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Cheng-I Hsieh,1–3 Kuo-Piao Chung,3 Ming-Chin Yang,3 Tsai-Chung Li4–61Division of Hematology and Oncology, Department of Internal Medicine, Taipei Medical University Hospital, 2Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, 3Institute of Health Policy and Management, College of Public Health, National Taiwan University, Taipei, 4Graduate Institute of Biostatistics, College of Public Health, China Medical University, 5Graduate Institute of Chinese Medicine Science, College of Chinese Medicine, China Medical University, 6Department of Healthcare Administration, College of Health Science, Asia University, Taichung, TaiwanBackground: A variety of unfulfilled needs may trigger doctor-shopping behavior (DSB) in patients. In oncology, treatment results usually cause patients the most concern. This study investigated the association of DSB with active treatments received by patients with hepatocellular carcinoma (HCC) and outcomes.Methods: With approval from the institutional review board, all patients registered in the cancer database of a teaching hospital and diagnosed as having HCC by self-referral from outside hospitals or by in-house diagnosis were retrospectively identified. Patient data were then reviewed and analyzed via electronic medical records.Results: Hepatitis B carriers were significantly more likely than noncarriers to show first-time DSB. Recurrent disease was less likely to result in DSB than predicted. Patients from outside hospitals not receiving upfront first treatment after diagnosis were significantly more likely to show more frequent DSB than those receiving it. Male patients eligible for salvage treatment were less likely to have frequent occurrences of DSB than their female counterparts. Receiving first salvage treatment was not associated with more frequent DSB. Treatment recommendations offered in the study hospital did not influence patients' decisions to leave or stay. Only elderly patients (>70 years) were less likely to show DSB.Conclusion: DSB can occur throughout the entire course of treatment for HCC for a variety of reasons. Active treatments, disease status, and patient characteristics all exerted an influence on DSB.Keywords: doctor-shopping behavior, second opinion, hepatocellular carcinoma

PURPOSE: This study investigates how perception-induced stress (barrier) and social capital (facilitator) affect the health of female managers. METHODS AND MEASUREMENT: On the basis of the responses of 229 valid questionnaires of middle- and high-level female managers in large-scale hospitals, using a multilevel data analysis approach, this study investigates how perception-induced stress and social capital influence self-reported poor health of female managers. RESULTS: Analysis results indicate that all 3 perception-induced stresses (i.e., promotion-related procedural justice, promotion rate, and work-family conflict) and 2 social capital variables (i.e., mentor-assisted promotion and higher ranking mentor in other departments) are significantly associated with the health of female mangers. Factors involving the career success of women also affect their health. IMPLICATIONS AND CONCLUSIONS: Health care organizations expecting to benefit from the long-term contribution of female elites must promote organizational equity and more heavily emphasize flexible work schedules, family-friendly policies, and perception management practices. In addition, adequately designed mentorship practices can greatly benefit female managers. [ABSTRACT FROM AUTHOR]

Background: Secondary pneumonia has a significant clinical impact on critically ill patients with COVID-19., Aim: Considering potential geographic variations, this study explores the clinical implications of secondary pneumonia within East Asian populations., Methods: This multicenter, retrospective cohort study enrolled critical COVID-19 patients requiring intensive care units (ICUs) admission in Taiwan from December 31, 2020, to June 1, 2022., Findings: Among the 187 critical COVID-19 patients, 80 (42.8%) developed secondary pneumonia. The primary causative pathogens were gram-negative bacilli (GNB) (76.8%). Gram-positive cocci and fungi were mainly observed during the initial two weeks of ICU stay. Notably, the incidence of pulmonary aspergillosis was 9.2% during the first week of ICU stay and all Staphylococcus aureus were susceptible to methicillin. Multi-drug resistant organisms (MDROs) were responsible for 28.3% of the cases, exhibiting significantly longer ICU stays compared to the non-MDRO group (median, 27 vs. 14 days, P < 0.001). In the multivariate analysis, Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were associated with a significantly increased risk of secondary pneumonia. In-hospital mortality was significantly higher in patients with secondary pneumonia than in those without (37.7% vs. 16.7%, P = 0.02) and survival analysis demonstrated gram-negative bacilli-related secondary pneumonia contributed to a worse prognosis., Conclusion: Secondary pneumonia in critical COVID-19 patients significantly raised in-hospital mortality and extended hospital and ICU stays. Moreover, the presence of GNB notably predicted an unfavorable prognosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

The World Health Organization emphasizes the importance of providing integrated care for older people. Taiwan is the fastest aging country in the world. In 2016, Taiwan implemented the Long-Term Care Plan 2.0 (TLTCP 2.0), aimed at providing integrated long-term care (LTC) services in communities. However, LTC service agencies have not been able to evaluate the level of integrated care they provide due to the lack of an effective assessment tool. To address this need, this study sets out to develop an integration assessment tool, namely the Self-Assessment for Service Integration in Long-Term Care (SASI-LTC), which will allow LTC agencies to self-evaluate their current level of integration from multiple perspectives. The SASI-LTC was developed based on Evashwick's framework, underwent two rounds of Delphi panels with twenty-six experts, and a pilot test with 243 valid questionnaires from administrators of Tier A agencies who are responsible for integrating LTC. The Delphi experts assessed the content with high levels of agreement using medians, the scale content validity index (SCVI) and item content validity index (ICVI). The SASI-LTC included four domains (inter-entity organization and management, integrated care coordination, integrated resources, and integrated information systems) with thirty items. The SASI-LTC showed good reliability (Cronbach's α = 0.94) and good validity, and a confirmatory factor analysis showed a good model fit index [χ2/df = 1.38; RMSEA = 0.040; CFI = 0.963; SRMR = 0.049] in pilot testing. While the SASI-LTC is a useful and feasible tool for Taiwan's LTC service agencies to evaluate their level of integration in providing LTC services, it could also be used in other countries with minor adjustments to localization of items related to financial integration.

Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS., (© 2024. The Author(s).)

Cell-free DNA (cfDNA) is released from injured cells and aggravates inflammation. Patients with coronavirus disease (COVID-19) often develop pneumonia and respiratory failure, and require oxygen therapy (OT), including mechanical ventilation (MV). It remains unclear whether cfDNA predicts the risk of receiving OT or MV in COVID-19 patients. Therefore, we hypothesized that circulating cfDNA levels could reflect the severity of respiratory failure and determine a therapeutic approach for oxygenation in patients with COVID-19. We analyzed cfDNA levels in serum samples from 95 hospitalized patients with COVID-19 at Showa University Hospital (Tokyo, Japan). cfDNA levels were assessed by measuring the copy numbers of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) using quantitative real-time PCR (qPCR). Both cf-nDNA and cf-mtDNA levels were negatively correlated with adjusted SpO 2 for FiO 2 (SpO 2 /FiO 2 ratio). Elevated cf-nDNA and cf-mtDNA levels were associated with the requirement for OT or MV during patient admission. Multivariate logistic regression analysis revealed that cf-nDNA and cf-mtDNA levels were independent risk factors for OT and MV. These results suggest that both serum cf-nDNA and cf-mtDNA could serve as useful early biomarkers to indicate the necessity of OT or MV in patients with COVID-19., (© 2024. The Author(s).)

