IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

Effects of 3S business intelligence systems for nursing students: a repeated-measures randomized control trial.

BACKGROUND: The growing need for healthcare services as a result of a consistently rising prevalence of chronic diseases and rapid population aging calls for a new set of activities and practices. Therefore, we developed a program-3S (Simple, Smart, and Speed) Business Intelligence Systems (3S-BIS), which is an ERP software system that helps nursing business to support nursing entrepreneurship -and analyzed its effects on nursing students. METHODS: A repeated-measures randomized controlled trial was performed with two groups: experimental (n = 29) and control (n = 30) groups. The former group underwent the five-day 3S-BIS education program. Each session comprised four components: lectures 1 and 2, simulation case study, and debriefing. Post-tests were performed immediately post-intervention and four and eight weeks later. The effectiveness was measured using the following variables: simulation design assessment, evaluation of educational practices in simulation, education satisfaction, self-efficacy for learning, and entrepreneurship. The differences before and after intervention between the experimental and control groups were analyzed using the Friedman test. The Mann-Whitney U test was used for comparisons between groups at each time point, and the Wilcoxon signed-rank test was used for comparisons within groups at each time point. RESULTS: Post-intervention (8 weeks after intervention), the experimental group demonstrated higher simulation design assessment (z = -3.88, p = < .001), evaluation of educational practices in simulation (z = -3.34, p = .001), education satisfaction (z = -3.11, p = .002), self-efficacy for learning (z = -3.04, p = .002), and entrepreneurship (z = -2.15, p = .031) compared to controls. Furthermore, simulation design assessment score in the experimental group significantly differed between T1 (immediately after intervention) and T0 (baseline), and between T3 (8 weeks after intervention) and T0. Evaluation of educational practices in the simulation, education satisfaction, and self-efficacy also significantly differed between T1 and T0, and between T3 and T0. Entrepreneurship significantly differed between T3 and T2 (4 weeks after intervention), and between T3 and T0. CONCLUSIONS: The 3S-BIS program contributes to enhancing nursing start-up competency. Subsequent studies should evaluate the effects of the program on nurses who work in home healthcare services.

Responsiveness and Minimal Clinically Important Difference of the Canadian Occupational Performance Measure Among Patients With Frozen Shoulder.

IMPORTANCE: Patient-reported outcome measures provide insights into intervention effects on patients. The Canadian Occupational Performance Measure (COPM) emphasizes identifying priorities in daily activity engagement and evaluating an individual's perception of changes over time. OBJECTIVE: To assess the responsiveness of the COPM and the minimal clinically important difference (MCID) among patients with frozen shoulders. DESIGN: Prospective, single-blind, randomized controlled trial. SETTING: Two physical medicine and rehabilitation clinics. PARTICIPANTS: Ninety-four patients with frozen shoulders enrolled in a previous study. OUTCOMES AND MEASURES: Baseline and 3-mo evaluations of the COPM and other measures. Responsiveness was assessed using effect size (ES) and standardized response mean (SRM). The MCID values were determined through a distribution-based approach, which used the 0.5 standard deviation and ES methods, and an anchor-based approach, which used the receiver operating characteristic curve method. RESULTS: The ES and SRM results indicated that the COPM had high responsiveness. The distribution-based MCID values for COPM Performance and COPM Satisfaction were 1.17 and 1.44, respectively. The anchor-based MCID values were 2.5 (area under the curve [AUC] = 0.78, 95% confidence interval [CI] [0.64-0.91]) and 2.1 (AUC = 0.76, 95% CI [0.60-0.91]), respectively. CONCLUSIONS AND RELEVANCE: The findings suggest that the COPM is a responsive outcome measure for patients with frozen shoulder. The established MCID values for the COPM can be valuable for interpreting changes in patient performance and satisfaction, thus aiding clinical interventions and research planning. Plain-Language Summary: This is the first study to review the effectiveness of the Canadian Occupational Performance Measure (COPM) to determine the success of occupational therapy interventions for people with a frozen shoulder. The findings suggest that the COPM is an effective and valuable tool for clients with a frozen shoulder to understand their experiences and treatment priorities and to detect meaningful changes in their performance and satisfaction after an occupational therapy intervention.

