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One-carbon metabolism plays a central role in a broad array of metabolic processes required for the survival and growth of tumor cells. However, the molecular basis of how one-carbon metabolism may influence RNA methylation and tumorigenesis remains largely unknown. Here we show MTHFD2, a mitochondrial enzyme involved in one-carbon metabolism, contributes to the progression of renal cell carcinoma (RCC) via a novel epitranscriptomic mechanism that involves HIF-2α. We found that expression of MTHFD2 was significantly elevated in human RCC tissues, and MTHFD2 knockdown strongly reduced xenograft tumor growth. Mechanistically, using an unbiased methylated RNA immunoprecipitation sequencing (meRIP-Seq) approach, we found that MTHFD2 plays a critical role in controlling global N 6 -methyladenosine (m 6 A) methylation levels, including the m 6 A methylation of HIF-2α mRNA, which results in enhanced translation of HIF-2α. Enhanced HIF-2α translation, in turn, promotes the aerobic glycolysis, linking one-carbon metabolism to HIF-2α-dependent metabolic reprogramming through RNA methylation. Our findings also suggest that MTHFD2 and HIF-2α form a positive feedforward loop in RCC, promoting metabolic reprograming and tumor growth. Taken together, our results suggest that MTHFD2 links RNA methylation status to the metabolic state of tumor cells in RCC.

To study mechanisms underlying resistance to the BCL2 inhibitor venetoclax in acute myeloid leukemia (AML), we used a genome-wide CRISPR/Cas9 screen to identify gene knockouts resulting in drug resistance. We validated TP53 , BAX , and PMAIP1 as genes whose inactivation results in venetoclax resistance in AML cell lines. Resistance to venetoclax resulted from an inability to execute apoptosis driven by BAX loss, decreased expression of BCL2, and/or reliance on alternative BCL2 family members such as BCL2L1. The resistance was accompanied by changes in mitochondrial homeostasis and cellular metabolism. Evaluation of TP53 knockout cells for sensitivities to a panel of small-molecule inhibitors revealed a gain of sensitivity to TRK inhibitors. We relate these observations to patient drug responses and gene expression in the Beat AML dataset. Our results implicate TP53 , the apoptotic network, and mitochondrial functionality as drivers of venetoclax response in AML and suggest strategies to overcome resistance. SIGNIFICANCE: AML is challenging to treat due to its heterogeneity, and single-agent therapies have universally failed, prompting a need for innovative drug combinations. We used a genetic approach to identify genes whose inactivation contributes to drug resistance as a means of forming preferred drug combinations to improve AML treatment. See related commentary by Savona and Rathmell, p. 831 . This article is highlighted in the In This Issue feature, p. 813 ., (©2019 American Association for Cancer Research.)

Progressive remodeling of the bone marrow microenvironment is recognized as an integral aspect of leukemogenesis. Expanding acute myeloid leukemia (AML) clones not only alter stroma composition, but also actively constrain hematopoiesis, representing a significant source of patient morbidity and mortality. Recent studies revealed the surprising resistance of long-term hematopoietic stem cells (LT-HSC) to elimination from the leukemic niche. Here, we examine the fate and function of residual LT-HSC in the BM of murine xenografts with emphasis on the role of AML-derived extracellular vesicles (EV). AML-EV rapidly enter HSC, and their trafficking elicits protein synthesis suppression and LT-HSC quiescence. Mechanistically, AML-EV transfer a panel of miRNA, including miR-1246, that target the mTOR subunit Raptor, causing ribosomal protein S6 hypo-phosphorylation, which in turn impairs protein synthesis in LT-HSC. While HSC functionally recover from quiescence upon transplantation to an AML-naive environment, they maintain relative gains in repopulation capacity. These phenotypic changes are accompanied by DNA double-strand breaks and evidence of a sustained DNA-damage response. In sum, AML-EV contribute to niche-dependent, reversible quiescence and elicit persisting DNA damage in LT-HSC., (© 2019 The Authors.)

Flavonoids are secondary metabolites that help plants resist insect attack, but pest insects have evolved enzymes that reduce the toxicity of these secondary metabolites. We studied the response of the grasshopper Oedaleus asiaticus Bey-Bienko fed different concentrations of quercetin, a representative flavonoid. Oedaleus asiaticus growth (survival rate and growth rate) was significantly reduced at high quercetin concentrations. Reactive oxygen species (ROS) increased significantly in response to the diet stress associated with high quercetin concentrations. Gene expression and protein phosphorylation level of the IGF→FOXO cascade related to the stress response in the O. asiaticus insulin-like signaling pathway (ILP) were also reduced. Multiple protective enzyme activities were regulated by FOXO. Mixed-function oxidase (MFO), superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), were all significantly increased with exposure to high quercetin concentrations. Quercetin negatively regulated the ILP pathway, and was detrimental to O. asiaticus growth and survival, as more energy was required for detoxification. This study showed how flavonoids impact on O. asiaticus biochemical pathways, physiology, and development. Flavonoids offer a new option for the development of biological pesticides for application to grasshopper biological control., (© The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Phosphorylation of Dynamin-related protein1 (Drp1) represents an important regulatory mechanism for mitochondrial fission. Here we established the role of Drp1 Serine 600 (S600) phosphorylation on mitochondrial fission in vivo, and assessed the functional consequences of targeted elimination of the Drp1S600 phosphorylation site in progression of diabetic nephropathy (DN). We generated a knockin mouse in which S600 was mutated to alanine (Drp1S600A). We found that diabetic Drp1S600A mice exhibited improved biochemical and histological features of DN along with reduced mitochondrial fission and diminished mitochondrial ROS in vivo. Importantly, we observed that the effect of Drp1S600 phosphorylation on mitochondrial fission in the diabetic milieu was stimulus- but not cell type-dependent. Mechanistically, we showed that mitochondrial fission in high glucose conditions occurs through concomitant binding of phospho-Drp1S600 with mitochondrial fission factor (Mff) and actin-related protein 3 (Arp3), ultimately leading to accumulation of F-actin and Drp1 on the mitochondria. Taken together, these findings establish that a single phosphorylation site in Drp1 can regulate mitochondrial fission and progression of DN in vivo, and highlight the stimulus-specific consequences of Drp1S600 phosphorylation on mitochondrial dynamics.

Purpose: This study was designed to allow a student at School of Medicine, Kyungpook National University (KNUSOM) to self-assess how well they had achieved competency and to analyze the differences and trends of the scores by year. Furthermore, students are asked to evaluate the need for curriculum improvement by competency, the tendency of the score is analyzed by year, and the results are reflected in the improvement of the curriculum., Methods: We conducted a questionnaire survey for fourth-year students of KNUSOM who took medical education classes from 2015 to 2018. Questionnaire items were evaluated on the basis of their current achievement of 30 subordinate competencies of competency and the degree of necessity with respect to revising the curriculum. One-way analysis of variance was performed for the yearly difference analysis., Results: The students' scores on the graduation competency were 2.03 to 4.06. In the yearly difference analysis, there was no significant difference in the average of 30 total competencies, but 16 of the sub-competencies showed significant year-to-year differences. The scores for the 30 graduation competencies were different for each year, but the competencies showing high scores and low scores were found to be similar each year., Conclusion: We found that the achievement level of the students was approximately 60% to 70%. We were able to confirm the contents of the education that the students continuously demand. The curriculum trend graphs for each year showed that the students' scores improved when the curriculum was being revised. We found that it is necessary to accept the students' self-evaluation reliable as the students indicated that the contents of the curriculum should be added to the areas where the contents were lacking in the present curriculum.

