Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

BACKGROUND: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies. METHODS: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily. The primary end points were safety and platelet response (defined as at least two consecutive platelet counts of ≥50×103 per cubic millimeter and an increase from baseline of ≥20×103 per cubic millimeter without the use of rescue medication). RESULTS: Sixty patients were enrolled. At baseline, the median platelet count was 15×103 per cubic millimeter, the median duration of disease was 6.3 years, and patients had received a median of four different immune thrombocytopenia therapies previously. All the treatment-related adverse events were of grade 1 or 2 and transient. There were no treatment-related bleeding or thrombotic events of grade 2 or higher. At a median of 167.5 days (range, 4 to 293) of treatment, 24 of 60 patients (40%) overall and 18 of the 45 patients (40%) who had started rilzabrutinib treatment at the highest dose met the primary end point of platelet response. The median time to the first platelet count of at least 50×103 per cubic millimeter was 11.5 days. Among patients with a primary platelet response, the mean percentage of weeks with a platelet count of at least 50×103 per cubic millimeter was 65%. CONCLUSIONS: Rilzabrutinib was active and associated with only low-level toxic effects at all dose levels. The dose of 400 mg twice daily was identified as the dose for further testing. Overall, rilzabrutinib showed a rapid and durable clinical activity that improved with length of treatment. (Funded by Sanofi; ClinicalTrials.gov number, NCT03395210; EudraCT number, 2017-004012-19.).

Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma.

BACKGROUND: In the myeloid compartment of the tumor microenvironment, CD244 signaling has been implicated in immunosuppressive phenotype of monocytes. However, the precise molecular mechanism and contribution of CD244 to tumor immunity in monocytes/macrophages remains elusive due to the co-existing lymphoid cells expressing CD244. METHODS: To directly assess the role of CD244 in tumor-associated macrophages, monocyte-lineage-specific CD244-deficient mice were generated using cre-lox recombination and challenged with B16F10 melanoma. The phenotype and function of tumor-infiltrating macrophages along with antigen-specific CD8 T cells were analyzed by flow cytometry and single cell RNA sequencing data analysis, and the molecular mechanism underlying anti-tumorigenic macrophage differentiation, antigen presentation, phagocytosis was investigated ex vivo. Finally, the clinical feasibility of CD244-negative monocytes as a therapeutic modality in melanoma was confirmed by adoptive transfer experiments. RESULTS: CD244fl/flLysMcre mice demonstrated a significant reduction in tumor volume (61% relative to that of the CD244fl/fl control group) 14 days after tumor implantation. Within tumor mass, CD244fl/flLysMcre mice also showed higher percentages of Ly6Clow macrophages, along with elevated gp100+IFN-γ+ CD8 T cells. Flow cytometry and RNA sequencing data demonstrated that ER stress resulted in increased CD244 expression on monocytes. This, in turn, impeded the generation of anti-tumorigenic Ly6Clow macrophages, phagocytosis and MHC-I antigen presentation by suppressing autophagy pathways. Combining anti-PD-L1 antibody with CD244-/- bone marrow-derived macrophages markedly improved tumor rejection compared to the anti-PD-L1 antibody alone or in combination with wild-type macrophages. Consistent with the murine data, transcriptome analysis of human melanoma tissue single-cell RNA-sequencing dataset revealed close association between CD244 and the inhibition of macrophage maturation and function. Furthermore, the presence of CD244-negative monocytes/macrophages significantly increased patient survival in primary and metastatic tumors. CONCLUSION: Our study highlights the novel role of CD244 on monocytes/macrophages in restraining anti-tumorigenic macrophage generation and tumor antigen-specific T cell response in melanoma. Importantly, our findings suggest that CD244-deficient macrophages could potentially be used as a therapeutic agent in combination with immune checkpoint inhibitors. Furthermore, CD244 expression in monocyte-lineage cells serve as a prognostic marker in cancer patients.

