Fluorescent tagging of endogenous IRS2 with an auxin-dependent degron to assess dynamic intracellular localization and function.

Insulin Receptor Substrate 2 (IRS2) is a signaling adaptor protein for the insulin (IR) and Insulin-like Growth Factor-1 (IGF-1R) receptors. In breast cancer, IRS2 contributes to both the initiation of primary tumor growth and the establishment of secondary metastases through regulation of cancer stem cell (CSC) function and invasion. However, how IRS2 mediates its diverse functions is not well understood. We used CRISPR/Cas9-mediated gene editing to modify endogenous IRS2 to study the expression, localization, and function of this adaptor protein. A cassette containing an auxin-inducible degradation (AID) sequence, 3x-FLAG tag, and mNeon-green was introduced at the N-terminus of the IRS2 protein to provide rapid and reversible control of IRS2 protein degradation and analysis of endogenous IRS2 expression and localization. Live fluorescence imaging of these cells revealed that IRS2 shuttles between the cytoplasm and nucleus in response to growth regulatory signals in a PI3K-dependent manner. Inhibition of nuclear export or deletion of a putative nuclear export sequence in the C-terminal tail promotes nuclear retention of IRS2, implicating nuclear export in the mechanism by which IRS2 intracellular localization is regulated. Moreover, the acute induction of IRS2 degradation reduces tumor cell invasion, demonstrating the potential for therapeutic targeting of this adaptor protein. Our data highlight the value of our model of endogenously tagged IRS2 as a tool to study IRS2 localization and function.

Medical care costs at the end of life among older adults with cancer: a national health insurance data-based cohort study.

OBJECTIVE: Along with aging, the elderly population with cancers is increasing. The costs of end-of-life (EOL) care are particularly high among cancer patients. The purpose of this study was to investigate the trends in medical costs in the last year of life among older adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: Using the Health Insurance Review and Assessment Services (HIRA) database for the period 2016-2019, we identified older adults aged ≥ 65 years who had a primary diagnosis of cancers and high-intensity treatment at least once in the intensive care unit (ICU) of tertiary hospitals. MAIN OUTCOMES AND MEASURES: High-intensity treatment was defined as receiving at least one of the following treatments: cardiopulmonary resuscitation, mechanical ventilation, extracorporeal membrane oxygenation, hemodialysis, and transfusion. The EOL medical treatment costs were calculated by dividing periods 1, 2, 3, 6, and 12 months from the time of death, respectively. RESULTS: The mean total EOL medical expense per older adult during the year before death was $33,712. The cost of EOL medical expenses for three months and one month before subjects' death accounted for 62.6% ($21,117) and 33.8% ($11,389) of total EOL costs, respectively. Among subjects who died while receiving high-intensity treatment in the ICU, the costs associated with medical treatments that occurred during the last month before death were 42.4% ($13,841) of the total EOL expenses during the year. CONCLUSION: The findings indicate that EOL care expenditures for the older population with cancer are highly concentrated until the last month. The intensity of medical care is an important and challenging issue in terms of care quality and cost suitability. Efforts are needed to properly use medical resources and provide optimal EOL care for older adults with cancer.

Pulsed Electromagnetic Field (PEMF) Treatment Ameliorates Murine Model of Collagen-Induced Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease of the joint synovial membranes. RA is difficult to prevent or treat; however, blocking proinflammatory cytokines is a general therapeutic strategy. Pulsed electromagnetic field (PEMF) is reported to alleviate RA's inflammatory response and is being studied as a non-invasive physical therapy. In this current study, PEMF decreased paw inflammation in a collagen-induced arthritis (CIA) murine model. PEMF treatment at 10 Hz was more effective in ameliorating arthritis than at 75 Hz. In the PEMF-treated CIA group, the gross inflammation score and cartilage destruction were lower than in the untreated CIA group. The CIA group treated with PEMF also showed lower serum levels of IL-1ß but not IL-6, IL-17, or TNF-α. Serum levels of total anti-type II collagen IgG and IgG subclasses (IgG1, IgG2a, and IgG2b) remained unchanged. In contrast, tissue protein levels of IL-1ß, IL-6, TNF-α, receptor activator of nuclear factor kappa-Β (RANK), RANK ligand (RANKL), IL-6 receptor (IL-6R), and TNF-α receptor1 (TNFR1) were all lower in the ankle joints of the PEMF-treated CIA group compared with the CIA group. The results of this study suggest that PEMF treatment can preserve joint morphology cartilage and delay the occurrence of CIA. PEMF has potential as an effective adjuvant therapy that can suppress the progression of RA.

