Enhancement of dendritic cell immunotherapy by recalling antigens for hepatocellular carcinoma in mice.

Background: The therapeutic efficacy of dendritic cell (DC)-immunotherapy for large hepatoma in mice is unsatisfactory. Materials & methods: DC-based immunotherapy was used to treat Hepa1-6 tumors measuring 6 ± 1 mm in diameter, enhanced by boosting tumor antigens. Results: CD4+ and CD8+ T-cells were contracted and transformed into memory phenotypic cells after DC-based vaccination. When T-cells were re-stimulated, T-cells obtained from mice boosted by tumor antigen injection showed highest proliferation capacity. When mice with large tumors were treated, DC-based vaccination boosted by tumor antigen and an additional DC-infusion yielded curative rates of 50% and 23.1%, respectively. Conclusion: DC vaccination induced effector memory cells. Antigen presentation recalled by DC or tumor antigens increased the curative rate in mice with large tumors.

Hepatocellular carcinoma is the most common liver malignancy and is often found at advanced stage. Immune checkpoint inhibitor combined with a molecular targeting agent is a new strategy for the treatment of advanced hepatocellular carcinoma and yields 30% of objective response rate. However, we still need another treatment for the patients who are not responsive to immune checkpoint inhibitor combined with a molecular targeting agent. Dendritic cell-based immunotherapy is one of the treatments for advanced hepatocellular carcinoma. In this animal study, dendritic cells can activate T-lymphocytes to kill cancer cells. Dendritic cells can also induce memory T-lymphocytes, which can be reactive by boost tumor antigens and increase therapeutic efficacy. This treatment strategy, dendritic cell infusion followed by tumor-antigen injection, can be translated into clinical practice in the future.

Effects of Professional Autonomy and Leadership Style on the Team-Based Practice of Acute Care Nurse Practitioners in Taiwan.

BACKGROUND: Little is known regarding the factors that affect the team-based practice of nurse practitioners (NPs). Examining the relationships between these factors and team-based practice may provide important insights into the strength of the NP practice. PURPOSE: This study was designed to examine the effects of practice autonomy and leadership style on the team-based practice of acute care NPs working in hospitals. METHODS: A cross-sectional, national survey design was conducted to examine the autonomy, leadership, and team-based practice of NPs. One thousand three hundred ninety-one NPs completed the questionnaire, which included demographic and practice variables, the Dempster Practice Behavior Scale, the Multifactor Leadership Questionnaire, and the NP-physician relations subscale of the Nurse Practitioner Primary Care Organizational Climate Questionnaire. The hierarchical linear model was used to differentiate between the NP-level and organization-level effects on team-based practice. Multiple regression was applied to explore the factors associated with team-based practice. RESULTS: The hierarchical linear model results identified no organization-level effect on team-based practice. Moreover, the results of the regression model found that NPs with greater autonomy in actualization, empowerment and readiness, and idealized influence leadership style enhanced the performance of the doctor of medicine-NP team-based practice. The final model explained 39% of the variance in doctor of medicine-NP team-based practice. Autonomy in actualization and empowerment were identified as the two most important predictors. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The practice autonomy and leadership style of NPs influence the efficiency of team-based practice in Taiwan. To improve the team-based practice of NPs, healthcare administrators must support the practice autonomy of NPs.

Immunological discrepancy in aged mice facilitates skin allograft survival.

More and more aged people are undergoing organ transplantation. Understanding aging effects on immunity will be helpful for post-transplantation care and adjustment of immunosuppressants for aged recipients. A mouse model, using C3H mice as donors and aged/young C57BL/10J mice as recipients, was employed to study aging effects on immunity. The results showed that frequency of myeloid-derived suppressor cells (MDSC) and level of TGF-ß was higher in aged mice than in young mice (4.4 ± 1.4% versus 1.6 ± 1.1%, p = 0.026 for MDSC; 21.04 ± 3.91 ng/ml versus 15.26 ± 5.01 ng/ml, p = 0.026 for TGF-ß). In vivo, skin allograft survived longer on the aged than on young mice (19.7 ± 5.2 days versus 11.9 ± 4.1 days, p = 0.005). When entinostat was applied to block MDSC, the survival of skin allografts on aged mice was shorten to 13.5 ± 4.7 days which was not different from the survival on young mice (p = 0.359). In conclusion, allogeneic immunity was different in aged from young mice in high frequency of MDSC and high serum level of TGF-ß. Blocking the function of MDSC reversed the low immunity in aged mice and caused skin allograft rejection similar to young recipients.

Stem cell factor produced by tumor cells expands myeloid-derived suppressor cells in mice.