Effectiveness of personalized treatment stage-adjusted digital therapeutics in colorectal cancer: a randomized controlled trial.

BACKGROUND: Colorectal cancer survivors often experience decline in physical performance and poor quality of life after surgery and during adjuvant therapies. In these patients, preserving skeletal muscle mass and high-quality nourishment are essential to reduce postoperative complications and improve quality of life and cancer-specific survival. Digital therapeutics have emerged as an encouraging tool for cancer survivors. However, to the best of our knowledge, randomized clinical trials applying personalized mobile application and smart bands as a supportive tool to several colorectal patients remain to be conducted, intervening immediately after the surgical treatment. METHODS: This study is a prospective, multi-center, single-blinded, two-armed, randomized controlled trial. The study aims to recruit 324 patients from three hospitals. Patients will be randomly allocated to two groups for one year of rehabilitation, starting immediately after the operation: a digital healthcare system rehabilitation (intervention) group and a conventional education-based rehabilitation (control) group. The primary objective of this protocol is to clarify the effect of digital healthcare system rehabilitation on skeletal muscle mass increment in patients with colorectal cancer. The secondary outcomes would be the improvement in quality of life measured by EORTC QLQ C30 and CR29, enhanced physical fitness level measured by grip strength test, 30-sec chair stand test and 2-min walk test, increased physical activity measured by IPAQ-SF, alleviated pain intensity, decreased severity of the LARS, weight, and fat mass. These measurements will be held on enrollment and at 1, 3, 6 and 12 months thereafter. DISCUSSION: This study will compare the effect of personalized treatment stage-adjusted digital health interventions on immediate postoperative rehabilitation with that of conventional education-based rehabilitation in patients with colorectal cancer. This will be the first randomized clinical trial performing immediate postoperative rehabilitation in a large number of patients with colorectal cancer with a tailored digital health intervention, modified according to the treatment phase and patient condition. The study will add foundations for the application of comprehensive digital healthcare programs focusing on individuality in postoperative rehabilitation of patients with cancer. TRIAL REGISTRATION: NCT05046756. Registered on 11 May 2021.

Effectiveness of interactive augmented reality-based telerehabilitation in patients with adhesive capsulitis: protocol for a multi-center randomized controlled trial.

BACKGROUND: As the primary treatment for adhesive capsulitis, intensive and accurate home exercise is as important as physical therapy in hospitals. Augmented reality (AR)-based telerehabilitation has been implemented recently in various musculoskeletal conditions to increase patient compliance and enable patients to exercise with the correct posture. The objective of this study is to present a protocol for investigating the additive effect of interactive AR-based telerehabilitation in comparison with the usual care for patients with adhesive capsulitis. METHODS: This study presents the protocol of a prospective, multi-center, single-blinded, two-armed randomized controlled trial (RCT). One hundred patients with stage I or II adhesive capsulitis will be recruited at the physical medicine and rehabilitation clinic. Patients will be randomly divided into two groups with 1:1 allocation. The intervention group will receive 3 months of hospital-based physical therapy in conjunction with home-based telerehabilitation. The control group will receive 3 months of hospital-based physical therapy in conjunction with a home-based exercise described in a brochure provided by the hospital. The primary outcome will be the change in passive range of motion (ROM) of the affected shoulder joint from baseline to 12 weeks after baseline assessment. The secondary outcomes will be active ROM, pain measured with the numeric rating scale, shoulder pain and disability index, 36-Item Short Form Survey, EuroQoL-5D-5L, and Canadian Occupational Performance Measure. DISCUSSION: This will be the first RCT study protocol to investigate the effect of telerehabilitation in patients with adhesive capsulitis. The result of this RCT will determine whether AR-based telerehabilitation is more effective than a brochure-based home exercise program and will provide evidence of the usefulness of "telerehabilitation" using hardware (IoT) and software (monitoring platform) technologies to develop "digital therapeutics" for the future. TRIAL REGISTRATION: This trial was retrospectively registered at the Clinicaltrials.gov website on 20 March 2020, with the identifier NCT04316130 .

Predictive impact of circulating microRNA-193a-5p on early relapse after autologous stem cell transplantation in patients with multiple myeloma.

