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Adi Yugatama,1,2,&ast; Ya-Lin Huang,1,&ast; Ming-Jen Hsu,3 Jia-Pei Lin,1 Fang-Ching Chao,4 Jenny KW Lam,5 Chien-Ming Hsieh1,5,6 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan; 2Department of Pharmacy, Sebelas Maret University, Surakarta, 57126, Indonesia; 3Department of Pharmacology, Taipei Medical University, Taipei, 11031, Taiwan; 4CNRS UMR 8612, Institut Galien Paris-Saclay, Université Paris-Saclay, Orsay, 91400, France; 5Department of Pharmaceutics, School of Pharmacy, University College, London, WC1N 1AX, UK; 6Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan&ast;These authors contributed equally to this workCorrespondence: Jenny KW Lam, Department of Pharmaceutics, School of Pharmacy, University College London, 29– 39 Brunswick Square, London, WC1N 1AX, UK, Email jenny.lam@ucl.ac.uk Chien-Ming Hsieh, School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan, Email cmhsieh@tmu.edu.twBackground: Gemcitabine (GEM) faces challenges of poor oral bioavailability and extensive first-pass metabolism. Currently, only injectable formulations are available for clinical use. Hence, there is an urgent demand for the development of advanced, efficacious, and user-friendly dosage forms to maintain its status as the primary treatment for pancreatic ductal adenocarcinoma (PDAC). Nanogels (NGs) offer a novel oral drug delivery system, ideal for hydrophilic compounds like GEM. This study aims to develop NGs tailored for GEM delivery, with the goal of enhancing cellular uptake and gastrointestinal permeability for improved administration in PDAC patients.Methods: We developed cross-linked NGs via photopolymerization of methacryloyl for drug delivery of GEM. We reveal characterization, cytotoxicity, and cellular uptake studies in Caco-2 and MIA PaCa-2 cells. In addition, studies of in vitro permeability and pharmacokinetics were carried out to evaluate the bioavailability of the drug.Results: Our results show NGs, formed via photopolymerization of methacryloyl, had a spherical shape with a size of 233.91± 7.75 nm. Gemcitabine-loaded NGs (NGs-GEM) with 5% GelMA exhibited efficient drug loading (particle size: 244.07± 19.52 nm). In vitro drug release from NGs-GEM was slower at pH 1.2 than pH 6.8. Cellular uptake studies indicated significantly enhanced uptake in both MIA PaCa-2 and Caco-2 cells. While there was no significant difference in GEM’s AUC and Cmax between NGs-GEM and free-GEM groups, NGs-GEM showed markedly lower dFdU content (10.07 hr∙μg/mL) compared to oral free-GEM (19.04 hr∙μg/mL) after oral administration (p< 0.01), highlighting NGs’ efficacy in impeding rapid drug metabolism and enhancing retention.Conclusion: In summary, NGs enhance cellular uptake, inhibit rapid metabolic degradation of GEM, and prolong retention after oral administration. These findings suggest NGs-GEM as a promising candidate for clinical use in oral pancreatic cancer therapy.Keywords: oral delivery, nanogel, gemcitabine, pancreatic cancer

Wei-Jie Cheng,1,&ast; Shyr-Yi Lin,2,3,&ast; Kuo-Hsiang Chuang,4,5,&ast; Michael Chen,4 Hsiu-O Ho,1 Ling-Chun Chen,6 Chien-Ming Hsieh,1 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; 4Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan; 5PhD Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan; 6Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan&ast;These authors contributed equally to this workCorrespondence: Chien-Ming Hsieh; Ming-Thau Sheu, Email cmhsieh@tmu.edu.tw; mingsheu@tmu.edu.twIntroduction: Approximately 15%~30% of breast cancers have gene amplification or overexpression of the human epidermal growth factor receptor 2 (HER2), resulting in the chemotherapy resistance, a more-aggressive phenotype and poor prognosis.Methods: We propose a strategy of nanocarriers co-loaded with docetaxel (DTX) and pictilisib (PIC) at a synergistic ratio and non-covalently bound with dual anti-HER2 epitopes bispecific antibodies (BsAbs: anti-HER2-IV/methoxy-polyethylene glycol (mPEG) and anti-HER2-II/methoxy-PEG) for synergistic targeting to overcome the therapeutic dilemmas of the resistance for HER2-targetable chemodrugs. DTX/PIC-loaded nanocarriers (D/P_NCs) were prepared with single emulsion methods and characterized using dynamic light scattering analysis, and the drug content was assayed by high-performance liquid chromatographic method. The integrity and function of BsABs were evaluated using sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). The in vitro cell studies and in vivo breast tumor-bearing mice model were used to evaluate the anti-cancer effect and biosafety of formulations.Results: D/P_NCs optimally prepared exhibited a spherical morphology with small particle sizes (~140 nm), high drug loading (~5.5%), and good colloidal stability. The synergistic tumor cytotoxicity of loading DTX and PIC at 2:1 ratio in D/P_NCs was discovered. The BsAbs are successfully decorated on mPEGylated DTX/PIC-loaded nanocarriers via anti-mPEG moiety. In vitro studies revealed that non-covalent decoration with dual BsAbs on D_P-NCs significantly and synergistically increased cellular uptake, while with loading DTX and PIC at a synergistic ratio of 2:1 in D/P_NCs further resulted in synergistic cytotoxicity. In vivo tumor inhibition studies showed the comparable results for synergistic antitumor efficacy while minimizing systemic toxicity of chemodrugs.Conclusion: Non-covalent modification with dual distinct epitopes BsAbs on the nanocarriers loaded with dual chemodrugs at a synergistic ratio was expected to be a promising therapeutic platform to overcome the chemoresistance of various cancers and warrants further development for future therapy in the clinical.Graphical Abstract: Keywords: docetaxel, pictilisib, nanocarriers, bispecific antibodies, dual epitopes, HER2-positive breast cancer

Hong-Liang Lin,1 Wen-Ting Cheng,2 Ling-Chun Chen,3 Hsiu-O Ho,2 Shyr-Yi Lin,4,5 Chien-Ming Hsieh2 1School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan, Republic of China; 2School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan, Republic of China; 3Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu 30015, Taiwan, Republic of China; 4Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan, Republic of China; 5Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, Republic of ChinaCorrespondence: Shyr-Yi Lin; Chien-Ming Hsieh 250 Wu-Hsing Street, Taipei 11031, Taiwan, Republic of ChinaTel +886-2-27361661 ext 6112Fax +886-2-23771942Email sylin@tmu.edu.tw; cmhsieh@tmu.edu.twObjective: This study was intended to utilize lecithin-based mixed polymeric micelles (lbMPMs) for enhancing the solubility and bioavailability of honokiol and magnolol to resolve the hindrance of their extreme hydrophobicity on the clinical applications.Methods: Lecithin was selected to increase the volume of the core of lbMPMs, thereby providing a greater solubilization capacity. A series of amphiphilic polymers (sodium deoxycholate [NaDOC], Cremophor®, and Pluronic® series) were included with lecithin for screening and optimization.Results: After preliminary evaluation and subsequentially optimization, two lbMPMs formulations composed of honokiol/magnolol:lecithin:NaDOC (lbMPMs[NaDOC]) and honokiol/magnolol:lecithin:PP123 (lbMPMs[PP123]) in respective ratios of 6:2:5 and 1:1:10 were optimally obtained with the mean particle sizes of 80– 150 nm, encapsulation efficacy (EEs) of > 90%, and drug loading (DL) of > 9.0%. These lbMPMs efficiently stabilized honokiol/magnolol in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C. PK study demonstrated that lbMPMs[NaDOC] showed much improvement in enhancing bioavailability than that by lbMPMs[PP123] for both honokiol and magnolol. The absolute bioavailability for honokiol and magnolol after intravenous administration of lbMPMs[NaDOC] exhibited 0.93- and 3.4-fold increases, respectively, compared to that of free honokiol and magnolol. For oral administration with lbMPMs[NaDOC], the absolute bioavailability of honokiol was 4.8%, and the absolute and relative bioavailability of magnolol were 20.1% and 2.9-fold increase, respectively.Conclusion: Overall, honokiol/magnolol loaded in lbMPMs[NaDOC] showed an improvement of solubility with suitable physical characteristics leading to enhance honokiol and magnolol bioavailability and facilitating their wider application as therapeutic agents for treating human disorders.Keywords: lecithin, mixed polymeric micelles, honokiol, magnolol, sodium deoxycholate, pluronic