Background: Recent trends toward regionalization of complex surgical procedures may increase the risk for care fragmentation during readmissions. Conflicting conclusions have been reported regarding risk factors and consequences of nonindex readmissions (ie, readmission to a separate hospital than the one where surgery was originally performed). We seek to perform a comprehensive review of existing literature., Methods: Four electronic databases were searched to identify all eligible studies examining the risk factors and outcomes of postoperative nonindex readmission. The pooled odds ratio and 95% confidence interval were calculated using a random-effects model., Results: A total of 444 studies were retrieved from database searches and 23 were included after applying eligibility criteria. Nonindex readmissions constituted 10%-47% of 30-day readmissions. Risk factors for nonindex readmission predominantly represented proxy variables for patient care access that may not be modifiable, such as residing in a location further away from the original hospital, being older in age, living in rural areas, and having lower income. Nonindex readmissions occurred more commonly under urgent conditions. Ten of the 14 studies that employed short-term mortality as the primary outcome concluded that nonindex readmissions were significantly associated with higher mortality after adjusting for available confounders., Conclusion: The findings of the current study suggest that nonindex readmission is a common phenomenon after surgery and is associated with increased mortality. Further studies are required to evaluate whether enhancing health information continuity between hospitals would be helpful for mitigating the adverse consequences of care fragmentation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Protein tyrosine phosphatase (PTPs) and protein tyrosine kinase (PTKs) genes are responsible for the regulation of insect insulin-like pathway (ILP), cells growth, metabolism initiation, gene transcription and observing immune response. Signal transduction in insect cell is also associated with PTPs and PTKs. The grasshopper (Oedaleus asiaticus) 'Bey-Bienko' were treated with dsRNA of protein tyrosine non-receptor type 4 (PTPN4) and protein tyrosine kinase 5 (PTK5) along with control (water). Applying dsPTK5 treatments in 5th instar of Oedaleus asiaticus, significant reduction was recorded in body dry mass, growth rate and overall performance except survival rate. Whereas with PTPN4, no such significant impact on all of these growth parameters was recorded. Expression of genes in ILP 5th instar of Oedaleus asiaticus by the application of dsPTPN4 and dsPTK5 revealed that PTK, INSR (insulin receptor), IRS (insulin receptor substrate), PI3K (phosphoinositide 3-kinase), PDK (3-phosphoinositide-dependent protein kinase), Akt (protein kinase B) and FOXO (forkhead transcription factor) significantly expressed with downregulation except PTPN4, which remained non-significant. On the other hand, the phosphorylation level of ILP four proteins in O. asiaticus with the treatment of dsPTPN4 and dsPTK5 significantly affected P-IRS and P-FOXO, while P-INSR and P-AKT remained stable at the probability level of 5%. This indicated that the stress response in the O. asiaticus insulin-like signalling pathway (ILP) reduced. Regarding association of protective enzymatic activities, ROS (relative oxygen species), CAT (catalase) and PO (phenol oxidase) increased significantly with exposure to dsPTK5 as compared to dsPTPN4 and control, while exposure of 5th instar of O. asiaticus to dsPTPN4 treatment slightly raised CAT and PO activities with but significant contribution. No such significant effect on MFO and POD was seen using dsPTPN4 and dsPTK5. This showed that in the ILP of O. asiaticus, PTK5 was detrimental to growth, body mass and overall performance, which ultimately benefited insect detoxification with high-energy cost.

Aim: To assess the utility of using external databases for quality improvement (QI) evaluations in the context of an innovative QI collaborative aimed to reduce three infections and improve patient safety across the cardiac surgery service line., Methods: We compared changes in each outcome between 15 intervention hospitals (infection reduction protocols plus safety culture intervention) and 52 propensity score-matched hospitals (feedback only)., Results: Improvement trends in several outcomes among the intervention hospitals were not statistically different from those in comparison hospitals., Conclusion: Using external databases such as those of professional societies may permit comparative effectiveness assessment by providing concurrent comparison groups, additional outcome measures and longer follow-up. This can better inform evaluation of continuous QI in healthcare organizations.

The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML. We show that the response to drugs is associated with mutational status, including instances of drug sensitivity that are specific to combinatorial mutational events. Integration with RNA sequencing also revealed gene expression signatures, which predict a role for specific gene networks in the drug response. Collectively, we have generated a dataset-accessible through the Beat AML data viewer (Vizome)-that can be leveraged to address clinical, genomic, transcriptomic and functional analyses of the biology of AML.

Diabetes has become a chronic metabolic disorder, and the growing diabetes population makes medical care more important. We investigated using a portable and noninvasive contact lens as an ideal sensor for diabetes patients whose tear fluid contains glucose. The key feature is the reversible covalent interaction between boronic acid and glucose, which can provide a noninvasive glucose sensor for diabetes patients. We present a phenylboronic acid (PBA)-based HEMA contact lens that exhibits a reversible swelling/shrinking effect to change its thickness. The difference in thickness can be detected in a picture taken with a smartphone and analyzed using software. Our novel technique offers the following capabilities: (i) non-enzymatic and continuous glucose detection with the contact lens; (ii) no need for an embedded circuit and power source for the glucose sensor; and (iii) the use of a smartphone to detect the change in thickness of the contact lens with no need for additional photo-sensors. This technique is promising for a noninvasive measurement of the glucose level and simple implementation of glucose sensing with a smartphone.

Expression of the transmembrane pseudokinase ROR1 is required for survival of t(1;19)-pre-B-cell acute lymphoblastic leukemia (t(1;19) pre-B-ALL), chronic lymphocytic leukemia, and many solid tumors. However, targeting ROR1 with small-molecules has been challenging due to the absence of ROR1 kinase activity. To identify genes that regulate ROR1 expression and may, therefore, serve as surrogate drug targets, we employed an siRNA screening approach and determined that the epigenetic regulator and E3 ubiquitin ligase, UHRF1, is required for t(1;19) pre-B-ALL cell viability in a ROR1-dependent manner. Upon UHRF1 silencing, ROR1 protein is reduced without altering ROR1 mRNA, and ectopically expressed UHRF1 is sufficient to increase ROR1 levels. Additionally, proteasome inhibition rescues loss of ROR1 protein after UHRF1 silencing, suggesting a role for the proteasome in the UHRF1-ROR1 axis. Finally, we show that ROR1-positive cells are twice as sensitive to the UHRF1-targeting drug, naphthazarin, and undergo increased apoptosis compared to ROR1-negative cells. Naphthazarin elicits reduced expression of UHRF1 and ROR1, and combination of naphthazarin with inhibitors of pre-B cell receptor signaling results in further reduction of cell survival compared with either inhibitor alone. Therefore, our work reveals a mechanism by which UHRF1 stabilizes ROR1, suggesting a potential targeting strategy to inhibit ROR1 in t(1;19) pre-B-ALL and other malignancies.