We explored prognostic roles of circulating microRNAs (miRs) in multiple myeloma (MM) treated with autologous stem cell transplantation (ASCT) following induction chemotherapy. In part I of the study (n = 40), we identified a decreasing dynamics of circulating miR-193a-5p expression from diagnosis to pre-ASCT. In patients who experienced early relapse within one year post ASCT (n = 9) these patterns were distinctive compared to those without early relapse in a 1:2 matched cohort (n = 18). In part II (n = 90), multivariate analyses showed that the International Staging System score and miR-193a-5p expression before ASCT were independent prognostic factors. Conclusively, expression of circulating miR-193a-5p before ASCT could be a prognostic biomarker for transplant-eligible MM.

Alteration of the Intestinal Microbiota by Broad-Spectrum Antibiotic Use Correlates with the Occurrence of Intestinal Graft-versus-Host Disease.

Patients undergoing hematopoietic stem cell transplantation (HSCT) frequently receive empiric antibiotics during the neutropenic period before engraftment. Several recent studies have shown that anaerobes in the intestine are important mediators of intestinal homeostasis, and that commensal bacteria can be potent modulators of the severity of acute graft-versus-host disease (aGVHD). However, the relationships among the type of antibiotic used during the neutropenic period, changes in the intestinal microbiota, and subsequent occurrence of aGVHD are not clear. In this study, a total of 211 patients undergoing HSCT were stratified into 3 groups: patients not treated with any antibiotics during the neutropenic period (group 1; n = 43), patients treated with cefepime only (group 2; n = 87), and patients treated with carbapenem antibiotics, defined as meropenem or prepenem with or without previous cefepime therapy (group 3; n = 81). Intestinal microbiota analyses were performed on pre- and post-HSCT stool samples, and immunophenotypic analyses were performed on pre- and post-HSCT peripheral blood samples. Among the 211 patients, 95 (45%) developed aGVHD (grade ≥II), including 54 with intestinal GVHD. The incidence of intestinal GVHD was higher in group 3 compared with group 1 and group 2 (32.1%, 11.6%, and 26.4%, respectively; P = .044). After adjusting for potentially significant variables identified by univariate analysis, multivariate analyses identified broad-spectrum antibiotic use during the neutropenic period as associated with the occurrence of intestinal GVHD (hazard ratio, 3.25; 95% confidence interval, 1.13 to 9.34; P = .029). Accordingly, loss of bacterial diversity in terms of alterations in intestinal microbiota after HSCT was observed in patients who received broad-spectrum antibiotics. Moreover, alterations in the frequencies of several intestinal bacteria phyla were associated with the occurrence of intestinal GVHD. Evaluation of circulating immune cell subsets according to type of antibiotic used during the neutropenic period revealed delayed recovery of myeloid-derived suppressor cells in the broad-spectrum antibiotic use group. Our data indicate that the use of broad-spectrum antibiotics during the neutropenic period is associated with a higher incidence of intestinal GVHD via loss of microbiome diversity. Further studies are needed to determine whether maintaining bacterial diversity can help prevent the development of aGVHD.

Walking velocity and modified rivermead mobility index as discriminatory measures for functional ambulation classification of chronic stroke patients.

BACKGROUND: The cut-off values of walking velocity and classification of functional mobility both have a role in clinical settings for assessing the walking function of stroke patients and setting rehabilitation goals and treatment plans. OBJECTIVE: The present study investigated whether the cut-off values of the modified Rivermead Mobility Index (mRMI) and walking velocity accurately differentiated the walking ability of stroke patients according to the modified Functional Ambulation Category (mFAC). METHODS: Eighty two chronic stroke patients were included in the study. The comfortable/maximum walking velocities and mRMI were used to measure the mobility outcomes of these patients. To compare the walking velocities and mRMI scores for each mFAC point, one-way analysis of variance and the post-hoc test using Scheffe's method were performed. The patients were categorized according to gait ability into either mFAC = VII or mFAC ≤ VI group. The cut-off values for mRMI and walking velocities were calculated using a receiver-operating characteristic curve. The odds ratios of logistic regression analysis (Wald Forward) were analyzed to examine whether the cut-off values of walking velocity and mRMI can be utilized to differentiate functional walking levels. RESULTS: Except for mFACs III and IV, maximum walking velocity differed between mFAC IV and mFAC V ( p < 0 . 01 ) , between mFAC V and mFAC VI ( p < 0 . 001 ) , and between mFAC VI and mFAC VII ( p < 0 . 05 ) . The cut-off value of mRMI is > 26 . 5 and the area under the curve is 0.87, respectively; the cut-off value for comfortable walking velocity is > 0 . 77 m/s and the area under the curve is 0.92, respectively; also, the cut-off value for maximum walking velocity is > 0 . 92 m/s and the area under the curve is 0.97, respectively. In the logistic regression analysis, the maximum walking velocity ( > 0 . 92 m/s, OR = 22 . 027 ) and mRMI ( > 26 . 5 scores, OR = 10 . 283 ) are able to distinguish mFAC = VII from mFAC ≤ VI. CONCLUSION: The cut-off values of maximum walking velocity and mRMI are recommended as useful outcome measures for assessing ambulation levels in chronic stroke patients during rehabilitation.