SARS-CoV-2 vaccination and ITP in patients with de novo or preexisting ITP.

Cases of de novo immune thrombocytopenia (ITP), including a fatality, following SARS-CoV-2 vaccination in previously healthy recipients led to studying its impact in preexisting ITP. In this study, 4 data sources were analyzed: the Vaccine Adverse Events Reporting System (VAERS) for cases of de novo ITP; a 10-center retrospective study of adults with preexisting ITP receiving SARS-CoV-2 vaccination; and surveys distributed by the Platelet Disorder Support Association (PDSA) and the United Kingdom (UK) ITP Support Association. Seventy-seven de novo ITP cases were identified in VAERS, presenting with median platelet count of 3 [1-9] ×109/L approximately 1 week postvaccination. Of 28 patients with available data, 26 responded to treatment with corticosteroids and/or intravenous immunoglobulin (IVIG), and/or platelet transfusions. Among 117 patients with preexisting ITP who received a SARS-CoV-2 vaccine, 19 experienced an ITP exacerbation (any of: ≥50% decline in platelet count, nadir platelet count <30 × 109/L with >20% decrease from baseline, and/or use of rescue therapy) following the first dose and 14 of 70 after a second dose. Splenectomized persons and those who received 5 or more prior lines of therapy were at highest risk of ITP exacerbation. Fifteen patients received and responded to rescue treatment. In surveys of both 57 PDSA and 43 UK patients with ITP, prior splenectomy was associated with worsened thrombocytopenia. ITP may worsen in preexisting ITP or be identified de novo post-SARS-CoV2 vaccination; both situations responded well to treatment. Proactive monitoring of patients with known ITP, especially those postsplenectomy and with more refractory disease, is indicated.

Tumor-derived miR-6794-5p enhances cancer growth by promoting M2 macrophage polarization.

BACKGROUND: Solid tumors promote tumor malignancy through interaction with the tumor microenvironment, resulting in difficulties in tumor treatment. Therefore, it is necessary to understand the communication between cells in the tumor and the surrounding microenvironment. Our previous study revealed the cancer malignancy mechanism of Bcl-w overexpressed in solid tumors, but no study was conducted on its relationship with immune cells in the tumor microenvironment. In this study, we sought to discover key factors in exosomes secreted from tumors overexpressing Bcl-w and analyze the interaction with the surrounding tumor microenvironment to identify the causes of tumor malignancy. METHODS: To analyze factors affecting the tumor microenvironment, a miRNA array was performed using exosomes derived from cancer cells overexpressing Bcl-w. The discovered miRNA, miR-6794-5p, was overexpressed and the tumorigenicity mechanism was confirmed using qRT-PCR, Western blot, invasion, wound healing, and sphere formation ability analysis. In addition, luciferase activity and Ago2-RNA immunoprecipitation assays were used to study the mechanism between miR-6794-5p and its target gene SOCS1. To confirm the interaction between macrophages and tumor-derived miR-6794-5p, co-culture was performed using conditioned media. Additionally, immunohistochemical (IHC) staining and flow cytometry were performed to analyze macrophages in the tumor tissues of experimental animals. RESULTS: MiR-6794-5p, which is highly expressed in exosomes secreted from Bcl-w-overexpressing cells, was selected, and it was shown that the overexpression of miR-6794-5p increased migratory ability, invasiveness, and stemness maintenance by suppressing the expression of the tumor suppressor SOCS1. Additionally, tumor-derived miR-6794-5p was delivered to THP-1-derived macrophages and induced M2 polarization by activating the JAK1/STAT3 pathway. Moreover, IL-10 secreted from M2 macrophages increased tumorigenicity by creating an immunosuppressive environment. The in vitro results were reconfirmed by confirming an increase in M2 macrophages and a decrease in M1 macrophages and CD8+ T cells when overexpressing miR-6794-5p in an animal model. CONCLUSIONS: In this study, we identified changes in the tumor microenvironment caused by miR-6794-5p. Our study indicates that tumor-derived miR-6794-5p promotes tumor aggressiveness by inducing an immunosuppressive environment through interaction with macrophage.