The emergence of new SARS-CoV-2 variants with a higher contagious capability and faster transmissible speed has imposed an incessant menace on global health and the economy. The SARS-CoV-2 infection might reoccur and last much longer than expected. Thence, there is a high possibility that COVID-19 can cause long-term health problems. This condition needs to be investigated thoroughly, especially the post-COVID-19 complications. Respiratory tract disorders are common and typical complications after recovery. Until now, there has been a lack of data on specialized therapeutic medicine for post-COVID-19 complications. The clinical efficacy of NRICM101 has been demonstrated in hospitalized COVID-19 patients. This herbal medicine may also be a promising therapy for post-COVID-19 complications, thanks to its phytochemical constituents. The potential pharmacological mechanisms of NRICM101 in treating post-COVID-19 respiratory complications were investigated using network pharmacology combined with molecular docking, and the results revealed that NRICM101 may exert a beneficial effect through the three primary pathways: PI3K/AKT, HIF-1, and TNF signaling pathways. Flavonoids (especially quercetin) have a predominant role and synergize with other active compounds to produce therapeutic effectiveness. Most of the main active compounds exist in three chief herbal ingredients, including Liquorice root (Glycyrrhiza glabra), Scutellaria root (Scutellaria baicalensis), and Mulberry leaf (Morus alba). To our knowledge, this is the first study of the NRICM101 effect on post-COVID-19 respiratory complications. Our findings may provide a better understanding of the potential mechanisms of NRICM101 in treating SARS-CoV-2 infection and regulating the immunoinflammatory response to improve post-COVID-19 respiratory complications., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Accurate solute solubility measuring and modeling in supercritical carbon dioxide (ScCO 2 ) would address the best working conditions and thermodynamic boundaries for material processing with this type of fluid. Theory- and data-driven methods are two general modeling approaches. Using theory-driven methods, the solubility is estimated based on the principles of thermodynamics, while data-driven methods are developed by training the algorithms. Despite acceptance of each of these methods, more experimental solubility data are still needed to promote modeling performances. In this study, for the first time, solubility of morphine sulfate is determined and modeled by a set of 13 semi-empirical (theory-driven) and random forest (data-driven) models. Using a laboratory system with an ultraviolet-visible (UV-Vis) spectroscopy, the experimental solubilities including 48 data points were obtained at different temperatures (308-338 K) and pressures (12-27 MPa). The minimum (0.806 × 10 -5 ) and maximum (5.902 × 10 -5 ) equilibrium mole fractions were observed at working pressures of 12 and 27 MPa, respectively, both at the same temperature of 338 K. It was indicated that random forest model (with AARD% of 1.29%) had an excellent predictive performance against semi-empirical models (with AARD% from 9.33 to 19.76%). The results showed that solute molecular weight had the highest effect on random forest modeling. Using modeling results from Chrastil and Bartle models, total and vaporization enthalpies of dissolution of morphine sulfate in ScCO 2 were found to be 35.12 and 59.04 kJ/mole, respectively., (© 2024. The Author(s).)

CO 2 -based aliphatic polycarbonates (aPCs), produced through the alternating copolymerization of epoxides with CO 2 , present an appealing option for sustainable polymeric materials owing to their renewable feedstock and degradable characteristics. An ongoing challenge in working with aPCs is modifying their mechanical properties to meet specific demands. Herein, we report that monomer ratio and polymer architecture of aPCs impact not only printability by digital light processing (DLP) additive manufacturing, but also dictate the thermomechanical and degradation properties of the printed objects. We found that block copolymers exhibit tailorable thermomechanical properties ranging from soft elastomeric to strong and brittle as the proportion of hard blocks increases, whereas the homopolymer blend failed to print objects and statistical copolymers delaminated or overcured, displaying the weakest mechanical properties. In addition, the hydrolytic degradation of the prints was demonstrated under various conditions, revealing that BCP prints containing a higher proportion of hard blocks had slower degradation and that statistical copolymer prints degraded more slowly than their BCP counterparts. This study underscores that polymer composition and architecture both play key roles in resin printability and bulk properties, offering significant prospects for advancing sustainable materials in additive manufacturing through polymer design., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

The relationship between workplace justice and nonfatal occupational accidents in a single-payer healthcare system has rarely been explored. As countries strive to achieve and sustain universal health coverage, healthcare workers' occupational safety and health require greater concerns. We used the data from a national survey conducted on randomly sampled Taiwanese workers. One hundred forty eight males and 567 females, with a total of 715 healthcare workers aged 20 to 65, were analyzed. The workplace scale consisted of 4 subcomponents, including distributive justice, interpersonal justice, information justice, and procedural justice, and was dichotomized into low and high groups in each dimension. Logistic regression models examined the relationship between workplace justice and self-evaluated occupational accidents among healthcare employees. The prevalence of self-evaluated occupational accidents in healthcare employees was 15.54% and 11.64% for men and women, respectively. After adjusting variables such as sociodemographic variables, physical job demands, shift work status, work contract, and psychological job demands, regression analyses indicated that health employees with lower distributive justice, interpersonal justice, information justice, and procedural justice were significantly associated with self-evaluated occupational accidents both in males and females. Expanding the study to include healthcare systems in different countries could enhance the generalizability of the findings. Offering specific recommendations for policymakers and healthcare administrators to improve workplace justice and reduce occupational accidents., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Chimeric antigen receptor (CAR) and T-cell receptor (TCR) T-cell therapies are effective in a subset of patients with solid tumors, but new approaches are needed to universally improve patient outcomes. Here, we developed a technology to leverage the cooperative effects of IL15 and IL21, two common cytokine-receptor gamma chain family members with distinct, pleiotropic effects on T cells and other lymphocytes, to enhance the efficacy of adoptive T cells., Experimental Design: We designed vectors that induce the constitutive expression of either membrane-tethered IL15, IL21, or IL15/IL21. We used clinically relevant preclinical models of transgenic CARs and TCRs against pediatric and adult solid tumors to determine the effect of the membrane-tethered cytokines on engineered T cells for human administration., Results: We found that self-delivery of these cytokines by CAR or TCR T cells prevents functional exhaustion by repeated stimulation and limits the emergence of dysfunctional natural killer (NK)-like T cells. Across different preclinical murine solid tumor models, we observed enhanced regression with each individual cytokine but the greatest antitumor efficacy when T cells were armored with both., Conclusions: The coexpression of membrane-tethered IL15 and IL21 represents a technology to enhance the resilience and function of engineered T cells against solid tumors and could be applicable to multiple therapy platforms and diseases. See related commentary by Ruffin et al., p. 1431., (©2023 American Association for Cancer Research.)

Background: Vibrio is a genus of Gram-negative bacteria found in various aquatic environments, including saltwater and freshwater. Vibrio bacteremia can lead to sepsis, a potentially life-threatening condition in which the immune system enters overdrive in response to the disease, causing widespread inflammation and damage to tissues and organs. V. vulnificus had the highest case fatality rate (39%) of all reported foodborne infections in the United States and a high mortality rate in Asia, including Taiwan. Numerous scoring systems have been created to estimate the mortality risk in the emergency department (ED). However, there are no specific scoring systems to predict the mortality risk of Vibrio bacteremia. Therefore, this study modified the existing scoring systems to better predict the mortality risk of Vibrio bacteremia., Methods: Cases of Vibrio bacteremia were diagnosed based on the results from at least one blood culture in the ED. Patient data were extracted from the electronic clinical database, covering January 2012 to December 2021. The primary outcome was in-hospital mortality.This study used univariate and multivariate analyses to evaluate the mortality risk., Results: This study enrolled 36 patients diagnosed with Vibrio bacteremia, including 23 males (63.9%) and 13 females (36.1%), with a mean age of 65.1 ± 15.7 years. The in-hospital mortality rate amounted to 25% (9/36), with 31.5% in V. vulnificus (6/19) and 17.6% in V. non- vulnificus (3/17). The non-survivors demonstrated higher MEDS (10.3 ± 2.4) than the survivors (6.2 ± 4.1) ( p = 0.002). Concerning the qSOFA, the survivors scored 0.3 ± 0.5, and the non-survivors displayed a score of 0.6 ± 0.7 ( p = 0.387). The AUC of the ROC for the MEDS and qSOFA was 0.833 and 0.599, respectively. This study modified the scoring systems with other predictive factors, including BUN and pH. The AUC of the ROC for the modified MEDS and qSOFA reached up to 0.852 and 0.802, respectively., Conclusion: The MEDS could serve as reliable indicators for forecasting the mortality rate of patients grappling with Vibrio bacteremia. This study modified the MEDS and qSOFA to strengthen the predictive performance of mortality risk for Vibrio bacteremia. We advocate the prompt initiation of targeted therapeutic interventions and judicious antibiotic treatments to curb fatality rates.

Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique pharmacokinetic behavior (e.g. high volume of distribution and affinity to extra-plasma tissue compartments), we proposed a modified PBPK model structure and developed the model with multispecies extrapolation to compensate for the limitation of obtaining clinical tissue data. Our model predicted the disposition of doxorubicin in multiple tissues including clinical tissue data with an overall absolute average fold error (AAFE) of 2.12. The model's performance was further validated with 8 clinical datasets in combined with intracellular doxorubicin concentration with an average AAFE of 1.98. To assess the potential cellular toxicity, toxicity levels and area under curve (AUC) were defined for different dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of doxorubicin in multiple organ sites associated with commonly observed adverse effects (AEs) were simulated and calculated the AUC for quantitative assessments. Our findings supported the clinical dosing regimen of 75 mg/m 2 with a 21-day interval and suggest that slow infusion and separated single high doses may lower the risk of developing AEs from a cellular level, providing valuable insights for the risk assessment of doxorubicin chemotherapy. In conclusion, our work highlights the potential of PBPK modelling to provide quantitative assessments of cellular toxicity and supports the use of clinical dosing regimens to mitigate the risk of adverse effects., Competing Interests: Declaration of Competing Interest There are none., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Albumin nanoparticles (NPs) and PEGylated liposomes have garnered tremendous interest as therapeutic drug carriers due to their unique physicochemical properties. These unique properties also have significant effects on the composition and structure of the protein corona formed around these NPs in a biological environment. Herein, protein corona formation on albumin NPs and liposomes was simultaneously evaluated through in vitro and simulation studies. The sizes of both types of NPs increased with more negatively charged interfaces upon being introduced into fetal bovine serum. Gel electrophoresis and label-free quantitative proteomics were performed to identify proteins recruited to the hard corona, and fewer proteins were found in albumin NPs than in liposomes, which is in accordance with isothermal titration calorimetry. The cellular uptake efficiency of the two NPs significantly differed in different serum concentrations, which was further scrutinized by loading an anticancer compound into albumin NPs. The presence of the hard protein corona increased the cellular uptake of albumin NPs in comparison with liposomes. In our simulation study, a specific receptor present in the membrane was greatly attracted to the albumin-apolipoprotein E complex. Overall, this study not only evaluated protein corona formation on albumin NPs, but also made promising advancements toward albumin- and liposome-based therapeutic systems.

Aim: With the advent of an aging society and the development of end-of-life care, there is an increasing need to understand the older generation's attitude toward end-of-life resuscitation. The study aimed to develop and validate a novel attitude scale toward end-of-life resuscitation in older inpatients., Method: Instrumental development and a psychometric evaluation were used. First, a new attitude scale toward end-of-life resuscitation was formulated from literature views, expert content validity, and face validity. Next, the new scale was evaluated using a principal component analysis and internal consistency reliability in a sample from 106 medical-surgical inpatients in a southern Taiwan hospital 1 enrolled through convenience sampling. Serving as an indicator of concurrent validity, a logistic regression analysis was performed to analyze the association between scores on the scale and intention to discuss end-of-life CPR issues., Results: After being validated by the expert content validity and face validity, a draft of a 20-item scale was created. Throughout the exploratory factor analysis, two items with low factor loadings were removed from the draft scale and an 18-item scale of attitude was generated. This 18-item scale had a three-factor structure that accounted for 64.1% of the total variance; the three components were named 'stress, avoidance, and ignorance', 'a peaceful death', and 'self-determination and ambivalence'. The Cronbach's alpha of the total scale and three components were 0.845, 0.885, 0.879, and 0.857, respectively, which indicated a favorable reliability. Scores on the scale were significantly associated with the intention to discuss end-of-life CPR issues, which also indicated a favorable concurrent validity., Conclusions: A 18-item attitude scale with three factors is a valid scale to measure the attitude toward end-of-life resuscitation. The result provides preliminary evidence of the psychometric properties of the scale. Further research with larger samples or other populations is required.

Salt hydrate phase change materials are important in advancing thermal energy storage technologies for the development of renewable energies. At present, their widespread use is limited by undesired undercooling and phase separation, as well as their tendency to corrode container materials. Herein, we report a direct ink writing (DIW) additive manufacturing technique to print noncorrosive salt hydrate composites with thoroughly integrated nucleating agents and thermally conductive additives. First, salt hydrate particles are prepared from nonaqueous Pickering emulsions and then employed as rheological modifiers to formulate thixotropic inks with polymer dispersions in toluene serving as the matrix. These inks are successfully printed at room temperature and cured by solvent evaporation under ambient conditions. The resulting printed and cured composites, containing up to 70 wt % of the salt hydrate, exhibit reliable thermal cyclability for 10 cycles and suppressed undercooling compared to the bulk salt hydrate. Remarkably, the composites consistently maintain their structural integrity and thermal performance throughout the entirety of both the melting and solidification processes. We demonstrate the versatility of this approach by utilizing two salt hydrates, magnesium nitrate hexahydrate (MNH, T m = 89 °C) and zinc nitrate hexahydrate (ZNH, T m = 36 °C), to achieve desired thermal characteristics across a wide range of temperatures. Further, we establish that the incorporation of carbon black in these inks enhances the thermal conductivity by at least 33%. This approach consolidates the strengths of additive manufacturing and salt hydrate phase change materials to harness customizable thermal properties, well suited for targeted thermal energy management applications., Competing Interests: The authors declare no competing financial interest., (© 2023 American Chemical Society.)

Feedback-based wavefront shaping is a promising and versatile technique for enhancing the contrast of a target signal for both coherent and incoherent light through a highly scattering medium. However, this technique can fail for a dynamic sample with a short correlation time. So far, most proposed methods for high-speed wavefront shaping can only directly enhance the intensity of coherent light but not incoherent light. Here we try to fill this gap to directly enhance incoherent light with high speed, such as fluorescence, which is essential in extending wavefront shaping to biomedical applications. For this purpose, we develop a technique based on a single acousto-optic deflector (AOD) with field-programmable gate array (FPGA) acceleration for spatiotemporal focusing within milliseconds. With the digital time gating of the feedback signal, spatiotemporal focusing of laser light with high contrast can be formed behind dynamic scattering media in milliseconds resulting in fluorescence enhancement. Furthermore, FPGA-based wavefront shaping is shown to effectively enhance fluorescence directly behind dynamic samples with short correlation times.