Eukaryotic cells are highly compartmentalized, requiring elaborate transport mechanisms to facilitate the movement of proteins between membrane-bound compartments. Most proteins synthesized in the endoplasmic reticulum (ER) are transported to the Golgi apparatus through COPII-mediated vesicular trafficking. Sar1, a small GTPase that facilitates the formation of COPII vesicles, plays a critical role in the early steps of this protein secretory pathway. Sar1 was characterized in yeast, animals and plants, but no Sar1 homolog has been identified and functionally analyzed in algae. Here we identified a putative Sar1 homolog (CrSar1) in the model green alga Chlamydomonas reinhardtii through amino acid sequence similarity. We employed site-directed mutagenesis to generate a dominant-negative mutant of CrSar1 (CrSar1DN). Using protein secretion assays, we demonstrate the inhibitory effect of CrSar1DN on protein secretion. However, different from previously studied organisms, ectopic expression of CrSar1DN did not result in collapse of the ER-Golgi interface in Chlamydomonas . Nonetheless, our data suggest a largely conserved role of CrSar1 in the ER-to-Golgi protein secretory pathway in green algae., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Plant Direct published by American Society of Plant Biologists and the Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: The increasing trend of multiple chronic conditions across the world has worsened the problem of medication duplication in health care systems without gatekeeping or referral requirement. Thus, to overcome this problem, a reminder letter has been developed in Taiwan to nudge patients to engage in medication management., Objective: To evaluate the effect of reminder letter on reducing duplicated medications., Research Design: A 2-arm randomized controlled trial design., Subjects: Patients with duplicated medications in the first quarter of 2019., Measures: The Taiwanese single-payer National Health Insurance Administration identified the eligible patients for this study. A postal reminder letter regarding medication duplication was mailed to the patients in the study group, and no information was provided to the comparison group. Generalized estimation equation models with a difference-in-differences analysis were used to estimate the effects of the reminder letters., Results: Each group included 11,000 patients. Those who had received the reminder letter were less likely to receive duplicated medications in the subsequent 2 quarters (postintervention 1: odds ratio [OR]=0.95, 95% CI=0.87-1.03; postintervention&#95;2: OR=0.99, 95% CI=0.90-1.08) and had fewer days of duplicated medications (postintervention 1: β=-0.115, P =0.015; postintervention 2 (β=-0.091, P =0.089) than those who had not received the reminder letter, showing marginal but significant differences., Conclusions: A one-off reminder letter nudge could mildly decrease the occurrence of duplicated medications. Multiple nudges or nudges incorporating behavioral science insights may be further considered to improve medication safety in health systems without gatekeeping., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Immunosuppression increases the risk of nosocomial infection in patients with chronic critical illness. This exploratory study aimed to determine the immunometabolic signature associated with nosocomial infection during chronic critical illness. We prospectively recruited patients who were admitted to the respiratory care center and who had received mechanical ventilator support for more than 10 days in the intensive care unit. The study subjects were followed for the occurrence of nosocomial infection until 6 weeks after admission, hospital discharge, or death. The cytokine levels in the plasma samples were measured. Single-cell immunometabolic regulome profiling by mass cytometry, which analyzed 16 metabolic regulators in 21 immune subsets, was performed to identify immunometabolic features associated with the risk of nosocomial infection. During the study period, 37 patients were enrolled, and 16 patients (43.2%) developed nosocomial infection. Unsupervised immunologic clustering using multidimensional scaling and logistic regression analyses revealed that expression of nuclear respiratory factor 1 (NRF1) and carnitine palmitoyltransferase 1a (CPT1a), key regulators of mitochondrial biogenesis and fatty acid transport, respectively, in natural killer (NK) cells was significantly associated with nosocomial infection. Downregulated NRF1 and upregulated CPT1a were found in all subsets of NK cells from patients who developed a nosocomial infection. The risk of nosocomial infection is significantly correlated with the predictive score developed by selecting NK cell-specific features using an elastic net algorithm. Findings were further examined in an independent cohort of COVID-19-infected patients, and the results confirm that COVID-19-related mortality is significantly associated with mitochondria biogenesis and fatty acid oxidation pathways in NK cells. In conclusion, this study uncovers that NK cell-specific immunometabolic features are significantly associated with the occurrence and fatal outcomes of infection in critically ill population, and provides mechanistic insights into NK cell-specific immunity against microbial invasion in critical illness., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chung, Su, Wang, Budiarto, Yeh, Cheng, Keng, Chen, Lu, Juan, Nakahira, Ruan, Chien, Chang, Jerng, Huang, Chen and Yu.)

Newly synthesized proteins are delivered to the apoplast via conventional or unconventional protein secretion in eukaryotes. In plants, proteins are secreted to perform various biological functions. Conserved from yeast to mammals, both conventional and unconventional protein secretion pathways have been revealed in plants. In the conventional protein secretion pathway, secretory proteins with a signal peptide are translocated into the endoplasmic reticulum and transported to the extracellular region via the endomembrane system. On the contrary, unconventional protein secretion pathways have been demonstrated to mediate the secretion of the leaderless secretory proteins. In this chapter, we summarize the updated findings and provide a comprehensive overview of protein secretion pathways in plants., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Riboregulators such as riboswitches and RNA thermometers provide simple, protein-independent tools to control gene expression at the post-transcriptional level. In bacteria, RNA thermometers regulate protein synthesis in response to temperature shifts. Thermometers outside of the bacterial world are rare, and in organellar genomes, no RNA thermometers have been identified to date. Here we report the discovery of an RNA thermometer in a chloroplast gene of the unicellular green alga Chlamydomonas reinhardtii. The thermometer, residing in the 5' untranslated region of the psaA messenger RNA forms a hairpin-type secondary structure that masks the Shine-Dalgarno sequence at 25°C. At 40°C, melting of the secondary structure increases accessibility of the Shine-Dalgarno sequence to initiating ribosomes, thus enhancing protein synthesis. By targeted nucleotide substitutions and transfer of the thermometer into Escherichia coli, we show that the secondary structure is necessary and sufficient to confer the thermometer properties. We also demonstrate that the thermometer provides a valuable tool for inducible transgene expression from the Chlamydomonas plastid genome, in that a simple temperature shift of the algal culture can greatly increase recombinant protein yields., (© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.)

As a fundamental metabolic pathway, autophagy plays important roles in plant growth and development, particularly under stress conditions. A set of autophagy-related (ATG) proteins is recruited for the formation of a double-membrane autophagosome. Among them, the essential roles of ATG2, ATG18, and ATG9 have been well established in plant autophagy via genetic analysis; however, the underlying molecular mechanism for ATG2 in plant autophagosome formation remains poorly understood. In this study, we focused on the specific role of ATG2 in the trafficking of ATG18a and ATG9 during autophagy in Arabidopsis (Arabidopsis thaliana). Under normal conditions, YFP-ATG18a proteins are partially localized on late endosomes and translocated to ATG8e-labeled autophagosomes upon autophagic induction. Real-time imaging analysis revealed sequential recruitment of ATG18a on the phagophore membrane, showing that ATG18a specifically decorated the closing edges and finally disassociated from the completed autophagosome. However, in the absence of ATG2, most of the YFP-ATG18a proteins are arrested on autophagosomal membranes. Ultrastructural and 3D tomography analysis showed that unclosed autophagosome structures are accumulated in the atg2 mutant, displaying direct connections with the endoplasmic reticulum membrane and vesicular structures. Dynamic analysis of ATG9 vesicles suggested that ATG2 depletion also affects the association between ATG9 vesicles and the autophagosomal membrane. Furthermore, using interaction and recruitment analysis, we mapped the interaction relationship between ATG2 and ATG18a, implying a possible role of ATG18a in recruiting ATG2 and ATG9 to the membrane. Our findings unveil a specific role of ATG2 in coordinating ATG18a and ATG9 trafficking to mediate autophagosome closure in Arabidopsis., Competing Interests: Conflict of interest statement. None declared., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Alveolar epithelial type II (AEC2) cells strictly regulate lipid metabolism to maintain surfactant synthesis. Loss of AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking-related lung disease chronic obstructive pulmonary disease (COPD). Whether smoking alters lipid synthesis in AEC2 cells and whether altering lipid metabolism in AEC2 cells contributes to COPD development are unclear. In this study, high-throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN), in AEC2 cells (FasniΔAEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, and more severe airspace enlargement. FasniΔAEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins, and polyunsaturated fatty acid-containing phospholipids, as well as increased BALF surface tension. FasniΔAEC2 mice exposed to CS also had higher levels of protective ferroptosis markers in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome.

