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Shu-Wan Chiang, Shiou-Fang Lu, Shu-Chen Wu, Tai-Chu Peng Department of Nursing, Tzu Chi University, Hualien, TaiwanCorrespondence: Tai-Chu Peng, Department of Nursing, Tzu Chi University, Hualien, Taiwan, Email ptc2008@gms.tcu.edu.twPurpose: The purpose of this study was to explore the experiences of nursing managers in implementing palliative care in long-term care facilities and to provide recommendations for managers who plan to introduce palliative care into their facilities.Methods: This study used semi-structured interviews and grounded theory methodology, with purposive sampling. A total of 11 long-term care facilities in eastern Taiwan that had implemented palliative care were selected, and 11 facility nursing managers participated in in-depth, face-to-face interviews.Results: The introduction of palliative care in long-term care facilities can be divided into four stages: (1) the opportunity for change, (2) playing a supportive role, (3) a new collaboration model, and (4) facility transformation. The core category shared by the participants may be summed up as “the palliative care captain in the facility”. It reflects the spirit of the successful implementation of palliative care by managers in long-term care facilities.Conclusion: The study reveals that during the initial phases of implementing palliative care, the palliative care teams assume a crucial leadership role, while the facilities play a supportive role. At this stage, managers should focus on personnel training and addressing internal issues within the facilities to facilitate successful collaboration with the palliative care teams. In the later stages, the facilities transition from a supportive role to one of independence, marking a critical juncture for the facilities’ potential stable development. During this period, managers are tasked not only with establishing the facilities’ own palliative care team but also with facilitating the transformation of staff from learners to instructors. Finally, even after successful implementation, managers must contemplate how to innovate and set more ambitious goals.Keywords: nursing managers, long-term care, palliative care, hospice, grounded theory

En-Bo Wu,1,* Chia-Chi Hsiao,2,* Kuo-Chuan Hung,3 Chao-Ting Hung,1 Chih-Chun Chen,1 Shao-Chun Wu,1 Jo-Chi Chin,4 I-Wen Chen,3 Sheng-Dean Luo5 1Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan; 2Department of Family Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan; 3Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan; 4Department of Anesthesiology, Park One International Hospital, Kaohsiung, Taiwan; 5Division of Otolaryngology, Kaohsiung Chang Gung Memorial Hospital and Graduate Institute of Clinical Medical Science, College of Medicine, Chang Gung University, Kaohsiung, Taiwan*These authors contributed equally to this workCorrespondence: Sheng-Dean Luo, No. 123, Ta-Pei Road, Niao-Song District, Kaohsiung City, 833, Taiwan, Tel +886-7-7317123 (ext. 2788), Email rsd0323@cgmh.org.tw I-Wen Chen, No. 901, Zhonghua Road, Yongkang District, Tainan City, 710, Taiwan, Tel +886-6-2812811, Email mavising@gmail.comPurpose: Ultrasound-guided interscalene nerve block (UISB) is commonly used to alleviate postoperative pain during shoulder arthroscopy. This retrospective observational study aimed to evaluate the intraoperative advantages and analgesic effects of preoperative UISB.Patients and Methods: In this retrospective observational study, a total of 170 patients underwent shoulder arthroscopy at a tertiary medical center in southern Taiwan throughout 2019. After applying the exclusion criteria, 142 of these cases were included, with 74 and 68 in the UISB group and control groups, respectively. The primary outcome was the evaluation of intraoperative morphine milligram equivalent (MME) consumption. Secondary outcomes were sevoflurane consumption, the use of intraoperative antihypertensive drugs, and postoperative visual analog scale (VAS) scores in the post-anesthesia care unit (PACU) and in the ward at 24 h after surgery.Results: Preoperative UISB effectively reduced opioids and volatile gases during surgery, supported by a 48.1% and 14.8% reduction in the median intraoperative MME and sevoflurane concentrations, respectively, and showed less need for antihypertensive drugs. The preoperative UISB group also showed significantly better performance on the VAS in both the PACU and ward.Conclusion: Taken together, the preoperative UISB reduced not only intraoperative MME and sevoflurane consumption but also had satisfactory VAS scores in both the PACU and ward without any symptomatic respiratory complications. In summary, preoperative UISB is a reliable adjuvant analgesic technique and a key factor in achieving opioid-sparing and sevoflurane-sparing anesthesia and multimodal analgesia during shoulder arthroscopy.Graphical Abstract: Keywords: interscalene block, multimodal analgesia, opioid-sparing anesthesia, shoulder arthroscopy, volatile-sparing anesthesia

Johnson Chia-Shen Yang,1,2 Lien-Hung Huang,1,2 Shao-Chun Wu,3,4 Yi-Chan Wu,1,4 Chia-Jung Wu,1,4 Chia-Wei Lin,1,4 Pei-Yu Tsai,1,4 Peng-Chen Chien,1,4 Ching-Hua Hsieh1,2 1Division of Plastic and Reconstructive Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 2Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; 4Chang Gung University College of Medicine, Taoyuan, TaiwanCorrespondence: Ching-Hua HsiehGraduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine, 123 Dapi Road, Niaosong District, Kaohsiung City, 833, Taiwan, Tel +886-7-7317123, ext.8002, Fax +886-7-7354309, Email prs581126@gmail.comPurpose: This study aims at profiling the expression of dysregulated genes in circulating monocytes of patients with cancer-related lower limb lymphedema before and after treatment with supermicrosurgical lymphaticovenous anastomosis (LVA).Materials and Methods: This prospective longitudinal cohort study enrolled 51 women with post-treatment gynecological cancer, including those with unilateral lymphedema (study group, n = 25) and those without (control group, n = 26). Venous blood samples obtained from the study group before and after LVA and those from the controls were sent for next-generation sequencing, which was validated by real-time PCR. Dysregulated gene expression in the study group, relative to expression in the controls, was recorded before LVA. After one month, postoperative changes in the expression of the identified genes were evaluated. Protein-protein interaction (PPI) was used to investigate dysregulated genes whose expression returned to baseline levels after LVA.Results: Of the 148 preoperative dysregulated genes, which comprised 108 up- and 40 down-regulated genes, 78 genes, consisting of 69 up- and 9 down-regulated genes, showed post-LVA recovery to baseline levels. Through PPI analysis, five functional modules involving immunity, lipid metabolism, oxidative stress, transcriptional regulators, and tumor suppression, as well as six hub genes (CCL2, LPL, PDK4, FOXO3, EGR1, and DUSP5), were identified. Cross-linking and co-regulated genes between modules were also identified.Conclusion: Localized lymphedema leads to dysregulated gene expression in circulating monocytes. The current study is the first to identify the hub genes related to lymphedema and demonstrate the recovery of some dysregulated genes after LVA.Keywords: transcriptome, NGS, real-time PCR, hub gene, functional modules

Akkermansia muciniphila and Faecalibacterium prausnitzii are next-generation probiotics, which has been reported to protect disease and effectively utilize various carbohydrates (starch and pectin) as nutrients for growth. Atemoya exhibiting fruity flavor, which is suitable for enhancing aroma and attenuating unpleasant taste caused by the koji metabolites. Results indicated that malic acid was increased (from 42.4 to 70.1 mg/100 g) in fermented Atemoya-Amazake. In addition, fermented Atemoya-Amazake elevated growthes in A. muciniphila and F. prausnitzii. Similarly, the populations of Parabacteroides (5.7 fold) and Akkermansia (1.66 fold) were elevated by fermented Atemoya-Amazake treatment in an in vitro simulated gastrointestinal system compared to the control group. Results revealed that fermented Atemoya-Amazake modulated the intestinal microbiota through increasing the production of short-chain fatty acids (exhibiting anti-pathogenic activity) for 2.1, 2.5, 2.6, and 2.1 folds in acetic acid, propionic acid, isobutyric acid, and butyric acid, respectively; suggesting this fermented Atemoya-Amazake could be applied in intestinal protection., 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. Published by Elsevier Ltd.)