Promotion of Colitis in B Cell-Deficient C57BL/6 Mice Infected with Enterotoxigenic Bacteroides fragilis.

Enterotoxigenic Bacteroides fragilis (ETBF) causes colitis and is implicated in inflammatory bowel diseases and colorectal cancer. The ETBF-secreted B. fragilis toxin (BFT) causes cleavage of the adherence junction, the E-cadherin, resulting in the large intestine showing IL-17A inflammation in wild-type (WT) mice. However, intestinal pathology by ETBF infection is not fully understood in B-cell-deficient mice. In this study, ETBF-mediated inflammation was characterized in B-cell-deficient mice (muMT). WT or muMT C57BL/6J mice were orally inoculated with ETBF and examined for intestinal inflammation. The indirect indicators for colitis (loss of body weight and cecum weight, as well as mortality) were increased in muMT mice compared to WT mice. Histopathology and inflammatory genes (Nos2, Il-1ß, Tnf-α, and Cxcl1) were elevated and persisted in the large intestine of muMT mice compared with WT mice during chronic ETBF infection. However, intestinal IL-17A expression was comparable between WT and muMT mice during infection. Consistently, flow cytometry analysis applied to the mesenteric lymph nodes showed a similar Th17 immune response in both WT and muMT mice. Despite elevated ETBF colonization, the ETBF-infected muMT mice showed no histopathology or inflammation in the small intestine. In conclusion, B cells play a protective role in ETBF-induced colitis, and IL-17A inflammation is not attributed to prompted colitis in B-cell-deficient mice. Our data support the fact that B cells are required to ameliorate ETBF infection-induced colitis in the host.

Skeletal muscle satellite cell-derived mesenchymal stem cells ameliorate acute alcohol-induced liver injury.

Cultured human skeletal-muscle satellite cells have properties of mesenchymal stem cells (skeletal muscle satellite cell-derived mesenchymal stem cells, SkMSCs) and play anti-inflammatory roles by secreting prostaglandin E2 and hepatocyte growth factor (HGF). To evaluate the utility of SkMSCs in treating liver diseases, we determined whether SkMSCs could ameliorate acute liver and gut inflammation induced by binge ethanol administration. Binge drinking of ethanol led to weight loss in the body and spleen, liver inflammation and steatosis, and increased serum ALT and AST levels (markers of liver injury), along with increased IL-1ß, TNF-α, and iNOS expression levels in mice. However, levels of these binge-drinking-induced indicators were reduced by a single intraperitoneal treatment of SkMSCs. Furthermore, levels of bacteria-derived lipopolysaccharide decreased in the livers and sera of ethanol-exposed mice after SkMSC administration. SkMSCs decreased the extent of tissue inflammation and reduced villus and crypt lengths in the small intestine after alcohol binge drinking. SkMSCs also reduced the leakage of blood albumin, an indicator of leaky gut, in the stool of ethanol-exposed mice. Alcohol-induced damage to human colonic Caco-2/tc7 cells was also alleviated by HGF. Therefore, a single treatment with SkMSCs can attenuate alcoholic liver damage by reducing inflammatory responses in the liver and gut, suggesting that SkMSCs could be used in cell therapy to treat alcoholic liver diseases.

Pulsed Electromagnetic Field (PEMF) Treatment Reduces Lipopolysaccharide-Induced Septic Shock in Mice.