Ex Vivo Generated Human Cord Blood Myeloid-Derived Suppressor Cells Attenuate Murine Chronic Graft-versus-Host Diseases.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells with anti-inflammatory activity, and expanded murine MDSCs are capable of attenuating preclinical acute graft-versus-host disease (aGVHD) severity. Two murine cGVHD models were used to evaluate the effectiveness of ex vivo cultured human cord blood (hCB) MDSCs in chronic GVHD (cGVHD). First, GVHD recipients surviving in a classic C57BL/6 into MHC-mismatched BALB/c aGVHD model developed cGVHD. Second, donor pretreatment with granulocyte colony-stimulating factor (G-CSF) induced cGVHD. hCB-MDSCs (1 × 106) were intravenously injected to determine their preventive effects (on days 5, 7, 10, and 21) or therapeutic effects (on days 21, 28, and 35). In the first model the onset of clinical cutaneous cGVHD was significantly delayed in preventive hCB-MDSCs-treated allogeneic recipients. Pathologic scoring of target organs confirmed these clinical results. Importantly, thymic tissues of GVHD mice treated with hCB-MDSCs were less severely damaged, showing higher numbers of double (CD4 and CD8) positive T cells with reduced expansion of donor-type CD4 and CD8 T cells. Moreover, late infusion of hCB-MDSCs controlled the severity of established cGVHD that had occurred in control recipients. In the second model, cGVHD induced by G-CSF-mobilized stem cell graft was associated with promotion of Th 17 and Th 2 differentiation. hCB-MDSCs attenuated clinical and pathologic cGVHD severity. Increased production of IL-17 and more infiltration of T cells and macrophages in cGVHD mice were markedly reduced after hCB-MDSCs treatment. Importantly, Foxp3+ regulatory T cells and IFN-γ-producing T cells were expanded, whereas IL-17- and IL-4-producing T cells were decreased in allogeneic recipients of hCB-MDSCs. Taken together, these results showed that hCB-MDSCs have preclinical capability of attenuating cGVHD by preserving thymus function and regulating Th 17 signaling, suggesting a possible therapeutic strategy for clinical application.

Matrix Metalloproteinase-9 in Monocytic Myeloid-Derived Suppressor Cells Correlate with Early Infections and Clinical Outcomes in Allogeneic Hematopoietic Stem Cell Transplantation.

The recovery of myeloid-derived suppressor cells (MDSCs) and its relevance in clinical acute graft-versus-host disease (GVHD) and post-hematopoietic stem cell transplantation (HSCT) infections remain to be fully characterized. We examined the expansion of circulating monocytic (M-) MDSCs and granulocytic (G-) MDSCs at the time of engraftment in 130 patients undergoing allogeneic HSCT (allo-HSCT). Compared with the G-MDSC group, the high M-MDSC group had a higher infection rate within 100 days, along with worse 1-year cumulative incidence of treatment-related mortality (TRM) and 2-year probability of event-free survival (EFS). The frequency of M-MDSCs was associated with preceding severe mucositis. Transcriptome profiling analysis of 2 isolated MDSC subtype showed significantly greater matrix metalloproteinase-9 (MMP-9) expression in M-MDSCs than in G-MDSCs. M-MDSCs produced abundantly more MMP-9. Importantly, compared with G-MDSCs, M-MDSCs isolated from patients post-HSCT had a greater capacity to suppress T cell responses, and MMP-9 blockade more forcefully inhibited their immunosuppressive effect. MMP-9 levels also were associated with the occurrence of infections and with transplantation outcomes. Based on these findings, we identify M-MDSCs as a major contributor to infections early after allo-HSCT and worse clinical outcomes via MMP-9.