Two-photon high-speed fluorescence calcium imaging stands as a mainstream technique in neuroscience for capturing neural activities with high spatiotemporal resolution. However, challenges arise from the inherent tradeoff between acquisition speed and image quality, grappling with a low signal-to-noise ratio (SNR) due to limited signal photon flux. Here, a contrast-enhanced video-rate volumetric system, integrating a tunable acoustic gradient (TAG) lens-based high-speed microscopy with a TAG-SPARK denoising algorithm is demonstrated. The former facilitates high-speed dense z-sampling at sub-micrometer-scale intervals, allowing the latter to exploit the spatial redundancy of z-slices for self-supervised model training. This spatial redundancy-based approach, tailored for 4D (xyzt) dataset, not only achieves >700% SNR enhancement but also retains fast-spiking functional profiles of neuronal activities. High-speed plus high-quality images are exemplified by in vivo Purkinje cells calcium observation, revealing intriguing dendritic-to-somatic signal convolution, i.e., similar dendritic signals lead to reverse somatic responses. This tailored technique allows for capturing neuronal activities with high SNR, thus advancing the fundamental comprehension of neuronal transduction pathways within 3D neuronal architecture., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 led to the coronavirus infection diseases 2019 (COVID-19) pandemic, significantly impacting global public health and the economy. Numerous COVID-19 vaccines based on the receptor binding domain (RBD) of SARS-CoV-2 spike protein have been developed, utilizing various protein expression platforms and adjuvant systems. In a previous study, we reported using the direct fusion of the A subunit of type IIb E. coli heat-labile enterotoxin with the SARS-CoV-2 RBD protein (RBD-LTA) as an intranasal vaccine candidate (Hsieh et al., 2023). In this study, we investigated the effects of an intranasal booster of RBD-LTA/RBD mixture proteins after one or two doses of intramuscular bivalent BA.4/5 mRNA vaccination over 17 and 35 weeks. Our results indicate that the intranasal RBD-LTA/RBD mixture proteins booster maintains high levels of anti-RBD IgG and neutralizing antibodies, comparable to those elicited by a two-dose mRNA vaccination regimen. An additional RBD-LTA/RBD mixture proteins booster significantly increased antibody titers, demonstrating the potential of this approach for long-term immunity against SARS-CoV-2. Our findings suggest that combining primary mRNA vaccination with an intranasal RBD-LTA/RBD mixture proteins booster can effectively sustain antibody levels over extended periods, providing a promising strategy for long-term protection against SARS-CoV-2 and its variants., Competing Interests: Declaration of competing interest The National Tsing Hua University has filed a patent application on the RBD-based COVID-19 mucosal vaccine candidates., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

ABO blood group antigens, which are complex carbohydrate moieties, and the first human polymorphisms identified, are critical in transfusion medicine and transplantation. Despite their discovery over a century ago, significant questions remain about the development of anti-ABO antibodies and the structural features of ABO antigens that cause hemolytic transfusion reactions. Anti-ABO antibodies develop naturally during the first few months of life, in contrast to other red blood cell (RBC) alloantibodies which form after allogeneic RBC exposure. Anti-ABO antibodies are the most common immune barrier to transfusion and transplantation, but the factors driving their formation are incompletely understood. Some studies suggest that microbes that express glycans similar in structure to the blood group antigens could play a role in anti-blood group antibody formation. While the role of these microbes in clinically relevant anti-blood group antibody formation remains to be defined, the presence of these microbes raises questions about how blood group-positive individuals protect themselves against blood group molecular mimicry. Recent studies suggest that galectins can bind and kill microbes that mimic blood group antigens, suggesting a unique host defense mechanism against microbial molecular mimicry. However, new models are needed to fully define the impact of microbes, galectins, or other factors on the development of clinically relevant naturally occurring anti-blood group antibodies., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Air pollution has become a major global threat to human health. Urbanization and industrialization over the past few decades have increased the air pollution. Plausible connections have been made between air pollutants and dementia. This study used machine learning algorithms (k-nearest neighbors, random forest, gradient-boosted decision trees, eXtreme gradient boosting, and CatBoost) to investigate the association between cognitive impairment and air pollution. Data from the Taiwan Biobank and 75 air-pollution-monitoring stations in Taiwan were analyzed to determine individual levels of exposure to air pollutants. The pollutants examined were particulate matter with a diameter of ≤ 2.5 μm (PM 2.5 ), nitrogen dioxide, nitric oxide, carbon monoxide, and ozone. The results revealed that the most strongly correlated with cognitive impairment were ozone, PM 2.5 , and carbon monoxide levels with adjustment of educational level, age, and household income. The model based on these factors achieved accuracy as high as 0.97 for detecting cognitive impairment, indicating a positive association between air pollutions and cognitive impairment., 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.)

Background: Existing prognostic scoring systems for intensive care unit (ICU) trauma patients require extensive data collection. The Geriatric Trauma Outcome Score (GTOS), which is based on age, injury severity, and transfusion need, has been validated for predicting mortality in elderly patients with trauma; however, its utility in the general ICU trauma population remains unexplored., Methods: This retrospective study included 2952 adult ICU trauma patients admitted between 2016 and 2021. The GTOS was calculated as follows: age + (Injury Severity Score × 2.5) + 22 (if transfused within 24 h). The area under the receiver operating characteristic curve (AUROC) was used to assess GTOS's ability to predict mortality. The optimal GTOS cutoff was determined using Youden's index. Mortality rates were compared between the high and low GTOS groups, including a propensity score-matched analysis adjusted for baseline characteristics., Results: This study included 2952 ICU trauma patients, with an overall mortality rate of 11.0% ( n = 325). GTOS demonstrated good predictive accuracy for mortality (AUROC 0.80). The optimal cutoff was 121.8 (sensitivity, 0.791; specificity, 0.685). Despite adjustments, patients with GTOS ≥ 121.8 had significantly higher mortality (17.4% vs. 6.2%, p < 0.001) and longer hospital stays (20.3 vs. 15.3 days, p < 0.001) compared to GTOS < 121.8., Conclusions: GTOS showed a reasonable ability to predict mortality in ICU trauma patients across all ages, although not as accurately as more complex ICU-specific models. With its simplicity, the GTOS may serve as a rapid screening tool for risk stratification in acute ICU trauma settings when combined with other data.

Aim: Fascin is an actin-binding protein that promotes tumor metastasis. The inhibition of fascin on the progress of non-small cell lung cancer (NSCLC) is not very clear. Hence, this study explored the potential effect of NP-G2-044, a novel fascin inhibitor, in human NSCLC lines and the Lewis lung cancer (LCC) mice model., Methods: The growth of cells was analyzed via CCK-8 assays, and the flow cytometry was adopted for cell cycle and apoptosis analysis, as well as the migration and invasion of NSCLC cells with or without NP-G2-044. The therapy of NP-G2-044, which synergizes with cisplatin and PD-1, was evaluated in the established xenograft Lewis's lung cancer of mice., Results: Fascin was overexpressed in human NSCLC cells, and inhibition of fascin by NP-G2-044 attenuated NSCLC cell growth and remarkably undermined the ability of migration and invasion in vitro, which was related to the reduced epithelialmesenchymal transition (EMT) including downregulation of N-cadherin and vimentin, and upregulation of E-cadherin. Further results implied that the above changes may be partially mediated by the Wnt/β-catenin pathway. In vivo, NP-G2-044 slowed down tumor development and enhanced overall survival alone, leading to synergistic anticancer effects with cisplatin or PD-1 inhibitor., Conclusion: Fascin inhibition could inhibit the metastasis of NSCLC and has the potential to enhance the efficacy of cisplatin and PD-1 inhibitors by blocking the Wnt/β- catenin pathway., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Coxsackievirus A16 (CVA16) is one of the primary pathogens that causes hand, foot, and mouth disease (HFMD) in young children. In previous studies, CVA16 vaccine development has encountered several challenges, such as inefficient replication of the CVA16 virus in present culture systems, the induction of only mild neutralizing antibody titers, and neutralizing antibodies induced by certain vaccine candidates that are unable to protect against CVA16 viral challenge. In this study, we constructed a DNA-launched CVA16 infectious clone (CVA16ic) based on the genomic sequence of the CVA16 N5079 strain to minimize interference from viral quasispecies. The biochemical properties of this CVA16ic strain were similar to those of its parental strain. Serum-free HEK293A suspension cells, which produced higher virus titers than Vero cells, were demonstrated to improve CVA16 production yields. In addition, our study showed that inactivated EV-A71 antigens could enhance the immunogenicity of inactivated CVA16 mature/full particles (F-particles), suggesting that a bivalent CVA16 and EV-A71 vaccine may be an effective strategy for CVA16 vaccine development. These findings are expected to provide novel strategies and accelerate the development of bivalent HFMD vaccines., Competing Interests: 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., (© 2024 The Author(s).)