Background/purpose: Acute oral mucositis (OM) is a painful complication of concurrent chemoradiotherapy (CCRT). This severe adverse symptom may impact on patient's quality of life, lead to malnutrition. Thus, finding more effective methods in OM management is very important. The purpose of this study is to evaluate the efficacy of polyacrylate silver salt/Polyvinylpyrrolidone-based liquid oral gel (named as polyacrylate silver salt oral gel) in improving the symptomatic relief of CCRT-induced oral mucositis and oral dysfunction in neck and head cancer patients., Methods: In this study, 24 oral cancer patients underwent CCRT and having OM grade 2 or higher were randomly assigned into the test group and the control group. Both groups followed Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines for the management of mucositis, but adding rinsing with 15 g oral gel right after oral hygiene treaded the test group. Clinical OM and oral function were assessed weekly for 4 consecutive weeks till 5-10 days after the completion of radiotherapy. For evaluation, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 was used for collecting the data of OM grade., Results: The results showed that polyacrylate silver salt oral gel had better effect for relieving the oral mucositis. There were statistically significant differences in OM grades (1.59 vs. 2.8, p < 0.0001) between the test group and the control group., Conclusion: Our clinical studies demonstrated that polyacrylate silver salt oral gel is an effective interventional option in terms of rapid mucositis healing., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2023. Published by Elsevier B.V.)

Background: In Taiwan, breast cancer patients usually take conventional medicine and traditional Chinese medicine simultaneously. The utilization of traditional Chinese medicine among breast cancer patients at various stages has not been examined. This study aims to compare the intention of utilization and experience toward traditional Chinese medicine among early- and late-stage breast cancer patients., Method: This qualitative research collected data from breast cancer patients through focus groups interview by convenience sampling. Conducted in 2 branches of Taipei City Hospital, a public hospital managed by the Taipei City government. Breast cancer patients > 20 years old and had used TCM for breast cancer therapy for at least 3 months were included in the interview. A semi-structured interview guide was adopted in each focus group interview. In the following data analysis, stages I and II were considered early-stage, and stages III and IV were late-stage. For analyzing the data and reporting the results, we used qualitative content analysis as the approach for data analysis, assisted by NVivo 12. Categories and subcategories were identified through content analysis., Results: Twelve and seven early- and late-stage breast cancer patients were included in this study, respectively. The side effects were the main intention of utilizing traditional Chinese medicine. Improving side effects and constitution was the main benefit for patients in both stages. Additionally, early-stage breast cancer patients used traditional Chinese medicine to prevent recurrence or metastasis. Late-stage breast cancer patients responded more frequently to the use of traditional Chinese medicine due to the side effects of western medicine. However, some of their symptoms were not fully relieved., Conclusions: Breast cancer staging may influence the intention and utilization of traditional Chinese medicine. Health policymakers should consider the results of this research and the evidence-based illustrations to establish guidelines for integrating traditional Chinese medicine among various stages of breast cancer to improve the outcome and quality of care for cancer patients., (© 2023. The Author(s).)

Background: Diabetes is one of the most prevalent chronic diseases with subsequent complications. The positive effects of diabetes pay-for-performance (P4P) programs on treatment outcomes have been reported. The program provides financial incentives based on physiological care indicators, but common mental disorder complications such as depression are not covered., Methods: This study employed a natural experimental design to examine the spillover effects of diabetes P4P program on patients with nonincentivized depressive symptoms. The intervention group consisted of diabetes patients enrolled in the DM P4P program from 2010 to 2015. Unenrolled patients were selected by propensity score matching to form the comparison group. Difference-in-differences analyses were conducted to evaluate the effects of P4P programs. We employed generalized estimating equation (GEE) models, difference-in-differences analyses and difference-in-difference-in-differences analyses to evaluate the net effect of diabetes P4P programs. Changes in medical expenses (outpatient and total health care costs) over time were analysed for the treatment and comparison groups., Results: The results showed that enrolled patients had a higher incidence of depressive symptoms than unenrolled patients. The outpatient and total care expenses of diabetes patients with depressive symptoms were lower in the intervention group than in the comparison group. Diabetes patients with depressive symptoms enrolled in the DM P4P program had lower expenses for depression-related care than those not enrolled in the program., Conclusions: The DM P4P program benefits diabetes patients by screening for depressive symptoms and lowering accompanying health care expenses. These positive spillover effects may be an important aspect of physical and mental health in patients with chronic disease enrolled in disease management programs while contributing to the control of health care expenses for chronic diseases., (© 2023. The Author(s).)

Intracellular purine- and pyrimidine-related derivatives are vital molecules for preserving genetic information and are essential for cellular bioenergetics and signal transduction. This study developed a practical liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for quantifying intracellular purine- and pyrimidine-related derivatives. To solve the distorted peak shape related to di- and triphosphate nucleotides, in-sample addition of medronic acid and ammonium phosphate was performed. Using the BEH-amide column, the results showed that adding 0.5 mM medronic acid to the sample significantly improved the peak shape without causing an obvious ion suppressive effect. Method validation confirmed that the coefficients of determination ( R 2 ) values for linearity evaluation were above 0.94 for all analytes. The intraday and interday accuracies ranged from 85.1 to 128.4%, with the precision below 16.6%. The validated method was successfully applied in characterizing the alterations of purine- and pyrimidine-related derivatives in the A549 cell line with perturbed mitochondrial fission or blockade of the electron transport chain. Collectively, this study demonstrates that the strategy of in-sample medronic acid addition is effective in improving the quantification of intracellular purine- and pyrimidine-related derivatives. We believe that our proposed platform can facilitate the development of novel drugs targeting purine and pyrimidine metabolism in the future.

Background: This study conducted in-depth interviews to explore the factors that influence the choice of a post-acute care (PAC) model (inpatient rehabilitation hospital, skilled nursing facility, home health, and outpatient rehabilitation) among stroke patients and their families., Methods: We conducted semi-structured, in-depth interviews of 21 stroke patients and their families at four hospitals in Taiwan. Content analysis was used in this qualitative study., Results: Results revealed five main factors that influence respondents' choice of PAC: (1) medical professionals' suggestions, (2) health care accessibility, (3) continuity and coordination of care, (4) willingness and prior experience of patients and their relatives and friends, and (5) economic factors., Conclusions: This study identifies five main factors that affect the choice of PAC models among stroke patients and their families. We suggest that policymakers establish comprehensive health care resources based on the needs of patients and families. Health care providers shall provide professional recommendations and adequate information to support decision-making, which aligns with the preferences and values of patients and their families. From this research, we hope to improve the accessibility of PAC services in order to enhance the quality of care for stroke patients., (© 2023. The Author(s).)

The genomes of cytoplasmic organelles (mitochondria and plastids) are maternally inherited in most eukaryotes, thus excluding organellar genomes from the benefits of sexual reproduction and recombination. The mechanisms underlying maternal inheritance are largely unknown. Here we demonstrate that two independently acting mechanisms ensure maternal inheritance of the plastid (chloroplast) genome. Conducting large-scale genetic screens for paternal plastid transmission, we discovered that mild chilling stress during male gametogenesis leads to increased entry of paternal plastids into sperm cells and strongly increased paternal plastid transmission. We further show that the inheritance of paternal plastid genomes is controlled by the activity of a genome-degrading exonuclease during pollen maturation. Our data reveal that (1) maternal inheritance breaks down under specific environmental conditions, (2) an organelle exclusion mechanism and a genome degradation mechanism act in concert to prevent paternal transmission of plastid genes and (3) plastid inheritance is determined by complex gene-environment interactions., (© 2023. The Author(s).)