CD1d is a novel cell-surface marker for human monocytic myeloid-derived suppressor cells with T cell suppression activity in peripheral blood after allogeneic hematopoietic stem cell transplantation.

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer and various pathological conditions. However, the phenotypic and functional heterogeneity of human MDSCs represents a major hurdle for the development of therapeutic strategies targeting or regulating MDSCs in tumor progression, inflammation, and graft-versus-host disease (GVHD). We previously shown that circulating HLA-DR-CD14+ monocytic MDSCs are a major contributor to clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we identified, using high-throughput screening, a set of surface markers that are strongly expressed in HLA-DR-CD14+ monocytic MDSCs isolated from the peripheral blood (PB) of patients receiving allo-HSCT. Subsequent experiments showed the consistent dominant expression of CD1d in monocytic MDSCs of allo-HSCT PB in comparison with granulocytic MDSCs. In addition, CD1d-expressing cells isolated from PB of allo-HSCT patients showed the suppressive activity of T cell proliferation and higher expression of MyD88 and IDO compared with CD1d- cells. Our results suggest that CD1d could be a valuable marker for further therapeutic evaluation of human monocytic MDSCs for immune-related diseases, including GVHD.

Low frequency of CD3+CD4+CD161+ T cells correlates with the occurrence of infections in refractory/relapsed multiple myeloma patients receiving lenalidomide plus low-dose dexamethasone treatment.

The aim of this study was to explore the predictive implications of the composition of immune cell populations prior to lenalidomide plus high-dose dexamethasone (Len-Dex) initiation for the occurrence of infections. We prospectively examined immune cell populations in peripheral blood taken at baseline of lenalidomide plus low-dose dexamethasone (Len-dex) therapy and reviewed clinical and microbiology records in 90 patients with refractory/relapsed multiple myeloma (RRMM). Risk factors for infection were analyzed using logistic regression. During a median of 11 cycles of Len-dex treatment, 52 (57.8%) patients experienced at least 1 infection episode. Of a total of 92 episodes of infection, 58 (63%) episodes were clinically defined, 29 (31.5%) episodes were microbiologically defined, and 5 (5.4%) episodes were fever of unknown origin. Severe episodes were more frequently observed during the first 3 cycles. After adjusting for risk factors for infection based on univariate analyses, multivariate analyses showed that lower Hb (< 10 g/dL) was a clinically independent factor associated with occurrence of infections. Lower frequency (P = 0.044) and absolute count (P = 0.014) of circulating CD3+CD4+CD161+ cells prior to Len-dex treatment were also associated with the occurrence of infection, especially during the first 3 cycles of Len-dex therapy. In addition to several clinical predictive factors, we found that CD3+CD4+CD161+ cells may provide additional information for predicting the occurrence of infection in the early period of Len-dex therapy.

A model of adaptation for families of elderly patients with dementia: focusing on family resilience.

OBJECTIVES: We constructed a model explaining families' positive adaptation in chronic crisis situations such as the problematic behavior of elderly patients with dementia and attendant caregiving stress, based on the family resilience model. Our aim was to devise an adaptation model for families of elderly patients with dementia. METHOD: A survey of problematic behavior in elderly patients with dementia, family stress, family resilience, and family adaptation was conducted with 292 consenting individuals. The collected data were analyzed using structural equation modeling. RESULTS: The communication process, family stress, and problematic behavior of elderly patients with dementia had direct and indirect effects on family adaptation, while belief system, organization pattern, and social support had indirect effects. Specifically, family stress and more severe problematic behavior by elderly patients with dementia negatively influenced family adaptation, while greater family resilience improved such adaptation. CONCLUSION: Interventions aiming to enhance family resilience, based on the results of this study, are required to help families with positive adaptation. Such family programs might involve practical support such as education on the characteristics of elderly persons with dementia and coping methods for their problematic behavior; forming self-help groups for families; revitalizing communication within families; and activating communication channels with experts.