Introduction: Early identification of high-risk traumatic brain injury (TBI) patients is crucial for optimizing treatment strategies and improving outcomes. The C-reactive protein-to-lymphocyte ratio (CLR) reflects systemic immunology and inflammation function and serves as a new biomarker for patient stratification. This study aimed to assess the predictive value of the CLR for mortality in patients with isolated moderate to severe TBI. Methods: A retrospective analysis of trauma registry data from 2009 to 2022 was conducted, including 1641 adult patients with isolated moderate to severe TBI. Patient demographics, the CLR, injury characteristics, and outcomes were compared between deceased and surviving patients. Univariate and multivariate analyses were performed to identify mortality risk factors. The optimal CLR cut-off value for predicting mortality was determined using receiver operating characteristic (ROC) curve analysis. Results: The CLR was significantly higher in deceased patients compared to survivors (60.1 vs. 33.9, p < 0.001). The optimal CLR cut-off value for predicting mortality was 54.5, with a sensitivity of 0.328 and a specificity of 0.812. The area under the ROC curve was 0.566, indicating poor discriminative ability. In the multivariate analysis, the CLR was not a significant independent predictor of mortality (OR 1.03, p = 0.051). After propensity score matching to attenuate the difference in baseline characteristics, including sex, age, comorbidities, conscious level, and injury severity, the high-CLR group (CLR ≥ 54.5) did not have significantly higher mortality compared to the low-CLR group (CLR < 54.5). Conclusion: While the CLR was associated with mortality in TBI patients, it demonstrated poor discriminative ability as a standalone predictor. The association between a high CLR and worse outcomes may be primarily due to other baseline patient and injury characteristics, rather than the CLR itself.

Carrot (Daucus carota L.), a widely cultivated economically vegetable from the Apiaceae family, is grown globally. However, carrots can be adversely impacted by cadmium (Cd) pollution in the soil due to its propensity to accumulate in the fleshy root, thus impeding carrot growth and posing health hazards to consumers. Given the potential of hydrogen sulfide (H 2 S) to improve plant resistance against Cd stress, we treated germinating carrot seeds with varying concentrations of sodium hydrosulfide (NaHS), aiming to alleviate the toxic impacts of Cd stress on carrot seed germination. The results revealed that carrot seeds treated with a concentration of 0.25 mM NaHS displayed better seed germination-associated characteristics compared to seeds treated with NaHS concentrations of 0.1 mM and 0.5 mM. Further investigation revealed a rise in the expression levels of L-cysteine desulfhydrase and D-cysteine desulfhydrase, along with enhanced activity of L-cysteine desulfhydrase and D-cysteine desulfhydrase among the NaHS treatment group, thereby leading to H 2 S accumulation. Moreover, NaHS treatment triggered the expression of pyrroline-5-carboxylate synthase and pyrroline-5-carboxylate reductase and promoted the accumulation of endogenous proline, while the contents of soluble sugar and soluble protein increased correspondingly. Interestingly, since the application of exogenous proline did not influence the accumulation of endogenous H 2 S, suggesting that H 2 S served as the upstream regulator of proline. Histochemical staining and biochemical indices revealed that NaHS treatment led to elevated antioxidant enzyme activity, alongside a suppression of superoxide anion and hydrogen peroxide generation. Furthermore, high performance liquid chromatography analysis revealed that NaHS treatment reduced Cd 2+ uptake, thereby promoting germination rate, seed vitality, and hypocotyl length of carrot seeds under Cd stress. Overall, our findings shed light on the application of NaHS to enhance carrot resistance against Cd stress and lay a foundation for exploring the regulatory role of H 2 S in plants responding to Cd stress., 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 Elsevier GmbH. All rights reserved.)

Background: Although colistin is widely recognized as the last line of antibiotics against gram-negative bacteria, the emergence and spread of colistin resistance severely diminish its clinical efficacy and application. An alternative strategy to alleviate this crisis is to identify promising colistin adjuvants with enhanced antibacterial activity., Purpose: In this study, the adjuvant effects of paeonol on colistin and the underlying mechanisms were investigated., Method: Minimum Inhibitory Concentration (MIC) and checkerboard assays were used to investigate the adjuvant activity and structure-activity relationship of paeonol on the antibacterial effect of colistin in vitro. Time-dependent killing and resistance development assays were used to investigate the bactericidal effects and emergence of colistin resistance. Different fluorescent probes and competitive inhibition tests were used to investigate bacterial membrane functions and potential targets. Skin infection and peritonitis-sepsis models were used to evaluate the combined in vivo effects of colistin and paeonol in vivo., Result: Paeonol enhanced the antibacterial effects of colistin against gram-negative bacteria, particularly Klebsiella pneumoniae. Structure-activity relationship analysis showed that the hydroxyl, 4-methoxy and ketone carbonyl side chains of the benzene ring contributed to the adjuvant effect of paeonol. Paeonol enhances the bactericidal effects of colistin and minimizes the emergence of colistin resistance. Notably, mechanistic studies demonstrated that the combination of colistin and paeonol enhances membrane disruption and oxidative damage, possibly via interactions with phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and cardiolipin (CAL). Importantly, paeonol enhanced the efficacy of colistin in both the skin and peritonitis infection models., Conclusion: This is the first report on the adjuvant potential of paeonol in colistin to combat K. pneumoniae by promoting membrane disruption and oxidative damage via targeting membrane phospholipids. Notably, the verified target, PE, provides an additional avenue for screening new colistin adjuvants.The combination therapy of paeonol and colistin is a promising strategy for treating infections caused by gram-negative pathogens to address antibiotic resistance issues., 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, and all authors report no conflicts of interest in this work., (Copyright © 2024. Published by Elsevier GmbH.)

Background: This study tested whether combined shock wave (SW)-facilitated melatonin (Mel) delivered into endothelial progenitor cells (EPCs) (EPC SW-Mel ) plus S-nitroso-N-acetyl-DL-penicillamine (SNAP) was superior to merely one modality alone for improving critical limb ischemia (CLI) in rats., Methods: SD rats (n = 50) were equally categorized into group 1 (sham-control), group 2 (CLI), group 3 (CLI + SNAP), group 4 (CLI + EPC SW-Mel ), and group 5 (CLI + EPC SW-Mel + SNAP), and ischemia-involved quadriceps were harvested by day 14., Results: An in vitro study showed that at time points of 24/48/72 h, the cell viability/protein expression of endothelial nitric oxide synthase (eNOS)/and cellular expression of nitric oxide (NO) were highest in EPCs, lowest in EPCs + menadione, and much higher in EPC SW-Mel + Mena than in EPCs + Mena + Mel. Protein levels of oxidative-stress (NOX-1/NOX-2/oxidized protein)/early (AN-V + /PI - )/late (AN-V + /PI + ) apoptosis and total intracellular/mitochondrial reactive oxygen species ROS exhibited an antithetical trend of cell viability among the groups (all P<0.0001). Matrigel assay of angiogenesis/positively-stained NO cells showed that they were much higher in EPCs + SNAP than in EPCs only (all P<0.0001). Ex vivo angiogenesis/arterial relaxation of carotid-artery rings were highest in left-common-carotid-artery (LCCA) + SNAP, lowest in LCCA + Mena, and notably higher in LCCA than in LCCA + Mena + SNAP (all P<0.0001). Laser Doppler showed ischemic to normal-blood-flow (INBF) ratio was highest in group 1, lowest in group 2, and it progressively increased from groups 3 to 5 (all P<0.0001). The protein levels of oxidative-stress (NOX-1/NOX-4/oxidized protein)/apoptotic [cleaved-caspase-3/cleaved apoptosis/mitochondrial-damage (cytosolic-cytochrome-C/p-DRP-1)]/fibrotic (Smad3/TGF-β)/inflammatory (MMP-9/IL-1β/TNF-α/NF-κB) biomarkers, exhibited an opposite trend, whereas the protein level of endothelial-cell surface markers (CD31/vWF/eNOS) and number of small vessels exhibited an identical pattern of INBF ratio among the groups (all P<0.0001)., Conclusions: Combined EPC SW-Mel and SNAP therapy offered a synergic effect toward rescuing from CLI., Competing Interests: None., (AJTR Copyright © 2024.)

Medulloblastoma is a heterogeneous embryonal tumor of the cerebellum comprised of four distinct molecular subgroups that differ in their developmental origins, genomic landscapes, clinical presentation, and survival. Recent characterization of the human fetal cerebellum at single-cell resolution has propelled unprecedented insights into the cellular origins of medulloblastoma subgroups, including those underlying previously elusive groups 3 and 4. In this review, the molecular pathogenesis of medulloblastoma is examined through the lens of cerebellar development. In addition, we discuss how enhanced understanding of medulloblastoma origins has the potential to refine disease modeling for the advancement of treatment and outcomes., (© 2024 Tao et al.; Published by Cold Spring Harbor Laboratory Press.)

