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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]

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.

Background: Although blood oxygen level-dependent (BOLD) functional MRI (fMRI) is a standard method, major BOLD signals primarily originate from intravascular sources. Magnetic resonance electrical properties tomography (MREPT)-based fMRI signals may provide additional insights into electrical activity caused by alterations in ion concentrations and mobilities., Purpose: This study aimed to investigate the neuronal response of conductivity during visual stimulation and compare it with BOLD., Materials and Methods: A total of 30 young, healthy volunteers participated in two independent experiments using BOLD and MREPT techniques with a visual stimulation paradigm at 3 T MRI. The first set of MREPT fMRI data was obtained using a multi-echo spin-echo (SE) echo planar imaging (EPI) sequence from 14 participants. The second set of MREPT fMRI data was collected from 16 participants using both a single-echo SE-EPI and a single-echo three-dimensional (3D) balanced fast-field-echo (bFFE) sequence. We reconstructed the time-course Larmor frequency conductivity to evaluate hemodynamics., Results: Conductivity values slightly increased during visual stimulation. Activation strengths were consistently stronger with BOLD than with conductivity for both SE-EPI MREPT and bFFE MREPT. Additionally, the activated areas were always larger with BOLD than MREPT. Some participants also exhibited decreased conductivity values during visual stimulations. In Experiment 1, conductivity showed significant differences between the fixation and visual stimulation blocks in the secondary visual cortex (SVC) and cuneus, with conductivity differences of 0.43 % and 0.47 %, respectively. No significant differences in conductivity were found in the cerebrospinal fluid (CSF) areas between the two blocks. In Experiment 2, significant conductivity differences were observed between the two blocks in the SVC, cuneus, and lingual gyrus for SE-EPI MREPT, with differences of 0.90 %, 0.67 %, and 0.24 %, respectively. Again, no significant differences were found in the CSF areas., Conclusion: Conductivity values increased slightly during visual stimulation in the visual cortex areas but were much weaker than BOLD responses. The conductivity change during visual stimulation was less than 1 % compared to the fixation block. No significant differences in conductivity were observed between the primary visual cortex (PVC)-CSF and SVC-CSF during fixation and visual stimulations, suggesting that the observed conductivity changes may not be related to CSF changes in the visual cortex but rather to diffusion changes. Future research should explore the potential of MREPT to detect neuronal electrical activity and hemodynamic changes, with further optimization of the MREPT technique., Competing Interests: Declaration of Competing Interest 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 Elsevier B.V. All rights reserved.)

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.

Relative belief inferences are shown to arise as Bayes rules or limiting Bayes rules. These inferences are invariant under reparameterizations and possess a number of optimal properties. In particular, relative belief inferences are based on a direct measure of statistical evidence.

KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRAS G12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRAS G12R tumors are associated with decreased distant recurrence and improved survival as compared to KRAS G12D . To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRAS G12D and increased nuclear factor κB (NF-κB) signaling in KRAS G12R tumors. Orthogonal studies of mouse Kras G12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology., Competing Interests: Declaration of interests E.M.O., research funding: Genentech/Roche, BioNTech, AstraZeneca, Arcus, Elicio, Parker Institute, NIH/NCI, Pertzye; consulting/DSMB: Boehringer Ingelheim, BioNTech, Ipsen, Merck, Novartis, AstraZeneca, BioSapien, Astellas, Thetis, Autem, Novocure, Neogene, BMS, Tempus, Fibrogen, Merus, Agios (spouse), Genentech-Roche (spouse), Eisai (spouse). G.M.C.:A full listing of G.M.C.’s interests can be found at http://arep.med.harvard.edu/gmc/tech/html. C.E.M., founder: Onegevity, Twin Orbit, and Cosmica Biosciences; consulting: Nanostring. L.E.D., research funding/consulting: Revolution Medicines; scientific advisory board: Mirimus. R.C., research funding: Sanofi; consulting/DSMB: Boston Scientific., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Obesity, characterized by excessive fat accumulation, poses a significant public health challenge globally. Recent advancements in medical technology have heralded the emergence of endoscopic bariatric treatments (EBTs) as innovative alternatives to conventional obesity interventions. Despite previous systematic reviews and network meta-analyses, they also highlighted discrepancies in outcomes and efficacy among different EBTs. Here, we will update a systematic review and network meta-analysis of randomized controlled trials (RCTs) focusing on EBTs and presents a protocol for the reproducibility and transparency., Methods: The core protocol of this study was registered at PROSPERO database (CRD42024514249) on Jan 2024. Core databases including MEDLINE through PubMed, Embase, and Cochrane library will be searched relevant studies, and a systematic review with network meta-analysis will be performed. Two evaluators (EJ Gong and CS Bang) will independently screen the titles and abstracts following the eligibility criteria; (1) RCTs investigated the compared the efficacy of EBTs and controls; (2) studies published in English; and (3) studies in full-text format. We will exclude studies meeting the following criteria; (1) studies that did not report the treatment outcomes, such as percent excess weight loss or percent total body weight loss; (2) case reports and review articles; (3) ineligible research objects, for example, animals or children; and (4) insufficient data regarding treatment outcome. The primary outcomes will be the common efficacy metric found after systematic review of relevant studies, such as percent excess weight loss or percent total body weight loss with a follow-up of at least 6 months. Narrative (descriptive) synthesis is planned and quantitative synthesis will be used if the included studies are sufficiently homogenous. The quality of the identified studies will be assessed using the Cochrane Risk of Bias assessment tool version 2.0 (ROB 2.0). All the systematic review and network meta-analysis process will be undertaken keeping the principles of the Preferred Reporting Items for a Systematic Review and Meta-analysis for systematic review protocols (PRISMA-P) and PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (PRISMA-NMA)., Discussion: This updated systematic review and network meta-analysis will provide information about comparative efficacy of various EBTs and this will help physicians in the decision-making process for the selection of treatment modalities in the clinical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Gong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Targeting altered expression and/or activity of GABA 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 (IFN I)-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 GATs expression in a cell autonomous manner and therefore could be a novel target for GABAergic cognitive deficits. Significance Statement GABA concentration in extracellular space is maintained by GABA release and clearance of GABA back to brain cells for degradation. GABA clearance from the synaptic cleft predominantly depends on level and activity of GABA transporters (GATs) in the brain. Insufficient GABA clearance resulted to an aberrant tonic GABA A inhibition in brain. In this study, we have identified an unusually high GABA content in brain of STING-deficient mice, resulting in cognitive impairment. Our results show that STING regulates GATs expression through STING-TBK1-IRF3 pathway and thus regulates GABAergic tone. This is the first study that indicates that the STING-TBK1-IRF3 signaling pathway maintains GABA homeostasis in brain, which may offer a novel therapeutic target for modulating GABAergic tone in cases of cognitive dysfunction., (Copyright © 2024 the authors.)

Background and Aims: Despite its relatively low incidence rate compared to others, pancreatic cancer has a poor prognosis owing to its late detection and poor response to systemic chemotherapy. Because the effectiveness of chemotherapy is still restricted, the need for locoregional treatment is increasing. Cryoablation is an effective and minimally invasive treatment for some cancers, but its efficiency in pancreatic cancer is limited. Despite recent reports about promising outcomes, the optimal method and conditions of treatment are not known. In this preliminary study, we aimed to develop a cryoablation needle which can control the ablated area considering application through endoscopic ultrasonography. Methods: Here, we used a novel cryoneedle cooling system which can adjust the ablation range based on a liquid carbon dioxide refrigerant. Applied to the livers of swine, the cryoablation needle rapidly reached -60 °C within 30 s and cryoablation was performed for approximately 240 s. Based on the distance and depth, we collected real-time temperature data during the procedure. To compare the extent of cell death over time, tissue samples were collected hourly from 3 to 6 h after the procedure. Results: Approximately 4-5 mm of tissue was ablated via cryoablation, and cell death progressed over time after cryoablation. Moreover, the ablated lesions could be regulated using an insulating agent on the needle. Conclusions: This preliminary study on a novel surgical cooling needle system compatible with endoscopic ultrasound for cryoablation-based pancreatic cancer treatment confirmed the efficacy of cryoablation and identified the conditions necessary to induce necrosis. Additionally, this study evaluated the effectiveness of the insulation component of the system in protecting normal cells and assessed the extent of necrosis over time after the procedure.