Clinical significance of pre-transplant circulating CD3+ CD4+ CD161+ cell frequency on the occurrence of neutropenic infections after allogeneic stem cell transplantation.

BACKGROUND: Few studies have been performed to identify factors that are associated with an increased risk of infections during the neutropenic period in patients undergoing allogeneic stem cell transplantation (allo-SCT). The aim of this study was to identify the host immune cells responsible for infections before engraftment. METHODS: A total of 282 patients who underwent allo-SCT were enrolled. Peripheral blood samples were collected before conditioning therapy. Expression of CD161-expressing T cells, natural killer cells, and immature myeloid cells was analyzed by flow cytometry. Microbially and clinically defined infections and fevers of unknown origin as proposed by the Immunocompromised Host Society were included in this study. RESULTS: The median age was 45 years (range, 16-68 years). Patients had various hematologic disorders and were transplanted from human leukocyte antigen (HLA)-matched siblings, unrelated donors, and familial HLA-mismatched donors. In univariate analysis, younger age and a familial HLA-mismatched donor were risk factors for the occurrence of infections. After adjusting for potential variables in univariate analysis, multivariate analyses revealed that a lower frequency of CD3+ CD4+ CD161+ cells was significantly associated with the occurrence of neutropenic infections. An age of 35 years or younger and allografting from familial HLA-mismatched donors showed a trend toward higher infection rates. CONCLUSION: Our data indicated that a lower frequency of CD3+ CD4+ CD161+ T cells in peripheral blood before conditioning therapy was associated with a higher incidence of infection during the neutropenic period. These results suggest that recipient innate T cells with expression of C-type lectin CD161 can guard against infections before engraftment.

Comparison of Loop Electrosurgical Excision Procedure Using a Ring-Shaped Loop Versus a Right-Angled Triangular Loop.

OBJECTIVE: To compare the resection margin (RM) status and postoperative severe hemorrhage using different loop electrosurgical excision procedure (LEEP) techniques for cervical intraepithelial neoplasia (CIN) 2/3 treatment. STUDY DESIGN: We retrospectively reviewed 278 patients who underwent LEEPs for CIN 2/3 treatment at our institute between 2005­2014. In type A surgery (N=148), a ring-shaped loop was used. If the first pass failed to remove the entire lesion, separate loop excisions for the intracervical portion were performed. In type B surgery (N=130), a right-angled triangular loop in a single pass was used. Surgical outcomes and postoperative severe hemorrhage were compared between the two groups. Logistic regression analysis was performed to identify the independent predictors of RM status. RESULTS: The mean LEEP depth was larger after type A surgery (2.2 vs. 2.0 cm, respectively; p=0.04). Type B surgery showed lower rate of 30-day postoperative hemorrhage (13.8% vs. 26.4%, p<0.05) and higher rate of negative RM (68.9% vs. 82.3%, p<0.05). Multivariate analysis identified the surgery type (p=0.01, OR=0.45 [0.24­0.83]) and a postoperative pathological diagnosis of CIN3 (p=0.01, OR=2.53 [1.22­5.26]) as independent risk factors for positive RM. CONCLUSION: LEEPs using a right-angled triangular loop could reduce positive RMs.

Circulating immune cell phenotype can predict the outcome of lenalidomide plus low-dose dexamethasone treatment in patients with refractory/relapsed multiple myeloma.

Although the antimyeloma effect of lenalidomide is associated with activation of the immune system, the exact in vivo immunomodulatory mechanisms of lenalidomide combined with low-dose dexamethasone (Len-dex) in refractory/relapsed multiple myeloma (RRMM) patients remain unclear. In this study, we analyzed the association between immune cell populations and clinical outcomes in patients receiving Len-dex for the treatment of RRMM. Peripheral blood samples from 90 RRMM patients were taken on day 1 of cycles 1 (baseline), 2, 3, and 4 of Len-dex therapy. Peripheral blood CD3(+), CD4(+), and CD8(+) cell frequencies were significantly decreased by 3 cycles of therapy, whereas NK cell frequency was significantly increased after the 3rd cycle. For the myeloid-derived suppressor cell (MDSC) subset, the frequency of granulocytic MDSCs transiently increased after the 1st cycle, whereas there was an increase in monocytic MDSC (M-MDSC) frequency after the 1st and 3rd cycles. Among 81 evaluable patients, failure to achieve a response of VGPR or greater was associated with a decrease in CD8(+) cell frequency and increase in M-MDSC frequency after 3 cycles of Len-dex treatment. A high proportion of natural killer T (NKT)-like cells (CD3(+)/CD56(+)) prior to Len-dex treatment might predict a longer time to progression. In addition, patients with a smaller decrease in the frequency of both CD3(+) cells and CD8(+) cells by 3 cycles exhibited a longer time to the next treatment. These results demonstrated that early changes in immune cell subsets are useful immunologic indicators of the efficacy of Len-dex treatment in RRMM.