The increasing contamination of water sources by heavy metals necessitates the development of efficient and sustainable adsorption materials. This study evaluates the potential of nano-hydroxyapatite (HA) powders synthesized from chemical reagents (Chem-HA) and clam shells (Bio-HA) as adsorbents for Cu ions in aqueous solutions. Both powders were synthesized using microwave irradiation at 700 W for 5 min, resulting in nano-sized rod-like particles confirmed as HA by X-ray diffraction (XRD). Bio-HA exhibited higher crystallinity (67.5%) compared to Chem-HA (34.9%), which contributed to Bio-HA's superior adsorption performance. The maximum adsorption capacities were 436.8 mg/g for Bio-HA and 426.7 mg/g for Chem-HA, as determined by the Langmuir isotherm model. Kinetic studies showed that the Cu ion adsorption followed the pseudo-second-order model, with Bio-HA achieving equilibrium faster and displaying a higher rate constant (6.39 × 10⁻ 4 g/mg·min) than Chem-HA (5.16 × 10⁻ 4 g/mg·min). Thermodynamic analysis indicated that the adsorption process was spontaneous and endothermic, with Bio-HA requiring less energy (ΔH° = 39.00 kJ/mol) compared to Chem-HA (ΔH° = 43.77 kJ/mol). Additionally, the activation energy for Bio-HA was lower (41.62 kJ/mol) than that for Chem-HA (46.39 kJ/mol), suggesting better energy efficiency. The formation of a new Cu 2 (OH)PO 4 phase after adsorption, as evidenced by XRD, confirmed that the Cu ions replaced the Ca ions in the HA lattice. These findings demonstrate that Bio-HA, derived from natural sources, offers environmental benefits as a recyclable material, enhancing heavy metal removal efficiency while contributing to sustainability by utilizing waste materials and reducing an environmental impact.

Background: Medication-related problem is a concerning issue in older adults with multimorbidity due to complexity of disease conditions and polypharmacy, and may lead to increase in risk for adverse health outcomes. This study aims to investigate the prevalence and associated factors of potentially inappropriate medication use among the growing population of older adults with multimorbidity in Taiwan., Method: The study population was composed of patients who were aged 65 years or older with multimorbidity (two or more chronic diseases) and had at least one outpatient clinic visit with drug prescription in 2018 identified from the Taiwan National Health Insurance Research Database. Potentially inappropriate medication use was defined using the 2019 Beers criteria for drugs to be avoided for older adults. Multiple logistic regression model was conducted to examine patient-related and prescriber-related factors associated with PIM use., Results: A total of 2 432 416 patients (69.7% of the entire older adult population) had multimorbidity and received at least one drug prescription at the outpatient clinic in Taiwan in 2018. The prevalence of having at least one PIM in this population was found to be 85.6%. Patient-related factors (age, sex, specific chronic diseases, frequency of outpatient visits) and prescriber-related factors (physician characteristics, healthcare setting, total number of medications, prior PIM use) were found to be associated with use of PIM., Conclusion: High prevalence of PIM use was found in older patients with multimorbidity in Taiwan. Both patient-related and prescriber-related factors had been found to be predictors of PIM use, and should be addressed when trying to improve the medication quality in this population., (© 2024 The Author(s). Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

The significance of anterior cruciate ligament (ACL) remnants during reconstruction remains unclear. Co-culturing ACL remnant cells and bone marrow stromal cells (BMSCs) may reduce apoptosis and enhance hamstring tendon activity. This study investigated whether extracellular vesicles (EVs), which facilitate cell-cell interactions, act as the active components, improving graft maturation in this co-culture. The effects of EVs on cell viability, proliferation, migration and gene expression in the rabbit ACL remnant cells and BMSCs were assessed using control (BMSC-only culture), co-culture (ACL remnant cells and BMSCs, CM) and co-culture without EVs (CM ∆ EVs) media. EVs were isolated from control (BMSC-EV) and co-culture (CM-EV) media and characterized. CM significantly enhanced the proliferation, migration and expression of transforming growth factor (TGF-β)-, vascular endothelial growth factor (VEGF)-, collagen synthesis- and tenogenesis-related genes. However, CM-induced effects were reversed by the CM ∆ EVs treatment. CM-EV treatment exhibited higher potential to enhance proliferation, migration and gene expression in the ACL remnant cells and BMSCs than BMSC-EV and non-EV treatments. In conclusion, EVs, secreted under the coexistence of ACL remnant cells and BMSCs, primarily increase the cell viability, proliferation, migration and gene expression of collagen synthesis-, TGF-β-, VEGF- and tenogenesis-related genes in both cell types., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background: Few studies have examined the preoperative risks and healthcare costs related to free flap revision in hypopharyngeal cancer (HPC) patients., Methods: A 20-year retrospective case-control study was conducted using the Chang Gung Research Database, focusing on HPC patients who underwent tumor excision and free flap reconstruction from January 1, 2001, to December 31, 2019. The impacts of clinical variables on the need for re-exploration due to free flap complications were assessed using logistic regression. The direct and indirect effects of these complications on medical costs were evaluated by causal mediation analysis., Results: Among 348 patients studied, 43 (12.4%) developed complications requiring re-exploration. Lower preoperative albumin levels significantly increased the risk of complications (OR 2.45, 95% CI 1.12-5.35), especially in older and previously irradiated patients. Causal mediation analysis revealed that these complications explained 11.4% of the effect on increased hospitalization costs, after controlling for confounders., Conclusions: Lower preoperative albumin levels in HPC patients are associated with a higher risk of microvascular free flap complications and elevated healthcare costs, underscoring the need for enhanced nutritional support before surgery in this population., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The N-terminal domain (NTD) of the SARS-CoV-2 S protein comprises five exposed protruding loops. Deletions, insertions, and substitutions within these NTD loops play a significant role in viral evolution and contribute to immune evasion. We reported previously that introducing the glycan masking mutation R158N/Y160T in the NTD loop led to increased titers of neutralizing antibodies against the SARS-CoV-2 Wuhan-Hu-01 strain, as well as the Alpha, Beta, and Delta variants. In this study, we conducted further investigations on 10 additional glycan-masking sites in the NTD loops. Our findings indicate that the introduction of glycan masking mutations, specifically N87/G89T, H146N/N148T, N185/K187T, and V213N/D215T significantly enhanced neutralizing antibody titers against the Delta variant. The combination of dual glycan-masking mutations R158N/Y160T+V213N/D215T and R158N/Y160T+G219N results in a shift toward the Omicron BA.1. Furthermore, the introduction of the Omicron receptor binding domain (RBD) alongside these two dual glycan masking mutations of Wuhan-Hu-1 and XBB.1 NTD sequences resulted in a noticeable shift in antigenic distances, aligning with the Omicron BA.4/5, BA.2.75.2, BQ.1.1, and XBB.1 subvariants on the antigenic map. This strategic combination, which involves the dual glycan masking mutations R158N/Y160T+V213N/D215T and R158N/Y160T+G219N in the NTD loops, along with the domain swap incorporating the Omicron RBD, emerges as a promising vaccine design strategy for the continuous development of next-generation SARS-CoV-2 vaccines., (© 2024 Wiley Periodicals LLC.)

CD19-targeted chimeric antigen receptor (CAR) T cell therapies have driven a paradigm shift in the treatment of relapsed/refractory B-cell malignancies. However, >50% of CD19-CAR-T-treated patients experience progressive disease mainly due to antigen escape and low persistence. Clinical prognosis is heavily influenced by CAR-T cell function and systemic cytokine toxicities. Furthermore, it remains a challenge to efficiently, cost-effectively, and consistently manufacture clinically relevant numbers of virally engineered CAR-T cells. Using a highly efficient piggyBac transposon-based vector, Quantum pBac™ (qPB), we developed a virus-free cell-engineering system for development and production of multiplex CAR-T therapies. Here, we demonstrate in vitro and in vivo that consistent, robust and functional CD20/CD19 dual-targeted CAR-T stem cell memory (CAR-TSCM) cells can be efficiently produced for clinical application using qPB™. In particular, we showed that qPB™-manufactured CAR-T cells from cancer patients expanded efficiently, rapidly eradicated tumors, and can be safely controlled via an iCasp9 suicide gene-inducing drug. Therefore, the simplicity of manufacturing multiplex CAR-T cells using the qPB™ system has the potential to improve efficacy and broaden the accessibility of CAR-T therapies., Competing Interests: GenomeFrontier Therapeutics TW Co., Ltd. funded the study and played a crucial role in the study design, data collection and analysis, decision to publish, and preparation of the manuscripts. The coauthors – Peter S. Chang, Yi-Chun Chen, Wei-Kai Hua, Jeff C. Hsu, Jui-Cheng Tsai, Yi-Wun Huang, Yi-Hsin Kao, Pei-Hua Wu, Kuo-Lan Karen Wen, and Sareina Chiung-Yuan Wu – are affiliated with GenomeFrontier Therapeutics TW Co., Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Chang 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.)