Single-port intragastric wedge resection using the tunnel method: a novel surgical approach for treating endophytic gastric subepithelial tumors.

BACKGROUND: Intragastric wedge resection is an effective method for treating endophytic gastric subepithelial tumors (SETs). However, retracting the stomach wall to the umbilicus is difficult in certain patients. In response, we developed a novel surgical technique for single-port intragastric wedge resection, which we termed the "tunnel method." METHODS: A transumbilical incision is made, and a wound retractor is applied. After diagnostic laparoscopy, a gastrostomy is made on the greater curvature, lower body. Another small wound retractor is inserted into the gastrostomy, and extracted through the transumbilical incision, creating a tunnel from the gastrostomy site to the umbilicus. Articulating laparoscopic instruments are inserted via the tunnel, and intragastric wedge resection is performed. We collected and analyzed the clinicopathologic and operative data of patients who underwent intragastric wedge resection via the tunnel method. RESULTS: Twenty-seven patients who underwent single-port intragastric wedge resection via the tunnel method in a single tertiary referral hospital were included in this study. The mean age of the patients was 54.6 ± 11.4 years, body mass index was 26.5 ± 3.4 kg/m2. Twenty-four (88.9%) patients had tumors located in the upper third of the stomach. The average operative time was 65.0 ± 24.2 min. None of the patients experienced Clavien-Dindo grade IIIa or higher postoperative complications. The average postoperative hospital stay length was 2.5 ± 0.8 days. Thirteen gastrointestinal stromal tumors, nine leiomyomas, and one neuroendocrine carcinoma, schwannoma, lipoma, spindle cell proliferative lesion, and fibrotic lesion were pathologically diagnosed. The average tumor size was 2.6 ± 1.3 cm. All cases had negative resection margins. CONCLUSIONS: Single-port intragastric wedge resection by the tunnel method is a feasible and safe approach for treating endophytic gastric SETs.

Hyperthermic pressurized intraperitoneal aerosol drug delivery system in a large animal model: a feasibility and safety study.

BACKGROUND: We developed a novel drug delivery system called hyperthermic pressurized intraperitoneal aerosol chemotherapy (HPIPAC) that hybridized Hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). The present study aims to assess the feasibility and safety of HPIPAC system in a large animal survival model. METHODS: Eleven pigs (eight non-survival models and three survival models) were used in the experiment. The heat module in the HPIPAC controller circulates hyperthermic CO2 in a closed-loop circuit and creates gas-based dry intraperitoneal hyperthermia. Three 12 mm trocars were placed on the abdomen. The afferent CO2 tube wound with heat generating coil was inserted into a trocar, and the efferent tube was inserted into another trocar. Heated CO2 was insufflated and circulated in a closed circuit until the intra-abdominal and peritoneal surface temperature reached 42 °C. 100 ml of 5% dextrose in water was nebulized for 5 min and the closed-loop circulation was resumed for 60 min at 42 °C. Tissue biopsies were taken from several sites from the pigs in the survival model. RESULTS: The average change in core temperature of the pigs was 2.5 ± 0.08 °C. All three pigs displayed no signs of distress, and their vital signs remained stable, with no changes in their diet. In autopsy, inflammatory and fibrotic responses at the biopsy sites were observed without serious pathologic findings. CONCLUSIONS: We successfully proved the feasibility and safety of our novel HPIPAC system in an in-vivo swine survival model.

Development and effects of advanced cardiac resuscitation nursing education program using web-based serious game: application of the IPO model.