Liposomes have been used to improve therapeutic efficacy of drugs by increasing their bioavailability and altering biodistribution. The loading capacity of small molecules in liposomes remains a critical issue. Besides, the manufacturing process of liposomes requires multi-step procedures which hinders the clinical development. In this study, we developed a promising lipid-based nanocarriers (LN) delivery system for hydrophilic charged compounds using doxycycline (Doxy) as a model drug. This Doxy-loaded lipid nanocarrier (LN-Doxy) was fabricated by microfluidic technology. Design of experiments (DoE) was constructed to outline the interactions among the critical attributes of formulation, the parameters of microfluidic systems and excipient compositions. Response surface methodology (RSM) was furthered used for the optimization of LN-Doxy formulation. The LN-Doxy developed in this study showed high drug to lipid ratio and uniform distribution of particle size. Compared to Doxy solution, this LN-Doxy has reduced in vitro cellular toxicity and significant therapeutic efficacy which was verified in a peritonitis animal model. These results show the feasibility of using microfluidic technology combined with QbD approach to develop the LN formulation with high loading efficiency for ionizable hydrophilic drugs., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that Tsuimin Tsai, the co-author, is employed by FormuRx Pharmaceuticals. Chin-Tin Chen, Chia Ying Lee and Tsuimin Tsai have patent “Lipid-Based Nanoparticle Delivery System for Hydrophilic Charged Compound” pending to National Taiwan University. They have no other known competing financial or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Oral delivery has become the route of choice among all other types of drug administrations. However, typical chronic disease drugs are often poorly water-soluble, have low dissolution rates, and undergo first-pass metabolism, ultimately leading to low bioavailability and lack of efficacy. The lipid-based formulation offers tremendous benefits of using versatile excipients and has great compatibility with all types of dosage forms. Self-microemulsifying drug delivery system (SMEDDS) promotes drug self-emulsification in a combination of oil, surfactant, and co-surfactant, thereby facilitating better drug solubility and absorption. The feasible preparation of SMEDDS creates a promising strategy to improve the drawbacks of lipophilic drugs administered orally. Selecting a decent mixing among these components is, therefore, of importance for successful SMEDDS. Quality by Design (QbD) brings a systematic approach to drug development, and it offers promise to significantly improve the manufacturing quality performance of SMEDDS. Furthermore, it could be benefited efficiently by conducting pre-formulation studies integrated with the statistical design of experiment (DoE). In this review, we highlight the recent findings for the development of microemulsions and SMEDDS by using DoE methods to optimize the formulations for drugs in different excipients with controllable ratios. A brief overview of DoE concepts is discussed, along with its technical benefits in improving SMEDDS formulations.

This study aimed to evaluate whether psychological resilience is an independent factor of self-rated health (SRH) among patients with knee osteoarthritis (KOA). A cross-sectional study with convenience sampling was designed. Patients with doctor-diagnosed KOA were recruited from the orthopedic outpatient departments of a hospital in southern Taiwan. Psychological resilience was measured by the 10-item Connor-Davidson Resilience Scale (CD-RISC-10), and SRH was measured by three items, including the current SRH, the preceding year-related SRH, and age-related SRH. The three-item SRH scale was categorized as "high" and "low-moderate" groups by terciles. Covariates included KOA history, site of knee pain, joint-specific symptoms measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), comorbidity measured by Charlson Comorbidity Index, and demographic variables (i.e., age, sex, education attainment, and living arrangements). A multiple logistic regression was used to detect the independent variables with significant odds ratios that can predict "high" SRH among participants. Results: In total, 98 patients with KOA (66 women and 32 men) with a mean age (±SD) of 68.3 ± 8.5 years were enrolled and were analyzed. A total of 38.8% (n = 38) of participants were categorized as "high SRH", while 61.2% (n = 60) were categorized as "low-moderate SRH". Multiple logistic regression showed that CD-RISC-10 had an increased odds ratio (OR) for high SRH (OR [95% CI] = 1.061 [1.003-1.122]; p = 0.038), whereas bilateral pain (vs. unilateral pain), WOMAC stiffness, and WOMAC physical limitation showed a decreased OR for high SRH (0.268 [0.098-0.732], 0.670 [0.450-0.998], and 0.943 [0.891-0.997], respectively). Our findings provide evidence indicating that psychological resilience plays a significant positive role in the SRH in our study sample. Further research is required to extend the growing knowledge regarding the application of psychological resilience on KOA.

Palbociclib is a poorly water-soluble medicine which acts against metastatic breast cancer cells. Among various techniques to improve the solubility of this medicine, applying supercritical technologies to produce micro- and nano-sized particles is a possible option. For this purpose, extraction of solubility data is required. In this research, the solubility of palbociclib in supercritical carbon dioxide (ScCO 2 ) at different equilibrium conditions was measured at temperatures between 308 and 338 K and pressures within 12-27 MPa, for the first time. The minimum and maximum solubility data were found to be 8.1 × 10 -7 (at 338 K and 12 MPa) and 2.03 × 10 -5 (at 338 K and 27 MPa), respectively. Thereafter, two sets of models, including ten semi-empirical equations and three Peng-Robinson (PR) based integrated models were used to correlate the experimental solubility data. Bian's model and PR equation of state using van der Waals mixing rules (PR + vdW) showed better accuracy among the examined semi-empirical and integrated models, respectively. Furthermore, the self-consistency of the obtained data was confirmed using two distinct semi-empirical models. At last, the total and vaporization enthalpies of palbociclib solubility in ScCO 2 were calculated from correlation results of semi-empirical equations and estimated to be 40.41 and 52.67 kJ/mol, respectively., (© 2023. The Author(s).)

In recent years, combining different types of therapy has emerged as an advanced strategy for cancer treatment. In these combination therapies, oral delivery of anticancer drugs is more convenient and compliant. This study developed an irinotecan/rapamycin-loaded oral lecithin-based self-nanoemulsifying nanoemulsion preconcentrate ( LB SNENP ir/ra ) and evaluated its synergistic combination effects on pancreatic cancer. LB SNENP loaded with irinotecan and rapamycin at a ratio of 1:1 ( LB SNENP ir10/ra10 ) had a better drug release profile and smaller particle size (<200 nm) than the drug powder. Moreover, LB SNENP ir10/ra10 exhibited a strong synergistic effect (combination index [CI] < 1.0) in cell viability and combination effect studies. In the tumor inhibition study, the antitumor activity of LB SNENP ir10/ra10/sily20 against MIA PaCa-2 (a human pancreatic cancer cell line) was significantly increased compared with the other groups. When administered with rapamycin and silymarin, the area under the curve and the maximum concentration of irinotecan significantly improved compared with the control. We successfully developed an irinotecan/rapamycin-loaded oral self-nanoemulsifying nanoemulsion system to achieve treatment efficacy for pancreatic cancer.

Background: A 23-gene classifier has been developed based on gene expression profiles of Taiwanese luminal-like breast cancer. We aim to stratify risk of relapse and identify patients who may benefit from adjuvant chemotherapy based on genetic model among distinct clinical risk groups. Methods: There were 248 luminal (hormone receptor-positive and human epidermal growth factor receptor II-negative) breast cancer patients with 23-gene classifier results. Using the modified Adjuvant! Online definition, clinical high/low-risk groups were tabulated with the genetic model. The primary endpoint was a recurrence-free interval (RFI) at 5 years. Results: There was a significant difference between the high/low-risk groups defined by the 23-gene classifier for the 5-year prognosis of recurrence (16 recurrences in high-risk and 3 recurrences in low-risk; log-rank test: p < 0.0001). Among the clinically high-risk group, the 5-year RFI of high risk defined by the 23-gene classifier was significantly higher than that of the low-risk group (15 recurrences in high-risk and 2 recurrences in low-risk; log-rank test: p < 0.0001). Conclusion: This study showed that 23-gene classifier can be used to stratify clinically high-risk patients into distinct survival patterns based on genomic risks and displays the potentiality to guide adjuvant chemotherapy. The 23-gene classifier can provide a better estimation of breast cancer prognosis which can help physicians make a better treatment decision.

When calculating structural or spectroscopic properties of molecular crystals, the question arises whether it is sufficient to simulate only a single molecule or a small molecular cluster or whether the simulation of the entire crystal is indispensable. In this work we juxtapose calculations on the high-pressure structural properties of the (periodic) HCN crystal and chains of HCN molecules of finite length. We find that, in most cases, the behavior of the crystal can be reproduced by computational methods simulating only around 15 molecules. The pressure-induced lengthening of the C-H bond in HCN found in calculations on both the periodic and finite material are explained in terms of orbital interaction. Our results pave the way for a more thorough understanding of high-pressure structural properties of materials and give incentives for the design of materials that expand under pressure. In addition, they shed light on the complementarity between calculations on periodic materials and systems of finite size., (© 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

The applicability of the Oncotype DX ® (Genomic Health, Inc., Redwood City, CA, USA) recurrence score (RS) in Asian populations is unclear. A 23-gene classifier, RecurIndex ® (Amwise Diagnostics, Pte. Ltd., Singapore), has been developed based on the gene expression profiles of early-stage breast cancer patients of ethnic Han Chinese population in Taiwan. This study aimed to compare the performance of the Oncotype DX ® RS with the RecurIndex ® recurrence index (RI) for predicting relapse-free survival. Therefore, we calculated both the RI and RS for 110 early stage breast cancer patients, with the cut-off value for high-risk recurrence set at 26 and 29 for the RS and the RI, respectively. With relapse-free interval (RFI) as the primary endpoint, the concordance between RS and RI was 78.2% (Kappa value = 0.297). For a median follow-up interval of 27 months, there was a statistically significant difference in RFI between the high- and low-risk groups defined by the RI ( p = 0.04) but not between risk groups defined by the RS ( p = 0.66). In conclusion, whereas there was high concordance between the RecurIndex ® RI and the Oncotype DX RS, the current data showed that the RI had a better discrimination for recurrence risk than the RS. Subsequent studies with larger sample sizes will be needed to confirm the superiority of the RI over the RS in the Asian population.