Calcium phosphate, particularly hydroxyapatite (HA), bears a close resemblance to human bones, rendering it a prevalent material in biomedical applications. This study focuses on the successful preparation of HA using a precipitation method with eggshell as a raw material. Subsequently, the HA powder was press-formed and sintered at various temperatures to investigate the impact of sintering temperature on the mechanical properties, including hardness, compressive strength, and fracture toughness, of the sintered HA samples (E-HA). Statistical analyses, including one-way ANOVA and Tukey's post-hoc test, were conducted to determine significant differences in these properties at different sintering temperatures. Experimental findings revealed that as the sintering temperature increased, HA partially transformed into β-TCP between 800 and 1300 °C, with α-TCP observed at 1400 °C. The elimination of pores led to an increase in relative density, with a maximum relative density of 94.5% achieved at 1200 and 1300 °C. E-HA sintered at 1200 °C exhibited the highest hardness (5.08 GPa), compressive strength (255.79 MPa), and fracture toughness (1.21 MPa·m0.5). However, at 1400 °C, a slight decrease in apparent density (2.90 g/cm 3 ) was noted due to the presence of α-TCP, along with significant grain growth. This study's objective is clearly aligned with the study design, incorporating detailed statistical analyses to validate the findings. Furthermore, bacterial culture experiments were conducted using sintered E-HA, Chem-HA (HA synthesized from reagent-grade calcium carbonate), and Comm-HA (commercial HA). Streptococcus mutans was cultured on the surfaces of sintered E-HA, Chem-HA, and Comm-HA samples for 20 h. After culturing, the OD values for all samples were below 0.2, indicating significant antibacterial efficacy. The comparable OD values and bacterial counts ( p > 0.05) suggest that the source of HA does not impact its antibacterial properties. This underscores the potential of eggshell-derived HA as an effective material for biomedical applications.

Purpose: Capillary Refill Time (CRT) measurement has gained increasing attention in the field of sepsis and septic shock. Recognizing pressure as a fundamental determinant in CRT measurement is crucial for establishing a standardized CRT measurement procedure. In this preliminary study, we elucidated the optimal pressing strength for CRT measurement by analyzing the CRTs measured under varying pressures., Method: Seventeen healthy individuals were enlisted to undergo CRT tests on their fingertips at various pressure levels. The applied force was initiated at 0.5N and incrementally increased by 0.5N until it reached 10.5N. An integrated Photoplethysmography (PPG) device was employed to capture fluctuations in light intensity. The CRT was automatically derived from the PPG signals via a specialized algorithm. The study included correlation assessment and reliability evaluation. Box plot and Bland-Altman plot were used to visualize the impact of pressure levels on CRTs., Results: A dataset of 1414 CRTs across 21 pressures showed significant differences (Kruskal-Wallis test, p < 0.0001), highlighting the impact of pressure on CRT. CRT values between 4.5N and 10.5N pressures varied less, with an Intraclass Correlation Coefficient (ICC) of 0.499 indicating moderate consistency. Notably, CRTs at 10N and 10.5N pressures revealed a high ICC of 0.790, suggesting strong agreement., Conclusion: A pressure range of 4.5N-10.5N is recommended for stable CRT measurements, with 10.0N-10.5N providing optimal consistency and reliability., Competing Interests: None to declare., (© 2024 The Authors.)

Objectives: To assess potential risk factors influencing diet outcomes after reconstruction of subtotal hypopharyngeal defects using free patch- or tube-shaped anterolateral thigh (ALT) fasciocutaneous flaps., Study Design: Retrospective cohort study., Setting: First-level referral hospital., Methods: Between January 2011 and December 2020, we studied hypopharyngeal cancer patients who underwent the reconstruction of hypopharyngeal defects using free patch- or tube-shaped ALT fasciocutaneous flaps. The choice between patch- or tube-shaped ALT flaps depended on the defect's nature, favoring patch-shaped for subtotal defects and tube-shaped for circumferential defects. A restricted diet was characterized by a history of enterostomy or endoscopic esophageal dilation treatment postreconstruction. We analyzed patients with restricted diets at 1- and 3-year follow-up visits., Results: Ninety-eight patients were enrolled; 39 patch-shaped flaps, and 59 tube-shaped flaps. No significances were noted in demographics, postoperative radiotherapy (RT) or chemotherapy, rates of free flap reoperation/salvage, or complications. However, a significant difference emerged in diet outcomes at the 1-year follow-up (P = .005). The rate of a restricted diet was 6.08 times higher in patients with tube-shaped flaps compared to patch-shaped flaps (95% confidence interval [CI]: 1.95-18.94). Stratifying based on postoperative RT revealed a 5.47 times higher rate of a restricted diet in tube-shaped flap recipients compared to patch-shaped flap recipients (95% CI: 1.44-20.48). No significances were observed in 5-year survival rates., Conclusion: Concerning postoperative RT, patch-shaped flaps exhibited a lower incidence of a restricted diet compared to tube-shaped flaps. Preservation of the posterior mucosa may play a crucial role in preventing RT-induced esophageal stricture., (© 2024 American Academy of Otolaryngology–Head and Neck Surgery Foundation.)

Nano-hydroxyapatite (nHA) demonstrates favorable biological activity, cell adhesion, cell proliferation, and osteoconductivity, making it highly valuable in biomedicine. It is extensively used as a bone substitute and in bone transplantation within the dental and orthopedic fields. This study employed oyster shells as a calcium source to synthesize nHA at 150 °C with various hydrothermal reaction durations (10 min, 1 h, 6 h, and 12 h). As a control, HA synthesized via a wet precipitation method for 1 h at room temperature was utilized. Subsequent material analyses, including XRD, FE-SEM, FTIR, and ICP-MS, were conducted, followed by comprehensive evaluations of the bioactivity, cell attachment, cell proliferation, and sintering properties of the synthesized nHA. The results indicated that nHA synthesized through the hydrothermal reaction produced nanoscale crystals, with the aspect ratio of nHA particles increasing with the duration of hydrothermal treatment. Notably, rod-like nHA particles became prominent with hydrothermal durations exceeding 6 h. nHA particles derived from oyster shells contained carbonate and trace elements (Na, Mg, K, and Sr), similar to constituents found in human hard tissue such as bone and teeth. The immersion of nHA synthesized at 150 °C for 1 h (HT2) in simulated body fluid (SBF) for 28 d led to the formation of a bone-like apatite layer on the surface, indicating the excellent bioactivity of the synthesized nHA. The cell culture results revealed superior cell attachment and proliferation for nHA (HT2). Following the sequential formation and sintering at 1200 °C for 4 h, HT2 ceramics exhibited enhanced microhardness (5.65 GPa) and fracture toughness (1.23 MPa·m 0.5 ), surpassing those of human tooth enamel.

Cross-individual variability is considered the essence of biology, preventing precise mathematical descriptions of biological motion 1-7 like the physics law of motion. Here we report that the cerebellum shapes motor kinematics by encoding dynamic motor frequencies with remarkable numerical precision and cross-individual uniformity. Using in-vivo electrophysiology and optogenetics in mice, we confirmed that deep cerebellar neurons encoded frequencies via populational tuning of neuronal firing probabilities, creating cerebellar oscillations and motions with matched frequencies. The mechanism was consistently presented in self-generated rhythmic and non-rhythmic motions triggered by a vibrational platform, or skilled tongue movements of licking in all tested mice with cross-individual uniformity. The precision and uniformity allowed us to engineer complex motor kinematics with designed frequencies. We further validated the frequency-coding function of the human cerebellum using cerebellar electroencephalography recordings and alternating-current stimulation during voluntary tapping tasks. Our findings reveal a cerebellar algorithm for motor kinematics with precision and uniformity, the mathematical foundation for brain-computer interface for motor control., Competing Interests: Declaration of interests: All authors declare no competing interests.

Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced squamous cell carcinoma of the head and neck (HNSCC). Pneumonia is a significant complication in these patients. This study aims to identify pneumonia risk factors and their impact on survival in HNSCC patients undergoing CCRT. Data from the Chang Gung Research Database (CGRD) were retrospectively reviewed for patients treated between January 2007 and December 2019. Of 6959 patients, 1601 (23.01%) developed pneumonia, resulting in a median overall survival (OS) of 1.2 years compared to 4.9 years in the non-pneumonia group ( p < 0.001). The pneumonia group included older patients with advanced tumors, more patients with diabetes mellitus (DM), more patients with invasive procedures, longer chemotherapy and radiotherapy durations, and lower body weight. The 2-year, 5-year, and 10-year OS rates were significantly lower in the pneumonia group. Multivariate analysis identified alcohol consumption, DM, gastrostomy, nasogastric tube use, longer chemotherapy, and a 2-week radiotherapy delay as independent risk factors. Understanding these risks can lead to early interventions to prevent severe pneumonia-related complications. A better understanding of the risks of pneumonia enables early and aggressive interventions to prevent severe complications.