BACKGROUND: The significant rise in cardiac arrest cases within hospitals, coupled with a low survival rate, poses a critical health issue. And in most situations, nurses are the first responders. To develop nursing students' competencies in advanced cardiopulmonary resuscitation, systematic and repetitive learner-centered self-directed education that can promote the integration of knowledge and practice is necessary. OBJECTIVES: To develop an advanced cardiopulmonary resuscitation training program using a web-based serious game for nursing students and verifying its efficacy. DESIGN: The program was developed based on the stages of analysis, design, development, implementation, and evaluation, and the Input Process Outcome Model of Serious Game Design formed the theoretical basis. SETTINGS AND PARTICIPANTS: The research design employed a before-and-after non-equivalent control group, and data collection took place among 2nd and 3rd year nursing students at K University in D City, Korea, from March 2, 2023, to March 24, 2023. METHODS: The program consisted of a 120-min video lecture, 30 min of a web-based serious game, 30-min of written self-reported debriefing, and individual feedback using a video conference system. The effectiveness of the program was measured for both groups using an 89-item structured questionnaire regarding knowledge, confidence in performance, problem-solving ability, and learning transfer expectations. RESULTS: The program was effective in improving nursing students' advanced cardiopulmonary knowledge, confidence in performance, problem-solving ability, and learning transfer expectation immediately after intervention. CONCLUSIONS: This program underscores the necessity of a new direction in nursing education, emphasizing learner-centered approaches, rather than the traditional focus on the mere transmission of basic knowledge and skills, to cultivate nurses with advanced cardiopulmonary resuscitation capabilities.

Maintenence rituximab following induction in autoimmune cytopenias.

About 50% of immune thrombocytopenia (ITP) patients respond to rituximab induction, but most relapse. The effectiveness of rituximab maintenance remains untested. This study included autoimmune cytopenia patients who had previously responded to rituximab induction but subsequently relapsed. After re-induction, patients received rituximab maintenance regimen consisting of a single 375 mg/m2 dose administered at 4 month intervals, with a maximum of 6 doses. Primary endpoints were duration of response and safety. Sixteen patients: ITP (9), autoimmune haemolytic anaemia (2), and Evans syndrome (5) received rituximab maintenance. 15/16 achieved complete response (CR); 8/15 CR + 1 partial reponse remain in remission. Median response: 43 months; estimated 5-year relapse-free >50%. Three developed hypogammaglobulinemia. Rituximab maintenance led to prolonged remissions in patients with autoimmune cytopenias who had previously responded to rituximab induction.

Unintended health benefits of adopting preventive behaviors during a virus outbreak.

This study investigates whether changes in risk perception play a critical role in improving of preventive behaviors and health outcomes by examining the 2009 H1N1 influenza (or swine flu) pandemic in Korea. We employ a difference-in-differences estimation strategy by comparing the differential effects of the H1N1 outbreak on the confirmed cases of diseases which can be prevented by preventive behaviors (e.g., intestinal infections) and the cases of diseases which cannot (e.g., injuries). Using unique administrative data from South Korea's National Health Insurance Service (NHIS), we find that the exogenous increase in health risk reduced the incidence of intestinal infections compared to the injuries during the H1N1 influenza outbreak. The reduction was the most substantial among children under five years of age, with a 25.4% decline in cases of intestinal infections relative to injuries. Our findings are robust across various alternative specifications. We provide suggestive evidence that active adoption of preventive behaviors is one of the channels underlying the unexpected decrease in diarrhea cases. The effects, however, faded away shortly after the end of the pandemic and did not last in the long run.

Postoperative pain and quality of life after single-incision distal gastrectomy versus multiport laparoscopic distal gastrectomy for early gastric cancer - a randomized controlled trial.