Recovery has emerged as a focus of mental health rehabilitation in the past decade. Many have suggested that various domains of recovery-orientated services are integrated to an efficacious mental health care system. In this study we examined the association of domains of recovery-oriented services with recovery outcomes among inpatients in a state psychiatric hospital. A convenience sample of 36 hospital patients participated in a survey that included two standardized scales, with one measuring 6 domains of recovery-orientation of hospital-based services and one measuring 5 aspects of patients' recovery outcomes. We used regression analysis to estimate the association between recovery-oriented services and recovery outcomes adjusting for gender, race, and education. Nearly 90% of patients had lengths of stay of more than 3 months. On average, patients reported receiving moderate levels of recovery-oriented services. Nevertheless those who reported receiving higher levels of recovery-oriented services also reported better recovery outcomes. Specifically three domains of recovery-oriented services, i.e., life goal vs. symptom management, individual tailored, and diversity of treatment options, are associated with better overall recovery and 3 specific aspects of recovery, namely willingness to ask for help, goal and success orientation, and reliance on others. The data from a small sample of patients at a state psychiatric hospital suggest that self-reported recovery-oriented services received are associated with better recovery outcomes. Future larger studies are warranted to confirm the study findings, and to examine whether a contemporary recovery-focused care model can facilitate even greater recovery outcomes.

Purpose Addition of imatinib to intensive chemotherapy improved survival for children and young adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Compared with imatinib, dasatinib has increased potency, CNS penetration, and activity against imatinib-resistant clones. Patients and Methods Children's Oncology Group (COG) trial AALL0622 (Bristol Myers Squibb trial CA180-204) tested safety and feasibility of adding dasatinib to intensive chemotherapy starting at induction day 15 in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia age 1 to 30 years. Allogeneic hematopoietic stem-cell transplantation (HSCT) was recommended for patients at high risk based on slow response and for those with a matched family donor regardless of response after at least 11 weeks of therapy. Patients at standard risk based on rapid response received chemotherapy plus dasatinib for an additional 120 weeks. Patients with overt CNS leukemia received cranial irradiation. Results Sixty eligible patients were enrolled. Five-year overall (OS) and event-free survival rates (± standard deviations [SD]) were 86% ± 5% and 60% ± 7% overall, 87% ± 5% and 61% ± 7% for standard-risk patients (n = 48; 19% underwent HSCT), and 89% ± 13% and 67% ± 19% for high-risk patients (n = 9; 89% underwent HSCT), respectively. Five-year cumulative incidence (± SD) of CNS relapse was 15% ± 6%. Outcomes (± SDs) were similar to those in COG AALL0031, which used the same chemotherapy with continuous imatinib: 5-year OS of 81% ± 6% versus 86% ± 5% ( P = .63) and 5-year disease-free survival of 68% ± 7% versus 60% ± 7% ( P = 0.31) for AALL0031 versus AALL0622, respectively. IKZF1 deletions, present in 56% of tested patients, were associated with significantly inferior OS and event-free survival overall and in standard-risk patients. Conclusion Dasatinib was well tolerated with chemotherapy and provided outcomes similar to those with imatinib in COG AALL0031, where all patients received cranial irradiation. Our results support limiting HSCT to slow responders and suggest a potential role for transplantation in rapid responders with IKZF1 deletions.

The protein tyrosine phosphatase PTPN11 is implicated in the pathogenesis of juvenile myelomonocytic leukemia (JMML), acute myeloid leukemia (AML), and other malignancies. Activating mutations in PTPN11 increase downstream proliferative signaling and cell survival. We investigated the signaling upstream of PTPN11 in JMML and AML cells and found that PTPN11 was activated by the nonreceptor tyrosine/serine/threonine kinase TNK2 and that PTPN11-mutant JMML and AML cells were sensitive to TNK2 inhibition. In cultured human cell-based assays, PTPN11 and TNK2 interacted directly, enabling TNK2 to phosphorylate PTPN11, which subsequently dephosphorylated TNK2 in a negative feedback loop. Mutations in PTPN11 did not affect this physical interaction but increased the basal activity of PTPN11 such that TNK2-mediated activation was additive. Consequently, coexpression of TNK2 and mutant PTPN11 synergistically increased mitogen-activated protein kinase (MAPK) signaling and enhanced colony formation in bone marrow cells from mice. Chemical inhibition of TNK2 blocked MAPK signaling and colony formation in vitro and decreased disease burden in a patient with PTPN11-mutant JMML who was treated with the multikinase (including TNK2) inhibitor dasatinib. Together, these data suggest that TNK2 is a promising therapeutic target for PTPN11-mutant leukemias., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Aims: This paper reports on rounding interventions employed at high performing hospitals, and provides three case studies on how proactive nurse rounding was successfully implemented to improve patient-centredness., Background: Proactive nurse rounding is a popular form of rounding that has shown promise for improving patient outcomes, yet, little evidence exists on how to implement it successfully., Methods: We identified high-performing hospitals in the domains of staff responsiveness and nurse communications in the Hospital Consumer Assessment of Health Providers and Systems survey nationally, and conducted case studies at three of these hospitals exploring their implementation of proactive nurse rounding. We partnered with leaders from these hospitals to describe the associated challenges and lessons learned., Results: Twenty-six high performing hospitals in the domains of staff responsiveness and/or nurse communication were identified. The majority of nursing units reported proactive nurse rounding as their main rounding intervention (96%)., Conclusions: Proactive rounding interventions are a feasible approach to help surface and address hospitalized patients' needs in a timely manner., Implications for Nursing Management: The information and tools provided in this paper build upon the learning from high performing hospitals' experiences and are useful to nurse leaders in their efforts to improve the patient-centeredness in the hospital., (© 2017 John Wiley & Sons Ltd.)

Many studies have shown that music therapy improves patients' symptoms. However, interventions using music creation as their core await further development for patients with severe mental illness (SMI). The current study investigated the effect of a music-creation programme on the anxiety, self-esteem, and quality of life of patients with SMI. A quasi-experimental design using convenience sampling was adopted to recruit patients with SMI from a psychiatric day care centre. Participants were grouped based on their willingness to undergo an intervention (26 patients in the experimental group and 23 patients in the control group). The control groups participated in conventional mental rehabilitation therapy activities. The experimental group participated in a music-creation session for 90 min every week over a 32-week period. The outcome indicators before and after the intervention were assessed using the Hamilton Anxiety Rating Scale (HAM-A), Rosenberg Self-Esteem Scale (RSES), and World Health Organization Quality of Life-BREF (WHOQOL-BREF). Finally, the intervention effect was determined using generalized estimating equations (GEEs). After 32 weeks of intervention activities, the experimental group showed significant improvements in their HAM-A total scores (P < 0.001) and RSES total scores (P = 0.005). Regarding quality of life, the improvements of the experimental group in terms of the psychological (P = 0.016) and social relationship domains (P = 0.033) were superior to those of the control group. Music-creation programmes are recommended for inclusion in the routine rehabilitation activities of patients with SMI., (© 2017 Australian College of Mental Health Nurses Inc.)

Background: Gene therapy is a potent method to increase the therapeutic efficacy against cancer. However, a gene that is specifically expressed in the tumor area has not been identified. In addition, nonspecific expression of therapeutic genes in normal tissues may cause side effects that can harm the patients' health. Certain promoters have been reported to drive therapeutic gene expression specifically in cancer cells; however, low expression levels of the target gene are a problem for providing good therapeutic efficacy. Therefore, a specific and highly expressive promoter is needed for cancer gene therapy., Methods: Bioinformatics approaches were utilized to analyze transcription factors (TFs) from high-throughput data. Reverse transcription polymerase chain reaction, western blotting and cell transfection were applied for the measurement of mRNA, protein expression and activity. C57BL/6JNarl mice were injected with pD5-hrGFP to evaluate the expression of TFs., Results: We analyzed bioinformatics data and identified three TFs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), cyclic AMP response element binding protein (CREB), and hypoxia-inducible factor-1α (HIF-1α), that are highly active in tumor cells. Here, we constructed a novel mini-promoter, D5, that is composed of the binding sites of the three TFs. The results show that the D5 promoter specifically drives therapeutic gene expression in tumor tissues and that the strength of the D5 promoter is directly proportional to tumor size., Conclusions: Our results show that bioinformatics may be a good tool for the selection of appropriate TFs and for the design of specific mini-promoters to improve cancer gene therapy.