Objective: Nutritional and inflammatory statuses have been associated with complications in microvascular-free flaps during head and neck surgeries. This study aimed to evaluate the potential of nutritional indicators in predicting postoperative free flap complications., Study Design: We conducted a 20-year retrospective, case-control study within a defined cohort., Setting: The study involved head and neck cancer patients from the Chang Gung Research Database who underwent simultaneous tumor ablation and free flap wound reconstruction between January 1, 2001, and December 31, 2019., Methods: We employed logistic regression and stratified analysis to assess the risk of free flap complications and the subsequent need for flap revision or redo in relation to nutritional indicators and other clinical variables., Results: Of the 8066 patients analyzed, 687 (8.5%) experienced free flap complications. Among these, 197 (2.4%) had free flap failures necessitating a redo of either a free flap or a pedicled flap. Beyond comorbidities such as chronic obstructive pulmonary disease, end-stage renal disease, and a history of prior radiotherapy, every 10-unit decrease in the preoperative prognostic nutritional index (PNI) was consistently associated with an increased risk of both free flap complications and failure. The covariate-adjusted odds ratios were 1.90 (95% confidence interval [CI]: 1.42-2.54) and 1.89 (95% CI: 1.13-3.17), respectively., Conclusion: A lower preoperative PNI suggests a higher likelihood of microvascular free flap complications in head and neck surgeries. Further randomized controlled trial designs are required to establish causality., (© 2024 The Authors. Otolaryngology‐Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology‐Head and Neck Surgery Foundation.)

Metal implants require an elastic modulus close to cortical bone (<30 GPa) to avoid stress shielding and ensure adequate load-bearing strength. The metastable β-type Ti-25Nb-8Sn alloy has a low elastic modulus (52 GPa), but its yield strength (<500 MPa) needs enhancement. This study enhances Ti-25Nb-8Sn's elastic admissible strain through cold rolling and aging heat treatments, investigating the microstructure's impact on mechanical and corrosion properties. The results show that lower-temperature aging (<450 °C) leads to ω-phase precipitation, yielding a 300% increase in yield strength (>1900 MPa). However, this also increases the elastic modulus (~80 GPa), limiting the deformation ability. Higher-temperature aging (>500 °C) eliminates the ω phase, transforming it into α precipitates, resulting in a lower elastic modulus (~65 GPa) and improved deformation ability, with substantial yield strength (>1000 MPa). In summary, the optimal process conditions are determined as 90% cold rolling followed by aging treatment at 550 °C. Under these conditions, Ti-25Nb-8Sn achieves the most suitable yield strength (1207 MPa) and high corrosion resistance, retaining a relatively low elastic modulus (64.7 GPa) and high elastic admissible strain (1.93%). This positions it as an ideal material for biomedical implants.

One-dimensional (1D) Zn-based heterostructures have attracted considerable interest in the field of photodetection because of their tunable properties, flexibility, and unique optoelectronic properties. However, designing 1D multi-component Zn-based heterostructures for advanced photodetectors is still a great challenge. Herein, comb-like 1D-1D ZnO-ZnSe heterostructures with ZnO and ZnSe nanowires (NWs) comprising the shaft and teeth of a comb are reported. The length of the ZnO NWs can be modulated in the range of 300-1200 nm. Microstructural characterizations confirm that the 1D heterostructure clearly shows the spatial distribution of individual components. The well-designed structure displays an extended broadband photoresponse and higher photosensitivity than pure ZnSe NWs. Furthermore, ZnSe NWs with an appropriate length of ZnO branches show increased photoresponses of 3835% and 798% compared to those of pure ZnSe NWs under green and red-light irradiation, respectively. In addition, the integrated flexible photodetector presents excellent folding endurance after 1000 bending tests. This well-designed structure has significant potential for other 1D-based semiconductors in optoelectronic applications.

Essential tremor (ET) is the most prevalent movement disorder, characterized primarily by action tremor, an involuntary rhythmic movement with a specific frequency. However, the neuronal mechanism underlying the coding of tremor frequency remains unexplored. Here, we used in vivo electrophysiology, optogenetics, and simultaneous motion tracking in the Grid2 dupE3 mouse model to investigate whether and how neuronal activity in the olivocerebellum determines the frequency of essential tremor. We report that tremor frequency was encoded by the temporal coherence of population neuronal firing within the olivocerebellums of these mice, leading to frequency-dependent cerebellar oscillations and tremors. This mechanism was precise and generalizable, enabling us to use optogenetic stimulation of the deep cerebellar nuclei to induce frequency-specific tremors in wild-type mice or alter tremor frequencies in tremor mice. In patients with ET, we showed that deep brain stimulation of the thalamus suppressed tremor symptoms but did not eliminate cerebellar oscillations measured by electroencephalgraphy, indicating that tremor-related oscillations in the cerebellum do not require the reciprocal interactions with the thalamus. Frequency-disrupting transcranial alternating current stimulation of the cerebellum could suppress tremor amplitudes, confirming the frequency modulatory role of the cerebellum in patients with ET. These findings offer a neurodynamic basis for the frequency-dependent stimulation of the cerebellum to treat essential tremor.

Background: Administering premixed drugs in commodity packets was first reported in Asia in 2015, but there continues to be a dearth of related population-based data. This study aimed at examining (1) the prevalence of drug-packet use in the population and (2) the sociodemographic profiles, particularly gender distribution, of drug-packet users., Methods: Data were derived from a survey of 18,626 Taiwanese civilians, aged 12-64 years, using stratified, multi-stage, random sampling in 2018. Participants anonymously completed a computer-assisted self-interview on tablet computers which covered the use and problematic use of illicit drugs/inhalants, prescription drugs, and other psychoactive substances., Results: Approximately 1.46% of respondents had a lifetime use of illicit drugs, with drugs in commodity packets (0.18%) being ranked the fifth-most commonly used illicit drugs, higher than nitrous oxide (0.14%) and heroin (0.09%). Ten formats of drug packets were endorsed by users. Approximately 81.6% of persons with drug packet use had lifetime use of other illicit drugs. The correlates of the use of drugs in commodity packets were different from those of the exclusive use of other drugs, particularly concerning the lack of gender differences in the former category in the whole sample and the subgroups of various sociodemographic characteristics and other substance use., Conclusion: Drugs in commodity packets have become a common way of administering illicit drugs in the population in Taiwan, and there were no gender differences among users. Our findings have implications for more efficient drug testing and culturally appropriate intervention for drug-packet use.