BACKGROUND: Although it has been more than ten years since its first introduction, single-incision distal gastrectomy (SIDG) still lacks solid evidence and there are also no reports on patient quality of life (QOL). This study evaluates the postoperative outcomes and patient QOL of SIDG compared to multiport laparoscopic distal gastrectomy (MLDG). METHODS: This study was designed as a prospective phase II randomized controlled study. Patients diagnosed with early gastric cancer in the distal 2/3rd of the stomach were randomized to either multiport or single-port group. Primary endpoint was pain using the visual analogue scale on postoperative day (POD) 1. Other outcomes include operative data, complications, and patient QOL using the EORTC C30 and STO22 modules. RESULTS: A total of 43 patients in the SIDG group and 40 patients in the MLDG group were enrolled from September 2017 to February 2020. Mean operation time was 154.3 ± 53.3 min in the MLDG group and 148.9 ± 50.1 min in the SIDG group (p = 0.631). There was no difference in POD1 pain scores between the two groups (MLDG = 4.0 ± 1.3, SIDG = 4.3 ± 1.3, p = 0.372). Mean hospital stay was 5.5 (range 4-12) days in the MLDG group and 5 (range 4-17) days in the SIDG group (p = 0.993). There was no statistical significance in postoperative QOL scores. CONCLUSION: Unlike previous reports, there was no difference in POD1 pain scores between SIDG and MLDG. Nevertheless, SIDG did not increase short-term morbidity compared to MLDG and had similar outcomes in QOL.

Social Media vs. Mass Media: Mitigating the Suspicion of Ulterior Motives in Public Health Communication.

Two experiments examined if persuasive effectiveness of health messages varies as a function of the communication channel (Facebook vs. news website), and if so, why. Specifically, we examined perceived ulterior motives of the communicator as an explanation for why public health campaigns may be less effective when conveyed via mass-directed (vs. interpersonal) channels, and further investigated if message recipients' health interest moderates such channel effects, if any. In Study 1 (N = 103), reading a medical news reporter's Facebook post on dental health (vs. a news article consisting of the identical content) lowered the participants' suspicion of ulterior motives of the source, which then promoted message-consistent attitudes and behavioral intention. Such effects, however, emerged only for those more interested in health. Using a different topic (a low-carb, high-fat diet), Study 2 (N = 338) replicated Study 1 findings, confirming the conditional persuasive advantages of social media over mass media as a health campaign channel.

Anti-S1/RBD-Specific Antibody Formation After SARS-CoV-2 Vaccination in Elderly Rheumatoid Arthritis Patients: Single-Center Prospective Observational Study.

BACKGROUND: The guidelines of coronavirus disease 2019 (COVID-19) vaccination in patients with rheumatoid arthritis (RA) have been continuously updated, with extensive discussion on the effectiveness of the COVID-19 booster vaccines and antibody generation associated with the different types of vaccine. We investigated the effects of the third dose of the mRNA vaccine on antibody titer and the factors associated with antibody production in patients with RA who had previously received two doses of the ChAdOx1-S nCoV-19 vaccine. METHODS: Between October 14, 2021 and June 17, 2022, two patient groups diagnosed with RA were recruited prospectively: one with two doses of ChAdOx1-S nCoV-19 and the second group with the additional third mRNA vaccine. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody titers were determined through semiquantitative anti-SARS-CoV-2 spike (S) electrochemiluminescence immunoassay. Antibody titers were compared in both groups considering clinical features and medications. Multivariate logistic regression was performed to identify the factors associated with antibody production. Also, we followed up the antibody titers of whom completed the 3rd mRNA vaccination. RESULTS: Among 261 patients, all patients were over 60 years old except for 7 patients and the average age was 65 years; 153 had completed two doses of ChAdOx1-S nCoV-19, while 108 patients had also received the third mRNA vaccine. The positive rates of anti-SARS-CoV-2 anti-S1/receptor binding domain-specific antibody (titer > 0.8 U/mL) were 97% (149/153) and 99% (107/108) respectively. However, positive rates for high antibody titer (> 250 U/mL) were found in only 31% (47/153) of group 1 but 94% (102/108) of group 2. Multivariate analysis revealed that corticosteroid use (odds ratio [OR], 0.35; 95% confidence interval [CI], 0.16-0.75), older age (OR, 0.91; 95% CI, 0.860-0.98), and male sex (OR, 0.23; 95% CI, 0.07-0.74) were associated with a lower rate of high antibody titer acquisition after two doses of ChAdOx1-S nCoV-19. Waning of antibody titers was observed in only two of 46 patients who followed up twice after the third mRNA vaccine inoculation. CONCLUSION: Our findings suggest that the third dose of the mRNA vaccine could be beneficial in RA patients with risk factors including older age, male sex, and corticosteroid use after two doses of ChAdOx1-S nCoV-19.