Oral proteasome inhibitor with strong preclinical efficacy in myeloma models.

BACKGROUND: The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles. METHOD: The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models. RESULTS: LC53-0110 is far more specific for the chymotrypsin-like proteolytic (ß5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model. CONCLUSIONS: In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate.

CD161(+) T cells as predictive markers for acute graft-versus-host disease.

CD161 is a type II transmembrane glycoprotein with characteristics of the C-type lectin superfamily, which has recently been shown to promote T cell expansion. In this study, the role of T cells expressing CD161 as a predictor for the occurrence of acute graft-versus-host disease (aGVHD) after allogeneic stem cell transplantation (SCT) was investigated. Sixty-one patients who underwent first allogeneic SCT were enrolled. At engraftment, the expression of CD3, CD4, CD8, CD161, CD16, and CD56 was analyzed by flow cytometry. After adjusting for potential variables by univariate analysis, we performed a multivariate analysis, which revealed a low frequency of CD8(+)CD161(+) cells (P = .034) and a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+) cells (P = .001) were associated with the occurrence of aGVHD with a grade of ≥ II. Moreover, the frequency of CD8(+)CD161(+) T cells was negatively correlated with aGVHD grade. A separate analysis for visceral aGVHD showed similar results, with a low frequency of CD8(+)CD161(+) T cells (P = .031) or a high ratio of CD4(+)CD161(+) to CD8(+)CD161(+)cells (P < .001), indicating a high risk. Also, the predictive role of serum IL-17 levels for the occurrence of aGVHD was identified, and RORγT was more highly expressed in CD4(+)CD161(+) T cells than in CD8(+)CD161(+) T cells after allogeneic SCT (P = .032). Although our study was limited by the heterogeneity and small number of patients, these results suggest that the CD8(+) subset of CD161(+) T cells may have regulatory effects and that they provide a basis for predicting the occurrence of aGVHD after allogeneic SCT.

Effects of Health Literacy and Social Capital on Health Information Behavior.

This study aimed to examine whether social capital (bonding and bridging social capital) attenuate the effect of low functional health literacy on health information resources, efficacy, and behaviors. In-person interviews were conducted with 1,000 residents in Seoul, Korea, in 2011. The authors found that respondents' functional health literacy had positive effects on the scope of health information sources and health information self-efficacy but not health information-seeking intention. Respondents' social capital had positive effects on the scope of health information sources, health information efficacy, and health information-seeking intention. The authors found (a) a significant moderation effect of bridging social capital on the relation between health literacy and health information self-efficacy and (b) a moderation effect of bonding social capital on the relation between health literacy and health information-seeking intention.

Key components of financial-analysis education for clinical nurses.

In this study, we identified key components of financial-analysis education for clinical nurses. We used a literature review, focus group discussions, and a content validity index survey to develop key components of financial-analysis education. First, a wide range of references were reviewed, and 55 financial-analysis education components were gathered. Second, two focus group discussions were performed; the participants were 11 nurses who had worked for more than 3 years in a hospital, and nine components were agreed upon. Third, 12 professionals, including professors, nurse executive, nurse managers, and an accountant, participated in the content validity index. Finally, six key components of financial-analysis education were selected. These key components were as follows: understanding the need for financial analysis, introduction to financial analysis, reading and implementing balance sheets, reading and implementing income statements, understanding the concepts of financial ratios, and interpretation and practice of financial ratio analysis. The results of this study will be used to develop an education program to increase financial-management competency among clinical nurses.