Although immune tolerance evolved to reduce reactivity with self, it creates a gap in the adaptive immune response against microbes that decorate themselves in self-like antigens. This is particularly apparent with carbohydrate-based blood group antigens, wherein microbes can envelope themselves in blood group structures similar to human cells. In this study, we demonstrate that the innate immune lectin, galectin-4 (Gal-4), exhibits strain-specific binding and killing behavior towards microbes that display blood group-like antigens. Examination of binding preferences using a combination of microarrays populated with ABO(H) glycans and a variety of microbial strains, including those that express blood group-like antigens, demonstrated that Gal-4 binds mammalian and microbial antigens that have features of blood group and mammalian-like structures. Although Gal-4 was thought to exist as a monomer that achieves functional bivalency through its two linked carbohydrate recognition domains, our data demonstrate that Gal-4 forms dimers and that differences in the intrinsic ability of each domain to dimerize likely influences binding affinity. While each Gal-4 domain exhibited blood group-binding activity, the C-terminal domain (Gal-4C) exhibited dimeric properties, while the N-terminal domain (Gal-4N) failed to similarly display dimeric activity. Gal-4C not only exhibited the ability to dimerize but also possessed higher affinity toward ABO(H) blood group antigens and microbes expressing glycans with blood group-like features. Furthermore, when compared to Gal-4N, Gal-4C exhibited more potent antimicrobial activity. Even in the context of the full-length protein, where Gal-4N is functionally bivalent by virtue of Gal-4C dimerization, Gal-4C continued to display higher antimicrobial activity. These results demonstrate that Gal-4 exists as a dimer and exhibits its antimicrobial activity primarily through its C-terminal domain. In doing so, these data provide important insight into key features of Gal-4 responsible for its innate immune activity against molecular mimicry., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Surgery is an essential treatment for early-stage breast cancer. However, various side effects of breast cancer surgery, such as arm dysfunction and lymphedema, remain causes for concern. Rehabilitation exercises to prevent such side effects should be initiated within 24 hours after surgery. Virtual reality (VR) can assist the process of rehabilitation; however, the feasibility of applying VR for rehabilitation must be explored, in addition to experiences of this application., Objective: This study explored patients' attitudes toward and experiences of using VR for their rehabilitation to determine the feasibility of such VR use and to identify potential barriers., Methods: A phenomenological qualitative study was conducted from September to December 2021. A total of 18 patients with breast cancer who had undergone surgical treatment were interviewed using open-ended questions. The Colaizzi 7-step procedure for phenomenological analysis was used for data analysis. To ensure high study reliability, this study followed previously reported quality criteria for trustworthiness., Results: Three themes were identified: (1) VR was powerful in facilitating rehabilitation, (2) early and repetitive upper limb movements were an advantage of VR rehabilitation, and (3) extensive VR use had challenges to be overcome. Most of the interviewed patients reported positive experiences of using VR for rehabilitation. Specifically, VR helped these patients identify appropriate motion and angle limits while exercising; in other words, knowledge gained through VR can play a key role in the rehabilitation process. In addition, the patients reported that the use of VR provided them company, similar to when a physiotherapist is present. Finally, the gamified nature of the VR system seemed to make VR-based rehabilitation more engaging than traditional rehabilitation, particularly with respect to early rehabilitation; however, the high cost of VR equipment made VR-based rehabilitation difficult to implement at home., Conclusions: The interviewed patients with breast cancer had positive experiences in using VR for rehabilitation. The high cost of both VR equipment and software development presents a challenge for applying VR-based rehabilitation., (© Shih-Chung Wu, Chia-Wen Chuang, Wen-Chun Liao, Chung-Fang Li, Hsin-Hsin Shih. Originally published in JMIR Serious Games (https://games.jmir.org).)

Background: Late-life depression (LLD) is associated with risk of dementia, yet intervention of LLD provides an opportunity to attenuate subsequent cognitive decline. Omega-3 polyunsaturated fatty acids (PUFAs) supplement is a potential intervention due to their beneficial effect in depressive symptoms and cognitive function. To explore the underlying neural mechanism, we used resting-state functional MRI (rs-fMRI) before and after omega-3 PUFAs supplement in older adults with LLD., Methods: A 52-week double-blind randomized controlled trial was conducted. We used multi-scale sample entropy to analyze rs-fMRI data. Comprehensive cognitive tests and inflammatory markers were collected to correlate with brain entropy changes., Results: A total of 20 patients completed the trial with 11 under omega-3 PUFAs and nine under placebo. While no significant global cognitive improvement was observed, a marginal enhancement in processing speed was noted in the omega-3 PUFAs group. Importantly, participants receiving omega-3 PUFAs exhibited decreased brain entropy in left posterior cingulate gyrus (PCG), multiple visual areas, the orbital part of the right middle frontal gyrus, and the left Rolandic operculum. The brain entropy changes of the PCG in the omega-3 PUFAs group correlated with improvement of language function and attenuation of interleukin-6 levels., Limitations: Sample size is small with only marginal clinical effect., Conclusion: These findings suggest that omega-3 PUFAs supplement may mitigate cognitive decline in LLD through anti-inflammatory mechanisms and modulation of brain entropy. Larger clinical trials are warranted to validate the potential therapeutic implications of omega-3 PUFAs for deterring cognitive decline in patients with late-life depression., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, a series of Ti-5Cr-xNb alloys with varying Nb content (ranging from 1 to 40 wt.%) were investigated to assess their suitability as implant materials. Comprehensive analyses were conducted, including phase analysis, microscopy examination, mechanical testing, and corrosion resistance evaluation. The results revealed significant structural alterations attributed to Nb addition, notably suppressing the formation of the ω phase and transitioning from α' + β + ω to single β phase structures. Moreover, the incorporation of Nb markedly improved the alloys' plastic deformation ability and reduced their elastic modulus. In particular, the Ti-5Cr-25Nb alloy demonstrated high values in corrosion potential and polarization resistance, signifying exceptional corrosion resistance. This alloy also displayed high bending strength (approximately 1500 MPa), a low elastic modulus (approximately 80 GPa), and outstanding elastic recovery and plastic deformation capabilities. These aggregate outcomes indicate the promising potential of the β-phase Ti-5Cr-25Nb alloy for applications in orthopedic and dental implants.

Developing a polymer-based photocrosslinked 3D printable scaffolds comprised of gelatin methacryloyl (G) and hyaluronic acid methacryloyl (H) incorporated with two molecular weights of polyethylene glycol diacrylate (P) of various concentrations that enables rabbit adipose-derived stem cells (rADSCs) to survive, grow, and differentiate into smooth muscle cells (SMCs). Then, the chemical modification and physicochemical properties of the PGH bioinks were evaluated. The cell viability was assessed via MTT, CCK-8 assay and visualized employing Live/Dead assay. In addition, the morphology and nucleus count of differentiated SMCs were investigated by adopting TRAP (tartrate-resistant acid phosphatase) staining, and quantitative RT-PCR analysis was applied to detect gene expression using two different SMC-specific gene markers α-SMA and SM-MHC. The SMC-specific protein markers namely α-SMA and SM-MHC were applied to investigate SMC differentiation ability by implementing Immunocytofluorescence staining (ICC) and western blotting. Moreover, the disk, square, and tubular cellular models of PGH7 (GelMA/HAMA=2/1) + PEGDA-8000 Da, 3% w/v) hybrid bioink were printed using an extrusion bioprinting and cell viability of rADSCs was also analysed within 3D printed square construct practising Live/Dead assay. The results elicited the overall viability of SMCs, conserving its phenotype in biocompatible PGH7 hybrid bioink revealing its great potential to regenerate SMCs associated organs repair., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Background: Contraction-type lymphatic vessels (LV) are considered suboptimal for lymphaticovenous anastomosis (LVA). However, despite these pathological changes, their functionality and link to outcomes have not been fully elucidated. The aim of this study was to determine the impact on outcomes when contraction-type LVs were used for LVA compared to the noncontraction-type (normal + ectatic) counterpart for treating lower limb lymphedema., Study Design: Eighty-three patients with gynecologic cancer-related unilateral lower-limb lymphedema who underwent LVA as their primary treatment were enrolled in this study. The study group included 20 patients who used only contraction-type LVs. An additional 63 patients (control group) received noncontraction-type LVs only. Patients with a history of LVA, liposuction, or excisional therapy were excluded. Patient characteristics, intraoperative findings, functional parameters, and pre-LVA and post-LVA volume changes were recorded and matched using propensity scores. The primary endpoint was the volume change at 6/12 months after LVA., Results: After matching, 20 patients were included in each group. All parameters were matched, except that the study group still had a significantly inferior indocyanine green (ICG)-positive ratio, lymph flow-positive ratio, and washout-positive ratios ( P <0.001, P =0.003, and P <0.001, respectively) when compared to the control group after matching. However, at 1-year follow-up, the postoperative percentage volume reduction was comparable between the groups ( P= 0.619)., Conclusion: The use of contraction-type LVs for LVA is encouraged when no other LVs are available., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Titanium and its alloys are extensively applied in artificial tooth roots because of their excellent corrosion resistance, high specific strength, and low elastic modulus. However, because of their biological inertness, their surface needs to be modified to improve the osteointegration of titanium implants. The preparation of biologically active calcium-phosphorus coatings on the surface of an implant is one effective method for enhancing the likelihood of bone integration. In this study, osteoinductive peptides were extracted from oyster shells by using acetic acid. Two peptide-containing hydroxyapatite (HA) composite coatings were then prepared: one coating was prepared by hydrothermally synthesizing an HA coating in the presence of peptides (HA/P/M), and the other coating was prepared by hydrothermally synthesizing HA and then immersing the hydrothermally synthesized HA in a peptide solution (HA/P/S). Characterization results indicated that the composite HA coatings containing oyster shell-based peptides were successfully prepared on the alkali-treated pure titanium surfaces. The HA/P/M and HA/P/S composite coatings were found to exhibit excellent hydrophilicity. Protein adsorption tests confirmed that the HA/P/M and HA/P/S coatings had an approximately 2.3 times higher concentration of adsorbed proteins than the pure HA coating.