This publisher's note contains corrections to Opt. Lett.47, 5192 (2022)10.1364/OL.467435.

Owing to the high technology maturity of thermally activated delayed fluorescence (TADF) emitter design with a specific molecular shape, extremely high-performance organic light-emitting diodes (OLEDs) have recently been achieved via various doping techniques. Recently, undoped OLEDs have drawn immense attention because of their manufacturing cost reduction and procedure simplification. However, capable materials as host emitters are rare and precious because general fluorophores in high-concentration states suffer from serious aggregation-caused quenching (ACQ) and undergo exciton quenching. In this work, a series of diboron materials, CzDBA, iCzDBA, and t BuCzDBA, is introduced to realize the effect of steric hindrance and the molecular aspect ratio via experimental and theoretical studies. We computed transition electric dipole moment (TEDM) and molecular dynamics (MD) simulations as a proof-of-concept model to investigate the molecular stacking in neat films. It is worth noting that the pure t BuCzDBA film with a high horizontal ratio of 92% is employed to achieve a nondoped OLED with an excellent external quantum efficiency of 26.9%. In addition, we demonstrated the first ultrathin emitting layer (1 nm) TADF device, which exhibited outstanding power efficiency. This molecular design and high-performance devices show the potential of power-saving and economical fabrication for advanced OLEDs., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Background: Physical activity (PA) is a basic and initiative conservative management for people with knee osteoarthritis (KOA). This study aimed to explore the potential indicators of PA levels in people with KOA., Methods: We designed a cross-sectional study where people with KOA were consecutively approached by the Orthopedic Outpatient Department in a hospital in southern Taiwan. People older than 50 years that could communicate and consent to the present study were enrolled. As a dependent variable, the Chinese version of the Physical Activity Scale for the Elderly (PASE-C) was used to assess the participant's PA levels. Considering differences in sex, a PASE-C score cut-off point of 140 for men and 120 for women was used. Participants were then divided into "active" and "inactive" groups. We measured independent variables consisting of the demographic and clinical characteristics, such as comorbidities measured by the Charlson Comorbidity Index (CCI), depression status measured by the Geriatric Depression Scale-5, body mass index, KOA history (<5, 5-<10, and ≥10 years), knee pain (unilateral or bilateral), the severity of symptoms measured by the Western Ontario and McMaster Universities Osteoarthritis Index, and 6-meter preferred walking speed. Multiple logistic regression was performed to identify significant relationships between PA among people with KOA., Results: We analyzed a total of 188 people with KOA (56 men and 132 women) with a mean age of 69.4 ± 7.9 (range: 51 to 90 years). Approximately 72.9% ( n  = 137) were categorized as "inactive PA," while 27.1% ( n  = 51) of participants were categorized as "active PA" (male: 32.1%; female: 25.0%). Multiple logistic regression showed a positive association of 6-meter preferred walking speed with active PA (OR: 7.08; 95% CI:1.14-44.13), whereas advanced age and comorbidity (CCI≥1 vs. CCI<1) were negatively associated with active PA with an OR (95% CI) score of 0.91 (0.86-0.97) and 0.37 (0.15-0.87), respectively., Conclusions: People with KOA require appropriate lifestyle management to increase PA. Walking speed may be an effective factor for predicting PA among people with KOA. Healthcare providers treating KOA patients should be aware of their PA levels, especially those at risk., Competing Interests: All authors declare no conflicts of interest., (Copyright © 2022 Min-Fen Hsu et al.)

The device efficiency of PM6 : Y6 -based nonfullerene organic solar cells is fast advanced recently. To maintain organic solar cells (OSCs) with high power conversion efficiency over 16% in long-term operation, however, remains a challenge. Here, a novel non-volatile additive, an open-cage [60]fullerene ( 8OC 60 Me ), is incorporated into PM6:Y6 -based OSCs for high-performance with high durability. With optimized addition of 1.0 wt % 8OC 60 Me , the PCE value of PM6:Y6/8OC 60 Me OSCs can be promoted to 16.5% from 15.0%. Most strikingly, such a high PCE performance can maintain nearly 100% for over 500 h at room temperature; at an elevated operation temperature of 80 °C, the PCE can be stabilized above 15.0% after 45 h of operation. Grazing incidence small- and wide- angle X-ray scattering studies reveal improved orientation and crystallinity of Y6 in a fractal-like network structure of PM6 in PM6:Y6 / 8OC 60 Me films under in situ annealing, parallel to the enhanced electron mobility. Analysis of charge distributions lines up possible van der Waals interaction between the thienyl/carbonyl moiety of 8OC 60 Me and difluorophenyl-based FIC-end groups of Y6 . This result is of great contrast to those devices with the best-selling PC 61 BM as the additives─ 8OC 60 Me might be of interest to be incorporated into future Y6 -based OSCs for concomitantly improved PCE and excellent stability.

The analysis of parent drug is usually the design of choice for a bioequivalence (BE) study. However, there is a controversy regarding the choice of analytes between EMA and USFDA for the BE study of ezetimibe (EZE). The EMA recommends measuring the total form alone, that means the sum of the concentration of "parent" EZE and "metabolite" ezetimibe-glucuronide (EZEG), as the BE determination. On the other hand, the USFDA recommends measuring not only total form but also EZE. The aim of this study was to employ a simulation approach to determine which analyte (e.g., EZE alone, EZEG alone, total form alone, or combination of EZE and total form) was more appropriate for use as a BE indicator. The previously published pharmacokinetic model of EZE and EZEG with enterohepatic circulation was used to generate virtual BE studies. Eight different scenarios were performed with changes in the rate of absorption of EZE and EZEG. Five hundred virtual BE studies were generated for each scenario. In addition, the discriminatory ability of selected analytes for detecting differences in the rate of absorption of EZE and EZEG was evaluated based on power curve performance. The results obtained through simulations indicated that none of the single analytes (EZE alone, EZEG alone, and total form alone) could have clear advantages in terms of discriminatory ability. Therefore, it was recommended that a combination of EZE and total form should be used in the BE assessment., (Copyright © 2022. Published by Elsevier B.V.)

A Quick Response Code (QR Code) aims to provide accurate and traceable information to consumers wanting to verify the quality of agri-food products. This study aimed to investigate the experiences and intentions of scanning QR Code in traditional markets and supermarkets. Furthermore, the types of egg information in the QR Code were explored to identify consumer interests when purchasing eggs. The empirical data were collected from 1112 valid responses throughout Taiwan from July to September, 2020. The Logit, Probit models, and the Bivariate Probit model were used to examine the data. Results showed that shoppers' propensity to scan QR Code revealed a significant difference between traditional markets and supermarkets, i.e., supermarket shoppers having higher a propensity to scan a QR Code. Of the 10 types of potential egg information in the QR Code, over half of respondents said that the production certificate label and inspection information were the top reasons that they would be interested in scanning a QR Code. This was particularly the case for homemakers aged between 51 and 60 years old and those who had scanned QR Code before and would like to pursue more egg information. Since the egg producers have resisted joining the traceability system, the implication of this study provides very practical strategies for government, policy makers, and producers in Taiwan.