Background: Within the field of behavioral health research, one of the most understudied populations is the US deaf and hard-of-hearing (D/HH) population-a diverse group of individuals with hearing loss that have varied language and communication preferences, community affiliations, and sociocultural norms. Recent research identified concerning behavioral health disparities experienced by the D/HH population; yet, little research has been conducted to extend these findings to the topic of substance use disorder., Methods: To begin to fill this gap, the authors conducted a secondary analysis of data from the 2013-2014 administration of the National Health and Nutrition Examination Survey, comparing alcohol and drug use between participants based on their reported hearing status, i.e., D/HH or hearing., Results: Findings suggest that the overall lifetime prevalence of alcohol and drug use does not differ based on hearing status, and that D/HH and hearing adolescents begin using cannabis on a similar timeline. However, findings also revealed that D/HH respondents were more likely to have been regular cannabis users and heavy alcohol users than hearing respondents. In other words, when D/HH individuals use substances, they tend to be heavy users., Conclusions: These findings stress the importance of directing resources to the prevention and treatment of heavy alcohol use in the D/HH population, given that binge drinking is associated with a number of health problems and social consequences. Additionally, the continuation of this empirical work is rather urgent given recent legislative changes regarding cannabis use. D/HH individuals possess a number of risk factors for substance use disorder and, as such, may be more greatly impacted by these legislative changes than individuals from the general US population. It is imperative that this impact be captured by future research efforts in order to inform the development of prevention and intervention efforts for the traditionally underserved D/HH population.

Purpose: This study aims to identify how problem-based learning (PBL) has been implemented in Korean medical education, and how it is evaluated by each medical school., Methods: For this study, a total of 40 medical schools in Korea were surveyed via e-mail. The survey tool was a questionnaire consisting of 22 questions which was developed independently by the researchers., Results: Of the 40 medical schools, 35 schools were implementing PBL programs in their medical curriculum, while five were found not currently to be running the program. A large number of the schools which introduced PBL (30 schools, 85.7%) used a hybrid PBL model. In over 70% of the medical schools surveyed, professors evaluated the effects of PBL as positive. Most medical schools (85.7%) stated they would maintain or expand their use of PBL. However, the lack of understanding and skeptical attitude of the faculty on PBL, the lack of self-study time and passive attitude of students, insufficiency of good PBL cases, and the perfunctory PBL introduction for school accreditation interfere with the successful PBL., Conclusion: PBL has been incorporated in Korean medical curriculum as hybrid PBL type. It is analyzed that intensive tutor training and good PBL case development are necessary for the success and effective operation of PBL.

While increased mitochondrial reactive oxygen species have been commonly implicated in a variety of disease states, their in vivo role in the pathogenesis of diabetic nephropathy remains controversial. Using a two-photon imaging approach with a genetically encoded redox biosensor, we monitored mitochondrial redox state in the kidneys of experimental models of diabetes in real-time in vivo. Diabetic (db/db) mice that express a redox-sensitive Green Fluorescent Protein biosensor (roGFP) specifically in the mitochondrial matrix (db/dbmt-roGFP) were generated, allowing dynamic monitoring of redox changes in the kidneys. These db/dbmt-roGFP mice exhibited a marked increase in mitochondrial reactive oxygen species in the kidneys. Yeast NADH-dehydrogenase, a mammalian Complex I homolog, was ectopically expressed in cultured podocytes, and this forced expression in roGFP-expressing podocytes prevented high glucose-induced increases in mitochondrial reactive oxygen species. Thus, in vivo monitoring of mitochondrial roGFP in diabetic mice confirms increased production of mitochondrial reactive oxygen species in the kidneys., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

During the 2016 Therapeutic Advances for Childhood Leukemia & Lymphoma (TACL) Consortium investigators' meeting (Los Angeles, CA), a Biology Working Group was established to support the consortium's mission of developing innovative therapies for currently incurable childhood leukemias and lymphomas. The charge of the Biology Working Group was to address how TACL could advance biological investigations of pediatric relapsed/refractory hematologic malignancies while undertaking forward-looking therapeutic trials. To this end, the TACL Biology Committee was established to provide the scientific platform needed to further develop preclinical and translational studies that will advance the understanding and treatment of relapsed and refractory disease. The Biology Committee will focus on ensuring state-of-the-art studies that address biological components of early phase clinical trials, and developing a central biology bank of materials from these early phase trials for interrogations into the mechanisms of disease resistance.

Background: Targeting CD30 with monoclonal antibodies in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL) has had profound clinical success. However, adverse events, mainly mediated by the toxin component of the conjugated antibodies, cause treatment discontinuation in many patients. Targeting CD30 with T cells expressing a CD30-specific chimeric antigen receptor (CAR) may reduce the side effects and augment antitumor activity., Methods: We conducted a phase I dose escalation study in which 9 patients with relapsed/refractory HL or ALCL were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR (CD30.CAR-Ts) encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 × 108 to 2 × 108 CD30.CAR-Ts/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CD30.CAR-T infusion. Seven patients had previously experienced disease progression while being treated with brentuximab., Results: No toxicities attributable to CD30.CAR-Ts were observed. Of 7 patients with relapsed HL, 1 entered complete response (CR) lasting more than 2.5 years after the second infusion of CD30.CAR-Ts, 1 remained in continued CR for almost 2 years, and 3 had transient stable disease. Of 2 patients with ALCL, 1 had a CR that persisted 9 months after the fourth infusion of CD30.CAR-Ts. CD30.CAR-T expansion in peripheral blood peaked 1 week after infusion, and CD30.CAR-Ts remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity., Conclusion: CD30.CAR-Ts are safe and can lead to clinical responses in patients with HL and ALCL, indicating that further assessment of this therapy is warranted., Trial Registration: ClinicalTrials.gov NCT01316146., Funding: National Cancer Institute (3P50CA126752, R01CA131027 and P30CA125123), National Heart, Lung, and Blood Institute (R01HL114564), and Leukemia and Lymphoma Society (LLSTR 6227-08).

Previous studies in our laboratory have established the presence of MTP in both white and brown adipose tissue in mice as well as in 3T3-L1 cells. Additional studies demonstrated an increase in MTP levels as 3T3-L1 cells differentiate into adipocytes concurrent with the movement of MTP from the juxtanuclear region of the cell to the surface of lipid droplets. This suggested a role for MTP in lipid droplet biogenesis and/or maturation. To probe the role of MTP in adipocytes, we used a Cre-Lox approach with aP2-Cre and Adipoq-Cre recombinase transgenic mice to knock down MTP expression in brown and white fat of mice. MTP expression was reduced approximately 55% in white fat and 65-80% in brown fat. Reducing MTP expression in adipose tissue had no effect on weight gain or body composition, whether the mice were fed a regular rodent or high fat diet. In addition, serum lipids and unesterified fatty acid levels were not altered in the knockdown mice. Importantly, decreased MTP expression in adipose tissue was associated with smaller lipid droplets in brown fat and smaller adipocytes in white fat. These results combined with our previous studies showing MTP lipid transfer activity is not necessary for lipid droplet initiation or growth in the early stages of differentiation, suggest that a structural feature of the MTP protein is important in lipid droplet maturation. We conclude that MTP protein plays a critical role in lipid droplet maturation, but does not regulate total body fat accumulation.