Immunotherapy is a novel treatment approach for cancers; however, its therapeutic effects are impeded by myeloid-derived suppressor cells (MDSCs). This study aimed to determine how MDSCs are expanded in cancer hosts. MDSCs were positive for Gr-1 and CD11b. Hepa1-6 hepatoma cells, EL4 lymphoma cells, and mice bearing Hepa1-6 hepatoma or lymphoma were examined. Following the inoculation of Hepa1-6 cells into the flanks of mice, a linear correlation was evident between the frequency of MDSCs in the spleen and tumor sizes. MDSC numbers diminished gradually and returned to the normal level within 3 weeks if the tumors were excised. To identify the cytokines produced by tumor cells that allowed expansion of MDSCs, cytokines in Hepa1-6 cell culture medium and murine serum were examined using a cytokine array. Stem cell factor (SCF) was implicated as the relevant cytokine. When recombinant SCF was added to the spleen cell culture medium, MDSC expansion could occur. In the presence of c-kit blockade, this effect of SCF was partially reversed. In conclusion, MDSCs can be expanded in tumor cells in a process that involves SCF released by tumor cells.

Early Epinephrine Improves the Stabilization of Initial Post-resuscitation Hemodynamics in Children With Non-shockable Out-of-Hospital Cardiac Arrest.

Background: In children with non-shockable out-of-hospital cardiac arrest, early epinephrine (EE) might help to establish the return of spontaneous circulation (ROSC) and be associated with survival. In the present study, we aimed to analyze the effects of EE on outcomes and post-resuscitation hemodynamics in children with non-shockable OHCA. Methods: This was a retrospective analysis of data from 216 children (<19 years) who had suffered non-traumatic and non-shockable OHCA and received epinephrine for resuscitation (Jan 1, 2006-Dec 31, 2014). Demographics, pre-/in-hospital information, and the time to the first dose of epinephrine were recorded. Early post-resuscitation hemodynamics (the first hour after sustained ROSC), survival and good neurological outcomes (Pediatric Cerebral Performance Category Scales 1 or 2) were analyzed by the time to epinephrine-classified as early (EE): <15 min, intermediate (IE): 15-30 min, or late (LE): >30 min. Results: Twenty-eight (13.0%) children survived to discharge, but only 17 (7.9%) had good neurological outcomes. In all, 41 (18.9%) children received EE; in comparison to IE and LE, this was significantly associated with tachycardia (73.9%) in the post-resuscitation period (p < 0.05). Tachycardia (OR: 7.41, 95% CI: 1.96-29.31) and hypertension (OR: 6.03, 95% CI: 1.85-13.77) were significantly associated with EE after adjusting for confounding factors. EE was also significantly associated with better overall outcomes than ME and LE (any ROSC, sustained ROSC, survival to the intensive care unit, admission, survival to discharge and good neurological outcomes, all p < 0.05). Conclusions: EE helped to establish ROSC but was also associated with more tachycardia and hypertension in the early post-resuscitation period. In children with non-traumatic and non-shockable OHCA, EE was associated with a higher survival rate and better neurological outcomes than were ME and LE.

Demographics of Pediatric OHCA Survivors With Postdischarge Diseases: A National Population-Based Follow-Up Study.

Background: Postdischarge diseases (PDDs) have been reported for adult survivors of out-of-hospital cardiac arrest (OHCA). However, the detailed demographics of pediatric OHCA survivors with PDDs are not well-documented, and information regarding functional survivors is particularly limited. We aimed to report detailed information on the PDDs of survivors of traumatic and non-traumatic pediatric OHCA using a national healthcare database. Methods: We retrospectively obtained data from the Taiwan government healthcare database (2011-2015). Information on the demographics of traumatic and non-traumatic pediatric OHCA survivors (<20 years) was obtained and reported. The patients who survived to discharge (survivors) and those classified as functional survivors were followed up for 1 year for the analysis of newly diagnosed PDDs. The time from discharge to PDD diagnosis was also reported. Results: A total of 2,178 non-traumatic and 288 traumatic OHCA pediatric cases were included. Among the non-traumatic OHCA survivors (n = 374, survival rate = 17.2%), respiratory tract (n = 270, 72.2%), gastrointestinal (n = 187, 50.0%), and neurological diseases (n = 167, 49.1%) were the three most common PDD categories, and in these three categories, the majority of PDDs were atypical/influenza pneumonia, non-infective acute gastroenteritis, and generalized/status epilepsy, respectively. Among the traumatic OHCA survivors (n = 21, survival rate = 7.3%), respiratory tract diseases (n = 17, 81.0%) were the most common, followed by skin or soft tissue (n = 14, 66.7%) diseases. Most functional survivors still suffered from neurological and respiratory tract diseases. Most PDDs, except for skin or soft tissue diseases, were newly diagnosed within the first 3 months after discharge. Conclusions: Respiratory tract (pneumonia), neurological (epilepsy), and skin or soft tissue (dermatitis) diseases were very common among both non-traumatic and traumatic OHCA survivors. More importantly, most PDDs, except for skin or soft tissue diseases, were newly diagnosed within the first 3 months after discharge.