Despite advances in medicine, mortality due to sepsis has not decreased. Pulsed electromagnetic field (PEMF) therapy is emerging as an alternative treatment in many inflammation-related diseases. However, there are few studies on the application of PEMF therapy to sepsis. In the current study, we examined the effect of PEMF therapy on a mouse model of lipopolysaccharide (LPS)-induced septic shock. Mice injected with LPS and treated with PEMF showed higher survival rates compared with the LPS group. The increased survival was correlated with decreased levels of pro-inflammatory cytokine mRNA expression and lower serum nitric oxide levels and nitric oxide synthase 2 mRNA expression in the liver compared with the LPS group. In the PEMF + LPS group, there was less organ damage in the liver, lungs, spleen, and kidneys compared to the LPS group. To identify potential gene targets of PEMF treatment, microarray analysis was performed, and the results showed that 136 genes were up-regulated, and 267 genes were down-regulated in the PEMF + LPS group compared to the LPS group. These results suggest that PEMF treatment can dramatically decrease septic shock through the reduction of pro-inflammatory cytokine gene expression. In a clinical setting, PEMF may provide a beneficial effect for patients with bacteria-induced sepsis and reduce septic shock-induced mortality.

Feasibility of an Advance Care Planning Program (ACP) for Korean Community-Dwelling Older Adults and ACP Training of Advance Practice Nurses.

This study aimed to develop a locally suitable advance care planning (ACP) program for older community-dwelling adults and a training program for nurse facilitators in Korea, and to evaluate their feasibility from the facilitators' experiences. This was a mixed methods pilot study that assessed the feasibility of an ACP program by analyzing survey, checklist, and focus group interview data. The ACP program was named CLOSE (Communicating and Listening to Our Seniors' voices about End-of-life care). Home health care nurses (N = 9) participated in this study. The participants reported that CLOSE was applicable to older community-dwelling adults and the training program was useful for increasing facilitator competency. We suggest some lessons from this pilot study that can be used to improve the ACP program and encourage community health nurses to participate in ACP as facilitators.

Oral administration of Korean propolis extract ameliorates DSS-induced colitis in BALB/c mice.

Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract characterized by inflammation. Although IBD is usually treated with anti-inflammatory agents, most of these treatments have limited efficacy. Propolis is a viscous mixture that honeybees produce by mixing saliva and honeycomb with exudate gathered from tree buds, sap flows, or other botanical sources. Although propolis has proved to ameliorate several inflammatory disorders, its therapeutic properties vary by geographical location, plant resources, bee species, and the solvents used in the extraction. In this study, we investigated the effects of Korean propolis in BALB/c mice with dextran sulfate sodium (DSS)-induced colitis. Korean propolis extract was diluted in drinking water, and the BALB/c mice were given DSS for 7 days and Korean propolis for 17 days. The mice were sacrificed on day 17. In the DSS-induced colitis model, Korean propolis significantly decreased the severity of colitis, as assessed by body weight, spleen weight, and colonic length. Furthermore, Korean propolis induced the reduction of the inflammatory cytokine KC, infiltration of immune cells, and colonic hyperplasia in mice with DSS-induced colitis. The Korean propolis also decreased the loss of goblet cells and antibody-reactivity to inflammatory markers in the colons of mice administered DSS. These results demonstrate for the first time that Korean propolis has an ameliorative effect on DSS-induced colonic inflammation in BALB/c mice.

Enterotoxigenic Bacteroides fragilis infection exacerbates tumorigenesis in AOM/DSS mouse model.

The azoxymethane (AOM)/dextran sulfate sodium (DSS) murine model is commonly used to study colitis-associated cancer. The human commensal bacterium, enterotoxigenic Bacteroides fragilis (ETBF) secretes the Bacteroides fragilis toxin (BFT) which is necessary and sufficient to cause colitis. We report that BALB/c mice infected with WT-ETBF and administered three cycles of AOM/DSS developed numerous, large-sized polyps predominantly in the colorectal region. In addition, AOM/DSS-treated BALB/c mice orally inoculated with wild-type nontoxigenic Bacteroides fragilis (WT-NTBF) overexpressing bft (rETBF) developed numerous polyps whereas mice infected with WT-NTBF overexpressing a biologically inactive bft (rNTBF) did not promote polyp formation. Unexpectedly, the combination of AOM+ETBF did not induce polyp formation whereas ETBF+DSS did induce polyp development in a subset of BALB/c mice. In conclusion, WT-ETBF promoted polyp development in AOM/DSS murine model with increased colitis in BALB/c mice. The model described herein provides an experimental platform for understanding ETBF-induced colonic tumorigenesis and studying colorectal cancer in wild-type mice.