Introduction: Medical-related long-term care (LTC) service use among community-dwelling older adults in Taiwan is resource-intensive, and planning is essential to promote aging-in-place., Methods: Administrative data from 4/1/2017 to 11/26/2019 among more than 14,000 residents were analyzed with generalized estimating equations (GEEs) to identify determinants of medical-related LTC service use., Results: Older adults using medical-related LTC services tended to be younger (79.9 vs. 80.7; p<.0001), male (42.7% vs. 38.5%; p<.0001), multi-morbid (3.1 vs. 2.5; p<.0001), and higher mean activities of daily living (ADL) disability (8.2 vs. 4.2; p<.0001), instrumental ADL (IADL) disability (11.0 vs. 9.1; p<.0001), and hospitalizations (1.1 vs. 0.4; p<.0001). Significant determinants of medical-related LTC services include age, education, stroke, coronary heart disease, diabetes, vision impairment, ADL disability, and prior hospitalization., Discussion: The success of LTC 2.0 will depend on ADL support and care coordination to manage chronic conditions such as diabetes, vision impairment, coronary heart disease, and stroke., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Heat shock protein (HSP) 40 has emerged as a key factor in both innate and adaptive immunity, whereas the role of HLJ1, a molecular chaperone in HSP40 family, in modulating endotoxin-induced sepsis severity is still unclear. During lipopolysaccharide (LPS)-induced endotoxic shock, HLJ1 knockout mice shows reduced organ injury and IFN-γ (interferon-γ)-dependent mortality. Using single-cell RNA sequencing, we characterize mouse liver nonparenchymal cell populations under LPS stimulation, and show that HLJ1 deletion affected IFN-γ-related gene signatures in distinct immune cell clusters. In CLP models, HLJ1 deletion reduces IFN-γ expression and sepsis mortality rate when mice are treated with antibiotics. HLJ1 deficiency also leads to reduced serum levels of IL-12 in LPS-treated mice, contributing to dampened production of IFN-γ in natural killer cells but not CD4 + or CD8 + T cells, and subsequently to improved survival rate. Adoptive transfer of HLJ1-deleted macrophages into LPS-treated mice results in reduced IL-12 and IFN-γ levels and protects the mice from IFN-γ-dependent mortality. In the context of molecular mechanisms, HLJ1 is an LPS-inducible protein in macrophages and converts misfolded IL-12p35 homodimers to monomers, which maintains bioactive IL-12p70 heterodimerization and secretion. This study suggests HLJ1 causes IFN-γ-dependent septic lethality by promoting IL-12 heterodimerization, and targeting HLJ1 has therapeutic potential in inflammatory diseases involving activated IL-12/IFN-γ axis., Competing Interests: WL, SY, CC, MC, YC, KL, PL, KC, YC, JC, PY, KS No competing interests declared, (© 2022, Luo et al.)

In selective macroautophagy/autophagy, cargo receptors are recruited to the forming autophagosome by interacting with Atg8 (autophagy-related 8)-family proteins and facilitate the selective sequestration of specific cargoes for autophagic degradation. In addition, Atg8 interacts with a number of adaptors essential for autophagosome biogenesis, including ATG and non-ATG proteins. The majority of these adaptors and receptors are characterized by an Atg8-family interacting motif (AIM) for binding to Atg8. However, the molecular basis for the interaction mode between ATG8 and regulators or cargo receptors in plants remains largely unclear. In this study, we unveiled an atypical interaction mode for Arabidopsis ATG8f with a plant unique adaptor protein, SH3P2 (SH3 domain-containing protein 2), but not with the other two SH3 proteins. By structure analysis of the unbound form of ATG8f, we identified the unique conformational changes in ATG8f upon binding to the AIM sequence of a plant known autophagic receptor, NBR1. To compare the binding affinity of SH3P2-ATG8f with that of ATG8f-NBR1, we performed a gel filtration assay to show that ubiquitin-associated domain of NBR1 outcompetes the SH3 domain of SH3P2 for ATG8f interaction. Biochemical and cellular analysis revealed that distinct interfaces were employed by ATG8f to interact with NBR1 and SH3P2. Further subcellular analysis showed that the AIM-like motif of SH3P2 is essential for its recruitment to the phagophore membrane but is dispensable for its trafficking in endocytosis. Taken together, our study provides an insightful structural basis for the ATG8 binding specificity toward a plant-specific autophagic adaptor and a conserved autophagic receptor. Abbreviations: ATG, autophagy-related; AIM, Atg8-family interacting motif; BAR, Bin-Amphiphysin-Rvs; BFA, brefeldin A; BTH, benzo-(1,2,3)-thiadiazole-7-carbothioic acid S-methyl ester; CCV, clathrin-coated-vesicle; CLC2, clathrin light chain 2; Conc A, concanamycin A; ER, endoplasmic reticulum; LDS, LIR docking site; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; LIR, LC3-interacting region; PE, phosphatidylethanolamine; SH3P2, SH3 domain containing protein 2; SH3, Src-Homology-3; UBA, ubiquitin-associated; UIM, ubiquitin-interacting motif.