Excess triglyceride (TG) accumulation in the liver underlies fatty liver disease, a highly prevalent ailment. TG occurs in the liver sequestered in lipid droplets, the major lipid storage organelle. Lipid droplets are home to the lipid droplet proteins, the most abundant of which are the perilipins (PLINs), encoded by 5 different genes, Plin1 to Plin5. Of the corresponding gene products, PLIN2 is the only constitutive and ubiquitously expressed lipid droplet protein that has been used as a protein marker for lipid droplets. We and others reported that plin2 -/- mice have an ∼60% reduction in TG content, and are protected against fatty liver disease. Here we show that PLIN2 overexpression protects lipid droplets against macroautophagy/autophagy, whereas PLIN2 deficiency enhances autophagy and depletes hepatic TG. The enhanced autophagy in plin2 -/- mice protects against severe ER stress-induced hepatosteatosis and hepatocyte apoptosis. In contrast, hepatic TG depletion resulting from other genetic and pharmacological manipulations has no effect on autophagy. Importantly, PLIN2 deficiency lowers cellular TG content in wild-type mouse embryonic fibroblasts (MEFs) via enhanced autophagy, but does not affect cellular TG content in atg7 -/- MEFs that are devoid of autophagic function. Conversely, adenovirus-shAtg7-mediated hepatic Atg7 knockdown per se does not alter the hepatic TG level, suggesting a more complex regulation in vivo. In sum, PLIN2 guards its own house, the lipid droplet. PLIN2 overexpression protects against autophagy, and its downregulation stimulates TG catabolism via autophagy.

Genome-wide DNA replication timing (RT) profiles reflect the global three-dimensional chromosome architecture of cells. They also provide a comprehensive and unique megabase-scale picture of cellular epigenetic state. Thus, normal differentiation involves reproducible changes in RT, and transformation generally perturbs these, although the potential effects of altered RT on the properties of transformed cells remain largely unknown. A major challenge to interrogating these issues in human acute lymphoid leukemia (ALL) is the low proliferative activity of most of the cells, which may be further reduced in cryopreserved samples and difficult to overcome in vitro. In contrast, the ability of many human ALL cell populations to expand when transplanted into highly immunodeficient mice is well documented. To examine the stability of DNA RT profiles of serially passaged xenografts of primary human B- and T-ALL cells, we first devised a method that circumvents the need for bromodeoxyuridine incorporation to distinguish early versus late S-phase cells. Using this and more standard protocols, we found consistently strong retention in xenografts of the original patient-specific RT features. Moreover, in a case in which genomic analyses indicated changing subclonal dynamics in serial passages, the RT profiles tracked concordantly. These results indicate that DNA RT is a relatively stable feature of human ALLs propagated in immunodeficient mice. In addition, they suggest the power of this approach for future interrogation of the origin and consequences of altered DNA RT in ALL., (Copyright © 2017 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)

Background: Many systematic reviews of randomized clinical trials lead to meta-analyses of odds ratios (ORs). The customary methods of estimating an overall OR involve weighted averages of the individual trials' estimates of the logarithm of the OR. That approach, however, has several shortcomings, arising from assumptions and approximations, that render the results unreliable. Although the problems have been documented in the literature for many years, the conventional methods persist in software and applications. A well-developed alternative approach avoids the approximations by working directly with the numbers of subjects and events in the arms of the individual trials., Objective: We aim to raise awareness of methods that avoid the conventional approximations, can be applied with widely available software, and produce more-reliable results., Methods: We summarize the fixed-effect and random-effects approaches to meta-analysis; describe conventional, approximate methods and alternative methods; apply the methods in a meta-analysis of 19 randomized trials of endoscopic sclerotherapy in patients with cirrhosis and esophagogastric varices; and compare the results. We demonstrate the use of SAS, Stata, and R software for the analysis., Results: In the example, point estimates and confidence intervals for the overall log-odds-ratio differ between the conventional and alternative methods, in ways that can affect inferences. Programming is straightforward in the 3 software packages; an appendix, Suppemental Digital Content 1 (http://links.lww.com/MLR/B335) gives the details., Conclusions: The modest additional programming required should not be an obstacle to adoption of the alternative methods. Because their results are unreliable, use of the conventional methods for meta-analysis of ORs should be discontinued.

Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL -AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs., (© 2017 by The American Society of Hematology.)

Objective: The main aim of this study was to examine the differences between triple therapy (T: SSZ and HCQ added to MTX) and etanercept (E) added to MTX with regard to the infectious and gastrointestinal (GI) adverse events (AEs) reported in The Rheumatoid Arthritis Comparison of Active Therapies Trial., Methods: The patients were 353 RA MTX incomplete responders who were randomized to T (n = 178) or E (n = 175). Of these, 88 patients were switched to the alternative treatment from the initial treatment (E or T) at 24 weeks per protocol. Infectious and GI serious AEs (SAEs) and non-serious AEs (NAEs) were reported during 48 and 4 weeks after the intervention period. Generalized linear models were used to estimate the incidence rate ratios (IRRs) of AEs between the two therapies., Results: Patients on E therapy were more likely to have infectious NAEs (IRR = 1.56, 95% CI: 1.11, 2.19). There was a greater number of infectious SAEs that occurred when patients received E than T therapy [12 E (6.9%) vs 4 T (2.2%), P = 0.19]. Pneumonia was the most common infectious SAE for both treatments [6 E (3.4%) and 2 T (1.1%)]. Conversely, patients who were on E were less likely to have GI NAEs than those on T therapy (IRR = 0.62, 95% CI: 0.40, 0.94). The most common GI SAE reported was GI haemorrhage, which occurred among three patients on E (1.7%)., Conclusion: This study provides evidence of different likelihoods of infectious and GI AEs associated with two common, equally effective treatments for RA patients who have had incomplete responses to MTX., Trial Registration: ClinicalTrials.gov, http://clinicaltrials.gov , NCT00405275., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

Progressive pancreatic β cell failure underlies the transition of impaired glucose tolerance to overt diabetes; endoplasmic reticulum (ER) stress expedites β cell failure in this situation. ER stress can be elicited by lipotoxicity and an increased demand for insulin in diabetes. We previously reported that the lipid droplet protein perilipin 2 (PLIN2) modulates lipid homeostasis in the liver. Here, we show that PLIN2 modulates the unfolded protein response (UPR) and ER stress in pancreatic β cells. PLIN2 expression goes up when β cells are exposed to a lipid load or to chemical ER stress inducers. Downregulation of PLIN2 ameliorates the effects of fatty acid- and chemical-induced ER stress, whereas PLIN2 overexpression exacerbates them. Diabetic Akita mice, which carry a heterozygous C96Y Ins2 mutation, exhibit elevated PLIN2 expression and ER stress in their β cells. Genetic ablation of Plin2 in Akita mice leads to mitigation of ER stress, forestalling β cell apoptosis, partially restoring β cell mass, and ameliorating diabetes. Mechanistic experiments showed that PLIN2 downregulation is associated with enhanced autophagic flux and accelerated ER stress resolution. In sum, we have identified a crucial role for PLIN2 in modulating autophagy, ER stress resolution, and β cell apoptosis and survival.