Due to the increasing rate of drug resistance in Candida spp., higher doses of antifungal agents are being used resulting in toxicity. Drug delivery systems have been shown to provide an effective approach to enhance the efficacy and reduce the toxicity of antifungal agents. Oleic acid was revealed to effectively inhibit biofilm formation, hence reducing the virulence of Candida albicans . In this study, oleic acid-based self micro-emulsifying delivery systems (OA-SMEDDS) were developed for delivering clotrimazole (CLT). Based on the pseudo-ternary phase diagram and loading capacity test, the optimal ratio of OA-SMEDDS with CLT was selected. CLT-loaded OA-SMEDDS not only bears a higher drug loading capacity but also maintains good storage stability. The minimum inhibitory concentration (MIC 50 ) of CLT-loaded OA-SMEDDS (0.01 μg/mL) in Candida albicans was significantly lower than that of CLT dissolved in DMSO (0.04 μg/mL). Moreover, we showed CLT-loaded OA-SMEDDS could effectively prevent biofilm formation and destroy the intact biofilm structure of Candida albicans. Furthermore, a CLT-loaded OA-SMEDDS gel was developed and evaluated for its antifungal properties. Disk diffusion assay indicated that both CLT-loaded OA-SMEDDS and CLT-loaded OA-SMEDDS gels were more effective than commercially available products in inhibiting the wild-type and drug-resistant species of Candida .

Breast cancer is the most common cancer and the leading cause of cancer-related deaths in women. The estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are the important biomarkers in the prognosis of breast cancer, and their expression is used to categorize breast cancer into subtypes. We aimed to analyze the concordance among ER, PR, and HER2 expression levels and breast cancer subtyping results obtained by immunohistochemistry (IHC, for protein) and reverse transcriptase-polymerase chain reaction (RT-PCR, for mRNA) and to assess the recurrence-free survival (RFS) of the different subtypes as determined by the two methods. We compared biomarker expression by IHC and RT-PCR in 397 operable breast cancer patients and categorized all patients into luminal, HER2, and triple-negative (TN) subtypes. The concordance of biomarker expression between the two methods was 81.6% (κ = 0.4075) for ER, 87.2% (κ = 0.5647) for PR, and 79.1% (κ = 0.2767) for HER2. The κ-statistic was 0.3624 for the resulting luminal, HER2, and TN subtypes. The probability of 5-year RFS was 0.78 for the luminal subtype versus 0.77 for HER2 and 0.51 for TN, when determined by IHC (P=0.007); and 0.80, 0.71, and 0.61, respectively, when determined by the RT-PCR method (P=0.008). Based on the current evidence, subtyping by RT-PCR performs similar to conventional IHC with regard to the 5-year prognosis. The PCR method may thus provide a complementary means of subtyping when IHC results are ambiguous., (© 2022 The Author(s).)

The olivine phosphate LiCoPO 4 is a prospective cathode material in high-voltage lithium-ion batteries. During lithium diffusion, the ions must overcome the diffusion energy barrier near the surface and in the bulk. Experimental studies have shown that Fe doping can enhance the electrochemical performance of LiCoPO 4 with a doping concentration of x = 0.2 (LiFe 0.2 Co 0.8 PO 4 ). DFT calculations can provide detailed understanding of the lithium diffusion mechanism, structural stability, and electronic properties for Fe-doped LiCoPO 4 and elucidate the origins for this improvement from a microscopic viewpoint. In this study, the electronic structure of Fe-doped LiCoPO 4 was calculated via first principles and compared with that of pristine LiCoPO 4 . To investigate the surface properties of LiCoPO 4 , surface energies with low indices were calculated. The results showed that the (010) surface has the lowest surface energy. Minimum energy diffusion pathways and energy barriers were calculated using the NEB method. Our calculations showed that the energy barrier for lithium-ion diffusion can be reduced by Fe doping modification. Furthermore, we investigated the diffusion processes of polarons and lithium ions migrating simultaneously. This study has implications for further application of LiCoPO 4 as a cathode material.

Background: The gel dosimeter is a chemical as well as a relative dosimeter., Objective: To evaluate the feasibility of using N-isopropylacrylamide (NIPAM) gel dosimeter to observe the dynamic dose effects and quantification of the respiration, and to help determine the safety margins., Methods: The NIPAM gel dosimeter combined with the dynamic phantom was used to simulate radiotherapy of lung or upper abdominal tumor. The field set to 4 × 5 cm2, simulate respiratory rate of 4 sec/cycle, and motion range 2 cm. MRI was used for reading, and MATLAB was used for analysis. The 3%/3 mm gamma passing rate > 95% was used as a clinical basis for evaluation., Results: The dynamic dose curve was compared with 4 × 5, 4 × 4, 4 × 3 cm2 TPS, and gamma passing rates were 74.32%, 54.83%, 30.18%. Gamma mapping demonstrated that the highest dose region was similar to the result of the 4 × 4 cm2 TPS. After appropriate selection and comparing that the ⩾ 60% part of the dose curve with TPS, the gamma passing rate was 96.49%., Conclusions: Using the NIPAM gel dosimeter with dynamic phantom to simulate organ motion during respiration for dynamic dose measurement and quantified the dynamic dose effect is feasible. The results are consistent with clinical evaluation standards.

Background: Radiotherapy plays an important role in cancer treatment today. Successful radiotherapy includes precise positioning and accurate dosimetry., Objective: To use NIPAM gel dosimeter and concentric swing machine to simulate and evaluate the feasibility of lung or upper abdominal tumor dose distribution during breathing., Methods: We used a concentric swing machine to simulate actual radiotherapy for lung or upper abdomen tumors. A 4 × 4 cm2 irradiation field area was set and MRI was performed. Next, readout analysis was performed using MATLAB and the 3 mm, 3% gamma passing rate > 95% was used as a basis for evaluation., Results: The concentric dynamic dose curve for a simulated respiratory rate of 3 seconds/breath and 4 × 4 cm2 field was compared with 4 × 4, 3 × 3, and 2 × 2 cm2 treatment planning systems (TPS), and the 3 mm, 3% gamma passing rate was 42.87%, 54.96%, and 49.92%, respectively. Pre-simulation showed that the high-dose region dose curve was similar to the 2 × 2 cm2 TPS result. After appropriate selection and comparison, we found that the 3 mm, 3% gamma passing rate was 97.92% on comparing the > 60% dose curve with the 2 × 2 cm2 TPS., Conclusions: NIPAM gel dosimeter and concentric swing machine use is feasible to simulate dose distribution during breathing and results conforming to clinical evaluation standards.

In this study, we designed, synthesized, and characterized an A-D-A'-D-A-type indacenodithienothiophene ( IDTT )-based molecular acceptor that exhibited a broader absorption range and higher lowest unoccupied molecular orbital energy level with a nearly comparable band gap compared to a well-known electron acceptor IT-M . The designed electron-deficient molecular acceptor FB-2IDTT-4Cl with a fluorinated benzene tether ( FB ), that is, p -tetrafluorophenylene divinylene, demonstrated long-wavelength absorption and high hole and electron charge mobility in the thin films blended with the electron donor PBDB-T for an inverted organic photovoltaic (OPV) binary device, resulting in a maximum power conversion efficiency (PCE) of 11.4%. Such a performance is comparably as high as that of the device with PBDB-T:IT-M , and particularly, it was 18.8% higher than that of the devices with ITIC-4Cl as the acceptor (PCE 9.1% ± 0.5%) and 24.9% higher than that of the devices with the thiophene-flanked benzothiadiazole-bridged acceptor CNDTBT-IDTT-FINCN (PCE 9.01% ± 0.13%). Furthermore, varying the illumination intensity from 200 to 2000 lux increased the J sc and V oc values as well as the FF values, thus leading to increased PCE levels. In addition, the best PCE of the PM6:Y6 device with 1% FB-2IDTT-4Cl as additives was 16.9%. Our stability test showed that the PM6:Y6 standard device efficiency downgraded very soon either at room temperature or under thermal-annealing conditions. However, with the addition of 1% FB-2IDTT-4Cl as additives, the device efficiency still can be maintained at 90-95% in 500 h at room temperature and 95% at 20 h and 85-95% in 45 h at an annealing temperature of 80 °C. These findings demonstrate FB-2IDTT-4Cl to be a promising candidate as an electron acceptor with a fluorinated π-bridging fused-ring design for OPV applications.

Pragmatic insertion of pargyline, a LSD1 inhibitor, as a surface recognition part in the HDAC inhibitory pharmacophore was planned in pursuit of furnishing potent antiprostate cancer agents. Resultantly, compound 14 elicited magnificent cell growth inhibitory effects against the PC-3 and DU-145 cell lines and led to remarkable suppression of tumor growth in human prostate PC-3 and DU-145 xenograft nude mouse models. The outcome of the enzymatic assays ascertained that the substantial antiproliferative effects of compound 14 were mediated through HDAC6 isoform inhibition as well as selective MAO-A and LSD1 inhibition. Moreover, the signatory feature of LSD1 inhibition by 14 in the context of H3K4ME2 accumulation was clearly evident from the results of western blot analysis. Gratifyingly, hydroxamic acid 14 demonstrates good human hepatocytic stability and good oral bioavailability in rats and exhibits enough promise to emerge as a therapeutic for the treatment of prostate cancer in the near future.