Background: Dynamin-related protein 1 (DRP1) is a key regulator of mitochondrial fission and is activated by phosphorylation at serine 616. We previously demonstrated that DRP1 activation is regulated by epidermal growth factor receptor (EGFR) signaling and multiple kinases in lung adenocarcinoma, and is significantly associated with an increased risk of postoperative recurrence in early stage lung adenocarcinoma. However, it is unclear whether DRP1 activation is associated with worse prognosis in patients with advanced lung adenocarcinoma. This study is aimed to examine whether P(S616)-DRP1 expression is significantly related to the survival of patients with advanced lung adenocarcinoma., Materials and Methods: Biopsy samples were obtained from patients with stage IV lung adenocarcinoma. The activation status of DRP1 in cancer cells was quantified based on the immunohistochemical stain of phosphorylated DRP1 at serine 616 [P(S616)-DRP1]. Results of EGFR, ALK, ROS1, and KRAS mutations were retrieved from the medical records. The staining intensity and the histological scores (H-scores) of P(S616)-DRP1 were analyzed for association with progression-free survival (PFS) under first-line tyrosine-kinase inhibitors (TKIs) and with overall survival (OS)., Results: Overall, 123 patients with stage IV lung adenocarcinoma constituted the study population, and 90 (73.2%) patients received TKIs as the first-line treatments. The median P(S616)-DRP1H-score was used to dichotomize the study population into the high (n = 61) and low (n = 62) DRP1 activation groups. DRP1 was significantly less phosphorylated in lung adenocarcinoma with EGFR, ALK, ROS1, and KRAS mutations. Importantly, in patients who received first-line TKIs, DRP1 phosphorylation was not significantly correlated with PFS and OS. Multivariate Cox proportional hazard models showed that high DRP1 activation in cancer cells was not significantly associated with worse OS in the study population (adjusted hazard ratio: 1.402, 95% confidence interval: 0.865-2.271, p = 0.170). Similar results were obtained in the analysis based on the intensities of P(S616)-DRP1 in cancer cells., Conclusions: Our data demonstrate that DRP1 phosphorylation is not related to the prognosis of patients with advanced lung adenocarcinoma., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Lung cancer with related pericardial effusion is not rare. Intervention is a crucial step for symptomatic effusion. It is unknown, however, whether the different invasive interventions for pericardial effusion result in different survival outcomes. This study analyzed the clinical characteristics and prognostic factors for patients with non-small-cell lung cancer (NSCLC) who have undergone different procedures., Methods: From January 2006 to June 2018, we collected data from patients with NSCLC who have received invasive intervention for pericardial effusions. The patients were divided into three categories: simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy. Kaplan-Meier curve and log-rank test were used to analyze the pericardial effusion recurrence-free survival (RFS) and overall survival (OS)., Results: A total of 244 patients were enrolled. Adenocarcinoma (83.6%) was the major NSCLC subtype. Invasive intervention, including simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy, had been carried out on 52, 170, and 22 patients, respectively. The 1-year RFS rates in simple pericardiocentesis, balloon pericardiotomy, and surgical pericardiectomy were 19.2%, 31.2%, and 31.8%, respectively (P = 0.128), and the median RFS was 1.67, 5.03, and 8.32 months, respectively (P = 0.008). There was no significant difference in OS, however, with the median OS at 1.67, 6.43, and 8.32 months, respectively (P = 0.064). According to the multivariable analysis, the gravity in pericardial fluid analysis, receiving systemic therapy after pericardial effusion, and the time period from stage IV lung cancer to the presence of pericardial effusion were independent prognostic factors for pericardial effusion RFS and OS., Conclusions: Patients who have undergone simple pericardiocentesis alone for the management of NSCLC-related pericardial effusion have lower 1-year RFS rates than those who have undergone balloon pericardiotomy and surgical pericardiectomy. Therefore, balloon pericardiotomy and surgical pericardiectomy should be carried out for patients with NSCLC-related pericardial effusion if tolerable., Competing Interests: Disclosure JYS has served as an advisory board member from AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharma, Ono Pharmaceutical, Takeda, CStone Pharmaceuticals, Janssen, and Bristol Myers Squibb and received speaking honoraria from AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Chugai Pharma, Ono Pharmaceutical, and Bristol Myers Squibb, as well as grant from Roche. SGW has received speaking honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Pfizer, Chugai, and Roche. All remaining authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To explore the relationships of health literacy, preferred involvement, and patient activation with perceived involvement in care among patients with breast and cervical cancer., Methods: A cross-sectional survey was conducted with patients aged 20 years or older, aware of their cancer diagnosis, and currently receiving care at the National Cancer Center, Mongolia. Descriptive statistics and multivariate regression analysis were used to identify the relationships among study variables., Results: Two hundred twenty-five patients were included in the final analysis. Patients' perceived involvement was examined as two subdomains: patient information seeking (PIS) and patient decision-making (PDM). Patient health literacy was found to only significantly influence PIS, and patient preferred involvement demonstrated a significant influence only on PDM. However, patient activation predictor was found to significantly influence both PIS and PDM (PIS [β = 0.22, p = 0.00] and PDM [β = 0.14, p = 0.00])., Conclusion: Health literacy, preferred involvement, and patient activation each demonstrated distinct influences on patients' perceived involvement subdomains, with patient activation being the most important predictor., Practice Implications: Comprehensive strategies at the healthcare organization, professional, and patient levels may help to facilitate and advance patient involvement in care, and ultimately improve the quality of healthcare services respective to domain of patient-centeredness., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This study investigates the expectations, perceptions, and gaps of the healthcare service quality (HSQ) from the patients' perspective, and explores the significant demographic and clinical factors associated with the HSQ in nurse practitioner practice (NPP)., Design: A cross-sectional design was carried out, with convenience sampling performed under the NPP in Taiwan, from June to November 2016., Methods: The Nurse Practitioner Healthcare Service Quality Scale was used to assess the expectations, perceptions, and gaps of the HSQ. The demographics, clinical characteristics, and symptom severity of patients were collected, and the Importance-Performance Analysis was applied to identify the priority of ranking items for the improvement of nurse practitioners (NPs). The Generalized Estimating Equation was used to explore the factors associated with the HSQ in NPP., Findings: A total of 200 patients completed the questionnaires. The results revealed that the patients had overall high expectations (M = 6.35, SD = 0.46), moderate perceptions (M = 4.21, SD = 0.95), and a mild HSQ gap (M = -2.14, SD = 0.69), with statistically significant differences (p < .001). In NPP, the largest gap in the HSQ dimensions was reliable responsiveness, followed by empathy, assurance, and tangibility. Patients with greater symptom severity and a longer in-hospital stay were associated with larger HSQ gaps; however, patients who were transferred from the emergency department had smaller gaps than those in the outpatient department., Conclusions: The patients' expectations were not fully satisfied in the NPP, especially for the dimensions of reliable responsiveness and empathy. The patients' symptom severity was a significant factor related to the gaps in the HSQ. The awareness of unmet needs, from the patients' perspective, could guide the convergence of a rational policy to promote healthcare delivery in the NPP., Clinical Relevance: The managers of NPP need to pay attention to increasing NPs' reliable responsiveness and empathy, by setting the appropriate scope of practice, regulating the NP-to-patient ratio, applying for certification programs in prescribing training, and cultivating patient-centered care with shared decision making. In addition, building up the knowledge and competency of symptom management is also suggested for NP training., (© 2021 Sigma Theta Tau International.)

Recent studies revealed the role of dynamin-related protein 1 (DRP1), encoded by the DNM1L gene, in regulating the growth of cancer cells of various origins. However, the regulation, function, and clinical significance of DRP1 remain undetermined in lung adenocarcinoma. Our study shows that the expression and activation of DRP1 are significantly correlated with proliferation and disease extent, as well as an increased risk of postoperative recurrence in stage I to stage IIIA lung adenocarcinoma. Loss of DRP1 in lung adenocarcinoma cell lines leads to an altered mitochondrial morphology, fewer copies of mitochondrial DNA, decreased respiratory complexes, and impaired oxidative phosphorylation. Additionally, the proliferation and invasion are both suppressed in DRP1-depleted lung adenocarcinoma cell lines. Our data further revealed that DRP1 activation through serine 616 phosphorylation is regulated by ERK/AKT and CDK2 in lung adenocarcinoma cell lines. Collectively, we propose the multikinase framework in activating DRP1 in lung adenocarcinoma to promote the malignant properties. Biomarkers related to mitochondrial reprogramming, such as DRP1, can be used to evaluate the risk of postoperative recurrence in early-stage lung adenocarcinoma., (© 2020 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Objective: The aim of this study was to systematically and simultaneously examine the association of intrinsic and extrinsic motivating factors with physician burnout and job dissatisfaction., Design: A nationally representative survey was fielded from September to November 2017., Setting: Hospitals and clinics throughout Taiwan., Participants: A total of 6674 physicians., Main Exposure Measure: The main exposure measures were intrinsic motivators (sense of calling, personally rewarding hours per day and meaningful, long-term relationships with patients) and extrinsic motivators (income, work hours, autonomy, and pay-for-performance (P4P) and bundled payment initiatives)., Main Outcome Measures: The main outcome measures were physician burnout and job dissatisfaction., Results: A total of 1152 physicians returned the surveys. More sense of calling and personally rewarding hours per day were associated with less physician burnout (OR 0.16, 95% CI 0.10 to 0.26 and OR 0.25, 95% CI 0.13 to 0.47, respectively) and job dissatisfaction (OR 0.35, 95% CI 0.21 to 0.57 and OR 0.46, 95% CI 0.26 to 0.83, respectively). Longer work hours were associated with more physician burnout (OR 2.67, 95% CI 1.54 to 4.63) and job dissatisfaction (OR 1.71, 95% CI 1.05 to 2.79). Not receiving P4P bonuses from their organisations was associated with more physician burnout (OR 1.56, 95% CI 1.02 to 2.38). Not sharing the losses from caring for patients included in the bundled payment system was associated with less physician burnout (OR 0.59, 95% CI 0.36 to 0.97)., Conclusions: Fostering a healthcare work environment that supports intrinsic motivation and improves work hours may reduce physician burnout and job dissatisfaction. Rewarding physicians fairly and equitably may prevent them from feeling burned out. Value-based care delivery and payment model innovations, such as bundled payments, may encourage healthcare professionals to coordinate care through the standardisation of care to decrease burnout., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Ordinal responses are common in clinical studies. Although the proportional odds model is a popular option for analyzing ordered-categorical data, it cannot control the type I error rate when the proportional odds assumption fails to hold. The latent Weibull model was recently shown to be a superior candidate for modeling ordinal data, with remarkably better performance than the latent normal model when the data are highly skewed. In clinical trials with ordinal responses, a balanced design is common, with equal sample allocation for each treatment. However, a more ethical approach is to adopt a response-adaptive allocation scheme in which more patients receive the better treatment. In this paper, we propose the use of the doubly adaptive biased coin design to generate treatment allocations that benefit the trial participants. The proposed treatment allocation scheme not only allows more patients to receive the better treatment, it also maintains compatible test power for the comparison of treatment efficiencies. A clinical example is used to illustrate the proposed procedure.