Development and Effects of a Virtual Reality Simulation Nursing Education Program Combined With Clinical Practice Based on an Information Processing Model.

The need to strengthen patient human rights and create a patient-centered healthcare environment is growing. Also as science and technology develop, new educational methods using virtual reality in nursing education are emerging. This study aimed to develop a virtual reality simulation nursing education program related to postoperative patient nursing based on an information processing model and to verify its effectiveness. Clinical practice-linked virtual reality simulation nursing education was conducted for a total of 4 weeks. Nursing students were divided into an experimental group (n = 22) experiencing virtual reality simulation combined with clinical practice and a control group (n = 22) having routine clinical practice. The analytical results of this study indicated that the information processing model-based virtual reality simulation nursing education program was effective in improving nursing students' performance confidence and clinical decision-making ability. Therefore, the virtual reality simulation program developed in this study can provide basic data for the development of a simulation curriculum in the future and can contribute to the development of clinical competency as a professional nurse by improving the performance confidence and clinical decision-making ability of nursing students.

Polarization or Mainstreaming? How COVID-19 News Exposure Affects Perceived Seriousness of the Pandemic and the Susceptibility to COVID-19 Misinformation?

Two surveys investigated whether the exposure to COVID-19 news widens (polarization) or narrows (mainstreaming) the partisan gap in perceived seriousness of the pandemic, and how the perception affects individuals' susceptibility to COVID-19 misinformation that either exaggerates or downplays its health risks. Overall exposure to COVID-19 news homogenized the partisans' otherwise divergent risk perceptions, but the partisan divide was wider among those selectively approaching like-minded news outlets. Perceived seriousness of COVID-19 subsequently altered participants' susceptibility to either fear-arousing or fear-suppressing COVID-19 misinformation in a belief-confirming manner. It is discussed how news media shape the public's reality perception amid the global crisis.

Safety and Efficacy of Intraperitoneal Paclitaxel Plus Intravenous Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) for Gastric Cancer with Peritoneal Metastasis.

BACKGROUND: Peritoneal metastasis (PM) remains a major obstacle in the treatment of stage IV gastric cancer. This is a dose-escalation study of intraperitoneal (IP) paclitaxel combined with intravenous (IV) fluorouracil, leucovorin, and oxaliplatin (FOLFOX) to determine the recommended phase II dose in gastric cancer patients. METHODS: Patients with gastric adenocarcinoma and PM were enrolled. The recommended phase II dose of IP paclitaxel was determined using the standard "3 + 3" dose escalation with planned doses ranging from 40 to 100 mg/m2. IV FOLFOX was administered on the same day (oxaliplatin 100 mg/m2 (day 1), leucovorin 100 mg/m2 (day 1), fluorouracil 2,400 mg/m2 over 46 hours (day 1)). Both IP and IV regimens were repeated every 2 weeks. RESULTS: Among the 13 patients, there was no DLT at 40 and 60 mg/m2. Two patients had grade 3 febrile neutropenia at 80 mg/m2, and the recommended phase II dose was 60 mg/m2. Other patients underwent IP paclitaxel and FOLFOX without serious adverse events. Seven patients underwent second-look diagnostic laparoscopy, and the average change in PCI score was -7.0 ± 9.7. Conversion surgery rate was 23.1% (n = 3). The median overall survival was 16.6 months (95% confidence interval, 16.6-N/A), and progression-free survival was 9.6 months (95% confidence interval, 4.7-N/A). All adverse events were tolerable and manageable. CONCLUSIONS: The biweekly regimen of IP paclitaxel and FOLFOX is safe and the recommended dose of IP paclitaxel for a phase II trial is 60 mg/m2.