We report a joint system with both confocal Raman spectroscopy (CRS) and optical coherence tomography (OCT) modules capable of quickly addressing the region of interest in a tissue for targeted Raman measurements from OCT. By using an electrically tunable lens in the Raman module, the focus of the module can be adjusted to address any specific depth indicated in an OCT image in a few milliseconds. We demonstrate the performance of the joint system in the depth dependent measurements of an ex vivo swine tissue and in vivo human skin. This system can be useful in measuring samples embedded with small targets, for example, to identify tumors in skin in vivo and assessment of tumor margins, in which OCT can be used to perform initial real-time screening with high throughput based on morphological features to identify suspicious targets then CRS is guided to address the targets in real time and fully characterize their biochemical fingerprints for confirmation., Competing Interests: The authors declare no conflicts of interest., (© 2021 Optical Society of America under the terms of the OSA Open Access Publishing Agreement.)

Therapeutic efficacies of orally administrated hydrophobic chemodrugs are decreased by poor water solubilities and reduced oral bioavailabilities by P-glycoprotein (P-gp) and CYP450. In this study, CPT11 alone or combined with dual-function inhibitors (baicalein (BA) silymarin (SM), glycyrrhizic acid (GA), and glycyrrhetinic acid (GLA)) of P-gp and CYP450 loaded in a lecithin-based self-nanoemulsifying nanoemulsion preconcentrate (LBSNENP) to improve the solubility and inhibit the elimination by P-gp and CYP450. Results revealed that the LBSNENP composed of Capryol 90, lecithin/Tween 80/Cremophor EL, and propylene glycol at a weight ratio of 18:58:24 (designated PC90C10P0) was optimally selected. Encapsulating CPT11 with PEO-7000K in PC90C10P10/30 further enhanced the resultant hydrogel to be gastro-retainable and to release CPT11 in a sustained manner. Pharmacokinetic study of CPT11-loaded PC90C10P0 administered orally revealed an absolute bioavailability (FAB, vs. intravenous CPT11) of 7.8 ± 1.01% and a relative bioavailability (FRB1, vs. oral solution of CPT11) of 70.7 ± 8.6% with a longer half-life ( T 1/2 ) and mean residence time (MRT). Among the dual-function inhibitors, SM was shown to be the most influential in increasing the oral bioavailability of CPT11. SM also increased the plasma concentration of the SN-38 active metabolite, which formed from the enhanced plasma concentration of CPT11. It is concluded that treatment with CPT11 loaded in PC90C10P0 with or without solubilization with SM could expose tumors to higher plasma concentrations of both CPT11 and SN-38 leading to enhancement of tumor growth inhibition with no signs of adverse effects.

The development of the biotech industry is in full swing, and consumers have begun to value biotech brands. Since biotech products often focus on the future or special benefits, consumers inevitably bear certain risks when purchasing biotech products, and their trust in the biotech brand will have an important impact on their purchase intention. Previous studies have lacked a targeted understanding of consumer trust in biotech brands and a discussion of cultural viewpoints. This study introduced the concept of personal connections in Chinese relationalism and trust strategies in Chinese society to address this gap. In-depth interviews and focus group discussions were conducted in collaboration with Company X, a listed Taiwanese cord blood company, to extract the key factors influencing consumer trust and purchase intention of biotech brands. After constructing the structure model, the study was validated using a structural equation model through investigation and survey. The findings indicated that consumer trust in biotech brands was constructed by a combination of kinship trust transfer and emergent trust transfer within the consumer relationship network, as well as institutional trust and professional trust outside the relationship network and that a significant positive correlation existed between consumer trust in biotech brands and purchase intention. The acquaintances within the consumer relationship network include not only relatives and friends but also health care workers and netizens that consumers come into contact with. In addition, kinship trust transfer and emergent trust transfer within the consumer relationship network have a greater impact on trust in biotech brands than the institutional trust and professional trust outside the relationship network. The findings of this study deepen the understanding of consumer trust in biotech brands across cultures, and suggest that future marketing communication should be expanded to include key players within the consumer relationship network.

Histone deacetylase (HDAC) inhibitors have emerged as a new class of antitumor agent for various types of tumors. MPT0B291, a novel selective inhibitor of HDAC6, demonstrated significant antiproliferative activity in various human cancer cell types. However, MPT0B291 has very low water solubility, which limits its clinical use for cancer therapy. In the current study, MPT0B291 was encapsulated in human serum albumin (HSA), and its anticancer activities were investigated. Nanoparticles (NPs) were prepared using two-stage emulsification resulting in 100~200-nm NPs with a fine size distribution (polydispersity index of <0.3). The in vitro drug release profiles of MPT0B291-loaded HSA NPs presented sustained-release properties. The cytotoxic effect on MIA PaCa-2 human pancreatic carcinoma cells was found to be similar to MPT0B291-loaded HSA NPs and the free-drug group. The albumin-based formulation provided a higher maximum tolerated dose than that of a drug solution with reduced toxicity toward normal cells. Furthermore, in vivo pharmacokinetic studies demonstrated an effective increase (5~8-fold) in the bioavailability of NPs containing MPT0B291 loaded in HSA compared to the free-drug solution with an extended circulation time ( t 1/2 ) leading to significantly enhanced efficacy of anticancer treatment.

By enhancing vagal activity, auricle transcutaneous electric nerve stimulation (TENS) is developed as a non-invasive therapy for heart failure. Nevertheless, though shoulder TENS used for treating adhesive capsulitis could affect vagal tone, its potential impact on heart functions remains unclear. In this study, electrocardiogram (ECG) and heart rate (HR) of subjects in response to sham, right-sided, or left-sided shoulder TENS (TENS-S, TENS-R, and TENS-L, respectively; 5 min) were recorded and analyzed. During the stimulation period, TENS-R constantly and TENS-L transiently decreased the HR of subjects; both TENS-R and TENS-L increased powers of the low- and high-frequency spectra. While TENS-R exhibiting no effect, TENS-L increased the ratio of low/high-frequency power spectrum indicating TENS-R decreased the HR through potentiating cardiac vagal tone. Collectively, these results suggest TENS could be an early and non-invasive therapy for heart failure patients before considering implant devices or devices are not feasible; moreover, therapists/physicians need to carefully monitor the potential adverse events during treatment for patient safety.Trial registration: The study protocol was registered in ClinicalTrials.gov (NCT03982472; 11/06/2019)., (© 2021. The Author(s).)

Composite dressing composed of Rhizochitosan and Regenplex™ to promote wound healing were assessed. Rhizochitosan was fabricated by deacetylation of Rhizochitin, which obtained by simply depigmenting sporangium-free mycelial mattress produced from Rhizopus stolonifer F6. Physicochemical characterizations of Rhizochitosan demonstrated that it contained 13.5% chitosan with a water-absorption ability of 35-fold dry weight and exhibiting hydrogel nature after hydration. In a wound-healing study on SD rats with full-thickness injury, the composite dressing had a better healing effect than those for each individual components and control group and wound even healed as functional tissue instead of scar tissue. The underlying mechanism of the composite beneficial to wound remodeling is likely attributable to a more reduction level of matrix metalloproteinase (MMP)-9 expression in early stage and a higher MMP-2 expression level in a later stage of healing process. Conclusively, the composite dressing demonstrated to be highly beneficial to the healing of full-thickness injury wound., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Highly efficient thermally activated delayed fluorescence (TADF) molecules are in urgent demand for solid-state lighting and full-color displays. Here, the design and synthesis of three triarylamine-pyridine-carbonitrile-based TADF compounds, TPAPPC, TPAmPPC, and tTPAmPPC, are shown. They exhibit excellent photoluminescence quantum yields of 79-100% with small ΔE ST values, fast reverse intersystem crossing (RISC), and high horizontal dipole ratios (Θ //  = 86-88%) in the thin films leading to the enhancement of device light outcoupling. Consequently, a green organic light-emitting diode (OLED) based on TPAmPPC shows a high average external quantum efficiency of 38.8 ± 0.6%, a current efficiency of 130.1 ± 2.1 cd A -1 , and a power efficiency of 136.3 ± 2.2 lm W -1 . The highest device efficiency of 39.8% appears to be record-breaking among TADF-based OLEDs to date. In addition, the TPAmPPC-based device shows superior operation lifetime and high-temperature resistance. It is worth noting that the TPA-PPC-based materials have excellent optical properties and the potential for making them strong candidates for TADF practical application., (© 2021 Wiley-VCH GmbH.)