Background: Acute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it., Methods: A secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS., Results: Of the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); p<0.001] and baseline severity of illness was higher in patients with versus without persistent severe ARDS. Mortality at 60 days [95/232 (41%) versus 233/1299 (18%); p<0.001] was higher, and ventilator-free (p<0.001), intensive care unit-free [0 (0-14) versus 19 (7-23); p<0.001] and non-pulmonary organ failure-free [3 (0-21) versus 20 (1-26); p<0.001] days were fewer in patients with versus without persistent severe ARDS. PaO2:FiO2, FiO2, hepatic failure and positive end-expiratory pressure at enrollment were useful predictive variables., Conclusions: Patients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials., Competing Interests: The corresponding author has read the journal’s policy and the authors of this manuscript have the following competing interests: AMC is a co-founder of Proterris and serving as a consultant for an advisory board meeting of Teva Pharmaceutical Industries, July 2018. None declared (ES, DRP, KPC, CO, EJS, IIS). This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials.

Mitophagy, by maintaining mitochondrial quality control, plays a key role in maintaining kidney function and is impaired in pathologic states. Macrophages are well known for their pathogenic role in kidney fibrosis. Here, we report that PINK1/Parkin-mediated mitophagy in macrophages is compromised in experimental and human kidney fibrosis. We demonstrate downregulation of mitophagy regulators mitofusin-2 (MFN2) and Parkin downstream of PINK1 in kidney fibrosis. Loss of either Pink1 or Prkn promoted renal extracellular matrix accumulation and frequency of profibrotic/M2 macrophages. Pink1-/- or Prkn-/- BM-derived macrophages (BMDMs) showed enhanced expression of rictor. Mitochondria from TGF-β1-treated Pink1-/- BMDMs exhibited increased superoxide levels, along with reduced respiration and ATP production. In addition, mitophagy in macrophages involves PINK1-mediated phosphorylation of downstream MFN2, MFN2-facilitated recruitment of Parkin to damaged mitochondria, and macrophage-specific deletion of Mfn2 aggravates kidney fibrosis. Moreover, mitophagy regulators were downregulated in human CKD kidney and TGF-β1-treated human renal macrophages, whereas Mdivi1 treatment suppressed mitophagy mediators and promoted fibrotic response. Taken together, our study is the first to our knowledge to demonstrate that macrophage mitophagy plays a protective role against kidney fibrosis via regulating the PINK1/MFN2/Parkin-mediated pathway.

Background: Many hospitals in Taiwan currently use the nurse practitioner (NP) care model to ameliorate the chronic shortage of resident physicians. However, no healthcare service quality scale is presently available that allows the evaluation of the healthcare quality provided by NPs from the perspective of patients. A scale of this type is necessary in order to effectively monitor and improve care outcomes., Purpose: This project was designed to develop the Nurse Practitioner Healthcare Service Quality Scale (NPHSQS) and then to test its validity and reliability., Methods: A cross-sectional design combined with Parasuraman, Zeithaml, and Berry's Service Quality Model was adopted to construct the NPHSQS. After expert evaluation and confirmation of the model's content validity, 200 valid questionnaires were collected from a convenience sample of patients from medical center wards in northern Taiwan that regularly used the NP care model. The data were analyzed by group using item analysis, construct validity, internal consistency, and discriminant validity., Results: The 25-item NPHSQS developed in this study earned a CVI (content validity index) of .91 and a good CR (critical ratio). Exploratory factor analysis revealed that four factors extracted in the expectation level, including reliable responsiveness, assurance, empathy, and tangibility, explained 62.47% of the total variance. Furthermore, three factors extracted in the perception level, including reliable responsiveness, trust, and tangibility, explained 67.71% of the total variance. The NPHSQS has a good overall internal consistency coefficient and may also significantly distinguish differences in patient satisfaction between good and bad healthcare service quality groups (p < .001)., Conclusions: The developed NPHSQS has good reliability and validity and is a reliable instrument for assessing the quality of NP-provided healthcare services from the perspective of healthcare recipients.

This retrospective cohort study examined the effects of care continuity on the utilization of follow-up services and outcome of breast cancer patients (stages I-III) in the post-treatment phase of care. Propensity score matching and generalized estimation equations were used in the analysis of data obtained from national longitudinal databases. The continuity of care index (COCI) was calculated separately for primary care physicians (PCP) and oncologists. Our results revealed that breast cancer survivors with a higher oncology COCI were more likely than those with a lower oncology COCI to use mammography or breast ultrasound during the follow-up period (OR = 1.26, 95% CI: 1.19-1.32; OR = 1.12, 95% CI: 1.06-1.18; respectively). In terms of health outcomes, a higher oncology COCI was associated with a lower likelihood of hospitalization (OR = 0.78, 95% CI: 0.71-0.85) and emergency department use (OR = 0.88, 95% CI: 0.82-0.95). A higher PCP COCI was also associated with a lower likelihood of hospitalization (OR = 0.77, 95% CI: 0.70-0.85) and emergency department use (OR = 0.75, 95% CI: 0.68-0.82). Overall, this study determined that ambulatory care continuity is positively associated with the likelihood of using recommended follow-up care services and negatively associated with adverse health events among breast cancer survivors., Competing Interests: (B)

Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung.

Background and Objectives: Age is a traditional risk factor for open-heart surgery. The efficacy and safety of transcatheter edge-to-edge mitral valve repair, using MitraClip (Abbott Vascular), has been demonstrated in patients with severe mitral regurgitation (MR). Since octogenarians or older patients are usually deferred to receive open-heart surgery, the main interest of this study is to elucidate the procedural safety and long-term clinical impact of MitraClip in elderly patients., Methods: Patients with symptomatic severe MR were evaluated by the heart team. For those with high or prohibitive surgical risks, transcatheter mitral valve repair was performed in hybrid operation room. Transthoracic echocardiography (TTE), blood tests, and six-minute walk test (6MWT) were performed before, 1-month, 6-months, and 1 year after index procedure., Results: A total of 46 consecutive patients receiving MitraClip procedure were enrolled. Nineteen patients (84.2±4.0 years) were over 80-year-old and 27 (73.4±11.1 years) were younger than 80. Compare to baseline, the significant reduction in MR severity was achieved after the procedure and sustained. All the patients benefited from significant improvement in New York Heart Association functional class. The 6-minute walk test (6MWT) increased from 259±114 to 319±92 meters (p=0.03) at 1 year. The overall 1-year survival rate was 80% in the elderly and 88% in those <80 years, p=0.590. Baseline 6MWT was a predictor for all-cause mortality (odds ratio, 0.99; 95% confidence interval, 0.982-0.999; p=0.026) after the MitraClip procedure., Conclusions: Trans-catheter edge-to-edge mitral valve repairs are safe and have positive clinical impact in subjects with severe MR, even in advanced age., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2019. The Korean Society of Cardiology.)

Objectives: Recent metabolomic studies of sepsis showed that increased circulatory acylcarnitines were associated with worse survival. However, it is unknown whether plasma carnitine and acylcarnitines can reflect the severity of sepsis, and the role of specific acylcarnitines in prognostic assessment need further confirmation. This study aimed to clarify these questions., Design: Prospective multicenter cohort studies with derivation and validation cohort design., Setting: ICUs at two medical centers and three regional hospitals in Taiwan., Patients: Patients with sepsis and acute organ dysfunction were enrolled. Recruitment of the derivation (n = 90) and validation cohorts (n = 120) occurred from October 2010 through March 2012 and January 2013 through November 2014, respectively., Interventions: Plasma samples were collected immediately after admission, and the levels of carnitine and acylcarnitines were measured by ultra-high performance liquid chromatography-mass spectrometry., Measurements and Main Results: In the derivation cohort, increased plasma levels of short- and medium-chain acylcarnitines were significantly associated with hepatobiliary dysfunction, renal dysfunction, thrombocytopenia, and hyperlactatemia. However, acetylcarnitine is the only acylcarnitine significantly correlating with various plasma cytokine concentrations and also associated with blood culture positivity and 28-day mortality risk. The association between plasma acetylcarnitine and multiple organ dysfunction severity, blood culture positivity, and 28-day mortality, was confirmed in the validation cohort. Patients with high plasma acetylcarnitine (≥ 6,000 ng/mL) had significantly increased 28-day mortality compared with those with plasma acetylcarnitine less than 6,000 ng/mL (52.6% vs 13.9%; hazard ratio, 5.293; 95% CI, 2.340-11.975; p < 0.001 by Cox proportional hazard model)., Conclusions: We confirm that plasma acetylcarnitine can reflect the severity of organ dysfunction, inflammation, and infection in sepsis and can serve as a prognostic biomarker for mortality prediction.