Down-regulation of metabolic proteins in hepatocellular carcinoma with portal vein thrombosis.

BACKGROUND: Hepatocellular carcinoma is an aggressive malignancy with poor prognosis and easy to recur even the tumor is totally removed by surgery. Portal vascular invasion is one of the major factors contributing to tumor recurrence and poor prognosis. However, why hepatocellular carcinoma is easy to grow into vessels is unclear. METHODS: Surgical specimens from seven hepatocellular carcinoma patients with portal vein thrombosis and seven patients without vascular invasion were utilized to analyze protein expression by proteomic technique. The proteins in the tumors were separated by 2-dimensional electrophoresis. Protein patterns in the gels were recorded as digitalized images. The differences of expression in hepatocellular carcinoma with or without portal vein thrombosis were identified by mass spectrometry. RESULTS: Clinically, the tumors with portal vein thrombosis were larger than those without portal vein thrombosis. The median survival time for the patients with portal vein thrombosis was much shorter [4 (ranged 2.5-47) vs. 53 (ranged 33-85) months, p = 0.002]. By analyzing the protein expression in cancer tissues with or without portal vein thrombosis, the differences of protein expression were mainly metabolic enzymes. Carbonic anhydrase I, betaine-homocysteine S-methyltransferase 1, fumarate hydratase, isovaleryl-CoA dehydrogenase, short-chain specific acyl-CoA dehydrogenase and arginase-1 were all down-regulated in the tumors with portal vein thrombosis. CONCLUSION: Metabolic enzymes and cytosol carbonic anhydrases were downregulated in hepatocellular carcinoma with portal vein thrombus. The deficiency of metabolic enzymes and cytosol carbonic anhydrases may alter cellular metabolisms and acid-base balance in hepatocellular carcinoma, which may facilitate to invade portal vein.

Critical Thinking Disposition of Nurse Practitioners in Taiwan.

BACKGROUND: Critical thinking disposition (CTD) is crucial for nurse practitioners who face complex patient care scenarios. This study explored the CTD of nurse practitioners and related factors. METHOD: The study was a cross-sectional descriptive design. A purposive sample was recruited from a medical center and its hospital branches in central Taiwan. A structured questionnaire was used to collect data from 210 nurse practitioners. RESULTS: The participants obtained the highest average score on systematicity and analyticity. CTD had a significant positive correlation with fundamental knowledge readiness, professional knowledge readiness, and confidence in making clinical decisions. Professional knowledge readiness, education level, and on-the-job training predicted the score of the participants on overall CTD. CONCLUSION: On-the-job training and education level may influence the CTD of nurse practitioners. Providing formal or on-the-job continuing education training to nurse practitioners may help enhance their CTD. J Contin Educ Nurs. 2017;48(9):425-430.

Demographics and Clinical Features of Postresuscitation Comorbidities in Long-Term Survivors of Out-of-Hospital Cardiac Arrest: A National Follow-Up Study.

The outcome of patients suffering from out-of-hospital cardiac arrest (OHCA) is very poor, and postresuscitation comorbidities increase long-term mortality. This study aims to analyze new-onset postresuscitation comorbidities in patients who survived from OHCA for over one year. The Taiwan National Health Insurance (NHI) Database was used in this study. Study and comparison groups were created to analyze the risk of suffering from new-onset postresuscitation comorbidities from 2011 to 2012 (until December 31, 2013). The study group included 1,346 long-term OHCA survivors; the comparison group consisted of 4,038 matched non-OHCA patients. Demographics, patient characteristics, and risk of suffering comorbidities (using Cox proportional hazards models) were analyzed. We found that urinary tract infections (n = 225, 16.72%), pneumonia (n = 206, 15.30%), septicemia (n = 184, 13.67%), heart failure (n = 111, 8.25%) gastrointestinal hemorrhage (n = 108, 8.02%), epilepsy or recurrent seizures (n = 98, 7.28%), and chronic kidney disease (n = 62, 4.61%) were the most common comorbidities. Furthermore, OHCA survivors were at much higher risk (than comparison patients) of experiencing epilepsy or recurrent seizures (HR = 20.83; 95% CI: 12.24-35.43), septicemia (HR = 8.98; 95% CI: 6.84-11.79), pneumonia (HR = 5.82; 95% CI: 4.66-7.26), and heart failure (HR = 4.88; 95% CI: 3.65-6.53). Most importantly, most comorbidities occurred within the first half year after OHCA.