Myocardial infarction (MI) is a leading cause of death worldwide, resulting in extensive loss of cardiomyocytes and subsequent heart failure. Inducing cardiac differentiation of stem cells is a potential approach for myocardial regeneration therapy to improve post-MI prognosis. Mesenchymal stem cells (MSCs) have several advantages, including immune privilege and multipotent differentiation potential. This study aimed to explore the feasibility of chemically inducing human amniotic membrane MSCs (hAMSCs) to differentiate into cardiomyocytes in vitro. Human amniotic membrane (AM) samples were obtained from routine cesarean sections at Far Eastern Memorial Hospital. The isolated cells exhibited spindle-shaped morphology and expressed surface antigens CD73, CD90, CD105, and CD44, while lacking expression of CD19, CD11b, CD19, CD45, and HLA-DR. The SSEA-1, SSEA-3, and SSEA-4 markers were also positive, and the cells displayed the ability for tri-lineage differentiation into adipocytes, chondrocytes, and osteoblasts. The expression levels of MLC2v, Nkx2.5, and MyoD were analyzed using qPCR after applying various protocols for chemical induction, including BMP4, ActivinA, 5-azacytidine, CHIR99021, and IWP2 on hAMSCs. The group treated with 5 ng/ml BMP4, 10 ng/ml Activin A, 10 μM 5-azacytidine, 7.5 μM CHIR99021, and 5 μM IWP 2 expressed the highest levels of these genes. Furthermore, immunofluorescence staining demonstrated the expression of α-actinin and Troponin T in this group. In conclusion, this study demonstrated that hAMSCs can be chemically induced to differentiate into cardiomyocyte-like cells in vitro. However, to improve the functionality of the differentiated cells, further investigation of inductive protocols and regimens is needed., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Shinn-Chih Wu reports financial support was provided by National Science and Technology Council. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Okra contains a viscous substance rich in water-soluble material, including fibers, pectin, proteoglycans, gum, and polysaccharides. This study explored the use of okra polysaccharides by microorganisms and their potential to improve microbiota., Methods: The regulation of microcapsules prepared from okra polysaccharides with or without L. plantarum encapsulation on intestinal microbiota was assessed through 16S metagenomic analysis and short-chain fatty acids (SCFAs) in App NL-G-F/NL-G-F mice (Alzheimer's disease; AD model)., Results: We found that Lactobacillaceae and Lactobacillus were majorly regulated by microcapsules prepared from okra polysaccharides in AD mice. Similarly, microcapsules prepared from okra polysaccharides with L. plantarum encapsulation markedly elevated the abundance of Lactobacillaceae and Lactobacillus and increased SCFAs in AD mice., Conclusion: Our results suggest that microcapsules prepared from okra polysaccharides with or without L. plantarum encapsulation may improve intestinal microbiota by elevating Lactobacillus levels in AD mice., Competing Interests: Y-KH was employed by King Long Guan Company Ltd. The remaining 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 Hsiao, Lee and Wu.)

Background: a low PNI in patients with NPC is linked to poor survival, but prior studies have focused on single-timepoint measurements. Our study aims to employ joint modeling to analyze longitudinal PNI data from each routine visit, exploring its relationship with overall survival., Methods: In this retrospective study using data from the Chang Gung Research Database (2007-2019), we enrolled patients with NPC undergoing curative treatment. We analyzed the correlation between patient characteristics, including the PNI, and overall survival. A joint model combining a longitudinal sub-model with a time-to-event sub-model was used to further evaluate the prognostic value of longitudinal PNI., Results: A total of 2332 patient were enrolled for the analysis. Separate survival analyses showed that longitudinal PNI was an independent indicator of a reduced mortality risk (adjusted HR 0.813; 95% CI, 0.805 to 0.821). Joint modeling confirmed longitudinal PNI as a consistent predictor of survival (HR 0.864; 95% CI, 0.850 to 0.879). An ROC analysis revealed that a PNI below 38.1 significantly increased the risk of 90-day mortality, with 90.0% sensitivity and 89.6% specificity., Conclusions: Longitudinal PNI data independently predicted the overall survival in patients with NPC, significantly forecasting 90-day survival outcomes. We recommend routine PNI assessments during each clinic visit for these patients.

Background: Laparoscopic hepatectomy (LH) with oncological R0 resection combined with systemic therapy offers the best chance of cure for colorectal liver metastasis. However, tumors in vicinity of major hepatic veins require complex technique. Parenchyma-sparing resection with involved vein resection and peritoneal patch reconstruction could be an efficacious alternative to preserve liver volume for adjuvant chemotherapy and avoid venous congestion of the remnant liver. 1,2 METHODS: A 64-year-old female, with history of colon cancer, had new diagnosis of liver metastatic tumor of S8 (2.8 cm), which was considering encroached on middle hepatic vein (MHV) with distal part patent. Thus margin-negative, parenchyma-sparing liver resection with involved vein resection and proximal MHV reconstruction was indicated for oncological radicality., Results: With the patient in modified French position, we dissected falciform ligament and right coronary ligament to expose the crypt between right hepatic vein (RHV) and MHV. Intraoperative ultrasound localized the tumor and resection margin. Parenchymal dissection was performed caudally to cranially, left to right, to ligate dorsal branch of G8 (G8d) and V8 and expose main trunk of MHV. The involved side-wall of MHV was incised after the proximal and distal parts clamped. Peritoneal patch was harvested from falciform ligament to repair MHV side-wall before clamps released. The patient had an uneventful recovery and remained disease-free at 1 year postoperatively with patency of distal MHV by image., Conclusions: LH with MHV reconstruction by falciform ligament for metastatic lesion is technically demanding but feasible with oncological radicality and volume preservation for adjuvant chemotherapy., (© 2023. Society of Surgical Oncology.)

Circulating exosomes derived from polymicrobial sepsis contain various non-coding RNAs and proteins. Isobaric tags for a relative or absolute quantitation proteomic analysis of the exosomal content revealed 70 dysregulated proteins in the circulating exosomes from septic mice. Next-generation sequencing was used to profile the long non-coding RNA expression in primary cultured macrophages treated with exosomes obtained from the blood of septic C57BL/6 mice, and it was discovered that the nuclear factor-kappa B (NF-κB)/miR-17-92a-1 cluster host gene (MIR17HG) pathways were activated in the macrophages. The inhibition of MIR17HG expression by RNA interference resulted in significantly decreased cell viability. RNA pull-down assays of MIR17HG revealed that ten protein targets bind to MIR17HG. Interaction networks of proteins pulled down by MIR17HG were constructed using GeneMANIA, and their functions were mainly involved in ribonucleoprotein granules, type I interferons, the regulation of organelle assembly, the biosynthesis of acetyl coenzyme A, as a signal transducer and activator of transcription (STAT) protein phosphorylation, and mRNA splicing. Furthermore, RNA interference inhibited MIR17HG expression, resulting in significantly decreased cell survival. In conclusion, this work discovered considerable MIR17HG overexpression in macrophages treated with circulating exosomes from sepsis-affected animals. This study's findings assist us in comprehending the role of exosomes in modulating inflammatory responses and mediating pathogenic pathways in macrophages during sepsis.

The escalating menace of multidrug-resistant (MDR) pathogens necessitates a paradigm shift from conventional antibiotics to innovative alternatives. Antimicrobial peptides (AMPs) emerge as a compelling contender in this arena. Employing in silico methodologies, we can usher in a new era of AMP discovery, streamlining the identification process from vast candidate sequences, thereby optimizing laboratory screening expenditures. Here, we unveil cutting-edge machine learning (ML) models that are both predictive and interpretable, tailored for the identification of potent AMPs targeting World Health Organization's (WHO) high-priority pathogens. Furthermore, we have developed ML models that consider the hemolysis of human erythrocytes, emphasizing their therapeutic potential. Anchored in the nuanced physical-chemical attributes gleaned from the three-dimensional (3D) helical conformations of AMPs, our optimized models have demonstrated commendable performance-boasting an accuracy exceeding 75% when evaluated against both low-sequence-identified peptides and recently unveiled AMPs. As a testament to their efficacy, we deployed these models to prioritize peptide sequences stemming from PEM-2 and subsequently probed the bioactivity of our algorithm-predicted peptides vis-à-vis WHO's priority pathogens. Intriguingly, several of these new AMPs outperformed the native PEM-2 in their antimicrobial prowess, thereby underscoring the robustness of our modeling approach. To elucidate ML model outcomes, we probe via Shapley Additive exPlanations (SHAP) values, uncovering intricate mechanisms guiding diverse actions against bacteria. Our state-of-the-art predictive models expedite the design of new AMPs, offering a robust countermeasure to antibiotic resistance. Our prediction tool is available to the public at https://ai-meta.chem.ncu.edu.tw/amp-meta., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)