Recent evidence suggests that inhibition of protein phosphatase 2A (PP2A) tumor suppressor activity via the SET oncoprotein contributes to the pathogenesis of various cancers. Here we demonstrate that both SET and c-MYC expression are frequently elevated in T-ALL cell lines and primary samples compared to healthy T cells. Treatment of T-ALL cells with the SET antagonist OP449 restored the activity of PP2A and reduced SET interaction with the PP2A catalytic subunit, resulting in a decrease in cell viability and c-MYC expression in a dose-dependent manner. Since a tight balance between phosphatases and kinases is required for the growth of both normal and malignant cells, we sought to identify a kinase inhibitor that would synergize with SET antagonism. We tested various T-ALL cell lines against a small-molecule inhibitor screen of 66 compounds targeting two-thirds of the tyrosine kinome and found that combined treatment of T-ALL cells with dovitinib, an orally active multi-targeted small-molecule receptor tyrosine kinase inhibitor, and OP449 synergistically reduced the viability of all tested T-ALL cell lines. Mechanistically, combined treatment with OP449 and dovitinib decreased total and phospho c-MYC levels and reduced ERK1/2, AKT, and p70S6 kinase activity in both NOTCH-dependent and independent T-ALL cell lines. Overall, these results suggest that combined targeting of tyrosine kinases and activation of serine/threonine phosphatases may offer novel therapeutic strategies for the treatment of T-ALL.

The regulatory roles of long noncoding RNAs (lncRNAs) in transcriptional coactivators are still largely unknown. Here, we have shown that the peroxisome proliferator-activated receptor γ (PPARγ) coactivator α (PGC-1α, encoded by Ppargc1a) is functionally regulated by the lncRNA taurine-upregulated gene 1 (Tug1). Further, we have described a role for Tug1 in the regulation of mitochondrial function in podocytes. Using a murine model of diabetic nephropathy (DN), we performed an unbiased RNA-sequencing (RNA-seq) analysis of kidney glomeruli and identified Tug1 as a differentially expressed lncRNA in the diabetic milieu. Podocyte-specific overexpression (OE) of Tug1 in diabetic mice improved the biochemical and histological features associated with DN. Unexpectedly, we found that Tug1 OE rescued the expression of PGC-1α and its transcriptional targets. Tug1 OE was also associated with improvements in mitochondrial bioenergetics in the podocytes of diabetic mice. Mechanistically, we found that the interaction between Tug1 and PGC-1α promotes the binding of PGC-1α to its own promoter. We identified a Tug1-binding element (TBE) upstream of the Ppargc1a gene and showed that Tug1 binds with the TBE to enhance Ppargc1a promoter activity. These findings indicate that a direct interaction between PGC-1α and Tug1 modulates mitochondrial bioenergetics in podocytes in the diabetic milieu.

Unlabelled: The computational speed of many gene set analysis methods can be slow due to the computationally demanding permutation step. This article introduces GSA-Lightning, a fast implementation of permutation-based gene set analysis. GSA-Lightning achieves significant speedup compared with existing methods, particularly when the number of gene sets and permutations are large., Availability and Implementation: The GSA-Lightning R package is available on Github at https://github.com/billyhw/GSALightning and on R Bioconductor. The package also contains a comprehensive user's guide with a step-by-step tutorial vignette., Contact: weidong.tian@fudan.edu.cn, Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: This study evaluated three domains of job burnout (emotional exhaustion, depersonalization, and personal accomplishment) and factors associated with burnout in a national sample of peer specialists (PSs) employed at 138 Veterans Health Administration (VHA) health care systems in 49 states., Methods: Data were drawn from an observational study in which participants (N=152) completed online, self-report surveys about their mental health recovery, quality of life, and employment experiences at baseline, six months, and 12 months. Levels of burnout were analyzed at each time point, and regression analyses that controlled for baseline levels identified potential predictors of burnout (demographic, clinical, and employment characteristics) at six and 12 months., Results: Compared with previously published burnout levels of other mental health workers in the VHA, PSs reported similar levels of emotional exhaustion, depersonalization, and personal accomplishment. At baseline, increased burnout was correlated with white race, fewer hours providing direct services, greater psychiatric symptoms, and lower self-efficacy. However, analyses did not reveal strong predictors of burnout scores at six or 12 months., Conclusions: In the first study to prospectively examine job burnout among PSs employed by the VHA, results illustrate the nuanced experience of burnout over a 12-month period and suggest the need for replication and further research on employment experiences of this emerging workforce.

Mitochondrial fission has been linked to the pathogenesis of diabetic nephropathy (DN). However, how mitochondrial fission affects progression of DN in vivo is unknown. Here, we report the effect of conditional podocyte-specific deletion of dynamin-related protein 1 (Drp1), an essential component of mitochondrial fission, on the pathogenesis and progression of DN. Inducible podocyte-specific deletion of Drp1 in diabetic mice decreased albuminuria and improved mesangial matrix expansion and podocyte morphology. Ultrastructure analysis revealed a significant increase in fragmented mitochondria in the podocytes of wild-type diabetic mice but a marked improvement in mitochondrial structure in Drp1-null podocytes of diabetic mice. When isolated from diabetic mice and cultured in high glucose, Drp1-null podocytes had more elongated mitochondria and better mitochondrial fitness associated with enhanced oxygen consumption and ATP production than wild-type podocytes. Furthermore, administration of a pharmacologic inhibitor of Drp1, Mdivi1, significantly blunted mitochondrial fission and rescued key pathologic features of DN in mice. Taken together, these results provide novel correlations between mitochondrial morphology and the progression of DN and point to Drp1 as a potential therapeutic target in DN., (Copyright © 2016 by the American Society of Nephrology.)

Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) remains a challenge. Although the addition of targeted tyrosine kinase inhibitors (TKIs) to standard cytotoxic therapy has greatly improved upfront treatment, treatment-related morbidity and mortality remain high. TKI monotherapy provides only temporary responses and renders patients susceptible to the development of TKI resistance. Thus, identifying agents that could enhance the activity of TKIs is urgently needed. Recently, a selective inhibitor of B cell lymphoma 2 (BCL-2), ABT-199 (venetoclax), has shown impressive activity against hematologic malignancies. We demonstrate that the combination of TKIs with venetoclax is highly synergistic in vitro, decreasing cell viability and inducing apoptosis in Ph(+)ALL. Furthermore, the multikinase inhibitors dasatinib and ponatinib appear to have the added advantage of inducing Lck/Yes novel tyrosine kinase (LYN)-mediated proapoptotic BCL-2-like protein 11 (BIM) expression and inhibiting up-regulation of antiapoptotic myeloid cell leukemia 1 (MCL-1), thereby potentially overcoming the development of venetoclax resistance. Evaluation of the dasatinib-venetoclax combination for the treatment of primary Ph(+)ALL patient samples in xenografted immunodeficient mice confirmed the tolerability of this drug combination and demonstrated its superior antileukemic efficacy compared to either agent alone. These data suggest that the combination of dasatinib and venetoclax has the potential to improve the treatment of Ph(+)ALL and should be further evaluated for patient care., (Copyright © 2016, American Association for the Advancement of Science.)