An exploration of the correlates of nurse practitioners' clinical decision-making abilities.

AIMS AND OBJECTIVES: This study investigated nurse practitioners' clinical decision-making abilities and the factors that affect these abilities. BACKGROUND: Nurse practitioners play an important role in clinical care decision-making; however, studies exploring the factors that affect their decision-making abilities are lacking. DESIGN: A cross-sectional descriptive survey was employed. METHODS: A purposive sample of 197 nurse practitioners was recruited from a medical centre in central Taiwan. Structured questionnaires consisting of the Knowledge Readiness Scale, the Critical Thinking Disposition Inventory and the Clinical Decision-Making Model Inventory were used to collect data. RESULTS: The intuitive-analytical type was the most commonly used decision-making model, and the intuitive type was the least frequently used model. The decision-making model used was significantly related to the nurse practitioners' work unit. Significant differences were noted between the nurse practitioners' clinical decision-making models and their critical thinking dispositions (openness and empathy). The nurse practitioners' years of work experience, work unit, professional knowledge and critical thinking disposition (openness and empathy as well as holistic and reflective dispositions) predicted the nurse practitioners' analytical decision-making scores. Age, years of nurse practitioner work experience, work unit and critical thinking disposition (holistic and reflective) predicted the nurse practitioners' intuitive decision-making scores. CONCLUSIONS: This study contributes to the topic of clinical decision-making by describing various types of nurse practitioner decision-making. The factors associated with analytic and intuitive decision-making scores were identified. These findings might be beneficial when planning continuing education programmes to enhance the clinical decision-making abilities of nurse practitioners. RELEVANCE TO CLINICAL PRACTICE: The study results showed that nurse practitioners demonstrated various clinical decision-making types across different work units. Consideration of nurse practitioners' knowledge readiness and their specific needs while planning on-duty education programmes is necessary.

Application of three different sets of explicit criteria for assessing inappropriate prescribing in older patients: a nationwide prevalence study of ambulatory care visits in Taiwan.

OBJECTIVE: To investigate the national prevalence of potentially inappropriate medications (PIMs) prescribed in ambulatory care clinics in Taiwan according to three different sets of regional criteria and the correlates of PIM use. DESIGN: Cross-sectional study. SETTING: This analysis included older patients who visited ambulatory care clinics in 2009 and represented half of the older population included on the Taiwanese National Health Insurance Research Database. PARTICIPANTS: We identified 1,164,701 subjects who visited ambulatory care clinics and were over 65 years old in 2009. PRIMARY AND SECONDARY OUTCOME MEASURES: PIM prevalence according to the 2012 Beers criteria, the PIM-Taiwan criteria and the PRISCUS criteria was estimated separately, and characteristics of PIM users were explored. Multivariate logistic regression analysis was used to determine patient factors associated with the use of at least one PIM. Leading PIMs for each set of criteria were also listed. RESULTS: The prevalence of having at least one PIM at the patient level was highest with the Beers criteria (86.2%), followed by the PIM-Taiwan criteria (73.3%) and the PRISCUS criteria (66.9%). Polypharmacy and younger age were associated with PIM use for all three sets of criteria. The leading PIMs detected by the PIM-Taiwan and PRISCUS criteria were all included in the 2012 Beers criteria. Non-COX-selective non-steroidal anti-inflammatory drugs in the Beers criteria and benzodiazepines in the PIM-Taiwan and PRISCUS criteria accounted for most leading PIMs. CONCLUSIONS: The prevalence of PIMs was high among older Taiwanese patients receiving ambulatory care visits. The prevalence of PIM and its associated factors varied according to three sets of criteria at the population level.

Patient- and clinic visit-related factors associated with potentially inappropriate medication use among older home healthcare service recipients.