Dietary Salt Administration Decreases Enterotoxigenic Bacteroides fragilis (ETBF)-Promoted Tumorigenesis via Inhibition of Colonic Inflammation.

Consumption of a Western-type diet has been linked to gut-microbiota-mediated colon inflammation that constitutes a risk factor for colorectal cancer. A high salt diet (HSD) exacerbates IL-17A-induced inflammation in inflammatory bowel disease and other autoimmune diseases. Enterotoxigenic Bacteroides fragilis (ETBF) is a gut commensal bacterium and reported to be a potent initiator of colitis via secretion of the Bacteroides fragilis toxin (BFT). BFT induces ectodomain cleavage of E-cadherin in colonic epithelial cells, consequently leading to cell rounding, epithelial barrier disruption, and the secretion of IL-8, which promotes tumorigenesis in mice via IL-17A-mediated inflammation. A HSD is characteristic of the Western-type diet and can exhibit inflammatory effects. However, a HSD induces effects in ETBF-induced colitis and tumorigenesis remain unknown. In this study, we investigated HSD effects in ETBF-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis as well as ETBF colitis mice. Unexpectedly, ETBF-infected mice fed a HSD exhibited decreased weight loss and splenomegaly and reduction of colon inflammation. The HSD significantly decreased the expression of IL-17A and inducible nitric oxide synthase (iNOS) in the colonic tissues of ETBF-infected mice. In addition, serum levels of IL-17A and nitric oxide (NO) were also diminished. However, HT29/C1 colonic epithelial cells treated with sodium chloride showed no changes in BFT-induced cellular rounding and IL-8 expression. Furthermore, HSD did not affect ETBF colonization in mice. In conclusion, HSD decreased ETBF-induced tumorigenesis through suppression of IL-17A and iNOS expression in the colon. HSD also inhibited colonic polyp numbers in the ETBF-infected AOM/DSS mice. Taken together, these findings suggest that a HSD consumption inhibited ETBF-promoted colon carcinogenesis in mice, indicating that a HSD could have beneficial effects under certain conditions.

Protective Effects of Zerumbone on Colonic Tumorigenesis in Enterotoxigenic Bacteroides fragilis (ETBF)-Colonized AOM/DSS BALB/c Mice.

Chronic inflammation has been linked to colitis-associated colorectal cancer in humans. The human symbiont enterotoxigenic Bacteroides fragilis (ETBF), a pro-carcinogenic bacterium, has the potential to initiate and/or promote colorectal cancer. Antibiotic treatment of ETBF has shown promise in decreasing colonic polyp formation in murine models of colon cancer. However, there are no reported natural products that have shown efficacy in decreasing polyp burden. In this study, we investigated the chemopreventive effects of oral administration of zerumbone in ETBF-colonized mice with azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced tumorigenesis. Zerumbone significantly reduced the severity of disease activity index (DAI) scores as well as several parameters of colonic inflammation (i.e., colon weight, colon length, cecum weight and spleen weight). In addition, inflammation of the colon and cecum as well as hyperplasia was reduced. Zerumbone treatment significantly inhibited colonic polyp numbers and prevented macroadenoma progression. Taken together, these findings suggest that oral treatment with zerumbone inhibited ETBF-promoted colon carcinogenesis in mice indicating that zerumbone could be employed as a promising protective agent against ETBF-mediated colorectal cancer.

Zerumbone Suppresses Enterotoxigenic Bacteroides fragilis Infection-Induced Colonic Inflammation through Inhibition of NF-κΒ.