Continuous administration of mirabegron has advantages in inhibition of central sensitization compared with short-term treatment cessation in a mouse model of overactive bladder.

AIMS: There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model. METHODS: Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, ß-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization. RESULTS: OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51 vs. 5.76 ± 0.95 min in sham mice), increased non-voiding contractions (0.39 ± 0.11 vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG indicate bladder efferent and afferent hyperexcitability. In addition, CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in OAB mice. However, the CON group exhibited reduced ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder, reduced CCL2 and CCR2 in DRG, which are markers of afferent hyperexcitability, and reduced immunoreactivities of CX3CR1, GFAP, and CCR2 in the L6 spinal cord, which are markers of the central sensitization. Moreover, the CON group showed better improvements in nonvoiding contractions (0.16 ± 0.09 vs. 0.44 ± 0.17/min) and voiding efficiency (93.9 ± 7.4% vs. 76.5 ± 13.1%) and reductions in bladder ß3 receptors and CCL2 of L6-S1 DRG, and immunoreactivities of CX3CR1 and GFAP in the L6 spinal cord compared to the CES group. CONCLUSIONS: Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

Single-Site Robotic Myomectomy without Accessory Instrument Compared with Two-Port Laparoscopic Myomectomy: A Propensity Score Matching Analysis.

OBJECTIVES: Despite the advantages of robotic technology, single-site robotic myomectomy (SSRM) without an accessory instrument is limited by a restricted range of motion, weaker suturing of a thick myometrium, and non-articulating instruments. We present our novel gradual turning out method (GTOM) of SSRM and our assessment of its feasibility and safety by comparing its perioperative outcomes with those of two-port laparoscopic myomectomy (LM). DESIGN: A retrospective cohort case-control study was carried out. METHODS: This study included consecutive 46 patients who underwent SSRM for intramural myomas larger than 7 cm, from 2016 to 2019. Subsequently, 46 patients who underwent LM were selected by 1:1 propensity score matching by controlling for age, body mass index, myoma number, myoma diameter, and the presence of sexual intercourse. The perioperative outcomes of the two groups were compared using a Mann-Whitney U test and Fisher's exact test. The effect of covariates on operation time was analyzed using univariable and multivariable linear regression. RESULTS: SSRM was performed successfully with GTOM for myomas of up to 14 cm in the longest diameter, without conversion to laparotomy and intraoperative injuries. No differences between the groups were found in length of hospital stay, estimated blood loss, hemoglobin level decrease, transfusion rate, and postoperative pain, but operative time was significantly longer in the SSRM group than in the LM group (p < 0.001). Larger myomas, location of the lower segment, and the operation method of SSRM were significantly associated with a longer operation time. Whereas operation time for myomas located at the anterior wall, singleton myomas, and myomas <10 cm was significantly longer in the SSRM group than in the LM group, that for myomas at the posterior or lateral side of the uterus, multiple myomas, and myomas ≥10 cm did not differ significantly between the groups, indicating the advantage of SSRM for difficult myomectomy. LIMITATIONS: Retrospective nature of the study and limitation to a single-center study are the limitations of the study. CONCLUSIONS: Despite the lack of an accessory instrument, SSRM using the GOTM was feasible and safe as it yielded similar perioperative outcomes to those of LM.

Impact of workplace bullying and resilience on new nurses' turnover intention in tertiary hospitals.