OBJECTIVES: Taiwanese National Health Insurance (TNHI) provides home healthcare services to patients with skilled nursing needs who were homebound or lived in nursing homes. Studies on potentially inappropriate medications (PIMs) for older home healthcare service recipients (HHSRs) are growing, but comparisons among newer criteria of PIMs have not been applied. The aim of this study was to explore the prevalence and correlates of PIMs based on three different instruments published after 2010 among older HHSRs. MATERIALS AND METHODS: We performed cross-sectional analysis of the TNHI Research Database. A total of 25,187 HHSRs aged more than 65 years in 2009 were included. Medication lists independent of chronic conditions from the 2012 Beers criteria, PIM-Taiwan criteria, and the PRISCUS (Latin for "old and venerable") criteria were used. Analysis was performed separately at patient and clinic-visit level. T-tests, chi-square analysis, and multivariate logistic regressions were used where appropriate. RESULTS: The prevalence of having at least one PIM at patient and clinic-visit level was highest with the Beers (82.67%, 36.14% respectively), followed by the PRISCUS (68.49%, 25.13%) and PIM-Taiwan (63.04%, 19.21%) criteria. At patient level, polypharmacy (odds ratio (OR) 2.53 to 4.90), higher number of clinic (OR 1.15 to 1.41), hospital (OR 1.24 to 1.64), and physician (OR 1.15 to 1.41) visits were associated with PIM use for all 3 sets of criteria. At clinic-visit level, internist/family physicians (OR 1.26 to 1.72) and neurologists/psychiatrists (OR 1.73 to 5.87) were more likely to prescribe PIMs than others. Psychotropic drugs and first generation antihistamines accounted for most of the top ten PIMs. CONCLUSION: The prevalence of PIMs was high among older Taiwanese HHSRs. Polypharmacy and certain medical specialties were associated with a higher likelihood of PIM prescriptions. Provider education and medication review and reconciliation should be considered.

Using published criteria to develop a list of potentially inappropriate medications for elderly patients in Taiwan.

BACKGROUND: Explicit criteria for potentially inappropriate medications (PIMs) developed from other regions were often difficult to apply to a specific territory without significant modifications. PURPOSE: To describe a process of developing a country-specific explicit PIM criteria from quality review of several published PIM criteria, followed by consensus among regional experts in Taiwan. METHODS: After a review of the literature, we selected seven sets of published PIM criteria. Medications/medication classes listed in at least three of the seven sets of criteria were selected as preliminary core PIMs. We asked a group of 21 experts from various specialties to rate how appropriate they found inclusion of each medication/medication class in final PIM criteria after two rounds of modified Delphi methods. RESULTS: Table 1 of the instrument included 24 medication/medication classes to be generally avoided in older adults irrespective of co-morbidities, and Table 2 included 12 chronic conditions with six medication/medication classes that patients with these conditions should avoid. The Taiwan criteria contained only half the number of statements that were included in the Beers criteria (36 vs 68 statements) but detected nearly 70-75% as many PIMs in older patients with polypharmacy in a secondary data analysis. Features included straightforward statement arrangements, suggestions of alternatives, and clear definitions of long-acting benzodiazepine and anticholinergic drugs for Table 1 PIMs. CONCLUSION: A user-friendly instrument was developed to detect PIMs for Taiwanese older adults. Further prospective studies are needed to validate its use in clinical and research settings.

The impact of CD4+ CD25+ T cells in the tumor microenvironment of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common liver cancer. Therapeutic results are usually unsatisfactory because liver tumors recur often. Immunologic factors may be related to the recurrence of HCC; however, this possibility is mentioned only rarely. METHODS: Thirty HCC patients undergoing hepatectomies were divided into 3 groups according to the diameters of their HCCs: group A (n = 8), diameter ≤3 cm; group B (n = 8), diameter >3 cm and ≤5 cm; and group C (n = 14), diameter >5 cm. T-lymphocytes from peripheral blood, nontumor liver tissue, and the HCC were analyzed. RESULTS: The percentage of CD25+ in the CD4+ T cells did not differ between the peripheral blood and the nontumor liver tissue among the 3 groups. CD25+ cells were increased in the tumor tissue in group C patients (range, 6-41%; median, 22.9%; P = .003), compared to group A patients. The percentage of CD25+ in the CD4+ T cells in tumor tissue was positively correlated with tumor sizes (r = 0.556). These CD4+ CD25+ lymphocytes produced transforming growth factor-ß and interferon-γ but not interleukin-10, and were anergic to plate-coated monoclonal antibodies (anti-CD3/anti-CD28). The characteristics of these antibodies were comparable to those of regulatory T cells. When the infiltration lymphocytes including CD4+ CD25+ T cells were added to the mixed lymphocyte reaction activated by autologous tumor lysate-pulsed dendritic cells, the proliferation of lymphocytes was inhibited. CONCLUSION: The increase of CD4+ CD25+ T cells in the tumor microenvironment correlates with tumor sizes. These CD4+ CD25+ regulatory T cells appeared to suppress the immune response activated by dendritic cells.