Objectives: One feature unique to the Taiwanese healthcare system is the ability of physicians other than oncologists to prescribe systemic chemotherapy. This study investigated whether the care paths implemented by oncologists and non-oncologists differ with regard to patient outcomes., Setting: Data from the Taiwan Cancer Registry and National Health Insurance Database were linked to identify patients with colon cancer who underwent colectomy as first treatment within 3 months of diagnosis and adjuvant chemotherapy between 2005 and 2009., Participants and Methods: Postoperative patients who underwent adjuvant chemotherapy were included in this study. The exclusion criteria included patients with stage IV disease, a positive surgical margin and early disease recurrence. Among the patients presenting with multiple primary cancers, we also excluded patients who were diagnosed with colon cancer but for whom this was not the first primary cancer. The variables included sex, age, comorbidities, disease stage, chemotherapy cycle and changes in treatment regimen as well as the specialty of treatment providers and their case volume. Cox regression models and Kaplan-Meier analysis were used to examine differences in outcomes in the matched cohorts., Results: We examined 3534 patients who were prescribed adjuvant chemotherapy by physicians from different disciplines. In terms of 5-year disease-free survival, no significant difference was observed between the groups of oncologists or surgeons among patients with stage II (90.02%vs88.99%) or stage III (77.64%vs79.99%) diseases. Patients who were subjected to changes in their chemotherapy regimens presented recurrence rates higher than those who were not., Conclusions: The discipline of practitioners is seldom taken into account in most series. This is the first study to provide empirical evidence demonstrating that the outcomes of patients with colon cancer do not depend on the treatment path, as long as the selection criteria for adjuvant chemotherapy is appropriate. Further study will be required before making any further conclusions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background : Since Taiwan launched the Cancer Prevention Act in 2003, several prevention strategies and early detection programs have been implemented to reduce the incidence, morbidity and mortality rates of cancer. However, most of the programs have concentrated on healthcare providers. Evaluations from the patient's perspective have been lacking. Thus, in this study a cancer patient experience questionnaire was developed in the Taiwanese context and a preliminary nationwide investigation was conducted on the status of cancer care from the patient's perspective. Methods : An extensive literature review was first conducted to collect information on the existing instruments used to measure the cancer patient's experience. Thereafter, a multidisciplinary expert panel was convened to select an optimal instrument based on the IOM's six domains for evaluating patient-centered care. The European Organisation for Research and Treatment of Cancer (EORTC) translation procedure was applied to the questionnaire for cross-cultural adaptation. A nationwide field test was then implemented at certificated cancer care hospitals. Results : Fifteen questionnaires were collected for the literature review. The expert panel selected the National Cancer Patient Experience Survey based on the IOM's recommendations. After cross-cultural translation of the questionnaire, a total of 4000 questionnaires were administered in 19 certificated cancer care hospitals and two major cancer patient associations, with 1010 being returned (25.25% response rate). Most of the respondents were middle-aged, and 70% were female. The respondents reported they had a good experience with cancer care, except for "Home care and support" and "Finding out what was wrong with you". Stratified analysis was conducted, with the results showing that the cancer patients' experiences varied depending on their sociodemographic and cancer-related characteristics. Conclusions : A Taiwanese version of the cancer patient experience survey questionnaire was developed. Its results showed that the cancer patient's experiences varied, depending on the patient's age, cancer type, and cancer history. This study can be used as a basis to establish a patient-centered care model for cancer care in Taiwan.

The autophagosome is a double-membrane compartment formed during autophagy that sequesters and delivers cargoes for their degradation or recycling into the vacuole. Analyses of the AuTophaGy-related (ATG) proteins have unveiled dynamic mechanisms for autophagosome biogenesis. Recent advances in plant autophagy research highlight a complex interplay between autophagosome biogenesis and the endoplasmic reticulum (ER): on the one hand ER serves as a membrane source for autophagosome initiation and a signaling platform for autophagy regulation; on the other hand ER turnover is connected to selective autophagy. We provide here an integrated view of ER-based autophagosome biogenesis in plants in comparison with the newest findings in yeast and mammals, with an emphasis on the hierarchy of the core ATG proteins, ATG9 trafficking, and ER-resident regulators in autophagy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Context: Targeted therapies with epidermal growth factor receptor tyrosine kinase inhibitors have been widely used in the treatment of advanced non-small-cell lung cancer (NSCLC). However, little research has focused on the use of targeted therapies at the end of life (EOL)., Objectives: This study investigated the determinants of receiving targeted therapy during the last month of life and how targeted therapies affect the quality of EOL care., Methods: We conducted a retrospective population-based study using a cancer registry and National Health Insurance claims data among 42,678 Taiwanese NSCLC decedents in 2005-2012. Propensity score matching and generalized linear mixed models were used to estimate associations., Results: We identified 3439 (21.3%) NSCLC patients who received targeted therapy within 30 days of death. Younger age, adenocarcinoma histology, postdiagnosis survival exceeding six months, and later year of death were associated with receiving targeted agents at EOL. The odds increased when patients were treated by pulmonologists or oncologists or in district hospitals or facilities with a higher case volume. Patients who were prescribed targeted therapy near death were significantly more likely to undergo aggressive EOL care (odds ratio = 2.35, 95% CI = 1.83-3.02) including multiple emergency department visits, hospitalization exceeding 14 days, admission to intensive care units, use of intubation and mechanical ventilation, cardiopulmonary resuscitation, and late hospice referrals., Conclusions: Targeted therapy at EOL should be considered a quality-of-care indicator. Guidance in the cessation of targeted therapy and the ongoing monitoring of practice initiatives are warranted. The decision-making processes associated with EOL care also require further investigation., (Copyright © 2017 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Renal fibrosis is a common pathogenic response to injury in chronic kidney disease (CKD). The receptor-interacting protein kinase-3 (RIPK3), a regulator of necroptosis, has been implicated in disease pathogenesis. In mice subjected to unilateral ureteral obstruction-induced (UUO-induced) or adenine diet-induced (AD-induced) renal fibrosis, models of progressive kidney fibrosis, we demonstrate increased kidney expression of RIPK3. Mice genetically deficient in RIPK3 displayed decreased kidney fibrosis and improved kidney function relative to WT mice when challenged with UUO or AD. In contrast, mice genetically deficient in mixed-lineage kinase domain-like protein (MLKL), a downstream RIPK3 target, were not protected from UUO-induced kidney fibrosis. We demonstrate a pathway by which RIPK3 promotes fibrogenesis through the AKT-dependent activation of ATP citrate lyase (ACL). Genetic or chemical inhibition of RIPK3 suppressed the phosphorylation of AKT and ACL in response to TGF-β1 in fibroblasts. Inhibition of AKT or ACL suppressed TGF-β1-dependent extracellular matrix production and myofibroblast differentiation in fibroblasts. Pharmacological inhibition of ACL suppressed UUO-induced kidney fibrosis. RIPK3 expression was highly regulated in human CKD kidney. In conclusion, we identify a pathway by which RIPK3 promotes kidney fibrosis independently of MLKL-dependent necroptosis as a promising therapeutic target in CKD.

Soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptors (SNAREs) are well-known for their role in controlling membrane fusion, the final, but crucial step, in vesicular transport in eukaryotes. SNARE proteins contribute to various biological processes including pathogen defense and channel activity regulation, as well as plant growth and development. Precise targeting of SNARE proteins to destined compartments is a prerequisite for their proper functioning. However, the underlying mechanism(s) for SNARE targeting in plants remains obscure. Here, we investigate the targeting mechanism of the Arabidopsis thaliana Qc-SNARE BET12, which is involved in protein trafficking in the early secretory pathway. Two distinct signal motifs that are required for efficient BET12 ER export were identified. Pulldown assays and in vivo imaging implicated that both the COPI and COPII pathways were required for BET12 targeting. Further studies using an ER-export-defective form of BET12 revealed that the Golgi-localized Qb-SNARE MEMB12, a negative regulator of pathogenesis-related protein 1 (PR1; At2g14610) secretion, was its interacting partner. Ectopic expression of BET12 caused no inhibition in the general ER-Golgi anterograde transport but caused intracellular accumulation of PR1, suggesting that BET12 has a regulatory role in PR1 trafficking in A. thaliana ., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Protein secretion is an essential process in all eukaryotic cells and its mechanisms have been extensively studied. Proteins with an N-terminal leading sequence or transmembrane domain are delivered through the conventional protein secretion (CPS) pathway from the endoplasmic reticulum (ER) to the Golgi apparatus. This feature is conserved in yeast, animals, and plants. In contrast, the transport of leaderless secretory proteins (LSPs) from the cytosol to the cell exterior is accomplished via the unconventional protein secretion (UPS) pathway. So far, the CPS pathway has been well characterized in plants, with several recent studies providing new information about the regulatory mechanisms involved. On the other hand, studies on UPS pathways in plants remain descriptive, although a connection between UPS and the plant defense response is becoming more and more apparent. In this review, we present an update on CPS and UPS. With the emergence of new techniques, a more comprehensive understanding of protein secretion in plants can be expected in the future., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Studies on the relationship between vegetarian diet and breast cancer in Asian populations are limited. This study aimed to investigate the relationship between vegetarian diet, dietary patterns, and breast cancer in Taiwanese women., Methods: This case-control study compared the dietary patterns of 233 breast cancer patients and 236 age-matched controls. A questionnaire about vegetarian diets and 28 frequently-consumed food items was administered to these 469 patients in the surgical department of Taipei Tzu Chi Hospital. Serum biochemical status was also examined., Results: There were no significant differences between the two groups for age, education, family history, oral contraceptive usage, or regular exercise. However, the cancer group presented with both a higher body mass index and an older age of primiparity (P < 0.05). Two food items (shellfish and seafood) were highly correlated (correlation coefficient = 0.77), so shellfish was excluded to avoid multicollinearity. A factor analysis of 27 food items produced five dietary patterns: meat, processed meat, fruit/vegetable/soybean, dessert/sugar, and fermented food. Multivariate logistic regression showed that meat/fat and processed meat dietary patterns were associated with breast cancer risk (odds ratio (OR): 2.22, 95% CI 1.67-2.94, P < 0.001; OR: 1.49, 95% CI 1.09-2.04, P = 0.013, respectively). Vegetarian diet, high isoflavone intake, and high albumin levels were inversely associated with breast cancer risk (P < 0.05). Vegetarians had a higher daily soy isoflavone intake than non-vegetarians (25.9 ± 25.6 mg vs. 18.1 ± 15.6 mg, P < 0.001)., Conclusions: Vegetarian diets show as protective role against breast cancer risk, while meat and processed meat dietary patterns are associated with a higher breast cancer risk.

Background: Breast cancer is the most common female malignancy worldwide. The aim of this study was to investigate the influence of surgical procedures and quality-of-care (QoC) on quality-of-life (QoL) among breast cancer survivors who underwent breast-conserving therapy (BCT) or mastectomy, and to identify provider- and patient-related factors pertaining to QoL., Method: In this cross-sectional study, structured-questionnaires were distributed among breast cancer survivors in 19 hospitals. QoL was evaluated using the European Organization for Research and Treatment of Cancer core questionnaire (EORTC QLQ-C30) and the breast cancer specific module (EORTC QLQ-BR23). QoC is indicated by adherence to the core measures stipulated for the treatment of breast cancer. Multiple regression and hierarchical linear modeling were used for multivariate analysis., Results: A total of 544 female survivors of Stage 0-III breast cancer were included, among whom 217 (39.9%) underwent BCT and 327 (60.1%) underwent mastectomy. Surgical modality does not appear to have a notable impact on any QoL domains except body image; i.e. patients who underwent BCT reported better body image (diff = 11.20, P < 0.001), particularly at 1-5 years after the initial treatment. Independent factors including age, education, employment, marital status, income, chemotherapy, duration since treatment, recurrence status, primary hospital accreditation level and location all appear to be correlated to QoL., Conclusion: Patients with breast cancer should be informed of differences in QoL when discussing treatment options. Furthermore, physicians should recognize that the impact of surgical treatment modality on QoL may vary according to patients' sociodemographic and clinical characteristics., (© The Author 2017. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Studies about prognostic assessment in cancer patients requiring prolonged mechanical ventilation (PMV) for post-intensive care are scarce. We retrospectively enrolled 112 cancer patients requiring PMV support who were admitted to the respiratory care center (RCC), a specialized post-intensive care weaning facility, from November 2009 through September 2013. The weaning success rate was 44.6%, and mortality rates at hospital discharge and after 1 year were 43.8% and 76.9%, respectively. Multivariate logistic regression showed that weaning failure, in addition to underlying cancer status, was significantly associated with an increased 1-year mortality (odds ratio, 6.269; 95% confidence interval, 1.800-21.834; P = 0.004). Patients who had controlled non-hematologic cancers and successful weaning had the longest median survival, while those with other cancers who failed weaning had the worst. Patients with low maximal inspiratory pressure, anemia, and poor oxygenation at RCC admission had an increased risk of weaning failure. In conclusion, cancer status and weaning outcome were the most important determinants associated with long-term mortality in cancer patients requiring PMV. We suggest palliative care for those patients with clinical features associated with worse outcomes. It is unknown whether survival in this specific patient population could be improved by modifying the risk of weaning failure.

Background: Lymph node flap transfer popularity for treatment of extremity lymphedema is increasing quickly. Multiple flap donor sites were described in search of the optimal one. We describe the technique and outcomes of a laparoscopically harvested right gastroepiploic lymph node flap for treatment of extremity lymphedema., Methods: From January 2012 to January 2013, 10 consecutive female patients, average age 54.8 years, with International Society of Lymphology stage II-III extremity lymphedema refractory to conservative management were included. Five patients had upper limb breast cancer-related lymphedema and five patients had lower limb pelvic cancer-related lymphedema. All patients underwent laparoscopic harvest of the right gastroepiploic lymph node flap, transferred to the wrist and ankle as recipient sites. Flaps were covered with a small skin graft taken from the thigh. Perioperative assessment included physical exam, photography, circumference measurements, CT scans, lymphoscintigraphy, and Lymphedema Quality of Life (LYMQOL) questionnaire. Clinical and CT evaluation of donor-site morbidity were performed., Results: The flap survival rate was 100%, with a mean harvest time of 32 minutes and total operating time of 164 minutes. One case required regrafting for skin graft loss. The mean limb reduction rate was 39.5% at a mean follow-up of 14.7 months. Perioperative lymphoscintigraphy demonstrated transferred lymph node viability and lymphatic transport improvement. LYMQOL showed a 2.6-fold quality-of-life improvement (P < 0.01). No donor-site morbidity was encountered., Conclusions: The use of the laparoscopically harvested right gastroepiploic lymph node flap may be a safe technique that improves limb measurements and quality of life in extremity lymphedema patients. © 2015 Wiley Periodicals, Inc. Microsurgery 37:197-205, 2017., (© 2015 Wiley Periodicals, Inc.)