Enterotoxigenic Bacteroides fragilis (ETBF) is human intestinal commensal bacterium and a potent initiator of colitis through secretion of the metalloprotease Bacteroides fragilis toxin (BFT). BFT induces cleavage of E-cadherin in colon cells, which subsequently leads to NF-κB activation. Zerumbone is a key component of the Zingiber zerumbet (L.) Smith plant and can exhibit anti-bacterial and anti-inflammatory effects. However, whether zerumbone has anti-inflammatory effects in ETBF-induced colitis remains unknown. The aim of this study was to determine the anti-inflammatory effect of orally administered zerumbone in a murine model of ETBF infection. Wild-type C57BL/6 mice were infected with ETBF and orally administered zerumbone (30 or 60 mg/kg) once a day for 7 days. Treatment of ETBF-infected mice with zerumbone prevented weight loss and splenomegaly and reduced colonic inflammation with decreased macrophage infiltration. Zerumbone treatment significantly decreased expression of IL-17A, TNF-α, KC, and inducible nitric oxide synthase (iNOS) in colonic tissues of ETBF-infected mice. In addition, serum levels of KC and nitrite was also diminished. Zerumbone-treated ETBF-infected mice also showed decreased NF-κB signaling in the colon. HT29/C1 colonic epithelial cells treated with zerumbone suppressed BFT-induced NF-κB signaling and IL-8 secretion. However, BFT-mediated E-cadherin cleavage was unaffected. Furthermore, zerumbone did not affect ETBF colonization in mice. In conclusion, zerumbone decreased ETBF-induced colitis through inhibition of NF-κB signaling.

A systematic evaluation of websites offering information on chronic kidney disease.

In this study, we described the content and characteristics of 40 non-proprietary websites offering information about chronic kidney disease (CKD) and evaluated their information quality using the DISCERN scale and readability using Flesch Reading Ease and Flesch-Kincaid grade level. The areas in which the websites scored the lowest on the DISCERN scale were whether the website discussed knowledge gaps, presented balanced information, and was clear about the information source. Websites that rated higher quality on the DISCERN scale were more difficult to read. The quality and readability of many websites about CKD to be used as meaningful educational resources for patients who desire to learn more about CKD and treatment options remain inadequate.

Reduced dynamicity and increased high-order protein assemblies in dense fibrillar component of the nucleolus under cellular senescence.

Cellular senescence, which is triggered by various stressors, manifests as irreversible cell cycle arrest, resulting in the disruption of multiple nuclear condensates. One of the affected structures is the nucleolus, whose tripartite layout, separated into distinct liquid phases, allows for the stepwise progression of ribosome biogenesis. The dynamic properties of dense fibrillar components, a sub-nucleolar phase, are crucial for mediating pre-rRNA processing. However, the mechanistic link between the material properties of dense fibrillar components and cellular senescence remains unclear. We established a significant association between cellular senescence and alterations in nucleolar materiality and characteristics, including the number, size, and sphericity of individual subphases of the nucleolus. Senescent cells exhibit reduced fibrillarin dynamics, aberrant accumulation of high-order protein assemblies, such as oligomers and fibrils, and increased dense fibrillar component density. Intriguingly, the addition of RNA-interacting entities mirrored the diminished diffusion of fibrillarin in the nucleolus during cellular senescence. Thus, our findings contribute to a broader understanding of the intricate changes in the materiality of the nucleolus associated with cellular senescence and shed light on nucleolar dynamics in the context of aging and cellular stress.

Blockade of Piezo2 Pathway Attenuates Inflammatory and Neuropathic Pain in the Orofacial Area.

Although previous studies suggest that Piezo2 regulates chronic pain in the orofacial area, few studies have reported the direct evidence of Piezo2's involvement in inflammatory and neuropathic pain in the orofacial region. In this study, we used male Sprague Dawley rats to investigate the role of the Piezo2 pathway in the development of inflammatory and neuropathic pain. The present study used interleukin (IL)-1ß-induced pronociception as an inflammatory pain model. Subcutaneous injection of IL-1ß produced significant mechanical allodynia and thermal hyperalgesia. Subcutaneous injection of a Piezo2 inhibitor significantly blocked mechanical allodynia and thermal hyperalgesia induced by subcutaneously injected IL-1ß. Furthermore, the present study also used a neuropathic pain model caused by the misplacement of a dental implant, leading to notable mechanical allodynia as a consequence of inferior alveolar nerve injury. Western blot analysis revealed increased levels of Piezo2 in the trigeminal ganglion and the trigeminal subnucleus caudalis after inferior alveolar nerve injury. Furthermore, subcutaneous and intracisternal injections of a Piezo2 inhibitor blocked neuropathic mechanical allodynia. These results suggest that the Piezo2 pathway plays a critical role in the development of inflammatory and neuropathic pain in the orofacial area. Therefore, blocking the Piezo2 pathway could be the foundation for developing new therapeutic strategies to treat orofacial pain conditions.