Objective: This study was performed to evaluate the quality characteristics of reduced-nitrite boiled pork sausages (BPSs) with paprika oleoresin solution (POS) to compensate for the reduced sodium nitrite (NaNO2)., Methods: POS was prepared by diluting paprika oleoresin with sunflower seed oil at a ratio of 1:20. BPSs were subjected to four different treatments: reference (REF), BPS added with 150 ppm NaNO2; control (CTL), BPS added with 37.5 ppm NaNO2; treatment 1 (TRT1), BPS added with 37.5 ppm NaNO2 and 0.1% POS; treatment 2 (TRT2), BPS added with 75 ppm NaNO2 and 0.1% POS)., Results: The pH values of CTL were lower than those of other treatments. The a* values of TRT1 were higher than those of CTL, and those of REF were lower than those of TRT1 and TRT2. The b* values of TRT1 and TRT2 were higher than those of REF and CTL. The total plate counts of CTL were the highest among all treatments, and Enterobacteriaceae counts of CTL and TRT1 on the 14th day were higher than those of REF and TRT2., Conclusion: The combination of 75 ppm NaNO2 and 0.1% POS to BPS during storage had an antimicrobial effect similar to that of adding 150 ppm NaNO2. Thus, POS can be used to reduce the use of NaNO2 in meat products.

High-manganese steel (high-Mn) is valuable for its excellent mechanical properties in cryogenic environments, making it essential to understand its deformation behavior at extremely low temperatures. The deformation behavior of high-Mn steels at extremely low temperatures depends on the stacking fault energy (SFE) that can lead to the formation of deformation twins or transform to ε-martensite or α'-martensite as the temperature decreases. In this study, submerged arc welding (SAW) was applied to fabricate thick pipes for cryogenic industry applications, but it may cause problems such as an uneven distribution of manganese (Mn) and a large weldment. To address these issues, post-weld heat treatment (PWHT) is performed to achieve a homogeneous microstructure, enhance mechanical properties, and reduce residual stress. It was found that the difference in Mn content between the dendrite and interdendritic regions was reduced after PWHT, and the SFE was calculated. At cryogenic temperatures, the SFE decreased below 20 mJ/m 2 , indicating the martensitic transformation region. Furthermore, an examination of the deformation behavior of welded high-Mn steels was conducted. This study revealed that the tensile deformed, as-welded specimens exhibited ε and α'-martensite transformations at cryogenic temperatures. However, the heat-treated specimens did not undergo α'-martensite transformations. Moreover, regardless of whether the specimens were subjected to Charpy impact deformation before or after heat treatment, ε and α'-martensite transformations did not occur.

The electrocatalytic conversion of NO offers a promising technology for not only removing the air pollutant but also synthesizing valuable chemicals. We design an integrated-electrocatalysis cell featuring metal organic framework (MOF)-modified gas diffusion electrodes for simultaneous capture of NO and generation of NH 4 NO 3 under low-concentration NO flow conditions. Using 2% NO gas, the modified cathode exhibits a higher NH 4 + yield and Faradaic efficiency than an unmodified cathode. Notably, the modified cathode shows a twofold increase in NH 4 + production with 20 ppm NO gas supply. Theoretical calculations predict favorable transfer of adsorbed NO from the adsorption layer to the catalyst layer, which is experimentally confirmed by enhanced NO mass transfer from gas to electrolyte across the modified electrode. The adsorption layer-modified anode also exhibits a higher NO 3 - yield for NO electro-oxidation compared to the unmodified electrode under low NO concentration flow. Among various integrated-cell configurations, a single-chamber setup produces a higher NH 4 NO 3 yield than a double-chamber setup. Furthermore, a higher NO utilization efficiency is obtained with a single-gasline operation mode, where the NO-containing gas flows sequentially from the cathode to the anode., (© 2024. The Author(s).)