The turnover of new nurses is a critical issue that not only causes economic loss to hospitals but also negatively affects the quality of nursing services and patient care. This study examined the impact of workplace bullying, which is an external factor, and resilience, an internal factor, on new nurses' turnover intention. The participants of this study comprised 153 nurses from two tertiary hospitals located in Korea with more than 8 weeks but less than 12 months of work experience. The factors impacting the turnover intention of new nurses in tertiary hospitals were verbal and non-verbal bullying (ß = 0.27), tenacity (ß = -0.24), not getting placement in the desired department (ß = 0.17), and age group (ß = 0.12). The regression model was significant (F = 9.23, p<0.001) based on hierarchical regression analysis, and the explanatory power of the model was 29%. It was concluded that reduction of verbal and non-verbal bullying in the workplace, and programs that promote the tenacity of resilience, are necessary to reduce the turnover intention of new nurses in tertiary hospitals.

ß-TrCP1-variant 4, a novel splice variant of ß-TrCP1, is a negative regulator of ß-TrCP1-variant 1 in ß-catenin degradation.

ß-transducin repeats-containing protein-1 (ß-TrCP1) serves as the substrate recognition subunit for SCFß-TrCP E3 ubiquitin ligases, which specifically ubiquitinate phosphorylated substrates. Three variants of ß-TrCP1 are known and act as homodimer or heterodimer complexes. Here, we identified a novel full-sequenced variant, ß-TrCP1-variant 4, which harbours exon II instead of exon III of variant 1, with no change in the open reading frame. The expression of ß-TrCP1-variant 4 is lower than that of variant 1 or 2 in ovarian cancer cell lines, whereas it is abundantly expressed in normal and cancerous ovarian tissues. Moreover, ß-TrCP1-variant 2 was aberrantly expressed more than variant 1 in ovarian cancer tissues whereas variant 1 was expressed more in normal tissues. Similar to variants 1 and 2, ß-TrCP1-variant 4 directly interacts with ß-catenin, one of the substrates of SCFß-TrCP E3 ubiquitin ligase and down-regulates the transcriptional activity and protein expression of ß-catenin with a significantly weaker effect than that by variants 1 and 2. However, the co-expression of ß-TrCP1-variant 4 with variant 1 in same proportion has no effect, whereas other combinations effectively down-regulate the activity of ß-catenin, indicating that the heterodimer of variants 1 and 4 has no function. Thus, ß-TrCP1-variant 4 could play a critical role in SCFß-TrCP E3 ligase-mediated ubiquitination by acting as a negative regulator of ß-TrCP1-variant 1.

Urine ß-2-glycoprotein 1 as a biomarker for diagnosis of systemic lupus erythematosus.

OBJECTIVE: The need for a biomarker with robust sensitivity and specificity in diagnosing systemic lupus erythematosus (SLE) remains unmet. Compared with blood samples, urine samples are more easily collected; thus, we aimed to identify such a biomarker based on urinary proteomics which could distinguish patients with SLE from healthy controls (HCs). METHODS: Urine samples were collected from 76 SLE patients who visited rheumatology clinic in 2019 at Asan medical center and from 25 HCs. Urine proteins were analyzed using sequential windowed acquisition of all theoretical fragment ion spectra-mass spectrometry, and the candidate marker was confirmed by enzyme-linked immunosorbent assay (ELISA). Receiver operating characteristic curve analysis was used to determine the diagnostic value of the candidate biomarker. RESULTS: Of 1157 proteins quantified, 153 were differentially expressed in urine samples from HCs. Among them were previously known markers including α-1-acid glycoprotein 1, α-2-HS-glycoprotein, ceruloplasmin, and prostaglandin-H2 D-isomerase. Moreover, the amount of ß-2 glycoprotein (APOH) was increased in the urine of patients with SLE. The ELISA results also showed the level of urine APOH was higher in patients with SLE than in HCs and patients with rheumatoid arthritis. Moreover, the level was not different between SLE patients with and without nephritis. The urine APOH had an area under the curve value of 0.946 at a cut-off value of 228.53 ng/mg (sensitivity 91.5%, specificity 92.0%) for the diagnosis of SLE. CONCLUSION: The results indicate that the urine APOH level can be an appropriate screening tool in a clinical setting when SLE is suspected.