Korean Red Ginseng Extract Powder Mitigates Fasting And Postprandial Hyperglycemia in Type 2 Diabetic Mice.

Type 2 diabetes mellitus (T2DM) involves insulin resistance and elevated blood sugar levels, causing complications. Red ginseng extract powder (RGEP) from Panax ginseng Meyer shows promise for diabetes treatment. However, its efficacy in managing T2DM remains unclear. Therefore, this study aims to evaluate the effectiveness of RGEP in a mouse model of T2DM. The efficacy of RGEP in treating T2DM was assessed in db/db mice. Mice were divided into seven groups: control, db/db, metformin, and RGEP at 50, 100, 200, and 400 mg/kg. Administered orally for 9 weeks, RGEP effects on glucose regulation and insulin sensitivity were assessed through various metabolic parameters. In addition, mRNA expression levels of genes associated with hepatic gluconeogenesis and insulin sensitivity were examined. Fasting blood sugar showed a significant decrease in all RGEP concentration groups, but OGTT and insulin tolerance test showed a significant decrease at the RGEP concentration of 400 mg/kg, indicating enhanced glycemic control. Moreover, RGEP dose-dependently decreased serum glucose, HbA1c levels, and homeostatic model assessment of insulin resistance values, suggesting its effectiveness in reducing insulin resistance in db/db mice. Furthermore, RGEP downregulated mRNA expression of key components in the gluconeogenesis pathway (G6Pase, FOXO1, GLUT4, and PEPCK), insulin sensitivity (leptin, insulin1, PTP1B, GLP-1, and DPP-4), and mitochondria energy metabolism (PGC1) in either the liver or pancreas, while simultaneously upregulating GLP-1 expression. In conclusion, these findings highlight the potential of RGEP as a complementary therapy for T2DM, indicating therapeutic efficacy in managing diabetic complications through improved metabolic parameters.

Caffeic Acid Phenethyl Ester Administration Reduces Enterotoxigenic Bacteroides fragilis-Induced Colitis and Tumorigenesis.

The human colonic commensal enterotoxigenic Bacteroides fragilis (ETBF) is associated with chronic colitis and colon cancer. ETBF colonization induces colitis via the Bacteroides fragilis toxin (BFT). BFT secreted by ETBF cause colon inflammation via E-cadherin cleavage/NF-κB signaling. ETBF promotes colon tumorigenesis via interleukin 17A (IL-17A)/CXCL-dependent inflammation, but its bioactive therapeutics in ETBF-promoted tumorigenesis remain unexplored. In the current study, we investigated the caffeic acid phenethyl ester (CAPE) in the murine model of ETBF colitis and tumorigenesis. In this study, we observed that CAPE treatment mitigated inflammation induced by ETBF in mice. Additionally, our findings indicate that CAPE treatment offers protective effects against ETBF-enhanced colon tumorigenesis in a mouse model of colitis-associated colon cancer induced by azoxymethane (AOM) and dextran sulfate sodium. Notably, the decrease in colon tumorigenesis following CAPE administration correlates with a reduction in the expression of IL-17A and CXCL1 in the gastrointestinal tract. The molecular mechanism for CAPE-induced protection against ETBF-mediated tumorigenesis is mediated by IL-17A/CXCL1, and by NF-κB activity in intestinal epithelial cells. Our findings indicate that CAPE may serve as a preventive agent against the development of ETBF-induced colitis and colorectal cancer (CRC).

Effects of advance care planning training on advanced practice nurse students' knowledge, confidence, and perception of end-of-life care: A mixed-method study.