Antidepressants, including duloxetine, are a significant cause of drug-induced hyponatremia, which can disrupt the continuation of medication. Tolvaptan is beneficial for correcting hyponatremia caused by the syndrome of inappropriate antidiuresis, but its impact on duloxetine-induced hyponatremia remains unknown. We used male Sprague-Dawley rats to examine the impact of duloxetine treatment on lithium-induced nephrogenic diabetes insipidus (Li-NDI) and to evaluate whether the results were reversed by co-treatment with tolvaptan. To induce Li-NDI, lithium chloride (40 mmol lithium/kg dry food) was administered for 2 weeks. Duloxetine (50 mg/kg/day) and tolvaptan (10 mg/kg/day) were also administered in food to assess their individual effects over the same period. At the end of each animal experiment, kidneys were harvested to measure levels of cAMP, vasopressin-2 receptor (V2R), cAMP-responsive element binding protein 1 (CREB-1), aquaporin-2 (AQP2), and prostaglandin E2 (PGE2). Water diuresis was induced in the Li-NDI rats, and duloxetine treatment reduced polyuria while increasing urine osmolality. Duloxetine treatment prevented the decrease in total AQP2, AQP2 phosphorylation at serine 256, and CREB-1 phosphorylation in Li-NDI rats. The V2R mRNA level was also reduced in Li-NDI rats and restored by duloxetine treatment. In the subsequent experiment, the decreased water diuresis in Li-NDI rats treated with duloxetine was reversed by co-treatment with tolvaptan. Tolvaptan co-treatment also reversed the changes in AQP2 protein and CREB-1 phosphorylation in the renal cortex and medulla. The decreased cAMP levels in Li-NDI rat kidneys were elevated by duloxetine treatment, and this elevation was reversed by co-treatment with tolvaptan. However, the elevated PGE2 levels in Li-NDI rat kidneys were not affected by either duloxetine alone or tolvaptan co-treatment. In conclusion, antidiuresis was induced by duloxetine in Li-NDI and reversed by tolvaptan co-treatment through alterations in the V2R-cAMP-AQP2 pathway. These findings could underlie the mechanism of duloxetine-induced hyponatremia and suggest the potential usefulness of tolvaptan in treating drug-induced hyponatremia.

Background: This study aimed to assess the effect of faba bean (Vicia faba L.) protein isolate (FBPI) on the rheological properties of pork myofibrillar protein gels (MPGs) and the quality characteristics of pork low-fat model sausages (LFMSs)., Results: Pork MPGs with 5 or 10 g kg -1 FBPI had higher cooking yield, gel strength, and viscosity than controls. The addition of FBPI to MPGs increased the protein surface hydrophobicity and decreased sulfhydryl groups. Adding FBPI to MPGs changed the protein profile and microstructure. The cooking loss and expressible moisture of LFMSs with 5, 10, or 15 g kg -1 FBPI were lower than those of controls and showed similar results to those with 15 g kg -1 soy protein isolate (SPI). Hardness values of LFMSs with FBPI and SPI were no different, and were higher than those of controls., Conclusion: The addition of FBPI potentially improves rheological properties of MPGs and the functional properties of LFMSs, including water-holding capacity and textural properties. © 2024 Society of Chemical Industry., (© 2024 Society of Chemical Industry.)