Purpose: To determine a safe and biologically active dose of quizartinib (AC220), a potent and selective class III receptor tyrosine kinase (RTK) FLT3 inhibitor, in combination with salvage chemotherapy in children with relapsed acute leukemia., Experimental Design: Quizartinib was administered orally to children with relapsed AML or MLL-rearranged ALL following 5 days of high-dose cytarabine and etoposide (AE). A 3+3 dose escalation design was used to identify a safe and biologically active dose. Plasma inhibitory assay (PIA) testing was performed weekly to determine biologic activity., Results: Toxicities were consistent with intensive relapsed leukemia regimens. One of 6 patients experienced a dose-limiting toxicity (DLT) at 40 mg/m(2)/day (elevated lipase) and 1 of 9 had a DLT (hyperbilirubinemia) at the highest tested dose of 60 mg/m(2)/day. Of 17 response evaluable patients, 2 had complete response (CR), 1 complete response without platelet recovery (CRp), 1 complete response with incomplete neutrophil and platelet recovery (CRi), 10 stable disease (SD), and 3 progressive disease (PD). Of 7 FLT3-ITD patients, 1 achieved CR, 1 CRp, 1 Cri, and 4 SD. FLT3-ITD patients, but not FLT3 wild-type (WT) patients, had significantly lower blast counts post-quizartinib. FLT3 phosphorylation was completely inhibited in all patients., Conclusions: Quizartinib plus intensive chemotherapy is well tolerated at 60 mg/m(2)/day with near complete inhibition of FLT3 phosphorylation in all patients. The favorable toxicity profile, pharmacodynamic activity, and encouraging response rates warrant further testing of quizartinib in children with FLT3-ITD AML. Clin Cancer Res; 22(16); 4014-22. ©2016 AACR., (©2016 American Association for Cancer Research.)

How the kidney responds to the metabolic cues from the environment remains a central question in kidney research. This question is particularly relevant to the pathogenesis of diabetic nephropathy (DN) in which evidence suggests that metabolic events in podocytes regulate chromatin structure. Here, we show that miR-93 is a critical metabolic/epigenetic switch in the diabetic milieu linking the metabolic state to chromatin remodelling. Mice with inducible overexpression of a miR-93 transgene exclusively in podocytes exhibit significant improvements in key features of DN. We identify miR-93 as a regulator of nucleosomal dynamics in podocytes. miR-93 has a critical role in chromatin reorganization and progression of DN by modulating its target Msk2, a histone kinase, and its substrate H3S10. These findings implicate a central role for miR-93 in high glucose-induced chromatin remodelling in the kidney, and provide evidence for a previously unrecognized role for Msk2 as a target for DN therapy.

Purpose: To assess 10-year mortality in people who had undergone cataract surgery with no residual visual impairment (VI) and those who had persistent VI due to cataract using a population-based cohort., Methods: The Liwan Eye Study is a 10-year longitudinal study commenced in 2003. According to the World Health Organization, presenting VI was defined as visual acuity less than 20/63 in the better-seeing eye. History of cataract surgery was defined as cataract surgery performed on either eye. Information on the date of surgery was recorded. Dates of death occurring between baseline and April 30, 2014 were obtained from the National Death Index data. Information on socioeconomic factors was obtained from questionnaire interviews. Cox proportional hazards regression models were used to assess the hazard ratios (HRs) and 95% confidence intervals (CIs)., Results: Fifty-nine participants had undergone cataract surgery without residual VI and 67 participants had persistent cataract-related VI. The 10-year mortality rate for participants who had undergone cataract surgery without residual VI was statistically significant lower than that in participants who had VI due to cataract based on log-rank test (32.2% vs. 64.2%; P = 0.002). This finding remained significant in the unadjusted Cox proportional hazards model (HR, 0.43; 95% CI, 0.25-0.74; P = 0.002). After adjusting for age, sex, history of diabetes, and hypertension, body mass index (BMI), education level, and personal income, participants with cataract surgery and no residual VI did not have a higher chance of survival than participants with persistent VI due to cataract (HR, 0.56; 95% CI, 0.26-1.20; P = 0.136)., Conclusions: Cataract-related VI corrected by cataract surgery was not associated with better survival after adjusting for a number of possible confounders. Given our sample size is relatively small and limited power, further studies with larger sample are needed.

Objectives: Department of Veterans Affairs (VA) peer specialists and vocational rehabilitation specialists are Veterans employed in mental health services to help other Veterans with similar histories and experiences. Study objectives were to (a) examine job satisfaction among these employees, (b) compare them to other VA mental health workers, and (c) identify factors associated with job satisfaction across the 3 cohorts., Methods: The study sample included 152 VA-employed peer specialists and 222 vocational rehabilitation specialists. A comparison group included 460 VA employees from the same job categories. All participants completed the Job Satisfaction Index (11 aspects and overall satisfaction ratings). Linear regression was used to compare job satisfaction and identify its predictors among the 3 cohorts., Results: Job satisfaction was fairly high, averaging "somewhat satisfied" to "very satisfied" in 6 (peer specialists) and 9 (vocational rehabilitation specialists) of the 11 aspects and overall job ratings. Adjusting for length of employment, age and gender resulted in no significant group differences with 2 exceptions: White peer specialists were less satisfied with pay and promotion opportunities than vocational rehabilitation specialists and comparison-group employees. Across all cohorts, shorter length of time employed in the job was associated with higher job satisfaction., Conclusions and Implications for Practice: The high job satisfaction levels among the 2 peer cohorts suggest support for the policy of hiring peer specialists in the VA. Furthermore, the results are consistent with those of the nonveteran samples, indicating that integrating peer providers into mental health care is possible in VA and non-VA settings., ((c) 2016 APA, all rights reserved).)

Purpose: Kyungpook National University School of Medicine has been implementing hybrid problem-based learning (PBL) since 1999. The aim of this study was to investigate the changes in the students' perceptions and satisfaction levels of hybrid PBL., Methods: The target period of our study was from 1999 to 2014, and target subjects were second-year medical students in Kyungpook National University School of Medicine. The survey was conducted at the end of semester. We had a focused interview with group leaders and some volunteer students., Results: As for the scores regarding students' overall satisfaction with PBL, there was significant improvement in 2005 compared to 2002, but the scores decreased and no differences between the survey years noted after 2005. The students' preference ratio for the once a week PBL sessions, tutor presence, synchronization of contents, and arrangement of PBL sessions and related lectures was 60%-80%, 50%-90%, 52%-96%, and 78%-93%, respectively., Conclusion: In order to increase students' satisfaction with hybrid PBL and to improve the perception of it, firstly, it is necessary to arrange the date and the time of PBL sessions so that students can concentrate on PBL. Secondly, PBL cases should be selected and arranged to be well synchronized with the ongoing lectures. Finally, it is important to create a safe atmosphere so that students can engage actively in PBL sessions.

We recently demonstrated that acute myeloid leukemia (AML) cell lines and patient-derived blasts release exosomes that carry RNA and protein; following an in vitro transfer, AML exosomes produce proangiogenic changes in bystander cells. We reasoned that paracrine exosome trafficking may have a broader role in shaping the leukemic niche. In a series of in vitro studies and murine xenografts, we demonstrate that AML exosomes downregulate critical retention factors (Scf, Cxcl12) in stromal cells, leading to hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow. Exosome trafficking also regulates HSPC directly, and we demonstrate declining clonogenicity, loss of CXCR4 and c-Kit expression, and the consistent repression of several hematopoietic transcription factors, including c-Myb, Cebp-β and Hoxa-9. Additional experiments using a model of extramedullary AML or direct intrafemoral injection of purified exosomes reveal that the erosion of HSPC function can occur independent of direct cell-cell contact with leukemia cells. Finally, using a novel multiplex proteomics technique, we identified candidate pathways involved in the direct exosome-mediated modulation of HSPC function. In aggregate, this work suggests that AML exosomes participate in the suppression of residual hematopoietic function that precedes widespread leukemic invasion of the bone marrow directly and indirectly via stromal components.