This pretest-posttest pilot study was to examine the effects of how olfactory stimulation (OS) influenced swallowing function in older adults. Forty-four community-dwelling older residents (24 OS & 20 control) from southern Taiwan were recruited. Participants in the intervention group administered pre-meal OS using odor and flavor inhalation. The study found that physiological responses for different food textures significantly differed between groups at post-test ( p   ≤  .02). Within the experimental group, swallowing function, and individual satisfaction showed significant differences before and after the odor inhalation over time ( p  < .01, η p 2  = 0.16-0.33). An individual's satisfaction to their own swallowing capacity was largely enhanced by the significant interaction between time and group ( F [1, 42] = 11.34, p  = .002, η p 2  = 0.21), but not for physiological response to OS and swallowing function. The results suggest OS may be advantageous to improving physiological response to OS, swallowing function and satisfaction with swallowing capacity in older adults., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Hurdled and marred by the notorious nature of glioblastomas (GBM) in terms of resistance to therapy and limited drug delivery into the brain, the anti-GBM drug pipeline is required to be loaded with mechanistically diverse agents. The consideration of HDAC inhibition as a prudent approach to circumvent the resistance issue in GBM spurred us to pragmatically design and synthesizes hydroxamic acids endowed with CNS penetrating ability. By virtue of the blood brain barrier permeability (BBB), memantine was envisioned as an appropriate CAP component for the construction of the HDAC inhibitors. Diverse linkers were stapled for the tetheration of the zinc binding motif with the CAP group to pinpoint an appropriate combination (CAP and linker) that could confer inhibitory preference to HDAC6 isoform (overexpressed in GBM). Resultantly, hydroxamic acid 16 was identified as a promising compound that elicited striking antiproliferative effects against Human U87MG GBM cells as well as TMZ-resistant GBM cells and P1S cells, a concurrent chemo radiotherapy (CCRT)-resistant/patient-derived glioma cell line mediated through preferential HDAC6 inhibition (IC 50  = 5.42 nM). Furthermore, 16 exerted cell cycle arrest at G2 phase, induced apoptosis in GBM cells at high concentration and exhibited high BBB permeability. To add on, in-vivo study revealed that the administration of compound 16 prolonged the survival of TMZ-resistant U87MG inoculated orthotopic mice. Overall, the cumulative results indicate that 16 is a tractable CNS penetrant preferential HDAC6 inhibitor that might emerge as a potent weapon against GBM., 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 © 2021. Published by Elsevier Masson SAS.)

Background and Aims: Endoscopists experience upper extremity musculoskeletal injuries. The primary aim of this study was to compare distal upper extremity biomechanical risk factors during colonoscopy with established risk thresholds. Secondary aims were to determine which subtasks during colonoscopy are associated with the greatest risk and to evaluate an intervention to reduce risks., Methods: Twelve endoscopists performed 2 to 4 colonoscopies while thumb pinch force and forearm muscle loads of extensor carpi radialis (ECR) and flexor digitorum superficialis (FDS) muscles were collected. Peak exertion values were analyzed using amplitude probability distribution functions. An endoscope support device was evaluated during simulated colonoscopy (n = 8)., Results: Mean endoscopist age was 42.3 years; 67% were men. Peak thumb pinch force exceeded risk thresholds for pinch force (10 N) and percent of time spent in forceful pinch for all colonoscopy subtasks. Peak ECR and FDS muscle activity exceeded the action limit (10% maximum voluntary contraction [MVC]) in both forearms. Peak left FDS, left ECR, and right ECR activity exceeded the threshold limit value (>30% MVC). Peak left FDS and ECR activity were significantly greater during insertion than during withdrawal (P < .05). Peak right FDS and ECR activity were significantly greater during right colon insertion compared with withdrawal (P < .05). The endoscope support device reduced left ECR muscle activity (P = .02)., Conclusions: Thumb pinch forces and time spent in forceful pinch indicate high-risk exposures during colonoscopy. Left wrist extensor muscle activity exceeded established thresholds with the greatest risk occurring during insertion. An endoscope support device reduced loads to the left wrist extensors., (Published by Elsevier Inc.)

One-pot fabrication of sacchachitin (SC) for mass-production was developed and optimized by selecting KOH as alkaline agent in depigmentation step and utilizing NaClO 2 as bleaching agent in subsequent step in the same pot. Overall yield of one-pot-fabricated SC was up to 35 %w/w of initial weight with a fibrous texture soft enough for mechanical disintegration into SC nanofibers (SCNFs) and better dispersion for producing TEMPO-oxidized SCNFs (T033SC). Both SCNFs and T033SC could form a 3D gelatinous scaffold into which MC3T3-E1 cells were attracted. Higher calcium-trapping ability of T033SC resulting from a greater extent of carboxylate groups provided an excellent bone regeneration environment that resulted in better outcomes of bone regeneration in a femur defect rat model compared to those with SCNFs possessed fewer carboxylate groups. In conclusion, biomaterial scaffolds based on TEMPO-oxidized SCNFs produced from one-pot fabricated SC showed great potential for bone regeneration due to unique physical and chemical properties., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: This study was intended to utilize lecithin-based mixed polymeric micelles ( lb MPMs) for enhancing the solubility and bioavailability of honokiol and magnolol to resolve the hindrance of their extreme hydrophobicity on the clinical applications., Methods: Lecithin was selected to increase the volume of the core of lb MPMs, thereby providing a greater solubilization capacity. A series of amphiphilic polymers (sodium deoxycholate [NaDOC], Cremophor ®, and Pluronic ® series) were included with lecithin for screening and optimization., Results: After preliminary evaluation and subsequentially optimization, two lb MPMs formulations composed of honokiol/magnolol:lecithin:NaDOC ( lb MPMs[NaDOC]) and honokiol/magnolol:lecithin:PP123 ( lb MPMs[PP123]) in respective ratios of 6:2:5 and 1:1:10 were optimally obtained with the mean particle sizes of 80-150 nm, encapsulation efficacy (EEs) of >90%, and drug loading (DL) of >9.0%. These lb MPMs efficiently stabilized honokiol/magnolol in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C. PK study demonstrated that lb MPMs[NaDOC] showed much improvement in enhancing bioavailability than that by lb MPMs[PP123] for both honokiol and magnolol. The absolute bioavailability for honokiol and magnolol after intravenous administration of lb MPMs[NaDOC] exhibited 0.93- and 3.4-fold increases, respectively, compared to that of free honokiol and magnolol. For oral administration with lb MPMs[NaDOC], the absolute bioavailability of honokiol was 4.8%, and the absolute and relative bioavailability of magnolol were 20.1% and 2.9-fold increase, respectively., Conclusion: Overall, honokiol/magnolol loaded in lb MPMs[NaDOC] showed an improvement of solubility with suitable physical characteristics leading to enhance honokiol and magnolol bioavailability and facilitating their wider application as therapeutic agents for treating human disorders., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Lin et al.)

Researchers believe that health foods can promote health and that the consumption of health foods can effectively help people to maintain their health. This study mainly adopted the health belief model (HBM) integrated with perceived behavioral control to investigate the repurchase behavior of consumers with regard to health foods that improve gastrointestinal functions. We obtained 550 valid questionnaires from consumers who had purchased gastrointestinal health foods and conducted structural equation modeling. Results from our analysis revealed that perceived susceptibility, perceived severity, perceived benefits of action, and perceived behavioral control exert a positive influence on repurchase intention and that perceived barriers of action exerts a negative influence on repurchase intention. Furthermore, repurchase intention was found to have a positive impact on repurchase behavior. The results of this study can be used as a reference for health food marketing strategies and public health behavior promotions.