AIMS: This study aimed to assess how an advance care planning training program affected advanced practice nursing students' knowledge, confidence and perception of end-of-life care in South Korea. BACKGROUND: Effective communication between healthcare providers, patients and their families is one of the most important components of quality end-of-life care. However, nurses in South Korea may feel uncomfortable helping patients and families with advance care planning because of the cultural taboo against talking about dying. DESIGN: A mixed-method design was used with data obtained from self-administered questionnaires at the onset and end of the advance care planning training program and qualitative data from participant feedback after the program. METHODS: Data collected from 65 advanced practice nursing students who participated in advance care planning training programs in June-July 2020 and 2021, conducted as part of a graduate clinical practice course, were analyzed. Data were originally collected to examine students' course outcomes. A training program was provided to advanced practice nursing students to improve their knowledge, confidence and perception in advance care planning conversations with their patients. The program comprised three sessions: online lectures, face-to-face simulations and discussions on advance care planning and ethical issues. Changes in advance care planning knowledge, confidence in supporting patients' advance directives, perceived nursing roles in end-of-life treatment decisions and perception of a good death were examined before and after the training. RESULTS: There were statistically significant increases in participants' advance care planning knowledge, confidence in supporting patients' advance directives and perception of the active role of nurses in patients' end-of-life treatment decisions after the training. CONCLUSIONS: The results indicate the effects of training programs on advanced practice nursing students' knowledge, confidence and perception of advance care planning communication. They also provide evidence about what contents and methods can be helpful in developing end-of-life care training for advanced practice nursing students.

Differential Regulation of Intracisternally Injected Angiotensin II-Induced Mechanical Allodynia and Thermal Hyperalgesia in Rats.

The present study examined the underlying mechanisms of mechanical allodynia and thermal hyperalgesia induced by the intracisternal injection of angiotensin (Ang) II. Intracisternal Ang II injection decreased the air puff threshold and head withdrawal latency. To determine the operative receptors for each distinct type of pain behavior, we intracisternally injected Ang II receptor antagonists 2 h after Ang II injection. Losartan, an Ang II type 1 receptor (AT1R) antagonist, alleviated mechanical allodynia. Conversely, PD123319, an Ang II type 1 receptor (AT2R) antagonist, blocked only thermal hyperalgesia. Immunofluorescence analyses revealed the co-localization of AT1R with the astrocyte marker GFAP in the trigeminal subnucleus caudalis and co-localization of AT2R with CGRP-positive neurons in the trigeminal ganglion. Intracisternal pretreatment with minocycline, a microglial inhibitor, did not affect Ang II-induced mechanical allodynia, whereas L-α-aminoadipate, an astrocyte inhibitor, significantly inhibited Ang II-induced mechanical allodynia. Furthermore, subcutaneous pretreatment with botulinum toxin type A significantly alleviated Ang II-induced thermal hyperalgesia, but not Ang II-induced mechanical allodynia. These results indicate that central Ang II-induced nociception is differentially regulated by AT1R and AT2R. Thus, distinct therapeutic targets must be regulated to overcome pain symptoms caused by multiple underlying mechanisms.

Development and Evaluation: A Behavioral Activation Mobile Application for Self-Management of Stress for College Students.

College students are at a high risk of mental health problems due to continuous exposure to considerable stress as they transition into adulthood. It is necessary to reflect on young people's needs and provide brief, personalized support interventions via mobile applications. This study aimed to (1) describe the co-design development process of a behavioral activation (BA) mobile health application called MEndorphins to help youth manage stress; and (2) evaluate the ease of use and quality of the application and its effects on psychological distress. College students aged 18-25 in South Korea participated as co-designers throughout the MEndorphins development process, which involved prototyping workshops. Thirty-five students also evaluated the application's ease of use and quality, as well as its effects on psychological distress, using a self-reported online questionnaire. In the pilot evaluation, ease of use scored 74.21 out of 100 and quality 3.72 out of 5. There were statistically significant decreases in depression, anxiety, and stress after using MEndorphins (p ≤ 0.001 for depression and anxiety, p = 0.001 for stress) for 7 days. In this developed BA based mobile application, participants could monitor their mood, plan stress self-management strategies, and gain motivation by sharing experiences.