Introduction: Effective teamwork is known to be important to improving health care outcomes. Current research often highlights teamwork among health care professionals without consideration of approaches to including family as part of the health care team. In this study, the authors assess family and provider openness to expanding the care team to include family participation and introduce the Family Involvement Menu as a tool to facilitate family engagement., Method: They collected 37 family surveys and 37 clinician surveys to understand the perception, comfort level, experience, and interest of family and clinicians in including family in the care of the patient. The majority of family reported being interested and comfortable in participating in care (95% and 92%, respectively)., Results: The majority of clinicians considered family already to be part of the health care team (92%) though only 16% reported routinely inviting families to participate in direct patient care all the time. Multiple direct patient care activities were identified as promising opportunities for family engagement. Barriers to family engagement reported included the family being scared (19%), uncomfortable (19%), or unwilling (14%) or nurses not having enough time (14%) to involve families., Discussion: Engaging family has the potential to increase nursing availability for other tasks, enhance relationship building, and is an opportunity to introduce early education for family, better preparing them for transition of care and discharge. The Family Involvement Menu supports family engagement and can be a strategy to include family members as part of the health care team., ((c) 2015 APA, all rights reserved).)

Background: Patient-centered care is integral to health care quality, yet little is known regarding how to achieve patient-centeredness in the hospital setting. The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey measures patients' reports on clinician behaviors deemed by patients as key to a high-quality hospitalization experience., Objectives: We conducted a national study of hospitals that achieved the highest performance on HCAHPS to identify promising practices for improving patient-centeredness, common challenges met, and how those were addressed., Research Design: We identified hospitals that achieved the top ranks or remarkable recent improvements on HCAHPS and surveyed key informants at these hospitals. Using quantitative and qualitative methods, we described the interventions used at these hospitals and developed an explanatory model for achieving patient-centeredness in hospital care., Results: Fifty-two hospitals participated in this study. Hospitals used similar interventions that focused on improving responsiveness to patient needs, the discharge experience, and patient-clinician interactions. To improve responsiveness, hospitals used proactive nursing rounds (reported at 83% of hospitals) and executive/leader rounds (62%); for the discharge experience, multidisciplinary rounds (56%), postdischarge calls (54%), and discharge folders (52%) were utilized; for clinician-patient interactions, hospitals promoted specific desired behaviors (65%) and set behavioral standards (60%) for which employees were held accountable. Similar strategies were also used to achieve successful intervention implementation including HCAHPS data feedback, and employee and leader engagement and accountability., Conclusions: High-performing hospitals used a set of patient-centered care processes that involved both leaders and clinicians in ensuring that patient needs and preferences are addressed.

Purpose: To conduct a simulation study to estimate the prevalence of occludable angle (OA), a surrogate for primary angle closure glaucoma (PACG), with the increased rate of myopia in the Chinese population., Methods: People with phakic eyes in Liwan Eye Study were included as the study sample. Anterior chamber depth (ACD) was measured before dilation by A-mode ultrasound and OA was evaluated with static gonioscopy. Random sampling was used to generate 50 cohorts with sample size of 200 for each of myopic rates 10%, 20%, 40%, 50%, and 135 for myopic rate 60%, according to the multinomial distribution. The mean ACD and OA rates of each cohort were calculated. Logistic function model of nonlinear least-squares estimation was used to predict the prevalence of OA., Results: Data of the right eyes from 1160 subjects were qualified for analysis. The mean age was 64.2 ± 9.5 years, with 43% being male. The prevalence of myopia and OA was 32.5% (95% confidence interval [CI], 29.8%-35.3%) and 10.3% (95% CI, 8.7%-12.2%), respectively. The mean ACD in the sampling cohorts increased from 2.68 mm to 2.74 mm when the prevalence of myopia increased from 10% to 60%. The projected prevalence of OA in the cohorts with myopia prevalence of 10%, 20%, 40%, 50%, and 60% was 11.1% (95% CI, 10.5%-11.8%), 10.7% (95% CI, 10.1%-11.4%), 9.9% (95% CI, 9.3%-10.5%), 9.3% (95% CI, 8.8%-9.9%), and 9.6% (95% CI, 8.9-10.3%), respectively., Conclusions: The increasing prevalence of myopia has minimal impact on the prevalence of OA.

Background: Treatment of acute myeloid leukemia (AML) comes with a significant risk of life-threatening infection during periods of prolonged severe neutropenia. We studied the impact of preventive intravenous (IV) antibiotic administration at onset of absolute neutropenia on the incidence and outcome of life-threatening infections during treatment of childhood AML., Procedures: This is a retrospective study on pediatric patients (aged 0-18 years) consecutively diagnosed with de novo AML and treated at a single institution from April 2005 through February 2013. Patients were treated on the Children's Oncology Group (COG) AAML0531 protocol or with a modified United Kingdom Medical Research Council (UK MRC) AML 10 regimen. Pertinent data were extracted from hard copy or electronic chart review., Results: A total of 76 chemotherapy phases were analyzed from 29 patients. In each phase reported, preventive antibiotics were initiated when the daily absolute neutrophil count was <500 cells/mcl, before onset of fever. Seven episodes of bacteremia were documented with predominantly coagulase-negative staphylococci and viridans group streptococci. One infection-related death occurred, attributed to progressive respiratory failure occurring months after documented candidal pneumonia., Conclusions: Initiation of preventive antibiotics at the onset of absolute neutropenia was associated with no mortality from bacteremia. This preventive approach appears feasible and safe., (© 2015 Wiley Periodicals, Inc.)

Relapse remains the major cause of mortality for patients with Acute Myeloid Leukemia (AML). Improved tracking of minimal residual disease (MRD) holds the promise of timely treatment adjustments to preempt relapse. Current surveillance techniques detect circulating blasts that coincide with advanced disease and poorly reflect MRD during early relapse. Here, we investigate exosomes as a minimally invasive platform for a microRNA (miRNA) biomarker. We identify a set of miRNA enriched in AML exosomes and track levels of circulating exosome miRNA that distinguish leukemic xenografts from both non-engrafted and human CD34+ controls. We develop biostatistical models that reveal circulating exosomal miRNA at low marrow tumor burden and before circulating blasts can be detected. Remarkably, both leukemic blasts and marrow stroma contribute to serum exosome miRNA. We propose development of serum exosome miRNA as a platform for a novel, sensitive compartment biomarker for prospective tracking and early detection of AML recurrence.

Objective: Although combat experiences can have a profound impact on individuals' spirituality, there is a dearth of research in this area. Our recent study indicates that one unique spiritual need of veterans who are at the end of life is to resolve distress caused by combat-related events that conflict with their personal beliefs. This study sought to gain an understanding of chaplains' perspectives on this type of spiritual need, as well as the spiritual care that chaplains provide to help veterans ease this distress., Method: We individually interviewed five chaplains who have provided spiritual care to veterans at the end of life in a Veterans Administration hospital. The interviews were recorded, transcribed, and analyzed based on "grounded theory.", Results: Chaplains reported that they frequently encounter veterans at the end of life who are still suffering from thoughts or images of events that occurred during their military career. Although some veterans are hesitant to discuss their experiences, chaplains reported that they have had some success with helping the veterans to open up. Additionally, chaplains reported using both religious (e.g., confessing sins) and nonreligious approaches (e.g., recording military experience) to help veterans to heal., Significance of Results: Our pilot study provides some insight into the spiritual distress that many military veterans may be experiencing, as well as methods that a chaplain can employ to help these veterans. Further studies are needed to confirm our findings and to examine the value of integrating the chaplain service into mental health care for veterans.