A low arousal threshold (LAT) is a pathophysiological trait of obstructive sleep apnea (OSA) that may be associated with brainstem ascending reticular activating system-cortical functional connectivity changes. We evaluated resting-state connectivity between the brainstem nuclei and 105 cortical/subcortical regions in OSA patients with or without a LAT and healthy controls. Twenty-five patients with moderate to severe OSA with an apnea-hypopnea index between 20 and 40/hr (15 with and 10 without a LAT) and 15 age- and sex-matched controls were evaluated. Participants underwent functional magnetic resonance imaging after overnight polysomnography. Three brainstem nuclei-the locus coeruleus (LC), laterodorsal tegmental nucleus (LDTg), and ventral tegmental area (VTA)-associated with OSA in our previous study were used as seeds. Functional connectivity values of the two brainstem nuclei (LC and LDTg) significantly differed among the three groups. The connectivity of the LC with the precuneus was stronger in OSA patients than in controls regardless of the concomitant LAT. The connectivity between the LDTg and the posterior cingulate cortex was also stronger in OSA patients regardless of the LAT. Moreover, OSA patients without a LAT showed stronger LDTg-posterior cingulate cortex connectivity than those with a LAT (post hoc p = 0.013), and this connectivity strength was negatively correlated with the minimum oxygen saturation in OSA patients (r = - 0.463, p = 0.023). The LAT in OSA patients was associated with altered LDTg-posterior cingulate cortex connectivity. This result may suggested that cholinergic activity may play a role in the LAT in OSA patients., (© 2024. The Author(s).)

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management., (© 2024. The Author(s).)

Improving the hydroxide conductivity and dimensional stability of anion exchange membranes (AEMs) while retaining their high alkaline stability is necessary to realize the commercialization of AEM water electrolysis (AEMWE). A strategy for improving the hydroxide conductivity and dimensional stability of AEMs by inserting fluorine atoms in the core structure of the backbone is reported, which not only reduces the glass transition temperature of the polymer due to steric strain, but also induces distinct phase separation by inducing polarity discrimination to facilitate the formation of ion transport channels. The resulting PFPFTP-QA AEM with fluorine into the core structure shows high hydroxide conductivity (>159 mS cm -1 at 80 °C), favorable dimensional stability (>25% at 80 °C), and excellent alkaline stability for 1000 h in 2 m KOH solution at 80 °C. Moreover, the PFPFTP-QA is used to construct an AEMWE cell with a platinum group metal (PGM)-free NiFe anode, which exhibits the current density of 6.86 A cm -2 at 1.9 V at 80 °C, the highest performance in Pt/C cathode and PGM-free anode reports so far and operates stably for over 100 h at a constant current of 0.5 A cm -2 ., (© 2024 Wiley‐VCH GmbH.)

Genome sequencing studies have identified numerous cancer mutations across a wide spectrum of tumor types, but determining the phenotypic consequence of these mutations remains a challenge. Here, we developed a high-throughput, multiplexed single-cell technology called TISCC-seq to engineer predesignated mutations in cells using CRISPR base editors, directly delineate their genotype among individual cells and determine each mutation's transcriptional phenotype. Long-read sequencing of the target gene's transcript identifies the engineered mutations, and the transcriptome profile from the same set of cells is simultaneously analyzed by short-read sequencing. Through integration, we determine the mutations' genotype and expression phenotype at single-cell resolution. Using cell lines, we engineer and evaluate the impact of >100 TP53 mutations on gene expression. Based on the single-cell gene expression, we classify the mutations as having a functionally significant phenotype., (© 2023. The Author(s).)

The present study investigates how heritage speakers conduct good-enough processing at the interface of home-language proficiency, cognitive skills (inhibitory control; working memory), and task types (acceptability judgement; self-paced reading). For this purpose, we employ two word-order patterns (verb-final vs. verb-initial) of two clausal constructions in Korean-suffixal passive and morphological causative-which contrast pertaining to the mapping between thematic roles and case-marking and the interpretive procedures driven by verbal morphology. We find that, while Korean heritage speakers demonstrate the same kind of acceptability-rating behaviour as monolingual Korean speakers do, their reading-time patterns are notably modulated by construction-specific properties, cognitive skills, and proficiency. This suggests a heritage speaker's ability and willingness to conduct both parsing routes, induced by linguistic cues in a non-dominant language, which are proportional to the computational complexity involving these cues. Implications of this study are expected to advance our understanding of a learner's mind for underrepresented languages and populations in the field., Competing Interests: The author declares 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 Shin.)

The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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.)