low sensitivity. In this study, we evaluated the diagnostic performance of RUT using the sweeping method, which overcomes the limitations of conventional tissue sampling methods after eradication., Methods: Patients who received H pylori eradication treatment were enrolled. Each of the sweeping and conventional methods was performed on the same patients to compare diagnostic performance. Urea breath test (UBT), histology, and polymerase chain reaction were performed to determine true infection. Logistic regression analysis was conducted to investigate reasons for discrepancies between the results of the 2 methods., Results: In 216 patients, the eradication success rate was 68.1%, and the sensitivity and specificity of the sweeping method were 0.812 and 0.912, respectively, whereas those of the conventional method were 0.391 and 0.993, respectively (P < .05 for all). The area under the receiver operating characteristic curve for the sweeping method was higher than that for the conventional method (0.862 vs 0.692, P < .001). The mean time to H pylori detection for the sweeping method was 4.7 ± 4.4 minutes and 12.3 ± 16.1 minutes for the conventional method (P < .001). The risk for inconsistent results between the 2 methods was the highest for UBT values of 1.4‰ to 2.4‰ (odds ratio, 3.8; P = .016)., Conclusions: The RUT with the sweeping method could potentially replace the tissue sampling method as a test to confirm H pylori eradication and be an alternative option to UBT for patients requiring endoscopy., Competing Interests: Disclosure All authors disclosed no financial relationships. This work was partly supported by the Korean College of Helicobacter and Upper Gastrointestinal Research Foundation Grant (no. KCHUGR-202101002)., (Copyright © 2024 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Background and Aims: The prevalence of malnutrition in intensive care units (ICU) is high and can be caused by poor intake or absorption of nutrients in the digestive track, as well as disease-related inflammation. As strong catabolism restricts nutrient supply and potentially leads to subsequent malnutrition, appropriate nutrition should be provided based on the metabolic status. However, nutritional support strategies for considering the metabolic phase are not well established. Therefore, this study aimed to establish a strategy for nutritional support in each phase by implementing a phase-specific modified Nutrition Risk in Critically Ill (mNUTRIC) score., Methods: This prospective observational study was conducted on all adult patients admitted to the medical ICU for at least 36 h at Seoul National University Bundang Hospital between September 2020 and September 2022. Patient nutrition assessment (mNUTRIC score), clinical information, and nutritional supply (calories and proteins) were measured twice, in the acute phase (measured at 2 days) and late phase (measured at 7 days). The relationship between nutritional supply and 28-day mortality was analyzed using multiple logistic regression according to the mNUTRIC score in the acute and late phases. Risk factors related to 28-day mortality were analyzed using univariate and multivariate Cox proportional hazards regressions., Results: Of the 631 patients admitted to the ICU during the study period, 613 were included in the acute phase and 361 patients were included in the late phase. Nutritional supply was associated with 28-day mortality, with high mNUTRIC scores in both the acute and late phases. Cox proportional hazards regression analysis demonstrated that a high mNUTRIC score [hazard ratio (HR) 3.20 and 2.52, respectively], lactate >2.5 mg/dL were independent risk factors in both the acute and late phases. In addition, Albumin <2.5 mg/dL, the presence of neoplasm, and the need for dialysis in the acute phase, calorie adequacy <0.7 in the late phase (HR, 2.19) were identified as additional risk factors., Conclusion: The mNUTRIC score is a suitable tool for identifying critically ill patients who benefit from nutritional support. Nutritional supply should be considered for patients with high mNUTRIC scores in both the acute and late phases; however, careful supply should be provided in the acute phase and sufficient supply should be provided in the late phase., 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 © 2024 Lee, Kim, Park, Park, Lim and Choi.)

Background/aims: Early diagnosis of esophageal cancer (EC) remains challenging despite the increasing frequency of endoscopic screenings globally. The rapidly increasing number of endoscopic screenings performed over a certain period might influence diagnostic performance. This study evaluated the association between the number of endoscopic screenings and EC detection rates in a nationwide cohort., Methods: This retrospective population-based study used the Korean National Cancer Screening Program database, comprising 32,774,742 males and females aged ≥40 years between 2015 and 2019. Negative binomial regression model and least-squares mean evaluation were used to assess the association between month of the year and EC detection rates., Results: This study enrolled 28,032,590 participants who underwent upper endoscopy. The number of participants in the fourth quarter (October to December: 10,923,142 [39.0%]) was 2.1 times higher than that in the first quarter (January to March: 5,085,087 [18.1%]); this trend continued for all 5 years. Contrarily, detection rates for EC in the fourth quarter (0.08/1,000 person) were half that in the first quarter (0.15/1,000 person). The odds of detecting EC were lowest in November; in 2015 the odds were 0.57 (95% confidence interval, 0.41 to 0.79; p=0.001) times lower and in 2016, they were 0.51 (95% confidence interval, 0.37 to 0.68; p<0.001) times lower compared to January. The predicted detection rates showed a decreasing trend toward the end of the year (p>0.05 for all)., Conclusions: The workload of endoscopists increased excessively with the rising number of endoscopies toward the end of the year, which was reflected by the decreased EC detection rates during this period.

The pleiotropic roles of nSMase2-generated ceramide include regulation of intracellular ceramide signaling and exosome biogenesis. We investigated the effects of eliminating nSMase2 on early and advanced PDA, including its influence on the microenvironment. Employing the KPC mouse model of pancreatic cancer, we demonstrate that pancreatic epithelial nSMase2 ablation reduces neoplasia and promotes a PDA subtype switch from aggressive basal-like to classical. nSMase2 elimination prolongs survival of KPC mice, hinders vasculature development, and fosters a robust immune response. nSMase2 loss leads to recruitment of cytotoxic T cells, N1-like neutrophils, and abundant infiltration of anti-tumorigenic macrophages in the pancreatic preneoplastic microenvironment. Mechanistically, we demonstrate that nSMase2-expressing PDA cell small extracellular vesicles (sEVs) reduce survival of KPC mice; PDA cell sEVs generated independently of nSMase2 prolong survival of KPC mice and reprogram macrophages to a proinflammatory phenotype. Collectively, our study highlights previously unappreciated opposing roles for exosomes, based on biogenesis pathway, during PDA progression.

Multi-functional nanoparticles are useful for various applications, such as biomedical imaging, detection, and display technologies. Colour-tunable GdEu x Tb 1- x O 3 nanoparticles were synthesized with emission colour ranging from green (545 nm) to red (616 nm) by varying x ( x = 0, 0.1, 0.3, 0.5, 0.7, 0.9, and 1). These nanoparticles were surface-grafted with polyacrylic acid and a small quantity of 2,6-pyridinedicarboxylic acid. This modification aimed to ensure long-term colloidal stability (>1 year without precipitation) and high quantum yields (>30%) in aqueous media. Additionally, they exhibited long emission lifetimes (∼1 ms), high longitudinal water proton spin relaxivities (>30 s -1 mM -1 ), and high X-ray attenuation efficiencies (∼10 HU mM -1 ). These multiple exceptional properties within a single nanoparticle make them highly valuable for applications in biomedical imaging, noise-free signal detection, and colour display.